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n of research evidence into best practice guidelines requiring implementation across specialities and geographical areas. Best practice needs to become engrained in competency-based training, from undergraduate to specialist level.[13] These objectives require transdisciplinary national and international collaboration. The Size of the Problem Care of the acutely ill patient is a major activity for all health care systems. The proportion of patients who are admitted as emergencies varies between health care systems, and although precise figures are not available for many countries, they are likely to be between 30% (USA)[14] to over 60% (UK)[1516] or between 99 (Canada) to 205 (Germany) admissions per 1000 population (OECD).[17] These figures do not include additional numbers of patients who deteriorate while in hospital undergoing elective treatment. The number of emergency hospital admissions is also increasing worldwide.[18] Acutely ill patients are therefore a major part of the business of healthcare systems. As populations age and healthcare becomes more complex, patient dependency increases; simultaneous reductions in the number of acute hospital beds and increases in throughput place additional pressures on the system, thereby increasing opportunities for error. Hospitals will therefore need to evolve new strategies for improving patient safety focused at least in part on this large population of the acutely ill.

Introduction In 2000, the Institute of Medicine's report ‘To Err is Human’[1] estimated that as many as 98,000 patients could die from avoidable mistakes each year in the USA alone, with many more suffering complications and varying degrees of morbidity. The editors and contributors challenged healthcare systems in the USA and worldwide to focus our efforts on reducing harm to patients caused by errors in healthcare delivery. Since then many countries have established national patient safety organizations, with some coordination of effort through the World Health Organization's World Alliance for Patient Safety.[2] A Medline search reveals that between 2000 and May 2008, 29 566 articles have been published on aspects of patient safety - and this excludes a further 16 788 focused on quality assurance. There is now general recognition that error in healthcare is common, and that patients suffer avoidable harm as a result.

afety.[2] A Medline search reveals that between 2000 and May 2008, 29 566 articles have been published on aspects of patient safety - and this excludes a further 16 788 focused on quality assurance. There is now general recognition that error in healthcare is common, and that patients suffer avoidable harm as a result. Methodological Considerations However, less certain is the nature of the linkage - how and to what extent error actually contributes to adverse longterm outcomes - and how to demonstrate that improvements in processes of care result in improvements in outcome. Research methodology is central to unraveling these doubts and uncertainties. The first problem is how one identifies errors and links them to outcomes. For example, Hofer and colleagues have shown[3] that while it may be possible to identify errors using expert case note review, and to associate those errors with a shortterm adverse event, it is much more difficult to be certain that the error contributed to adverse longterm outcomes, for which the main determinant is usually the patient's underlying disease. Case note review is the standard method for retrospective audit, but there are substantial differences in the way in which doctors and nurses interpret processes and outcomes of care.[4] These discrepancies can be reduced by using explicit criterion-based audit rather than implicit ‘expert review’, provided that there is a strong evidence base for the criteria selected as the gold standard.[5] The problem is that for many diseases (particularly emergency care) the evidence base may not be strong, and where standards of care exist they may not fully reflect the complexity of potential treatment pathways, or may lack solid professional endorsement.

idence base for the criteria selected as the gold standard.[5] The problem is that for many diseases (particularly emergency care) the evidence base may not be strong, and where standards of care exist they may not fully reflect the complexity of potential treatment pathways, or may lack solid professional endorsement. The second problem is related to the context in which error may arise. To characterize a problem or determine the efficacy of an intervention, it is necessary to express these variables as ‘rates’ - that is, as numerator and denominator. In patient safety research, this means knowing the number of errors in relation to the number of opportunities for error in order to determine the prevalence. Complex acute care environments are likely to have more opportunities for error, as well as better monitoring and hence detection of errors when they occur. Measuring error frequency alone will give a false impression of the scale and the nature of the problem.

ortunities for error in order to determine the prevalence. Complex acute care environments are likely to have more opportunities for error, as well as better monitoring and hence detection of errors when they occur. Measuring error frequency alone will give a false impression of the scale and the nature of the problem. The third problem is in trial design. Virtually all studies of interventions to improve patient safety employ a before-and-after design, because in quality improvement research it is either unethical to omit best practice in a control group, or difficult to prevent ‘contamination’ between the intervention and control groups (often referred to as the Hawthorne effect). Moreover, in complex systems there are many potential confounders. Cluster randomization has been used to minimize some of these problems, but the difficulty of adequate sample size persists. Stepped cluster randomization[6] may be advantageous, as this permits all centers to participate in both the control and the intervention arms. Without some form of control, it will not be possible to attribute with confidence the effect of a health services intervention unless the effect size is very large, as was the case for a study demonstrating substantial reductions in central venous catheter-related blood stream infections.[7] It has not been possible to achieve this for complex interventions such as medical emergency teams (rapid response teams or outreach care), where improvements in outcome were equivalent between the intervention and non-intervention hospitals,[89] thus perhaps reflecting systems-wide changes. We need to become much more sophisticated in arguing for funding for quality improvement research, and to specify the precise content of complex interventions rather than just evaluating the vehicle.[10]

quivalent between the intervention and non-intervention hospitals,[89] thus perhaps reflecting systems-wide changes. We need to become much more sophisticated in arguing for funding for quality improvement research, and to specify the precise content of complex interventions rather than just evaluating the vehicle.[10] The Acutely III Patient: A Systems-wide challenge At the same time that healthcare systems worldwide are trying to improve patient safety, they also have to deal with a growing emergency workload while contending with cost containment. This makes the acutely ill patient a prime target for safety initiatives, particularly because these patients have a high risk of morbidity and mortality, and are particularly susceptible to healthcare error.[11] The problem is that few specialities regard the care of acutely ill patients as their main core business, being more focused on (and interested in) elective workload and predictable funding streams. As a result, emergency admissions and acutely ill patients in general could substantially impair the efficacy of national and international patient safety initiatives,[12] because of the special challenges they bring in terms of process control, multidisciplinary teamwork teamwork, and translation of research evidence into best practice guidelines requiring implementation across specialities and geographical areas. Best practice needs to become engrained in competency-based training, from undergraduate to specialist level.[13] These objectives require transdisciplinary national and international collaboration.

eous reductions in the number of acute hospital beds and increases in throughput place additional pressures on the system, thereby increasing opportunities for error. Hospitals will therefore need to evolve new strategies for improving patient safety focused at least in part on this large population of the acutely ill. Responsibility and Recognition Responsibility for the initial management of acutely ill patients in many hospital systems is often consigned to more junior staff, particularly at night or weekends. Although virtually all medical disciplines are responsible for acutely ill patients, they are not generally their ‘core business’, since most specialities tend to focus on out-patient care and elective interventions. Outside the core specialities of emergency medicine and critical care, many senior staff loose expertise in acute care management. Thus, the early warning signs of worsening acute illness are often overlooked, and patients may deteriorate to the point of cardiopulmonary arrest. Acutely ill patients are usually a source of considerable anxiety for junior medical and nursing staff, who welcome better training in acute care and support to enable them to provide more effective (i.e.: safer) care to unstable patients. Hospitals need to invest in providing both staff and training.[19]

onary arrest. Acutely ill patients are usually a source of considerable anxiety for junior medical and nursing staff, who welcome better training in acute care and support to enable them to provide more effective (i.e.: safer) care to unstable patients. Hospitals need to invest in providing both staff and training.[19] Integration, Teamwork and Decision Support Constraints on working hours and difficulties with adequate staffing requires health care systems to develop different ways of providing emergency care. Gaps and discontinuities are common causes of error and miscommunication[20] and communication failures are a common cause of discontent amongst patients and relatives.[21] Transdisciplinary teamworking teamwork is generally presented as the solution and aviation crew resource management as the model, but substantial investment in training and education will be needed to make this a reality. Acute care provides an ideal testing ground for team building, an appropriate analogy being the military, not civilian aviation. Electronic systems which integrate clinical and laboratory information with prescribing can substantially reduce errors, but their true potential requires the inclusion of clinical decision support - prompts and reminders which enforce and facilitate best practice. Hospital design can similarly promote or impede patient safety.[22]

stems which integrate clinical and laboratory information with prescribing can substantially reduce errors, but their true potential requires the inclusion of clinical decision support - prompts and reminders which enforce and facilitate best practice. Hospital design can similarly promote or impede patient safety.[22] Process Control: A Key Element in Acute Care Twenty or more years ago it was common for patients with diabetic ketoacidosis, asthma or myocardial infarction to receive suboptimal treatment and to require admission to intensive care. Such patients now receive better care both in the community, and in hospital through more prompt and effective protocol-driven therapy. In consequence, the great majority can be treated in emergency departments and discharged home without requiring hospital admission, or in wards and specialized units instead of being admitted to intensive care. This transformation has been slow, but has come about through improved process control - better application of current knowledge. By contrast, process control is poor for the generality of acutely ill patients, particularly those who deteriorate after hospital admission. The Surviving Sepsis Campaign[23] provides an example of what can be achieved by focusing on a specific but poorly characterized entity, sepsis. A similar approach is now required for all acutely ill patients at risk of critical illness.

acutely ill patients, particularly those who deteriorate after hospital admission. The Surviving Sepsis Campaign[23] provides an example of what can be achieved by focusing on a specific but poorly characterized entity, sepsis. A similar approach is now required for all acutely ill patients at risk of critical illness. Futile Care is Bad Care As populations age, so does the hospital population. The elderly are more susceptible to adverse events and error[24] and are also less able to withstand the consequences. Ageing populations have more chronic and comorbid disease, which in the end will present as an acute deterioration. Providing appropriate care to these patients requires not only an understanding of the ethical issues involved, but a practical understanding of what is possible in acute care. The public as well as health care professionals need to develop a better understanding of the likely outcomes from interventions intended to save lives, in order to avoid imposing burdensome and futile care with consequential waste of limited health care resources. Early recognition of high risk patients permits earlier intervention which can either result in treatment to prevent in-hospital cardiac arrest[25] or allows time for discussion about treatment limitation so that an inevitable death can occur peacefully, untroubled by useless technology. Patient safety: The reliable implementation of best practice care

Futile Care is Bad Care As populations age, so does the hospital population. The elderly are more susceptible to adverse events and error[24] and are also less able to withstand the consequences. Ageing populations have more chronic and comorbid disease, which in the end will present as an acute deterioration. Providing appropriate care to these patients requires not only an understanding of the ethical issues involved, but a practical understanding of what is possible in acute care. The public as well as health care professionals need to develop a better understanding of the likely outcomes from interventions intended to save lives, in order to avoid imposing burdensome and futile care with consequential waste of limited health care resources. Early recognition of high risk patients permits earlier intervention which can either result in treatment to prevent in-hospital cardiac arrest[25] or allows time for discussion about treatment limitation so that an inevitable death can occur peacefully, untroubled by useless technology. Patient safety: The reliable implementation of best practice care The key to greater safety is to improve the reliability of delivery of best practice. Until recently it was assumed that all that was required was high quality research demonstrating the superiority of one intervention or treatment over another. We now know that this is insufficient, and that failures of translation result in medical care that is not reliable.[26–28] What we do not know is why this should be so. What are the barriers to implementing best practice? Are they generic, or are there context-specific barriers as well? Reliability of care can be improved, but the effort required is considerable[29] and a formal strategy is needed to implement and sustain improvements in processes of care. Changing clinician behavior is a complex intervention, requiring leadership at multiple levels within an organization, and incorporation of best practice in life-long learning.[30–31] That in turn means that the professions have to develop methods for evaluating current evidence, work out what to do in the presence of uncertainty, and apply a greater degree of standardization in our practice than we have previously been willing to accept. While some clinicians may regard this as a loss of clinical freedom, for our patients it may make the difference between life and death.

ing current evidence, work out what to do in the presence of uncertainty, and apply a greater degree of standardization in our practice than we have previously been willing to accept. While some clinicians may regard this as a loss of clinical freedom, for our patients it may make the difference between life and death. Source of Support: Nil Conflict of Interest: None declared.

Intensive care medicine arguably began in Copenhagen in 1952, when victims of poliomyelitis were artificially ventilated in order to sustain life until the disease abated.[1] As a result, the mortality was reduced from 89% to 40% - a remarkable achievement. Soon the skills learnt in managing these patients was applied to other seriously ill patients, including patients with severe trauma, serious infections and other diseases such as tetanus. Patients were now able to be kept alive while their underlying disease was either actively treated or abated in the course of time. The development of intensive care also meant that complex surgery was able to be performed. Specialties such as cardiac surgery, vascular surgery and neurosurgery were able to be developed as a result of the parallel development of intensive care medicine.

se was either actively treated or abated in the course of time. The development of intensive care also meant that complex surgery was able to be performed. Specialties such as cardiac surgery, vascular surgery and neurosurgery were able to be developed as a result of the parallel development of intensive care medicine. The actual space that defines an intensive care unit (ICU) was essential to the development of the specialty of intensive care medicine. Specific training programs were developed in the specialty, firstly for nursing staff and then for physicians. The walls of the ICU nurtured the specialty. Monitoring of the seriously ill with specific machines was developed. Artificial ventilation, dialysis and inotropes were used to support vital functions. The specialty would not have developed if these devices and interventions had to be transferred to the general wards. However, the security and sense of accomplishment may have, at the same time, contained our thinking to within the four walls of the ICU. For many years patients were considered either sick enough to benefit from being in ICU or well enough to be able to be treated on the general wards. It was black or white. And yet, at the same time, our research clearly demonstrated that serious illness often began long before admission to the ICU. In fact, the specialty of intensive care often simply involved treating multi-organ failure as a result of untreated ischemia and hypoxia.

treated on the general wards. It was black or white. And yet, at the same time, our research clearly demonstrated that serious illness often began long before admission to the ICU. In fact, the specialty of intensive care often simply involved treating multi-organ failure as a result of untreated ischemia and hypoxia. While the management of the seriously ill within the four walls of the ICU improved markedly, the standard of care for at-risk patients outside the ICU was questionable. Over 80% of in-hospital cardiac arrests are preceded by serious abnormalities in vital signs within eight hours of the arrest.[23] Up to 40% of ICU admissions are potentially avoidable[4] and approximately half of those patients had received substandard care before admission to the ICU. Serious adverse events, including deaths, occur in up to 17% of hospital patients and approximately 70% of those are preventable.[5] Almost half of all patients who die without a "not for resuscitation" (NFR) order have serious and potentially reversible abnormalities in their vital signs in the 24 hours before death.[6]

rious adverse events, including deaths, occur in up to 17% of hospital patients and approximately 70% of those are preventable.[5] Almost half of all patients who die without a "not for resuscitation" (NFR) order have serious and potentially reversible abnormalities in their vital signs in the 24 hours before death.[6] Interestingly, early studies in patients who were admitted to the ICU hinted at the effects of delayed resuscitation. It was noted that the APACHE score was influenced by pre-ICU care – a phenomenon called “lead-time” bias.[7] The concept of the "golden hour" emphasizes one of the most important aims in the management of the critically ill – to rapidly restore oxygenated blood flow to tissues. There is good evidence that the beginnings of multi-organ dysfunction syndrome (MODS)[8–12] long before admission to the ICU. Despite this knowledge, much of the research conducted by intensive care specialists is around managing the seriously ill after they have been admitted to the ICU, such as defining ideal tidal volumes and selecting the best inotropes or antibiotics; and searching for magic bullets after MODS has been established.[13]

Interestingly, early studies in patients who were admitted to the ICU hinted at the effects of delayed resuscitation. It was noted that the APACHE score was influenced by pre-ICU care – a phenomenon called “lead-time” bias.[7] The concept of the "golden hour" emphasizes one of the most important aims in the management of the critically ill – to rapidly restore oxygenated blood flow to tissues. There is good evidence that the beginnings of multi-organ dysfunction syndrome (MODS)[8–12] long before admission to the ICU. Despite this knowledge, much of the research conducted by intensive care specialists is around managing the seriously ill after they have been admitted to the ICU, such as defining ideal tidal volumes and selecting the best inotropes or antibiotics; and searching for magic bullets after MODS has been established.[13] Paradoxically, there has been little research evaluating systems for early care of the seriously ill, before irreversible organ failure has occurred. For example, it was fashionable at one time to conduct research into the effect of supranormal oxygen delivery after the patient was admitted to the ICU. Careful reading of these studies suggest that this approach amounted to “too much, too late”.[14–18] It could be concluded from these articles that early restoration of the intravascular volume may have been more effective than late supranormal oxygen delivery. For example, when goal directed therapy was initiated at an earlier stage in the emergency department, patient outcome improved.[19]

oo much, too late”.[14–18] It could be concluded from these articles that early restoration of the intravascular volume may have been more effective than late supranormal oxygen delivery. For example, when goal directed therapy was initiated at an earlier stage in the emergency department, patient outcome improved.[19] In order to improve patient outcome it seems logical to recognize seriously ill patients early and to rapidly resuscitate them. This may seem logical but it involves establishing a hospital-wide system. Something health has not necessarily had a lot of experience with. The only hospital-wide system in many organizations is the cardiac arrest team which has not improved mortality in the almost 50 years since the concept was first implemented.[20] Hospitals, and indeed medical training, are built around the long tradition of individual physicians being responsible for the care of individual patients. To identify and manage patients within a different paradigm that crosses all the usual hospital silos is difficult. Even identifying at-risk patients is difficult[4] as is responding to their needs with staff skilled in all aspects of resuscitation is a challenge.[421] Nurses have traditionally recorded deteriorating signs and noted patients who were “going off” but have not been empowered, nor trained to act on those signs. They often rely on junior doctors who, themselves, have had little undergraduate training in advanced resuscitation.[2223] The specialist responsible for the patient's care is not always immediately available nor trained in advanced resuscitation.

ing off” but have not been empowered, nor trained to act on those signs. They often rely on junior doctors who, themselves, have had little undergraduate training in advanced resuscitation.[2223] The specialist responsible for the patient's care is not always immediately available nor trained in advanced resuscitation. Another reason for poor management of at-risk patients is related to the hierarchical medical system where problems in acute hospitals are passed up through levels of seniority. While individual specialists formally consult others when necessary, this process often takes hours or even days and potentially seriously ill patients require immediate attention. Trauma systems were the first to attempt to construct care around patient needs from the first point of immediate care at the site of injury, to transport to hospital, resuscitation in the emergency department, management in hospital and rehabilitation.[24–27] Ironically, often immediate and appropriate care is delivered better for the seriously ill in the community than it is in acute hospitals. A MET was first established in 1989 at Liverpool Hospital in Sydney, Australia, in an attempt to recognize seriously ill patients early and to respond rapidly to their needs.[28] The cardiac arrest team was renamed the MET and a set of criteria based on abnormal vital signs and observations were developed as triggers [Table 1].[29] Table 1 Criteria for calling the medical emergency team

A MET was first established in 1989 at Liverpool Hospital in Sydney, Australia, in an attempt to recognize seriously ill patients early and to respond rapidly to their needs.[28] The cardiac arrest team was renamed the MET and a set of criteria based on abnormal vital signs and observations were developed as triggers [Table 1].[29] Table 1 Criteria for calling the medical emergency team Acute changes in Physiology Airway Threatened Breathing All respiratory arrests Respiratory Rate <5 Respiratory Rate >36 Circulation All cardiac arrests Pulse rate <40 Pulse rate >140 Systolic blood pressure <90 mmHg Neurology Sudden fall in level of consciousness (Fall in GCS of >2 points) Repeated or prolonged seizures Other Any patient who you are seriously worried about that does not fit the above criteria The MET concept is based on recognizing seriously ill and at-risk patients early with the aim of preventing death and serious adverse events. The concept is a system with at least three separate components - criteria defining an at-risk patient; a rapid response by staff with appropriate skills, knowledge and experience; and ways of monitoring the system and closing the loop with that information so that continuous quality improvement occurs.

adverse events. The concept is a system with at least three separate components - criteria defining an at-risk patient; a rapid response by staff with appropriate skills, knowledge and experience; and ways of monitoring the system and closing the loop with that information so that continuous quality improvement occurs. For monitoring to occur, data must be collected.[30] Some data that can be used for monitoring include deaths, cardiac arrests and unanticipated admissions to the ICU. In order to exclude patients who are terminally ill, patients who have an explicit NFR entry are excluded and the remainder are called “unexpected.” “Unexpected” admissions to the ICU are those who are mainly from the general wards and do not include patients from emergency departments or operating suites. However, they may include patients from areas such as diagnostic suites or coronary care units. In order to facilitate the organization using the data for quality assurance purposes, clinical notes can be scanned to see if any MET criteria were present in the 24 hours before the event. The data should then inform all levels of the organization as a quality assurance tool. Other ways of monitoring the system include presenting details of MET activity at regular intervals. This would include not only the number of calls, but the site of the call, the nature of the intervention, how long each call took and the patient outcome.

In order to facilitate the organization using the data for quality assurance purposes, clinical notes can be scanned to see if any MET criteria were present in the 24 hours before the event. The data should then inform all levels of the organization as a quality assurance tool. Other ways of monitoring the system include presenting details of MET activity at regular intervals. This would include not only the number of calls, but the site of the call, the nature of the intervention, how long each call took and the patient outcome. The concept of early identification of at-risk patients, together with a rapid response has now been adapted in many ways. The criteria may vary slightly and the response may be multi-tiered, with perhaps the home team or attending nurse being the first response and then, if the patient requires a higher level of support, a more experienced team is called. Examples of these variations include the patient at-risk team (PART)[31] and the modified early warning score (MEWS).[32] Then there is the concept of outreach,[33] which usually involves staff who have been trained in caring for the seriously ill, playing a proactive role in the general wards, which may decrease the need for emergency calls using education across the hospital and playing a consultative role in the care of the seriously ill.

Then there is the concept of outreach,[33] which usually involves staff who have been trained in caring for the seriously ill, playing a proactive role in the general wards, which may decrease the need for emergency calls using education across the hospital and playing a consultative role in the care of the seriously ill. There have been several studies[34–36] evaluating the impact of early response systems. In three important before and after studies, the introduction of the MET has been associated with a reduction in cardiac arrests and death rates as well as a reduction in intensive care and hospital stay. A case controlled study[37] demonstrated reduced mortality as well as the incidence of unanticipated admission rates to ICUs. The system has also improved postoperative care.[3839] The outreach system has also resulted in improved patient care across a large number of clinical indicators.[3840–44] A large cluster randomized trial involving 23 Australian hospitals failed to demonstrate a difference between the MET and control hospitals (MERlT study).[45] However, it did provide insight into the challenges of effective implementation of a system across an entire hospital. Less than half of all patients with the MET criteria actually had a call made. Approximately the same number had no vital signs recorded before serious adverse events occurred. Moreover, there was such a variation of outcomes in the MET hospitals that statistical significance would have only been possible if more than 100 hospitals had been recruited.

th the MET criteria actually had a call made. Approximately the same number had no vital signs recorded before serious adverse events occurred. Moreover, there was such a variation of outcomes in the MET hospitals that statistical significance would have only been possible if more than 100 hospitals had been recruited. No one would propose that we do not treat serious illness as early as possible. However, the challenge for hospitals is to effectively implement a system across the entire organization and this is something health has traditionally had little experience. Because early warning systems make sense they have now been implemented in many hospitals in Europe, North America and Australasia. They will almost certainly become, in one way or another, a critical part of all acute hospitals. Source of Support: Nil Conflict of Interest: None declared.

Introduction Scorpion sting is an acute life-threatening, time-limiting medical emergency more commonly seen in villagers.[1] Among the 86 species of scorpions in India, Mesobuthus tamulus and Palamneus are of medical importance.[2] Cardiovascular effects are particularly prominent following the stings by Indian red scorpion (Mesobuthus tamulus).[3] Cerbrovascular manifestations are uncommon presentations of scorpion sting in the Indian subcontinent. During the period of May 2005 to October 2007, a prospective study was done in patients with scorpion sting admitted to the intensive care unit of the Institute of Medical Sciences, Banaras Hindu University, Varanasi-05, INDIA. The diagnosis was based on positive history of scorpion sting, with scorpion being seen or killed by relatives or bystanders. In all the patients history, physical examination with a specific neurological examination and routine biochemical testing and fundus examination to specifically look for changes in the retinal vessels due to longstanding hypertension were done. Vitals were recorded on arrival and thereafter at one hourly interval. Electrocardiogram (ECG) was recorded to detect any evidence of scorpion sting induced myocarditis and to detect any evidence of left ventricular hypertrophy due to longstanding hypertension.

etinal vessels due to longstanding hypertension were done. Vitals were recorded on arrival and thereafter at one hourly interval. Electrocardiogram (ECG) was recorded to detect any evidence of scorpion sting induced myocarditis and to detect any evidence of left ventricular hypertrophy due to longstanding hypertension. Cases with neurological deficit were included in the further work-up. Computerized tomography and magnetic resonance imaging were done in cases with neurological deficit. All these patients also underwent a complete hematological work up in the form of complete blood count, hematocrit, peripheral smear, platelet count, coagulation profile, fibrin degradation products, serum homocysteine, rheumatological work-up of antinuclear antibody and cardiovascular work-up of lipid profile, transthoracic echocardiogram and carotid doppler. All these investigations were done at the time of admission.

hematocrit, peripheral smear, platelet count, coagulation profile, fibrin degradation products, serum homocysteine, rheumatological work-up of antinuclear antibody and cardiovascular work-up of lipid profile, transthoracic echocardiogram and carotid doppler. All these investigations were done at the time of admission. Out of the total of 42 patients with documented scorpion sting, focal neurological deficit was noted in three patients (7.15%). The commonest presentation of neurological deficit was hemiparesis, observed in all three cases. All the three patients were males. Their mean age was 35 years (range from 18 to 49 years). Hemorrhagic stroke was noted in two patients (4.77%) and thrombotic stroke was noted in one patient (2.39%). Among the patients with hemorrhagic stroke, one patient had an intraventricular hemorrhage, while one patient had hemorrhage in the putamen. The patient with thrombotic stroke had involvement of the middle cerebral artery (MCA) territory - due to disseminated intravascular coagulation (DIC). Patient with DIC producing a thrombotic stroke presented at 3 days after the scorpion sting, while patients with hemorrhagic stroke presented within 48 h of the scorpion sting. Patient with thrombotic stroke due to DIC had documented defibrination. All the three patients had a normal carotid doppler and a normal transthoracic echocardiogram with no evidence of left ventricular hypertrophy. All the patients with stroke had no evidence of myocarditis or pulmonary edema on clinical examination or echocardiogram. One patient with intralobar hemorrhage died on the fifth day of sting due to raised intracranial tension and coning. The other two patients did exceedingly well and recovered within a period of 3 months.

he patients with stroke had no evidence of myocarditis or pulmonary edema on clinical examination or echocardiogram. One patient with intralobar hemorrhage died on the fifth day of sting due to raised intracranial tension and coning. The other two patients did exceedingly well and recovered within a period of 3 months. Prazosin was initiated in all the three patients with scorpion sting. Patients with stroke, both thrombotic and hemorrhagic, were managed conservatively with prazosin and supportive measures. Discussion Scorpion venoms are species-specific complex mixtures of short neurotoxic proteins.[4] Alpha-receptor stimulation by the toxin results in hypertension, tachycardia, myocardial dysfunction, pulmonary edema.[5] Raised angiotensin I levels have also been documented, which facilitates the sympathetic outflow through conversion to angiotensin II.[6] The unopposed effects of alpha-receptor stimulation lead to myocarditis. Acute rise in blood pressure due to sympathetic stimulation, rupture of unprotected perforating arteries, intracerebral hemorrhage and cerebral infarction due to DIC and central respiratory failure are reported in scorpion stings.[7–9]

nsin II.[6] The unopposed effects of alpha-receptor stimulation lead to myocarditis. Acute rise in blood pressure due to sympathetic stimulation, rupture of unprotected perforating arteries, intracerebral hemorrhage and cerebral infarction due to DIC and central respiratory failure are reported in scorpion stings.[7–9] Our two patients with hemorrhagic stroke had an acute rise in blood pressure - of around 260/130 mm of Hg - at the time of admission due to autonomic storm, which would explain the hemorrhage inside the brain. By the use of carotid doppler, echocardiogram, electrocardiogram, lipid profile, we excluded patients with longstanding hypertension, which would have caused stroke in these patients. The other patient with thrombotic stroke due to DIC could be explained based on the toxin-induced alteration in the coagulation system inducing a defibrination syndrome.[7] There have been reports of cerebral vasospasm induced infarcts in the brain. Thacker et al. reported a case of scorpion sting induced multiple cerebral infarcts with optic neuropathy.[10]

due to DIC could be explained based on the toxin-induced alteration in the coagulation system inducing a defibrination syndrome.[7] There have been reports of cerebral vasospasm induced infarcts in the brain. Thacker et al. reported a case of scorpion sting induced multiple cerebral infarcts with optic neuropathy.[10] There have been a number of limitations in our study as vasospasm could not be proved by angiography. Protein C, Protein S and antithrombin III estimation was not done in thrombotic stroke in view of the fact that the deficiency of Protein C, Protein S and anti thrombin III usually produce venous infarcts rather than arterial infarcts, as in our series. Transesophageal echocardiogram was not done in our cases, which would have picked up thrombus in the heart missed by transthoracic echocardiogram. But it would be a highly unlikely event to expect thrombus in a patient with a well-contracting myocardium with no evidence of hypertrophy or dilatation of heart chambers. Conclusion Cerebrovascular manifestations were seen in three (7.15%) patients. Treatment with prazosin, if initiated early, may prevent many cerebrovascular manifestations of scorpion sting. Source of Support: Nil Conflict of Interest: None declared.

Introduction Multiple surveillance programmes have reported P. aeruginosa as one of the leading causes of nosocomial infection.[1–3] In our hospital, it represents 19% of micoorganisms causing nosocomial infections[4] and in our intensive care unit, it represents 44.7% of pathogens responsible for ICU acquired infections (unpublished data). This frequency had lead to a large use of antipseudomonal agents and concomitantly to a decline in antibiotic susceptibility of P. aeruginosa because of its ability to acquire resistance.[5–7] Indeed, many studies had reported the influence of previous exposure to antibiotic therapy on the susceptibility pattern of P. aeruginosa.[7–11] This impact was called “collateral damage” from antibiotic prescription to refer to ecological adverse effects of antibiotic consumption which are represented by the emergence of multi-drug resistant organisms via selection or mutation.[12] Because of the increasing frequency of isolation of P. aeruginosa and the emergence of multi-drug resistant strains in our unit, we had undertaken this epidemiological study in order to study the relationship between the use of antipseudomonal agents and the development of resistance to these drugs.

Introduction Multiple surveillance programmes have reported P. aeruginosa as one of the leading causes of nosocomial infection.[1–3] In our hospital, it represents 19% of micoorganisms causing nosocomial infections[4] and in our intensive care unit, it represents 44.7% of pathogens responsible for ICU acquired infections (unpublished data). This frequency had lead to a large use of antipseudomonal agents and concomitantly to a decline in antibiotic susceptibility of P. aeruginosa because of its ability to acquire resistance.[5–7] Indeed, many studies had reported the influence of previous exposure to antibiotic therapy on the susceptibility pattern of P. aeruginosa.[7–11] This impact was called “collateral damage” from antibiotic prescription to refer to ecological adverse effects of antibiotic consumption which are represented by the emergence of multi-drug resistant organisms via selection or mutation.[12] Because of the increasing frequency of isolation of P. aeruginosa and the emergence of multi-drug resistant strains in our unit, we had undertaken this epidemiological study in order to study the relationship between the use of antipseudomonal agents and the development of resistance to these drugs. Materials and Methods This study was conducted at the medical surgical intensive care unit of the Habib Bourguiba University Hospital (Sfax-Tunisia). Our unit is a 22-bed intensive care unit in a 510-bed tertiary-care teaching hospital that serves as first line medical center for an urban population of one million inhabitants and as a referral center for a larger population coming from south Tunisia.

re unit of the Habib Bourguiba University Hospital (Sfax-Tunisia). Our unit is a 22-bed intensive care unit in a 510-bed tertiary-care teaching hospital that serves as first line medical center for an urban population of one million inhabitants and as a referral center for a larger population coming from south Tunisia. This study is a retrospective analysis of data collected prospectively. It was conducted over a five year period (January 1st, 1999 to December 31, 2003) which was divided into 20 quarters. Antimicrobial usage Antipseudomonal agents available in our hospital are imipenem, ceftazidime, amikacine, and ciprofloxacin. Antibiotic utilization data were extracted on a quarterly basis from the inpatient pharmacy computer system and stored in a spreadsheet program (Excel®). Usage data was expressed as total grams of antibiotic dispensed per quarter and then converted to daily doses dispensed (DDD) by using the daily doses most frequently prescribed in our unit, which were as follows: imipenem, 2 g; ceftazidime, 3 g; amikacine, 1 g; intravenous ciprofloxacin, 0.4 g; oral ciprofloxacin, 1g.

Usage data was expressed as total grams of antibiotic dispensed per quarter and then converted to daily doses dispensed (DDD) by using the daily doses most frequently prescribed in our unit, which were as follows: imipenem, 2 g; ceftazidime, 3 g; amikacine, 1 g; intravenous ciprofloxacin, 0.4 g; oral ciprofloxacin, 1g. Microbiology and susceptibility data P. aeruginosa was identified in the laboratory by using standard clinical microbiology methods.[13] Antimicrobial susceptibility was determined by disk diffusion methods according to the recommendations of the National Committee for Clinical Laboratory Standards (NCCLS).[14] An isolate was considered susceptible, intermediate, or resistant according to the criteria of the NCCLS. The isolates with intermediate susceptibility were classified as resistant for analysis. Susceptibility data for P. aeruginosa were obtained quarterly using a computer based documentation system. The system is adjusted to count not only primary isolates from individual patients, but also to include follow-up isolates if the primary isolates show a different pattern of antibiotic resistance. Duplicate isolates, defined as the same bacterial species from the same patient with the same antibiogram, were removed.

. The system is adjusted to count not only primary isolates from individual patients, but also to include follow-up isolates if the primary isolates show a different pattern of antibiotic resistance. Duplicate isolates, defined as the same bacterial species from the same patient with the same antibiogram, were removed. Data analysis Categorical variables were expressed in percentage and continuous variables in means (±SD). Relationships between increasing antibiotic use and the resistance rates of P. aeruginosa were analyzed to determine the likelihood of a correlation between antibiotic utilization and the emergence of resistance. A linear curve regression was performed on relevant variables and the associations of primary interest from the correlation analysis were tabulated, showing correlation coefficient (r2) and significance (P). Statistical significance was defined as a P-value equal or less than 0.05 for the corresponding correlation coefficient (r2). In addition, the associations between consumption and resistance to ceftazidime, imipenem, amikacine and ciprofloxacin were quantified using non-partial and partial correlation coefficients according to Pearson and Spearman. Results Over the study period, the mean (±SD) number of patients hospitalized in our unit was 299 ± 20 hospitalizations per quarter (range: 267 and 339 hospitalizations per quarter). The mean number of hospitalization day was 1766 ± 250 hospitalization day per quarter (range, 1374 and 2358 hospitalization day per quarter) and the mean occupation rate in the unit was 88 ± 13% (range, 69 and 119%).

n our unit was 299 ± 20 hospitalizations per quarter (range: 267 and 339 hospitalizations per quarter). The mean number of hospitalization day was 1766 ± 250 hospitalization day per quarter (range, 1374 and 2358 hospitalization day per quarter) and the mean occupation rate in the unit was 88 ± 13% (range, 69 and 119%). Over the study period, 583 P. aeruginosa isolates were studied (29 ± 10 isolates per quarter). Three hundred and eighty-seven of them (66.4%) were isolated from pulmonary samples, 110 (18.9%) from blood samples and 86 (14.7%) from urinary samples. The resistance rate of P. aeruginosa to imipenem was 44.3 ± 9.5% (range, 30 and 60%). The most frequently used antipseudomonal agents were imipenem (152 ± 46 DDD/1000 patients-day) and amikacine (106 ± 34 DDD/1000 patients-day). Over the study period, imipenem use correlated significantly with imipenem resistance (r2 = 0.26, P < 0.05) [Figures 1 and 2]. This correlation was seen not only when quarterly prescription rates were compared with resistance data from the same quarter, but also when compared with those of the following quarter [Figure 3]. In addition, ciprofloxacin use correlated significantly with resistance to ciprofloxacin observed in the following quarter. However, no apparent association was found between use and resistance for ceftazidime (r2 = 0.045, P > 0.1) nor for amikacine (r2 = 0.000, P > 0.1). Table 1, [Figures 4–6]. In addition, resistance of P. aeruginosa to imipenem does not correlate with its resistance to ciprofloxacin (r2 = 0.01, P > 0.1) [Figures 7 and 8].

owever, no apparent association was found between use and resistance for ceftazidime (r2 = 0.045, P > 0.1) nor for amikacine (r2 = 0.000, P > 0.1). Table 1, [Figures 4–6]. In addition, resistance of P. aeruginosa to imipenem does not correlate with its resistance to ciprofloxacin (r2 = 0.01, P > 0.1) [Figures 7 and 8]. Figure 1 Correlation between consumption of imipenem and resistance of P. aeruginosa to imipenem: quarterly resistance rates plotted against quarterly consumption rates during the 20 quarters of the study Figure 2 Linear regression showing the statistically significant association between quarterly imipenem consumption and resistance of P. aeruginosa to imipenem in the same quarter during the 20 quarters of the study (P < 0.05) Figure 3 Non-partial correlation coefficients between quarterly imipenem consumption and resistance in the quarter of consumption (designated “0”) and the 2 quarters prior to and following consumption. Asterisks indicate statistical significance (P<0.05) Table 1 Partlal coefficient of correlation between antibiotic consumption and resistance of P. aeruginosa. Coefficients for the quarter of antibiotic consumption and quarter following and before consumption are given. Boldface indicates significance (P ≤ 0.005)

Figure 3 Non-partial correlation coefficients between quarterly imipenem consumption and resistance in the quarter of consumption (designated “0”) and the 2 quarters prior to and following consumption. Asterisks indicate statistical significance (P<0.05) Table 1 Partlal coefficient of correlation between antibiotic consumption and resistance of P. aeruginosa. Coefficients for the quarter of antibiotic consumption and quarter following and before consumption are given. Boldface indicates significance (P ≤ 0.005) Last quarter Same quarter Next quarter Ceftazidime 0.039 −0.9 0.308 Imipenem 0.22 0.52 0.443 Amikacin −0.002 −0.131 −0.17 Ciprofloxacine −0.04 −0.98 0.473 Figure 4 Correlation between consumption of ceftazidime and resistance of P. aeruginosa to ceftazidime: quarterly resistance rates plotted against quarterly consumption rates during the 20 quarters of the study Figure 5 Correlation between consumption of amikacine and resistance of P. aeruginosa to amikacin: quarterly resistance rates plotted against quarterly consumption rates during the 20 quarters of the study Figure 6 Correlation between consumption of ciprofloxacine and resistance of P. aeruginosa to ciprofloxacine: quarterly resistance rates plotted against quarterly consumption rates during the 20 quarters of the study Figure 7 Correlation between resistance of P. aeruginosa to imipenem and to ciprofloxacine: quarterly resistance rates of P. aeruginosa to imipenem plotted against quarterly resistance rates to ciprofloxacine during the 20 quarters of the study

Figure 6 Correlation between consumption of ciprofloxacine and resistance of P. aeruginosa to ciprofloxacine: quarterly resistance rates plotted against quarterly consumption rates during the 20 quarters of the study Figure 7 Correlation between resistance of P. aeruginosa to imipenem and to ciprofloxacine: quarterly resistance rates of P. aeruginosa to imipenem plotted against quarterly resistance rates to ciprofloxacine during the 20 quarters of the study Figure 8 Linear regression showing no statistically significant association between quarterly resistance of P. aeruginosa to imipenem and quarterly resistance of P.aeruginosa to ciprofloxacine (P > 0.05) Discussion Our study shows the high level of resistance of P. aeruginosa against ceftazidime, amikacine, imipenem and ciprofloxacin in our unit. In addition, it shows the high level of use of antipseudomonal agents and confirms the correlation between the evolution of resistance to imipenem or ciprofloxacine and that of their consumption. Different studies had reported P. aeruginosa as one of the most frequently isolated microorganisms in intensive care unit[2315] and emphasized its ability to acquire resistance toward antipseudomonal agents mainly to imipenem.[891617] Indeed, the resistance rate of P. aeruginosa to imipenem is increasing and can reach 24% in certain institutions[18] rekindling interest in polymixins as a last resort in the treatment of nosocomial infections caused by multidrug resistant P. aeruginosa.[1920]

e toward antipseudomonal agents mainly to imipenem.[891617] Indeed, the resistance rate of P. aeruginosa to imipenem is increasing and can reach 24% in certain institutions[18] rekindling interest in polymixins as a last resort in the treatment of nosocomial infections caused by multidrug resistant P. aeruginosa.[1920] The multidrug resistance of P. aeruginosa had been correlated to prior exposure to antibiotics mainly to β-lactams.[7–9111721] Indeed, Loeffler et al,[16] found a correlation between the resistance of P. aeruginosa to piperacillin and the consumption of piperacillin (r = 0.73; P < 0.005) or that of piperacillin-tazobactam (r = 0.61; P < 0.05), between the resistance to ceftazidime and the consumption of cephalosporins (r = 0.79; P < 0.001), between the resistance to gentamicin and the consumption of gentamicin (r = 0.64; P < 0.05) or that of aminoglycosides (r = 0.76; P < 0.005). Lepper et al,[9] found a correlation between the consumption of imipenem and the resistance of P. aeruginosa to imipenem, to ceftazidime and to piperacillin-tazobactam. This association existed between the consumption and the resistance during the same month and during the following month. Moreover, Mutnick et al,[21] reported a correlation between the use of meropenem (r = 0.98), ciprofloxacine (r = 0.92) and ceftazidime (r = 0.83) and the resistance of P. aeruginosa toward these antibiotics. Carmeli et al,[11] in a retrospective study demonstrated that the consumption of imipenem was the independent factor related to the development of resistance of P. aeruginosa (OR = 2.8; IC95% = 1.2-6.6; P = 0.02) toward piperacillin, imipenem or ciprofloxacine. In a case-control study, Paramythiotou et al,[8] demonstrated that the resistance of P. aeruginosa to ceftazidime was correlated to the previous consumption of piperacillin or of ticarcillin (P = 0.01) and that the resistance to imipenem was correlated to the previous consumption of imipenem (P = 0.01). El Amari et al,[7] in a retrospective study had looked for the factors correlated with the resistance of P. aeruginosa. Using multivariate analysis, they found that the exposure to any antipseudomonal antibiotic as a monotherapy was associated with an increased risk of subsequent resistance to itself (P = 0.006; OR = 2.5; IC95% = 1.3-4.8). Troillet et al,[17] demonstrated that a previous exposure to imipenem was statistically correlated to the resistance of P. aeruginosa to imipenem (P = 0.0004; OR: 23.2; IC 95%: 4.1-132.7).

c as a monotherapy was associated with an increased risk of subsequent resistance to itself (P = 0.006; OR = 2.5; IC95% = 1.3-4.8). Troillet et al,[17] demonstrated that a previous exposure to imipenem was statistically correlated to the resistance of P. aeruginosa to imipenem (P = 0.0004; OR: 23.2; IC 95%: 4.1-132.7). All these correlations translate the impact of antibiotic prescription on ecology. In addition, they demonstrate that the resistance of P. aeruginosa to antibiotics mainly to imipenem is associated with previous exposure to the antibiotic under question and that the exposure to an antipseudomonal agent as a monotherapy can lead to a great risk of development of resistance against this drug. In our study, we found a statistically significant relationship between the use of imipenem and the resistance of P. aeruginosa to imipenem in the same and in the following quarter; and a statistically significant relationship between the consumption of ciprofloxacin and the resistance of P. aeruginosa to ciprofloxacine in the following quarter. This correlation is consistent with many other studies where resistance to imipenem or ciprofloxacin was found to correlate with their previous use. This consideration justifies the large effort provided by intensivists to avoid the misusage of antibiotics. Indeed, in many studies the antibiotic prescription was found to be inadequate or abusive in a large part of the cases.[22]

resistance to imipenem or ciprofloxacin was found to correlate with their previous use. This consideration justifies the large effort provided by intensivists to avoid the misusage of antibiotics. Indeed, in many studies the antibiotic prescription was found to be inadequate or abusive in a large part of the cases.[22] There are three types of epidemiological studies which can potentially link the antibiotic use with the ecological adverse effects.[12] The first type is case-control studies,[81117] the second type of study assesses accumulated data on antibiotic use and correlates them with rates of antibiotic resistance[910] and the third type assesses an intervention aimed at limiting the use of an antibiotic to decrease the resistance to this antibiotic.[9] Our study's design corresponds to the second type of studies. It analyzes the evolution of antibiotic use and the emergence of resistance in the unit. It provides information about the impact of the overuse of antipseudomonal agents and the beneficial effect of their restriction on the ecology of an intensive care unit. Conclusion Our data support that the large use of imipenem or ciprofloxacin in intensive care unit may lead to the emergence of imipenem-resistant or ciprofloxacin-resistant strains of P. aeruginosa. Thus, they support the concept that antibiotic prescription policy of an intensive care unit has a significant impact on bacterial resistance rates. Source of Support: Nil Conflict of Interest: None declared.

Introduction An intensive care unit (ICU) is a continuously busy ward in which critically ill patients are on life support treatment under intensive monitoring. Doctors, nurses and technicians vigilantly work on the patients and handle the life support equipment, pipeline and monitors. The concept of recording a critical event was adapted from studies in aviation psychology in the US Air-force during and after the World War II. It was extensively applied in anaesthesia by Cooper et al. in 1978.[1–2] With this background, the present study was conducted to do an audit of reported critical events during intensive care stay and to develop a critical event reporting system in the ICU of our hospital. Errors in the management of the patient may creep in due to various reasons. There is a very narrow zone to allow for any errors whatsoever in the ICU, as these may significantly increase the morbidity and mortality of critically ill patients. Critical Event is any occurrence during the treatment of patient in an ICU, which if not detected and corrected in time would adversely affect the outcome of the patient. The importance of vigilant monitoring by a trained person is thereby emphasized.

Errors in the management of the patient may creep in due to various reasons. There is a very narrow zone to allow for any errors whatsoever in the ICU, as these may significantly increase the morbidity and mortality of critically ill patients. Critical Event is any occurrence during the treatment of patient in an ICU, which if not detected and corrected in time would adversely affect the outcome of the patient. The importance of vigilant monitoring by a trained person is thereby emphasized. Materials and Methods A prospective study of critical events was performed in a 13-bedded multidisciplinary ICU of Dr. RML Hospital, New Delhi over a period of 6 months, i.e., from January to June 2006. All the ICU beds are equipped with state-of-the-art monitors and ICU ventilators. Two beds have been earmarked as disaster beds and are kept vacant for serving the need of disaster as a policy of the hospital. The ICU is under supervision of the Department of Anaesthesia. The patients are admitted under medicine or surgery and are referred to ICU whenever an indication for ICU care arises. The protocol for ICU admission is fixed. Moribund/terminal patients are generally not brought to ICU as they are kept in wards on simple ventilators with basic modes. Patient-nurse ratio is fixed at three nurses for two patients, with an aim of keeping it as one for one. A consultant anaesthetist is incharge of ICU with a qualified resident anaesthetist on 12-h-shift duty. This study was designed to have a self-appraisal of ICU working. A proforma was designed for reporting critical events, keeping the patient and doctor identities anonymous. These proformas were collected in ICU in a special collection box. The box was emptied every 3 months and critical events were appraised. The ICU incharge had to encourage the resident doctors to report the events encountered during ICU duty. Critical event reporting was started as a practice when this study commenced and has been continued since then.

ICU in a special collection box. The box was emptied every 3 months and critical events were appraised. The ICU incharge had to encourage the resident doctors to report the events encountered during ICU duty. Critical event reporting was started as a practice when this study commenced and has been continued since then. Result These events can be classified into mechanical errors and human errors. Mechanical errors could be due to ventilator, monitor or some other equipment failure. In an ICU, a patient remains continuously on life support for a prolonged period of time. During this period, equipments may sometimes malfunction due to various reasons. If this is not detected well in time, it may affect the patient outcome critically. In the present study, 29.62% events were due to mechanical errors and 70.37% due to human errors. Observed critical events - n = 54 Mechanical errors i.e. ventilator failure - n = 16 (29.62%) Human errors - n = 38 (70.37%) Proforma for critical events in intensive care unit Age Sex Diagnosis Status of the patient - whether on/off ventilator On/off ionotropes Any other relevant history/clinical detail Critical event Time Details of event Intervention done Intervention done by whom Observed by Outcome observed Expected outcome without intervention Designation of reporter Human errors included endotracheal tube-related problems and disconnection.

ventilator On/off ionotropes Any other relevant history/clinical detail Critical event Time Details of event Intervention done Intervention done by whom Observed by Outcome observed Expected outcome without intervention Designation of reporter Human errors included endotracheal tube-related problems and disconnection. Human error n = 38 70.37% a) Extubation 16 29.62% b) Intubation problem 4 7.40% c) Blocked endotracheal tube 4 7.40% d) Ventilator disconnection 6 11.11% e) Oxygen disconnection from central pipe line 2 3.70% f) Fail from bed 2 3.70% g) Improper mode of ventilator 2 3.70% h) CVP related 2 3.70% Endotracheal tube-related errors were observed during: Extubation, which could either be self-extubation or inadvertent slipping out of the endotracheal tubes. This accounted for 29.62% of total human errors. The time at which these complications were observed could be related to bed-making or position-changing and back care in ICU. It shows that either the staff is not vigilant enough to take care of the endotracheal tube or it was not fastened well. In conscious patients, the hands should be kept tied so that self-extubation is not possible. Intubation, which could be either oesophageal or delayed due to difficult anatomy or untrained personnel attempting it. This accounted for 7.40% of total human errors. Endotracheal tube blockade, which could be because of thick secretions or kinking and it accounted for 7.40% of total human errors observed.

Extubation, which could either be self-extubation or inadvertent slipping out of the endotracheal tubes. This accounted for 29.62% of total human errors. The time at which these complications were observed could be related to bed-making or position-changing and back care in ICU. It shows that either the staff is not vigilant enough to take care of the endotracheal tube or it was not fastened well. In conscious patients, the hands should be kept tied so that self-extubation is not possible. Intubation, which could be either oesophageal or delayed due to difficult anatomy or untrained personnel attempting it. This accounted for 7.40% of total human errors. Endotracheal tube blockade, which could be because of thick secretions or kinking and it accounted for 7.40% of total human errors observed. Disconnection-related errors were due to either ventilator disconnection (11.11% of total human errors) or disconnection of central oxygen supply to the ventilator (3.7% of total human errors). Both the causes of disconnection mentioned above accounted for 14.81% of total human errors. Other human errors included fall from bed as the siderails were not raised after carrying out some the ICU procedure. Faulty setting of ventilator and CVP-related problems were observed during the posting of new doctors in ICU.

Disconnection-related errors were due to either ventilator disconnection (11.11% of total human errors) or disconnection of central oxygen supply to the ventilator (3.7% of total human errors). Both the causes of disconnection mentioned above accounted for 14.81% of total human errors. Other human errors included fall from bed as the siderails were not raised after carrying out some the ICU procedure. Faulty setting of ventilator and CVP-related problems were observed during the posting of new doctors in ICU. Mechanical errors in our study included ventilator breakdown repeatedly with one make of ventilator. After every breakdown, the company people were informed. The problem would be rectified and the ventilator would work alright for a few days and would again break down. The ventilator undergoing repeated breakdowns was having a proximal flow sensor which would get stuck while ventilating the patient. Patients were put on standby portable ventilators whenever these breakdowns happened. Fortunately, no mortality was reported. Medication errors often reported as adverse drug events (ADE) are another set of critical human errors in an ICU setting. Fortunately, in our ICU, no medication errors were observed which could be a matter of sheer chance.

Mechanical errors in our study included ventilator breakdown repeatedly with one make of ventilator. After every breakdown, the company people were informed. The problem would be rectified and the ventilator would work alright for a few days and would again break down. The ventilator undergoing repeated breakdowns was having a proximal flow sensor which would get stuck while ventilating the patient. Patients were put on standby portable ventilators whenever these breakdowns happened. Fortunately, no mortality was reported. Medication errors often reported as adverse drug events (ADE) are another set of critical human errors in an ICU setting. Fortunately, in our ICU, no medication errors were observed which could be a matter of sheer chance. Discussion Although critical events keep on happening in different ICUs, yet reporting of these events needs to be encouraged. Unless these events are reported, it would not be possible to develop a system to detect and overcome these. Reporting will also help to know the status and working profile of different ICUs and enable us to improve the existing status for better outcome of patients. Harvard Medical Practice study II, published in 1991,[3] showed the nature of adverse events in hospitalized patients. It showed equipment and monitor malfunctions and human errors as the cause of adverse events. “Human errors” is by far the biggest risk and accounts for two-thirds of ICU complications. These complications contribute to hospital mortality.

lished in 1991,[3] showed the nature of adverse events in hospitalized patients. It showed equipment and monitor malfunctions and human errors as the cause of adverse events. “Human errors” is by far the biggest risk and accounts for two-thirds of ICU complications. These complications contribute to hospital mortality. A study conducted by Donchin et al.[4] brought to notice an estimated iatrogenic 1.7 error per patient per day (out of every 178 directed activities) in ICU. This study shows that human error is by far the biggest risk and accounts for two-thirds of ICU complications. Physicians had the highest rate of errors, though physicians and nurses were equal contributors to the total number of errors. Twenty-nine percent of these errors if uncorrected, had the potential to cause significant morbidity or even death. Critical incident reporting in intensive care unit, published in 1997,[5] reported 281 critical incidents in a period of over 3 years. Detection of critical incidents in over 50% of cases resulted from direct observation of the patient, while monitoring systems accounted for another 27%. The most important events reported concerned airway management and invasive lines, tubes and drains. Human error was a factor in 55% of incidents, while violation of standard practice contributed to 28%.

er 50% of cases resulted from direct observation of the patient, while monitoring systems accounted for another 27%. The most important events reported concerned airway management and invasive lines, tubes and drains. Human error was a factor in 55% of incidents, while violation of standard practice contributed to 28%. The present study includes both equipment and ventilator malfunctions as human errors, as these should have been recognized by the ICU personnel. Non-recognition could be because of ignored alarms, inadequate knowledge about the alarms and their interpretation, which in itself implies inadequately trained staff or lesser vigilance due to understaffing in ICU. We encountered 70.3% human errors, which included 44.4% errors due to endotracheal tube-related problems like accidental extubation, which in the present study was mainly due to accidental slipping out of the endotracheal tube during bed-making at 8 a.m. or posture changes of the patient, which is scheduled every 3-hourly in our ICU. Blocked endotracheal tube and difficult intubation were the other endotracheal tube-related problems. The patients on ventilator are having disposable HME filters, which are changed everyday. Closed system suction catheter is used in all the intubated patients in our ICU. Every patient on ventilator is put on short-acting opioid (fentanyl) and benzodiazepine (midazolam) infusion or as bolus dose. The idea is to counter awareness in case of conscious patients who are intubated. Patients on elective ventilation who need to be weaned or assessed in the morning do not receive any sedation after 6 a.m. as per ICU protocol. Chest X-ray is done routinely in intubated patients. Senior resident on night duty manages the sedative requirements of these patients.

of conscious patients who are intubated. Patients on elective ventilation who need to be weaned or assessed in the morning do not receive any sedation after 6 a.m. as per ICU protocol. Chest X-ray is done routinely in intubated patients. Senior resident on night duty manages the sedative requirements of these patients. Intubation trolley is kept ready with all the essential requirements to handle difficult intubation. End tidal carbon dioxide is always available by the side of the patient. Senior resident on duty performs the intubation. ICU staff is fully trained to assist intubation. In our study, the incidence of human errors due to ventilator events is almost 21% out of 70.3%; so this is a valid zone where improvement in alarm recognition and interpretation will be useful to prevent critical events in ICU. That is why new doctors and nurses posted in ICU are given an observer posting for 15 days prior to independent posting to make them aware of ICU working, equipments and protocols. Mechanical ventilators generate alarms for patient disconnection or for some critical ventilator events due to ICU procedures; circuit obstruction by condensed water or undetermined factors or extubation. In the study of Evans et al.,[6] they designed new audio/video ventilator alerts distinct from other alarms in ICU which were impossible to ignore. Patient safety was increased by these enhanced alerts, which alerted all medical staff in ICU of all critical ventilator events in a timely manner.

d factors or extubation. In the study of Evans et al.,[6] they designed new audio/video ventilator alerts distinct from other alarms in ICU which were impossible to ignore. Patient safety was increased by these enhanced alerts, which alerted all medical staff in ICU of all critical ventilator events in a timely manner. In case of repeated ventilator failures observed in one specific type of ventilator in our ICU, a decision was taken to stop using those ventilators and written information was sent to the purchase department to abandon future purchase of this ventilator in our hospital. A study sponsored by HHS agency for healthcare research and quality ‘The Critical Care Safety Study’, published in Critical Care Medicine Aug 2005, mentioned that 20% of patients admitted to Medical ICU and Coronary Care Unit experienced adverse events as these patients are among the sickest, they may be more vulnerable to errors in care and therefore more susceptible to injury of these events. Over 90% of all incidents occurred during routine care, out of which 45% were preventable. A study of preventable adverse drug events in hospitalized patients comparing intensive care and general care units, published in 1997,[7] mentions that ICU patients receive up to 50% more drugs than their general medical or surgical cohorts; so they have a greater likelihood of experiencing an adverse drug reaction (ADR). Preventable adverse drug events and potential adverse drug events occur at a rate of 19 per 1000 patient ICU days, a rate twice that of non-ICU-care wards.

ients receive up to 50% more drugs than their general medical or surgical cohorts; so they have a greater likelihood of experiencing an adverse drug reaction (ADR). Preventable adverse drug events and potential adverse drug events occur at a rate of 19 per 1000 patient ICU days, a rate twice that of non-ICU-care wards. In another study on systems analysis of adverse drug events published in 1995,[8] 75% of drug errors are preventable, out of which 39% were due to wrong ordering by the physician and 38% were due to wrong administration by the nurse. However, fortunately in our study, we did not observe any adverse drug event in the ICU, which could be a matter of sheer chance. However, it is one of the major critical events in an ICU. Inferences of the Study Junior doctors and new nurses joining the ICU need to be trained in the equipment usage and management protocols of ICU. They should handle the patients and equipment under the guidance of trained people in the beginning. This is important to safeguard against the failed intubations or accidental extubations. So, new personnel should first be posted as observer for 1-2 weeks in the ICU. New senior residents were encouraged to report and document the critical events to ICU incharge immediately, as the prompt action taken may sometimes reverse the adverse effects of critical events. So, ICU work should be considered a team work and nothing should be hidden from each other. Basically, the decision taken to abandon the use of ventilators of one particular type was the result of this documentation and analysis.

, as the prompt action taken may sometimes reverse the adverse effects of critical events. So, ICU work should be considered a team work and nothing should be hidden from each other. Basically, the decision taken to abandon the use of ventilators of one particular type was the result of this documentation and analysis. Most of the accidental extubations occur during bedding and repositioning of the patient during nursing care. So, care should be taken to avoid extubation, disconnection and malpositioning of the tube. A senior nurse was therefore told to supervise bedding and posture-changing of the patient. Source of Support: Nil Conflict of Interest: None declared.

Introduction Fat embolism syndrome was first described in 1873 by Von Bergman[1] in patients with fracture of the femur. Whereas two decades earlier than this description of fat embolism syndrome, fat emboli were noted by Zenker[2] in a crush injury patient. Fat embolism develop in nearly all patients with long bone fractures or during orthopedic surgical procedures but are usually asymptomatic. However, in a small number of cases, patients develop signs and symptoms due to multisystem dysfunction, mainly involving the lungs, brain and skin. For these cases the term fat embolism FES is applied.[3] Exact incidence of fat embolism syndrome is not known, but Fabian et al. reported an incidence of up to 30% in their study.[4] The diagnosis of fat embolism remains a difficult task as there are no universal criteria for diagnosis and laboratory studies are non-specific. Here we present two cases of fat embolism syndrome suspected initially on clinical grounds subsequently correlated with findings on magnetic resonance imaging of the brain. Diagnosis is much easier when imaging observations are correlated clinically. Case 1 A 21-year-old dark male patient, involved in a road traffic accident, was admitted to the hospital with a closed fracture of the femur and tibia. On admission he was fully awake, obeying commands and hemodynamically stable.

Here we present two cases of fat embolism syndrome suspected initially on clinical grounds subsequently correlated with findings on magnetic resonance imaging of the brain. Diagnosis is much easier when imaging observations are correlated clinically. Case 1 A 21-year-old dark male patient, involved in a road traffic accident, was admitted to the hospital with a closed fracture of the femur and tibia. On admission he was fully awake, obeying commands and hemodynamically stable. After 12 h of admission he became tachypnoeic, developed tachycardia and started to desaturate. He was put on oxygen supplementation via facemask, which improved his saturation. He remained stable for the next 12 h but later became irritable, confused, was not obeying commands and started to desaturate again. Patient was intubated, sedated and shifted to ICU and connected to a ventilator. He was put on Midazolam and Remifentail infusions. Blood workup showed slight drop in his hemoglobin and platelets levels. X-ray chest on admission showed diffuse bilateral infiltrates; ECG showed right ventricular strain pattern with tachycardia. Accordingly as per Gurds classification he was diagnosed as a case of Fat embolism syndrome.

Patient was intubated, sedated and shifted to ICU and connected to a ventilator. He was put on Midazolam and Remifentail infusions. Blood workup showed slight drop in his hemoglobin and platelets levels. X-ray chest on admission showed diffuse bilateral infiltrates; ECG showed right ventricular strain pattern with tachycardia. Accordingly as per Gurds classification he was diagnosed as a case of Fat embolism syndrome. Computed tomographic (CT) study of the head was done next day showed a low attenuation area in the occipital region. CT examination of the chest revealed bilateral basal airspace filling lesions. MRI of the brain done on day three, in T2 weighted images, showed multiple, bilateral, scattered, hyperintense lesions in the deep pariventricular region, centrum semiovale, corpus callosum and bilateral basal ganglionic regions. Few tiny similar bright spots were noted in the pons and cerebellar peduncles as well. Clinical features and MRI appearances were suggestive of cerebral fat embolism and/or associated hypoxic sequelae. With supportive treatment in ICU, hydration and enteral feeding he started to improve, was arousable and started to obey commands. On day 11 he was operated for (fixation of) fracture femur and subsequently was extubated on day 13. He remained in ICU for a further five days and was shifted from nasogastric feedings to oral diet, transferred on day 18 to the ward fully awake, obeying commands, was hemodynamically stable and was sent home after three days.

Computed tomographic (CT) study of the head was done next day showed a low attenuation area in the occipital region. CT examination of the chest revealed bilateral basal airspace filling lesions. MRI of the brain done on day three, in T2 weighted images, showed multiple, bilateral, scattered, hyperintense lesions in the deep pariventricular region, centrum semiovale, corpus callosum and bilateral basal ganglionic regions. Few tiny similar bright spots were noted in the pons and cerebellar peduncles as well. Clinical features and MRI appearances were suggestive of cerebral fat embolism and/or associated hypoxic sequelae. With supportive treatment in ICU, hydration and enteral feeding he started to improve, was arousable and started to obey commands. On day 11 he was operated for (fixation of) fracture femur and subsequently was extubated on day 13. He remained in ICU for a further five days and was shifted from nasogastric feedings to oral diet, transferred on day 18 to the ward fully awake, obeying commands, was hemodynamically stable and was sent home after three days. Case 2 A Twenty-two years old male pedestrian was involved in a road traffic accident and sustained closed fracture of the femur on the right side. He was a known case of homocysteinurea. He was fully awake and conscious at the time of admission. There were no other injuries; He had normal vital signs and was admitted to the orthopedic ward.

rs old male pedestrian was involved in a road traffic accident and sustained closed fracture of the femur on the right side. He was a known case of homocysteinurea. He was fully awake and conscious at the time of admission. There were no other injuries; He had normal vital signs and was admitted to the orthopedic ward. On the third day following admission he became tachypnoeic, tachycardic, irritable and started to desaturate and was put on supplemental oxygen. He continued to deteriorate; showed decreased level of consciousness hence was intubated and was shifted to ICU put on ventilatory support, started on remifentanil and midazolam infusions. He was found having petichea all over his upper trunk including axillae. Fundoscopy showed retinal hemorrhages. Blood workup showed drop in platelet counts and hemoglobin level, with increased coagulation profile. He received blood and blood products accordingly. Septic work-up done for his persistent fever was found to be negative. X-ray chest showed diffuse scattered infiltrates. He was diagnosed as fat embolism syndrome by Gurd's criteria.

On the third day following admission he became tachypnoeic, tachycardic, irritable and started to desaturate and was put on supplemental oxygen. He continued to deteriorate; showed decreased level of consciousness hence was intubated and was shifted to ICU put on ventilatory support, started on remifentanil and midazolam infusions. He was found having petichea all over his upper trunk including axillae. Fundoscopy showed retinal hemorrhages. Blood workup showed drop in platelet counts and hemoglobin level, with increased coagulation profile. He received blood and blood products accordingly. Septic work-up done for his persistent fever was found to be negative. X-ray chest showed diffuse scattered infiltrates. He was diagnosed as fat embolism syndrome by Gurd's criteria. CT examination of head showed subtle hypodense changes in centrum semiovale and periventricular region and CT chest showed bilateral basal consolidation [Figure 1]. MRI was done on the sixth day of admission, showed multiple hyperintense areas in the cerebral white matter and basal ganglia, in diffusion weighted images (DWI) and T2 weighted images (T2WI), consistent with the impression of Fat Embolism [Figure 2]. He started to improve after good hydration, and good intensive care management and other supportive measures. He had fixation of the femur done on day15 and subsequently improved further and was extubated on day 19. Figure 1 AP radiograph of chest showing bilateral basal air space filling lesions consolidation

CT examination of head showed subtle hypodense changes in centrum semiovale and periventricular region and CT chest showed bilateral basal consolidation [Figure 1]. MRI was done on the sixth day of admission, showed multiple hyperintense areas in the cerebral white matter and basal ganglia, in diffusion weighted images (DWI) and T2 weighted images (T2WI), consistent with the impression of Fat Embolism [Figure 2]. He started to improve after good hydration, and good intensive care management and other supportive measures. He had fixation of the femur done on day15 and subsequently improved further and was extubated on day 19. Figure 1 AP radiograph of chest showing bilateral basal air space filling lesions consolidation Figure 2 CT image showing minimal hypodense changes in periventricular region, which are more evident in DWI and T2WI as areas of high signals. Constellation of findings along with clinical data is characteristic for FES He remained in the ICU for two more days. He became fully awake, started to obey commands, was started on normal diet and was transferred to the ward on the 21st day with stable vitals signs and was subsequently discharged from the hospital after two days. Discussion Fat embolism could be difficult to diagnose. Fat embolism occurs in closed fractures of large bones and pelvis, but rarely it can occur with nontraumatic conditions such as pancreatitis, sickle cell disease, liposuction, decompression sickness and fatty liver.[5]

He remained in the ICU for two more days. He became fully awake, started to obey commands, was started on normal diet and was transferred to the ward on the 21st day with stable vitals signs and was subsequently discharged from the hospital after two days. Discussion Fat embolism could be difficult to diagnose. Fat embolism occurs in closed fractures of large bones and pelvis, but rarely it can occur with nontraumatic conditions such as pancreatitis, sickle cell disease, liposuction, decompression sickness and fatty liver.[5] Actual incidence of fat embolism is rather unknown as mild cases of fat embolism may be unnoticed. Fat embolism typically manifests 24 to 72 h after initial insult. Affected patients presents with the classic triad of hypoxemia, neurological abnormality and petechial rash. Pathology of FES is poorly understood. According to Glosslin et al.,[6] FES results when large fat droplets are released into venous system and result in physical obstruction of pulmonary system vessel. Whereas Baker et al.,[7] incriminates free fatty acid, local hydrolyses of triglycerides together with excessive mobilization of free fatty acid resulting in production of toxic intermediaries. Delay of 24-72 h after insult indicates production of toxic intermediaries. Among the clinical triad pulmonary manifestation are the earliest to appear. These include tachypnoea, dyspnoea and cyanosis which progress to respiratory failure in 10% of the cases. Cerebral changes are seen in 86% of cases and these range from headache and confusion, to stupor, rigidity, convulsions and coma.

aries. Among the clinical triad pulmonary manifestation are the earliest to appear. These include tachypnoea, dyspnoea and cyanosis which progress to respiratory failure in 10% of the cases. Cerebral changes are seen in 86% of cases and these range from headache and confusion, to stupor, rigidity, convulsions and coma. Petechial rash is reddish brown, non palpable, appears on the upper chest, neck and conjunctiva. It results from occlusion of dermal capillaries and increased capillary fragility.[10] The distribution is related to fat particles floating in the aortic arch, like oil in water and embolized to non dependent skin areas via aortic arch vessels (subclavian or carotid arteries.)[10] Other signs are not specific. For diagnosis of fat embolism there is no universal criteria, various criteria were proposed by different authors. According to Gurd's et al.,[8] diagnosis of FES need at least two major criteria or one major and four minor criteria to be present in order to diagnose FES [Table 1]. Table 1 Gurd's criteria[8] Major criteria Petechial rash Respiratory insufficiency Cerebral involvement Minor criteria Fever Retinal changes Jaundice Renal signs Thrombocytopenia Anaemia High ESR Fat macroglobinneamia Schonfeld et al.,[11] gave quantitative means of diagnosis of FES [Table 2] Cumulative score > 5 are required for diagnosis Lindegue et al.,[12] suggested that FES can be diagnosed on basis of respiratory status alone [Table 3]. Table 2 Schonfeld criteria[11]

Major criteria Petechial rash Respiratory insufficiency Cerebral involvement Minor criteria Fever Retinal changes Jaundice Renal signs Thrombocytopenia Anaemia High ESR Fat macroglobinneamia Schonfeld et al.,[11] gave quantitative means of diagnosis of FES [Table 2] Cumulative score > 5 are required for diagnosis Lindegue et al.,[12] suggested that FES can be diagnosed on basis of respiratory status alone [Table 3]. Table 2 Schonfeld criteria[11] Criteria Score Petechiae 5 X-ray chest diffuse infiltrâtes 4 Hypoxemia 3 Fever 1 Tachycardia 1 Tachycardia 1 Confusion 1 Table 3 Lindegue criteria[12] 1 Sustained po2 < 8 kpa 2 Sustained pco2 > 7.3 kpa. 3 Sustained respiratory rate > 35/min, inspite of sedation 4 Increased work of breathing, dyspnoea, tachycardia, anxiety For rapid and specific diagnosis of FES few author suggested brochoalveolar lavage[13] but invasive nature of the procedure limits the usefulness of this technique. Imaging studies are the most useful in diagnosis of FES, X-ray chest radiograph often show increased pulmonary markings and flake like pulmonary shadow (snowstorm appearance).[12]

1 Sustained po2 < 8 kpa 2 Sustained pco2 > 7.3 kpa. 3 Sustained respiratory rate > 35/min, inspite of sedation 4 Increased work of breathing, dyspnoea, tachycardia, anxiety For rapid and specific diagnosis of FES few author suggested brochoalveolar lavage[13] but invasive nature of the procedure limits the usefulness of this technique. Imaging studies are the most useful in diagnosis of FES, X-ray chest radiograph often show increased pulmonary markings and flake like pulmonary shadow (snowstorm appearance).[12] Computed tomographic study is insensitive in the diagnosis of FES. It may be of some value in excluding alternative clinical considerations. MR imaging is the most sensitive technique in demonstrating cerebral changes of FES. Sensitivity of the DWI sequences[14] and fluid attenuated inversion recovery images[15] over conventional imaging, in this situation is highlighted in the recent literature. Lesions can be demonstrated as early as within 30 min of ictus in experimental studies using these sequences. The findings described in FES are multiple small, non-confluent hyperintense lesions on DWI and T2-weighted images, usually situated within the cerebral white matter and deep gray matter often at the watershed zones. Typically lesions are distributed in centrum semiovale, subcortical white matter, ganglionic regions and in thalami. The number and size of the lesions is variable but correlates with the degree of neurologic disability as measured by the GCS.[16] These findings are thought to represent micro infarcts arising from fat emboli occluding cerebral arterioles may further lead to permanent pathologic changes such as cyst formation and gliosis. Some of the lesions may represent vasogenic edema due to the toxic effects of free fatty acids and may show complete resolution. Free fatty acids have been shown to be particularly toxic to brain tissue. MRI is more sensitive than CT, now increasingly available hence the modality of choice in the investigation of FES. Takahashi et al. graded these changes into four grades, based on size and distribution of the lesions in T2 weighted images in to grade 0 (normal) to grade 3 (most severe). Authors even showed that resolution of high intensity MRI lesions paralleled with clinical recovery.[16]

ity of choice in the investigation of FES. Takahashi et al. graded these changes into four grades, based on size and distribution of the lesions in T2 weighted images in to grade 0 (normal) to grade 3 (most severe). Authors even showed that resolution of high intensity MRI lesions paralleled with clinical recovery.[16] MRI changes of FES and changes of hypoxic encephalopathy in the subacute phase, appear different. Lesion distribution in both instances involve cerebral cortex, basal ganglia, as grey matter is more vulnerable to global ischemia and anoxia than white matter. Global ischemic lesions tend to show confluent diffuse changes,[17] rather than multifocal discrete lesions of FFS. Following entities can be considered in the differential diagnosis of disseminated hyperintense lesions on T2WI and DWI: namely diffuse axonal injury, areas of vasogenic edema associated with microinfarcts, foci of gliosis, dilated perivascular Virchow-Robin spaces and demyelinating disease.[18] In our patient group we did not find contrast enhancement useful whereas DWI and FLAIR images consistently showed higher sensitivity in lesion detection. Distribution of the lesion was classical except for one patient who had more extensive lesions which included posterior fossa and fronto-temporal lobes.

MRI changes of FES and changes of hypoxic encephalopathy in the subacute phase, appear different. Lesion distribution in both instances involve cerebral cortex, basal ganglia, as grey matter is more vulnerable to global ischemia and anoxia than white matter. Global ischemic lesions tend to show confluent diffuse changes,[17] rather than multifocal discrete lesions of FFS. Following entities can be considered in the differential diagnosis of disseminated hyperintense lesions on T2WI and DWI: namely diffuse axonal injury, areas of vasogenic edema associated with microinfarcts, foci of gliosis, dilated perivascular Virchow-Robin spaces and demyelinating disease.[18] In our patient group we did not find contrast enhancement useful whereas DWI and FLAIR images consistently showed higher sensitivity in lesion detection. Distribution of the lesion was classical except for one patient who had more extensive lesions which included posterior fossa and fronto-temporal lobes. Treatment of fat embolism, is only supportive. The role of steroids is controversial. Good hydration, restoration of intravascular volume is important. Albumin has been recommended for resuscitation, as it restores blood volume, also binds with fatty acids hence may decrease the tissue injury.[19] Incidence of FES can be decreased by early stabilization of long bone fractures.

steroids is controversial. Good hydration, restoration of intravascular volume is important. Albumin has been recommended for resuscitation, as it restores blood volume, also binds with fatty acids hence may decrease the tissue injury.[19] Incidence of FES can be decreased by early stabilization of long bone fractures. Conclusion Diagnosis of fat embolism syndrome may be complex. High index of suspicion in an appropriate clinical setting, in combination of cerebral MRI and chest imaging findings are the key for diagnosis of fat embolism syndrome. MR imaging, including diffusion weighted sequences should be the initial imaging procedure of choice when diagnosis is clinically entertained. Authors would like to acknowledge the members of neuroradiology team and radiology specialists who were involved in the evaluation of some of our patients. Source of Support: Nil Conflict of Interest: None declared.

Introduction Acute severe hyperkalemia can present with arrhythmias, heart block, hypotension, sudden death, ascending flaccid paralysis and type II respiratory failure. Hyperkalemia commonly produces cardiac manifestations with typical electrocardiographic (ECG) changes because cardiac muscle is more sensitive to hyperkalemia. Classical ECG changes of hyperkalemia are: peaked T-waves, PR interval prolongation, flattening of P-wave, widening of QRS complex and “sine-wave” appearance at severely elevated levels.[12] Rarely acute severe hyperkalemia can present with acute paraplegia without life-threatening cardiac or typical ECG manifestations which requires early identification and immediate hemodialysis especially when serum potassium is lethally elevated or resistant to conservative measures. Case Report A 60-year-old gentleman was admitted with the presenting complaint of acute onset weakness of both the lower limbs (started as inability to stand up after squatting), inability to move both the lower limbs and breathlessness. He had no other presenting complaints including history of back pain, trauma, chest pain, palpitations or syncope. He had bilateral cystic bronchiectasis of the lungs of unknown etiology, cor pulmonale and he was a diabetic on oral hypoglycemic agents (glibenclamide, glimepiride) and a hypertensive on atenolol and spironolactone. His other medications were frusemide and theophylline + etofylline.

hest pain, palpitations or syncope. He had bilateral cystic bronchiectasis of the lungs of unknown etiology, cor pulmonale and he was a diabetic on oral hypoglycemic agents (glibenclamide, glimepiride) and a hypertensive on atenolol and spironolactone. His other medications were frusemide and theophylline + etofylline. On admission, he was conscious oriented and his vitals were: Temperature - 99°F, pulse-110/min, BP-130/80 mm Hg, RR-26/min reg and O2 saturation-95% with 10litres/min of oxygen flow. He had clubbing, bilateral pitting pedal edema and bilateral symmetrical areflexic motor weakness of the lower limbs (Power 1/5) and absent bilateral plantar response. Lung examination showed bilateral coarse crepitations. All peripheral pulses were equally felt and the rest of the system examination was unremarkable. His average urine output was > 1000 ml/day. His previous renal function tests were normal, with a normal serum potassium level. Magnetic resonance imaging (MRI) spine was advised by the neurologist. Arterial blood gas analysis showed pH 7.28, pCO2 60, pO2 159 and bicarbonate 27.8. ECG showed normal sinus rhythm, right axis deviation, PR interval of 0.20 ms, right bundle branch block (RBBB), right ventricular hypertrophy (RVH) and ST depression/T inversion in leads III, aVF and V1-V3.

On admission, he was conscious oriented and his vitals were: Temperature - 99°F, pulse-110/min, BP-130/80 mm Hg, RR-26/min reg and O2 saturation-95% with 10litres/min of oxygen flow. He had clubbing, bilateral pitting pedal edema and bilateral symmetrical areflexic motor weakness of the lower limbs (Power 1/5) and absent bilateral plantar response. Lung examination showed bilateral coarse crepitations. All peripheral pulses were equally felt and the rest of the system examination was unremarkable. His average urine output was > 1000 ml/day. His previous renal function tests were normal, with a normal serum potassium level. Magnetic resonance imaging (MRI) spine was advised by the neurologist. Arterial blood gas analysis showed pH 7.28, pCO2 60, pO2 159 and bicarbonate 27.8. ECG showed normal sinus rhythm, right axis deviation, PR interval of 0.20 ms, right bundle branch block (RBBB), right ventricular hypertrophy (RVH) and ST depression/T inversion in leads III, aVF and V1-V3. Laboratory investigations revealed blood sugar of 493 mg/dL, blood urea nitrogen (BUN) of 88 mg/dL, serum creatinine of 1.6 mg/dL, serum sodium of 119 mEq/L, serum potassium of 8.9 mEq/L, Hb-19.4g/dL, hematocrit-67% and WBC-8,200/cu.mm, creatine phosphokinase, was 95 IU L and thyroid profile was normal. Daily measurements of hemoglobin and PCV level did not show any evidence of ongoing hemolysis.

n (BUN) of 88 mg/dL, serum creatinine of 1.6 mg/dL, serum sodium of 119 mEq/L, serum potassium of 8.9 mEq/L, Hb-19.4g/dL, hematocrit-67% and WBC-8,200/cu.mm, creatine phosphokinase, was 95 IU L and thyroid profile was normal. Daily measurements of hemoglobin and PCV level did not show any evidence of ongoing hemolysis. Chest X-ray and computed tomography chest showed bilateral cystic bronchiectasis of the lungs. Echocardiography showed dilated right atrium and ventricle, severe pulmonary artery hypertension, normal left ventricle size and systolic function and EF of 68%. Arterial Doppler of both lower limbs revealed thin plaques along the arteries with normal flow velocity.

showed bilateral cystic bronchiectasis of the lungs. Echocardiography showed dilated right atrium and ventricle, severe pulmonary artery hypertension, normal left ventricle size and systolic function and EF of 68%. Arterial Doppler of both lower limbs revealed thin plaques along the arteries with normal flow velocity. Immediate treatment for hyperkalemia included intravenous calcium gluconate, nebulised salbutamol, insulin infusion and potassium binding resin and potassium free diet. Repeat serum potassium after one hour of conservative management was still 8.7 mg/dL. The Nephrologist started him on immediate hemodialysis, as the serum potassium did not respond adequately to medical therapy and as he was still at high risk of life-threatening cardiac events. Salbutamol nebulization and insulin infusion were continued. After one cycle of hemodialysis, medications and potassium restriction, his serum potassium was 7.1 mg/dL but his motor power improved to 4/5 in both the lower limbs (he was able to lift both his legs against gravity and mild resistance). Repeat ECG post-hemodialysis was the same. Imaging was not performed initially as he required urgent treatment for the hyperkalemia. Subsequently there was remarkable improvement in motor power, MRI spine was withheld.

4/5 in both the lower limbs (he was able to lift both his legs against gravity and mild resistance). Repeat ECG post-hemodialysis was the same. Imaging was not performed initially as he required urgent treatment for the hyperkalemia. Subsequently there was remarkable improvement in motor power, MRI spine was withheld. He was kept on non-invasive ventilation which was discontinued the next day. He required three cycles of hemodialysis before his serum potassium reached the normal range. Throughout the course of the illness, he had no episode of arrhythmia, heart block or cardiac arrest. At discharge, his serum potassium and renal function were within the normal range. He was able to walk normally without any disturbances in posture or balance and his motor power was 5/5 in all the 4 limbs. Follow-up was done after two weeks of discharge when he had normal motor power (able to walk and ride motorcycle) and normal potassium and renal function tests. Discussion Acute hyperkalemic paraplegia in this patient was probably caused by a combination of factors including prerenal azotemia (due to right heart failure), beta-blocker, aldosterone antagonist and insulin deficiency. He required hemodialysis to bring the potassium level to a normal range and the rapid improvement of neurological symptoms was impressive. We report this interesting case of acute paraplegia caused by severe hyperkalemia without any typical ECG manifestations. There are three similar case reports of hyperkalemic paralysis without classic ECG changes.[3–5]

potassium level to a normal range and the rapid improvement of neurological symptoms was impressive. We report this interesting case of acute paraplegia caused by severe hyperkalemia without any typical ECG manifestations. There are three similar case reports of hyperkalemic paralysis without classic ECG changes.[3–5] Szerlip et al. reported two cases of severe hyperkalemia (Serum potassium > 9.0 mEq/L) in whom the ECGs did not reveal the expected manifestations of hyperkalemia.[6] Shakil et al. suggested that the absence of ECG changes in hyperkalaemic hemodialysis patients should be interpreted with caution.[7] Wrenn et al. reported that ECG is not sensitive for detecting hyperkalemia even in high risk patients and empiric treatment of hyperkalemia based on ECG alone will lead to mistreatment of at least 15% of patients.[8] Martinez et al., reported seven hyperkalemic patients (K+ ≥ 8 mmol/L) without typical ECG changes.[9] So ECG is neither sensitive nor specific for diagnosis or to guide therapy of hyperkalemia. Hyperkalemia should always be considered in the differential diagnosis of acute onset paraplegia even in the absence of typical ECG manifestations or cardiac effects. Hence ECG cannot be reliably used to exclude the presence of even potentially lethal serum potassium elevations or to monitor therapy of hyperkalemia.[6–9] Source of Support: Nil Conflict of Interest: None declared.

Sir, In their case report titled “Severe hyperkalemia with normal electrocardiogram” “the authors authors report a serum potassium level of 11.3 without electrocardiogram (ECG) changes. The serum potassium is out of proportion to the degree of acidosis and azotemia. They also report a white blood cell count of (WBC) 31.4 and a platelet count of 834. They mention fictitious or pseudohyperkalemia, but do not explore it adequately. One form of pseudohyperkalemia occurs in patients with high WBCs or platelets. This occurs as an in vitro effect during clot formation in the test tube with extrusion of potassium from the excess number of WBCs or platelets. The clue to such a situation lies in the very high potassium and a normal ECG. The confirmation is done by measuring the plasma potassium (normal) rather than serum potassium (high). I suspect that this child's hyperkalemia was partly due to this.”

Sir, Prolonged QT interval can lead to Torsades de pointes and is an established risk factor for sudden death. Though prolonged QT-interval has been conventionally linked to many antiarrhythmic and antipsychotics drugs,[1] it is being increasingly recognized in relation to opiod agonist like methadone.[2–5] A 42-year-old Caucasian male, came to the Emergency Room in a disoriented, confused and drowsy state following inadvertent consumption of “his friend's pain control pills” which he had taken for his chronic back pain relief. On further history it was found that he had consumed methadone pills (at least three). The pills were not his own prescription medication. On physical examination his temperature was 98.8 °F, respiratory rate 20/min and his pupils pin point. His EKG showed QTc interval of 520 msec, heart rate of 113/ min. His serum studies showed potassium of 4.2 mmol/l, sodium of 136 mmol/l and calcium of 2.15 mmol/l. His urine drug screen was negative. There was no known history of arrhythmias in the family nor did the patient have any history of palpitations. There was no history of any other drug intake. His past medical history was significant for only chronic back pain, while his past surgical history was non-contributory. He was given Naloxone 0.4 mg as antidote in the ER. A repeat EKG after 12h showed heart rate of 81/min and QTc interval of 450 msec.

A 42-year-old Caucasian male, came to the Emergency Room in a disoriented, confused and drowsy state following inadvertent consumption of “his friend's pain control pills” which he had taken for his chronic back pain relief. On further history it was found that he had consumed methadone pills (at least three). The pills were not his own prescription medication. On physical examination his temperature was 98.8 °F, respiratory rate 20/min and his pupils pin point. His EKG showed QTc interval of 520 msec, heart rate of 113/ min. His serum studies showed potassium of 4.2 mmol/l, sodium of 136 mmol/l and calcium of 2.15 mmol/l. His urine drug screen was negative. There was no known history of arrhythmias in the family nor did the patient have any history of palpitations. There was no history of any other drug intake. His past medical history was significant for only chronic back pain, while his past surgical history was non-contributory. He was given Naloxone 0.4 mg as antidote in the ER. A repeat EKG after 12h showed heart rate of 81/min and QTc interval of 450 msec. Methadone is a long-acting synthetic opiod (opiod), pharmacologically very similar to morphine, used in the management of acute and chronic pain syndromes and opiod de-addiction. The methadone metabolite levacetylmethadol (produced in the liver) is effective in the treatment of opiod dependency, but has been linked with QT prolongation, torsade de pointes and sudden death. For this reason levacetylmethadol was withdrawn from the European market. The half life of methadone is between 8-59 hours, due to high tissue binding and slow release from these tissue proteins. This explains the negative drug screen that can occur as in our patient.[6] The effect on QT interval is dose dependent.[4]

For this reason levacetylmethadol was withdrawn from the European market. The half life of methadone is between 8-59 hours, due to high tissue binding and slow release from these tissue proteins. This explains the negative drug screen that can occur as in our patient.[6] The effect on QT interval is dose dependent.[4] In our patient acute overdose of methadone had led to prolongation of his baseline QTc interval of 450 msec to 520 msec. Methadone is been increasingly used by primary care physicians for pain management. Because of its role in QT prolongation, a baseline EKG is warranted before starting the drug. Patients with a history of narcotic drug abuse on methadone maintenance should be screened for prolonged QT interval by measuring their baseline and periodic EKG's.

Introduction The platelet count, which was related only with bleeding and hemostasis, is now considered to be a predictor of outcome in the ICU setting as an independent parameter.[1] It is found to be as good a predictor as the various mortality scores used in the ICU.[2] This is attributed to the important role played by platelets in the inflammatory process apart from their role in thrombus formation.[3] Thrombocytopenia is one of the commonest laboratory abnormalities encountered in ICU and the reported incidence varies from 13 to 58% in various studies.[4–7] Various causes have been identified for the occurrence of thrombocytopenia, like presence of disseminated intravascular coagulation, immune mechanisms, reduced production, increased consumption or abnormal sequestration of platelets or a combination of these.[89]

incidence varies from 13 to 58% in various studies.[4–7] Various causes have been identified for the occurrence of thrombocytopenia, like presence of disseminated intravascular coagulation, immune mechanisms, reduced production, increased consumption or abnormal sequestration of platelets or a combination of these.[89] The advantage of using platelets as a predictor of ICU outcome, is the dynamic nature of daily platelet counts which takes the disease progression into account in contrast to various mortality scores which use only the worst parameters within first 24h after admission or at admission.[1] Various adult studies have shown an initial decrease in platelet count followed by increase, but no such study has been carried out in critically ill children.[10–12] This reflects the initial inflammatory phase when the patient is admitted to the ICU with the increase in platelet counts predicting onset of anti-inflammatory action. Hence, we undertook this study to establish the variations in platelet counts in the critically ill pediatric patients, the factors associated with thrombocytopenia and outcome in the Pediatric Intensive Care Unit (PICU), the factors associated with outcome in thrombocytopenic patients and the prognostic value of serial platelet counts in the PICU. Design This study was a prospective, observational cohort analysis. It was undertaken in the Pediatric Intensive Care Unit of a tertiary care, teaching hospital in New Delhi, India over a period of 7 months from 1st January 2003 to 31st July 2003.

The advantage of using platelets as a predictor of ICU outcome, is the dynamic nature of daily platelet counts which takes the disease progression into account in contrast to various mortality scores which use only the worst parameters within first 24h after admission or at admission.[1] Various adult studies have shown an initial decrease in platelet count followed by increase, but no such study has been carried out in critically ill children.[10–12] This reflects the initial inflammatory phase when the patient is admitted to the ICU with the increase in platelet counts predicting onset of anti-inflammatory action. Hence, we undertook this study to establish the variations in platelet counts in the critically ill pediatric patients, the factors associated with thrombocytopenia and outcome in the Pediatric Intensive Care Unit (PICU), the factors associated with outcome in thrombocytopenic patients and the prognostic value of serial platelet counts in the PICU. Design This study was a prospective, observational cohort analysis. It was undertaken in the Pediatric Intensive Care Unit of a tertiary care, teaching hospital in New Delhi, India over a period of 7 months from 1st January 2003 to 31st July 2003. Materials and Methods All consecutively admitted patients staying for 48h or more in the PICU over a period of 7 months were included in the study. The patients were followed-up prospectively until they left the PICU or died. Besides patients' demography, source of admission, primary diagnosis, pediatric risk of mortality score (PRISM), presence or absence of sepsis, bleeding, use of central venous or arterial lines and mechanical ventilation were recorded. Laboratory data collected at admission included complete blood counts (CBC), C- reactive protein (CRP), blood urea nitrogen (BUN), serum creatinine, serum bilirubin, serum lactate and coagulation profile. These were also repeated with the occurrence of thrombocytopenia. Daily platelet counts were recorded in each patient. If any patient had platelet counts done more than once in 24h, the lowest value was recorded for analysis. No informed consent was taken, as the study was purely observational. The hospital ethics and review board's approval was taken before undertaking the study.

a. Daily platelet counts were recorded in each patient. If any patient had platelet counts done more than once in 24h, the lowest value was recorded for analysis. No informed consent was taken, as the study was purely observational. The hospital ethics and review board's approval was taken before undertaking the study. Definitions Thrombocytopenia was defined as a platelet count of <150.0/nL. It was categorized depending on the severity as mild, moderate, severe or very severe on the basis of platelet counts below 150.0/nL, 100.0/nL, 50.0/nL or 20.0/nL, respectively. Correction of thrombocytopenia was defined when the platelet counts normalized after falling below 150.0/nL. The lowest platelet count for any patient was considered as nadir platelet count. A drop in platelet count was taken as a difference between the admission platelet counts and the nadir platelet counts for each patient. Intensive care unit acquired thrombocytopenia was considered when the patient was admitted with normal platelet count, which dropped below 150.0/nL subsequently during the PICU stay.

A drop in platelet count was taken as a difference between the admission platelet counts and the nadir platelet counts for each patient. Intensive care unit acquired thrombocytopenia was considered when the patient was admitted with normal platelet count, which dropped below 150.0/nL subsequently during the PICU stay. Sepsis was defined in patients with documented or assumed infection in presence of positive acute phase reactants and total leukocyte counts (TLC); (as defined by the American College of Chest Physicians and Society of Critical Care Medicine).[13] Coagulopathy was defined when the APTT was 1.5 times the normal reference range for the laboratory with an associated increase in INR more than 1.5. Bleeding was defined as an episode resulting in a drop in hemoglobin of >2 g/dL within 24h, episodes requiring local tamponade or transfusions within 24h, and any intracranial hemorrhage. Multiple bleeding events at the same site were counted only once for each patient. Circulatory failure was defined as the need for vasoactive drugs for at least one hour (>5μg/kg/mt dopamine/dobutamine or any dose of epinephrine/nor-epinephrine).

al tamponade or transfusions within 24h, and any intracranial hemorrhage. Multiple bleeding events at the same site were counted only once for each patient. Circulatory failure was defined as the need for vasoactive drugs for at least one hour (>5μg/kg/mt dopamine/dobutamine or any dose of epinephrine/nor-epinephrine). Statistical analysis Statistical Analysis was done using STATA 9.1 (College Station, Texas, USA). Data were presented as number (%) or median (range) as appropriate. Categorical variables were compared with the outcome variable using Chi-square or Fisher Exact test. Receiver Operating Characteristic Curve analysis was used to find the cut-off value for PRISM score in relation to the outcome of thrombocytopenia. Simple Logistic regression followed by forward stepwise multiple logistic regression with the significance level 0.10 for removal and of 0.05 for addition to the model to identify the factors associated with thrombocytopenia. The p value less than 0.05 was considered statistically significant. Results Out of the 268 total admissions in PICU during the study period, 138 patients who remained in the unit for at least 48h were included in the study [Table 1]. Table 1 Demographic Data of the patients admitted to the PICU (n= 138)

Statistical analysis Statistical Analysis was done using STATA 9.1 (College Station, Texas, USA). Data were presented as number (%) or median (range) as appropriate. Categorical variables were compared with the outcome variable using Chi-square or Fisher Exact test. Receiver Operating Characteristic Curve analysis was used to find the cut-off value for PRISM score in relation to the outcome of thrombocytopenia. Simple Logistic regression followed by forward stepwise multiple logistic regression with the significance level 0.10 for removal and of 0.05 for addition to the model to identify the factors associated with thrombocytopenia. The p value less than 0.05 was considered statistically significant. Results Out of the 268 total admissions in PICU during the study period, 138 patients who remained in the unit for at least 48h were included in the study [Table 1]. Table 1 Demographic Data of the patients admitted to the PICU (n= 138) Parameter Total Age, median months (range) 32 (1–192) Gender ratio (M: F) 1.76: 1 PRISM score (median (range) 5 (0–30) Source of admission Emergency room 110 Hospital ward 18 Operation theatre 10 Admission category Neurological 33 (23.9%) Monitoring 25 (18%) Circulatory failure 24 (17.3%) Respiratory failure 23 (16.6%) Cardiopulmonary resuscitation 16 (11.5%) Hepatic failure 12 (8.6%) Renal failure 6 (4.3%) ICU stay median (range) days 4 (2 – 98) < 7 d 99 (71%) 7–14 d 19 (13.7%) > 14 d 20 (14.5%) Mechanical ventilation 33 (23.9%) Central venous catheter 76 (55%) Arterial catheter 63 (45.6%) Sepsis 49 (35.5%) Coagulopathy 21 (15.2%) Bleeding 27 (19.5%) Transfusion 30 (21.7%) ICU mortality 10.9% Platelet counts At least one episode of thrombocytopenia was seen in 35 patients (25%), of these 8 patients had thrombocytopenia on admission; the rest developed it during the course of PICU stay. Mild, moderate, severe, and very severe thrombocytopenia was present in 8.6%, 42.5%, 28%, and 20% of patients respectively. Seventy one percent of patients had PICU acquired thrombocytopenia by fourth day of admission (range: 2-5 d). About 59% of the patients staying in PICU for more than 7 days had at least one episode of thrombocytopenia. Patients with PICU acquired thrombocytopenia had statistically significant lower baseline, nadir and day- 4 platelet counts corresponding to a 56% drop from median baseline values vs. 6% in non-thrombocytopenic patients (p value <0.001). Platelet counts dropped more than 10% in 66 patients (48%). Platelet counts had normalized by the time of discharge or death in 65% of thrombocytopenic patients.

r baseline, nadir and day- 4 platelet counts corresponding to a 56% drop from median baseline values vs. 6% in non-thrombocytopenic patients (p value <0.001). Platelet counts dropped more than 10% in 66 patients (48%). Platelet counts had normalized by the time of discharge or death in 65% of thrombocytopenic patients. Factors associated with thrombocytopenia Age, gender, source of admission, CRP and total leukocyte counts (TLC), and mechanical ventilation had no significant correlation with the development of thrombocytopenia. Cardiopulmonary resuscitation (CPR) and circulatory failure as admission category were found to be significant factors for the development of thrombocytopenia (5/103 vs. 11/35 patients, P < 0.00 and 14 of 103 vs. 10 of 35, P = 0.002, respectively). The other factors found associated with development of thrombocytopenia are shown in Table 2. A higher platelet count on admission was associated with reduced risk of thrombocytopenia (P-0.00, OR- 1.00 for every 100.0/nL, 95% CI: 1.00007 – 1.00016). Table 2 Clinical parameters associated with thrombocytopenia Variable Thrombocytopenia P value

Cardiopulmonary resuscitation (CPR) and circulatory failure as admission category were found to be significant factors for the development of thrombocytopenia (5/103 vs. 11/35 patients, P < 0.00 and 14 of 103 vs. 10 of 35, P = 0.002, respectively). The other factors found associated with development of thrombocytopenia are shown in Table 2. A higher platelet count on admission was associated with reduced risk of thrombocytopenia (P-0.00, OR- 1.00 for every 100.0/nL, 95% CI: 1.00007 – 1.00016). Table 2 Clinical parameters associated with thrombocytopenia Variable Thrombocytopenia P value Yes (n= 35) No (n= 103) PRISM scorea < 8 6 (17) 74 (71.8) 0.00 > 8 29 (82. 8) 29 (28) 0.00 Admission categoryb 0.00 CPR 11 (31.4) 5 (4.8) Circulatory Failure 10 (28.6) 14 (13.6) Admission Sourceb 0.23 Emergency Room 24 (88.5) 86 (83.4) Operation Theatre 3 (8.5) 7 (6.8) Hospital Ward 8 (22.8) 10 (9.7) Surgical procedureb 12 (34) 21 (20.3) 0.09 Coagulopathyb 15 (42.8) 6 (5.8) 0.00 Central venous catheterb 35 (100) 41 (39.8) 0.00 Arterial catheterb 29 (82.8) 34 (33) 0.00 Sepsisb 23 (65.7) 26 (25) 0.00 Bleedingb 12 (34) 15 (14.5) 0.01 Transfusionb 19 (54) 11 (10.6) 0.00 TLC (/mm3)b 0.098 > 15000 9 (25.7) 12 (11.6) < 4000 1 (2.8) 8 (7.7) BUN (> 20 mg/dl)b 6 (17) 6 (5.8) 0.04 S. Creatinine (> 1.2 mg/dl)b 5 (14) 4 (3.8) 0.031 Bilirubin (> 1 mg/dl)b 19 (54.2) 22 (21) 0.00 CRP (> 6 mg/dl)b 22 (62.8) 46 (44.6) 0.063 ICU stay (days)b 0.00 < 7 days 8 (22.9) 91 (88.3) 7-14 days 9 (25.7) 10 (9.7) > 14 days 18 (51.4) 2 (1.9) Lactate (>2 mg/dl) 31 (96.8) 87 (98.8) 0.45 a Data represented as median with 25th and 75th quartiles in the parentheses

Figure 2 Receiver operating characteristic curve for drop in platelet counts (pc- solid line), PRISM (interrupted line) On forward stepwise multi-regression analysis, leucopenia, leucocytosis, thrombocytopenia and coagulopathy were found to be the risk factors independently associated with mortality [Table 5]. Table 5 Significant Risk Factors for Outcome (Regression Analysis) Variables OR (95% Confidence Interval Unadjusted Adjusted Sepsis 5.7 (2.5- 12.9) TLC (< 4000/mm3) 1.56 (0.17- 14.1) 2.08 (0.18- 23.9) TLC (> 15000/mm3) 5 (1.5- 16.4) 4.3 (1.14- 16.5) Coagulopathy 6.8 (2.14- 21.67) 3.5 (0.8- 14.5) Transfusion 3.8 (1.25- 11.5) BUN 3.3 (1- 11) CRP 3.18 (0.96- 10.5) Bilirubin 3.11 (1.1- 9.27) PRISM 4.4 (1.34- 14.7) Thrombocytopenia 7.84 (2.45- 25) 4.15 (1.05- 16.3) Discussion The present study has demonstrated an association of a drop in platelet counts during PICU stay with the outcome. At least one episode of thrombocytopenia occurred in 25% of patients. The incidence of thrombocytopenia and PICU acquired thrombocytopenia is comparable to one adult study,[1] but less in our study as compared to similar recent study by Strauss et al,[4] where 44% of the patients acquired thrombocytopenia while in the ICU. The incidence of thrombocytopenia has ranged from 13-58% in various studies.[4–7] The difference in the ranges can be explained by the differences in study population and different inclusion criteria and definitions used in various studies. The incidence of platelet counts <100.0/nL was 23.2%, which is comparable to other studies; 22% in a neonatal ICU,[1516] 23% in a medical ICU,[14] 22% in medical-surgical ICU[1] and 21% in a non-coronary medical ICU.[4] The incidence of thrombocytopenia was significantly correlated with the baseline platelet counts, nadir platelet counts and a drop in platelet counts as has been evident in other similar studies.[14]

.031 Bilirubin (> 1 mg/dl)b 19 (54.2) 22 (21) 0.00 CRP (> 6 mg/dl)b 22 (62.8) 46 (44.6) 0.063 ICU stay (days)b 0.00 < 7 days 8 (22.9) 91 (88.3) 7-14 days 9 (25.7) 10 (9.7) > 14 days 18 (51.4) 2 (1.9) Lactate (>2 mg/dl) 31 (96.8) 87 (98.8) 0.45 a Data represented as median with 25th and 75th quartiles in the parentheses b Data presented as no. of patients with percentage in parentheses On forward stepwise multiple regression analysis, length of PICU stay, PRISM, Sepsis, coagulopathy and creatinine were the only factors found significantly associated with thrombocytopenia [Table 3]. Table 3 Significant Risk Factors associated with thrombocytopenia (regression analysis) Variables OR (95% Confidence Interval) Unadjusted Adjusted Sepsis 5.7 (2.5- 12.9) 6.22 (1.4- 27.9) Coagulopathy 12 (4.2- 35.1) 14.8 (2.4- 93.2) Arterial Catheter 8.6 (3.3- 22.7) Bleeding 3.1 (1.3- 7.4) Transfusion 9.9 (3.9- 24.7) BUN 3.3 (1- 11) Creatinine 4 (1.04- 16.3) 17.4 (1.3- 233.6) CRP 2.1 (0.9- 4.6) Bilirubin 4.4 (1.9- 9.9) PRISM 12.3 (4.6- 32.8) 9.2 (2.02- 42) ICU stay 12.5 (4.2- 37.4) Outcome and factors associated with mortality There was a significant association between mortality and the presence of sepsis, coagulopathy, and higher mean PRISM score, leucocytosis, leucopenia, hyperbilirubinemia, and CRP levels. There was no difference in mortality with age, gender, source of admission and diagnosis, and the use of mechanical ventilation, arterial or venous catheters or bleeding [Table 4]. Table 4 Clinical parameters associated with outcome

Unadjusted Adjusted Sepsis 5.7 (2.5- 12.9) 6.22 (1.4- 27.9) Coagulopathy 12 (4.2- 35.1) 14.8 (2.4- 93.2) Arterial Catheter 8.6 (3.3- 22.7) Bleeding 3.1 (1.3- 7.4) Transfusion 9.9 (3.9- 24.7) BUN 3.3 (1- 11) Creatinine 4 (1.04- 16.3) 17.4 (1.3- 233.6) CRP 2.1 (0.9- 4.6) Bilirubin 4.4 (1.9- 9.9) PRISM 12.3 (4.6- 32.8) 9.2 (2.02- 42) ICU stay 12.5 (4.2- 37.4) Outcome and factors associated with mortality There was a significant association between mortality and the presence of sepsis, coagulopathy, and higher mean PRISM score, leucocytosis, leucopenia, hyperbilirubinemia, and CRP levels. There was no difference in mortality with age, gender, source of admission and diagnosis, and the use of mechanical ventilation, arterial or venous catheters or bleeding [Table 4]. Table 4 Clinical parameters associated with outcome Variable Survivors Non survivors P value PRISM scorea 0.009 < 8 76 (61.8) 4 (26.7) > 8 47 (38.2) 11 (73.3) Admission categoryb CPR 13 (10.6) 3 (20) 0.28 Admission Sourceb 0.13 Emergency Room 99 (80.4) 11 (73.3) Operation Theatre 9 (7.3) 1 (6.7) Hospital Ward 15 (12.2) 3 (20) Surgical procedureb 29 (23.6) 4 (26.7) 0.79 Coagulopathyb 14 (11.3) 7 (46.7) 0.00 Central venous catheterb 57 (46.3) 9 (60) 0.31 Sepsisb 40 (32.5) 9 (60) 0.03 Bleeding 23 (18.7) 4 (26.7) 0.46 Transfusionb 23 (18.7) 7 (46.7) 0.01 TLC (/mm3)b 0.017 > 15000 15 (12) 6 (40) < 4000 8 (6.5) 1 (6.7) BUN (> 20 mg/dl)b 10 8 2 (13.3) 0.5 S. Creatinine (>1.2 mg/dl)b 8 (6.5) 1 (6.7) 0.98 Bilirubin (>1 mg/dl)b 33 (26.8) 8 (53.3) 0.034 CRP (> 6 mg/dl)b 57 (46.3) 11 (73.3) 0.048 ICU stayb 0.30 < 7 days 90 (73) 9 (60) 7- 14 days 15 (12) 4 (26.7) > 14 days 18 (14.6) 2 (13.3) Lactate (> 2 mg/dl)b 103 (98) 15 (100) 0.59 a Data represented as median with 25th and 75th quartiles in the parentheses

1 (6.7) 0.98 Bilirubin (>1 mg/dl)b 33 (26.8) 8 (53.3) 0.034 CRP (> 6 mg/dl)b 57 (46.3) 11 (73.3) 0.048 ICU stayb 0.30 < 7 days 90 (73) 9 (60) 7- 14 days 15 (12) 4 (26.7) > 14 days 18 (14.6) 2 (13.3) Lactate (> 2 mg/dl)b 103 (98) 15 (100) 0.59 a Data represented as median with 25th and 75th quartiles in the parentheses b Data presented as no. of patients with percentage in parentheses

1 (6.7) 0.98 Bilirubin (>1 mg/dl)b 33 (26.8) 8 (53.3) 0.034 CRP (> 6 mg/dl)b 57 (46.3) 11 (73.3) 0.048 ICU stayb 0.30 < 7 days 90 (73) 9 (60) 7- 14 days 15 (12) 4 (26.7) > 14 days 18 (14.6) 2 (13.3) Lactate (> 2 mg/dl)b 103 (98) 15 (100) 0.59 a Data represented as median with 25th and 75th quartiles in the parentheses b Data presented as no. of patients with percentage in parentheses The mortality showed a significant association with platelet counts. The presence of thrombocytopenia was associated with increased mortality (33% vs 66.6%, P - 0.00). The mortality was significantly higher with lower platelet counts on day-1, day-4 and lower nadir platelet counts irrespective of the presence of thrombocytopenia. For the study population, platelet counts were lower in the non-survivors than survivors throughout the ICU stay. The admission platelet counts were lower in non-survivors than in survivors (P - 0.006) [Figure 1]. Thirty-nine (28.3%) patients stayed in the PICU for > 7 days (median stay 15 days, range 7-98 days) and in this group the mortality was 15.4%. Platelet counts decreased significantly in the initial 4-5 days of PICU stay in both survivors and non-survivors and gradually increased to near admission value by the end of first week [Figure 1]. In non-survivors the platelets counts did not rise significantly after the first week as compared to the survivors. A drop of > 27% from the baseline platelet counts increased the mortality (Receiver operator curve); survivors had a mean drop of 8% (range 0-29.6%) compared to 83% (range: 27-85%) in non-survivors from the baseline (P<0.00). Drop in platelet counts was found to have slightly higher discriminative value for mortality prediction than PRISM score on the receiver operating characteristic curve (ROC) curve. The area under the curve of PRISM ROC was 0.73 and that of the drop in platelet count was 0.84. This difference was not statistically significant [Figure 2]. On day 4, 26 (28.3%) patients had thrombocytopenia and the mortality in this group was 23.1% as compared to 6.1% in nonthrombocytopenic patients (P = 0.02). Normal platelet counts on admission were associated with better survival than normal platelet counts on day 4 and day 7 (P<0.05).

istically significant [Figure 2]. On day 4, 26 (28.3%) patients had thrombocytopenia and the mortality in this group was 23.1% as compared to 6.1% in nonthrombocytopenic patients (P = 0.02). Normal platelet counts on admission were associated with better survival than normal platelet counts on day 4 and day 7 (P<0.05). Figure 1 Mortality Rate in thrombocytopenic vs. non-thrombocytopenic patients on admission, day-4, day-7 and day-14 Figure 2 Receiver operating characteristic curve for drop in platelet counts (pc- solid line), PRISM (interrupted line) On forward stepwise multi-regression analysis, leucopenia, leucocytosis, thrombocytopenia and coagulopathy were found to be the risk factors independently associated with mortality [Table 5]. Table 5 Significant Risk Factors for Outcome (Regression Analysis) Variables OR (95% Confidence Interval

a neonatal ICU,[1516] 23% in a medical ICU,[14] 22% in medical-surgical ICU[1] and 21% in a non-coronary medical ICU.[4] The incidence of thrombocytopenia was significantly correlated with the baseline platelet counts, nadir platelet counts and a drop in platelet counts as has been evident in other similar studies.[14] Sepsis was also found to have an association with thrombocytopenia, 65 % of the patients with sepsis had thrombocytopenia (23 of 49), which is comparable to other adult studies.[1514] Coagulopathy was another factor associated with thrombocytopenia, which is comparable to the significant association of DIC in the evolution of thrombocytopenia found by Strauss et al.[4] This has been explained by the intravascular destruction of platelets, which accompanies the activation and consumption of coagulation factors and is described as the leading cause of thrombocytopenia in critically ill patients.[14]

cant association of DIC in the evolution of thrombocytopenia found by Strauss et al.[4] This has been explained by the intravascular destruction of platelets, which accompanies the activation and consumption of coagulation factors and is described as the leading cause of thrombocytopenia in critically ill patients.[14] Cardio-pulmonary resuscitation has also been quoted as a risk factor for development of thrombocytopenia[4] and a similar association was found in the present study (11 of 16, 31.4%). The other admission category, which was found, significantly associated with thrombocytopenia was circulatory failure (peripheral or cardiovascular) (14 of 103 vs. 10 of 35, P = 0.002). The association of shock with thrombocytopenia is well established.[1] A higher initial PRISM score and disturbed biochemical markers in the form of elevated blood urea nitrogen, serum creatinine, bilirubin, lactate, which identify sicker patients, were also predictive of thrombocytopenia. Invasive intravascular catheters (arterial or venous) and mechanical ventilation have been described in the literature as an independent risk factor for development of thrombocytopenia, though this may only reflect the disease severity and local ICU preferences.[46] In our study, there was no such association observed. This may be due to small patient number.

l or venous) and mechanical ventilation have been described in the literature as an independent risk factor for development of thrombocytopenia, though this may only reflect the disease severity and local ICU preferences.[46] In our study, there was no such association observed. This may be due to small patient number. Patients who stayed in the PICU for a longer period had a higher incidence of thrombocytopenia reflecting the disease severity necessitating prolonged stay and increased risk of intensive care acquired sepsis. The increased risk of thrombocytopenia with prolonged ICU stay is also seen in adult studies.[141114] The present study clearly shows significantly higher mortality in thrombocytopenic patients especially low platelet counts on admission, in first week of PICU stay and failure of platelet counts to return to normal. The study further shows a bimodal pattern of platelet counts with the counts falling to a nadir in the initial 3-4 days of PICU admission followed by increase to near the admission value by the end of first week. This rise in platelet count after an acute decrease occurs because of the bone marrow response and is a common observation in other studies.[561112] A drop in platelet counts of > 27% was associated with significantly higher mortality irrespective of the actual counts. This finding is comparable with a recent adult study with > 30% drop in platelet counts.[4]

e decrease occurs because of the bone marrow response and is a common observation in other studies.[561112] A drop in platelet counts of > 27% was associated with significantly higher mortality irrespective of the actual counts. This finding is comparable with a recent adult study with > 30% drop in platelet counts.[4] Cardio-pulmonary resuscitation was not found to be significantly associated with mortality as has been found in other studies.[4] This can probably be due to the fact that very few patients needed cardio-pulmonary resuscitation and a substantial number of these were performed within the hospital. Furthermore, the ROC curve for PRISM and drop in platelet counts showed a slightly higher discriminative value of drop in platelet counts for mortality, which is similar to what was found in certain adult studies. The mortality in thrombocytopenic patients was significantly higher in patients with prolonged PICU stay, lower nadir and D-4 platelet counts and with disease severity markers. The mortality in this group was not found associated to the admission platelet counts signifying that the predictive power of low platelet counts does take the disease progression in account.

ignificantly higher in patients with prolonged PICU stay, lower nadir and D-4 platelet counts and with disease severity markers. The mortality in this group was not found associated to the admission platelet counts signifying that the predictive power of low platelet counts does take the disease progression in account. There are no similar pediatric studies to compare the data with, though there are a few neonatal studies done on the incidence and prognostic value of low platelet counts on admission.[1516] The studies on thrombocytopenia in pediatric ICU are few and the ones which have been done have very different objectives than our study rendering it difficult to compare the present work with any pediatric study.[10]

neonatal studies done on the incidence and prognostic value of low platelet counts on admission.[1516] The studies on thrombocytopenia in pediatric ICU are few and the ones which have been done have very different objectives than our study rendering it difficult to compare the present work with any pediatric study.[10] The present study had its own limitations. Besides small sample size, various confounding factors are present at any given point of time in critically ill children, which cannot be controlled. Many pre-existing conditions and drugs in use may influence the platelet counts, which were not studied in this cohort. The limited number of patients in certain groups does not allow great precision in the estimation of odds ratio and this may have missed some important risk factors. So the results need to be validated in a larger cohort. Bleeding can be both a risk factor and cause for thrombocytopenia and this was not elaborated sufficiently in the present study, though most of the patients had bleeding secondary to thrombocytopenia rather than vice-versa. The study is not powered to actually work out the cause and effect and can only suggest an association between various factors.

tor and cause for thrombocytopenia and this was not elaborated sufficiently in the present study, though most of the patients had bleeding secondary to thrombocytopenia rather than vice-versa. The study is not powered to actually work out the cause and effect and can only suggest an association between various factors. Conclusions Platelet counts < 150.0/nL is at least as common in PICU as in adult intensive care. Thrombocytopenic children have higher incidence of bleeding, longer ICU stay and a higher mortality. Probability of PICU acquired thrombocytopenia is higher in patients requiring cardiopulmonary resuscitation, having circulatory failure, sepsis, coagulopathy and higher admission PRISM score and patients having other parameters defining increased disease severity. Serial platelet counts are easily available markers of disease progression. A drop in platelet counts irrespective of thrombocytopenia is an unfavorable prognostic marker and is associated independently with the mortality. Similar studies are required with larger number of patients in the pediatric age group to further consolidate the present study's findings. Source of Support: Nil Conflict of Interest: None declared.

ally in 75% to 90% of the patients[8] which is similar to our findings. Kuniyoshi et al, observed many patients of diaphragmatic palsy who were absolutely asymptomatic and could be weaned off from the ventilator easily. They considered diaphragmatic palsy as a significant cause of postoperative respiratory dysfunction. Diaphragmatic palsy is usually suspected when diaphragmatic elevation is seen on the X-ray chest. However, in the postoperative period, with the patient in the supine position and on ventilatory support, it may not be easily detected because positive pressure ventilation tends to mark abnormal findings. Furthermore, in the spontaneously breathing patients, common sequel of cardiac surgery e.g. left pleural effusion, lower lobe atelectasis and elevation of the hemidiaphragm can mask phrenic nerve injury. Confirmatory tests for the diagnosis of diaphragmatic palsy include esophageal and gastric pressure measurements, fluoroscopy, ultrasonography, and electro-neuromyography.[9] The diagnosis of the diaphragmatic palsy should be made on the basis of the results of the multiple examinations including the symptoms.

Introduction Systemic lupus erythematosis (SLE) is diagnosed by the presence of four or more of the following criteria, serially or simultaneously: malar rash, discoid rash, photosensitivity, oral ulcers, non erosive arthritis, serositis, renal abnormalities including proteinuria or active urinary sediments, neuropsychiatric features, hematological abnormalities including hemolytic anemia, leucopenia, lymphopenia and thrombocytopenia, immunological markers like anti-ds DNA or anti-Smith antibody and high Antinuclear antibody titres. Thrombotic thrombocytopenic purpura (TTP) in patients with SLE is extremely rare. The overall incidence of TTP in SLE patients is unclear and has been reported to be as low as 0.5%. A review includes about 40 cases of TTP related to SLE.[1] Very rarely TTP presents simultaneously with SLE in ICU. Case Report A 30-year-old lady was admitted with fever and jaundice. A week earlier she had undergone an uncomplicated medical termination of pregnancy at another hospital, at 13 weeks of gestation. She had an uneventful pregnancy with twins two years earlier and the twins were diagnosed to have thalassemia major. She was subsequently diagnosed to have thalassemia minor and her husband had thalassemia minor trait. No earlier history of spontaneous first trimester abortions was present.

l, at 13 weeks of gestation. She had an uneventful pregnancy with twins two years earlier and the twins were diagnosed to have thalassemia major. She was subsequently diagnosed to have thalassemia minor and her husband had thalassemia minor trait. No earlier history of spontaneous first trimester abortions was present. She had weight loss and alopecia for a year with a rash noticed on her face and limbs for 12 weeks. No neurological, cardiopulmonary, gastrointestinal or urinary symptoms were present. On examination, she had non scarring alopecia and a macular, erythematous rash on her face with mild pallor and icterus. She was normotensive and had low grade pyrexia. Mild hepatosplenomegaly was detected. Respiratory,cardiovascular and neurological, evaluation was normal. Investigations prior to admission revealed normal hematological and renal parameters with mildly deranged LFT -with direct hyperbilirubinemia(Total Bilirubin- 3.3 mg/dL, Direct Bilirubin- 2.7 mg/ dL), elevated transaminases Aspartate aminotransferase- 593 U/L, Alanine aminotransferase- 73 U/L) and elevated Alkaline Phosphatase -668 U/L.

or to admission revealed normal hematological and renal parameters with mildly deranged LFT -with direct hyperbilirubinemia(Total Bilirubin- 3.3 mg/dL, Direct Bilirubin- 2.7 mg/ dL), elevated transaminases Aspartate aminotransferase- 593 U/L, Alanine aminotransferase- 73 U/L) and elevated Alkaline Phosphatase -668 U/L. Her condition deteriorated on the second day after admission, necessitating ICU admission with worsening jaundice and altered sensorium along with severe abdominal pain. Investigations revealed anemia, with a hemoglobin of 5.7 g/dl, reticulocytosis (corrected 3.4%), normal total and differential counts, schistocytes in the peripheral blood smear and normal prothrombin/ partial thromboplastin time [Figure 1]. Platelet count was 148000/cu.mm and lactate dehydrogenase (LDH) level was 1047 IU/dl. The serum creatinine rose to 2.3 mg/dl. Liver function showed worsening direct bilirubinemia with mild elevation of transaminases (Total Bilirubin- 13.5 mg/dL, Direct Bilirubin- 9.4 mg/ dL, Aspartate aminotransferase- 323 U/L, Alanine aminotransferase- 46 U/L.) Viral hepatitis serology for hepatitis A, B, C and E were negative Leptospira antibody was not detected. Urinanalysis showed increasing proteinuria to 3+ and 50 - 60 RBCs per high power field. Direct antiglobulin (Coomb's) test was positive. ANA and anti-DsDNA titres were high at 17.4 and 46.2 units respectively with normal complement levels. Renal and liver biopsy were not attempted in view of the patient's poor condition for the procedure. Figure 1 Peripheral blood film showing many schistocytes, (Leishman, ×1000)

Her condition deteriorated on the second day after admission, necessitating ICU admission with worsening jaundice and altered sensorium along with severe abdominal pain. Investigations revealed anemia, with a hemoglobin of 5.7 g/dl, reticulocytosis (corrected 3.4%), normal total and differential counts, schistocytes in the peripheral blood smear and normal prothrombin/ partial thromboplastin time [Figure 1]. Platelet count was 148000/cu.mm and lactate dehydrogenase (LDH) level was 1047 IU/dl. The serum creatinine rose to 2.3 mg/dl. Liver function showed worsening direct bilirubinemia with mild elevation of transaminases (Total Bilirubin- 13.5 mg/dL, Direct Bilirubin- 9.4 mg/ dL, Aspartate aminotransferase- 323 U/L, Alanine aminotransferase- 46 U/L.) Viral hepatitis serology for hepatitis A, B, C and E were negative Leptospira antibody was not detected. Urinanalysis showed increasing proteinuria to 3+ and 50 - 60 RBCs per high power field. Direct antiglobulin (Coomb's) test was positive. ANA and anti-DsDNA titres were high at 17.4 and 46.2 units respectively with normal complement levels. Renal and liver biopsy were not attempted in view of the patient's poor condition for the procedure. Figure 1 Peripheral blood film showing many schistocytes, (Leishman, ×1000) The presence of microangiopathic anemia, alteration in neurological status, fever, thrombocytopenia and renal dysfunction with a background of malar and discoid rash, high titre of ANA and anti ds-DNA, proteinuria with active urinary sediment suggested a diagnosis of TTP and Systemic Lupus SLE. The patient was promptly treated with pulse therapy with methylprednisolone 1 gm daily for three days and plasma exchange. She underwent daily plasma exchanges with fresh frozen plasma (FFP) for five days and her sensorium improved. The platelet count rose to 229,000/cu.mm, with a reduction in the number of schistocytes in the peripheral blood smear. The LDH level also returned to the normal value. Plasma exchange was withheld. Two days later, she became stuporose, the platelet count fell to 34,000/cu.mm, renal failure worsened and she required ventilatory support. The LDH rose to 682 IU/dL. Mycophenolate mofetil was initiated thereafter in view of deteriorating clinical status with multisystem involvement and plasma exchange was continued for another seven sessions. Over the next two weeks, her sensorium improved, renal and pulmonary functions normalized, no active hemolysis was noticed and the facial rash resolved. The LDH continued to be marginally raised. She developed a ventilator associated chest infection which was treated with meropenem and satisfactory resolution over the next two weeks. The patient was discharged thereafter on prednisolone 1 mg/kg/day and mycophenolate mofetil 2 gm/day. She is in disease remission after three years, with normal renal function, on low dose prednisolone and tapering dose of mycophenolate mofetil.

reated with meropenem and satisfactory resolution over the next two weeks. The patient was discharged thereafter on prednisolone 1 mg/kg/day and mycophenolate mofetil 2 gm/day. She is in disease remission after three years, with normal renal function, on low dose prednisolone and tapering dose of mycophenolate mofetil. Discussion TTP was initially described with thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, renal abnormalities, and fever. There was no effective treatment and ninety percent of patients died. Plasma exchange has improved survival rates since then from 10% to between 75% and 92%, creating urgency for initiation of treatment. This has resulted in the diagnostic criteria to be revised from the earlier pentad to the current dyad of thrombocytopenia and microangiopathic hemolytic anemia, with no clinically apparent alternative explanation for thrombocytopenia and anemia.[2] Patients with TTP have a severe deficiency of von Willebrand Factor (VWF) cleaving metalloproteinase (ADAMTS-13), which normally cleaves the unusually large(UL)VWF into smaller and less adhesive VWF,[3] resulting in microvascular thrombosis and thrombocytopenia when deficient. Connective tissue disorders like SLE have low levels of ADAMTS-13[4] suggesting a possible common pathophysiology for this disease association.

(ADAMTS-13), which normally cleaves the unusually large(UL)VWF into smaller and less adhesive VWF,[3] resulting in microvascular thrombosis and thrombocytopenia when deficient. Connective tissue disorders like SLE have low levels of ADAMTS-13[4] suggesting a possible common pathophysiology for this disease association. TTP occurring in patients with SLE can be difficult to diagnose because of overlapping features of the two disorders.[5] SLE may present with hemolytic anemia, thrombocytopenia, neurologic deficits, fever, and renal insufficiency but the finding of fragmented RBC's or schistocytes favours the diagnosis of TTP.[6] An initial schistocyte count of more than 1% in the absence of any other cause for thrombocytopenia is strongly suggestive of TTP.[7]

present with hemolytic anemia, thrombocytopenia, neurologic deficits, fever, and renal insufficiency but the finding of fragmented RBC's or schistocytes favours the diagnosis of TTP.[6] An initial schistocyte count of more than 1% in the absence of any other cause for thrombocytopenia is strongly suggestive of TTP.[7] However because of the complexity in identifying schistocytes on a blood film, a wide variation is seen amongst laboratory personnel.[8] This could be disastrous for the patient if the schistocytes are not identified or diagnosis is delayed. Attempts at improving diagnosis with automation (ADVIA 120) and direct measurement of the RBC fragments have not been successful because despite the absence of false negatives, the specificity was low and had to be reconfirmed by a manual examination of the peripheral blood smear.[9] Careful examination of the blood film is therefore mandatory and specifically sensitizing the lab personnel to look for schistocytes will improve the outcomes of the disease by reducing false negatives. In our practice the peripheral blood film is immediately evaluated by a senior pathologist enabling plasma exchange to be initiated with shortest possible delay. This is important because the disease responds well to early plasma exchange treatment.

will improve the outcomes of the disease by reducing false negatives. In our practice the peripheral blood film is immediately evaluated by a senior pathologist enabling plasma exchange to be initiated with shortest possible delay. This is important because the disease responds well to early plasma exchange treatment. TTP in association with SLE appears to be under diagnosed. A positive Coombs test is not against the diagnosis of TTP in this setting.[5] Interestingly this patient also possibly had a rare manifestation of liver disease in SLE- cholestatic hepatitis, as evidenced by the direct hyperbilirubinemia with mild elevation of transaminases and raised alkaline phosphatase, in the absence of any infective causes for the same and gradual resolution with prednisolone.[10] Histopathological confirmation of this suspicion was not possible. Pregnancy often presents with a diagnostic dilemma in TTP due a similar presentation in pre eclampsia, eclampsia and HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelets) syndrome. An important distinguishing feature in these conditions is an improvement post delivery.[11]

Histopathological confirmation of this suspicion was not possible. Pregnancy often presents with a diagnostic dilemma in TTP due a similar presentation in pre eclampsia, eclampsia and HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelets) syndrome. An important distinguishing feature in these conditions is an improvement post delivery.[11] No clinical parameters predict the required duration for plasma exchange and the decision to stop plasma exchange at this time is empirical. The British Committee for Standards in Hematology (BCHS) guidelines recommends that plasma-exchange therapy be continued for a minimum of two days after the platelet count returns to normal (>150,000 /cu. mm), normal neurological status, rising hemoglobin and normal LDH. The presence of residual schistocytes on peripheral blood film after normalization of platelet counts is common and is not predictive of a relapse.[12] High dose plasma infusion may be used in an emergency till plasma exchange can be done[13] and would logically be the next best option if plasma exchange facilities are unavailable.

of residual schistocytes on peripheral blood film after normalization of platelet counts is common and is not predictive of a relapse.[12] High dose plasma infusion may be used in an emergency till plasma exchange can be done[13] and would logically be the next best option if plasma exchange facilities are unavailable. BCHS also recommends the use of glucocorticoids for all patients with TTP and intensive immunosuppression in severe, refractory or recurrent disease.[14] Platelet transfusion is contraindicated in TTP.[15] Cyclophosphamide has been extensively used to manage lupus nephritis but its use in fertile women is limited by premature ovarian failure and infection. Mycophenolate mofetil, an immunosuppressive agent that inhibits purine nucleotide synthesis in activated lymphocytes, is being widely accepted to be equally effective and beneficial in patients showing resistance to cyclophosphamide. It also inhibits vascular smooth muscle proliferation and atherosclerosis, which is of immense concern in patients with SLE.[16] TTP with organ dysfunction necessitating ICU admission has high mortality (35%) with good outcome in survivors. Neurological impairment is an adverse prognostic marker for mortality but not renal dysfunction.[17] Infections are not uncommon (12.8%) in patients undergoing plasma exchange[18] but infective risk due to the procedure was disapproved in a large study of patients with severe lupus nephritis on immunosupression.[19] Therefore emphasis must be given to infection prevention in the ICU with hand-washing, optimal care of indwelling catheters and preventing ventilator acquired infections, in this highly susceptible group. Once an ICU infection does take place, as in our patient, it is prudent to institute high line antibiotic support and continue immunosupression and plasma exchange, evaluating closely for deterioration with daily leucocyte counts and rising trend of acute phase reactants. No guidelines are available for modification of plasma exchange regimes in a severe infection and it should be continued due to high mortality associated with the underlying disease.

pression and plasma exchange, evaluating closely for deterioration with daily leucocyte counts and rising trend of acute phase reactants. No guidelines are available for modification of plasma exchange regimes in a severe infection and it should be continued due to high mortality associated with the underlying disease. SLE presenting as TTP is rare, emphasizing the importance of looking out for the association, early diagnosis and aggressive management with plasma exchange and immunosuppression which is life-saving. Critical care specialists need to evolve an urgent multi-disciplinary approach, emphasizing on early recognition and institution of treatment to ensure better outcomes in this scenario. Source of Support: Nil Conflict of Interest: None declared.

Introduction Pulmonary fat embolism is a life-threatening complication for patients with long-bone fractures undergoing surgery.[1–4] The incidence of the fat embolism syndrome ranges between 0.9 and 2.2%, and the mortality rate has been reported to be 13-87%.[5–8] We report a patient with severe haemodynamic instability following fat embolism, who was successfully treated using percutaneous cardiopulmonary support (PCPS).

es undergoing surgery.[1–4] The incidence of the fat embolism syndrome ranges between 0.9 and 2.2%, and the mortality rate has been reported to be 13-87%.[5–8] We report a patient with severe haemodynamic instability following fat embolism, who was successfully treated using percutaneous cardiopulmonary support (PCPS). Case Report A 65 year old woman had a fall in her bathroom, and presented to the hospital with Fracture shaft of femur. She was admitted to hospital for repair of the left femur fracture. An ORIF with an intramedullary nail, was planned to repair the fracture. Intraoperatively basic monitoring with continuous ECG, non-invasive blood pressure, and pulse oximetry was carried out. The procedure was done with epidural anaesthesia, given in the lumbar region -L3-L4 space, using isobaric bupivacaine 0.5% (16ml). The patient was sedated using intermittent Midazolam 2 mg IV, and the patient received oxygen through a venti-mask. After epidural block her blood pressure was 110/64 mm Hg, heart rate was 83 / min, and the SpO2 was 99%. Approximately 15 min after the insertion of the intramedullary nail, the patient suddenly became restless and this excitement progressed to generalized seizures. The oxygen saturation decreased from 99 to 80%. The patient became tachypnoeic, and the ECG showed ventricular bigeminy. Within seconds, she developed profound hypotension and shock The oxygen saturation could not be recorded. The patient was immediately intubated with a 7.5 mm endotracheal tube and positive pressure ventilation commenced. The initial end tidal CO2 was noted to be between 0 and 2.02. An arterial line was inserted, and an arterial blood gas analysis obtained, which showed a pH 7.019 of pCO2 was 20.17 mmHg, and paO2 was 107.57 mm of Hg, with a base deficit of 3.6 meq litre while breathing 100% oxygen. We urged the surgeon to complete suturing the skin as soon as possible. While the surgeon was suturing the skin, we inserted a pulmonary artery (PA) catheter. The systolic pulmonary arterial pressure was 48 mm Hg and the diastolic pressure was 32 mm Hg. A Transthoracic echocardiogram revealed massive dilatation of the right ventricle, the diameter of the inferior vena cava was 26 mm, and diametric change accompanying respiration was not observed. The left ventricular function was normal.

pulmonary arterial pressure was 48 mm Hg and the diastolic pressure was 32 mm Hg. A Transthoracic echocardiogram revealed massive dilatation of the right ventricle, the diameter of the inferior vena cava was 26 mm, and diametric change accompanying respiration was not observed. The left ventricular function was normal. We diagnosed the cause for the circulatory collapse as due to acute right heart failure (acute cor pulmonale) The patient then developed atrial fibrillation and subsequently pulseless ventricular tachycardia and required defibrillation, and cardiopulmonary resuscitation. CPR was continued in the operating theatre. Blood gas analysis during CPR showed a pH 7.075 of pO2 - 340.64 mm of Hg, and pCO2 - 41.84 mm of Hg with a base deficit of 16.9 mEq litre while breathing 100% oxygen. The end-tidal carbon dioxide was between 0 and 12 mm of Hg, and oxygen saturation could not be monitored.

on. CPR was continued in the operating theatre. Blood gas analysis during CPR showed a pH 7.075 of pO2 - 340.64 mm of Hg, and pCO2 - 41.84 mm of Hg with a base deficit of 16.9 mEq litre while breathing 100% oxygen. The end-tidal carbon dioxide was between 0 and 12 mm of Hg, and oxygen saturation could not be monitored. After successful CPR using epinephrine, atropine, vasopressin, and debfibrillation, continuous infusion of Norepinephrine 2 µg / kg / min and Dobutamine 20 µg / kg / min were started and the rates of infusions were adjusted to maintain the arterial systolic blood pressure >80 mm Hg. Systolic PA pressure was 51 mm Hg and pulmonary capillary wedge pressure (PCWP) was 33 mm Hg. A repeat Transthoracic echocardiogram (TTE) showed that the right ventricle was severely dilated but left ventricular function was maintained. After about an hour of continuous resuscitation, despite optimal maximal doses of pharmacological support, we could not maintain the systolic blood pressure >80 mm Hg; at this stage, we decided to place a portable PCPS.

) showed that the right ventricle was severely dilated but left ventricular function was maintained. After about an hour of continuous resuscitation, despite optimal maximal doses of pharmacological support, we could not maintain the systolic blood pressure >80 mm Hg; at this stage, we decided to place a portable PCPS. The PCPS is composed of heparin-coated circuits (Carmeda™ Closed Chest Support System), a biopump, a heat exchange unit, and a Maxima™ membrane oxygenator (Medtronic Cardiopulmonary CO, Anaheim, CA, USA). We inserted a 19 Fr drainage cannula into a femoral vein and 17 Fr re-infusion cannula into the femoral artery percutaneously. The initial blood flow was 2.5 litre min and the rotation rate of the biopump was 2500 rpm. The oxygen fraction was 1.0 at 4.0 litre min-1. About one hour after PCPS was started, the patient started showing signs of recovery, Her ECG returned to normal sinus rhythm and her circulatory failure began to improve, her systolic blood pressure was 92 mm Hg and her heart rate was between 90 - 100 beats / min. The PA pressure gradually decreased from 51 to 34 mm Hg, and her general condition became stable. The patient's blood gas analysis at this time showed a pH pH 7.34, pO2 of pO2 -477.34 mm of Hg, and pCO2 - 27.74 mm of Hg with 100% oxygen. The mixed venous oxygen saturation increased from 48 to 75%. The blood flow was maintained at 2.5 litre min and her core temperature had been lowered to less than 34°C for the protection of cerebral function. After the initiation of PCPS and having stabilized her cardiovascular condition, we transferred the patient from the operating theatre to a radioscintigraphic examination room as by this time we had strong suspicion of fat embolism. The radioscintigram showed diffuse multiple defects of blood flow in both lungs. After scintigraphic examination, we brought the patient to the intensive care unit (ICU).

transferred the patient from the operating theatre to a radioscintigraphic examination room as by this time we had strong suspicion of fat embolism. The radioscintigram showed diffuse multiple defects of blood flow in both lungs. After scintigraphic examination, we brought the patient to the intensive care unit (ICU). We diagnosed the patient as having pulmonary fat embolism from the presence of lipid granules, sampled from the tip of the PA catheter and stained with oil red O.[9] On day one in ICU, the patient's condition was stable on PCPS. On day two, since the patient was cardiovascularly stable, we lowered the PCPS flow to 1.0 litre min and then to 0.5 litre min. Throughout this time, the systolic blood pressure was maintained above 120 mm Hg and her heart rate was between 80 - 90 beats/min. The cardiac output (CO) was more than 3.5 litre min. The PA pressure had been between 25 and 30 mm Hg. We therefore decided to stop and remove the PCPS from the patient. Immediately after disconnecting the drainage cannula from the femoral vein, the patient crashed and had a very low systolic blood pressure with the ECG showing wide QRS complexes. PCPS was resumed immediately. An echocardiogram showed dilatation of the right ventricle, septal akinesis, and hypo kinesis of the left ventricle and the LV ejection fraction was less than 10%. We therefore continued to support the patient on PCPS. We had to give more time for the recovery of her cardiac function. On day three in ICU, the patient;s CO was 4.0 litre min-1 and PCWP 20 mm Hg. On the fourth ICU day, the systolic blood pressure was 140 mm Hg, heart rate between 80 and 90 beats min, systolic PA pressure between 25 and 30 mm Hg, PCWP 20 mm Hg, and cardiac index 3.6 litre m-2 min using a PCPS flow of 1.0 litre min. IV digital subtraction angiography at this stage showed adequate blood supply to both the lungs, except for a small apical part of the left lung. Good wall motion of the heart was observed at the same time. PCPS was then stopped for 30 min and we confirmed that the patient's haemodynamic condition remained stable. We then proceeded to wean the patient off PCPS. When the PCPS drainage cannula was withdrawn from the femoral vein, the PA systolic pressure suddenly increased from 30 to 65 mm Hg. and the ECG showed paroxysmal supra-ventricular tachycardia with a heart rate between 180-190/ min. The arrhythmia was successfully treated with cardioversion. The systolic arterial blood pressure was between 100 and 120 mm Hg.

rawn from the femoral vein, the PA systolic pressure suddenly increased from 30 to 65 mm Hg. and the ECG showed paroxysmal supra-ventricular tachycardia with a heart rate between 180-190/ min. The arrhythmia was successfully treated with cardioversion. The systolic arterial blood pressure was between 100 and 120 mm Hg. However the PA pressure remained as high as 65 mm Hg and we administered Prostaglandin 0.5 µg / kg. After PGE1 infusion, the PA systolic pressure gradually decreased from 65 to 40 mm Hg. One hour after weaning from PCPS, the patient had a blood pressure of 120/90 mm Hg, 90-100 /min, cardiac index of 3.0 L/min, and mixed venous oxygen saturation of 73%. However, she continued to have high pulmonary pressures So we continued PGE1 at 0.2 µg / kg / min, which gradually relieved pulmonary hypertension and the PA pressure decreased to 25 mm Hg (mean). On the tenth postoperative day, the patient's PA pressure was pressure was 33/15 mm Hg (mean 19 mm Hg) and PCWP was 10 mm Hg, so we discontinued the PGE1 infusion. Sedation was ceased and the patient gradually woke up and was obeying commands. She was extubated, and subsequently transferred to HDU and then shifted to the ward without neurological complications. Discussion In this case report, soon after a clinical diagnosis of cardiovascular collapse due to acute right heart failure secondary to massive fat embolism was suspected, an urgent echocardiogram helped us support our diagnosis. We have then described the successful management of this patient with aggressive resuscitation along with the use of cardiopulmonary bypass.

al diagnosis of cardiovascular collapse due to acute right heart failure secondary to massive fat embolism was suspected, an urgent echocardiogram helped us support our diagnosis. We have then described the successful management of this patient with aggressive resuscitation along with the use of cardiopulmonary bypass. It is known that increase in pulmonary arterial pressure and resistance induce right ventricular failure that may persist for several hours.[1011] Subsequent right ventricular dilatation may result in septal shift resulting in a decrease in left ventricular filling volume, leading to low CO. High right ventricular end-diastolic pressure in addition to low systemic blood pressure results in ischaemia of the right ventricle, potentiating the vicious cycle of right ventricular depression, dysfunction, and death. In our patient we kept cardiac massage going for an hour. Conventional treatment for right ventricular dysfunction includes the use of pulmonary vasodilators, volume loading, use of inotropes / vasopressors, Mechanical circulatory support is indicated for patients with right heart failure who show no improvement in response to conventional therapy.[10–12]

e going for an hour. Conventional treatment for right ventricular dysfunction includes the use of pulmonary vasodilators, volume loading, use of inotropes / vasopressors, Mechanical circulatory support is indicated for patients with right heart failure who show no improvement in response to conventional therapy.[10–12] PCPS is a powerful resuscitative tool that may be used to support patients with cardiac arrest and improve their survival.[12–14] PCPS is an extracorporeal life support that involves the continuous drainage of venous blood to a pump and membrane oxygenator and re-infusion to a major vein or artery. Venovenous support is the primary mode for respiratory failure, known as extracorporeal membrane oxygenation; this is primarily used in respiratory failure when improved oxygenation is the main goal Venoarterial bypass provides full support for both respiratory and cardiovascular failure and is called as PCPS in Japan. Venoarterial bypass involves accessing the right atrium or inferior vena cava for venous drainage and infusion into femoral artery; this type of support is used for patients who require cardiovascular support. PCPS can be used for patients with circulatory collapse and patients with damaged pulmonary circulation. PCPS drains blood from the right atrium, bypassing the right ventricle and pulmonary circulation, and oxygenated blood is returned to the systemic circulation. Therefore, we think the use of PCPS for patients with severe pulmonary embolism with catastrophic cardiopulmonary failure is worth considering in appropriate patients.,

ins blood from the right atrium, bypassing the right ventricle and pulmonary circulation, and oxygenated blood is returned to the systemic circulation. Therefore, we think the use of PCPS for patients with severe pulmonary embolism with catastrophic cardiopulmonary failure is worth considering in appropriate patients., The advantage of PCPS is that cannulation of the femoral vessels can be performed relatively quickly percutaneously. PCPS can be started within 15 min. The heparin-coated PCPS circuit can be used for the patients soon after surgery. The main complications of PCPS are hemorrhage, ischemia to lower legs, infection, and hemolysis. Arterial blood flow is mechanically returned into the femoral artery in the antegrade direction to spontaneous heart beat that increases the afterload of the left ventricle and might cause left ventricular dysfunction. Considering the limitation and complications during longer PCPS, we had tried rapid initial weaning from PCPS, but we should have continued the PCPS until we had confirmed the recovery of cardiac function as acknowledged on the fourth postoperative day. Administration of a large dose of PGE1 reduces the afterload of the right ventricle and improves refractory right heart failure. PGE1 is reported to be more pulmonary specific than Nitroglycerin, Sodium Nitroprusside, and Hydralazine, and resulted in the largest decrease in PA pressure.[15] PGE1 induced the largest decrease in PA pressure compared with the other pulmonary vasodilators Isoproterenol, Prostacyclin, and Nifedipine.[16] PCPS maintained our patient's condition well so that we did not use PGE1 while PCPS support was continued. However, retrospectively, we think we should have administered PGE1 from the start of the PCPS, then perhaps the cardiopulmonary status of the patient might have been stabilized better. If conventional pharmacological measures are not capable of stabilizing a patient with severe pulmonary fat embolism, PCPS is worth considering. This case shows that PCPS could provide effective support for the patients with fatal pulmonary fat embolism syndrome. Administration of PGE1 seemed effective for PH after weaning from the PCPS support.

ical measures are not capable of stabilizing a patient with severe pulmonary fat embolism, PCPS is worth considering. This case shows that PCPS could provide effective support for the patients with fatal pulmonary fat embolism syndrome. Administration of PGE1 seemed effective for PH after weaning from the PCPS support. Source of Support: Nil Conflict of Interest: None declared.

Background Blood is a special type of connective tissue that is composed of white cells, red cells, platelets, and plasma. It has a variety of functions in the body. Plasma is the extracellular material made up of water, salts, and various proteins that, along with platelets, encourages blood to clot. Proteins in the plasma react with air and harden to prevent further bleeding. The white blood cells are responsible for the immune defense. They seek out invading organisms or materials and minimize their effect in the body. The red cells in blood create the bright red color. As little as two drops of blood contains about one billion red blood cells. These cells are responsible for the transportation of oxygen and carbon dioxide throughout the body. They are also responsible for the “typing” phenomena. On the membranes of these cells are proteins that the body recognizes as its own. For this reason, a person can use only blood that is compatible with her type. Currently, artificial blood products are only designed to replace the function of red blood cells. It might even be better to call the products being developed now, oxygen carriers instead of artificial blood.

the body recognizes as its own. For this reason, a person can use only blood that is compatible with her type. Currently, artificial blood products are only designed to replace the function of red blood cells. It might even be better to call the products being developed now, oxygen carriers instead of artificial blood. History There has been a need for blood replacements for as long as patients have been bleeding to death because of a serious injury. According to medical folklore, the ancient Incas were responsible for the first recorded blood transfusions. No real progress was made in the development of a blood substitute until 1616, when William Harvey described how blood is circulated throughout the body. In the years to follow, medical practitioners tried numerous substances such as beer, urine, milk, plant resins, and sheep blood as a substitute for blood. They had hoped that changing a person's blood could have different beneficial effects such as curing diseases or even changing a personality. The first successful human blood transfusions were done in 1667. Unfortunately, the practice was halted because patients who received subsequent transfusions died.

ute for blood. They had hoped that changing a person's blood could have different beneficial effects such as curing diseases or even changing a personality. The first successful human blood transfusions were done in 1667. Unfortunately, the practice was halted because patients who received subsequent transfusions died. Of the different materials that were tried as blood substitutes over the years, only a few met with minimal success. Milk was one of the first of these materials. In 1854, patients were injected with milk to treat Asiatic cholera. Physicians believed that the milk helped regenerate white blood cells. In fact, enough of the patients given milk as a blood substitute seemed to improve that it was concluded to be a safe and legitimate blood replacement procedure. However, many practitioners remained skeptical so milk injections never found widespread appeal. It was soon discarded and forgotten as a blood replacement. Another potential substitute was salt or saline solutions. In experiments done on frogs, scientists found that they could keep frogs alive for some time if they removed all their blood and replaced it with a saline solution. These results were a little misleading, however, because it was later determined that frogs could survive for a short time without any blood circulation at all. After much research, saline was developed as a plasma volume expander.

ve for some time if they removed all their blood and replaced it with a saline solution. These results were a little misleading, however, because it was later determined that frogs could survive for a short time without any blood circulation at all. After much research, saline was developed as a plasma volume expander. Other materials that were tried during the 1800s include hemoglobin and animal plasma. In 1868, researchers found that solutions containing hemoglobin isolated from red blood cells could be used as blood replacements. In 1871, they also examined the use of animal plasma and blood as a substitute for human blood. Both of these approaches were hampered by significant technological problems. First, scientists found it difficult to isolate a large volume of hemoglobin. Second, animal products contained many materials that were toxic to humans. Removing these toxins was a challenge during the nineteenth century.

te for human blood. Both of these approaches were hampered by significant technological problems. First, scientists found it difficult to isolate a large volume of hemoglobin. Second, animal products contained many materials that were toxic to humans. Removing these toxins was a challenge during the nineteenth century. A significant breakthrough in the development of artificial blood came in 1883 with the creation of Ringer's solution—a solution composed of sodium, potassium, and calcium salts. In research using part of a frog's heart, scientists found that the heart could be kept beating by applying the solution. This eventually led to findings that the reduction in blood pressure caused by a loss of blood volume could be restored by using Ringer's solution. This product evolved into a human product when lactate was added. While it is still used today as a blood-volume expander, Ringer's solution does not replace the action of red blood cells so it is not a true blood substitute.

blood pressure caused by a loss of blood volume could be restored by using Ringer's solution. This product evolved into a human product when lactate was added. While it is still used today as a blood-volume expander, Ringer's solution does not replace the action of red blood cells so it is not a true blood substitute. Karl Landsteiner [Figure 1], who has been called the father of immunology, was the only child of Leopold Landsteiner, a prominent Austrian journalist and editor, and Fanny Hess Landsteiner. Landsteiner was educated at the University of Vienna, where he received his medical degree in 1891. While in medical school, Landsteiner began experimental work in chemistry, as he was greatly inspired by Ernst Ludwig, one of his professors. After receiving his medical degree, Landsteiner spent the next five years doing advanced research in organic chemistry for Emil Fischer, although medicine remained his chief interest. During 1886-1897, he combined these interests at the Institute of Hygiene at the University of Vienna where he researched immunology and serology. Immunology and serology then became Landsteiner's lifelong focus. Landsteiner was primarily interested in the lack of safety and effectiveness of blood transfusions. Prior to his work, blood transfusions were dangerous and underutilized because the donor's blood frequently clotted in the patient. Landsteiner was intrigued by the fact that when blood from different subjects was mixed, the blood did not always clot. He believed there were intrinsic biochemical similarities and dissimilarities in blood.

blood transfusions were dangerous and underutilized because the donor's blood frequently clotted in the patient. Landsteiner was intrigued by the fact that when blood from different subjects was mixed, the blood did not always clot. He believed there were intrinsic biochemical similarities and dissimilarities in blood. Figure 1 Karl Landsteiner Using blood samples from his colleagues, he separated the blood's cells from its serum, and suspended the red blood cells in a saline solution. He then mixed each individual's serum with a sample from every cell suspension. Clotting occurred in some cares; in others there was no clotting. Landsteiner determined that human beings could be separated into blood groups according to the capacity of their red cells to clot in the presence of different serums. He named his blood classification groups A, B, and O. A fourth group AB, was discovered the following year. The result of this work was that patient and donor could be blood-typed beforehand, making blood transfusion a safe and routine medical practice. This discovery ultimately earned Landsteiner the 1930 Nobel Prize in physiology or medicine.

ication groups A, B, and O. A fourth group AB, was discovered the following year. The result of this work was that patient and donor could be blood-typed beforehand, making blood transfusion a safe and routine medical practice. This discovery ultimately earned Landsteiner the 1930 Nobel Prize in physiology or medicine. Blood transfusion research did not move forward until scientists developed a better understanding of the role of blood and the issues surrounding its function in the body. During World War I, a gum-saline solution containing galactoso-gluconic acid was used to extend plasma. If the concentration, pH, and temperature were adjusted, this material could be designed to match the viscosity of whole blood, allowing physicians to use less plasma. In the 1920s, studies suggested that this gum solution had some negative health effects. By the 1930s, the use of this material had significantly diminished. World War II reignited an interest in the research of blood and blood substitutes. Plasma donated from humans was commonly used to replace blood and to save soldiers from hemorrhagic shock. Eventually, this led to the establishment of blood banks by the American Red Cross in 1947.

material had significantly diminished. World War II reignited an interest in the research of blood and blood substitutes. Plasma donated from humans was commonly used to replace blood and to save soldiers from hemorrhagic shock. Eventually, this led to the establishment of blood banks by the American Red Cross in 1947. In 1966, experiments with mice suggested a new type of blood substitute, perfluorochemicals (PFC). These are long chain polymers similar to Teflon. It was found that mice could survive even after being immersed in PFC. This gave scientists the idea to use PFC as a blood thinner. In 1968, the idea was tested on rats. The rat's blood was completely removed and replaced with a PFC emulsion. The animals lived for a few hours and recovered fully after their blood was replaced. However, the established blood bank system in developed countries worked so well that research on blood substitutes waned in those countries. It received renewed interest when the shortcomings of the blood bank system were discovered during the Vietnam conflict. This prompted some researchers to begin looking for hemoglobin solutions and other synthetic oxygen carriers. Research in this area was further fueled in 1986 when it was discovered that HIV and hepatitis could be transmitted via blood transfusions.

of the blood bank system were discovered during the Vietnam conflict. This prompted some researchers to begin looking for hemoglobin solutions and other synthetic oxygen carriers. Research in this area was further fueled in 1986 when it was discovered that HIV and hepatitis could be transmitted via blood transfusions. Design The ideal artificial blood product has the following characteristics. First, it must be safe to use and compatible within the human body. This means that different blood types should not matter when an artificial blood is used. It also means that artificial blood can be processed to remove all disease-causing agents such as viruses and microorganisms. Second, it must be able to transport oxygen throughout the body and release it where it is needed. Third, it must be shelf stable. Unlike donated blood, artificial blood can be stored for over a year or more. This is in contrast to natural blood which can only be stored for one month before it breaks down. There are two significantly different products that are under development as blood substitutes. They differ primarily in the way that they carry oxygen. One is based on PFC, while the other is a hemoglobin-based product.

This is in contrast to natural blood which can only be stored for one month before it breaks down. There are two significantly different products that are under development as blood substitutes. They differ primarily in the way that they carry oxygen. One is based on PFC, while the other is a hemoglobin-based product. Perfluorocarbons (PFC) As suggested, PFC are biologically inert materials that can dissolve about 50 times more oxygen than blood plasma. They are relatively inexpensive to produce and can be made devoid of any biological materials. This eliminates the real possibility of spreading an infectious disease via a blood transfusion. From a technological standpoint, they have two significant hurdles to overcome before they can be utilized as artificial blood. First, they are not soluble in water, which means to get them to work they must be combined with emulsifiers—fatty compounds called lipids that are able to suspend tiny particles of perfluorochemicals in the blood. Second, they have the ability to carry much less oxygen than hemoglobin-based products. This means that significantly more PFC must be used. One product of this type has been approved for use by the Federal Drug Administration (FDA), but it has not been commercially successful because the amount needed to provide a benefit is too high. Improved PFC emulsions are being developed but have yet to reach the market.

eans that significantly more PFC must be used. One product of this type has been approved for use by the Federal Drug Administration (FDA), but it has not been commercially successful because the amount needed to provide a benefit is too high. Improved PFC emulsions are being developed but have yet to reach the market. Hemoglobin-based products Hemoglobin carries oxygen from the lungs to the other tissues in the body. Artificial blood based on hemoglobin takes advantage of this natural function. Unlike PFC products where dissolving is the key mechanism, oxygen covalently bonds to hemoglobin. These hemoglobin products are different than whole blood in that they are not contained in a membrane so the problem of blood typing is eliminated. However, raw hemoglobin cannot be used because it would break down into smaller, toxic compounds within the body. There are also problems with the stability of hemoglobin in a solution. The challenge in creating a hemoglobin-based artificial blood is to modify the hemoglobin molecule so these problems are resolved. Various strategies are employed to stabilize hemoglobin. This involves either chemically cross-linking molecules or using recombinant DNA technology to produce modified proteins. Just as Polyethylene Glycol-Modified Liposome-Encapsulated Hemoglobin, nanoparticle and polymersome encapsulated hemoglobin, stabilized hemoglobin solutions, polymerized hemoglobin solutions, conjugated hemoglobin solutions.

cally cross-linking molecules or using recombinant DNA technology to produce modified proteins. Just as Polyethylene Glycol-Modified Liposome-Encapsulated Hemoglobin, nanoparticle and polymersome encapsulated hemoglobin, stabilized hemoglobin solutions, polymerized hemoglobin solutions, conjugated hemoglobin solutions. Artificial blood can be produced in different ways using synthetic production, chemical isolation, or recombinant biochemical technology. Synthetic hemoglobin-based products are produced from hemoglobin harvested from an E. coli bacteria strain. The hemoglobin is grown in a seed tank and then fermented Conjugation of hemoglobin effectively increases its molecular size and reduces antigenicity, resulting in a slow rate of removal from the circulation and reduced “visibility” to the reticuloendothelial system. Unique features of conjugated hemoglobins are their high oncotic pressure, which makes them very potent plasma-volume expanders, and their viscosity. Intramolecular cross-linked hemoglobins are not significantly increased in molecular weight but have specific chemical cross-links between polypeptide chains that prevent dissociation to dimers or monomers. These modified hemoglobins are stable and soluble in solutions. Theoretically, these modifications should result in products that have a greater ability to carry oxygen than our own red blood cells. It is anticipated that the first of these products will be available within one to two years.

Intramolecular cross-linked hemoglobins are not significantly increased in molecular weight but have specific chemical cross-links between polypeptide chains that prevent dissociation to dimers or monomers. These modified hemoglobins are stable and soluble in solutions. Theoretically, these modifications should result in products that have a greater ability to carry oxygen than our own red blood cells. It is anticipated that the first of these products will be available within one to two years. Raw Materials Depending on the type of artificial blood that is made, various raw materials are used. Hemoglobin-based products can use either isolated hemoglobin or synthetically produced hemoglobin. To produce hemoglobin synthetically, manufacturers use compounds known as amino acids. These are chemicals that plants and animals use to create the proteins that are essential for life. There are 20 naturally occurring amino acids that may be used to produce hemoglobin. All of the amino acid molecules share certain chemical characteristics. They are made up of an amino group, a carboxyl group, and a side chain. The nature of the side chain differentiates the various amino acids. Hemoglobin synthesis also requires a specific type of bacteria and all of the materials needed to incubate it. This includes warm water, molasses, glucose, acetic acid, alcohols, urea, and liquid ammonia.

ino group, a carboxyl group, and a side chain. The nature of the side chain differentiates the various amino acids. Hemoglobin synthesis also requires a specific type of bacteria and all of the materials needed to incubate it. This includes warm water, molasses, glucose, acetic acid, alcohols, urea, and liquid ammonia. For other types of hemoglobin-based artificial blood products, the hemoglobin is isolated from human blood. It is typically obtained from donated blood that has expired before it is used. Other sources of hemoglobin come from spent animal blood. This hemoglobin is slightly different from human hemoglobin and must be modified before being used. The Manufacturing Process The production of artificial blood can be done in a variety of ways. For hemoglobin-based products, this involves isolation or synthesization of hemoglobin, molecular modification then reconstitution in an artificial blood formula. PFC products involve a polymerization reaction. A method for the production of a synthetic hemoglobin-based product is outlined below. Hemoglobin synthesis To obtain hemoglobin, a strain of E. coli bacteria that has the ability to produce human hemoglobin is used. Over the course of about three days, the protein is harvested and the bacteria are destroyed. To start the fermentation process, a sample of the pure bacteria culture is transferred to a test tube that contains all the nutrients necessary for growth. This initial inoculation causes the bacteria to multiply. When the population is great enough, they are transferred to a seed tank.

and the bacteria are destroyed. To start the fermentation process, a sample of the pure bacteria culture is transferred to a test tube that contains all the nutrients necessary for growth. This initial inoculation causes the bacteria to multiply. When the population is great enough, they are transferred to a seed tank. A seed tank is a large stainless steel kettle that provides an ideal environment for growing bacteria. It is filled with warm water, food, and an ammonia source which are all required for the production of hemoglobin. Other growth factors such as vitamins, amino acids, and minor nutrients are also added. The bacterial solution inside the seed tank is constantly bathed with compressed air and mixed to keep it moving. When enough time has passed, the contents of the seed tank is pumped to the fermentation tank. The fermentation tank is a larger version of the seed tank. It is also filled with a growth media needed for the bacteria to grow and produce hemoglobin. Since pH control is vital for optimal growth, ammonia water is added to the tank as necessary. When enough hemoglobin has been produced, the tank is emptied so isolation can begin. Isolation begins with a centrifugal separator that isolates much of the hemoglobin. It can be further segregated and purified using fractional distillation. This standard column separation met hod is based on the principle of boiling a liquid to separate one or more components and utilizes vertical structures called fractionating columns. From this column, the hemoglobin is transferred to a final processing tank.

rther segregated and purified using fractional distillation. This standard column separation met hod is based on the principle of boiling a liquid to separate one or more components and utilizes vertical structures called fractionating columns. From this column, the hemoglobin is transferred to a final processing tank. Final processing Here, it is mixed with water and other electrolytes [Figure 2] to produce the artificial blood. The artificial blood can then be pasteurized and put into an appropriate packaging. The quality of compounds is checked regularly during the entire process. Particularly important are frequent checks made on the bacterial culture. Also, various physical and chemical properties of the finished product are checked such as pH, melting point, moisture content, etc. This method of production has been shown to be able to produce batches as large as 2,640 gal (10,000 L). Figure 2 Once fermented, the hemoglobin is purified and then mixed with water and other electrolytes to create useable artificial blood

finished product are checked such as pH, melting point, moisture content, etc. This method of production has been shown to be able to produce batches as large as 2,640 gal (10,000 L). Figure 2 Once fermented, the hemoglobin is purified and then mixed with water and other electrolytes to create useable artificial blood The Future Currently, there are several companies working on the production of a safe and effective artificial blood substitute. The various blood substitutes all suffer from certain limitations. For example, most of the hemoglobin-based products last no more than 20-30h in the body. This compares to transfusions of whole blood that lasts 34 days. Also, these blood substitutes do not mimic the blood's ability to fight diseases and clot. Consequently, the current artificial blood technology will be limited to short-term blood replacement applications. In the future, it is anticipated that new materials to carry oxygen in the body will be found. Additionally, longer lasting products should be developed, as well as products that perform the other functions of blood. Source of Support: Nil Conflict of Interest: None declared.

Sampling from blood has been performed for over 200 years. However clinically useful arterial blood gas sampling became a reality after the development of robust methods for measuring oxygen tension from humans in the 1940s. Thus the development of the Clark electrode and subsequent safe tools for sampling plasma, heralded an era of blood sampling, and analysis from which we have not looked back.[1] As with many new medical technologies of their time, it was borne out of a combination of the need for investigational improvements, inventive spirit and serendipity. Arterial Blood gas sampling has been the standard of care for monitoring acid-base disturbance for decades - a testimony to its value in diverse settings. Despite this, concerns remain regarding its risks to the patient from repeated same site sampling.[2] This in part led to the alternative approach of arterialized blood samples (AzB), using either an earlobe or finger pulp skin prick.[3] In theory AzB are more easily obtained than ABG, repeatable with better patient tolerance, and accurate. Thus it was surprising to know of the relatively poor uptake of this technique in the ambulatory setting.[4] Despite better utilisation in the UK, ongoing concerns regarding equipment, reliability and accuracy hamper its wider use.[5] Quality control remains a crucial issue. Thus, a rigorous sampling technique, with adequate blood flow after topical vascularisation of the earlobe, sufficient volume and speed of collection, the appropriate sampling blade and rapid time to analysis has been proposed.[6]

injury. Confirmatory tests for the diagnosis of diaphragmatic palsy include esophageal and gastric pressure measurements, fluoroscopy, ultrasonography, and electro-neuromyography.[9] The diagnosis of the diaphragmatic palsy should be made on the basis of the results of the multiple examinations including the symptoms. The incidence of pulmonary complications was although numerically higher in patients in group I and group II but it was not significantly different from patients without diaphragmatic palsy owing to early recognition of diaphragmatic palsy and preventive measures taken to avoid respiratory complications (i.e. chest physiotherapy, steam inhalation, CPAP, BiPAP as required.) The incidence of postoperative respiratory infections e.g. tracheal bronchitis, Ventilator associated pneumonia, hospital acquired pneumonia etc were significantly low compared to historical controls in our observation group as well as study group. This may be clearly attributable to all surgeries being performed Off Pump CABG hence facilitating fast track extubation and expertise of our dedicated team in postoperative cardiac critical care owing to large number of surgeries done per year. Also, early anticipation and all necessary actions to prevent the development of postoperative pulmonary infection contributed to reduced incidence of above complications.

Sampling from blood has been performed for over 200 years. However clinically useful arterial blood gas sampling became a reality after the development of robust methods for measuring oxygen tension from humans in the 1940s. Thus the development of the Clark electrode and subsequent safe tools for sampling plasma, heralded an era of blood sampling, and analysis from which we have not looked back.[1] As with many new medical technologies of their time, it was borne out of a combination of the need for investigational improvements, inventive spirit and serendipity. Arterial Blood gas sampling has been the standard of care for monitoring acid-base disturbance for decades - a testimony to its value in diverse settings. Despite this, concerns remain regarding its risks to the patient from repeated same site sampling.[2] This in part led to the alternative approach of arterialized blood samples (AzB), using either an earlobe or finger pulp skin prick.[3] In theory AzB are more easily obtained than ABG, repeatable with better patient tolerance, and accurate. Thus it was surprising to know of the relatively poor uptake of this technique in the ambulatory setting.[4] Despite better utilisation in the UK, ongoing concerns regarding equipment, reliability and accuracy hamper its wider use.[5] Quality control remains a crucial issue. Thus, a rigorous sampling technique, with adequate blood flow after topical vascularisation of the earlobe, sufficient volume and speed of collection, the appropriate sampling blade and rapid time to analysis has been proposed.[6] What is known of its value in the clinical setting? The partial pressure of oxygen (PaO2) in AzB approaches but underestimates ABG due to venous admixture.[7] In the ambulatory setting, there appears to be a good correlation, both at rest, and after exercise in normal volunteers.[8] Values obtained for pH, PCO2, and HCO3 show a tighter correlation to, and accuracy with ABG. As venous admixture is partly determined by the arterio-venous (A-V) difference in PO2, the greater this difference, the less accurate AzB values become, particularly for PaO2.[49]

t, and after exercise in normal volunteers.[8] Values obtained for pH, PCO2, and HCO3 show a tighter correlation to, and accuracy with ABG. As venous admixture is partly determined by the arterio-venous (A-V) difference in PO2, the greater this difference, the less accurate AzB values become, particularly for PaO2.[49] The technique has been studied in the pediatric intensive care setting with favorable accuracy,[10] although it has not been universally adopted. The study by Honarmand and Safavi in this edition of the IJCCM,[11] offers a relook at this long established but underused alternative blood gas sampling technique, in the setting of adult critically ill patients. They compared simultaneously collected AzB and ABG samples from 67 mechanically ventilated patients admitted with acute respiratory failure to a single centre general ICU, and looked at their correlation and accuracy with the 'gold standard ABG data. Using Bland and Altman regression analysis,[12] the mean difference between the two methods approached zero for PaCO2 with a significantly good correlation (r=0.956), narrow limits of agreement and a range of ∼3kPa. This was also true for pH, and HCO3. However the limits were notably less for PaO2 with a range of difference upto ∼6Kpa. Patients found sampling acceptable and there were no complications from this.

roached zero for PaCO2 with a significantly good correlation (r=0.956), narrow limits of agreement and a range of ∼3kPa. This was also true for pH, and HCO3. However the limits were notably less for PaO2 with a range of difference upto ∼6Kpa. Patients found sampling acceptable and there were no complications from this. A significant proportion of these patients had head injury, without systemic illness. All were apparently normotensive although inotropic/vasopressor requirements are unclear. Thus the impact of underlying lung disease, deadspace ventilation and shunt fraction are unknown. These would all increase venous admixture and likely reduce the accuracy of AzB estimates of PaO2. So does this study shed light on the implications for AzB as a clinically useful tool? A number of points emerge. First, it is an easily learnt technique that is acceptable to patients,[11] although not necessarily less uncomfortable than ABG sampling.[13] Second, it may provide clinically acceptable accuracy for the measurement of pH, pCO2, and HCO3, and trend analysis therein. However this can be offered equally well by standard venous blood sampling.[14] Third, it underestimates PaO2 and its accuracy declines at higher Fractional inspired Oxygen concentrations (FiO2). So hypothetically, it would more accurately define PaO2 in the most hypoxaemic patients, but this is the very group in who continuous inline monitoring of ABG is crucial to management.

blood sampling.[14] Third, it underestimates PaO2 and its accuracy declines at higher Fractional inspired Oxygen concentrations (FiO2). So hypothetically, it would more accurately define PaO2 in the most hypoxaemic patients, but this is the very group in who continuous inline monitoring of ABG is crucial to management. It should be clear then, that an adult ICU setting is not the environment for the technique of AzB to be clinically useful. So is that the end of the road then for AzB? Perhaps not. Careful selection of the patient group in whom chronic hypoxaemia is established, and indwelling or multiple ABG sampling is undesirable, may lend itself to AzB for point-of-care testing. An acute-on-chronic deterioration may allow serial AzB trend analysis and facilitate management, perhaps in the acute medical setting. Another place for point-of-care AzB testing may be altitude, where the inaccuracies of venous admixture would be conveniently reduced due to relative hypoxaemia. The value of socially acceptable, user friendly, rapid diagnostic testing tools in medicine that offer accurate clinical utility, continue to fuel research and development in the field of blood sampling. Whether a 40-year-old technique can be resurrected in a modern era will be down to further studies to identify its niche. That area will not likely be the adult critically ill.

ostic testing tools in medicine that offer accurate clinical utility, continue to fuel research and development in the field of blood sampling. Whether a 40-year-old technique can be resurrected in a modern era will be down to further studies to identify its niche. That area will not likely be the adult critically ill. So for once, it is not a case of the operator blaming his tools. Rather the tool has reached the limit of acceptable accuracy because of the intrinsic compensatory mechanisms that govern acid-base and gas-exchange homeostasis in the critically ill adult. Source of Support: Nil Conflict of Interest: None declared.

Introduction The respiratory system functions as a vital pump that moves air in and out of the lungs to help in gas exchange. The dome-shaped diaphragm is the most important component of this respiratory muscle pump. It contributes up to 60-70% of the total ventilation at rest both in the sitting and supine positions. The diaphragm is innervated by cervical motor neurons (C3-5) via phrenic nerves. The incidence and prevalence of diaphragmatic palsy (DP) after cardiac surgery is not exactly defined in the literature, partly because partial or unilateral impairment may go unrecognized. However incidence of diaphragmatic palsy after coronary artery bypass grafting (CABG) ranges from 10% to 60% in English literature. Although in most cases, it is transient and of no clinical significance. But on other hand, diaphragmatic palsy causes further deterioration of pulmonary function in patients with poor cardiopulmonary reserve and may lead to secondary hypoxemia, prolonged ventilator use, pneumonia and atelectasis leading to increased ICU and hospital stay as well as increased morbidity and mortality. The causes of the diaphragmatic palsy during cardiac surgery are also not clearly understood. Direct injury during harvesting of the internal mammary artery,[1] cold injury owing to pericardial ice slush[2–5] and inadvertent stretch injuries during intra-pericardial manipulation of the heart are some documented causes, but the injury may occur without an apparent reason.

surgery are also not clearly understood. Direct injury during harvesting of the internal mammary artery,[1] cold injury owing to pericardial ice slush[2–5] and inadvertent stretch injuries during intra-pericardial manipulation of the heart are some documented causes, but the injury may occur without an apparent reason. Post cardiac surgery diaphragmatic palsy usually tends to be unilateral but rarely may be bilateral with consequent ventilatory failure. With paralysis of the diaphragm, the patient has to put more effort into breathing, which results in fatigue of the respiratory muscles and may lead to ventilatory failure. Conventional chest physiotherapy (including coughing, deep breathing exercises and incentive spirometry) may have a beneficial effect in the post operative pulmonary impairment. On the basis of the above hypothesis, an observational prospective interventional study was performed to see the effectiveness of chest physiotherapy in diaphragmatic palsy in post cardiac surgery patients. The other objective of this study was to observe the incidence of diaphragmatic palsy (DP) after off pump CABG (OPCAB) in adult patients.

e hypothesis, an observational prospective interventional study was performed to see the effectiveness of chest physiotherapy in diaphragmatic palsy in post cardiac surgery patients. The other objective of this study was to observe the incidence of diaphragmatic palsy (DP) after off pump CABG (OPCAB) in adult patients. Materials and Methods After approval from the institutional ethics committee and getting informed consents, all consecutive adult patients who underwent cardiac surgery from February 2005 to August 2005, were studied. 30 patients out of 2280 (Off Pump CABG n=1943, cardiac valve surgery n=337) developed diaphragmatic palsy. The diagnosis was suspected on clinico-radiological grounds in patients with respiratory distress and unexplained hypoxemia and /or hypercapnia in the post operative period, with a post operative chest X-ray showing an elevated hemi-diaphragmatic shadow. The diagnosis was subsequently confirmed by ultrasonography. Demonstration of a relatively fixed diaphragm (i.e the diaphragm failed to move or moved paradoxically in a cephalad direction on inspiration. The clinical data and course of the diaphragmatic palsy of these patients were obtained by their hospital records. After confirmation of diaphragmatic palsy, patients were divided in to two groups based on presence or absence of symptoms. Group I - Symptomatic (dyspnoea at rest or minimal exertion, unexplained hypoxemia) Group II - Asymptomatic

Materials and Methods After approval from the institutional ethics committee and getting informed consents, all consecutive adult patients who underwent cardiac surgery from February 2005 to August 2005, were studied. 30 patients out of 2280 (Off Pump CABG n=1943, cardiac valve surgery n=337) developed diaphragmatic palsy. The diagnosis was suspected on clinico-radiological grounds in patients with respiratory distress and unexplained hypoxemia and /or hypercapnia in the post operative period, with a post operative chest X-ray showing an elevated hemi-diaphragmatic shadow. The diagnosis was subsequently confirmed by ultrasonography. Demonstration of a relatively fixed diaphragm (i.e the diaphragm failed to move or moved paradoxically in a cephalad direction on inspiration. The clinical data and course of the diaphragmatic palsy of these patients were obtained by their hospital records. After confirmation of diaphragmatic palsy, patients were divided in to two groups based on presence or absence of symptoms. Group I - Symptomatic (dyspnoea at rest or minimal exertion, unexplained hypoxemia) Group II - Asymptomatic Analgesia in both groups was managed by intravenous Tramadol hydrochloride 50-100 mg thrice daily till the maximum dose of 200 mg per day was reached, to remove the bias of different modes of pain relief between the two groups. In all patients, emphasis was given to the optimization of cardiopulmonary status.

Group II - Asymptomatic Analgesia in both groups was managed by intravenous Tramadol hydrochloride 50-100 mg thrice daily till the maximum dose of 200 mg per day was reached, to remove the bias of different modes of pain relief between the two groups. In all patients, emphasis was given to the optimization of cardiopulmonary status. Physiotherapy protocol All patients were seen by a physiotherapist before surgery, who explained the need to expectorate excess bronchial secretions after surgery. Patients were also taught Huffing, Coughing and deep breathing with sternal support, incentive spirometry and active exercises of the upper and lower limbs. In addition to this treatment, patients in both groups were treated according to the following protocol in three different phases. Phase I (During Intubation): Chest physiotherapy with endotracheal suction every 2 hourly. Phase II (Post extubation): Local expansion (lateral costal and abdominal), three to four consecutive deep breaths were interspersed between periods of quiet breathing. Patients practiced these exercises in sitting or half lying positions. Humidifier, venturi mask, continuous positive airway pressure / Bi-level positive airway pressure were also used as needed. Phase III (Pre discharge): A fixed set of maneuvers like local expansion, diaphragmatic breathing exercises, deep breathing and Incentive spirometry was taught to the patients and were asked to do the same three to four times a day after discharge, for the next three months. Pulmonary function tests (PFT) were done in both the groups immediately before discharge.

euvers like local expansion, diaphragmatic breathing exercises, deep breathing and Incentive spirometry was taught to the patients and were asked to do the same three to four times a day after discharge, for the next three months. Pulmonary function tests (PFT) were done in both the groups immediately before discharge. At three months follow-up, a well-designed questionnaire was distributed to all the patients enrolled in the diaphragmatic palsy group to check the frequency of exercises being performed and to assess symptomatic improvement during three month follow up. Chest X-ray interpretation and ultrasonography were done by the same radiologist (to remove the observer bias) to record the magnitude of improvement of diaphragmatic palsy. Results Out of 30 patients, 14 patients (47%)(CABG n=13, post cardiac valve surgery n=1) were symptomatic (Group I) and 16 patients(53%) (12 CABG n=12, post cardiac valve surgery n=4) were asymptomatic (Group II) [Table 1]. Table 1 Patients' characteristics * Variable Patients with DP (n=30) Patients without DP (n=2250) Symptomatic (n=14) (%) Asymptomatic (n=16) (%) Age, (years) 59.3 ± 12.08 57.4 ± 11.06 56.13 ± 10.13 Male: Female ratio 12:3.8 10:4 9:6 LVEF% 43.5 ± 9.83 46.64 ± 8.65 47.53 ± 7.87 Pre-op pulmonary problem 495 (22%) 4 (28.5) 3 (18.75) * All results are expressed as mean ± SD, LVEF - Left Ventricular Ejection Fraction; n - number of patients, DP-Diaphragmatic palsy

%) Age, (years) 59.3 ± 12.08 57.4 ± 11.06 56.13 ± 10.13 Male: Female ratio 12:3.8 10:4 9:6 LVEF% 43.5 ± 9.83 46.64 ± 8.65 47.53 ± 7.87 Pre-op pulmonary problem 495 (22%) 4 (28.5) 3 (18.75) * All results are expressed as mean ± SD, LVEF - Left Ventricular Ejection Fraction; n - number of patients, DP-Diaphragmatic palsy The overall incidence of diaphragmatic palsy was 1.31% among the studied population. 83% (25 patients) had left sided diaphragmatic palsy and 16% (5 patients) had right sided diaphragmatic palsy. Five patients in Group I and one patient in Group II required postural drainage along with chest percussor to encourage expectoration [Table 2]. Table 2 Clinical variables * Variable Patients without DP (n=30) Patients with DP n=2250 Group I (n=14) (%) Group II (n=16) (%) Mechanical ventilation (hours) mean ± SD 12.2 ± 7.43 22.79 ± 19.51 20 ± 15.56 Pulmonary complication (n) % 57 (2.53%) 5 (35.7) 1 (6.25) Chest Infection (n) % 12 (0.5%) 0 (0) 0 (0) Mortality (n) % 7 (0.31%) 0 (0) 1 (6.25) * DP-Diaphragmatic palsy Pulmonary Complications: The incidence of pulmonary complication (viz. atelectasis, retained secretions) was 36% (n=5) for group I and 6.25% (n=1) for Group II. Oxygenation Parameters: In phase I, oxygenation parameters were same for both the groups. In phase II, parameters were better for Group II than Group I. In phase III again better parameters were recorded for Group II than Group I, although no statistical significance could be established due to small sample size [Table 3]. Table 3 Clinical oxygenation parameters in 3 phases *

Oxygenation Parameters: In phase I, oxygenation parameters were same for both the groups. In phase II, parameters were better for Group II than Group I. In phase III again better parameters were recorded for Group II than Group I, although no statistical significance could be established due to small sample size [Table 3]. Table 3 Clinical oxygenation parameters in 3 phases * Variable Phase I (intubation) Phase II (extubation) Phase III (pre-discharge) Group I (n=14) FiO260% PaO2 mm Hg 156 ± 34.09 136.07 ± 48.74 73.93 ± 19.6 PaCO2 mm Hg 38.64 ± 4.09 40.14 ± 4.38 36.04 ± 2.92 SaO2% 99.5 ± 1.16 98.79 ± 1.97 94.96 ± 3.85 RR 15.21 ± 2.86 20.14 ± 1.61 20.56 ± 2.42 Group II (n=16) FiO2 60% PaO2 mm Hg 150.75 ± 25.62 176.75 ± 55.79 77.03 ± 11.96 PaCO2 mm Hg 38.42 ± 4.48 39.8 ± 2.52 34.19 ± 3.25 SaO2% 99.50 ± 0.89 99.63 ± 0.89 96.24 ± 1.95 RR 16.75 ± 2.82 21.31 ± 2.52 19.63 ± 1.44 • All results are expressed as mean ± SD, (PaO2) Partial pressure of oxygen in arterial blood, (PaCO2) Partial pressure of carbon-di-oxide in arterial blood; (SaO2%) saturation % of oxygen, (RR) respiratory rate. Pulmonary function test: Forced vital capacity (FVC), forced expiratory volume in 1 sec.(FEV1), FEV1 /FVC, peak expiratory flow rate (PEFR), peak inspiratory flow rate (PIFR) were compared and found to be better for Group II [Table 4]. Table 4 Pulmonary function test value comparison *

Variable Phase I (intubation) Phase II (extubation) Phase III (pre-discharge) Group I (n=14) FiO260% PaO2 mm Hg 156 ± 34.09 136.07 ± 48.74 73.93 ± 19.6 PaCO2 mm Hg 38.64 ± 4.09 40.14 ± 4.38 36.04 ± 2.92 SaO2% 99.5 ± 1.16 98.79 ± 1.97 94.96 ± 3.85 RR 15.21 ± 2.86 20.14 ± 1.61 20.56 ± 2.42 Group II (n=16) FiO2 60% PaO2 mm Hg 150.75 ± 25.62 176.75 ± 55.79 77.03 ± 11.96 PaCO2 mm Hg 38.42 ± 4.48 39.8 ± 2.52 34.19 ± 3.25 SaO2% 99.50 ± 0.89 99.63 ± 0.89 96.24 ± 1.95 RR 16.75 ± 2.82 21.31 ± 2.52 19.63 ± 1.44 • All results are expressed as mean ± SD, (PaO2) Partial pressure of oxygen in arterial blood, (PaCO2) Partial pressure of carbon-di-oxide in arterial blood; (SaO2%) saturation % of oxygen, (RR) respiratory rate. Pulmonary function test: Forced vital capacity (FVC), forced expiratory volume in 1 sec.(FEV1), FEV1 /FVC, peak expiratory flow rate (PEFR), peak inspiratory flow rate (PIFR) were compared and found to be better for Group II [Table 4]. Table 4 Pulmonary function test value comparison * Variable Patients without DP n=2250 Patients with DP (n=30) Group I (n=14) Group II (n=16) FVC (% Pred) 62.3 ± 16.28 39 ± 10.5 44.29 ± 8.18 FEV1 (%Pred) 55.7 ± 11.16 44.57 ± 10.9 47.14 ± 9.08 FEV1 /FVC 89.40 ±15.8 121.14±18.9 109.57 ± 5.5 PEFR (% Pred) 68.2 ± 17.1 49.29 ± 21.3 61.8 ± 25.94 PIFR (% Pred) 65.61 ±13.32 47.43 ± 27 52.8 ± 24.5 • DP-Diaphragmatic palsy, • All results are expressed as mean ±SD, • FVC - Forced vital capacity (% Pred), FEV1- forced expiratory volume in 1 sec (% Pred), PEFR - peak expiratory flow rate (% Pred), PIFR - peak inspiratory flow rate (% Pred)

1 49.29 ± 21.3 61.8 ± 25.94 PIFR (% Pred) 65.61 ±13.32 47.43 ± 27 52.8 ± 24.5 • DP-Diaphragmatic palsy, • All results are expressed as mean ±SD, • FVC - Forced vital capacity (% Pred), FEV1- forced expiratory volume in 1 sec (% Pred), PEFR - peak expiratory flow rate (% Pred), PIFR - peak inspiratory flow rate (% Pred) Table 5 reveals comparative analysis of PFT at three time intervals (Preoperative, pre discharge and three months follow-up) Table 5 Pulmonary function test variables in both groups at different time interval PFT variable Group I (n=14) Group II (n=16) Preoperative At discharge 3 month follow up Preoperative At discharge 3 month follow up FVC % pred. 63.2±12.1 39±10.5 54.7±8.68 61.8±9.0 44.2±8.18 57.3±9.16 FEV1 % pred. 58.1±8.69 44.5±10.9 51.8±12.48 56±13.2 47.14±9.08 54.1±8.76 FEV1/FVC 91.93±12.8 121.14±18.9 94.69±11.18 90.61±17.6 109±5.5 94.41±9.21 PEFR % pred 64.1±10.2 49.29±21.3 57.3±18.23 63.4±18.6 61.8±25.9 62.6±21.4 PIFR %pred 61±8.9 47.43±27 54±11.6 64.2±16.3 52.8±24.5 61.3±18.5 Follow-up (After three months): 85% pts (n=12) from Group I and 75% patients (n=12) from Group II performed the exercise regime at home regularly as advised. 64% patients (n=9) from Group I and 25% patients (n=4) from Group II showed complete recovery from diaphragmatic palsy as demonstrated by ultrasonographically. This reveals objective improvement and documents the efficacy of postoperative chest physiotherapy in cases of diaphragmatic palsy. All patients from Group I showed symptomatic improvement and led a normal healthy lifestyle.

Preoperative At discharge 3 month follow up Preoperative At discharge 3 month follow up FVC % pred. 63.2±12.1 39±10.5 54.7±8.68 61.8±9.0 44.2±8.18 57.3±9.16 FEV1 % pred. 58.1±8.69 44.5±10.9 51.8±12.48 56±13.2 47.14±9.08 54.1±8.76 FEV1/FVC 91.93±12.8 121.14±18.9 94.69±11.18 90.61±17.6 109±5.5 94.41±9.21 PEFR % pred 64.1±10.2 49.29±21.3 57.3±18.23 63.4±18.6 61.8±25.9 62.6±21.4 PIFR %pred 61±8.9 47.43±27 54±11.6 64.2±16.3 52.8±24.5 61.3±18.5 Follow-up (After three months): 85% pts (n=12) from Group I and 75% patients (n=12) from Group II performed the exercise regime at home regularly as advised. 64% patients (n=9) from Group I and 25% patients (n=4) from Group II showed complete recovery from diaphragmatic palsy as demonstrated by ultrasonographically. This reveals objective improvement and documents the efficacy of postoperative chest physiotherapy in cases of diaphragmatic palsy. All patients from Group I showed symptomatic improvement and led a normal healthy lifestyle. Discussion In normal adults, diaphragm excursion may contribute 30% to 60% of the total minute ventilation.[6] With unilateral diaphragm palsy, there is decrease of 20% to 30% of vital capacity and maximum voluntary ventilation and a 20% decrease in oxygen uptake on the affected side.[7] Adult patients with diaphragm palsy can generally be weaned from mechanical ventilation because of the compensation from the intercostal muscles or the accessory muscles of respiration.

ecrease of 20% to 30% of vital capacity and maximum voluntary ventilation and a 20% decrease in oxygen uptake on the affected side.[7] Adult patients with diaphragm palsy can generally be weaned from mechanical ventilation because of the compensation from the intercostal muscles or the accessory muscles of respiration. The main cause of diaphragm palsy after adult cardiac surgery is attributed to the topical cooling.[234] Other causes include cutting, detrition, traction, and thermal burns from the electric knife.[8] Some reports have explained the relationship of the use of internal mammary artery (IMA) and postoperative phrenic nerve dysfunction in patients with CABG.[9] The phrenic nerves cross the internal mammary artery anteriorly in 54% of cases and posteriorly in 14%.[10] Phrenic nerve injury can also result from injury to the pericardiophrenic artery, in addition to the direct injury. Phrenic nerve regeneration is estimated at a rate of 1 mm/day.[11] Cohen et al, noted that phrenic nerve recovery occurs at least partially in 75% to 90% of the patients[8] which is similar to our findings. Kuniyoshi et al, observed many patients of diaphragmatic palsy who were absolutely asymptomatic and could be weaned off from the ventilator easily. They considered diaphragmatic palsy as a significant cause of postoperative respiratory dysfunction.

g fast track extubation and expertise of our dedicated team in postoperative cardiac critical care owing to large number of surgeries done per year. Also, early anticipation and all necessary actions to prevent the development of postoperative pulmonary infection contributed to reduced incidence of above complications. Objective improvement in PFT parameters when compared at three time intervals revealed that there was remarkable decline in PFT values in patients with diaphragmatic palsy as compared to preoperative values, but after vigorous chest physiotherapy the PFT values return back to near preoperative values, indicating significant improvement in lung function in both the groups. We did not collect data at the time of discharge and follow-up of patients without diaphragmatic palsy because it was a large group and due to cost and resource considerations. At three months, our study showed improvement in lung function in both the groups, which was attributed to regular physiotherapy exercises. For ethical reasons, it was not possible to include a control group of patients with diaphragmatic palsy who received no physiotherapy treatment. Conversely it was also not considered worthwhile to compare the effects of chest physiotherapy in patients with or without diaphragmatic palsy.

gular physiotherapy exercises. For ethical reasons, it was not possible to include a control group of patients with diaphragmatic palsy who received no physiotherapy treatment. Conversely it was also not considered worthwhile to compare the effects of chest physiotherapy in patients with or without diaphragmatic palsy. Most patients with post-cardiac surgery diaphragmatic dysfunction improves with conservative measure such as chest physiotherapy, prevention and treatment of pneumonia, optimum treatment of underlying pulmonary disease and optimization of cardiovascular / hemodynamic and oxygenation parameters. Same was true for marked and sustained improvement of patients in our study. Conclusion There was subjective as well as objective improvement in functional outcome following diaphragmatic palsy in both the groups. Chest physiotherapy helps to preserve lung function and hasten recovery from diaphragmatic palsy. Our study also emphasizes that ultrasonography is a simple and effective bed side tool in ICU to rapidly diagnose diaphragmatic palsy and hence avoiding cumbersome methods e.g. trans diaphragmatic pressure measurement or fluoroscopy which are also less available in many hospitals. Early diagnosis and prevention of pulmonary complications along with intensive physiotherapy leads to good outcome in patients with diaphragmatic palsy. Based on our observation, a well designed randomized controlled trial is recommended in order to establish the role of chest physiotherapy after post cardiac surgery diaphragmatic palsy. Source of Support: Nil Conflict of Interest: None declared.

Introduction Measurement of arterial blood gas tensions is routinely used to assess gas exchange in patients with acute and chronic respiratory disorders. Arterial blood gas (ABG) sampling represents the gold standard method for acquiring patients' acid-base status. The most common complications associated with arterial puncture are pain, arterial injury, aneurysm formation, hemorrhage, and thrombosis with distal ischaemia. The risks increase with repeated arterial punctures, especially with insertion of a catheter when performed by inexperienced individuals.[1] Additionally, this procedure carries a small but appreciable risk of needle stick injury to health care workers, with the consequent risk of transmission of blood borne viruses such as hepatitis C and human immunodeficiency virus (HIV).[2] In the 1960s, it was proposed that blood gas values could be measured using arterialized earlobe blood samples.[3] Arterialized ear lobe blood gas samplings are easier to obtain and a less invasive way of evaluating acid-base status in intensive care unit. It avoids the risks of arterial punctures. It is based on the assumption that provided sufficient vasodilatation can be achieved locally by means of topical application of a vaso-active cream on the earlobe, the arterialized earlobe oxygen tension resembles the arterial oxygen tension due to convergence of arterial and venous oxygen tension.[4] Techniques for sampling arterialized capillary blood from the finger pulp and the earlobe were first described over two decades ago but, although close agreement between arterial values and earlobe samples has been demonstrated in normal subjects, this technique is not in common usage. The main reasons for this appear to be lack of knowledge of its existence and uncertainty over its accuracy.[5] Initial[367] or more recent[5] studies have concluded that the earlobe method might be accurate enough to replace arterial blood samples for clinical purposes. This opinion is based mainly on positive and strong correlations that have been found between the two methods.

s existence and uncertainty over its accuracy.[5] Initial[367] or more recent[5] studies have concluded that the earlobe method might be accurate enough to replace arterial blood samples for clinical purposes. This opinion is based mainly on positive and strong correlations that have been found between the two methods. However, most investigators have sought correlation using simple regression analysis instead of the method of BLAND and ALTMAN.[8] This approach has probably rendered the conclusion of most studies flawed by statistical bias. In fact, two recent studies using BLAND and ALTMAN[8] analysis have stated that arterialized earlobe PO2 often underestimates arterial PO2, therefore making this method unsuitable for clinical assessment.[910] Several studies have shown good correlation between capillary blood, venous blood, and arterial blood gas values in pediatric intensive care units.[11–13] However, arterialized earlobe oxygen tension often underestimates arterial oxygen tension[4] and is not fully validated in adult patients with acute respiratory failure receiving mechanical ventilation. The purpose of this study was to investigate the correlation between simultaneous arterial blood gas and arterialized earlobe blood samples and to establish whether pH, partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), base excess (BE), and bicarbonate (HCO3-) values of arterialized earlobe blood samples could accurately predict their arterial blood gas analogs for patients with acute respiratory failure treated by mechanical ventilation in an intensive care unit (ICU).

sure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), base excess (BE), and bicarbonate (HCO3-) values of arterialized earlobe blood samples could accurately predict their arterial blood gas analogs for patients with acute respiratory failure treated by mechanical ventilation in an intensive care unit (ICU). Materials and Methods Sixty seven patients with acute respiratory failure who were admitted to a multidisciplinary adult intensive care unit between May 2005 and August 2005 receiving mechanical ventilation, were enrolled in this prospective descriptive study. The study protocol was approved by the local institutional ethics committee, and written informed consent was obtained from each patient or his or her family. Patients with hypotension (systolic blood pressure less than or equal to 90 mm Hg), hypertension (systolic pressure above 140 with a diastolic pressure above 90), hypothermia (axillary temperature <36°C), and hyperthermia (axillary temperature >38°C), severe sepsis, multiorgan failure, or chronic lung disease were excluded from the study. No patient was in cardiovascular shock. Blood samples were drawn simultaneously from the radial artery and the arterialized earlobe of each patient in a sitting position. Blood gases were obtained if the patient needed blood gases for clinical decisions. All patients were receiving mechanical ventilation for 48h or more with a fraction of inspired oxygen (FiO2) of 0.5 or less and positive end-expiratory pressure of 5 cm H2O.

he arterialized earlobe of each patient in a sitting position. Blood gases were obtained if the patient needed blood gases for clinical decisions. All patients were receiving mechanical ventilation for 48h or more with a fraction of inspired oxygen (FiO2) of 0.5 or less and positive end-expiratory pressure of 5 cm H2O. Arterial samples If the patient had an arterial line, they were used for blood sampling. After withdrawing 5 ml of blood from the lines with a non-heparinised syringe, 1 ml of arterial blood was obtained with another similar syringe and transferred, as soon as possible, to a heparinized 0.75 ml capillary tube. If the patient did not have an arterial line, arterial punctures with aseptic precautions were carried out, and blood was transferred directly into an identical capillary tube. Earlobe samples After aseptic cleaning, the lateral distal portion of the earlobe was punctured with a scalpel blade (surgical blade No. 11, Troge®Blades, Hamburge, Germany) and blood gases samples were obtained by “contact” with the capillary tube's tip. A short manual massage was necessary in some instances. Two sides of the tube were closed by fingers to avoid air bubbles. All samples were obtained by the investigators. Arterialized samples were collected in heparinized glass capillaries (Modulohm A/S, Vasekaer, Herlev, Denmark) and immediately introduced into the blood gas analyzer (AVL Compact 3, Roche Diagnostics GmbH, Mannheim, Germany) followed within 2 min by arterial samples. pH, PO2, PCO2, BE, and HCO3 values were recorded.

s. Arterialized samples were collected in heparinized glass capillaries (Modulohm A/S, Vasekaer, Herlev, Denmark) and immediately introduced into the blood gas analyzer (AVL Compact 3, Roche Diagnostics GmbH, Mannheim, Germany) followed within 2 min by arterial samples. pH, PO2, PCO2, BE, and HCO3 values were recorded. Statistical methods The statistical analysis for assessing agreement between arterial and arterialized blood gases was performed according to BLAND and ALTMAN.[8] SPSS.11.5 for Windows was used for statistical analysis. Pearson correlation coefficients were determined for correlation and regression equations and mean percentage-difference equations were derived to predict arterial pH, PCO2, BE, and HCO3 - values from their arterialized ear lobe blood gas analogs. For all analyses, P<0.05 was considered statistically significant.

ysis. Pearson correlation coefficients were determined for correlation and regression equations and mean percentage-difference equations were derived to predict arterial pH, PCO2, BE, and HCO3 - values from their arterialized ear lobe blood gas analogs. For all analyses, P<0.05 was considered statistically significant. Results Sixty-seven consecutive adult patients were studied. Blood samples were drawn simultaneously from arterialized earlobe and radial artery. Admission diagnoses included head trauma, abdominal mass, gastrointestinal bleeding, lung contusion, bowel obstruction, myasthenia gravis, epilepsy, pneumonia, meningitis, diabetic ketoacidosis, stroke, brain tumor, lung cancer, and intoxication [Table 1]. The mean (SD) age of the patients was 47.57 (19.51). Fifty (74.6%) were males and 17 (25.4%) were females. No complication in the drawing of blood samples was observed with either method. pH, PCO2, BE, and HCO3 were all significantly correlated in ABG and earlobe samples [Tables 2 and 3]. The range of arterial PO2 values was 6.8–19.5 kPa (51.1–146.5mmHg), mean 11.3 kPa (84.77mmHg). The range and mean of arterial PCO2 values was 3.01–6.5 kPa (22.6–48.6 mmHg) and 4.7 kPa (35.08 mmHg) respectively. The relationships between arterial and earlobe samples for PO2 and PCO2 are shown in [Figure 1a and b]. The correlation coefficients were 0.734 (P<0.0001) and 0.956 (P<0.0001) respectively. Despite this highly significant correlation, regression lines were slightly different from lines of identity, particularly for PO2. In Figure 2a and b, differences between the two methods (arterial - arterialized values) were plotted against means of arterial and arterialized PO2PO2 or PCO2. The mean (bias) ±SD and the range of the differences, as well as the 95% confidence intervals for the lower and upper limit of agreement were reported in Table 4. Arterialized earlobe PO2 was lower than arterial PO2 in most cases, and the difference increased as the arterial PO2 increased. These results show that the limits of agreement for PO2 were wide, reveal a lack of agreement between the two methods. For PCO2, on the other hand, the mean difference between the two methods was close to zero, and the limits of agreement were narrower.

cases, and the difference increased as the arterial PO2 increased. These results show that the limits of agreement for PO2 were wide, reveal a lack of agreement between the two methods. For PCO2, on the other hand, the mean difference between the two methods was close to zero, and the limits of agreement were narrower. Regression equations for prediction of pH, PCO2,, BE, and HCO3 - values were: arterial pH (pHa) = 1.81+ 0.76 × earlobe pH (pHe) [r = 0.791, P < 0.001]; PCO2, = 1.224+ 1.06 × earlobe PCO2, (PeCO2) [r = 0.956, P < 0.001]; arterial BE (BEa) = 1.14+ 0.95 × earlobe BE (BEe) [r= 0.894, P < 0.001], and arterial HCO3- (HCO3-a) = 1.41+ earlobe HCO3 (HCO3-e) [r = 0.874, P < 0.001]. The predicted ABG values from the mean percentage-difference equations were derived as follows: pHa = pHe × 1.001; PCO2, = PeCO2 × 0.33; BEa = BEe × 0.57; and HCO3-a = HCO3-e × 1.06. Table 1 Clinical diagnoses of the patients Diagnosis n (%) Head trauma 27 (40) Stroke 11 (16.5) Pneumonia 8 (12) Epilepsy 4 (6) Gastrointestinal bleeding 3 (4.5) Bowel obstruction 3 (4.5) Abdominal mass 2 (3) Lung contusion 2 (3) Meningitis 2 (3) Myasthenia gravis 1 (1.5) Diabetic ketoacidosis 1 (1.5) Brain tumor 1 (1.5) Lung cancer 1 (1.5) Intoxication 1 (1.5) Total 67 (100) Table 2 Correlation of arterial and arterialized earlobe blood samples for pH, PO2, PCO2, BE, and HCO3 in patients pH PO2 PCO2 BE HCO3

Diagnosis n (%) Head trauma 27 (40) Stroke 11 (16.5) Pneumonia 8 (12) Epilepsy 4 (6) Gastrointestinal bleeding 3 (4.5) Bowel obstruction 3 (4.5) Abdominal mass 2 (3) Lung contusion 2 (3) Meningitis 2 (3) Myasthenia gravis 1 (1.5) Diabetic ketoacidosis 1 (1.5) Brain tumor 1 (1.5) Lung cancer 1 (1.5) Intoxication 1 (1.5) Total 67 (100) Table 2 Correlation of arterial and arterialized earlobe blood samples for pH, PO2, PCO2, BE, and HCO3 in patients pH PO2 PCO2 BE HCO3 Arterial Earlobe Arterial Earlobe Arterial Earlobe Arterial Earlobe Arterial Earlobe Arterial 1.000 0.791 1.000 0.734 1.000 0.774 1.000 0.894 1.000 0.874 P<0.001 P <0.001 P <0.001 P <0.001 P <0.001 Earlobe 0.791 1.000 0.734 1.000 0.774 1.000 0.894 1.000 0.874 1.000 P<0.001 P <0.001 P <0.001 P <0.001 P <0.001 Table 3 Regression of arterial blood gas values on arterialized earlobe blood samples values Arterial Earlobe Constant (SE) β (SE) R2 SE of estimate pH 1.81 (0.537) 0.757 (0.073) 0.626 0.029 PCO2 11.438 (2.483) 0.703 (0.071) 0.599 5.271 PO2 10.522 (9.877) 1.093 (0.126) 0.538 16.199 BE 1.138 (0.317) 0.952 (0.059) 0.800 2.183 HCO3 1.406 (1.438) 0.996 (0.069) 0.764 2.644 Table 4 Limits of agreement of the differences in PO2 and PCO2 values between arterial and arterialized earlobe blood samples ΔPO2 ΔPCO2

Arterial Earlobe Constant (SE) β (SE) R2 SE of estimate pH 1.81 (0.537) 0.757 (0.073) 0.626 0.029 PCO2 11.438 (2.483) 0.703 (0.071) 0.599 5.271 PO2 10.522 (9.877) 1.093 (0.126) 0.538 16.199 BE 1.138 (0.317) 0.952 (0.059) 0.800 2.183 HCO3 1.406 (1.438) 0.996 (0.069) 0.764 2.644 Table 4 Limits of agreement of the differences in PO2 and PCO2 values between arterial and arterialized earlobe blood samples ΔPO2 ΔPCO2 kPa mmHg kPa mmHg Mean±SD 1.02±2.15 7.7±16.14 0.19±0.78 1.45±5.88 Range 0.04-6.32 0.3-47.4 -3.52-0.32 -26.5-2.4 95% CI of mean+ 2SD 3.78-6.89 28.35-51.61 1.37-2.15 10.33-16.09 mean - 2SD -4.83− -1.68 -36.21− -12.59 -1.77− -0.99 -13.19− -7.43 ΔPO2: Difference in partial pressure of oxygen (arterial-arterialized); ΔPCO2: Difference in partial pressure of carbon dioxide (arterial-arterialized). 95% CI: 95% confidence interval. (1 mmHg=133.32 Pa) Figure 1 Correlation between radial artery and and arterialized earlobe blood gas, a) Partial pressure of oxygen (PO2) values, b) Partial pressure of carbon dioxide (PCO2) values …………., line of identity: ———— regression lines Discussion Acid-base analysis is essential for management of patients in ICU, yielding valuable information about a variety of disease processes.[11214] Non-invasive methods, such as pulse oximetry, transcutaneous monitoring of oxygen and carbon dioxide, and end tidal carbon dioxide have been proven to be useful,[1] but they do not give information about pH, PO2, BE and bicarbonate.

ents in ICU, yielding valuable information about a variety of disease processes.[11214] Non-invasive methods, such as pulse oximetry, transcutaneous monitoring of oxygen and carbon dioxide, and end tidal carbon dioxide have been proven to be useful,[1] but they do not give information about pH, PO2, BE and bicarbonate. Arterial blood gases are frequently determined in the ICU. This is, however, an invasive way of monitoring blood gas and there are complications, mostly local hematoma related to arterial puncture. The procedure itself is technically difficult and painful. Arterial lines are usually placed in unstable patients in the ICU who need close monitoring of PO2. When an arterial line is not in place, arterial or venous blood gas (VBG) values continue to be obtained and used for clinical monitoring and management decisions. Earlobe blood gas sampling is a less invasive way of evaluating acid-base status in a well perfused patient. If a blood gas value determined by earlobe samples could be used to show patients' acid-base status and guide their management with the same accuracy as arterial sampling, this would be preferable because of ease of blood sample collection. For many years, clinicians have been looking for alternatives to ABG sampling in both children and adults, and studies have investigated ABG, VBG, and capillary (CBG) blood gas samples and the correlation between the values.[15–17]

Earlobe blood gas sampling is a less invasive way of evaluating acid-base status in a well perfused patient. If a blood gas value determined by earlobe samples could be used to show patients' acid-base status and guide their management with the same accuracy as arterial sampling, this would be preferable because of ease of blood sample collection. For many years, clinicians have been looking for alternatives to ABG sampling in both children and adults, and studies have investigated ABG, VBG, and capillary (CBG) blood gas samples and the correlation between the values.[15–17] Numerous studies published many years ago concluded that the method using arterialized earlobe blood for PO2 and PCO2 analysis was accurate enough to replace arterial blood samples for clinical purposes.[36718–20] However, the validity of this method has been discussed in two studies,[910] showing with the analysis of BLAND and ALTMAN,[8] PO2 was usually lower in earlobe than in arterial blood, and that the limits of agreement were wide between the two methods. Studies comparing ABG and CBG, ABG and VBG samples in diabetic ketoacidosis, and ABG–CBG blood gases values in stable pediatric intensive care unit patients have shown good correlation among ABG, VBG, and CBG samples.[13] However, there have been no studies comparing simultaneously obtained ABG and earlobe samplings in stable adult ICU patients treated by mechanical ventilation.

c ketoacidosis, and ABG–CBG blood gases values in stable pediatric intensive care unit patients have shown good correlation among ABG, VBG, and CBG samples.[13] However, there have been no studies comparing simultaneously obtained ABG and earlobe samplings in stable adult ICU patients treated by mechanical ventilation. We studied sixty-seven simultaneously obtained arterial blood gas and arterialized earlobe blood samples of patients and showed pH, PCO2, BE, HCO3 were all correlated in arterial and earlobe blood gases in normotensive and normothermic patients. Although there was a significant correlation for PO2 in these patients, it was lower. Sauty et al, compared arterial and arterialized earlobe blood samples in 115 consecutive adult patients and concluded that, in adult patients, arterialized earlobe blood PO2 is not a reliable mirror of arterial PO2.[9] The main cause of underestimation of arterial PO2 in earlobe samples is insufficient arterialization of blood, corresponding to a certain venous admixture. The effect of a given venous admixture in earlobe blood depends on the arterio-venous PO2 difference: the larger the arterio-venous PO2 difference, the wider the discrepancy between earlobe and arterial PO2. This is one likely reason for the unreliable PO2 values measured in arterialized earlobe blood in patients breathing 100% oxygen.[192122]

ous admixture in earlobe blood depends on the arterio-venous PO2 difference: the larger the arterio-venous PO2 difference, the wider the discrepancy between earlobe and arterial PO2. This is one likely reason for the unreliable PO2 values measured in arterialized earlobe blood in patients breathing 100% oxygen.[192122] Because the arterio-venous PO2 difference is large in subjects with normal arterial PO2, a small venous admixture in earlobe blood will result in a greater discrepancy between earlobe and arterial PO2. Our data supports this observation. It must be emphasized that in our study, there was no patient with severe sepsis, multiorgan failure, cardiovascular shock, or chronic lung disease because inclusion of these patients might have caused poorer correlation between ear and arterial PO2values due to venous admixture. Indeed, [Figure 2a] shows that arterial PO2, when in the normal range, was often markedly underestimated by the earlobe sample. Interestingly and despite fewer normal PO2 values, the study of PITKIN et al,[5] also showed a trend towards increased difference between arterial and arterialized PO2 with increasing mean PO2 values. Accordingly, and as reported by the same authors, we observed a better agreement between the two methods for arterial PO2 values lower than 8.0 kPa (60 mmHg), where the effect of venous admixture is smaller.

owed a trend towards increased difference between arterial and arterialized PO2 with increasing mean PO2 values. Accordingly, and as reported by the same authors, we observed a better agreement between the two methods for arterial PO2 values lower than 8.0 kPa (60 mmHg), where the effect of venous admixture is smaller. Figure 2 a) Differences in arterial –arterialized partial pressure of oxygen values (ΔPO2) plotted against mean of arterial and arterialized PO2 values. b) Differences in arterial-arterialized partial pressure of carbon dioxide values (ΔPCO2) plotted against mean of arterial and arterialized PCO2 values On the other hand, there was a good agreement between earlobe and arterial values of PCO2, as previously reported.[5] This reflects the insignificant effect of venous admixture, due to the comparatively smaller arterio-venous PCO2 difference. The usefulness of each method should be weighed according to its advantages and inconveniences. The advocated advantages of the earlobe method are that it is safe and can be performed by non-medical staff.[23] However, as the collection of an earlobe blood sample must be fully aseptic,[6] the method requires trained personnel. Although complications of arterial punctures have been described,[24] complications of radial arterial punctures are extremely low and in our experience none were observed in the present experiment.

The usefulness of each method should be weighed according to its advantages and inconveniences. The advocated advantages of the earlobe method are that it is safe and can be performed by non-medical staff.[23] However, as the collection of an earlobe blood sample must be fully aseptic,[6] the method requires trained personnel. Although complications of arterial punctures have been described,[24] complications of radial arterial punctures are extremely low and in our experience none were observed in the present experiment. In conclusion, we showed a good correlation in pH, PCO2, BE, and HCO3 between simultaneous samples of arterialized earlobe and arterial blood in normotensive and normothermic patients receiving mechanical ventilation. So, earlobe blood gas measurements may be useful alternatives to arterial blood gas samples for critically ill patients who do not require regular continuous blood pressure measurements and close monitoring of arterial PO2 measurements. We do not recommend arterialized earlobe blood samples for determining PO2 of arterial blood gas samples. Source of Support: Nil Conflict of Interest: None declared.

Introduction Multidrug resistant (MDR) Gram-negative bacterial sepsis poses an increasingly daunting challenge in the critical care setting worldwide.[1–2] Especially the lactose nonfermenters Pseudomonas and Acinetobacter, which are opportunistic niche pathogens affecting primarily the critically ill and the immunocompromised, ubiquitous in the hospital environment and notorious for developing multiresistance to available antibiotics, are making management of sepsis not only difficult but also very expensive even for the industrialized countries.[3–5] Hence, the worldwide interest in the polymyxins, which have shown consistent efficacy against aerobic Gram-negative bacilli including Pseudomonas and Acinetobacter by their detergent-like cell-membrane-disrupting and antiendotoxin actions,[6–7] yet their use has been restricted as the last resort in cases of clinical or microbiologic resistance to other available antibiotics, owing to the reports of nephrotoxicity and neurotoxicity.[8–9] We reviewed our recent experience in the use of intravenous polymyxin B against MDR Gram-negative organisms with particular attention to its nephrotoxicity in the critical care unit in the 350-bed tertiary-level multispecialty Apollo-Gleneagles Hospital situated in Kolkata.

Introduction Multidrug resistant (MDR) Gram-negative bacterial sepsis poses an increasingly daunting challenge in the critical care setting worldwide.[1–2] Especially the lactose nonfermenters Pseudomonas and Acinetobacter, which are opportunistic niche pathogens affecting primarily the critically ill and the immunocompromised, ubiquitous in the hospital environment and notorious for developing multiresistance to available antibiotics, are making management of sepsis not only difficult but also very expensive even for the industrialized countries.[3–5] Hence, the worldwide interest in the polymyxins, which have shown consistent efficacy against aerobic Gram-negative bacilli including Pseudomonas and Acinetobacter by their detergent-like cell-membrane-disrupting and antiendotoxin actions,[6–7] yet their use has been restricted as the last resort in cases of clinical or microbiologic resistance to other available antibiotics, owing to the reports of nephrotoxicity and neurotoxicity.[8–9] We reviewed our recent experience in the use of intravenous polymyxin B against MDR Gram-negative organisms with particular attention to its nephrotoxicity in the critical care unit in the 350-bed tertiary-level multispecialty Apollo-Gleneagles Hospital situated in Kolkata. Materials and Methods Forty-five patients were identified from pharmacy records who had received more than two doses of intravenous polymyxin B during the period March 2006 and June 2007. The medical records were reviewed retrospectively for demographic details, underlying diseases, presence, severity and source of sepsis, organisms isolated and their antibiotic sensitivity, length of stay in the ICU, dose, frequency and duration of polymyxin B, other antibiotics used, mechanical ventilation and creatinine levels, development of any new rash or neurological problems, and clinical outcomes.

seases, presence, severity and source of sepsis, organisms isolated and their antibiotic sensitivity, length of stay in the ICU, dose, frequency and duration of polymyxin B, other antibiotics used, mechanical ventilation and creatinine levels, development of any new rash or neurological problems, and clinical outcomes. The main outcomes of interest included resolution of sepsis, as well as microbiological response to polymyxin B, survival and renal failure temporally linked to the use of polymyxin B. Sepsis was identified by the presence of systemic inflammatory response parameters like temperature, tachycardia, tachypnoea, leucocytosis, and/or leucopenia. Severe sepsis was defined as the presence of organ dysfunction and septic shock as hypotension unresponsive to fluids.[10] Lower respiratory tract secretions were considered pathological if these systemic signs were associated with radiological changes in chest X-ray. Renal failure was defined as acute increase in the serum creatinine level by >0.5 mg/dL above the baseline over 24 hours. Baseline serum creatinine was defined as the most recent value available at the start of the treatment with polymyxin B. Results As detailed in Table 1, the study population comprised 45 critically ill patients with the mean age of the patients being 53 years and 56% being males. Mean duration of stay in the ICU was 38 days (range 6–92 days). Table 1 Demography, clinical, and microbiologic details of 45 patients receiving polymyxin B

Sepsis was identified by the presence of systemic inflammatory response parameters like temperature, tachycardia, tachypnoea, leucocytosis, and/or leucopenia. Severe sepsis was defined as the presence of organ dysfunction and septic shock as hypotension unresponsive to fluids.[10] Lower respiratory tract secretions were considered pathological if these systemic signs were associated with radiological changes in chest X-ray. Renal failure was defined as acute increase in the serum creatinine level by >0.5 mg/dL above the baseline over 24 hours. Baseline serum creatinine was defined as the most recent value available at the start of the treatment with polymyxin B. Results As detailed in Table 1, the study population comprised 45 critically ill patients with the mean age of the patients being 53 years and 56% being males. Mean duration of stay in the ICU was 38 days (range 6–92 days). Table 1 Demography, clinical, and microbiologic details of 45 patients receiving polymyxin B Details Values* Age (years) Mean 53 Range 19–82 Males 25 (56) Sites of isolation of MDR organisms LRT 22 (49) Surgical wound 10 (22) Abdomen 7 (16) Blood 5 (11) Pleural fluid 4 (9) Urine 3 (7) Burn wound 2 (5) Organisms Pseudomonas 20 (44) Acinetobacter 19 (42) Pseudomonas + Acinetobacter 2 (4) None identified 4 (8) Mechanical Ventilation 38 (84) Septic shock at the start of Polymyxin B 19 (42) Comorbidities Malignancy 13 (29) Diabetes 6 (13) Cardiac 5 (11) CRF 4 (9) COPD 4 (9) ICH 3 (7) Burns 2 (4) Recent CABG 2 (4) Pancreatitis 2 (4) AIDP 2 (4) Pemphigus vulgaris, Polytrauma, 1each (2) Bomb blast inj, Corrosive esophagitis * Values expressed as numbers (percentages) of Patients; LRT, lower respiratory tract; MDR, multidrug resistant; ICH, intracranial hemorrhage; CRF, chronic renal failure; CABG, coronary artery bypass grafting; AIDP, acute inflammatory demyelinating polyneuropathy

ytrauma, 1each (2) Bomb blast inj, Corrosive esophagitis * Values expressed as numbers (percentages) of Patients; LRT, lower respiratory tract; MDR, multidrug resistant; ICH, intracranial hemorrhage; CRF, chronic renal failure; CABG, coronary artery bypass grafting; AIDP, acute inflammatory demyelinating polyneuropathy Malignancy was the most prevalent underlying comorbidity (29%) followed by diabetes mellitus (13%) and chronic renal failure (9%). Polymyxin B was used in severe sepsis with microbiological or clinical refractoriness to carbapenem antibiotics. Forty-two percent of the subjects were in septic shock and 84% of patients were receiving mechanical ventilation at the time of initiation of polymyxin B. Dose of 15,000 to 25,000 units/kg of ideal body weight in two divided doses per day was used. Total daily dose was reduced by 25% and 50% when the calculated creatinine clearance was 20–50 mL/min and <20 mL/min, respectively. The mean total daily dose used was 1.2 × 106 units and the mean duration 7.6 days. The mean number of days between ICU admission and start of polymyxin was 22 days. All patients received carbapenems, 90% received piperacillin–tazobactam or cefoperazone–sulbactam combination before polymyxin was used. All the patients received other potentially nephrotoxic agents like NSAIDs and diuretics. Fifty-two percent received Amikacin and 16% received Vancomycin [Table 2]. Table 2 Antibiotics use

All patients received carbapenems, 90% received piperacillin–tazobactam or cefoperazone–sulbactam combination before polymyxin was used. All the patients received other potentially nephrotoxic agents like NSAIDs and diuretics. Fifty-two percent received Amikacin and 16% received Vancomycin [Table 2]. Table 2 Antibiotics use Antibiotics Values Total daily dose of polymyxin B (106 Units) Mean 1.2 Range 1–1.5 Duration of Polymyxin B use (days) Mean 7.6 Range 2–32 Additional Antibiotics Cephalosporins 42 (93) Amoxicillin-Sulbactam 40 (89) Carbapenems 35 (78) Piperacillin-Tazobactam 30 (67) Aminoglycosides 28 (62) Metronidazole 24 (53) Fluoroquinolones 20 (44) Aztreonam 20 (44) Macrolides 14 (31) Fluconazole 13 (29) Vancomycin 7 (16) Linezolid, Tetracyclines, Chloram-phenicol, <5 (11) each Clindamycin, Rifampin, Acyclovir, AmphotericinB, * Values indicate numbers (Percentages) of patients In our study, the MDR organisms were most commonly isolated from the lower respiratory tract (49%) and surgical wounds (22%). Pseudomonas was isolated in 22 patients and Acinetobacter in 21. Clinical outcomes: Overall mortality was 52% and 40% of patients died or had to be discharged before an eight-day course. Among patients who received at least eight days of intravenous polymyxin B, 67% patients with initial septic shock and 62% with severe sepsis survived and recovered.

In our study, the MDR organisms were most commonly isolated from the lower respiratory tract (49%) and surgical wounds (22%). Pseudomonas was isolated in 22 patients and Acinetobacter in 21. Clinical outcomes: Overall mortality was 52% and 40% of patients died or had to be discharged before an eight-day course. Among patients who received at least eight days of intravenous polymyxin B, 67% patients with initial septic shock and 62% with severe sepsis survived and recovered. Acute renal failure developed in only two of the 45 patients treated with polymyxin B (4%). Two patients, a 69-year-old man with esophageal cancer and a 36-year-old lady with vasculitis-induced intracranial bleed developed acute renal failure following treatment with polymyxin B. Acute renal failure developed on day 5 of polymyxin B therapy in the former patient and on day 3 in the later. They died respectively two and nine days after developing acute renal impairment. The mean dose of polymyxin B used was 0.85 × 106 units. The mean rise in creatinine level was 0.6 compared to negative 0.1 in patients without renal failure. None of the four patients with background chronic renal impairment developed any acute deterioration after receiving polymyxin B at mean dose of 1.38 × 106 units.

The mean dose of polymyxin B used was 0.85 × 106 units. The mean rise in creatinine level was 0.6 compared to negative 0.1 in patients without renal failure. None of the four patients with background chronic renal impairment developed any acute deterioration after receiving polymyxin B at mean dose of 1.38 × 106 units. Microbiologic outcome: Repeat microbiologic culture was obtained in 55% of patients. Thirty-two percent of them cleared the target MDR organism, 56% revealed either a different species or the same organism with sensitivity toward safer broad-spectrum antibiotics. Among patients who failed to clear the target organism, 72% had anatomically uncontrollable surgical site infection and 20% had nosocomial pneumonia. Survival among the patients who received at least eight days of therapy was 67% in the septic shock group and 62% in the nonseptic shock group. Discussion Our study is unique as there is very limited data on the efficacy and safety of polymyxin B in critically ill patients with severe sepsis and septic shock. Polymyxin E, that is, colistin has a large body of evidence,[12–18] studies involving polymyxin B[19–20] are limited and our study has the largest number of patients. All patients in our study were critically ill and a majority had severe sepsis and septic shock at time of starting therapy with polymyxin B pointing toward a good efficacy in this group of patients.

y of evidence,[12–18] studies involving polymyxin B[19–20] are limited and our study has the largest number of patients. All patients in our study were critically ill and a majority had severe sepsis and septic shock at time of starting therapy with polymyxin B pointing toward a good efficacy in this group of patients. The relative slow development of safe and new antibiotics[21] has prompted renewed interest in older agents like the polymyxins which were discontinued from clinical practice due to early reports of nephrotoxicity. However, the absence of a unanimous definition of acute renal failure until recently and the significant variation in the incidence of nephrotoxicity shown by Falagas et al, in their review of literature on polymyxins from 1960–2005[13] call for critical enquiry into the issue. Reported incidence of nephrotoxicity in the earlier literature[22–25] varied widely between 20–25% and up to 100% of recipients. Recent Western estimates on nephrotoxicity have been much more moderate with 10–14%[1920] for polymyxin B and 24% for colistimethate sodium.[13] Sepsis itself has adverse effects on renal function[28] and hence becomes a confounding factor in assessing the nephrotoxicity of polymyxins when therapy is initiated as a last resort in advanced stage of septicemia.

y have been much more moderate with 10–14%[1920] for polymyxin B and 24% for colistimethate sodium.[13] Sepsis itself has adverse effects on renal function[28] and hence becomes a confounding factor in assessing the nephrotoxicity of polymyxins when therapy is initiated as a last resort in advanced stage of septicemia. Nosocomial sepsis with septic shock has a very high mortality and an acceptable clinical and microbiologic improvement was obtained with polymyxin B in our study. Overall mortality was 52% in our study. Forty-two percent of patients were in septic shock before initiation of polymyxin B. Polymyxin B was started after results of cultures were obtained in most of the patients with sepsis. Late use of polymyxin B might have blunted its efficacy as definite prognostic advantage is derived with early use of appropriate antibiotics in sepsis.[27] Previous studies with polymyxin B have shown mortality between 20–48%. Mortality in respiratory tract infections treated with polymyxin B[19] is about 48%, and in the study published by Ouderkirk et al,[20] the overall mortality was 20%. However, data as to number of patients in shock is not available, so comparative conclusions on efficacy is difficult. Microbiologic response with polymyxin B in our study is also comparable to the efficacy reported in the study by Ouderkirk.

in the study published by Ouderkirk et al,[20] the overall mortality was 20%. However, data as to number of patients in shock is not available, so comparative conclusions on efficacy is difficult. Microbiologic response with polymyxin B in our study is also comparable to the efficacy reported in the study by Ouderkirk. Our limitation is the lack of a comparative cohort treated with other antibiotics. The retrospective nature of this study is also a drawback. Hence, as the stigmata of nephrotoxicity associated with the use of polymyxin B is being questioned worldwide, we need to consider it early in severe nosocomial sepsis where MDR organisms are suspected, with careful monitoring of renal function. Source of Support: Nil Conflict of Interest: None declared.

Introduction Acute renal failure is a frequent complication in critically ill patients and carries a mortality of 50 to 70%.[1] The traditionally held belief has been that kidney failure does not kill on its own as long as complications such as hyperkalaemia, acidosis and volume overload are prevented. There is evidence to suggest that this may not always be the case. We know today that acute renal failure in the critical care setting may be an independent predictor of mortality.[23] The management of acute renal failure in the setting of multi-organ failure is considerably different from that of renal failure as a single organ failure (e.g.; due to nephrotoxic drugs). The traditional criteria for initiating dialysis only in the face of diuretic resistant volume overload, metabolic acidosis or hyperkalaemia are largely unsuited to the management of acute renal failure in modern intensive care practice. There is strong evidence to suggest that early and more intense renal replacement therapy (RRT) can result in improved survival in the critically ill patient.[45] Although a recent trial did not show superiority of intensive RRT compared with more conventional treatments, continuous renal replacement therapy (CRRT) and 3 days per week of conventional haemodialysis were combined in one arm, making the results difficult to interpret.[6] This review focuses on current concepts in defining acute renal failure, its optimal management in the intensive care setting and the available evidence in regard to commonly employed modalities of RRT.

3 days per week of conventional haemodialysis were combined in one arm, making the results difficult to interpret.[6] This review focuses on current concepts in defining acute renal failure, its optimal management in the intensive care setting and the available evidence in regard to commonly employed modalities of RRT. The “RIFLE” criteria The Acute Dialysis Quality Initiative (ADQI) has put forward a new classification for stratification of acute renal dysfunction.[7] This classification is meant to provide a uniform definition for Acute Kidney Injury similar to the consensus criteria for SIRS and ALI / ARDS. The severity of acute kidney injury increases from class “R” to “E” [Table 1]. Worsening kidney injury by the RIFLE criteria has been shown to increase mortality.[8] Table 1 The RIFLE criteria for classification of Acute Kidney Injury

The “RIFLE” criteria The Acute Dialysis Quality Initiative (ADQI) has put forward a new classification for stratification of acute renal dysfunction.[7] This classification is meant to provide a uniform definition for Acute Kidney Injury similar to the consensus criteria for SIRS and ALI / ARDS. The severity of acute kidney injury increases from class “R” to “E” [Table 1]. Worsening kidney injury by the RIFLE criteria has been shown to increase mortality.[8] Table 1 The RIFLE criteria for classification of Acute Kidney Injury Class GFR criteria Urine output criteria Risk Creatinine × 1.5 or GFR decrease > 25% Urine output < 0.5 mls/kg × 6 hours Injury Creatinine × 2 or GFR decrease > 50% Urine output < 0.5 mls/kg × 12 hours Failure Creatinine × 3 or GFR decrease > 75%, creatinine > 4.0 mg/dl or acute rise of > 0.5 mg/dl Urine output < 0.3 mls/kg × 24 hours or anuria × 12 hours Loss Complete loss of renal function for > 4 weeks End Stage > 12 weeks Renal Disease When to initiate RRT in the ICU Conventional criteria for initiation of RRT include volume overload, metabolic acidosis, hyperkalaemia, uraemic encephalopathy, pericarditis, etc. These are clearly appropriate triggers to initiate therapy in stable patients with renal failure presenting as a single organ failure. However, in sick patients with multiorgan failure, RRT should probably be begun much earlier; however, the exact timing of initiation of therapy depends on individual clinical circumstances. In haemodynamically unstable, oliguric patients, it will obviously be difficult or impossible to administer fluid resuscitation to meet their requirements if RRT and appropriate volumes of fluid removal cannot be employed. Provision of nutritional support in a highly catabolic state would also be facilitated if early RRT is initiated. However, survival benefit with the use of early RRT has not been clearly demonstrated. Bouman et al. randomised 106 patients with AKI into 3 arms-early high volume, early low volume and late low volume haemofiltration.[9] The early group received treatment for urine output < 30 mls/hr for 6 hours and creatinine clearance < 20 mls/mt; while the late group received treatment if plasma urea level was more than 40 mg/dl, K more than 6.5 and severe pulmonary oedema. There was no difference in 28 day survival or renal recovery between the groups. However, the small sample size was not powered to demonstrate a survival benefit.

nine clearance < 20 mls/mt; while the late group received treatment if plasma urea level was more than 40 mg/dl, K more than 6.5 and severe pulmonary oedema. There was no difference in 28 day survival or renal recovery between the groups. However, the small sample size was not powered to demonstrate a survival benefit. Dialysis modalities Intermittent haemodialysis (IHD) This has been the conventional mode of renal replacement therapy. By this method, solute clearance takes place by diffusion across a semi-permeable membrane. Blood is allowed to pass through a bundle of hollow fibres, surrounded by dialysate fluid. The dialysate fluid typically has a pH and electrolyte compostion similar to plasma and runs opposite to the direction of blood flow on the outside of the fibres. Molecules with a higher concentration in the blood diffuse through the membrane in to the dialysate fluid. The rate of transfer depends on the concentration gradient, the molecular size and the permeability of the membrane. Membranes are designed to limit the size of the molecules that can be transferred across. This is to prevent the movement of higher molecular weight solutes such as proteins and peptides.

ialysate fluid. The rate of transfer depends on the concentration gradient, the molecular size and the permeability of the membrane. Membranes are designed to limit the size of the molecules that can be transferred across. This is to prevent the movement of higher molecular weight solutes such as proteins and peptides. IHD is initiated with a blood flow rate of 150 to 200 mls/mt and increased gradually, up to 500 mls/mt. The dialysate flow rate is usually set around 200 to 300 mls/mt to start with, up to a maximum of 500 mls/mt. Increasing blood and dialysate flow rates will increase clearance, but the increase is not proportional to the rise in flow rates. In critically ill patients, hypotension is common at the initiation of IHD. Haemodynamic instability may be attenuated by starting with low blood and dialysate flows and titrating upwards as tolerated. IHD is typically done for about four hours, 3 to 4 times a week.

crease is not proportional to the rise in flow rates. In critically ill patients, hypotension is common at the initiation of IHD. Haemodynamic instability may be attenuated by starting with low blood and dialysate flows and titrating upwards as tolerated. IHD is typically done for about four hours, 3 to 4 times a week. IHD, practiced in the manner described is very efficient and safe in the patient with end stage renal disease. However, several problems may arise when this modality is applied to the critically ill patient in multi-organ failure. Hypotension is a commonly encountered problem with IHD; this can be immediately life threatening and may be an added insult to the recovering kidneys.[10] In addition, the control of volume overload and uraemia can only be episodic with IHD. Thus, conventional IHD can often be a hazardous undertaking in the critically ill patient with multi-organ failure. However, once haemodynamic stability is attained and if the patient continues to be dialysis dependent, IHD may be the preferred modality. Profound and rapid osmotic shifts within the brain can happen during IHD leading to brain swelling;[1112] hence it is relatively contraindicated in conditions like hepatic encephalopathy where cerebral oedema and raised intracranial pressure is a concern.

ues to be dialysis dependent, IHD may be the preferred modality. Profound and rapid osmotic shifts within the brain can happen during IHD leading to brain swelling;[1112] hence it is relatively contraindicated in conditions like hepatic encephalopathy where cerebral oedema and raised intracranial pressure is a concern. Continuous Renal Replacement Therapies The haemodynamic instability that is often associated with IHD along with the risk of injury to the recovering kidney led to the evolution of continuous renal replacement therapies (CRRT). Kramer et al first described the technique of continuous arterio-venous haemofiltration, using the patient's blood pressure to drive blood through the haemofilter. The rate of ultrafiltration was controlled by adjusting the height of the drainage bag.[13] Blood flow rate depended on the patient's blood pressure; this was often low in hypotensive patients. Continuous veno-venous techniques using double lumen catheters inserted into a central vein have supplanted these early arterio-venous techniques [Figure 1]. Figure 1 Continuous Veno-venous haemofiltration. Patient's blood is passed through a haemofilter. The ultrafiltration and replacement rate are controlled by roller pumps CRRT results in continuous control over solutes, acid-base and electrolyte balance and removes fluid in a slow, controlled fashion according to patient requirements. There are several methods of doing CRRT, based on the mechanism of clearance.

Figure 1 Continuous Veno-venous haemofiltration. Patient's blood is passed through a haemofilter. The ultrafiltration and replacement rate are controlled by roller pumps CRRT results in continuous control over solutes, acid-base and electrolyte balance and removes fluid in a slow, controlled fashion according to patient requirements. There are several methods of doing CRRT, based on the mechanism of clearance. Continous Veno-venous Haemofiltration (CVVH) With this technique solute clearance is through convection or “solvent drag”. As fluid filters through the membrane, it “drags” solutes along with it. The volume of ultrafiltration depends on the transmembrane pressure, permeability, membrane thickness, surface area and pore size. Small and middle sized molecules are cleared by convection. The volume of fluid ultrafiltered is usually about 1-3 L/ hr; this is substituted with a “clean” replacement fluid with an appropriate electrolyte concentration. The replacement fluid can be administered pre or post filter. Pre-filter administration helps in prolonging the life of the filter by reducing the viscosity of the fluid that enters the filter; however this might also result in marginally reduced clearance. Post-filter administration concentrates blood inside the filter, resulting in an increased gradient and theoretically, might improve clearance at the expense of possible reduced filter life. Uchino et al in their study of 48 patient involving 309 filters showed predilution was a significant independent predictor of increased filter life. Pre-dilution also resulted in a reduction in the heparin dose and higher platelet counts. No favourable changes on the daily creatinine or urea levels were observed with the post-dilution technique.[14]

48 patient involving 309 filters showed predilution was a significant independent predictor of increased filter life. Pre-dilution also resulted in a reduction in the heparin dose and higher platelet counts. No favourable changes on the daily creatinine or urea levels were observed with the post-dilution technique.[14] Continuous Veno-venous Haemodialyis (CVVHD) With this modality, a dialysate fluid is run countercurrent to the blood flow. The dialysate flow is set below the blood flow rate, usually 1-3 L/hr, unlike IHD, where the dialysate flow is higher. Ultrafiltrate is set according to requirement. Clearance occurs mainly by diffusion; however, if the ultrafiltrate flow is set high, some amount of convective clearance may also occur. Diffusion being the primary mechanism, only the small molecular weight solutes are cleared. Clearance of intermediate sized molecules like the cytokines is poor. Diffusive and convective clearance can be combined by using high ultrafiltrate volumes with replacement fluid and adding countercurrent dialysate flow as well, at an appropriate rate (CVVHDF).

Continuous Veno-venous Haemodialyis (CVVHD) With this modality, a dialysate fluid is run countercurrent to the blood flow. The dialysate flow is set below the blood flow rate, usually 1-3 L/hr, unlike IHD, where the dialysate flow is higher. Ultrafiltrate is set according to requirement. Clearance occurs mainly by diffusion; however, if the ultrafiltrate flow is set high, some amount of convective clearance may also occur. Diffusion being the primary mechanism, only the small molecular weight solutes are cleared. Clearance of intermediate sized molecules like the cytokines is poor. Diffusive and convective clearance can be combined by using high ultrafiltrate volumes with replacement fluid and adding countercurrent dialysate flow as well, at an appropriate rate (CVVHDF). Practical Management of CRRT In practice, a double lumen catheter is inserted into the internal jugular or femoral vein. The subclavian vein is usually avoided because of the high incidence of stenosis or thrombosis that would render the ipsilateral arm unusable for the creation of an AV fistula in case long term dialysis is required.[15] For long term use, tunneled catheters with a dacron or silver impregnated collagen cuff is preferable. Internal jugular catheters with the proximal end curved downward allows easier fixation and is more comfortable for the patient. High flux, biocompatible membranes such as polyacrylonitrile and polysulfone membranes are preferred. CRRT is usually initiated with a blood flow rate of 100mls/mt and gradually increased up to 200mls/mt. In CVVH, the ultrafiltrate volume is usually set around 1 to 3 litres/hr. Ronco et al showed in a randomised controlled trial that ultrafiltrate volumes of 35mls/kg/hr are superior to 20 or 45mls/kg/hr.[5] In an average adult, this would be around 2.5L/hr. Replacement fluid is adjusted based on the rate of fluid removal required - this would depend on the haemodynamic and volume status of the patient. High volume haemofiltration using high flux membranes is an area of ongoing interest. Although Inflammatory mediators such as interleukin-1β, interleukin-6, interleukin-8 and other middle molecules that mediate sepsis may be effectively removed by haemofiltration,[16] whether such therapy leads to improved outcomes is not clear. An ongoing randomised controlled trial involving 35 ICUs in Australia and New Zealand is currently recruiting patients to compare outcomes between normal (25mls/kg) versus “augmented” (40mls/kg) ultrafiltrate volumes.

ectively removed by haemofiltration,[16] whether such therapy leads to improved outcomes is not clear. An ongoing randomised controlled trial involving 35 ICUs in Australia and New Zealand is currently recruiting patients to compare outcomes between normal (25mls/kg) versus “augmented” (40mls/kg) ultrafiltrate volumes. Slow Continuous Ultrafiltration (SCUF) Fluid removal at a constant rate is targeted with this therapy. No dialysate or replacement fluid is used; hence solute clearance is negligible. Fluid removal is set between 100 to 300 mls /hr depending on the haemodynamic status of the patient. This is very effective therapy when fluid removal is the only goal in patients who are not azotaemic. Patients who would benefit from SCUF are those with fluid overload that is resistant to diuretic therapy as in refractory cardiac failure or in patients with ARDS who require fluid removal. Excess fluid removal may benefit by improving gas exchange as well as haemodynamic parameters.

in patients who are not azotaemic. Patients who would benefit from SCUF are those with fluid overload that is resistant to diuretic therapy as in refractory cardiac failure or in patients with ARDS who require fluid removal. Excess fluid removal may benefit by improving gas exchange as well as haemodynamic parameters. Anticoagulation during CRRT RRT involves passing the patient's blood though plastic tubings and membranes. This results in triggering of the clotting as well as the complement cascade. IHD can be done without any systemic anticoagulation, but CRRT usually requires some degree of anticoagulation to prevent frequent clotting of filters and down time that would significantly reduce of the efficacy of treatment. In practice, the circuit is rinsed with saline, containing 5000 to 20,000 units of heparin. A bolus dose of 500 to 1000 units is given, followed by an infusion of 5-10 units/kg/hr. An APTT of 30 to 45 seconds may be optimal.[17] APTT measurements must be done every 6 hourly for monitoring efficacy of anticoagulation with heparin. It may not be safe to use heparin in post-operative patients and those who are at a high risk of bleeding due to other reasons. There are several options available to prolong filter life in such situations. Prostaglandin I2 or E1 may be used in place of heparin. The prostaglandins work by inhibition of platelet aggregation, sparing the normal coagulation mechanism. They also cause vasodilatation, that might cause systemic hypotension. Fiaccadori et al,[18] studied 51 patients undergoing CVVH using prostacyclin 4ng/kg/mt as a continuous infusion pre-filter. The mean circuit life was 15 hrs with 4 instances of major bleeding. Hypotension requiring fluids or pressors occurred in 15.5% of CVVH sessions. The authors concluded that prostacycline carries low risk of haemorrhagic complications while allowing maintenance of filter patency to carry out effective CRRT. If systemic anticoagulation is not advisable (e.g.; post operative patients), regional anticoagulation can be considered by giving heparin pre-filter and reversing it with protamine post-filter.[19] It is also possible to provide regional anticoagulation with sodium citrate pre-filter calcium post-filter.[20] The citrate chelates calcium ions which are co-factors at multiple steps of the coagulation cascade. Metabolic alkalosis can occur during citrate anticoagulation as the citrate gets converted to bicarbonate.

It is also possible to provide regional anticoagulation with sodium citrate pre-filter calcium post-filter.[20] The citrate chelates calcium ions which are co-factors at multiple steps of the coagulation cascade. Metabolic alkalosis can occur during citrate anticoagulation as the citrate gets converted to bicarbonate. Hypocalcaemia may develop if calcium supplementation is inadequate as citrate causes chelation of calcium ions. Hypomagnesaemia can also occur due to chelation;[21] however this is uncommon probably because magnesium shifts from the intracellular to the extracellular compartment. The high magnesium content of bicarbonate buffered solutions may also help prevent hypomagnesaemia. Hence it is crucial to monitor ionised calcium, magnesium and acid-base status at regular intervals during citrate calcium anticoagulation. Other modes of anticoagulation using low molecular weight heparin, danaparoid and hirudin have also been described. If no form of anticoagulation is possible, normal saline at the rate of 50 to 100 mls/hr can be used to flush the circuit to maintain filter patency. This can add to the fluid intake and needs to be taken into account while calculating fluid removal. It is also important to use as large-bored a catheter as possible, as frequent filter clotting may often be associated with sluggish flows. Administration of replacement fluids pre-filter also might prolong filter life.

This can add to the fluid intake and needs to be taken into account while calculating fluid removal. It is also important to use as large-bored a catheter as possible, as frequent filter clotting may often be associated with sluggish flows. Administration of replacement fluids pre-filter also might prolong filter life. Filter life The filter and and the venous chamber are the two most common sites of clot formation. Anticoagulation as described previously, will play an important role in maintaining circuit patency. The maintenance of adequate blood flow is another crucial factor that prevents premature clotting. Increased negative pressure on the arterial side and positive pressure on the venous side could mean an early sign of clotting and would necessitate action. Change of limb or neck position could impede flow and needs constant vigilance and repositioning if required. Rinsing the circuit with normal saline containing 5,000 to 20,000 units of heparin may be effective in prolonging circuit life.[22] Polysulfone membranes may be less thrombogenic compared to polyacrylonitrile membranes.[23] Administration replacement fluid as predilution might also enchance circuit patency without any adverse effect on clearance.[14] Venous chamber clotting may be prevented by keeping the blood level almost full, moving it down at the earliest sign of clot formation, adding post-dilution fluid to this chamber and priming it with heparin.[24]

cement fluid as predilution might also enchance circuit patency without any adverse effect on clearance.[14] Venous chamber clotting may be prevented by keeping the blood level almost full, moving it down at the earliest sign of clot formation, adding post-dilution fluid to this chamber and priming it with heparin.[24] Cost effectiveness of CRRT AKI requiring CRRT in the critical care setting adds considerably to the cost of care. The cost of CRRT involves the filter and circuit as well as the cost of large volumes of fluid that is required for this mode of therapy. If the circuit life is short, the costs multiply several times. Personnel involved with providing CRRT need special training as well as ongoing educational programs to keep their skills updated. However, cost effectiveness depends to a large extent on clinical outcomes. Although the cost of IHD may be considerably cheaper compared to CRRT in the short term, the short and long term clinical outcomes would need to be taken in to account. Although a definite survival benefit has not been shown with CRRT compared with IHD in the critical care setting, there is some evidence that CRRT might result in a lower incidence of end stage kidney disease. Thus, it is possible that the possible long term advantage of a higher rate of renal recovery might make CRRT more attractive in economic terms as well.[25]

een shown with CRRT compared with IHD in the critical care setting, there is some evidence that CRRT might result in a lower incidence of end stage kidney disease. Thus, it is possible that the possible long term advantage of a higher rate of renal recovery might make CRRT more attractive in economic terms as well.[25] Slow Low Efficiency Daily Dialysis (SLEDD) Continuous therapies tend to be more complex, associated with the requirement for anticoagulation and costlier, with the requirement for high volumes of fluid. The lack of flexibility to move patients for procedures, interventions etc while on continuous therapies is also a disadvantage. This has resulted in the increasing use of “hybrid” therapies that try to match the physiological advantages that CRRT offers. SLEDD involves the use of blood and dialysate flows significantly less than that used with conventional IHD. Typically, blood flow rates of around 100 to 200 mls/mt and dialysate flows of less than 300 mls/mt is used. Treatment time is extended to 6 to 12 hours every day. This results in slower solute clearance and fluid removal and results in haemodynamic stability that may be comparable to CRRT. SLEDD therapies are also less expensive as there is no requirement for large volumes of customised fluids. Besides, there is greater flexibility in terms of the ability to move patients out of the intensive care unit for investigations or interventions by allowing a scheduled down time.

that may be comparable to CRRT. SLEDD therapies are also less expensive as there is no requirement for large volumes of customised fluids. Besides, there is greater flexibility in terms of the ability to move patients out of the intensive care unit for investigations or interventions by allowing a scheduled down time. Continuous Vs Intermittent therapies - what's the evidence? The physiological superiority of CRRT over conventional IHD is unquestioned. Does this result in improved clinical outcomes? Many trials that compare these modalities involve patients with different severity of illness at baseline; crossover from one arm to the other was also allowed in many studies, making it difficult to interpret the results. Besides, the majority of trials do not include patients with significant haemodynamic instability - precisely the subgroup of patients who are likely to have a survival advantage with continuous therapies. Kellum et al did a meta-analysis of 13 clinical trials involving 1400 patients.[26] Out of this, only 3 were randomised. On unadjusted analysis, there was no difference survival between CRRT and IHD. However, when adjusted for study quality or baseline severity of illness, or both, CRRT was associated with improved survival. Under no conditions, either of inclusion criteria or adjustment method did CRRT fare worse. Mehta et al, in their study, randomised 166 patients to receive either IHD or CRRT.[27] CRRT was associated with increased ICU and hospital mortality. However, patients in the CRRT group had a higher baseline severity of illness by APACHE II and III scores, more hepatic failure and more organ failures. There was strong bias in favour of IHD by all these counts, thus obviating meaningful analysis. In a more recent trial, Vinsonneau et al, for the haemodiafe group compared alternate day IHD with CRRT and reported no survival benefit at 60 days. However, the trial did not standardise the time of initiation of therapy or the dose of delivered dialysis. The actual CRRT dose delivered was only 25 ml/kg/hr, significantly less than the optimal 35 ml/kg/hr that has been associated with improved outcomes.[28]

IHD with CRRT and reported no survival benefit at 60 days. However, the trial did not standardise the time of initiation of therapy or the dose of delivered dialysis. The actual CRRT dose delivered was only 25 ml/kg/hr, significantly less than the optimal 35 ml/kg/hr that has been associated with improved outcomes.[28] SLEDD holds the promise of combining the advantages of continuous therapy with the inherent simplicity of haemodialysis. Initial trials with SLEDD have been promising.[29] Slow low efficiency diafiltration (SLEDD-f) by combining SLEDD with ultrafiltration has been shown to provide stable renal replacement therapy with low molecular weight solute removal that is comparable with CRRT or IHD and possibility of large molecular weight clearance.[30] Who should be responsible for RRT in the ICU - intensivist or nephrologist? In India, most ICUs follow an “open” structure and the skills required for RRT may not be readily available within the unit. Nephrologists are involved early in the management of patients with AKI and contribute to their care. RRT in the ICU is mostly carried out by technicians from the nephrology department. However, critical care nephrology as a subspecialty is fast emerging and critical care physicians are likely to be more intricately involved with the management of patients who develop AKI. It is also likely that critical care nursing would emerge as a nursing subspecialty with RRT in critical care as part of the curriculum.

r, critical care nephrology as a subspecialty is fast emerging and critical care physicians are likely to be more intricately involved with the management of patients who develop AKI. It is also likely that critical care nursing would emerge as a nursing subspecialty with RRT in critical care as part of the curriculum. Summary Acute renal failure is an independent predictor of mortality in the ICU. IHD, as applied in the conventional manner is largely unsuited to the sick ICU patient with multiorgan failure. CRRT is clearly superior to IHD in regard to physiological end points - clinical outcomes have not been adequately studied in patients with equal baseline severity of illness. CRRT is inherently complex with the requirement for anticoagulation and the use of high volumes of fluid and is much costlier compared to IHD. Modifications of IHD, with low blood and dialysate flows, extending it to 6 to 12 hours and administering it on a daily basis has resulted in several forms of “hybrid” therapy. Such therapies are able to combine the advantages of both IHD and CRRT. In effect, modifications of conventional IHD has made it similar to CRRT in many ways. There is a pressing need to study “hybrid” therapies for further evaluation related to clinical outcomes. Source of Support: Nil Conflict of Interest: None declared.

Biologicals are proteins produced by living organisms to target specific sites of the inflammatory cascade, including antibodies against cell surface markers, cytokines and adhesion molecules.[1] The biological agents represent an important addition to the therapies for immuno-inflammatory conditions and have a great impact on the disease course and quality of life of these patients. However, recent reports of reactivation of TB (tuberculosis) after anti-TNF therapy raised question on their safety. TNF-α plays an important role in the host defense against mycobacterial infection, particularly in granuloma formation and inhibition of mycobacterial dissemination.[2] FDA recommended a black box for TB on the product labeling of infliximab.[4] Other serious infections reported with etanercept include sepsis secondary to Listeria monocytogenes and Histoplasma capsulatum.[2] Severe disseminated opportunistic infections have been reported in the HIV positive patients.[2] SLE syndrome, demyelinating diseases, neurodegenerative diseases, pancytopenia, cardiovascular diseases, new onset or flare-up of chronic iridocyclitis, thyroid cancer, hypoglossal nerve paralysis, severe cytomegalovirus pulmonary infection, reactivation of Crohn's disease etc. are the other important adverse effects reported with anti-TNF-α therapy.[45]

, neurodegenerative diseases, pancytopenia, cardiovascular diseases, new onset or flare-up of chronic iridocyclitis, thyroid cancer, hypoglossal nerve paralysis, severe cytomegalovirus pulmonary infection, reactivation of Crohn's disease etc. are the other important adverse effects reported with anti-TNF-α therapy.[45] However, the success of TNF blockade clearly indicates that there are various checkpoints in cytokine-mediated inflammation. Hence, the identification and development of molecules targeting such critical ‘regulatory cytokines’ (beyond TNF) may have the potential to become a novel addition in the armamentarium against various immuno-inflammatory conditions. Hence, in the present article we are reviewing some of these non-TNF-α biological. Search Methodology: Prominent rheumatology and general/internal medicine journals (MEDLINE, EMBASE, PUBMED between 2000 and 2006) were searched for review papers and clinical trials published on drugs targeting inflammatory cytokines other than TNF-α. All the data was collected and important evidences regarding pharmacology and uses of non-TNF-α biologicals were summarized in the present article.

ls (MEDLINE, EMBASE, PUBMED between 2000 and 2006) were searched for review papers and clinical trials published on drugs targeting inflammatory cytokines other than TNF-α. All the data was collected and important evidences regarding pharmacology and uses of non-TNF-α biologicals were summarized in the present article. Cytokine networks and their therapeutic targets in clinical practice[6–8] Cytokines are soluble (glyco) proteins, non-immunoglobulin in nature, released by living cells of the host, which act non-enzymatically in picomolar to nanomolar concentrations through specific receptors to regulate host cell function. Cytokines are pleiotropic in their biological activities and play pivotal roles in a variety of responses, including the immune response, hematopoiesis, neurogenesis, embryogenesis and oncogenesis. The main types of cytokines are lymphokines, interleukins, monokines, tumor necrosis factors (TNF), interferons, colony-stimulating factors, transforming growth factors, peptide growth factors, heat shock and other stress proteins. Cytokines have been classified on the basis of their biological responses into pro- or anti-inflammatory cytokines, depending on their effects on immunocytes [Table 1]. TNF, interleukin (IL)-1, IL-6, IL-7, IL-8, IL-12, IL-15, IL-17, IL-18, IL-23, lymphotoxin, macrophage migration inhibitory factor, resistin, interferon-γ, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, fibroblast growth factor and vascular endothelial growth factor are the proinflammatory cytokines. Whereas, IL-1Ra, IL-18 binding protein, IL-10, transforming growth factors, IL-11, IL-13, osteoprotegerin, adiponectin, etc are the anti-inflammatory cytokines. IL-22, oncostatin M etc are equivocal. Cytokines can be released not only by immune cells but also by host tissue cells. Various molecules (anakinra, tocilizumab, atlizumab, abatacept, alefacept, efalizumab, rituximab) targeting these cytokines are in clinical development.

ctin, etc are the anti-inflammatory cytokines. IL-22, oncostatin M etc are equivocal. Cytokines can be released not only by immune cells but also by host tissue cells. Various molecules (anakinra, tocilizumab, atlizumab, abatacept, alefacept, efalizumab, rituximab) targeting these cytokines are in clinical development. Table 1 Cytokines and their role[6–84344]

ctin, etc are the anti-inflammatory cytokines. IL-22, oncostatin M etc are equivocal. Cytokines can be released not only by immune cells but also by host tissue cells. Various molecules (anakinra, tocilizumab, atlizumab, abatacept, alefacept, efalizumab, rituximab) targeting these cytokines are in clinical development. Table 1 Cytokines and their role[6–84344] Cytokines Function IL-1 Activates APC and CD4+ lymphocytes; affects the differentiation of the B and T-Cells and other immunocompetent cells, takes part in the regulation of productions of other cytokines and GMCSF. IL-2 Stimulates the proliferation and activation of B-Cells and T-Cells. IL-4 Plays a role in the differentiation of TH2, in allergic responses and in the switching of antibody types. IL-5 Stimulates the production and maturation of eosinophils during inflammation. IL-8 Acts as a chemotactic factor that attracts neutrophils, basophils and T-Cells to sites of inflammation. IL-12 A critical linker between the innate immunity and adaptive immunity, capable of TH1 differentiation and IFN-Gamma release by T-Cells and NK cells IL-10 Acts to repress secretion of pro-inflammatory cytokines. IL-3 Potent activator of the hemopoietic cells. It stimulates NK-Cells and acts as a synergist with IL-4 during the induction of CD4+ lymphocyte activation process. IL-7 Induces apoptosis of tumor cells and causes differentiation of cells from a subgroup of acute myeloblastic leukemia. IL-9 Stimulates the excretion of IL-2, IL-4, IL-6, IL-11 and cytotoxicity of T-killers and NK-Cells, inducing apoptosis. IL-11 Regulates the functions of B-Cells and T-Cells, induces various killer cells' activities and acts as an autocrine factor for the proliferation of megacaryocytes. IL-13 Inhibits the proliferation of leukemic pro-B-Cells IL-14 BCGF and the hyper production of this interleukin enables the progression of NHL-B. IL-15 Increases the antitumor activities of T-killers and NK-Cells, and the production of cytokines CD4+ lymphocytes. IL-17 Takes part in the regulation of many cytokines and can reinforce the antibody dependant tumor cell destructions. IL-18 Synergist with IL-12, especially in the induction of IFN-Gamma production and inhibition of angiogenesis. IL-19 Regulates the functions of macrophages and suppresses the activities of TH1 and TH2. IL-21 Promotes a high production of T-Cells, fast growth and maturation of NK-Cells and B-Cells population. IL-22 Similar to IL-10, but does not prohibit the production of pro-inflammatory cytokines through monocytes.

giogenesis. IL-19 Regulates the functions of macrophages and suppresses the activities of TH1 and TH2. IL-21 Promotes a high production of T-Cells, fast growth and maturation of NK-Cells and B-Cells population. IL-22 Similar to IL-10, but does not prohibit the production of pro-inflammatory cytokines through monocytes. TNFs Activates macrophages, inhibits apoptosis of neutrophils and eosinophils, induces vascular endothelial cells to bind to phagocytes, induce proliferation of NK-Cells and stimulate innate and adaptive immune responses. On activation NK cells release IFN-γ. Resistin Promote TNF and IL-6 release. Adiponectin It modulates TNF-induced inflammation. APC= Antigen presenting cell, GMCSF =Granulocyte-Macrophage Colony-Stimulating Factor, TH2 =T Helper Type-2, TH1 =T Helper Type-1, NK= natural killer, INF= interferone, IL=interleukins, BCGF=B-Cell Growth Factor, NHL-B =B-cell type non Hodgkin's lymphoma. Existing therapeutic targets include the biologicals acting as antagonists of various inflammatory cytokines and modulators of CD80 or CD86-CD28 co-stimulatory signal, CD2 receptors on T-cells, CD11a, sub-unit of leukocyte function-associated antigen 1 (LeFA-1), vitronectin receptor and CD20 antigen on pre-B, immature and mature B cells [Table 2]. Table 2 Biologics agents beyond anti-TNF-therapy [2–1218–35]

Existing therapeutic targets include the biologicals acting as antagonists of various inflammatory cytokines and modulators of CD80 or CD86-CD28 co-stimulatory signal, CD2 receptors on T-cells, CD11a, sub-unit of leukocyte function-associated antigen 1 (LeFA-1), vitronectin receptor and CD20 antigen on pre-B, immature and mature B cells [Table 2]. Table 2 Biologics agents beyond anti-TNF-therapy [2–1218–35] Drugs Binding target Dose Adverse drug reaction FDA approval Anakinra a recombinant human IL-1 {RA} IL-1 receptor 1-2 mg/kg/day S/C. Neutropenia, cardiopulmonary arrest, influenza like symptoms, production of anti anakinra antibodies and serious infections. RA(2001), Studied in Asp, psoriasis and PA. Atlizumab: Mab IL-6 receptor 2-8 mg/kg I.V. every 2 wkly Increased blood cholesterol levels. Studied in RA. Abatacept: a recombinant fusion protein Selectively modulates the CD80 or CD86-CD28 co-stimulatory signal required for full T-cell activation 10 mg/kg I.V. every 2 wkly for 3 doses followed by 4 wkly. -- RA(2005) Studied in Asp, psoriasis and PA, CD-UC. Rituximab: specific mouse and human chimeric Mab CD 20 antigen on B cells ---- Antibody levels against HSV 1/2 and VZV are not significantly affected Cancers, B-cell NHL(2001), RA(march 2006). Studied in Asp, psoriasis, PA Alefacept a bivalent recombinant fusion protein LFA-3 portion of alefacept binds to CD2 receptors on T-cells, IgG1 portion of alefacept binds to Fc▭R receptor on natural killer cells to induce T-cell apoptosis. 10-15 mg IM wkly or 7.5 mg IV wkly for 12 wks. Cytotoxic effect is selective for the activated memory T-cells. reduces total lymphocyte count and CD4+ and CD8+cell counts. Psoriasis(jan 2003), Efalizumab a recombinant humanized IgG1 Mab It interferes with the interaction between LeFA-1 and ICAM-1, a cell surface molecule expressed by APCs. 1 mg/kg (max 200mg) wkly S.C. for 12wks -Acute flu- like symptoms, exacerbation of psoriasis on discontinuation, autoimmune hemolytic anemia, thrombocytopenia Psoriasis(2003) Vitaxin humanized monoclonal IgG1 antibody Antagonizes vitronectin receptors involved in osteoclast mediated bone resorption, angiogenesis and macrophage dependent inflammation. --- --- Early stages of study in RA.

acerbation of psoriasis on discontinuation, autoimmune hemolytic anemia, thrombocytopenia Psoriasis(2003) Vitaxin humanized monoclonal IgG1 antibody Antagonizes vitronectin receptors involved in osteoclast mediated bone resorption, angiogenesis and macrophage dependent inflammation. --- --- Early stages of study in RA. Asp= ankylosing spondylitis, RA= Rheumatoid arthritis, APCs= antigen presenting cells, LeFA-1 = leukocyte function-associated antigen 1, ICAM-1 = intercellular adhesion molecules, LFA-3 = lymphocyte function antigen 3, CTLA4 = cytotoxic T-lymphocyte antigen 4, IL = Interleukin, PA =psoriatic arthritis, CD-UC = crohn's disease and ulcerative colitis, Mab = monoclonal antibody, HSV=.herpes simplex virus, VZV= varicella-zoster virus,{RA}= receptor antagonist, wkly = weekly, NHL= non-Hodgkin's lymphoma, S.C=subcutaneous,Wks= weeks.

en 3, CTLA4 = cytotoxic T-lymphocyte antigen 4, IL = Interleukin, PA =psoriatic arthritis, CD-UC = crohn's disease and ulcerative colitis, Mab = monoclonal antibody, HSV=.herpes simplex virus, VZV= varicella-zoster virus,{RA}= receptor antagonist, wkly = weekly, NHL= non-Hodgkin's lymphoma, S.C=subcutaneous,Wks= weeks. Anakinra:[9–11] It is recombinant form of nonglycosylated human IL-1 receptor antagonist expressed in Escherichia coli. Natural IL-1 receptor antagonist is produced by macrophages and activated monocytes in response to various inflammatory stimuli. Anakinra competitively binds to both type-I and type-II IL-1 receptors, at least partially blocking cellular responses mediated by IL-1-α and IL-1-β. It has a binding affinity similar to IL-1, but it lacks IL-1 agonist activity. Its daily dose is 100 mg/day subcutaneously (SC). Prior hypersensitivity to anakinra or E-coli derived proteins and active infection are the important contraindications with the use of anakinra. Common adverse reactions reported with it are headache, nausea, diarrhea, sinusitis, erythema, ecchymosis, pruritis at injection site, influenza like symptoms, production of anti-anakinra antibodies, neutropenia, cardiopulmonary arrest and serious infections. Live vaccines should not be administered concurrently with anakinra. It should be used with caution in patients with neutropenia, immuno-suppression, moderate to severe renal impairment, pregnancy or breastfeeding period, and concomitant use of TNF blocking agents.

openia, cardiopulmonary arrest and serious infections. Live vaccines should not be administered concurrently with anakinra. It should be used with caution in patients with neutropenia, immuno-suppression, moderate to severe renal impairment, pregnancy or breastfeeding period, and concomitant use of TNF blocking agents. Clinical Trials: In a dosage ranging multi-center placebo controlled trial patients of Rheumatic arthritis (RA) on 1-2 mg/kg/day of anakinra with MTX 15-25 mg/week achieved more ACR (American College of Rheumatology preliminary criteria for improvement) 20 response than MTX alone at 12 weeks.[12] In another study with 100 mg/day of anakinra in combination with MTX showed more efficacy in retarding radiographic progression than MTX alone.[13] In a two-year prospective, in part retrospective, cohort study drug survival was 78%, 54%, and 14% after 3, 6 and 24 months, respectively.[14] However, National institute of clinical excellence of the united kingdom recommended its use in patients who are not responding to anti-TNFα therapy alone or in patients with juvenile idiopathic arthritis.[1215]

retrospective, cohort study drug survival was 78%, 54%, and 14% after 3, 6 and 24 months, respectively.[14] However, National institute of clinical excellence of the united kingdom recommended its use in patients who are not responding to anti-TNFα therapy alone or in patients with juvenile idiopathic arthritis.[1215] In a clinical trial on 419 patients with moderate-to-severe active RA, who were receiving MTX for six consecutive months, the ACR20 responses at week 12 in the 5 active treatment (0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra) plus MTX groups demonstrated a statistically significant (P = 0.001) dose-response relationship compared with the ACR20 response in the placebo plus MTX group.[16] In another trial 218 patients received subcutaneous injections of anakinra (30, 75, or 150 mg) once daily.[17] The ACR20 response was 51% at week 24 and 46% at week 48 and this effect was consistent across all dose groups. Anakinra was well-tolerated for 76 weeks.[17] Role of anakinra in chronic infantile neurological cutaneous and articular (CINCA) syndrome with a novel missense mutation in exon 4 of the CIAS1 gene (unresponsive to several treatments including prednisolone, immunosuppressants, DMARDs and TNF-blocker infliximab) has been documented.[18] Anakinra, has a positive impact on both function and quality of life of the patients with RA.[19] However, further clinical studies are needed to establish the additive benefits of the combination of TNF-α blockade plus IL-1 receptor antagonism in RA.

essants, DMARDs and TNF-blocker infliximab) has been documented.[18] Anakinra, has a positive impact on both function and quality of life of the patients with RA.[19] However, further clinical studies are needed to establish the additive benefits of the combination of TNF-α blockade plus IL-1 receptor antagonism in RA. Abatacept:[20] It is a recombinant fusion protein comprising of the extra-cellular domain of human CTLA4 (cytotoxic T-lymphocyte antigen 4) and a fragment of the Fc domain of human IgG1, which has been modified to prevent complement fixation. It modulates the CD80 or CD86-CD28 co-stimulatory signal required for full T-cell activation. It is given in a dose of 10 mg/kg by IV infusion (three doses at the interval of two weeks, followed by infusion after every four weeks).

of the Fc domain of human IgG1, which has been modified to prevent complement fixation. It modulates the CD80 or CD86-CD28 co-stimulatory signal required for full T-cell activation. It is given in a dose of 10 mg/kg by IV infusion (three doses at the interval of two weeks, followed by infusion after every four weeks). Clinical Trials: In a Phase IIb multi-center international study in RA patients with inadequate response to MTX, ACR 20 response was achieved in 60%, 41.9% and 35.3% patients with abatacept in a dose of 10 mg/kg, 2 mg/kg and placebo respectively after 6 months of the treatment as add on therapy to MTX.[12] In a randomized double blind phase-III trial on patients with active RA refractory to anti-TNF-α therapy, abatacept therapy for 6 months, in addition to at least one DMRDs (disease modifying antirheumatic drugs) produced ACR 20 response rate of 50.4% as compare to 19.5% in the placebo group (P< 0.001).[20] At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function (47.3 percent vs 23.3 percent, P<0.001) with incidence of serious infections as 2.3% in both the groups.[20]

% as compare to 19.5% in the placebo group (P< 0.001).[20] At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function (47.3 percent vs 23.3 percent, P<0.001) with incidence of serious infections as 2.3% in both the groups.[20] Alefacept:[2] Alefacept is approved by US food and drug administration (FDA) in January 2003 for treatment in adult patients with moderate to severe chronic plaque psoriasis, who are candidates for systemic therapy or phototherapy. It is a bivalent recombinant fusion protein composed of the first extra-cellular domain lymphocyte function antigen 3 (LFA-3), fused to the hinge CH2 domain and CH3 domain of human IgG1. The LFA-3 portion of alefacept binds to CD2 receptors on T-cells, thereby blocking their natural interaction with LFA-3. The IgG1 portion of alefacept binds to FcγR on natural killer cells to induce T-cell apoptosis. Its dose is 10-15 mg IM (intramuscular) weekly or 7.5 mg IV (intravenous) weekly and a 12 week course is recommended.

ion of alefacept binds to CD2 receptors on T-cells, thereby blocking their natural interaction with LFA-3. The IgG1 portion of alefacept binds to FcγR on natural killer cells to induce T-cell apoptosis. Its dose is 10-15 mg IM (intramuscular) weekly or 7.5 mg IV (intravenous) weekly and a 12 week course is recommended. Clinical Trials: In a double-blind RCT (randomized clinical trial) two 12-week courses of once-weekly IV alefacept 7.5 mg and placebo were given and patients were followed for 12 weeks after each course.[21] Significantly more patients achieved greater reduction in the PASI (psoriasis area and severity index) than placebo both after first and second course of therapy.[21] In an international, double-blind, placebo-controlled, RCT, 507 patients with chronic plaque psoriasis, were randomized to receive either 10 mg or 15 mg of alefacept once weekly for 12 weeks, followed by 12 weeks of observation.[22] Thirty three percent and 28% patients achieved 75% reduction in PASI, two weeks after the last dose in 15 mg and 10 mg group respectively.[22] The selective immuno-modulatory effect of alefacept against potentially pathogenic T-cells is associated with maintenance of immune function to fight infection and response to vaccinations.[23] It has been reported that it reduces total lymphocyte count and CD4+ and CD8+cell counts. Hence, it is recommended to monitor CD4 counts weekly during therapy.

ffect of alefacept against potentially pathogenic T-cells is associated with maintenance of immune function to fight infection and response to vaccinations.[23] It has been reported that it reduces total lymphocyte count and CD4+ and CD8+cell counts. Hence, it is recommended to monitor CD4 counts weekly during therapy. Efalizumab:[23] It is approved by the US FDA in October 2003 for the treatment of psoriasis. It is a recombinant humanized monoclonal IgG1 antibody that binds to CD11a, subunit of leukocyte function-associated antigen 1 (LeFA-1). It interferes with the interaction between LeFA-1 and intercellular adhesion molecules (ICAM-1). By destabilizing the binding of APCs (antigen presenting cells) and T-cells, it reduces the efficiency of initial T-cell activation in lymph nodes. It interferes with the secondary activation of memory-effector T-cells in the target tissues. Its dose is 1 mg/kg (max 200mg) weekly, subcutaneous injection for 12 weeks, following a first conditioning dose of 0.7 mg/kg.

esenting cells) and T-cells, it reduces the efficiency of initial T-cell activation in lymph nodes. It interferes with the secondary activation of memory-effector T-cells in the target tissues. Its dose is 1 mg/kg (max 200mg) weekly, subcutaneous injection for 12 weeks, following a first conditioning dose of 0.7 mg/kg. Clinical trials: In four large phase III studies in 2000 patients with moderate-to-severe chronic plaque psoriasis, efalizumab (1 mg/kg weekly) produced PASI 75 (>75% in reduction in baseline PASI score) in 27% of patients as compared to 4% patients in placebo group by week 12.[24–27] Continuation of therapy beyond 12 weeks increased the response rate further in efalizumab group. The relapse of psoriasis was evident after 2 months of discontinuation of therapy with rebound in approximately 5% of the patients, as defined by flaring>125% of baseline.Acute flu-like symptoms including headache, chills, fever, nausea and myalgia, an exacerbation of psoriasis after discontinuation of therapy, autoimmune hemolytic anemia, and thrombocytopenia are the common adverse events reported with its use.[2]

approximately 5% of the patients, as defined by flaring>125% of baseline.Acute flu-like symptoms including headache, chills, fever, nausea and myalgia, an exacerbation of psoriasis after discontinuation of therapy, autoimmune hemolytic anemia, and thrombocytopenia are the common adverse events reported with its use.[2] Rituximab:[28–30] Rituximab is a specific mouse and human chimeric monoclonal antibody. This IgG1 has a long half-life of 76 to 200h and targets the CD20 antigen. The CD 20 antigen is present on pre-B, immature and mature B cells and is important for B-cell activation and proliferation. Binding of rituximab to CD 20 results in complement and antibody-dependent cyto-toxicity (apoptosis) of cells exhibiting this antigen. CD20 is not expressed on stem cells and plasma cells. Hence, depletion of the B-cell subpopulation is transient and does not affect immunoglobulin synthesis. Normal levels of total serum IgG are maintained and antibody levels against HSV (herpes simplex virus) 1/2 and VZV (varicella-zoster virus) are not significantly affected after rituximab treatment. Rituximab was the first therapeutic antibody approved for treating cancer. A supplemental Biological License Application (sBLA) was approved for it in April 2001, adding several new uses related to B-cell non-Hodgkin's lymphoma. In 2006 rituximab in combination with MTX is approved for adult patients with moderately-to-severely active RA, who have had an inadequate response to one or more TNF antagonist therapies.

cal License Application (sBLA) was approved for it in April 2001, adding several new uses related to B-cell non-Hodgkin's lymphoma. In 2006 rituximab in combination with MTX is approved for adult patients with moderately-to-severely active RA, who have had an inadequate response to one or more TNF antagonist therapies. Clinical Studies: REFLEX, a Phase III clinical study of Rituximab in RA, met its primary endpoint and underpins the FDA's approval.[29] It is also being evaluated in Phase II/III clinical trials for primary progressive and relapsed remitting multiple sclerosis, ANCA-associated vasculitis, systemic lupus erythematosus.[29] In an open label study Rituximab in combination with cyclophosphamide and prednisolone in five patients of refractory RA showed dramatic and sustained clinical improvement.[31] In a phase III multi-center double blind trial on 161 patients Rituximab in combination with MTX or cyclophosphamide showed more efficacy than MTX alone.[31] Rituximab is the first treatment for RA that selectively targets immune cells known as CD20-positive B-cells. Atlizumab:[1232–35] It is a humanized anti-IL-6 receptor monoclonal antibody. It is efficacious in management of RA in a dose of 2-8 mg\kg\dose IV once every two weeks. It is a well-tolerated drug without any increase in antinuclear, anti-DNA or anti-atlizumab antibody. However, increase in blood cholesterol levels has been reported after its use for 24 weeks.

-IL-6 receptor monoclonal antibody. It is efficacious in management of RA in a dose of 2-8 mg\kg\dose IV once every two weeks. It is a well-tolerated drug without any increase in antinuclear, anti-DNA or anti-atlizumab antibody. However, increase in blood cholesterol levels has been reported after its use for 24 weeks. Clinical Trial:[12] In a phase I/II double blind RTC, atlizumab (5 mg/kg with MTX single dose) produced ACR20 response in 50% patients of RA as compare to placebo at week two. Improvement was maintained for eight weeks. In a multi-center double blind RCT, 78%, 57% and 11% RA patients achieved ACR20 response after three months of therapy with atlizumab 8 mg/kg, 4 mg/kg and placebo respectively. Tocilizumab:[3637] It is a recombinant humanized anti-IL-6R monoclonal antibody. Phase I and II studies of tocilizumab in children with JIA (juvenile idiopathic arthritis), showed significant improvement in the typical symptoms of inflammation and laboratory abnormalities. AMG714 (previously HuMax-IL15):[6] IL-15 enhances synovial T-cell proliferation and cytokine release and optimizes cognate interactions between T cells and macrophages. IL-15 induces synovial neutrophil activation, granule release from natural-killer cells, activation and migration of endothelial cells and prevents fibroblast apoptosis. AMG714, a fully human IgG1 monoclonal anti-IL-15 antibody, neutralizes soluble and membrane-bound IL-15 in vitro.

ons between T cells and macrophages. IL-15 induces synovial neutrophil activation, granule release from natural-killer cells, activation and migration of endothelial cells and prevents fibroblast apoptosis. AMG714, a fully human IgG1 monoclonal anti-IL-15 antibody, neutralizes soluble and membrane-bound IL-15 in vitro. Clinical Trials: In a 12-week, dose-ascending, placebo-controlled study, AMG714 (0.5–8 mg/kg) produced significant improvement in disease activity in RA patients as compared to placebo.[38] In another dose-finding study 60% of recipients receiving higher doses of AMG714 (160 mg or 240 mg) showed significant improvement as compared to lower doses.[6] No significant alterations in the levels of circulating leukocyte subsets, including natural-killer cells and CD8+ memory T cells, were observed. Alternate approaches to targeting IL-15 include the use of soluble IL-15R-α-derived proteins or antagonistic IL-15–Fc fusion proteins. CRB-15, an IL-15–Fc fusion protein, suppressed delayed-type hypersensitivity and allograft transplant rejection in rodent models.[39]

Clinical Trials: In a 12-week, dose-ascending, placebo-controlled study, AMG714 (0.5–8 mg/kg) produced significant improvement in disease activity in RA patients as compared to placebo.[38] In another dose-finding study 60% of recipients receiving higher doses of AMG714 (160 mg or 240 mg) showed significant improvement as compared to lower doses.[6] No significant alterations in the levels of circulating leukocyte subsets, including natural-killer cells and CD8+ memory T cells, were observed. Alternate approaches to targeting IL-15 include the use of soluble IL-15R-α-derived proteins or antagonistic IL-15–Fc fusion proteins. CRB-15, an IL-15–Fc fusion protein, suppressed delayed-type hypersensitivity and allograft transplant rejection in rodent models.[39] Vitaxin (MEDI-522):[4] It is humanized monoclonal IgG1 antibody that binds to a conformational epitope formed by both the integrin alpha V and beta 3 subunits. Alpha V and beta 3 integrin (vitronectin receptor) is expressed in low levels in most of the normal tissues (intestinal, vascular and smooth muscle cells) and in high levels in bone, mid-menstrual cycle endometrium, placenta, inflammatory sites and invasive tumors. Vitronectin receptors have major role in osteoclast mediated bone resorption, angiogenesis and macrophage dependent inflammation. In RA, activated macrophages are increased in both subchondrial bone and inflamed synovial tissue; whereas, osteoclasts are increased in subchondrial bone at the site of bone erosion and resorption. Hence, antagonists of alpha V and beta 3 integrin have a potential role in the therapeutics of RA. Echistatin is another molecule under development.

s are increased in both subchondrial bone and inflamed synovial tissue; whereas, osteoclasts are increased in subchondrial bone at the site of bone erosion and resorption. Hence, antagonists of alpha V and beta 3 integrin have a potential role in the therapeutics of RA. Echistatin is another molecule under development. Anti Interleukins in Critical Pathological Conditions Bronchial Asthma:[4041] Accumulation of eosinophils in the bronchial mucosa of individuals with asthma is considered to be a central event in the pathogenesis of asthma. Mepolizumab is a humanized anti–IL-5 monoclonal antibody. In animal models, airway eosinophil recruitment and airway hyperresponsiveness in response to allergen challenge are reduced by specific targeting of IL-5. However mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy. In a clinically relevant model of chronic allergic asthma in mice neutralizing antibodies to IL-13 effectively suppressed eosinophil recruitment and accumulation of chronic inflammatory cells in the airways. It also partially suppressed changes of airway wall remodeling, including goblet cell hyperplasia/metaplasia and subepithelial fibrosis, but had limited ability to inhibit airway hyperreactivity (AHR). However, treatment with anti–IFN-γ markedly suppressed AHR.

accumulation of chronic inflammatory cells in the airways. It also partially suppressed changes of airway wall remodeling, including goblet cell hyperplasia/metaplasia and subepithelial fibrosis, but had limited ability to inhibit airway hyperreactivity (AHR). However, treatment with anti–IFN-γ markedly suppressed AHR. Crohn's disease:[43] Crohn's disease is characterized by increased production of IL-12 by antigen-presenting cells in intestinal tissue and interferon-γ and TNF-α by intestinal lymphocytes and macrophages. Anti–IL-12 monoclonal antibody therapy induces clinical response and remission in patients with active Crohn's disease. In a clinical trial 79 patients with active Crohn's disease were randomized to receive seven weekly subcutaneous injections of anti– IL-12 human monoclonal antibody (1 mg/kg body weight or 3 mg/kg body weight) or placebo, in an interrupted (one-month span after first dose, n = 40) or continuous regimen (n = 39). Continuous weekly therapy with 3-mg/kg anti–interleukin-12 resulted in significantly higher response rates at seven weeks compared with placebo. Acute respiratory distress syndrome:[42] Anti-IL8 antibodies are high in patients of acute respiratory distress syndrome and molecules targeting them can be of potential help in these patients.

Crohn's disease:[43] Crohn's disease is characterized by increased production of IL-12 by antigen-presenting cells in intestinal tissue and interferon-γ and TNF-α by intestinal lymphocytes and macrophages. Anti–IL-12 monoclonal antibody therapy induces clinical response and remission in patients with active Crohn's disease. In a clinical trial 79 patients with active Crohn's disease were randomized to receive seven weekly subcutaneous injections of anti– IL-12 human monoclonal antibody (1 mg/kg body weight or 3 mg/kg body weight) or placebo, in an interrupted (one-month span after first dose, n = 40) or continuous regimen (n = 39). Continuous weekly therapy with 3-mg/kg anti–interleukin-12 resulted in significantly higher response rates at seven weeks compared with placebo. Acute respiratory distress syndrome:[42] Anti-IL8 antibodies are high in patients of acute respiratory distress syndrome and molecules targeting them can be of potential help in these patients. Septic shock: [44] Patients with septic shock have T cell hyporesponsiveness and immune suppression, which, if persistent, are associated with increased mortality. In the murine cecal ligation and puncture (CLP) model of sepsis, it has been reported that early treatment with the anti-inflammatory cytokine IL-10 delays the onset of irreversible shock.

septic shock have T cell hyporesponsiveness and immune suppression, which, if persistent, are associated with increased mortality. In the murine cecal ligation and puncture (CLP) model of sepsis, it has been reported that early treatment with the anti-inflammatory cytokine IL-10 delays the onset of irreversible shock. Cytokine targets in preclinical development Interferon (IFN)-γ blockade using a polyclonal anti-IFN-γ antibody has been shown to produce suppression of RA disease activity in a small RCT.[45] Suppression of IL-17, anti-IL-18 antibody and the inhibition of IL-18 secretion via inhibition of caspase 1or antagonism of the proinflammatory purinergic receptor P2X7 are other approaches under development. [646–49] Several adipokines (adeponectin) have been shown to modulates TNF-induced inflammation.[5051] Resistin is a cysteine-rich secretory protein originally implicated in insulin resistance and atherogenesis. It is expressed at high levels in RA synovial tissues, can promote TNF and IL-6 release.[651] Therapeutic targeting of resistin offers the potential to modify not only local inflammation, but also the systemic insulin resistance that is characteristic of RA and other chronic inflammatory conditions.

and atherogenesis. It is expressed at high levels in RA synovial tissues, can promote TNF and IL-6 release.[651] Therapeutic targeting of resistin offers the potential to modify not only local inflammation, but also the systemic insulin resistance that is characteristic of RA and other chronic inflammatory conditions. A number of biological agents are being studied actively at the present time and it is hoped that they may generate novel therapies for and a greater understanding of immuno-inflammatory diseases (Table 3). The future for immunomodulatory intervention in rheumatology looks very promising. Greater understanding of the intricacies of the immune response that underlie the disease should continue to yield viable, specific targets for novel therapies. Advances in biopharmaceuticals should generate treatments that maximize efficacy while minimizing toxicity. These novel therapeutic agents could give new hopes to the clinician truly to modify the disease and achieve tangible improvements in the lives of the patients. Table 3 Clinical evidences showing efficacy of non-TNF biologic in immuno-inflammatory conditions

A number of biological agents are being studied actively at the present time and it is hoped that they may generate novel therapies for and a greater understanding of immuno-inflammatory diseases (Table 3). The future for immunomodulatory intervention in rheumatology looks very promising. Greater understanding of the intricacies of the immune response that underlie the disease should continue to yield viable, specific targets for novel therapies. Advances in biopharmaceuticals should generate treatments that maximize efficacy while minimizing toxicity. These novel therapeutic agents could give new hopes to the clinician truly to modify the disease and achieve tangible improvements in the lives of the patients. Table 3 Clinical evidences showing efficacy of non-TNF biologic in immuno-inflammatory conditions Study Disease Drugs Duration Results DRM RCT RA Anakinra+MTX vs placebo+MTX 12 wks >ACR 20 response in anakinra group than placebo group.[12] Cohort study RA Anakinra 2 yr prospectively Significant response at 3 months Survival 14% after 2 yrs.[14] RCT RA Anakinra+MTX vs placebo+MTX 24 wks ACR response was dose dependent and >ACR 20 response in anakinra group than placebo group.[16] MDBP group extension phase study. RA Anakinra vs placebo 48wks ACR 50 and ACR 70 responses are more in anakinra group than placebo group.[17] Case report CINCA Anakinra - Improved condition in patient refractory to other DMRDs and biologicals.[18] Phase II b multi-center international study RA with inadequate response to MTX Abatacept vs placebo. 6 months ACR 20 response was achieved in 60%, 41.9% and 35.3% patients with 10mg/kg, 2 mg/kg abatacept and placebo respectively.[12] Phase-III double blind RCT RA refractory to anti-TNF-α therapy Abatacept + 1 DMRD 6 months ACR 20 response rate of 50.4% in abatacept group as compare to 19.5% in the placebo group (P<0.001); ACR 50 and ACR 70 responses were also higher in the abatacept group.[20] Double-blind RCT Psoriasis Alefacept vs placebo 12 wks treatment and 12 wks follow-up.

efractory to anti-TNF-α therapy Abatacept + 1 DMRD 6 months ACR 20 response rate of 50.4% in abatacept group as compare to 19.5% in the placebo group (P<0.001); ACR 50 and ACR 70 responses were also higher in the abatacept group.[20] Double-blind RCT Psoriasis Alefacept vs placebo 12 wks treatment and 12 wks follow-up. Greater reduction in the PASI was achieved by alefacept group than placebo group ( p <0.001).[21] International, double-blind, placebo-controlled, RCT Chronic plaque psoriasis Alefacept 10 mg or 15 mg once wkly 12 wks treatment and 12 wks follow-up In the 15 mg group, 33% patients achieved 75% reduction in PASI, 2 wks after the last dose and 28% patients achieved 75% reduction in PASI in the 10 mg group.[22] Four large phase III studies in 2000 patients Chronic plaque psoriasis Efalizumab vs placebo >12 wks 27% of patients in efalizumab group, achieved PASI 75 compared to 4% in placebo group by wk 12.[24–27] Phase I/II double blind RTC RA Atlizumab+MTX Single dose vs placebo 8 wks 50% patients achieved ACR20 in atlizumab group at wk 2,but non in placebo group.[12] MDBP RCT RA Atlizumab vs placebo 3 months 78%, 57% and 11% patients achieved ACR20 response in atlizumab 8mg/kg, 4 mg/kg and placebo group respectively.[12] Phase III MDBP RA Rtuximab+MTX or CP vs MTX --- More improvement in Rituximab group.[31] RCT = randomized control trial, RA= rheumatoid arthritis, PASI= psoriasis area and severity index., ACR= American College of Rheumatology preliminary criteria for improvement, CINCA = chronic infantile neurological cutaneous and articular, MTX= methotrexate, CP =cyclophosphamide, TNF = tumour necrosis factor, DMRDs = disease modifying anti-rheumtic drugs, DRM = dose ranging multicenter, MDBP = multicenter double blind parallel, wks =weeks.

f Rheumatology preliminary criteria for improvement, CINCA = chronic infantile neurological cutaneous and articular, MTX= methotrexate, CP =cyclophosphamide, TNF = tumour necrosis factor, DMRDs = disease modifying anti-rheumtic drugs, DRM = dose ranging multicenter, MDBP = multicenter double blind parallel, wks =weeks. Source of Support: Nil Conflict of Interest: None declared.

Introduction Calcium channel blockers are the leading cause of cardiovascular drug overdose and are responsible for 48% of deaths related to cardiovascular drug exposure.[1] Treating patients with overdose of these medications can challenge even the most experienced physician. The difficulty arises because patients severely poisoned with calcium channel blockers may have profound refractory bradycardia and hypotension.[1] Reports of calcium channel blocker overdose are scarce in Indian literature. We report two cases of Amlodipine overdose treated in our ICU.

the most experienced physician. The difficulty arises because patients severely poisoned with calcium channel blockers may have profound refractory bradycardia and hypotension.[1] Reports of calcium channel blocker overdose are scarce in Indian literature. We report two cases of Amlodipine overdose treated in our ICU. Case Reports Case 1 A 25-year-old physiotherapist was brought to our hospital with complaints of recurrent vomiting following ingestion of 100 mg of Amlodipine and few sustained release tablets of Diclofenac, four hours earlier. Initially she was taken to a local hospital, where gastric lavage was performed and she was treated with intravenous fluids and Dopamine infusion in view of low blood pressure. There was no history of syncope/seizure, dyspnoea or palpitations. She was a known case of bronchial asthma on inhaled Salbutamol as and when required. On examination, in the ICU of our hospital, she was drowsy but arousable on light stimuli. She was pale with cold, clammy extremities, her heart rate was 80/min, regular, sinus rhythm and her blood pressure was 60 mm Hg systolic. There were no heart murmurs or gallop, and her lungs were clear on auscultation. Abdominal examination revealed mild epigastric tenderness. Her initial hemogram, liver & renal function tests, ABG and electrolytes were unremarkable. The serum lactate level was 2.3 mmol/L (Normal reference range – 0.5-2.2 mmol/L). No abnormality was detected in the chest X-ray and electrocardiogram. Echocardiography revealed normal chamber size with normal LV systolic function.

initial hemogram, liver & renal function tests, ABG and electrolytes were unremarkable. The serum lactate level was 2.3 mmol/L (Normal reference range – 0.5-2.2 mmol/L). No abnormality was detected in the chest X-ray and electrocardiogram. Echocardiography revealed normal chamber size with normal LV systolic function. In addition to the standard resuscitative measures, the patient was treated with 30 ml of 10% Calcium Gluconate over 5 min followed by an infusion of 10 ml/hr of calcium gluconate. 10 mg of Glucagon was administered intravenously as a stat dose, and an infusion of Glucagon at 3 mg/hr was continued. Infusions of normal saline (totaling 5.5 L during first 24 hours) and noradrenaline was used to support the blood pressure. With these measures, the patient started showing improvement in her hemodynamics, only to deteriorate after 24h with shortness of breath and clinical/radiological features suggestive of pulmonary edema. Repeat echocardiogram was performed which did not reveal any abnormal findings. The patient was treated with diuretics and oxygen. Over the next 48h she showed gradual improvement in her clinical condition. Inotropes, Calcium and Glucagon infusions were ceased after 72h of admission. On day five, she was discharged in good health after a psychiatry consultation.

d not reveal any abnormal findings. The patient was treated with diuretics and oxygen. Over the next 48h she showed gradual improvement in her clinical condition. Inotropes, Calcium and Glucagon infusions were ceased after 72h of admission. On day five, she was discharged in good health after a psychiatry consultation. Case 2 A 65-year-old male was admitted to our ICU with a history of restlessness following accidental ingestion of 50 mg of Amlodipine along with his usual dose of 50 mg Atenolol, six hours earlier. He was a known case of hypertension for 15 years, on regular medications. He was diagnosed to have mild renal insufficiency 6 years prior to present admission, with a stable serum creatinine level. On examination he was conscious, oriented with normal sinus rate of 62/ min, blood pressure of 112/76 mmHg and bilateral pedal edema. Respiratory, cardiovascular and neurological examinations were normal. Electrocardiograph showed normal sinus rhythm. Initial hemogram, random blood sugar, serum electrolytes, arterial blood gas and electrocardiogram were unremarkable. Blood urea and serum creatinine values were 79 mg/dl and 4.3 mg/dl respectively. Echocardiography revealed left ventricular hypertrophy with normal LV systolic and diastolic function.

rmal sinus rhythm. Initial hemogram, random blood sugar, serum electrolytes, arterial blood gas and electrocardiogram were unremarkable. Blood urea and serum creatinine values were 79 mg/dl and 4.3 mg/dl respectively. Echocardiography revealed left ventricular hypertrophy with normal LV systolic and diastolic function. The patient was given 30 ml of 10 % calcium gluconate - over 5 mins, followed by an infusion of calcium gluconate at a rate of 10 ml/hr and after a bolus dose of Glucagon of 10 mgm, an infusion of Glucagon at a rate of 3 mg/hr was commenced. Over the next six hours the patient became hypotensive not responding to volume resuscitation and requiring inotropic support with adrenaline and dopamine infusion. His sensorium gradually deteriorated. Twelve hours following the overdose he was unresponsive to painful stimuli. Arterial blood gas analysis revealed mixed respiratory and metabolic acidosis with a pH of 6.8, pCO2 of 115 mmHg, pO2 of 76 mmHg and a HCO3 of 16 mmol/L. He was on high dose inotropic support with normal central venous pressure and there was a drop in the hourly urine output. Gastric aspirate was coffee ground. He was electively intubated and ventilated. Ultrasonography of the abdomen showed normal kidney size with increased echogenicity. UGI endoscopy revealed erythematous gastric mucosa without any ulcer crater.

rmal central venous pressure and there was a drop in the hourly urine output. Gastric aspirate was coffee ground. He was electively intubated and ventilated. Ultrasonography of the abdomen showed normal kidney size with increased echogenicity. UGI endoscopy revealed erythematous gastric mucosa without any ulcer crater. The next day the patient started showing signs of improvement. His sensorium improved but he remained oliguric. Arterial blood gas analysis showed pH of 7.2 pCO2 of 34. mm Hg, pO2 of 115 mmHg and a bicarbonate of 13.7 mmol/L. Repeat potassium was 7.8 mEq/L. In view of oliguria, persistent acidosis and hyperkalemia hemodialysis was started. Over the next 24h, his condition stabilised and inotropic support, glucagon, calcium infusions were tapered off. He was successfully weaned off from the ventilator on the following day. On day 10 of admission he was discharged from the hospital. Discussion Amlodipine is a dihydropyridine group of calcium channel blockers (CCBs) having a half life of 30-50 hours and a large volume of distribution (21 L/Kg).[1] Unlike nondihydropyridine CCBs like Verapamil and Diltiazem, dihydropyridines as a group have predominant effect on vascular smooth muscle cells with little effect on cardiac pacemaker cells or contractility.[2] But in significant overdose some of this pharmacological selectivity may be lost.[1]

tribution (21 L/Kg).[1] Unlike nondihydropyridine CCBs like Verapamil and Diltiazem, dihydropyridines as a group have predominant effect on vascular smooth muscle cells with little effect on cardiac pacemaker cells or contractility.[2] But in significant overdose some of this pharmacological selectivity may be lost.[1] In both the cases described, the effect of Amlodipine on vascular smooth muscle was evident. Both the patients developed profound hypotension requiring prolonged inotropic support without significant effect on cardiac pacemaker or conduction system and preserved systolic function of the heart. The first case was complicated by transient pulmonary edema which might have resulted from the combined effects of the drug itself, prolonged hypotension and fluid resuscitation during the initial phase of therapy. Normal cardiac function on echocardiography, excluded myocardial depression as an etiologic factor. Noncardiogenic pulmonary edema following CCB overdose is well described in the literature.[3–5] Pre-capillary vasodilatation resulting in excessive pulmonary capillary transudation was suggested as the possible mechanism of non-cardiogenic pulmonary edema by Humbert et al.[3]

ocardial depression as an etiologic factor. Noncardiogenic pulmonary edema following CCB overdose is well described in the literature.[3–5] Pre-capillary vasodilatation resulting in excessive pulmonary capillary transudation was suggested as the possible mechanism of non-cardiogenic pulmonary edema by Humbert et al.[3] The second patient was complicated by acute on chronic renal failure and had mixed respiratory and metabolic acidosis, requiring mechanical ventilation and hemodialysis. CCB overdose is frequently complicated by renal failure, related to the severe hypoperfusion and end-organ ischemia.[1] Metabolic acidosis in our patient could be attributed to the renal failure and prolonged hypotension, well described in the literature. Decreased insulin secretion and increased insulin resistance may also lead to the metabolic acidosis in CCB poisoning.[5] Additionally, CCB mediated inhibition of calcium-stimulated mitochondrial activity may lead to interference with glucose catabolism resulting in increased lactate production and ATP hydrolysis contributing to the acidosis.[1] Respiratory acidosis complicating CCB overdose has not been described in the past. Only possible explanation for this ventilation failure could be the decreased respiratory drive caused by the cerebral hypoperfusion in the absence of any primary pulmonary pathology.

n and ATP hydrolysis contributing to the acidosis.[1] Respiratory acidosis complicating CCB overdose has not been described in the past. Only possible explanation for this ventilation failure could be the decreased respiratory drive caused by the cerebral hypoperfusion in the absence of any primary pulmonary pathology. There is no definitive evidence that gastrointestinal decontamination either in the form of activated charcoal or the whole bowel irrigation alters the clinical outcome in the CCB overdose. However, GI decontamination is still advocated because of the potential lethal nature of this overdose and lack of specific efficacious antidote. But potential risks of GI decontamination should be kept in mind e.g. gastric lavage should probably be withheld in patients who are already bradycardic or have conduction disturbances.[6] There is potential for delayed toxicity by sustained release preparations of calcium channel blockers due to delayed absorption. Case reports have suggested the importance of whole bowel irrigation in these cases.[78]

hould probably be withheld in patients who are already bradycardic or have conduction disturbances.[6] There is potential for delayed toxicity by sustained release preparations of calcium channel blockers due to delayed absorption. Case reports have suggested the importance of whole bowel irrigation in these cases.[78] Hyperinsulinemic euglycemia has emerged as possible adjuvant therapy for CCB toxicity. Several possible roles of Insulin are described. Insulin increases plasma levels of ionized calcium, improves hyperglycemic acidotic state, improves myocardial utilization of carbohydrates and exerts its own independent inotropic effect.[9] Currently all available information on hyperinsulinemic euglycemia therapy is limited to case reports and series. Probably it should be considered for patients CCB overdose who do not respond to initial supportive therapy.[9]

es myocardial utilization of carbohydrates and exerts its own independent inotropic effect.[9] Currently all available information on hyperinsulinemic euglycemia therapy is limited to case reports and series. Probably it should be considered for patients CCB overdose who do not respond to initial supportive therapy.[9] Many other treatment modalities have been described in the literature. Transvenous pacing may be required in patients with severe symptomatic bradycardia not responding to Atropine or Isoprenaline infusion.[10] Standard cardiopulmonary bypass has been used in some cases to allow sufficient time for liver detoxification.[11] Extracorporeal membrane oxygenation was described in massive Diltiazem overdose for temporary hemodynamic support.[12] Therapeutic plasma exchange was also utilized in the management of certain cases of Amlodipine overdose.[13] Hemofiltration and dialysis may not be of help in Calcium Channel Blocker overdose because of high protein binding, extensive tissue distribution and rapid rate of metabolism of this group of drugs.[10] We conclude that Amlodipine overdose can be treated successfully with early GI decontamination, resuscitation with calcium and glucagon infusion, judicious use of inotropes and careful monitoring of possible complications. Prospective trial on the use of hyperinsulinemic euglycemia therapy is required to define its role as the first line treatment in CCB overdose. Source of Support: Nil Conflict of Interest: None declared.

Introduction The cuff-pressure of endotracheal tubes play an important role on the development of tracheal damage. To minimize this injury, use of high volume and low pressure cuff endotracheal tubes are advocated. Surgical resection for the management of post intubation tracheal stenosis remains a controversial issue because of the risk of recurrence at the site of anastomosis and also these patients are often at higher surgical risk. Other alternative therapies like laser resection, stent placement and balloon bronchoplasty can also be tried. Laser resection, stent placement are expensive and require expertise and available only at tertiary care centres. Balloon bronchoplasty is a relatively simple procedure, which can be done under sedation and even at the bedside.

therapies like laser resection, stent placement and balloon bronchoplasty can also be tried. Laser resection, stent placement are expensive and require expertise and available only at tertiary care centres. Balloon bronchoplasty is a relatively simple procedure, which can be done under sedation and even at the bedside. Case Report A fifty six year old gentleman was referred to our hospital with the complaints of gradually increasing difficulty in breathing and dry cough for one month and an audible wheeze for the last seven days. He denied any history of fever, weight loss or anorexia. His background history revealed that he was a smoker and had quit smoking three months earlier, and was taking antihypertensive medicines for the last three years. Three months prior to the present complaints, the patient had received thrombolytic therapy (Urokinase) for an inferior wall-plus right ventricular myocardial infarction. Few hours after thrombolysis, he had developed severe cardiogenic shock with left ventricular dysfunction and was put on mechanical ventilatory support, and also needed an intra aortic balloon pump to support his heart. Subsequently, he underwent angiography and PTCA to the left circumflex coronary artery. The patient made a good recovery after definitve treatment for heart failure was initiated and was extubated four days later and was discharged from the unit in a stable condition after twelve days.

alloon pump to support his heart. Subsequently, he underwent angiography and PTCA to the left circumflex coronary artery. The patient made a good recovery after definitve treatment for heart failure was initiated and was extubated four days later and was discharged from the unit in a stable condition after twelve days. The patient's general physical examination was unremarkable except for an audible wheeze. A Chest radiograph was normal. Pulmonary function tests showed reduction in the expiratory flow rate. Direct laryngoscopy showed normal movement of both the vocal cords. He underwent diagnostic bronchoscopy and on bronchoscopy, multiple membranous web like stenosis on the upper tracheal cartilages with small pedunculated soft tissue growth distal to the stenosis was seen [Figure 1]. Punch biopsy was taken from the growth and histopathological examination showed chronic granulation tissue comprising of numerous thick wall blood vessels with dense stroma and reactive fibroblasts. Figure 1 Bronchoscopic image showing multiple web like stenosis Under short general anesthesia, the granulation tissue was removed by electrosurgery and the stenosed segment was dilated by PPD™ esophageal progressive balloon Dilator (TeleMed System Inc. USA, Balloon length 8 cm and largest external diameter of 17mm with 118 PSI). The maximum diameter was held for 30s and the procedure was repeated thrice. The patent was hyperoxygenated before each maneuver. After the third dilation, the achieved diameter was as per expectation [Figure 2]. Figure 2 Bronchoscopic image after successful dilation

Under short general anesthesia, the granulation tissue was removed by electrosurgery and the stenosed segment was dilated by PPD™ esophageal progressive balloon Dilator (TeleMed System Inc. USA, Balloon length 8 cm and largest external diameter of 17mm with 118 PSI). The maximum diameter was held for 30s and the procedure was repeated thrice. The patent was hyperoxygenated before each maneuver. After the third dilation, the achieved diameter was as per expectation [Figure 2]. Figure 2 Bronchoscopic image after successful dilation After the procedure, the patient received prednisolone 30mg once daily and Amoxy-clavulanic acid combination 625mg twice daily for three days. After three months, the follow up bronchoscopy showed no further narrowing and the patient remains asymptomatic for the last one year.

Figure 2 Bronchoscopic image after successful dilation After the procedure, the patient received prednisolone 30mg once daily and Amoxy-clavulanic acid combination 625mg twice daily for three days. After three months, the follow up bronchoscopy showed no further narrowing and the patient remains asymptomatic for the last one year. Discussion In earlier days, post intubation tracheal stenosis was one of the common complications of prolonged intubation. With the introduction of endotracheal tubes with a large area of contact (high volume, low pressure cuff) the incidence of post intubation tracheal stenosis in intensive care units has remarkably reduced. However, post intubation stenosis still remains an important cause of acquired tracheal obstruction. When the cuff pressure exceeds the mucosal capillary pressure (30 mm of Hg) of the trachea, the mucosa that lies between the cuff of the balloon and the underlying cartilages develops ischemia. Long standing ischemia can leads to ulceration and chondritis of tracheal cartilages, followed by fibrotic healing, leading to progressive tracheal stenosis. One prospective study had shown even intubation with high volume low pressure cuffed tubes, 11% of critically ill patients had developed tracheal stenosis at the cuff site.[1] Usual factors responsible for stenosis are: cuff pressure, size of the tube relative to the tracheal lumen, duration of intubation, cardiovascular status during intubation, movement of tube during the period of intubation, sex and age of the patient, material from which cuff is manufactured and the possible adverse effects of steroids etc.[2] However, tracheal stenosis can also be developed by intubation lasting as short as 24 hours only.[3]

ation, cardiovascular status during intubation, movement of tube during the period of intubation, sex and age of the patient, material from which cuff is manufactured and the possible adverse effects of steroids etc.[2] However, tracheal stenosis can also be developed by intubation lasting as short as 24 hours only.[3] These patients may remain asymptomatic for a variable period and then develop difficulty in expectoration and dyspnea on exertion and can progress to airway obstruction with the development of a stridor. Post intubation tracheal stenosis is often misdiagnosed as asthma and is not diagnosed at initial presentation in as many as 44% of patients.[4] Patients usually remain asymptomatic until the trachea has stenosed to 30% of its original diameter, and it may take as long as three months before the diagnosis.[4] During spirometry, flow-volume loops exhibit a characteristic reduction in peak expiratory flow, with a plateau in the expiratory curve. However, a classical loop cannot be seen unless the diameter is narrowed to 8-10mm. Spirometry results are often complicated by concomitant lung diseases and it is not a reliable diagnostic technique. Chest X-ray rarely detects stenosis but a CT scan will provide precise information regarding exact location, extent of stenosis and the nature of surrounding soft tissues.

diameter is narrowed to 8-10mm. Spirometry results are often complicated by concomitant lung diseases and it is not a reliable diagnostic technique. Chest X-ray rarely detects stenosis but a CT scan will provide precise information regarding exact location, extent of stenosis and the nature of surrounding soft tissues. Bronchoscopy is the mainstay of diagnosis and it also rules out other diseases (i.e. vocal cord palsy, tracheomalacia). A simple bronchoscopic procedure for tracheal stenosis had been developed by Freitag et al,[5] for the classification of tracheobronchial stenosis and to compare the results and analyze the outcome over a wide range of interventions. They divided tracheal stenosis into structural or functional types and further classified it by the degree of stenosis, location and the transition zone. Post intubation web like tracheal stenosis is an example of Type 4 stenosis.

is and to compare the results and analyze the outcome over a wide range of interventions. They divided tracheal stenosis into structural or functional types and further classified it by the degree of stenosis, location and the transition zone. Post intubation web like tracheal stenosis is an example of Type 4 stenosis. The various options for treating tracheal stenosis are dilation, laser resection, stenting and resection anastomosis. Brichet et al,[6] reviewed 32 consecutive cases of post intubation tracheal stenosis at their institution and proposed rigid bronchoscopy with neodymium ±yttrium aluminium garnet (Nd-YAG) laser resection or stent implantation (removable stent) as the first-line of treatment. In their study, laser resection was curative in 66% of web-like stenosis. In patients with complex stenosis or failed laser treatment (up to three sessions) removable stents were inserted. Subsequently, if the patient was judged operable, the stent was removed and the patient underwent definitive surgery. The serious complications of laser therapy are perforation of major intrathoracic blood vessels, pneumothorax or pneumomediastinum secondary to perforation of the airway wall and endobronchial ignition.

Subsequently, if the patient was judged operable, the stent was removed and the patient underwent definitive surgery. The serious complications of laser therapy are perforation of major intrathoracic blood vessels, pneumothorax or pneumomediastinum secondary to perforation of the airway wall and endobronchial ignition. Tracheal sleeve resection is the definitive surgical treatment. The stenotic segments are resected and end to end anastomosis are done. Alternatively, various synthetic materials can be used to bridge the gap. However, sleeve resection can only be possible for patients with good neurological, cardiovascular and respiratory condition. Usual contraindications for surgery are, a possibility of the requirement for prolonged ventilatory support in the post operative period, medical contraindications and a long length of stenosis which is not technically feasible for resection and anastomosis. The failure rate of surgery is about 15%. In the series of 340 patients reported by Bonette et al,[7] definitive cure was obtained at the first attempt in 265 patients, after a second tracheal resection in six patients.

tions and a long length of stenosis which is not technically feasible for resection and anastomosis. The failure rate of surgery is about 15%. In the series of 340 patients reported by Bonette et al,[7] definitive cure was obtained at the first attempt in 265 patients, after a second tracheal resection in six patients. Balloon bronchoplasty can be done via a rigid or flexible bronchoscope with or without fluoroscopic guidance. A guide wire can be inserted first through the working channel of a bronchoscope, and a balloon is passed over the guide wire, and the guidewire later removed. Alternatively, the balloon can be passed by the side of the bronchoscope. The length of the balloon should be sufficient to reach at least one cm below and above the stenosed segment. The balloon can be filled with saline or dilute contrast medium and inflation can be done by a pressure syringe device to achieve the specified pressure. The balloon should stretch 2-3 mm beyond the desired diameter. The balloon can be kept inflated for 15-150 seconds and there is no such definitive study for the adequate dilation time. The patients should be hyperventilated in between the procedure to maintain the oxygen saturation above 90%, during the procedure. The mechanism of balloon bronchoplasty is expanding the tracheal wall by creating a longitudinal split on posterior tracheal wall. Balloon bronchoplasty is an easy and effective way to relieve both the proximal and distal airway stenosis and can also be repeated. Those patients who require more than one balloon dilation may need additional therapies i.e. laser or stent placement. The overall complication rates are as less as 5%. Balloon bronchoplasty can often cause superficial and deep ulceration of the tracheal mucosa, which usually heals without much granulation tissue or fibrosis. If the tracheal cartilages are not damaged, a good outcome can be achieved by a single dilation. Excessive balloon inflation may cause rupture of the airway leading to hemorrhage, pneumothorax, pneumomediastinum, or mediastinitis.

of the tracheal mucosa, which usually heals without much granulation tissue or fibrosis. If the tracheal cartilages are not damaged, a good outcome can be achieved by a single dilation. Excessive balloon inflation may cause rupture of the airway leading to hemorrhage, pneumothorax, pneumomediastinum, or mediastinitis. Mayse et al,[8] evaluated the efficiency and safety of balloon bronchoplasty in 26 patients. Balloon dilation as the only mode of therapy was used in 26% of their cases and when used as a part of a multimodal approach, the success rate was 100%. No significant adverse events were observed. For benign non inflammatory stenosis and annular cicatrical stenosis, the success rate of balloon bronchoplasty is high. Long term efficacy of balloon bronchoplasty in benign stenosis after 32 months is reported as 43%.[9] The systemic use of corticosteroids or antibiotics are probably unnecessary, although no definitive data is available.

Mayse et al,[8] evaluated the efficiency and safety of balloon bronchoplasty in 26 patients. Balloon dilation as the only mode of therapy was used in 26% of their cases and when used as a part of a multimodal approach, the success rate was 100%. No significant adverse events were observed. For benign non inflammatory stenosis and annular cicatrical stenosis, the success rate of balloon bronchoplasty is high. Long term efficacy of balloon bronchoplasty in benign stenosis after 32 months is reported as 43%.[9] The systemic use of corticosteroids or antibiotics are probably unnecessary, although no definitive data is available. In spite of the use of a high volume and low pressure cuffed endotracheal tube, our patient developed post intubation tracheal stenosis within 4 days of intubation, possibly due to underlying hypotension. As more and more patients receive prolonged mechanical ventilatory support in ICU or undergo a tracheostomy for ventilatory support, the risk of developing stenosis remains high. Tracheal damage and subsequent stenosis can occur in any patient after intubation of any duration and a high index of suspicion is required to diagnose these cases at the earliest. Tracheal stenosis should be treated with Laser therapy or by surgical resection. However, Laser therapy is not readily available because of the prohibitory cost and the surgical management is often not possible because of associated risk factors.

h index of suspicion is required to diagnose these cases at the earliest. Tracheal stenosis should be treated with Laser therapy or by surgical resection. However, Laser therapy is not readily available because of the prohibitory cost and the surgical management is often not possible because of associated risk factors. Balloon bronchoplasty is an inexpensive procedure. The disposable esophageal balloon dilator is sufficient for the procedure, cost of which is approximately INR 6500 and can be reused. The other advantages are: it can be done at the bedside, can be repeated and short term improvement can sustain the patient for other definitive and complex management. So balloon bronchoplasty should be offered as the initial treatment for post intubation web like stenosis, especially in the developing countries. Source of Support: Nil Conflict of Interest: None declared.

Introduction Central venous catheterization is an essential component of modern day critical care. But the insertion of central venous catheters is not free of complications. Numerous complications described both during placement of the catheter and later in the long-term maintenance, are both hazardous to the patients and expensive to treat. Malposition of the catheter tip is one of such complications, which usually involves placement of the catheter in various large tributaries of superior vena cava. This case report illustrates a rare malposition of a central venous catheter tip in a small tributary of left brachiocephalic vein.

s and expensive to treat. Malposition of the catheter tip is one of such complications, which usually involves placement of the catheter in various large tributaries of superior vena cava. This case report illustrates a rare malposition of a central venous catheter tip in a small tributary of left brachiocephalic vein. Case Report A 28-year-old male, was admitted to our ICU with surgical site infection and severe sepsis. Ten days prior to the present admission he underwent ileal resection and ileostomy for ileal perforation with underlying ileocaecal tuberculosis. On examination, he was in respiratory distress with tachypnoea, tachycardia and bilateral crepitations on chest auscultation. Arterial blood gas showed severe hypoxia. Possibilities of fluid overload as a result of aggressive fluid resuscitation and ARDS were considered and it was decided to place a central venous catheter for monitoring of central venous pressure. A catheter was placed through the left internal jugular vein with all aseptic precautions using the Seldinger technique. The catheter was gradually advanced up to the 13 cm mark without difficulty. After free return of venous blood was obtained, the catheter was felt to be placed correctly in the superior vena cava. Only unusual thing observed was patient complaining of left sided back pain on flushing the catheter with heparinized saline.

e catheter was gradually advanced up to the 13 cm mark without difficulty. After free return of venous blood was obtained, the catheter was felt to be placed correctly in the superior vena cava. Only unusual thing observed was patient complaining of left sided back pain on flushing the catheter with heparinized saline. An anteroposterior chest radiograph, obtained to confirm the position of the catheter, revealed the left paramedian location of the catheter following the aortic knob and pointing laterally [Figure 1]. The inability to properly position the acutely dypnoeic patient barred us from taking a lateral film. The catheter was removed, as it was considered to be in one of the small tributaries of left brachiocephalic vein and an alternate venous access was obtained subsequently via the right internal jugular vein. Figure 1 Anteroposterior Chest Radiograph showing central venous catheter lying in the left paramedian location following the aortic knob Discussion Malposition of central venous catheters was reported to be between 1 to 33 percent by different investigators.[1] These are usually limited within the larger tributaries of the superior vena cava.[1] Malposition of the central venous catheter in the smaller tributaries of the central veins is only rarely reported. Muhm et al, with their experience of 2104 central venous catheterization could find only one incidence of misdirected catheter in the smaller tributary.[2]

larger tributaries of the superior vena cava.[1] Malposition of the central venous catheter in the smaller tributaries of the central veins is only rarely reported. Muhm et al, with their experience of 2104 central venous catheterization could find only one incidence of misdirected catheter in the smaller tributary.[2] Thoracic pain syndromes on flushing of misplaced central venous catheters in the smaller tributaries have been described in the literature. Webb et al,[1] reported three cases of accidental cannulation of the internal thoracic vein, presenting with retrosternal pain. Patients are reported to complain of midthoracic back pain following cannulation of superior intercostal and azygos venous system.[1–3] Though characteristic chest pain often provides clue to the erroneous catheter position, catheter malposition is more often identified by a post-procedure chest radiograph.[45] A properly placed subclavian or internal jugular catheter should run parallel to the shadow of superior vena cava.[6] In the posteroanterior or anteroposterior view, the internal thoracic vein catheter will be located more laterally, a catheter in the superior intercostal vein will follow the aortic knob and pericardiophrenic vein catheter will follow the left cardiac border.[4] In the lateral view catheters in the internal thoracic, pericardiophrenic and superior intercostal veins will occupy the anterior, middle and posterior mediastinum respectively. Placement of the catheter in the remnant of the left-sided superior vena cava should also be kept in mind,[7] in which case the catheter will be in the left paramedian location in the frontal view and will occupy the middle mediastinum in the lateral view.

py the anterior, middle and posterior mediastinum respectively. Placement of the catheter in the remnant of the left-sided superior vena cava should also be kept in mind,[7] in which case the catheter will be in the left paramedian location in the frontal view and will occupy the middle mediastinum in the lateral view. Because of the lack of experience, the importance of back pain on flushing of the misplaced catheter in our patient was appreciated only retrospectively. The malposition was evident only on review of the postprocedural chest X-ray. The characteristic location of the catheter in the frontal view and the associated classical back pain on flushing the catheter makes the left superior intercostal vein as the most likely position of the catheter. A lateral film and a venogram could have established the exact location of the catheter beyond any doubt. Because of the longer course and more transverse lie of the left brachiocephalic and more frequent smaller tributaries, malposition of the venous catheter is commoner when cannulation attempt is made via the left brachiocephalic vein rather than its right sided counterpart.[14] The malposition of the venous catheter in the smaller tributaries can be prevented by avoiding the left internal jugular/subclavian vein cannulation, limiting the depth of insertion of the guidewire during cannulation and the use of J-tipped guidewire.[8]

rachiocephalic vein rather than its right sided counterpart.[14] The malposition of the venous catheter in the smaller tributaries can be prevented by avoiding the left internal jugular/subclavian vein cannulation, limiting the depth of insertion of the guidewire during cannulation and the use of J-tipped guidewire.[8] After placement of all central venous catheters, a chest radiograph should be obtained. A posteroanterior or anteroposterior film is usually adequate; if not, a lateral view may be taken. If uncertainty still exists, a venogram through the catheter should be performed for precise localization.[9] Source of Support: Nil Conflict of Interest: None declared.

Introduction Cerebral malaria is usually secondary to P. falciparum infection. However, there are infrequent reports of cerebral malaria associated with P. vivax infection. To our knowledge, only 45 cases of central nervous system P. vivax malaria are reported in the scientific literature since 1920, about half of these cases have occurred in children.[12] Here we report three rare cases of cerebral malaria caused by P. vivax. Case Report Three male patients, each aged over 18 years, presented with high-grade intermittent fever of more than four days duration. The fever was associated with chills and rigors. All the three patients had presented with altered consciousness There was history of generalized tonic clonic convulsions prior to admission, in each case. Two of them were severely dehydrated. Their capillary blood sugar level was normal at presentation.

days duration. The fever was associated with chills and rigors. All the three patients had presented with altered consciousness There was history of generalized tonic clonic convulsions prior to admission, in each case. Two of them were severely dehydrated. Their capillary blood sugar level was normal at presentation. In all cases, routine blood counts, liver function tests, and serum electrolytes, serum urea, and serum creatinine were within normal limits. Peripheral blood smear revealed trophozoites of P. vivax. Antigen test for P. vivax was positive, while that for P. falciparum was negative in all cases. Their cerebrospinal fluid and electroencephalogram (EEG) findings were unremarkable. The patients were treated with supportive therapy and intravenous Artesunate in the recommended dose. Repeat blood smears after two days of therapy showed clearance of the parasites. All the three patients were discharged from ICU in a clinically stable condition and were advised to take Primaquine for 14 days. Follow-up evaluation after one month showed no residual neurological deficit.

sunate in the recommended dose. Repeat blood smears after two days of therapy showed clearance of the parasites. All the three patients were discharged from ICU in a clinically stable condition and were advised to take Primaquine for 14 days. Follow-up evaluation after one month showed no residual neurological deficit. Discussion Organ dysfunction characteristic of P. falciparum malaria is unusual in P. vivax infections. Any patient infected with P. viva who exhibits severe malaria is presumed to be suffering from mixed infection.[2] However, that may not be always true. As evident from the present report, P. vivax infection can also present as cerebral malaria. Clinical data provided by Kochar et al, indicates that P. vivax can cause both sequestration-related and nonsequestration-related complications of severe malaria, all of which are commonly associated with P. falciparum infections.[3] The exact pathogenetic mechanism however remains elusive. Sachdev and Mohan[4] studied the clinicolaboratory profile of six patients with P. vivax cerebral malaria. The presenting features were of acute febrile encephalopathy, convulsions, and coma. Focal neurological signs were observed in one patient. Ozen et al,[1] have recently described a case of cerebral P. vivax malaria that presented with status epilepticus. Some experts also suggest that cerebral malaria subjects might have an underlying seizure disorder and those seizures are precipitated by the high fever associated with the disease. Source of Support: Nil Conflict of Interest: None declared.

Background The World Health Organization has reported that 60% of deaths in developing countries occurred as a result of communicable diseases.[1] A total of 50% of the deaths due to severe sepsis in these countries occurred within the first 24 hours of admission and often shock preceded death.[2] In India, a lack of responsive emergency medical systems,[3] late presentation with little pre-hospital resuscitation,[4] and very few well-equipped and appropriately staffed pediatric emergency departments (PED),[5] are some of the reasons contributing to the high mortality in pediatric septic shock. In addition, front-line physicians often fail to recognize early signs of septic shock resulting in the failure to institute appropriate therapy. Literature reports that when shock was unresolved, progression to multi-organ failure would be inevitable resulting in an overall mortality of 46% to 54%.[6–9]

septic shock. In addition, front-line physicians often fail to recognize early signs of septic shock resulting in the failure to institute appropriate therapy. Literature reports that when shock was unresolved, progression to multi-organ failure would be inevitable resulting in an overall mortality of 46% to 54%.[6–9] Cognizant of the need for early recognition and treatment, a time sensitive, goal directed, step-wise protocol was published by the American College of Critical Care Medicine (ACCM)[10] to guide the bedside physician in the recognition and management of shock in the initial hours of presentation. This protocol was incorporated into the Pediatric Advanced Life Support (PALS) Course Manual in 2002.[11] Aggressive emergency management using this protocol has been successful in decreasing mortality from septic shock in various countries.[12–17] In 1993, the PALS was formally accredited by the Indian Academy of Pediatrics (IAP) as a separate cell of the IAP. Since then, this course has been conducted by certified PALS instructors.[18] We chose to conduct this survey to determine whether physicians involved in the care of children were aware of the ACCM/PALS sepsis guidelines, and whether they had the skills necessary to implement the guidelines.

Cognizant of the need for early recognition and treatment, a time sensitive, goal directed, step-wise protocol was published by the American College of Critical Care Medicine (ACCM)[10] to guide the bedside physician in the recognition and management of shock in the initial hours of presentation. This protocol was incorporated into the Pediatric Advanced Life Support (PALS) Course Manual in 2002.[11] Aggressive emergency management using this protocol has been successful in decreasing mortality from septic shock in various countries.[12–17] In 1993, the PALS was formally accredited by the Indian Academy of Pediatrics (IAP) as a separate cell of the IAP. Since then, this course has been conducted by certified PALS instructors.[18] We chose to conduct this survey to determine whether physicians involved in the care of children were aware of the ACCM/PALS sepsis guidelines, and whether they had the skills necessary to implement the guidelines. Methods The ACCM/PALS sepsis guidelines were taught as a separate interactive presentation during the PALS courses conducted in 4 academic institutions in Chennai, Manipal, Mangalore, and Trivandrum - cities representing the three southern states of Tamil Nadu, Karnataka, and Kerala, respectively, between February and April 2006. Various case scenarios were discussed in the shock work station. Each respondent was required to provide some demographic data and answer 11 clinical questions testing their knowledge and ten questions testing their comfort level in performing interventions related to the initial resuscitation in septic shock. The 7th question had three sub-components testing the choice of inotrope in the different clinical scenarios in shock. We assigned a score of 1 for each correct answer resulting in a maximum score of 11. Acceptable answers were based on the recommendations provided by the ACCM/PALS sepsis guidelines 2002. A student t test was used to compare the mean scores of correctly answered individual questions pre and post lecture. A p-value of less than 0.05 was considered significant.

answer resulting in a maximum score of 11. Acceptable answers were based on the recommendations provided by the ACCM/PALS sepsis guidelines 2002. A student t test was used to compare the mean scores of correctly answered individual questions pre and post lecture. A p-value of less than 0.05 was considered significant. Results A total of 118 delegates participated of whom 114 (97%) were pediatricians and four (3%) were anesthetists. A total of 105 (89%) had less than three years of experience in their specialties. Eighty-two (75%) worked in teaching institutions that catered to both adults and children. Sixty-two (53%) physicians worked in hospitals with an outpatient census of less than 20,000, 35 physicians worked in hospitals that had between 20,000 to 30,000 patients in the out patient department (OPD), while 15 physicians (13%) were employed in institutions that register more than 40,000 patients every year. While all institutions treated children with serious sepsis, the number of children managed in each institution is unknown. (a) Knowledge There were more correct answers to all questions post lecture than before the lecture [Table 1Figure 1]. The overall mean number of correct responses for the 9 questions testing knowledge before and after the lecture was 2.1 and 4.07, respectively (P=0.001 paired t test). Figure 1 ACCM/PALS protocol for the management of septic shock in the ED Table 1 Answers to questions posed in a pre- and post-questionnaire Questions testing knowledge Pre test Post test t df P value

(a) Knowledge There were more correct answers to all questions post lecture than before the lecture [Table 1Figure 1]. The overall mean number of correct responses for the 9 questions testing knowledge before and after the lecture was 2.1 and 4.07, respectively (P=0.001 paired t test). Figure 1 ACCM/PALS protocol for the management of septic shock in the ED Table 1 Answers to questions posed in a pre- and post-questionnaire Questions testing knowledge Pre test Post test t df P value Mean ± SD Mean ± SD 1. Volume of fluids needed to correct shock in the first hour 0.05 ± 0.22 0.56 ± 0.50 10.32 118 0.000 2. Correct parameters used to judge response to the initial fluid therapy 0.56 ± 0.50 0.62 ± 0.49 1.15 118 0.252 3. Important early maneuvers in resuscitation of septic shock 0.26 ± 0.44 0.47 ± 0.50 3.92 118 0.000 4. Definition of fluid refractory shock 0.03 ±0.16 0.08 ±0.28 1.96 118 0.052 5. Interventions recommended for the management of fluid refractory shock 0.38 ±0.49 0.47 ±0.50 1.63 118 0.105 6. Management of dopamine/ dobutamine resistant septic shock 0.45 ±0.50 0.42± 0.49 0.54 118 0.588 7a. Choice of vaso dilator/ appropriate catecholamine in the management of fluid refractory dopamine unresponsive normotensive cold shock 0.02 ±0.13 0.08 ±0.27 2.14 118 0.034 7b. Choice of vaso dilator/ appropriate catecholamine in the management of fluid refractory dopamine unresponsive hypotensive cold shock 0.03 ± 0.16 0.08 ±0.28 2.14 118 0.034 7c. Choice of vaso dilator/ appropriate catecholamine in the management of fluid refractory dopamine unresponsive hypotensive warm shock 0.01 ± 0.09 0.08 ± 0.28 3.11 118 0.002 8. The indication of corticosteroids in the management of septic shock 0.26 ± 0.44 0.56 ± 0.50 5.47 118 0.000 9. Appropriate therapeutic endpoints for shock resolution 0.52 ± 0.50 0.65 ± 0.48 2.66 118 0.009 Total 2.51 ± 1.66 4.07 ±2.07 −8.50 118 0.000 (b) Skills and Attitude Although 42% respondents (n=50) were aware of the ACCM/PALS sepsis guidelines, 88% (n=104) did not adhere to it in their practice. However, 98% (n=115) were interested in learning the protocol. A total of 86% (n=101) and 66% (n=78), respectively did not feel comfortable titrating inotropes or intubating in the ED, 78% (n=92) and 67% (n=78), respectively felt that CVA and AP monitoring were unimportant in the management of fluid refractory shock. Of the physicians, 20% (n=24) had never intubated a patient, 78% (n=92) had not introduced a CV catheter, and 76% (n=90) had never introduced an arterial pressure catheter [Table 2].

ED, 78% (n=92) and 67% (n=78), respectively felt that CVA and AP monitoring were unimportant in the management of fluid refractory shock. Of the physicians, 20% (n=24) had never intubated a patient, 78% (n=92) had not introduced a CV catheter, and 76% (n=90) had never introduced an arterial pressure catheter [Table 2]. Table 2 Comfort levels and confidence in performing the following maneuvers in the ED Competence and perceptions Yes No No % No % Performed central venous cannulation 76 64.4 43 35.6 Performed intra-arterial cannulation 87 73.7 31 26.3 Initiation of inotropes 17 14.4 101 85.6 Titration of inotropes 36 30.5 82 69.5 Intubation 40 33.9 78 66.1 Need for CVP monitoring 26 22.0 92 78.0 Need IAP monitoring 39 33.1 79 66.9 Aware of pediatric sepsis protocol 50 42.4 68 57.6 Use of pediatric sepsis protocol 14 11.9 104 88.1 Need to learn more about the treatment of sepsis 3 2.5 115 97.5 Discussion We conducted this survey to determine the knowledge of the ACCM/PALS sepsis guidelines, the skills needed to treat sepsis using these guidelines, and the immediate impact of an interactive presentation. Although, we found modest improvement in knowledge following the lecture, physicians lacked the skills needed to implement this protocol.

rvey to determine the knowledge of the ACCM/PALS sepsis guidelines, the skills needed to treat sepsis using these guidelines, and the immediate impact of an interactive presentation. Although, we found modest improvement in knowledge following the lecture, physicians lacked the skills needed to implement this protocol. On recognition of septic shock, the ACCM/PALS 2002 sepsis protocol recommended attention to the airway, establishment of ventilation, and administration of 20 ml/kg fluid boluses up to or more than 60 ml/kg. If shock was still refractory, it suggested the initiation of an inotrope and placement of CVA and AP catheters to estimate ventricular filling pressures.[19]

2002 sepsis protocol recommended attention to the airway, establishment of ventilation, and administration of 20 ml/kg fluid boluses up to or more than 60 ml/kg. If shock was still refractory, it suggested the initiation of an inotrope and placement of CVA and AP catheters to estimate ventricular filling pressures.[19] Various barriers unique to India prevent the successful translation of these guidelines to practice. Although the ACCM/PALS septic shock guidelines were published in Indian text books,[20–22] contemporary resuscitation in the PED is not widely known. Typically, emergency care in India is provided in areas known as “casualty” where infra-structure is poor.[2324] Specialty training is neither available nor mandatory for personnel involved in Pediatric Emergency Medicine (PEM). Besides, currently there is no Medical Council of India accredited residency program in emergency medicine.[3] Although there are a few hospitals with organized PED services, these are located in large cities affiliated with corporate hospitals and a few apex medical schools. Mostly, the majority of institutions catering to the economically disadvantaged children in India do not have separate PEDs.[8] Furthermore, the medical curriculum fails to place sufficient emphasis on resuscitation training in PEM.[25]

in large cities affiliated with corporate hospitals and a few apex medical schools. Mostly, the majority of institutions catering to the economically disadvantaged children in India do not have separate PEDs.[8] Furthermore, the medical curriculum fails to place sufficient emphasis on resuscitation training in PEM.[25] The lack of hands-on experience and comfort levels in performing procedures such as intubation, CVA or AP catheter placement, and resuscitation pharmacology is therefore not surprising. Skippen, et al. observed that the ACCM/PALS sepsis guidelines cannot be used in environments that lack the skills necessary to implement the guidelines.[26] Our findings lend evidence to this observation. In fact, although, these guidelines were nicely laid out, even community pediatricians in the USA were found lacking in their performance of critical care procedures and in the coordination of the temporal aspects of a prolonged resuscitation.[19]

ment the guidelines.[26] Our findings lend evidence to this observation. In fact, although, these guidelines were nicely laid out, even community pediatricians in the USA were found lacking in their performance of critical care procedures and in the coordination of the temporal aspects of a prolonged resuscitation.[19] Predictably therefore, the death rates in severe sepsis cases reported by apex pediatric intensive care units in India are high at 30 to 50%.[27–29] The surviving sepsis campaign for 2008 envisages a global fall in mortality to 10%.[30] In order to move closer to this goal, a protocol less dependent on invasive monitoring and more dependent on clinical assessment may be more appropriate in the Indian context.[4] Indeed, class 1a evidence from an academic PED of a government children's hospital in Southern India showed that administration of fluids at the rate of 20 ml/kg over 20 minutes up to 60 ml/kg of fluid in the first hour and initiation of an inotrope and performance of intubation when “intubation triggers” were identified followed by further fluids boluses until clinical goals of shock resolution were achieved had demonstrated a dramatic drop in mortality from 50% to 17.6% (P=0.0001) 95%; CI 11.9-24.8%. This data also established the impact of meticulous and serial clinical cardiopulmonary assessment on survival. (OR for survival if shock due to sepsis was corrected in the initial hour was 9.2; 95% CI, 2.1-40.8).[4]

achieved had demonstrated a dramatic drop in mortality from 50% to 17.6% (P=0.0001) 95%; CI 11.9-24.8%. This data also established the impact of meticulous and serial clinical cardiopulmonary assessment on survival. (OR for survival if shock due to sepsis was corrected in the initial hour was 9.2; 95% CI, 2.1-40.8).[4] Another major barrier highlighted by our survey was our inability to provide a reasonable educational experience even for those who chose to seek this knowledge. The experience from other continuing medical education strategies has also not been encouraging. A review of 32 studies, with almost 3,000 health professionals[31] found didactic teaching to be ineffective, interactive workshops to be moderately effective and combining workshops with didactic learning only moderately effective. In a Canadian report of 17 studies examining all resuscitation courses, five showed no improvement in knowledge and eight showed no improvement in skills retention.[32] In a study from Baltimore, 45 PALS trained doctors showed poor performance for skills and prolonged time to skill completion.[33] In another study, successful performance improved for airway management, intra-osseous access, and defibrillation immediately after completion of the PALS course.[34] Pediatric residents were confident in their ability to manage emergencies in two surveys.[3536] However, when they were examined, none of the residents were able to successfully perform both basic and advanced airway skills, and only 11% completed two vascular skills. In the UK, a survey of 88 pediatricians reported poor knowledge in resuscitation with only 9% having had training in PEM.[35] In a later survey, only 26% of 57 physicians (1/3rd who had training in PEM) provided satisfactory answers to questions about cardiac arrest protocols.[36] These surveys, however, did not include the PALS/ACCM sepsis guidelines and cannot be directly compared with our current study. Computerized mannequins with realistic cardio-respiratory responses may improve mastering of skills in emergency care.[3738] The expense and non availability of these mannequins limit its use in the predominantly non-profit PALS courses conducted in India.

delines and cannot be directly compared with our current study. Computerized mannequins with realistic cardio-respiratory responses may improve mastering of skills in emergency care.[3738] The expense and non availability of these mannequins limit its use in the predominantly non-profit PALS courses conducted in India. However, despite the barriers to knowledge transfer, the eagerness of virtually all delegates to learn current concepts is heartening. Perhaps, inclusion of a module demonstrating the management of septic shock using clinical goals[4] may be more appropriate in the Indian context.[39] Conclusion In view of the lack of skills and suboptimal knowledge, the ACCM/PALS sepsis guidelines may be inappropriate in its current format in the Indian setting. More emphasis needs to be placed on educating community pediatricians with a simpler clinical protocol that has the potential to save many more children. Source of Support: Nil Conflict of Interest: None declared.

Introduction Septic shock remains the most common cause of death in non coronary intensive care units (ICUs).[1] To tackle this problem, numerous anti-inflammatory therapies have been tested during the past decade, but all of them have been unable to improve survival in patients with severe sepsis.[2] Thus, there is an urgent need to better characterize septic patients with the worst outcome. Several clinical prognostic factors have already been identified (i.e., preexisting underlying disease, presence of organ dysfunction, and severity of illness scores).[3] Moreover, the hormonal profile has been suggested to be a valid predictor of outcome in critically ill patients.[4] However, a pathophysiologic derangement that could help identify a group of patients who might benefit from a particular treatment has not yet been characterized.

tion, and severity of illness scores).[3] Moreover, the hormonal profile has been suggested to be a valid predictor of outcome in critically ill patients.[4] However, a pathophysiologic derangement that could help identify a group of patients who might benefit from a particular treatment has not yet been characterized. Corticosteroid insufficiency in acute illness can be difficult to discern clinically. When the basic features of Addisonian crisis are present, the diagnosis may be obvious, but features such as fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, delirium, and hypotension are common in patients with acute severe illness.[5] In the majority of cases, it remains extremely difficult to recognize adrenal insufficiency in a patient in the intensive care unit. However, important diagnostic clues are hemodynamic instability despite adequate fluid resuscitation (most often associated with a hyperdynamic circulation and decreased systemic vascular resistance) and ongoing evidence of inflammation without an obvious source that does not respond to empirical treatment.[67] Limitations of a physical examination suggest that the threshold for investigation should be low, especially in patients with septic shock.

yperdynamic circulation and decreased systemic vascular resistance) and ongoing evidence of inflammation without an obvious source that does not respond to empirical treatment.[67] Limitations of a physical examination suggest that the threshold for investigation should be low, especially in patients with septic shock. The integrity of the hypothalamic-pituitary-adrenal (HPA) axis is a major determinant of the host's response to stress.[89] During sepsis, the activation of the HPA axis is highlighted by increased corticotropin release from the pituitary gland,[10] enhanced adrenal secretory activity,[1112] and high plasma cortisol levels.[13–16] However, whether endogenous glucocorticoid levels are adequate or constitute an independent predictor of death remains controversial. [13–18] For instance, several studies showed that the higher the plasma cortisol concentrations, the worse the patient's outcome.[471019–21] In contrast, other studies reported lower cortisol levels in non survivors compared with survivors.[22–24] For this reason, in severe sepsis, the evaluation of the appropriateness of the activation of the HPA axis requires dynamic testing. In this respect, the most commonly used test is the short corticotropin stimulation test, normal adrenal function being defined by a plasma cortisol level (before or at 30 or 60 minutes after the injection of corticotropin) above 20 μg/dL.[25] However, basal plasma cortisol levels are commonly greater than 20 μg/dL in severe sepsis and the use of the absolute increase in plasma cortisol levels after the intravenous injection of corticotropin may be more useful to evaluate adrenal function.[1516] Indeed, occult adrenal insufficiency (i.e., an absolute increment of cortisol concentrations ≤ 9 μg/dL) after corticotropin may be associated with impaired pressor responsiveness to norepinephrine[26] and a high mortality rate.[2728] Such results must be confirmed since other investigators have not found any relationship between cortisol response to corticotropin and survival from sepsis.[29]

ol concentrations ≤ 9 μg/dL) after corticotropin may be associated with impaired pressor responsiveness to norepinephrine[26] and a high mortality rate.[2728] Such results must be confirmed since other investigators have not found any relationship between cortisol response to corticotropin and survival from sepsis.[29] So we undertook a prospective study to assess the factors associated with mortality, taking special interest in cortisol levels and cortisol response to corticotropin in patients with septic shock. Low-dose ACTH test for the diagnosis of HPA failure Due to the decreased sensitivity of the high-dose adrenocorticotropic hormone (HD-ACTH) test for diagnosis of adrenal insufficiency, many investigators evaluated the use of stress levels of ACTH (i.e., 1 to 2 μg) for the diagnosis of adrenal insufficiency. A number of studies have demonstrated that a 1 μg dose (low-dose corticotropin [LD-ACTH] stimulation test) of corticotropin is more sensitive and specific for diagnosing primary and secondary adrenal insufficiency than the 250 μg dose of corticotropin (HD-ACTH).[30–34] Materials and Methods Study Population A prospective inception cohort study was conducted in 2004 and 2005 in the adult intensive care unit of Sheri Kashmir Institute of Medical Sciences Soura, Srinagar, a tertiary care hospital where most of the modern facilities are available. Thirty consecutive patients admitted in the adult intensive care unit were prospectively enrolled in the study if they met the following criteria: Informed consent from the next of the kin Presence of septic shock as evidenced by

Materials and Methods Study Population A prospective inception cohort study was conducted in 2004 and 2005 in the adult intensive care unit of Sheri Kashmir Institute of Medical Sciences Soura, Srinagar, a tertiary care hospital where most of the modern facilities are available. Thirty consecutive patients admitted in the adult intensive care unit were prospectively enrolled in the study if they met the following criteria: Informed consent from the next of the kin Presence of septic shock as evidenced by A systemic inflammatory response as defined by two or more of the following: temperature higher than 38.5°C or lower than 35.0°C, heart rate of more than 90/min, respiratory rate of more than 20/min or a need for mechanical ventilation, white blood cell count of more than 12.0 × 109/L or less than 4.0 × 109/L or containing more than 10% immature forms Evidence of a nidus of infection Systolic blood pressure of less than 90 mm Hg (for at least one hour but less than 24 hours) despite adequate fluid replacement and perfusion of 5 μg/kg/min or more of dopamine or dobutamine and the presence of at least two signs of perfusion abnormalities (i.e, acidosis, oliguria, or an abrupt alteration in the mental status) Patients were excluded from the study if they met any of the following criteria: Had known previous conditions that may have disrupted the HPA axis Were less than 18 years old Had received immunosuppressive therapy Had haematological diseases Were pregnant The protocol was approved by our institutional ethical committee and informed consent was obtained from the patient's next of kin.

Patients were excluded from the study if they met any of the following criteria: Had known previous conditions that may have disrupted the HPA axis Were less than 18 years old Had received immunosuppressive therapy Had haematological diseases Were pregnant The protocol was approved by our institutional ethical committee and informed consent was obtained from the patient's next of kin. Clinical Evaluation At the onset of septic shock, the following variables were recorded: General characteristics including age, gender, date of ICU admission, medical or surgical admission (scheduled or unscheduled) Severity of illness as assessed by the number of organ system failures (OSF score), Simplified Acute Physiology Score II (SAPS II), and vital signs (temperature, mean arterial pressure, heart rate, urinary output. Interventions (at physician's discretion) including volume of fluid infusion per 24 hours, antibiotics, type and titration of vasopressors, surgical procedures, and the need for mechanical ventilation

Severity of illness as assessed by the number of organ system failures (OSF score), Simplified Acute Physiology Score II (SAPS II), and vital signs (temperature, mean arterial pressure, heart rate, urinary output. Interventions (at physician's discretion) including volume of fluid infusion per 24 hours, antibiotics, type and titration of vasopressors, surgical procedures, and the need for mechanical ventilation Laboratory Variables At the onset of septic shock, blood cultures and cultures of specimen drawn from the site of infection, hematologic and chemistry data, and blood gas determinations were done systematically. A short corticotropin stimulation test was performed with 1 μg of tetracosactrin (Synacthéne) given intravenously. Blood samples were taken immediately before the test (T0) and 30 (T30) and 60 (T60) minutes afterward. After centrifugation, samples were stored at -20°C until processed. Samples were thawed at room temperature 2-3 hours before processing. Serum cortisol was measured using the Gammacoat (1251) Cortisol Radioimmunoassay Kit (Diasorin Stillwater, Minnesota 55082, USA) based on the competitive binding principle of the radioimmunoassay. The cortisol response to the corticotropin stimulation test (Δmax) was defined as the difference between T0 and the highest of the T30 and T60 concentrations.

he Gammacoat (1251) Cortisol Radioimmunoassay Kit (Diasorin Stillwater, Minnesota 55082, USA) based on the competitive binding principle of the radioimmunoassay. The cortisol response to the corticotropin stimulation test (Δmax) was defined as the difference between T0 and the highest of the T30 and T60 concentrations. Follow-up All patients were evaluated for 28 days after inclusion in the study. The evaluation of the following variables was performed daily in each patient during shock: vital signs, arterial blood gases, plasma electrolytes, glucose levels, serum creatinine and liver function tests, and interventions as previously defined. Statistical Analysis The statistical analysis of the data was done using student's t-test for the difference of means and a chi-square test and Fishers Exact test were used for nominal data. These tests were referred for P-values for their statistical significance. The P-values (P<0.05) were considered statistically significant. The analysis was performed using comprehensive statistical software, Version 10.0 (Chicago, USA) for Windows®

d a chi-square test and Fishers Exact test were used for nominal data. These tests were referred for P-values for their statistical significance. The P-values (P<0.05) were considered statistically significant. The analysis was performed using comprehensive statistical software, Version 10.0 (Chicago, USA) for Windows® Results Patient Characteristics A total of 30 patients were admitted during the study period in the intensive care unit of Sheri Kashmir Institute of Medical Sciences Soura, Srinagar- a tertiary care hospital where most of the modern facilities are available. Of the 30 patients, 18 (60%; 95% CI, 53–67%) died within the 28-day period following the onset of septic shock. As noted in Table 1, the mean age in years of the survivors and non survivors was 47.25 years old (SD=16.62) and 58.72 years old (SD=19.63), respectively. This difference is statistically non significant (P= 0.108). Also noted in the same table is that there is a statistically non significant difference (p=0.534) in the distribution of gender with respect to survival in patients with septic shock. Table 1 Age and gender distribution of patients with respect to survival in septic shock (p-value is for a comparison between survivors and non survivors)

Results Patient Characteristics A total of 30 patients were admitted during the study period in the intensive care unit of Sheri Kashmir Institute of Medical Sciences Soura, Srinagar- a tertiary care hospital where most of the modern facilities are available. Of the 30 patients, 18 (60%; 95% CI, 53–67%) died within the 28-day period following the onset of septic shock. As noted in Table 1, the mean age in years of the survivors and non survivors was 47.25 years old (SD=16.62) and 58.72 years old (SD=19.63), respectively. This difference is statistically non significant (P= 0.108). Also noted in the same table is that there is a statistically non significant difference (p=0.534) in the distribution of gender with respect to survival in patients with septic shock. Table 1 Age and gender distribution of patients with respect to survival in septic shock (p-value is for a comparison between survivors and non survivors) Mean age (years) Male (n=19) Female (n=11) Total (n=30) Survivors 47.25 8 (42.11%) 4 (36.36%) 12 Non survivors 58.72 11 (57.89%) 7 (63.64%) 18 P-value 0.108 0.534 Tables 2 and 3 show the patient characteristics at the onset of septic shock and the results of the analysis between the groups of survivors and non survivors. Severity assessment scores, OSF scores (P=0.000), and the SAPS II (P= 0.000) were significantly associated with mortality. Table 2 Clinical and laboratory parameters at onset of septic shock

Mean age (years) Male (n=19) Female (n=11) Total (n=30) Survivors 47.25 8 (42.11%) 4 (36.36%) 12 Non survivors 58.72 11 (57.89%) 7 (63.64%) 18 P-value 0.108 0.534 Tables 2 and 3 show the patient characteristics at the onset of septic shock and the results of the analysis between the groups of survivors and non survivors. Severity assessment scores, OSF scores (P=0.000), and the SAPS II (P= 0.000) were significantly associated with mortality. Table 2 Clinical and laboratory parameters at onset of septic shock Variable Survivors (n= 12) Non survivors (n= 18) P-value Pulse beats/min 112.50(18.51) 112.56(19.96) 0.994 Temperature(0C) 38.57(1.05) 38.13(0.96) 0.245 Respiratory Rate (breaths/min) 31.50(6.33) 34.22(7.25) 0.299 MAP (mmHg) 71.42(4.74) 58.61(9.62) 0.000 Hb (g/dl) 11.73(1.96) 11.42(2.43) 0.717 TLC (×109/L) 15.73(3.16) 15.48(3.60) 0.846 Platelets (×109/L) 184(66.49) 113.17(67.24) 0.008 Creatinine (mg/dl) 1.82(0.75) 3.58(2.09) 0.010 Bilirubin (mg/dl) 1.62(1.19) 2.49(2.31) 0.240 paO2: FiO2 (mmHg) 222(114) 157(102) 0.000 Table 3 Distribution of Organ System Failure Assessment (OSFA) Score and SAPS II Score with respect to survival in patients with septic shock

ets (×109/L) 184(66.49) 113.17(67.24) 0.008 Creatinine (mg/dl) 1.82(0.75) 3.58(2.09) 0.010 Bilirubin (mg/dl) 1.62(1.19) 2.49(2.31) 0.240 paO2: FiO2 (mmHg) 222(114) 157(102) 0.000 Table 3 Distribution of Organ System Failure Assessment (OSFA) Score and SAPS II Score with respect to survival in patients with septic shock OSFA Score Total (n=30) Survivors (n=12) Non survivors (n=18) P value <2 0 1 1(100) 0(0) 1 9 8(89) 1(11) 0.000 ≥2 2 5 2(40) 3(60) 3 8 1(12.5) 7(87.5) 4 5 0(0) 5(100) 5 2 0(0) 2(100) SAPS II Score 49.17 (13.29) 39.42 (6.22) 55.67 (12.82) 0.000 Among clinical and biological factors, mean arterial pressure, platelet count, serum creatinine, and the ratio of the PaO2 to the fraction of inspired oxygen (FIO2) were significantly different between the survivors and non survivors. Compared with the survivors, the non survivors had significantly higher basal plasma cortisol levels (T0) and lower cortisol response to corticotropin (Δmax). The number of patients who had documented infection and strains diagnosed at the onset of septic shock are shown in Table 4. Gram-positive microorganisms were more common among non survivors and gram-negative microorganisms were more common among survivors, but the difference was statistically not significant (P= 0.200). In 5 patients, both gram-positive and gram-negative organisms were isolated. Table 4 Types of microorganisms isolated from patients at the onset of septic shock

The number of patients who had documented infection and strains diagnosed at the onset of septic shock are shown in Table 4. Gram-positive microorganisms were more common among non survivors and gram-negative microorganisms were more common among survivors, but the difference was statistically not significant (P= 0.200). In 5 patients, both gram-positive and gram-negative organisms were isolated. Table 4 Types of microorganisms isolated from patients at the onset of septic shock Microorganism Total N=35 Survivors N=17 Non-survivors N=18 P value Gram-Positive 18(51%) 7(41%) 11(61%) 0.200 Gram-Negative 17(49%) 10(59%) 7(39%) The median time to death was 12 days for all patients. The prevalence of occult adrenal insufficiency was 57% (95% CI, 50–64%). Among the variables, as shown in Tables 3–6, the following seven remained independently associated with death: OSF scores greater than two (P=0.000), SAPS II greater than 55 (P=0.000), mean arterial pressure of 60 mm Hg or less (P=0.000), low platelet count (P=0.008), PaO2:FIO2 < 160 mmHg (P=0.001), random baseline cortisol (T0) greater than 34 μg/dL (P=0.014), and maximum variation after test (Δmax) of ≤9 μg/dL (P =0.002).

th: OSF scores greater than two (P=0.000), SAPS II greater than 55 (P=0.000), mean arterial pressure of 60 mm Hg or less (P=0.000), low platelet count (P=0.008), PaO2:FIO2 < 160 mmHg (P=0.001), random baseline cortisol (T0) greater than 34 μg/dL (P=0.014), and maximum variation after test (Δmax) of ≤9 μg/dL (P =0.002). Cortisol Levels and Cortisol Response to Corticotropin The random baseline cortisol levels (T0) and response to corticotropin stimulation test (Δmax) for patients with septic shock (survivors and non survivors) are shown in Table 5. The mean serum baseline cortisol concentrations in survivors and non survivors was 28 μg/dL (±SD 5.46) and 38.66 μg/dL (±SD 13.33), respectively. This difference is statistically significant (P=0.014). Similarly, non survivors showed a significantly inadequate response to the low dose corticotropin stimulation test as compared with survivors (Δmax = 7.3±3.66 μg/dL in non survivors vs. 13±5.28 μg/dL in survivors; p=0.002), thereby showing that patients in septic shock who had higher basal serum cortisol levels (>34 μg/dL) and an inadequate response to the corticotropin stimulation test (Δm ≤ 9 μg/dL) had less chance of survival. Table 5 Random cortisol levels and response to short corticotropin stimulation test in patients with septic shock Cortisol (μg/dL) Total (n=30) Survivors (n=12) Non survivors (n=18) P value Level before test (T0) 34.40 (11.99) 28 (5.46) 38.66 (13.33) 0.014 Maximum variation after test (max) 9.61 (5.13) 13 (5.28) 7.35 (3.66) 0.002 Therefore, the following combinations of T0 and Δmax were studied:

Table 5 Random cortisol levels and response to short corticotropin stimulation test in patients with septic shock Cortisol (μg/dL) Total (n=30) Survivors (n=12) Non survivors (n=18) P value Level before test (T0) 34.40 (11.99) 28 (5.46) 38.66 (13.33) 0.014 Maximum variation after test (max) 9.61 (5.13) 13 (5.28) 7.35 (3.66) 0.002 Therefore, the following combinations of T0 and Δmax were studied: T0 of 34 μg/dL or less and Δmax of more than 9 μg/dL T0 of 34μg/dL or less and Δmax of 9 μg/dL or less or a T0 greater than 34 μg/dL and Δmax more than 9 μg/dL T0 greater than 34 μg/dL and Δmax of 9 μg/dL or less The information provided by T0 and Δmax together was significantly associated with death rates and distribution of survival times. Death occurred more rapidly for patients with T0 greater than 34 μg/dL and Δmax of 9 μg/dL or less. Three different mortality patterns appear in Table 6: (I) low (T0 ≤34 μg/dL and Δmax >9 μg/dL; 28-day mortality rate of 33%), (II) intermediate (T0 >34 μg/dL and Δmax >9μg/dL or T0 ≤ 34 μg/dL and Δmax ≤9 μg/dL); 28-day mortality rate of 71%), and (III) high (T0 >34 μg/dL and Δmax ≤9 μg/dL; 28-day mortality rate of 82%). Table 6 Prognostic value of cortisol levels and cortisol response to corticotropin

Death occurred more rapidly for patients with T0 greater than 34 μg/dL and Δmax of 9 μg/dL or less. Three different mortality patterns appear in Table 6: (I) low (T0 ≤34 μg/dL and Δmax >9 μg/dL; 28-day mortality rate of 33%), (II) intermediate (T0 >34 μg/dL and Δmax >9μg/dL or T0 ≤ 34 μg/dL and Δmax ≤9 μg/dL); 28-day mortality rate of 71%), and (III) high (T0 >34 μg/dL and Δmax ≤9 μg/dL; 28-day mortality rate of 82%). Table 6 Prognostic value of cortisol levels and cortisol response to corticotropin Group Basal cortisol level (T0) Increase in cortisol levels (Δmax) 28-day mortality rate I ≤ 34 μg/dL > 9 μg/dL 33% II > 34 μg/dL > 9 μg/dL 71% ≤ 34 μg/dL ≤ 9 μg/dL III > 34 μg/dL ≤ 9 μg/dL 82% Discussion In this study, 30 consecutive patients admitted in the adult intensive care unit with well-defined diagnosis of septic shock, complete clinical and physiological data, and a complete follow-up were included. The study was mainly designed to assess, at the early course of septic shock, the prognostic value of occult adrenal insufficiency.

onsecutive patients admitted in the adult intensive care unit with well-defined diagnosis of septic shock, complete clinical and physiological data, and a complete follow-up were included. The study was mainly designed to assess, at the early course of septic shock, the prognostic value of occult adrenal insufficiency. In our study, the 28-day mortality rate from septic shock was 60% (95% CI, 53–67%). This result is consistent with the 56% rate of ICU mortality at 28 days reported in literature.[3] The prevalence of occult adrenal insufficiency, in our patients with septic shock, was 57% (95% CI, 50–64%). This is consistent with the results of Annane, et al.[35] However, the results are lower than 81.6% reported by Chacko, et al.[36] Earlier literature quotes a wide range in the incidence of hypocortisolemia in the critically ill; this may be attributable to the different types of illnesses encountered from center to center.[36]

onsistent with the results of Annane, et al.[35] However, the results are lower than 81.6% reported by Chacko, et al.[36] Earlier literature quotes a wide range in the incidence of hypocortisolemia in the critically ill; this may be attributable to the different types of illnesses encountered from center to center.[36] Several factors have been suspected to be associated with mortality in cases of severe sepsis and septic shock.[337–42] The main prognostic factors reported to date are age, severity of the patient's underlying disease, number of organ system dysfunctions, severity of illness scores, hypothermia, neutropenia, thrombocytopenia, lactic acidosis, multisource of infection, positive blood culture, type of infecting organism, blood concentrations of endotoxin, and cytokines. In our study, we found seven factors remained significantly associated with death: OSF scores greater than two (P=0.000), SAPS II greater than 55 (P=0.000), mean arterial pressure of 60 mm Hg or less (P=0.000), low platelet count (P=0.008), PaO2:FIO2 < 160 mmHg (P =0.001), random baseline cortisol (T0) greater than 34 μg/dL (P =0.014), and maximum variation after test (Δmax) of ≤ 9 μg/dL (P =0.002).

OSF scores greater than two (P=0.000), SAPS II greater than 55 (P=0.000), mean arterial pressure of 60 mm Hg or less (P=0.000), low platelet count (P=0.008), PaO2:FIO2 < 160 mmHg (P =0.001), random baseline cortisol (T0) greater than 34 μg/dL (P =0.014), and maximum variation after test (Δmax) of ≤ 9 μg/dL (P =0.002). In the present study, the age and gender distribution of patients with septic shock was comparable between survivors and non survivors (P=0.108 and 0.534, respectively). The mean age of survivors and non survivors was 47.25 years old (±SD 16.62) and 58.72 years old (±SD 19.63), respectively. Survival rates in males and females were 42.1% and 36.36%, respectively. These findings are consistent with the findings of Annane, et al.[43] No significant difference (P=0.350) was found in the type of admission – whether medical or surgical in patients with septic shock.

nd 58.72 years old (±SD 19.63), respectively. Survival rates in males and females were 42.1% and 36.36%, respectively. These findings are consistent with the findings of Annane, et al.[43] No significant difference (P=0.350) was found in the type of admission – whether medical or surgical in patients with septic shock. Vital signs such as pulse, temperature, and respiratory rate were comparable in survivors and non survivors (P=0.994, 0.245 and 0.299, respectively). The mean ± SD mean arterial pressure (MAP) in mmHg was significantly different (P=0.000) in survivors and non survivors. The severity assessment scores, OSF scores, and SAPS II scores were significantly different between survivors and non survivors (P=0.000). An OSF score >2 was significantly associated with mortality. The findings are consistent with those reported in other studies.[43] Laboratory parameters like Hb, TLC, and bilirubin were comparable between survivors and non survivors (P=0.717, 0.846 and 0.245, respectively). However, a significant difference was observed in the distribution of platelets (0.008), creatinine (0.010), and the ratio of PaO2 to FiO2 (0.000) between survivors and non survivors.

ory parameters like Hb, TLC, and bilirubin were comparable between survivors and non survivors (P=0.717, 0.846 and 0.245, respectively). However, a significant difference was observed in the distribution of platelets (0.008), creatinine (0.010), and the ratio of PaO2 to FiO2 (0.000) between survivors and non survivors. This study showed that the mean serum baseline cortisol concentration in survivors and non survivors was 28 (±SD 5.46) and 38.66 (± SD 13.33), respectively. This difference is statistically significant (P =0.014). Chacko, et al. have found baseline serum cortisol levels of 23.24, which is lower than our study.[36] However, they have not compared the data between survivors and non survivors. The higher baseline serum cortisol found in our study could be because our patients could have been more sick and so more stressed, as plasma cortisol levels seem to reflect the severity of illness.[12] Similarly, non survivors showed significantly inadequate response to the low-dose corticotrophin stimulation test as compared with the survivors (Δmax= 7.35 ± 3.66 in non survivors vs. 13 ± 5.28 μg/dL in survivors; P =0.002), thereby showing that patients in septic shock who had higher baseline serum cortisol levels (>34 μg/dL) and inadequate response to the corticotrophin stimulation test (Δmax ≤ 9 μg/dL) had fewer chances of survival. These findings are consistent with previous studies.[294445]

vs. 13 ± 5.28 μg/dL in survivors; P =0.002), thereby showing that patients in septic shock who had higher baseline serum cortisol levels (>34 μg/dL) and inadequate response to the corticotrophin stimulation test (Δmax ≤ 9 μg/dL) had fewer chances of survival. These findings are consistent with previous studies.[294445] Thus, at the onset of septic shock, basal plasma cortisol values and cortisol response to corticotropin appear to be independent predictors of 28-day mortality, which allows us to substantiate the prognostic classification of 3 groups given by Annane, et al.[43] This classification requires only a short corticotropin test and has a good prognostic value. It should therefore be helpful in identifying a group of patients at high-risk for death and who may be benefited by treatment with corticosteroids. The role of corticosteroids in patients of septic shock with relative adrenal insufficiency has also been highlighted in an editorial by Mani.[46] Conclusion As per our study, a short corticotropin test using low-dose corticotropin (1 μg) has a good prognostic value and can be helpful in identifying patients with septic shock at high-risk for death. High basal cortisol levels and a low increase in cortisol on a corticotropin stimulation test are predictors of a poor outcome in patients with septic shock. The prevalence of occult adrenal insufficiency, using a low dose (1 μg) corticotropin stimulation test is 57% in patients with septic shock. The 28-day mortality rate for patients with septic shock is 60%. Source of Support: Nil Conflict of Interest: None declared.

Introduction Air embolism can complicate peripheral IV fluid therapy[1] or central venous catheter monitoring, including problems with IV infusion pumps,[2] improper flushing of IV sets,[3] incorrect injection of drugs into the infusion system,[3] and accidental disconnection of the hub or removal of central venous catheters.[4] The open to air system in glass bottles is also a potential hazard for life-threatening complications. Air embolism can cause blockage of small vessels in the pulmonary vasculature with compromise of gas exchange, cessation of ventricular pumping caused by blockage of air and arrhythmia,[5] and paradoxical air embolism to the systemic circulation through a probe-patent foramen ovale.[6] Glass bottles are widely used for administration of intravenous fluids. Various drugs e.g., mannitol are also available only in glass bottles in our part of the world. For the administration of fluids from glass bottles, a needle has to be inserted, which acts as an airway [Figure 1] and the fluid comes out through the infusion tubing on the basis of the beer can principle. The rate is controlled by a plastic regulating clamp. Figure 1 The needle acting as an airway in glass bottle Many times the fluid in the bottle finishes, but the regulating clamp is still open. The needle airway is in place and the infusion line eventually becomes open to air, which can lead to fatal air embolism.

Glass bottles are widely used for administration of intravenous fluids. Various drugs e.g., mannitol are also available only in glass bottles in our part of the world. For the administration of fluids from glass bottles, a needle has to be inserted, which acts as an airway [Figure 1] and the fluid comes out through the infusion tubing on the basis of the beer can principle. The rate is controlled by a plastic regulating clamp. Figure 1 The needle acting as an airway in glass bottle Many times the fluid in the bottle finishes, but the regulating clamp is still open. The needle airway is in place and the infusion line eventually becomes open to air, which can lead to fatal air embolism. For air embolism to occur through an intravenous drip set, there are two prerequisites. First, is that the patient is connected to an intravenous line that is open to air and second is that the intravenous tubing should be placed into a vein whose pressure is below the atmospheric pressure. Sub atmospheric pressure can develop in a vein when the intravenous tubing is attached to the central line, or the vein is on the upper arm in the lateral position.[7] A right-sided central line in the left lateral position and the patient attempting to breathe against a closed glottis are two other potential conditions of air embolism; there are high chances of sub atmospheric pressure developing in the vein. There is a definitive risk of air embolism when the fluid infusion is complete and the drip set is still open.

Sub atmospheric pressure can develop in a vein when the intravenous tubing is attached to the central line, or the vein is on the upper arm in the lateral position.[7] A right-sided central line in the left lateral position and the patient attempting to breathe against a closed glottis are two other potential conditions of air embolism; there are high chances of sub atmospheric pressure developing in the vein. There is a definitive risk of air embolism when the fluid infusion is complete and the drip set is still open. We have devised a novel way of preventing the chances of air embolism when the fluid in the glass bottle finishes. Weix the infusion tubing by giving it a “U” turn so that the loop is below the level of the vein into which the infusion set is attached [Figure 2]. This ensures that some fluid remains in the loop and an air embolism is prevented. The presence of a U turn loop increases the negative pressure that would be required to aspirate air. A simple maneuver acts as a safety mechanism from a potentially life-threatening complication and decreases the chances of an air embolism. Figure 2 The “U” turn of the infusion set to decrease the chances of an air embolism Methylene dye was put in the IV set for better pictorial presentation Source of Support: Nil Conflict of Interest: None declared.

Introduction Neurofibromatosis Type 1 (NF-1), or von Recklinghausen's disease, is one of the neurocutaneous syndromes also known as the phakomatoses. Although there may be as many as eight different clinical subgroups, Type 1 and Type 2 account for 99% of the cases.[1] Pheochromocytoma is a rare tumor of chromafin cells most commonly arising from the adrenal medulla and often in association with the familial multiple endocrine neoplasia syndromes (MEN, Type 2A and 2B), neurofibromatosis, von Hippel-Lindau disease, cerebellar hemangioblastoma, Sturge-Webers syndrome, and tuberous sclerosis.[23] We report a case of a patient with previously diagnosed von Recklinghausen's disease who presented with left upper quadrant pain, misdiagnosed as renal colic, followed by massive retroperitoneal hematoma and a fatal outcome due to a spontaneous rupture of an adrenal pheochromocytoma.

ndrome, and tuberous sclerosis.[23] We report a case of a patient with previously diagnosed von Recklinghausen's disease who presented with left upper quadrant pain, misdiagnosed as renal colic, followed by massive retroperitoneal hematoma and a fatal outcome due to a spontaneous rupture of an adrenal pheochromocytoma. Case Report A 35-year-old female was admitted to our hospital following a syncopal episode followed by pain in the left upper quadrant, radiating to the left flank accompanied by nausea and vomiting. She had a history of von Recklinghausen's disease (café au lait spots and numerous cutaneous nodules visible over her skin). Upon presentation, her blood pressure was 160/90 without significant oscillation and her pulse rate was 100/min. She had no previous history of hypertension. An abdominal examination had no abnormal finding except for a mild tenderness on percussion of the left hypochondriac region. In the emergency department, she underwent an abdominal ultrasound examination which showed mild hydronephrosis of the left ureter. There was no stone or mass in the kidneys. She was considered to have renal colic, which was conservatively treated with an antiemetic and analgesic, and she was discharged after pain relief and normalization of blood pressure. The patient was admitted to the hospital again 20 hours after the initial discharge, in a state of shock. Her blood pressure was undetectable, her heart rate was 140, and mucosal surfaces were dry and pale. A bedside abdomimal ultrasound examination revealed copious amount of free intra-abdominal fluid. After initial resuscitation, she immediately underwent an exploratory laparotomy. Following incision, a significant amount of free blood was found in the abdominal cavity. The retroperitonium contained an extensive hematoma. On exploration we found a hemorrhagic left adrenal tumor measured 1 × 1 cm, somewhat adhering to the kidney [Figure 1]. A left adrenalectomy was performed immediately and the patient was transferred to the surgical intensive care unit but despite good intensive care and comprehensive advanced resuscitation, the patient expired due to irreversible hemorrhagic shock. Histopathological examination of the tumor demonstrated a hemorrhagic pheochromocytoma.

ctomy was performed immediately and the patient was transferred to the surgical intensive care unit but despite good intensive care and comprehensive advanced resuscitation, the patient expired due to irreversible hemorrhagic shock. Histopathological examination of the tumor demonstrated a hemorrhagic pheochromocytoma. Figure 1 Hemorrhagic adrenal mass on operation

ctomy was performed immediately and the patient was transferred to the surgical intensive care unit but despite good intensive care and comprehensive advanced resuscitation, the patient expired due to irreversible hemorrhagic shock. Histopathological examination of the tumor demonstrated a hemorrhagic pheochromocytoma. Figure 1 Hemorrhagic adrenal mass on operation Discussion Families with von Recklinghausen's disease, which is now called neurofibromatosis, have been divided clinically into those without (neurofibromatosis 1) and with (neurofibromatosis 2) acoustic neuromas. Clinical diagnosis of von Recklinghausen's disease is based on the presence of two or more signs of six or more café au lait spots, two or more neurofibromas or one plexiform neurofibroma, axillary or inguinal freckling, optic glioma, two or more Lisch nodules (hamartomas of the iris), osseous lesions (sphenoid dysplasia, pseudarthrosis or scoliosis) or one sign and a first degree affected relative. Pheochromocytoma occurs in a small but defined number of patients with von Recklinghausen's disease (in 0.1 to 5.7% of patients with von Recklinghausen's disease), and can be associated with significant morbidity and mortality if not detected. Patients experience a lifetime of morbidity and increased risk of mortality, depending on the extent of the disease. An adrenal mass can be incidentally discovered in any patient and must be evaluated in those with von Recklinghausen's disease to exclude pheochromocytoma. Patients with von Recklinghausen's disease also have adrenal ganglioneuromas, which can be mistaken clinically for nonfunctional pheochromocytomas. Medullary hyperplasia has been reported with von Recklinghausen's disease but the clinical significance of this finding is not yet known.[4] Most patients with spontaneous rupture of pheochromocytoma are admitted to the hospital due to acute abdominal pain. In majority of cases, the bleeding occurs in the retroperitonium; however, some may bleed both in the retroperitonium and peritoneal cavity,[5] such as in the present case. The exact mechanism of a pheochromocytoma rupture is unknown, but a high intracapsular pressure may tear the capsule and also cause necrosis of the tumor. The high pressure may be caused by rapid tumor growth or intratumoral hemorrhage.

both in the retroperitonium and peritoneal cavity,[5] such as in the present case. The exact mechanism of a pheochromocytoma rupture is unknown, but a high intracapsular pressure may tear the capsule and also cause necrosis of the tumor. The high pressure may be caused by rapid tumor growth or intratumoral hemorrhage. Elevation of blood pressure is probably associated with vasoconstriction in the tumor and subsequent necrosis, causing massive release of catecholamine into circulation.[6] Our pathological findings of hemosiderin deposition and coagulation necrosis supported this assumption. Pheochromocytoma with hemorrhagic shock, especially in a clinically silent case of von Recklinghausen's disease is an extremely rare condition; however, it should always be taken into consideration in order to avoid a delay in diagnosis and the possibility of progression to death. Since pheochromocytoma is not common, evaluation of all patients with von Recklinghausen's disease with abdominal pain might be reasonable. Source of Support: Nil Conflict of Interest: None declared.

Introduction Injurious ventilation strategies can worsen lung damage in Acute Respiratory Distress Syndrome (ARDS).[1] During positive pressure ventilation, there are alveolar units in varying degrees of collapse adjacent to areas of fully open alveoli. When inflated, shear stresses develop between open and closed alveoli that may be injurious.[2] Cyclical opening and closure of alveolar units can also result in the generation of shear forces.[3] Both these mechanisms can cause endothelial and epithelial injury leading to loss of integrity of the alveolar capillary membrane, bacterial translocation from the lung, and cellular inflammatory damage.[45] Shear forces also lead to the activation of nuclear factor kappa B that results in the expression of cytokines, resulting in the initiation and propagation of multiorgan dysfunction syndrome.[6] There is strong evidence that low tidal volume ventilatory strategies improve survival.[7] However, the use of small tidal volumes can cause alveolar derecruitment and arterial hypoxemia. In the ARDSNet trial, patients randomized to the low tidal volume group had lower PO2 levels, possibly due to alveolar derecruitment.[7] Strategies to recruit closed lung units and prevent derecruitment might be beneficial in improving gas exchange as well as reduce the incidence of ventilator-induced lung injury.

mia. In the ARDSNet trial, patients randomized to the low tidal volume group had lower PO2 levels, possibly due to alveolar derecruitment.[7] Strategies to recruit closed lung units and prevent derecruitment might be beneficial in improving gas exchange as well as reduce the incidence of ventilator-induced lung injury. Effects of recruitment maneuvers Although ARDS is described as a diffuse disease process affecting both the lungs, CT scan based studies have revealed a nonuniform pattern of involvement.[8] There are regions within the lung that are collapsed or consolidated, mainly confined to the dependent areas, and other regions which are open and ventilate in a relatively normal fashion.[9] The considerably reduced portion of the lung that is amenable to ventilation has been referred to as the ‘baby lung’.[10] Injurious ventilatory strategies might aggravate damage to the lung. High peak pressures and high tidal volumes have been shown to be associated with a significantly higher incidence of barotrauma.[11] Mechanical ventilation using high tidal volumes also results in the release of inflammatory mediators such as interleukins 1 and 6, tumour necrosis factor alpha, etc, that may be attenuated by optimizing ventilator strategy.[12] Ventilation with low tidal volumes below the lower inflexion point might also result in progression of lung injury.[3] Thus, there needs to be a careful balance between strategies that use excessive pressures and volumes that might aggravate lung injury and the use of low tidal volume strategies that might lead to alveolar derecruitment and significant hypoxemia. It may be possible to open up or ‘recruit’ at least some of the collapsed areas by the use of continuous or repetitive application of increased levels of distending alveolar pressure, much higher than that recommended for the ventilation of patients with Acute Lung Injury (ALI). The applied pressure as well as the duration of its application is likely to determine the effectiveness of a Recruitment Maneuver (RM). The efficacy of an RM is likely to be directly related to the number of closed lung units. In other words, such maneuvers will be less effective if most of the lung units are already open.

pplied pressure as well as the duration of its application is likely to determine the effectiveness of a Recruitment Maneuver (RM). The efficacy of an RM is likely to be directly related to the number of closed lung units. In other words, such maneuvers will be less effective if most of the lung units are already open. Thus, the potential for recruitment may be greater when lower Positive End-Expiratory Pressure (PEEP) levels are being used compared to higher PEEP levels.[1314] However, the potential for recruitment may also depend on the number of closed alveolar units and may be predictable using physiological variables including PaO2/FiO2 (P/F) ratio, PCO2 and compliance.[15] It is important to understand that while PEEP can maintain recruitment, intermittent higher pressures would be required to initiate the process. After recruitment has been initiated, it may be possible to maintain it with lower pressures. In fact, alveolar to pleural pressure difference of more than 60cm of H2 O may be required to open collapsed lung units.[16]

EP can maintain recruitment, intermittent higher pressures would be required to initiate the process. After recruitment has been initiated, it may be possible to maintain it with lower pressures. In fact, alveolar to pleural pressure difference of more than 60cm of H2 O may be required to open collapsed lung units.[16] Techniques Several methods have been employed to carry out RMs in the clinical setting as well as in experimental models [Table 1]. Rothen et al. showed that a sustained inflation maneuver of 40cm of H2 O, for 7–8 seconds might re-expand all collapsed lung units as evident on CT scans of the chest and improve oxygenation in anesthetized subjects.[16] In another study, three consecutive sighs of plateau pressure 45cm of H2O were applied every minute for an hour. This resulted in an increase in the end- expiratory lung volume, reduction in the intrapulmonary shunt, and improvement in oxygenation. [17] Lapinsky et al. applied a sustained inflation maneuver of 45cm of H2O or the peak pressure at a tidal volume of 12mls/kg, whichever was lower, for a period of 20 seconds. An improvement in oxygen saturation was noted in all patients; in 10 out of 14 patients, this was sustained for up to four hours. No significant adverse effects were noted.[18] Lim et al. used an ‘extended sigh’ (e-sigh) as an RM.[19] This involved gradually reducing tidal volumes from 8–2mls/ kg and increasing the PEEP from 10–25cm of H2O in a stepwise manner, each step lasting 30 seconds. When a tidal volume of 2mls/kg and a PEEP of 25cm of H2O were reached, a Continuous Positive Airway Pressure (CPAP) level of 30cm of H2O was applied for 30 seconds following which a reverse sequence was applied till the baseline settings were reached. The authors could demonstrate a statistically significant increase in PO2 and static compliance with this maneuver. RMs may also be practicable in spontaneously breathing patients. Patroniti et al. applied a CPAP of 20% higher than the peak pressure on pressure support ventilation for 3–5seconds every minute, for at least an hour. The authors could demonstrate an improvement in oxygenation and lung compliance with this maneuver.[20] Constantin et al. compared two different RMs - (a) CPAP of 40cm of H2O for 40 seconds without tidal ventilation and (b) an e-sigh comprising of increasing the PEEP level to 10cm above the lower inflexion point on the pressure–volume curve for a period of 15 minutes, on volume-controlled ventilation.

this maneuver.[20] Constantin et al. compared two different RMs - (a) CPAP of 40cm of H2O for 40 seconds without tidal ventilation and (b) an e-sigh comprising of increasing the PEEP level to 10cm above the lower inflexion point on the pressure–volume curve for a period of 15 minutes, on volume-controlled ventilation. Both maneuvers improved oxygenation at 5 and 60 minutes; there was no statistically significant difference in the degree of improvement. However, only the e-sigh was associated with an increase of recruited volume at 5 and 60 minutes. The systolic pressure dropped below 70mm Hg during the CPAP maneuver on two occasions resulting in interruption of the RM while there was no significant blood pressure drop with the e-sigh.[21] Other studies also suggest that RMs using a sustained high inflation pressure may cause hemodynamic compromise and hence may not be the preferred technique.[2223] Some level of sedation is usually required to carry out an RM, but muscle paralysis is not absolutely necessary. The patient should be monitored for hypotension and fall in oxygen saturation during the RM. It is also important to emphasize that an RM should be followed up with an appropriate PEEP level, set in a decremental fashion; otherwise derecruitment may occur.[24] Table 1 Studies evaluating different types of recruitment maneuvers

Both maneuvers improved oxygenation at 5 and 60 minutes; there was no statistically significant difference in the degree of improvement. However, only the e-sigh was associated with an increase of recruited volume at 5 and 60 minutes. The systolic pressure dropped below 70mm Hg during the CPAP maneuver on two occasions resulting in interruption of the RM while there was no significant blood pressure drop with the e-sigh.[21] Other studies also suggest that RMs using a sustained high inflation pressure may cause hemodynamic compromise and hence may not be the preferred technique.[2223] Some level of sedation is usually required to carry out an RM, but muscle paralysis is not absolutely necessary. The patient should be monitored for hypotension and fall in oxygen saturation during the RM. It is also important to emphasize that an RM should be followed up with an appropriate PEEP level, set in a decremental fashion; otherwise derecruitment may occur.[24] Table 1 Studies evaluating different types of recruitment maneuvers Study Year of publication Technique/intervention Findings Pelosi et al.[17] 1999 Three consecutive sighs of plateau pressure 45 cm of H2O every minute for an hour Increase in the end expiratory lung volume, reduction in the intrapulmonary shunt and improvement in oxygenation Lapinsky et al.[18] 1999 Sustained inflation maneuver of 45 cm of H2O or the peak pressure at a tidal volume of 12 mls/kg, whichever was lower, for a period of 20 seconds Improvement in oxygen saturation in all 14 patients studied; sustained up to four hours in 10 patients. No significant adverse effects noted Rothen et al.[16] 1999 Sustained inflation of 40 cm of H2O for 26 seconds in anesthetized patients Inflation of the lungs to a pressure of 40 cm H2O, maintained for 7–8 seconds only, may re-expand all previously collapsed lung tissue, as detected by lung computed tomography, and improve oxygenation Lim et al.[19] 2001 On volume controlled mode, Vt (tidal volume) reduced by 2 mls/kg and PEEP increased by 5 cm of H2O every 30 seconds. At Vt 2 mls/kg and PEEP 25, CPAP 30 cm of H2O was applied for 30 seconds. Basal settings reached in reverse sequence Increase in PO2 and static compliance, sustained for the duration of the study.

or an additional of USD589 per CAUTI in diagnostic tests and in medications. The present study reveals that amikacin sulfate bladder wash is effective in preventing CAUTI. As a vial of amikacin sulfate (500 mg) costs INR58 (approximately USD1.4), this is very cost effective especially in a developing country like ours. Puri et al.,[21] in their study said that the risk was significantly higher for females, elderly patients, critically ill patients, and those on prolonged catheterization. The present study showed only severity of the disease (low motor score of GCS) as a statistically significant risk factor. This might be since a lower GCS corresponds to the severity of tissue injury, where there is hypermetabolism and increased protein catabolism, which eventually leads to decreased immunity that makes the person more susceptible to infections. However, the present study did not show any influence of sex, age, catheter size, duration of catheterization, and systemic use of antibiotics and steroids. This might be because of the small sample size and inclusion of long-term catheterized patients only.

] 2001 On volume controlled mode, Vt (tidal volume) reduced by 2 mls/kg and PEEP increased by 5 cm of H2O every 30 seconds. At Vt 2 mls/kg and PEEP 25, CPAP 30 cm of H2O was applied for 30 seconds. Basal settings reached in reverse sequence Increase in PO2 and static compliance, sustained for the duration of the study. No major respiratory or hemodynamic complications Bein et al.[41] 2002 Progressive increase in peak airway pressure (within 30 sec) up to 60 cm H2O and sustained for the next 30 seconds Marginal improvement in oxygenation Deterioration of cerebral hemodynamics Patroniti et al.[20] 2002 CPAP of 20% higher than peak airway pressure for 3–5 seconds every minute on pressure support ventilation PSV Improvement in oxygenation Improved lung compliance Grasso et al.[22] 2002 CPAP of 40 cm H2O for 40 seconds Improved oxygenation noted only in early ARDS and in patients with low lung elastance ARDSNet[32] 2003 CPAP of 35–45 cm H2O for 30 seconds Effects of RM were inconsistent and transient Constantin et al.[21] 2008 Comparative study between CPAP of 40 cm H2O for 40 sec and e-sigh by PEEP of 10 cm H2O above lower inflexion point on P–V curve for 15 minutes Both maneuvers improved oxygenation at 5 and 60 minutes Drop in systolic pressure <70 mm Hg on two occasions in the CPAP group No significant drop in BP during e-sigh Monitoring of the efficacy of recruitment maneuvers As more alveoli get recruited, the end-expiratory lung volume increases and arterial oxygenation would also be expected to rise. A practical measure of alveolar recruitment would be to monitor arterial blood gases. Malbouisson et al. showed a significant correlation between PEEP-induced alveolar recruitment and improved arterial oxygenation when recruitment was assessed by the volume of gas entering nonaerated or poorly aerated areas of the lung as seen on CT scans.[25] Apart from the obvious improvement in gas exchange, the efficacy of RMs can be assessed from the upward shift of the static volume-pressure curve[26] as well as the chest wall and lung elastance. Responders to RMs have been associated with a lower chest wall and lung elastance.[27]

of the lung as seen on CT scans.[25] Apart from the obvious improvement in gas exchange, the efficacy of RMs can be assessed from the upward shift of the static volume-pressure curve[26] as well as the chest wall and lung elastance. Responders to RMs have been associated with a lower chest wall and lung elastance.[27] Who will benefit from recruitment maneuvers? RMs have been studied extensively in patients with ARDS. Amato et al., in their landmark paper, studied 53 patients with ARDS using a low tidal volume of 6mls/ kg on one arm combined with RMs and compared this with a tidal volume of 12mls/kg on the other arm. They found a significant mortality reduction in the low tidal volume group - 38 vs 71%.[28] Grasso et al. showed that patients with early ARDS had greater potential for alveolar recruitment compared to patients who had late ARDS.[22] They found a positive correlation between chest wall elastance and the duration of mechanical ventilation, possibly due to pleural effusions that accumulated over time. It is also likely that with time, fibroproliferative changes set in making the lungs more difficult to recruit. Pelosi et al. showed higher end-expiratory lung volumes, greater improvement in PO2, and lower venous admixture in extrapulmonary ARDS compared to pulmonary ARDS, suggesting greater potential for recruitment in the former condition.[29] In another study on patients with early ARDS, RMs in the form of sighs were carried out in the supine position and after turning prone. There was an improvement in PO2 after RMs in both supine and prone positions; however, the end-expiratory lung volume increased only with RMs, not with proning per se.[30] The authors suggested that the prone position might make the lungs topographically more favorable for RMs. Loss of end-expiratory lung volumes and fall in oxygen saturation could be prevented by the use of an RM during endotracheal suctioning, especially if a closed suction system is used.[31] In the ARDS Net trial that compared high versus low PEEP in ARDS patients, RMs were used in the first 80 patients randomly assigned to the high PEEP arm using a CPAP of 35–40cm of H2O for 30 seconds. However, this strategy was abandoned later on as the mean increase in arterial oxygenation was small and transient.[32] This might lend further support to the theory that if maximal recruitment has already been achieved with high levels of PEEP, further applications of RMs are unlikely to be of benefit.

for 30 seconds. However, this strategy was abandoned later on as the mean increase in arterial oxygenation was small and transient.[32] This might lend further support to the theory that if maximal recruitment has already been achieved with high levels of PEEP, further applications of RMs are unlikely to be of benefit. RMs have also been shown to prevent derecruitment during anesthesia and in postoperative cardiac surgical patients on mechanical ventilation.[3334] Gattinoni et al. studied 67 patients with ALI or ARDS using CT scans to assess recruitability.[15] Whole lung CT scans were done at an inspiratory plateau pressure of 45cm of H2O followed by PEEP levels of 5 and 15cm of H2O. The extent of recruitable lung was highly variable, with a mean of 13 ± 11% of the total lung weight. Progressive increase of airway pressure resulted in an increase of hyperinflated and normally aerated lung. More recruitable lung correlated with a higher fraction of nonaerated lung tissue, a lower P/F ratio, lower compliance, higher PCO2, greater shunt fraction, and increased mortality. Physiological variables such as improved P/F ratio, compliance, and reduced PCO2 predicted recruitability with a sensitivity of 71% and specificity of 59%.

lung correlated with a higher fraction of nonaerated lung tissue, a lower P/F ratio, lower compliance, higher PCO2, greater shunt fraction, and increased mortality. Physiological variables such as improved P/F ratio, compliance, and reduced PCO2 predicted recruitability with a sensitivity of 71% and specificity of 59%. A recent large randomized controlled trial addressed the value of higher levels of PEEP and RMs along with low tidal volume ventilation.[35] The authors targeted tidal volumes of 6mls/kg with an upper limit of plateau pressure of 30cm of H2O. On the study arm, they used a higher level PEEP based on the FiO2 according to a set protocol along with RMs using a sustained inflation of 40cm of H2O for 40 seconds. There was no difference in mortality between the two groups; however, there were significantly lower rates of refractory hypoxemia, death with refractory hypoxemia, and the use of predefined rescue therapies in the study arm.

ng to a set protocol along with RMs using a sustained inflation of 40cm of H2O for 40 seconds. There was no difference in mortality between the two groups; however, there were significantly lower rates of refractory hypoxemia, death with refractory hypoxemia, and the use of predefined rescue therapies in the study arm. Possible harm from recruitment maneuvers RMs would seem to be generally well tolerated. However, systemic hypotension is often seen, especially when a sustained inflation pressure is used.[22] A rise in intrathoracic pressure might increase the right ventricular afterload, compress the intrathoracic veins, and reduce the cardiac output. Besides, high intrapulmonary pressures can increase the right ventricular pressures leading to a shift of the interventricular septum towards the left ventricle. This can impair the left ventricular function and reduce cardiac output further. The lungs may also exert a compressive effect on the heart and impair cardiac compliance.[36] RMs may result in barotrauma, although the incidence is unknown. Bacterial translocation from the lung due to increased stretch during RMs is a theoretical concern.[37–39] However, Cakar et al., in a rat model, showed that a sustained inflation RM of 45cm of H2O for 30 seconds at fifteen minute intervals did not result in bacterial translocation as evident on blood cultures. [40] Bein et al., applied RMs to 11 patients with traumatic and nontraumatic brain lesions and found a significant rise in the intracranial pressure.[41] The mean arterial pressure dropped, thus reducing the cerebral perfusion pressure. The jugular venous oxygen saturation also fell significantly. There was only a modest improvement in arterial oxygen saturation. The authors recommended that RMs should not be performed in brain-injured patients.

tracranial pressure.[41] The mean arterial pressure dropped, thus reducing the cerebral perfusion pressure. The jugular venous oxygen saturation also fell significantly. There was only a modest improvement in arterial oxygen saturation. The authors recommended that RMs should not be performed in brain-injured patients. Summary Recruitment maneuvers may prevent lung derecruitment and fall in oxygenation associated with low tidal volume ventilation strategies employed in ARDS. Patients who are already on optimal levels of PEEP are unlikely to benefit any further from RMs. Extrapulmonary ARDS is more likely to respond to RMs compared to pulmonary ARDS; consolidated lungs may not be recruitable. RMs are more likely to be successful during the early stages of ARDS, compared to the later stages when fibroproliferative changes set in. Over-recruitment can result in alveolar overdistension and diversion of blood away from ventilated to nonventilated areas, thus increasing the intrapulmonary shunt. Thus, RMs would always be a balancing act between opening of collapsed lung units and overdistending the already open units. Sustained inflation RMs may constitute an extreme increase of afterload to the right ventricle and result in significant hemodynamic compromise; hence, these may be less preferable to maneuvers involving intermittent high pressure. However, the optimal technique of recruitment is unclear and may vary depending on individual clinical circumstances. Although RMs have been clearly shown to improve gas exchange, there is no evidence that suggests improved morbidity or mortality. In fact, marginal improvements in gas exchange have not been shown to change clinical outcomes regardless of the strategy employed. On the other hand, the pursuit of better oxygenation using injurious ventilatory strategies is likely to cause harm. The primary role of RMs may be as rescue therapy in refractory hypoxia in patients with severe ARDS; their routine use in acute lung injury and ARDS may not be associated with benefit.

strategy employed. On the other hand, the pursuit of better oxygenation using injurious ventilatory strategies is likely to cause harm. The primary role of RMs may be as rescue therapy in refractory hypoxia in patients with severe ARDS; their routine use in acute lung injury and ARDS may not be associated with benefit. Source of Support: Nil Conflict of Interest: None declared.

Introduction Many recent studies have shown that mechanical ventilation (MV) in patients with acute respiratory distress syndrome (ARDS), using low tidal volumes and high levels of positive end-expiratory pressure (PEEP) reduces the mortality rate and this ventilatory strategy is now accepted as standard practice in patients with ARDS.[12] Although PEEP improves arterial oxygenation, it has adverse hemodynamic effects. PEEP reduces the venous return to the heart and the left ventricular end diastolic volume by pushing the inter ventricular septum towards the left, and thus reduces the cardiac output. These effects are proportional to the PEEP level. Regional perfusion can also be affected by PEEP, independently of cardiac output changes. The splanchnic perfusion is particularly sensitive, and any reduction can compromise its barrier function, promote bacterial translocation, and contribute to the development of multiple organ failure.[3] In experimental models, PEEP has markedly decreased mesenteric and portal blood flow, despite only moderate reductions in cardiac output.[4–8] Similar results have been reported in patients without lung injury.[910] These effects are usually dose related, becoming more pronounced with PEEP levels around 20 cmH2O.

e.[3] In experimental models, PEEP has markedly decreased mesenteric and portal blood flow, despite only moderate reductions in cardiac output.[4–8] Similar results have been reported in patients without lung injury.[910] These effects are usually dose related, becoming more pronounced with PEEP levels around 20 cmH2O. Kiefer reported that PEEP did not significantly alter splanchnic circulation in six patients with acute lung injury.[11] Nevertheless, caution should be exercised in extending these results to clinical practice, because only hemodynamically stable patients without adrenergic drugs were studied, and PEEP levels never exceeded 14 cmH2O.[12] Our aim was to evaluate the effects of PEEP levels up to 20 cmH2O on gastric mucosal perfusion and systemic hemodynamics in mechanically ventilated patients with ARDS on hemodynamic support. Materials and Methods Patients The study was performed in the Intensive Care Unit (department of Anesthesiology) of the Banaras Hindu University Hospital, Varanasi, India. Adult, mechanically ventilated patients were considered eligible for the study if they met the following criteria for ARDS during the 24 hours that preceded the study: Acute onset of respiratory failure; diffuse bilateral infiltrates in the chest radiograph involving more than three-fourths of both lung fields; a ratio of partial pressure of O2 (PaO2) to fraction of inspired oxygen (FiO2) of less than 200 mmHg; and a pulmonary arterial occlusion pressure less than 18 mmHg and no cardiac failure.

of respiratory failure; diffuse bilateral infiltrates in the chest radiograph involving more than three-fourths of both lung fields; a ratio of partial pressure of O2 (PaO2) to fraction of inspired oxygen (FiO2) of less than 200 mmHg; and a pulmonary arterial occlusion pressure less than 18 mmHg and no cardiac failure. Hemodynamic monitoring included an arterial line and a pulmonary artery catheter. Patients could be on vasopressor or inotropic support (Dopamine 5-20 microgram/kg/min with or without Noradrenaline 10-20 micrograms /min dose), but had to be hemodynamically stable (with a mean arterial blood pressure of more than 60mm of Hg, pulse rate should be less than 100/min and more than 50 per minute) for at least 5 hours before starting the protocol. Patients were excluded if they had any of the following conditions: Pregnancy, pre-existing respiratory dysfunction, cardiac index of less than 2.5 l min−1 m−2, or were receiving enteral nutrition.

Hemodynamic monitoring included an arterial line and a pulmonary artery catheter. Patients could be on vasopressor or inotropic support (Dopamine 5-20 microgram/kg/min with or without Noradrenaline 10-20 micrograms /min dose), but had to be hemodynamically stable (with a mean arterial blood pressure of more than 60mm of Hg, pulse rate should be less than 100/min and more than 50 per minute) for at least 5 hours before starting the protocol. Patients were excluded if they had any of the following conditions: Pregnancy, pre-existing respiratory dysfunction, cardiac index of less than 2.5 l min−1 m−2, or were receiving enteral nutrition. Interventions A nasogastric tonometer (TRIP® Tonometry Catheter 14F, with biofilter connector for TONOCAP™ Monitor) was inserted into the stomach and connected to an air automated tonometer (TONOCAP™ Monitor; Datex-Engstrom, Helsinki, Finland). All patients were sedated with midazolam, and paralyzed with vecuronium. Neuromuscular relaxation was measured by a Train of Four watch® device. A 40mg intravenous dose of pantoprazole was administered before starting the study. Patients were started on volume controlled ventilation. A pressure–volume curve was obtained for each patient by the airway occlusion technique[13]and ideal PEEP was defined as the lower inflection point + 2 cmH2O, or 12 cmH2O if no lower inflection point was found.

toprazole was administered before starting the study. Patients were started on volume controlled ventilation. A pressure–volume curve was obtained for each patient by the airway occlusion technique[13]and ideal PEEP was defined as the lower inflection point + 2 cmH2O, or 12 cmH2O if no lower inflection point was found. PEEP levels of 10, 15, 20 cmH2O, and ideal PEEP, with tidal volumes of 6 ml kg−1, were applied in four consecutive 30 min periods, respectively. Respiratory rate was modified to maintain end tidal CO2 within ±10mmHg of basal. All patients were receiving a constant infusion of 6% hetastarch before the beginning of the study (40–60 ml h−1). Cardiac output was optimized before and during the trial by determining the respiratory variation of systolic arterial pressure.[14] Whenever the variation was more than 10% a 100 ml bolus of 6% hetastarch was infused and the volume status was reassessed. No changes in vasopressor or inotropic support were allowed during the study. If hypotension (mean arterial pressure <60 mmHg) persisted for more than 2 min, the protocol was stopped.

pressure.[14] Whenever the variation was more than 10% a 100 ml bolus of 6% hetastarch was infused and the volume status was reassessed. No changes in vasopressor or inotropic support were allowed during the study. If hypotension (mean arterial pressure <60 mmHg) persisted for more than 2 min, the protocol was stopped. Measurements Hemodynamic, ventilatory and tonometric measurements were made at baseline, and at the end of each period, and arterial blood samples taken. Hemodynamic records included mean arterial pressure, heart rate, cardiac output, pulmonary artery occlusion pressure, central venous pressure and left ventricular stroke work index. Cardiac output was measured by thermodilution as the average of three values obtained after injections of 10ml of 5% dextrose in water at room temperature. Mean airway pressure, oxygenation index and PEEP levels were registered. Oxygenation index was calculated as mean airway pressure × FiO2 × 100/PaO2. The CO2gap (gastric partial pressure of CO2[pCO2] minus arterial pCO2) was calculated by comparing simultaneous measurements of tonometric gastric mucosal pCO2 and arterial pCO2. Statistical analysis Results are presented as median and range. The software Statview 5.0 was used to perform the statistical analysis. Nonparametric tests were used because of the small sample size. Data was analyzed with a Friedman test followed by a Wilcoxon signed-rank test if necessary. Results were considered statistically significant at P < 0.05.

esented as median and range. The software Statview 5.0 was used to perform the statistical analysis. Nonparametric tests were used because of the small sample size. Data was analyzed with a Friedman test followed by a Wilcoxon signed-rank test if necessary. Results were considered statistically significant at P < 0.05. Results Thirty-two patients with ARDS were enrolled. They had a median (range) age of 47 years, (25 were male and seven were female, and two of the female patients were in postpartum state, four patients had previous history of diabetes) and an Acute Physiology and Chronic Health Evaluation II score of 20 at admission to the intensive care unit. On the day of the study they had a median Sepsis-related Organ Failure Assessment (SOFA)[15] score of 10. All patients fulfilled criteria for ARDS, as defined by the inclusion criteria, during the 24 hours before the study and they had been on mechanical ventilation for 32 (12–72) hours. They were being ventilated with a median PEEP level of 9 (4–12) cmH2 O, had a PaO2/FiO2 ratio of 230 (140–386) mmHg and their respiratory system compliance was 45 (27–60)ml per cmH2O. Twenty-eight patients had sepsis (eight pneumonia and 20 extra pulmonary sepsis), and four had severe head and thoracic injury. Of the septic patients, 24 were in septic shock.

PEEP level of 9 (4–12) cmH2 O, had a PaO2/FiO2 ratio of 230 (140–386) mmHg and their respiratory system compliance was 45 (27–60)ml per cmH2O. Twenty-eight patients had sepsis (eight pneumonia and 20 extra pulmonary sepsis), and four had severe head and thoracic injury. Of the septic patients, 24 were in septic shock. No changes in cardiac index or in CO2 gap were found at any of the study periods [Table 1]. Oxygenation index, mean arterial pressure, pulmonary mean arterial pressure, pulmonary artery occlusion pressure, central venous pressure and left ventricular stroke work index also remained stable through the study. Only mean airway pressure and PaO2/FiO2 ratio differed between periods, as expected. Twenty patients required a 100ml bolus of hetastarch during the trial; in no patient was it necessary to repeat it. At baseline, 12 patients had already a CO2 gap of more than 20 mmHg. After starting the protocol with 10 cmH2O PEEP, 24 patients decreased their CO2 gap and eight increased it. When PEEP was increased from 15 to 20 cmH2O, 12 patients increased their CO2 gap, 12 decreased it and in four patients it remained unchanged. Table 1 Respiratory, hemodynamic and tonometric measurements

No changes in cardiac index or in CO2 gap were found at any of the study periods [Table 1]. Oxygenation index, mean arterial pressure, pulmonary mean arterial pressure, pulmonary artery occlusion pressure, central venous pressure and left ventricular stroke work index also remained stable through the study. Only mean airway pressure and PaO2/FiO2 ratio differed between periods, as expected. Twenty patients required a 100ml bolus of hetastarch during the trial; in no patient was it necessary to repeat it. At baseline, 12 patients had already a CO2 gap of more than 20 mmHg. After starting the protocol with 10 cmH2O PEEP, 24 patients decreased their CO2 gap and eight increased it. When PEEP was increased from 15 to 20 cmH2O, 12 patients increased their CO2 gap, 12 decreased it and in four patients it remained unchanged. Table 1 Respiratory, hemodynamic and tonometric measurements Parameter Baseline (n = 32) PEEP 10 (n = 32) PEEP 15 (n = 32) PEEP 20 (n = 32) Ideal PEEP (n = 32) P PEEP (cmH2O) 9 (4–12) 10 15 20 12 (8–15) Mean airway pressure (cmH2O) 12.1 (8–18.7) 14.3 (12–17) 20.2 (17–22.2) 24.7 (22–26.4) 15.9 (11.5–22.2) 0.0001a OI (cmH2O per mmHg) 5.3 (2.9–12.4) 7 (3–14.5) 6.7 (4.1–12.3) 7 (5–12.3) 6.6 (2.9–12.3) 0.31 PaO2/FiO2 (mmHg) 230 (140–386) 208 (115–412) 281 (151–421) 329 (197–438) 240 (169–469) 0.0009b PaCO2 (mmHg) 34 (31–51) 42 (28–61) 43 (31–66) 46 (36–59) 43 (29–52) 0.09 Cardiac index (I min−1 m−2) 4.7 (2.6–6.2) 4.4 (2.5–7) 4.4 (2.2–6.8) 4.8 (2.7–6.1) 4.9(2.4–6.3) 0.09 LVSWI (g mm−2) 45 (22–71) 43 (22–60) 40 (14–60) 36 (15–58) 42 (14–66) 0.13 MAP (mmHg) 76 (74–103) 79 (69–99) 77 (72–97) 76 (67–93) 75 (71–96) 0.24 PAOP (mmHg) 15 (10–18) 16 (8–20) 16 (11–21) 18 (12–24) 15 (13–23) 0.23 CVP (mmHg) 10 (9–17) 12 (10–19) 13 (11–24) 12 (10–19) 13 (8–18) 0.25 CO2 gap (mmHg) 18 (2–30) 18 (0–40) 17 (0–39) 16 (4–39) 19 (9–39) 0.19 Results are presented as median (range). CVP-central venous pressure; CO2 gap-arterial partial pressure of CO2[pCO2] minus gastric pCO2; FiO2-fraction of inspired oxygen; LVSWI-left ventricular stroke work index; MAP-mean arterial pressure; OI-oxygenation index-defined as mean airway pressure × FiO2 × 100/arterial pCO2; PaO2-partial pressure of O2; PaCO2-partial pressure of CO2; PAOP-pulmonary arterial occlusion pressure; PEEP-positive end-expiratory pressure.

action of inspired oxygen; LVSWI-left ventricular stroke work index; MAP-mean arterial pressure; OI-oxygenation index-defined as mean airway pressure × FiO2 × 100/arterial pCO2; PaO2-partial pressure of O2; PaCO2-partial pressure of CO2; PAOP-pulmonary arterial occlusion pressure; PEEP-positive end-expiratory pressure. a P < 0.05 for all comparisons except baseline versus PEEP 10 and PEEP 10 versus ideal PEEP. b P < 0.05 for all comparisons except baseline versus PEEP 10, baseline versus PEEP 15, baseline versus ideal PEEP, and PEEP 15 versus ideal PEEP Twenty-four of the 32 patients studied, survived (75%). The median length of stay in the intensive care unit was 18 days and the median duration of mechanical ventilation was 11 (5–34) days. Discussion Similar studies have been done previously, but the number of cases studied were very few; we have done this study with a relatively large number of patients and our results show that high PEEP levels (up to 20 cmH2O) do not compromise gastric mucosal perfusion, as assessed by tonometry, and do not affect systemic hemodynamics in most patients with ARDS. This is consistent with the findings of two other studies on the effects of PEEP on splanchnic perfusion in patients with ARDS. However, in contrast to our study, neither of those studies included patients in septic shock or on adrenergic support.[1116]

nd do not affect systemic hemodynamics in most patients with ARDS. This is consistent with the findings of two other studies on the effects of PEEP on splanchnic perfusion in patients with ARDS. However, in contrast to our study, neither of those studies included patients in septic shock or on adrenergic support.[1116] Shock and cardiovascular dysfunction are frequently associated with ARDS. This is an important issue, because hemodynamic safety concerns could preclude the use of high or optimal PEEP levels in that setting, even if necessary. A major finding of our study is that PEEP levels up to 20 cmH2O can be well tolerated, even in patients with ARDS and septic shock. Nevertheless, our trial was relatively short and we cannot exclude the possibility that keeping high PEEP levels for a longer period might result in increased fluid requirements, which could be deleterious in the longer term.

PEEP levels up to 20 cmH2O can be well tolerated, even in patients with ARDS and septic shock. Nevertheless, our trial was relatively short and we cannot exclude the possibility that keeping high PEEP levels for a longer period might result in increased fluid requirements, which could be deleterious in the longer term. Experimental and clinical research has demonstrated that in mechanically ventilated subjects without lung injury, PEEP decreases venous return and, secondarily, cardiac output.[17–19] In addition, Trager and colleagues showed that in patients with acute respiratory failure associated with septic shock, high PEEP levels induced a decrease in cardiac output.[20] In contrast, we found no decrease in cardiac output in our patients tested with increasing PEEP levels when fluid administration was optimized according to the respiratory variation in systolic arterial pressure. A similar result was reported by Kiefer et al. and by Akinci et al.[1116] Possible explanations for these contradictory results are a higher rate of fluid administration and the use of lower tidal volumes in the latter studies. Although we did not determine the upper inflection point of the pressure–volume curve, we think that by keeping tidal volume at 6 ml kg−1 any overdistension of the lungs was minimized. Lung volumes are a critical component of the hemodynamic effects of ventilation.[21] Thus, it seems that it is possible to preserve cardiac output in patients with ARDS, despite the use of high PEEP levels, by optimizing fluid administration and limiting tidal volumes.

g−1 any overdistension of the lungs was minimized. Lung volumes are a critical component of the hemodynamic effects of ventilation.[21] Thus, it seems that it is possible to preserve cardiac output in patients with ARDS, despite the use of high PEEP levels, by optimizing fluid administration and limiting tidal volumes. Gastric mucosal perfusion, as assessed by CO2 gap, also remained unchanged during the PEEP trial. This is consistent with the results reported by Kiefer and Akinci in similar studies. In all these studies cardiac output remained unchanged.[1116] In contrast, Trager reported, in a series of septic shock patients with acute respiratory failure, that an increase in PEEP from 5 to 15 cmH2O induced a decrease in cardiac output associated with a decrease in hepatic vein O2 saturation and in hepatic glucose production.[20] It therefore seems that by avoiding a decrease in cardiac output, splanchnic perfusion can be preserved in a majority of patients. One major limitation of our study is the small number of patients studied. Thus, a type II error cannot be excluded. We did not perform any a priori power analysis because we had no estimation of the possible magnitude of the effects that PEEP could have on gastric tonometry.

Gastric mucosal perfusion, as assessed by CO2 gap, also remained unchanged during the PEEP trial. This is consistent with the results reported by Kiefer and Akinci in similar studies. In all these studies cardiac output remained unchanged.[1116] In contrast, Trager reported, in a series of septic shock patients with acute respiratory failure, that an increase in PEEP from 5 to 15 cmH2O induced a decrease in cardiac output associated with a decrease in hepatic vein O2 saturation and in hepatic glucose production.[20] It therefore seems that by avoiding a decrease in cardiac output, splanchnic perfusion can be preserved in a majority of patients. One major limitation of our study is the small number of patients studied. Thus, a type II error cannot be excluded. We did not perform any a priori power analysis because we had no estimation of the possible magnitude of the effects that PEEP could have on gastric tonometry. Another limitation is the rather moderate severity of ARDS in our study. Although all patients fulfilled the criteria for ARDS during the 24 hours that preceded the study, at inclusion their PaO2/FiO2 ratio and their respiratory system compliance were only moderately decreased. Two recent papers provide an explanation for this observation.[2223] They show in patients diagnosed with ARDS that after a few hours of treatment with PEEP or a high FiO2, more than half of the patients present a PaO2/FiO2 ratio of more than 200 mmHg. In addition, the respiratory system compliance increased by more than 10 ml per cmH2O after 6 hours of treatment with PEEP.[23] At inclusion our patients had already been ventilated with a median PEEP level of 9 cmH2O for more than 12 hours, which could have explained the rather improved respiratory performance at baseline. In any event, this improvement demonstrated a less severe ARDS. It is possible that more severely compromised patients might present a lower tolerance to high PEEP levels.

ated with a median PEEP level of 9 cmH2O for more than 12 hours, which could have explained the rather improved respiratory performance at baseline. In any event, this improvement demonstrated a less severe ARDS. It is possible that more severely compromised patients might present a lower tolerance to high PEEP levels. Another limitation is that tonometry was the sole method used to assess gastric mucosal perfusion. Nevertheless, Elizalde et al. showed that gastric mucosal blood flow, measured by laser Doppler flowmetry and by reflectance spectrophotometry, is well correlated with gastric intramucosal acidosis in mechanically ventilated patients.[24] Conclusions Our study supports the findings of previous studies suggesting that high PEEP levels do not affect splanchnic perfusion and are hemodynamically well tolerated in most patients with ARDS. Furthermore, our study shows that gastric mucosal perfusion can be well preserved while high PEEP levels are applied even in patients presenting cardiovascular dysfunction and receiving vasopressor support, which is a frequent occurrence in critical care. Future studies should assess the effects of PEEP on splanchnic perfusion in a longer term. Source of Support: Nil Conflict of Interest: None declared.

Introduction The indwelling urinary catheter is an essential part of modern medical care and a variety of different indwelling urinary catheters can be used for various purposes. Each year, urinary catheters are inserted in more than five million patients in acute-care hospitals and extended-care facilities.[1] Unfortunately, when poorly managed, the indwelling catheter may present a hazard to the very patients it is designed to protect. Catheter-associated urinary tract infection (CAUTI) is the most common nosocomial infection in hospitals and nursing homes, comprising >40% of all institutionally acquired infections.[2–6] Interventions such as topical meatal antimicrobials, disinfectants added to the urinary drainage bag, and antimicrobials coatings for catheters have not been shown to decrease the incidence of UTI.[7] An effective measure to prevent the CAUTI has not yet been developed. The most common organisms responsible for CAUTI are Escherichia coli, Candida spp., Klebsiella pneumoniae, Streptococcus agalactiae, Enterococcus faecalis, and Pseudomonas aeruginosa. Amikacin has proven to be the most effective antibiotic in preventing the growth of all these species.[8]

TI has not yet been developed. The most common organisms responsible for CAUTI are Escherichia coli, Candida spp., Klebsiella pneumoniae, Streptococcus agalactiae, Enterococcus faecalis, and Pseudomonas aeruginosa. Amikacin has proven to be the most effective antibiotic in preventing the growth of all these species.[8] Previous studies have shown that using individualized regimens for bladder washouts minimizes the infection rate and catheter blockage, thus reducing the need for frequent recatheterization.[9] Since there is no significant systemic absorption of antibiotics used for bladder irrigation,[10] prophylactic bladder irrigations are considered to be safe. We performed an extensive review of literature which did not reveal any study done on the effectiveness of amikacin sulfate bladder wash. Materials and Methods This study was performed on a total of 60 catheterized patients who were admitted to the Neurosurgery Department of AIIMS, New Delhi, during June–December 2006 and met the inclusion criteria [Appendix 1]. The subject data sheet and procedure of amikacin sulfate bladder wash was developed under the guidance of a guide (Author 3) and co-guides (Authors 2 and 4), and was further validated by six experts from the Departments of Neurosurgery, Microbiology, and Nursing, AIIMS.

2006 and met the inclusion criteria [Appendix 1]. The subject data sheet and procedure of amikacin sulfate bladder wash was developed under the guidance of a guide (Author 3) and co-guides (Authors 2 and 4), and was further validated by six experts from the Departments of Neurosurgery, Microbiology, and Nursing, AIIMS. Informed written consent was taken from the patients or patients' relatives after providing appropriate information to the concerned. Confidentiality of the data was ensured. They were randomized after catheterization to either of the two groups – study and the control groups. Then urine samples were sent within 24 hours for culture and sensitivity (C/S), in case of positive C/S, patients were excluded from the study [Appendix 2]. Study group received amikacin sulfate bladder wash twice daily under strict aseptic precautions and the control group did not receive bladder wash [Appendix 3]. Urine C/S was performed on days 3, 7, and then weekly till the removal of catheter or discharge. Both groups received standard catheter care including perineal care; the only difference was the bladder wash. The researcher (Author 1) performed the bladder wash on all patients to eliminate bias. CAUTI was diagnosed when it met the respective criteria [Appendix 4].

n weekly till the removal of catheter or discharge. Both groups received standard catheter care including perineal care; the only difference was the bladder wash. The researcher (Author 1) performed the bladder wash on all patients to eliminate bias. CAUTI was diagnosed when it met the respective criteria [Appendix 4]. Statistical methods Descriptive and inferential statistical methods were used. Data were analyzed using SPSS-10th version. A probability of <0.05 was accepted as significant. For continuous variables having normal distribution, data were summarized using mean±SD, and the groups were compared using independent t test. Range and median were used for all continuous variables having non-normal distribution (age and duration of catheterization) and the two groups were compared using Mann-Whitney U test. Frequency and percentage were used for all categorical variables and the groups were compared using Pearson's chi-square test and Fisher's exact test. The study was conducted following the approval of ethics committee of All India Institute of Medical Sciences (AIIMS). Results Demographic profile of patients Age of the study subjects ranged from 18–68 years [Table 1]. The groups were homogenous in terms of age, sex, level of consciousness, size of catheter and duration of catheterization, and systemic usage of steroids and antibiotics. Bladder wash was well tolerated by all the subjects in the study group. Table 1 Age, sex, and duration of catheterization (n=60)

Results Demographic profile of patients Age of the study subjects ranged from 18–68 years [Table 1]. The groups were homogenous in terms of age, sex, level of consciousness, size of catheter and duration of catheterization, and systemic usage of steroids and antibiotics. Bladder wash was well tolerated by all the subjects in the study group. Table 1 Age, sex, and duration of catheterization (n=60) Variables Study group n = 30 Control group n = 30 P value Age (years) 19–65 (38) 18–68 (42.5) 0.399 Males (%) 16 (53) 16 (53) 1.0 Females (%) 14 (47) 14 (47) - Duration of catheterization (days) 3–29 (7) 4–20 (8) 0.823 Incidence of catheter-associated urinary tract infection and predisposing factors Incidence of CAUTI was 40% in the control group [Figure 1]. None of the subjects from the bladder wash group developed CAUTI. Amikacin bladder wash was effective in preventing CAUTI (P < 0.001). Lower levels of consciousness (i.e. the Glasgow coma scale (GCS)) increased the risk of developing CAUTI (P = 0.026) [Table 2]. Figure 1 Effect of amikacin sulfate bladder wash on catheter-associated urinary tract infection Table 2 Risk factors for catheter-associated urinary tract infection (n=60)

Variables Study group n = 30 Control group n = 30 P value Age (years) 19–65 (38) 18–68 (42.5) 0.399 Males (%) 16 (53) 16 (53) 1.0 Females (%) 14 (47) 14 (47) - Duration of catheterization (days) 3–29 (7) 4–20 (8) 0.823 Incidence of catheter-associated urinary tract infection and predisposing factors Incidence of CAUTI was 40% in the control group [Figure 1]. None of the subjects from the bladder wash group developed CAUTI. Amikacin bladder wash was effective in preventing CAUTI (P < 0.001). Lower levels of consciousness (i.e. the Glasgow coma scale (GCS)) increased the risk of developing CAUTI (P = 0.026) [Table 2]. Figure 1 Effect of amikacin sulfate bladder wash on catheter-associated urinary tract infection Table 2 Risk factors for catheter-associated urinary tract infection (n=60) Factors UTI-positive group n = 12 UTI-negative group n = 18 P value Age (years) 18–68 (46.5) 20–55 (41.5) 0.280 Sex 0.457 Females 7 (50) 7 (50) Males 5 (31.3) 11 (68.7) Motor score of GCS 0.026* M 1–3 5 (83.4) 1 (16.6) M 4–6 7 (29.2) 17 (70.8) Catheter size 0.131 12 0 2 (100) 14 7 (36.8) 12 (63.2) 16 5 (71.4) 2 (28.6) 18 0 2 (100) Duration of catheterization 6–20 (9) 4–14 (7.5) 0.135 Systemic antibiotics 0.255 Yes 12 (44.4) 15 (55.6) No 0 3 (100) Steroids 0.643 Yes 7 (36.8) 12 (63.2) No 5 (45.5) 6 (54.5) Organism and sensitivity profile P. aeruginosa was the most common organism responsible for 51% of CAUTI [Figure 2]. P. aeruginosa was completely sensitive to amikacin sulfate, cefaperazone plus sulbactam, and piperacillin plus tazobactam, while it was completely resistant towards ceftazidime.

3.2) No 5 (45.5) 6 (54.5) Organism and sensitivity profile P. aeruginosa was the most common organism responsible for 51% of CAUTI [Figure 2]. P. aeruginosa was completely sensitive to amikacin sulfate, cefaperazone plus sulbactam, and piperacillin plus tazobactam, while it was completely resistant towards ceftazidime. Figure 2 Pathogens causing catheter-associated urinary tract infection Discussion The present study is the first of its kind in which the effect of amikacin bladder wash has been analyzed. Efficiency of bladder irrigation using various different solutions have been studied in the past in an attempt to reduce the incidence of CAUTI, majority of the investigators found it to be a time consuming and costly procedure that did not have an impact on CAUTI.[11–15] In contrast, the present study revealed that amikacin bladder wash is effective in preventing CAUTI. In previous studies, the incidence of CAUTI ranged from 11.0–73.3%.[1617] In the present study, incidence of CAUTI was 40% since those who were catheterized for less than three days were excluded in the study. This inclusion criterion might be the chief reason for a higher incidence of CAUTI in the present study.

AUTI. In previous studies, the incidence of CAUTI ranged from 11.0–73.3%.[1617] In the present study, incidence of CAUTI was 40% since those who were catheterized for less than three days were excluded in the study. This inclusion criterion might be the chief reason for a higher incidence of CAUTI in the present study. CAUTI increases the burden of the patient in terms of increased morbidity and mortality, prolonged hospital stay, and cost of the tests and medicines.[17–19] Tambyah et al.,[20] found that CAUTI had been responsible for an additional of USD589 per CAUTI in diagnostic tests and in medications. The present study reveals that amikacin sulfate bladder wash is effective in preventing CAUTI. As a vial of amikacin sulfate (500 mg) costs INR58 (approximately USD1.4), this is very cost effective especially in a developing country like ours.

mmunity that makes the person more susceptible to infections. However, the present study did not show any influence of sex, age, catheter size, duration of catheterization, and systemic use of antibiotics and steroids. This might be because of the small sample size and inclusion of long-term catheterized patients only. Pathogenic organisms responsible for CAUTI and their antibiotic sensitivity pattern vary with time. In a study, Jha et al.,[22] found that most common organisms responsible for CAUTI were E. coli (49%), S. aureus (23%), Proteus spp. (3.6%), Klebsiella (9.71%), Pseudomonas (0.8%), and Citrobacter (2.8%). Whereas in the present study, Pseudomonas (51%), E. coli (17%), Proteus spp., Citrobacter, Klebsiella, and Acinetobacter (8% each) were the most common. Similarly, antibiotic resistance pattern also varied. In their study, Taneja et al.,[23] found the highest frequency of antibiotic resistance was for ciprofloxacin (68.6%) followed by netilmicin (60.7%), ceftazidime (58.8%), imipenem (43.7%), amikacin (43.1%), and piperacillin (39.2%). In the present study, the pattern of antibiotic resistance was ceftazidime (100%), netilmicin (83%), imipenem (75%), ciprofloxacin (75%), and meropenem (60%).

iotic resistance was for ciprofloxacin (68.6%) followed by netilmicin (60.7%), ceftazidime (58.8%), imipenem (43.7%), amikacin (43.1%), and piperacillin (39.2%). In the present study, the pattern of antibiotic resistance was ceftazidime (100%), netilmicin (83%), imipenem (75%), ciprofloxacin (75%), and meropenem (60%). In this study, we have shown that amikacin sulfate bladder wash is very effective in preventing CAUTI. Thus it can be included in the routine catheter care, especially if catheterization is needed for more than five days. It is easy to implement and cost effective. The main limitation of this study was the small sample size and the fact that the main researcher was not blinded to the study. Conclusions There is a varying pattern of antibiotic sensitivity and resistance in different institutions. The most important thing to note is the fact that the bacteria have started developing resistance to higher antibiotics. This is very important since the indiscriminate use of antibiotics can lead to resistance, thus potentially endangering the life of a patient. This increasing resistance calls for immediate measures to use methods other than oral or parenteral antibiotics in CAUTI. We believe that this study is important because if used can decrease the development of CAUTI. Source of Support: Nil Conflict of Interest: None declared. Appendix 1 Inclusion criteria Informed consent Age above 18 years Patients available within 24 hours of catheterization Appendix 2 Exclusion criteria Past history of recurrent UTI Urine culture positive within 24 hours after enrolment in to the study

Conclusions There is a varying pattern of antibiotic sensitivity and resistance in different institutions. The most important thing to note is the fact that the bacteria have started developing resistance to higher antibiotics. This is very important since the indiscriminate use of antibiotics can lead to resistance, thus potentially endangering the life of a patient. This increasing resistance calls for immediate measures to use methods other than oral or parenteral antibiotics in CAUTI. We believe that this study is important because if used can decrease the development of CAUTI. Source of Support: Nil Conflict of Interest: None declared. Appendix 1 Inclusion criteria Informed consent Age above 18 years Patients available within 24 hours of catheterization Appendix 2 Exclusion criteria Past history of recurrent UTI Urine culture positive within 24 hours after enrolment in to the study Immunocompromized patients (AIDS, chemotherapy) History of diabetes Patients with renal insufficiency Catheter removed before third day Appendix 3 Amikacin sulfate bladder wash Hundred milligrams amikacin sulfate is added to 500 ml normal saline and 250 ml of this solution is instilled into the bladder through a Foleys catheter (with drainage tube clamped) using an IV set. Solution is allowed to remain in the bladder for 15 minutes and then drained. This is done twice daily. Appendix 4 Catheter-associated urinary tract infection– The diagnosis of catheter-associated urinary tract infection can be made when the urine culture shows 105 CFU/ml of urine from a catheterized patient.

Introduction It has been reported that modern intensive or critical care medicine emerged in the 1950s, largely pioneered by the anesthetist, Dr. Bjorn Ibsen during the polio epidemic at the Kommune hospital in Copenhagen in 1953.[1] This area developed following advances in mechanical ventilation and cardiopulmonary resuscitation.[23] In most developing countries, especially those of Sub-Saharan Africa, intensive care medicine or critical care services are poorly developed, or at most, still in infancy. Special intensive care units (ICUs), like neurological and neonatal ICUs, are still a novel concept. The challenges faced during the development of critical care services in the region are enormous.[45] Most of the work on the challenges in critical care services in Sub-Saharan Africa, except South Africa, has been done by expatriate authors on short-term service and have mainly focused on regions outside West Africa, which ironically is one of the most populous regions of Africa.[67] These challenges include inadequate manpower, especially consultant anesthetists who run ICUs in the subregion.[89] This was partly due to the fact that the specialty was not popular among medical graduates, who had their eyes on specializing in areas that would enable them to operate private clinics in order to supplement their then meager salaries. The resulting increase in salary since the return of civilian rule in Nigeria in 1999 coincided with an increase in the number of doctors entering the specialty of intensive care with all specialists receiving the same salary scale.[8]

These challenges include inadequate manpower, especially consultant anesthetists who run ICUs in the subregion.[89] This was partly due to the fact that the specialty was not popular among medical graduates, who had their eyes on specializing in areas that would enable them to operate private clinics in order to supplement their then meager salaries. The resulting increase in salary since the return of civilian rule in Nigeria in 1999 coincided with an increase in the number of doctors entering the specialty of intensive care with all specialists receiving the same salary scale.[8] This shows that as often stated, the problem with healthcare delivery in most parts of the region has much to do with the political will of the government and its priorities (which does not often include human investment). Unlike most Sub-Saharan African countries, medical practice in Nigeria is mainly doctor-based even in rural areas, though this spread is in no way nationwide. The first ICU in Nigeria was established at the University of Nigeria Teaching Hospital (UNTH), Enugu, in 1973, following the successful management of cardiac surgery patients there.[10] Subsequently, other Federal Universities/tertiary care centers developed their own ICUs.

This shows that as often stated, the problem with healthcare delivery in most parts of the region has much to do with the political will of the government and its priorities (which does not often include human investment). Unlike most Sub-Saharan African countries, medical practice in Nigeria is mainly doctor-based even in rural areas, though this spread is in no way nationwide. The first ICU in Nigeria was established at the University of Nigeria Teaching Hospital (UNTH), Enugu, in 1973, following the successful management of cardiac surgery patients there.[10] Subsequently, other Federal Universities/tertiary care centers developed their own ICUs. Critical care nursing was introduced in the country in 1982 by the Department of Anesthesia of the Jos University Teaching Hospital (JUTH), Nigeria.[11] Currently, there are two hospitals that train critical care nurses in Nigeria. Their national association is a member of the World Federation of Critical Care Nurses (WFCCN), having been admitted in 2007. Currently, the Nigerian association has about 380 members. It is not clear if every critical care nurse is registered with the association.[11] However, the number is small for a nation of more than 140 million (figures vary) people. So, it can be safely assumed that there are not enough critical care nurses to work in the ICUs, making for an average of about ten critical care nurses for each of the nation's 36 states.

e is registered with the association.[11] However, the number is small for a nation of more than 140 million (figures vary) people. So, it can be safely assumed that there are not enough critical care nurses to work in the ICUs, making for an average of about ten critical care nurses for each of the nation's 36 states. Evolution of critical care services in Nigeria can be divided into phases based on the nation's economic resources. The oil boom era (from early 1970s to the mid-1980s) was a period of growth and development with employment of expatriate staff and overseas-trained Nigerians. Following the economic reversal from the mid-1980s to late 1990s, critical care services basically fell into disrepair, with serious regression, inadequate material and manpower, low morale, and manpower flight overseas. The increase in oil revenues coupled with political will has gradually improved the delivery of critical care services since the turn of this century, even if the number of specialist anesthetists remains grossly inadequate.[48] Due to this paucity of anesthetists, some tertiary care centers in the country do not have ICUs, even when there are funds to operate a few bedded ICU.

Evolution of critical care services in Nigeria can be divided into phases based on the nation's economic resources. The oil boom era (from early 1970s to the mid-1980s) was a period of growth and development with employment of expatriate staff and overseas-trained Nigerians. Following the economic reversal from the mid-1980s to late 1990s, critical care services basically fell into disrepair, with serious regression, inadequate material and manpower, low morale, and manpower flight overseas. The increase in oil revenues coupled with political will has gradually improved the delivery of critical care services since the turn of this century, even if the number of specialist anesthetists remains grossly inadequate.[48] Due to this paucity of anesthetists, some tertiary care centers in the country do not have ICUs, even when there are funds to operate a few bedded ICU. Another area of manpower limitation is the paucity of biomedical engineers and even anesthetic technicians. This has led to a poor maintenance culture which hinders critical care services in the region. There is also the need to train healthcare personnel on how to use the procured modern equipments, as there are reports of materials not being used due to a lack of knowledge on how to use these equipments.[5] This can be achieved by organizing workshops with hands-on experience. Unlike some other African countries, Nigeria has not been a major beneficiary of philanthropic or religious organizations who have helped greatly in other parts of the continent. These organizations provide manpower and materials that are, in some cases, of first-world standard in both practice and training of health personnel. Some Nigerians have been beneficiaries of their expertise, but are mainly self-sponsored.

eligious organizations who have helped greatly in other parts of the continent. These organizations provide manpower and materials that are, in some cases, of first-world standard in both practice and training of health personnel. Some Nigerians have been beneficiaries of their expertise, but are mainly self-sponsored. During the early years of medical postgraduate training in Nigeria, each trainee specialist spent a year in Western Europe, usually the United Kingdom, updating both knowledge and skills, before the reversal of economic fortunes led to its suspension. There is a need for that program to be revived, so as to help doctors from Nigeria to keep pace with the rapid advances in medicine. The Overseas Doctor's Training Scheme (ODTS) by the Royal Colleges in the UK can help by offering limited training posts to doctors from Sub-Saharan Africa willing to return to their countries to help train others. Exchange programs with other nations like South Africa and the Indian subcontinent with advanced healthcare systems and more hands-on experience should be encouraged. Unlike reports from some African studies regarding availability of therapies like oxygen,[1213] it is relatively cheap in Nigeria, oxygen being locally manufactured. This has made oxygen concentrators, which are expensive, unnecessary. Piped medical gases and vacuum are used in most teaching hospitals.

During the early years of medical postgraduate training in Nigeria, each trainee specialist spent a year in Western Europe, usually the United Kingdom, updating both knowledge and skills, before the reversal of economic fortunes led to its suspension. There is a need for that program to be revived, so as to help doctors from Nigeria to keep pace with the rapid advances in medicine. The Overseas Doctor's Training Scheme (ODTS) by the Royal Colleges in the UK can help by offering limited training posts to doctors from Sub-Saharan Africa willing to return to their countries to help train others. Exchange programs with other nations like South Africa and the Indian subcontinent with advanced healthcare systems and more hands-on experience should be encouraged. Unlike reports from some African studies regarding availability of therapies like oxygen,[1213] it is relatively cheap in Nigeria, oxygen being locally manufactured. This has made oxygen concentrators, which are expensive, unnecessary. Piped medical gases and vacuum are used in most teaching hospitals. Drugs for use in the ICU including potent parenteral antibiotics and inotropes, are generally available under generic names. Parental nutrition which was a standard practice two decades ago when I was a house officer is rarely used nowadays due to the massive de-evaluation of the local currency since that period, which has made it beyond reach for most patients.

renteral antibiotics and inotropes, are generally available under generic names. Parental nutrition which was a standard practice two decades ago when I was a house officer is rarely used nowadays due to the massive de-evaluation of the local currency since that period, which has made it beyond reach for most patients. Blood products like fresh frozen plasma and clotting factors are rarely available. This is somewhat surprising since hematological services are fairly well developed with well-trained practitioners. There is another side to this story as scoring systems like The Acute Physiological And Chronic Health Evaluation (APACHE) cannot be used routinely due to the high cost of the required laboratory investigations. Invasive monitoring, which is the standard practice in modern critical care, is rarely used due to the high cost of the material needed. The daily cost of an ICU bed is quite expensive in some centers (about USD 85 in our center). Since hospital bills are borne by patients in most cases, cost effectiveness and cost benefit are a major consideration in admitting patients. Though there is a National Health Insurance Scheme (NHIS) in the country, it is mainly restricted to government and large company employees.

enters (about USD 85 in our center). Since hospital bills are borne by patients in most cases, cost effectiveness and cost benefit are a major consideration in admitting patients. Though there is a National Health Insurance Scheme (NHIS) in the country, it is mainly restricted to government and large company employees. As reported in some studies from Africa, the main groups benefiting from ICU care are postoperative surgical patients.[14–17] Our center which is Nigeria's top hospital for cardiac surgery also has a separate ICU for open heart surgery patients. Predominant medical diagnoses in our ICU were cerebrovascular accidents, myasthenia gravis, Guillian Barre' syndrome,[9] and cardiomyopathies. Tetanus, reportedly a major player in some African ICUs,[618] is very rare in our ICU, similar to another Nigerian study.[19] This may be due to the effective immunization drives with special focus on rural areas. Erratic water and power supply can be considered a problem in Nigeria, but not in a few other West African countries like Ghana and Cote'd' Voire, with more stable power supply. It remains a major problem in Nigeria despite the government's efforts to improve the situation. These auxiliary services need to be developed in tandem with improved quality of critical care services. The abundance of disposable latex gloves and sharp object disposal bins has resulted in a decreased risk of staff infection.

Erratic water and power supply can be considered a problem in Nigeria, but not in a few other West African countries like Ghana and Cote'd' Voire, with more stable power supply. It remains a major problem in Nigeria despite the government's efforts to improve the situation. These auxiliary services need to be developed in tandem with improved quality of critical care services. The abundance of disposable latex gloves and sharp object disposal bins has resulted in a decreased risk of staff infection. Intensive care unit mortality rates vary according to the study population. In a study of severe head-injury patients in the ICU of an elite national hospital in the federal capital territory of Abuja, Nigeria, the mortality rate was 68.4%.[20] In another study of medical neurological and obstetric patients admitted to our ICU in Enugu, the mortality rates were 43.5[9] and 33%, respectively.[21] In critical care obstetric patients admitted to the ICU of the University College Hospital, Ibadan, Nigeria, the mortality rate was 52%,[22] lower than another obstetric group study from Burkina Faso (60%).[23] Mortality rates in the general ICU population in two studies from Nigeria and Uganda were 35.1[19] and 25%,[6] respectively.

Intensive care unit mortality rates vary according to the study population. In a study of severe head-injury patients in the ICU of an elite national hospital in the federal capital territory of Abuja, Nigeria, the mortality rate was 68.4%.[20] In another study of medical neurological and obstetric patients admitted to our ICU in Enugu, the mortality rates were 43.5[9] and 33%, respectively.[21] In critical care obstetric patients admitted to the ICU of the University College Hospital, Ibadan, Nigeria, the mortality rate was 52%,[22] lower than another obstetric group study from Burkina Faso (60%).[23] Mortality rates in the general ICU population in two studies from Nigeria and Uganda were 35.1[19] and 25%,[6] respectively. Corruption is believed by many to have adversely affected health care delivery in Nigeria, and conversely, critical care services. It is believed that if money budgeted for equipment is properly used, the improvement would be massive. The recent upgrading of most federal government funded teaching hospitals in Nigeria to international standard portends well for the future as internal audits have already shown some improvement in patient care. Future studies are needed to validate that trend. Source of Support: Nil Conflict of Interest: None declared.

Introduction Acute ischemic strokes are commonly encountered in medical practice. The commonest clinical presentation of acute stroke in the middle cerebral artery territory is contralateral hemiplegia. Weakness of upper and lower limbs, facial paresis and gaze palsy are well known clinical findings in hemiplegic stroke. Diaphragmatic palsy in acute hemiplegic stroke is not so well known and there is very little published data.[1–3] We report a case of left hemiplegic stroke associated with diaphragmatic palsy. The pathophysiology of diaphragmatic palsy in acute stroke and its clinical implications are discussed. Case Report A 60-year-old man presented with an acute episode of left hemiparesis of three days duration. Risk factors included diabetes mellitus, hypertension and chronic smoking. On examination, the patient's blood pressure was 140/90mmHg, pulse rate was 90/minute and regular. Carotids were normal. He had a left homonymous hemianopia and a mild left upper motor neuron facial paresis. He had a left hemiparesis with grade 3/5 power (Medical Research Council grading) in left upper and lower limbs.

On examination, the patient's blood pressure was 140/90mmHg, pulse rate was 90/minute and regular. Carotids were normal. He had a left homonymous hemianopia and a mild left upper motor neuron facial paresis. He had a left hemiparesis with grade 3/5 power (Medical Research Council grading) in left upper and lower limbs. Laboratory investigations including hematological and biochemical parameters, were unremarkable. Electrocardiogram, echocardiogram and carotid Doppler studies were normal. Noncontrast CT scan of the brain showed multiple infarcts located in the centrum semiovale, caudate nucleus, genu of internal capsule and parieto-occipital areas on the right side [Figure 1]. A routine chest radiograph showed an elevated left dome of the diaphragm [Figure 2]. A left-sided diaphragmatic palsy was suspected, which was confirmed by fluoroscopic imaging that showed grossly decreased diaphragmatic excursions on the left side. Peripheral nerve conduction study showed a normal compound muscle action potential (CMAP) from the diaphragm on stimulation of the left phrenic nerve that was similar to that of the right side. Diaphragmatic electromyogram (EMG) was also normal. Pulmonary function tests and arterial blood gas analysis were normal. Figure 1 Axial noncontrast computerized tomography of the brain showing infarcts in the right caudate nucleus, internal capsule and parietooccipital cortex Figure 2 Chest radiograph showing an elevated left hemidiaphragm

Laboratory investigations including hematological and biochemical parameters, were unremarkable. Electrocardiogram, echocardiogram and carotid Doppler studies were normal. Noncontrast CT scan of the brain showed multiple infarcts located in the centrum semiovale, caudate nucleus, genu of internal capsule and parieto-occipital areas on the right side [Figure 1]. A routine chest radiograph showed an elevated left dome of the diaphragm [Figure 2]. A left-sided diaphragmatic palsy was suspected, which was confirmed by fluoroscopic imaging that showed grossly decreased diaphragmatic excursions on the left side. Peripheral nerve conduction study showed a normal compound muscle action potential (CMAP) from the diaphragm on stimulation of the left phrenic nerve that was similar to that of the right side. Diaphragmatic electromyogram (EMG) was also normal. Pulmonary function tests and arterial blood gas analysis were normal. Figure 1 Axial noncontrast computerized tomography of the brain showing infarcts in the right caudate nucleus, internal capsule and parietooccipital cortex Figure 2 Chest radiograph showing an elevated left hemidiaphragm Electrophysiologic investigations were suggestive of a defect in the central conduction pathway - the corticodiaphragmatic pathway - that was related to the acute ischemic stroke. A final diagnosis of left diaphragmatic palsy with left hemiparesis related to the infarct in the right middle cerebral artery territory was made. Discussion The case described above highlights an unusual complication of stroke - diaphragmatic palsy on the side of hemiparesis.

Electrophysiologic investigations were suggestive of a defect in the central conduction pathway - the corticodiaphragmatic pathway - that was related to the acute ischemic stroke. A final diagnosis of left diaphragmatic palsy with left hemiparesis related to the infarct in the right middle cerebral artery territory was made. Discussion The case described above highlights an unusual complication of stroke - diaphragmatic palsy on the side of hemiparesis. Other workers have studied the subject of diaphragmatic palsy in stroke earlier. Diaphragmatic elevation in supine chest films in 62 patients with recent stroke was studied by Santamaria et al.[1] They found an excessive elevation of the diaphragm on the paretic side in patients with severe hemiparesis as compared to the controls. This finding was seen more commonly with lesions involving the genu of the internal capsule.

in supine chest films in 62 patients with recent stroke was studied by Santamaria et al.[1] They found an excessive elevation of the diaphragm on the paretic side in patients with severe hemiparesis as compared to the controls. This finding was seen more commonly with lesions involving the genu of the internal capsule. Electrophysiological studies have attempted to study the corticodiaphragmatic pathways. Cortical magnetic stimulation was used to study the central conduction times in patients with stroke and healthy volunteers.[2] In this study, left and right conduction times were found to be symmetrical in healthy subjects and patients with hemiplegia but without capsular lesion (16.5 to 20.1ms). Conversely, they were markedly asymmetrical in patients with capsular hemiplegia, diaphragm response being abolished or markedly delayed on the plegic side. This study also provided evidence supporting the presence of a “central diaphragm paralysis” in patients with stroke. In addition, it suggested that there is no bilateral cortical motor representation of each hemidiaphragm. Corticodiaphragmatic pathways were assessed in another study using magnetic stimulation of the scalp.[3] Decreased diaphragmatic excursion was found in 41% of patients with stroke and abnormal magnetic evoked potentials from the affected hemisphere were found in 70.5% of patients.

Electrophysiological studies have attempted to study the corticodiaphragmatic pathways. Cortical magnetic stimulation was used to study the central conduction times in patients with stroke and healthy volunteers.[2] In this study, left and right conduction times were found to be symmetrical in healthy subjects and patients with hemiplegia but without capsular lesion (16.5 to 20.1ms). Conversely, they were markedly asymmetrical in patients with capsular hemiplegia, diaphragm response being abolished or markedly delayed on the plegic side. This study also provided evidence supporting the presence of a “central diaphragm paralysis” in patients with stroke. In addition, it suggested that there is no bilateral cortical motor representation of each hemidiaphragm. Corticodiaphragmatic pathways were assessed in another study using magnetic stimulation of the scalp.[3] Decreased diaphragmatic excursion was found in 41% of patients with stroke and abnormal magnetic evoked potentials from the affected hemisphere were found in 70.5% of patients. An attempt has been made by some workers to localize the diaphragm motor cortical representation using magnetic stimulation in normal adult human subjects.[45] The average point of optimal excitability was determined to be 3-4cm lateral to the mid-sagittal plane and 1cm anterior to the pre-auricular plane. These studies also confirmed that both bilateral crossed and uncrossed corticospinal connections to the diaphragm were usually present, with the crossed tract predominating. Ultrasonographic techniques have also confirmed that the diaphragm responds to contralateral and not ipsilateral cortical stimulation.[5]

r plane. These studies also confirmed that both bilateral crossed and uncrossed corticospinal connections to the diaphragm were usually present, with the crossed tract predominating. Ultrasonographic techniques have also confirmed that the diaphragm responds to contralateral and not ipsilateral cortical stimulation.[5] What are the clinical implications of diaphragmatic palsy in stroke? This question cannot be answered well as there is a lack of studies on this aspect. In one study,[3] a greater degree of respiratory dysfunction including a higher incidence of hypoxia, hypocapnia, and acidosis was seen in patients with hemiplegia and it was significantly related to the diaphragmatic excursion and site of infarction on the CT scan. Pneumonia is one of the commonest complications occurring in patients with acute stroke and affects about 7% of all patients admitted.[67] Mortality is three times higher in patients with pneumonia as compared to those without it.[7] Common factors predisposing patients to pneumonia are altered consciousness, impaired swallowing and cough reflex. We hypothesize that diaphragmatic palsy may also be a contributing factor towards the development of pneumonia as an increased incidence of pneumonia has been observed on the hemiparetic side in patients with stroke.[8] This could be due to a weak cough on the side with diaphragmatic palsy. However, large prospective studies are required to validate this.

sy may also be a contributing factor towards the development of pneumonia as an increased incidence of pneumonia has been observed on the hemiparetic side in patients with stroke.[8] This could be due to a weak cough on the side with diaphragmatic palsy. However, large prospective studies are required to validate this. In conclusion, diaphragmatic palsy can occur in patients with stroke, especially if it affects the internal capsule. Diaphragmatic palsy predisposes patients to a greater degree of respiratory dysfunction and pneumonia on the hemiparetic side. Further prospective studies on this subject are warranted. Source of Support: Nil Conflict of Interest: None declared.

Introduction Aluminium phosphide (ALP) poisoning (Celphos) has emerged as a common cause of accidental poisoning in children with a mortality ranging from 37–100%.[1] Since ALP is commonly used as a fungicide and rodenticide in India, many reports of accidental poisoning with severe consequences have been noted both in adults and children. However, only a few cases from outside India have been reported. The spectrum of symptoms and signs and their severity depends upon the time lag between ALP ingestion and hospitalisation. The most common presentation is shock with cold and clammy skin, a weak thready pulse and severe hypotension often refractory to vasopressors. Arrhythmias are common in ALP poisoning and are attributed to various causes including hypomagnesemia. Neurological, gastrointestinal and renal involvement is also common and documented in many case reports. Myocardial depression is also reported in many cases. We report a case of ALP poisoning with severe myocardial depression. Serial ECGs and all cardiac events were recorded. A post mortem examination was conducted, with a special interest in the heart to record cardiac myocyte changes on biopsy.

ed in many case reports. Myocardial depression is also reported in many cases. We report a case of ALP poisoning with severe myocardial depression. Serial ECGs and all cardiac events were recorded. A post mortem examination was conducted, with a special interest in the heart to record cardiac myocyte changes on biopsy. Case Report A 40-year-old male patient came to the hospital with a history of ingestion of ALP with a suicidal intent (one tablet of Celphos - 3 gm). The time between consumption and hospital arrival was approximately 3 hours. On arrival the patient complained of epigastric pain and had tried to vomit three to four times in an attempt to remove the tablets. He was conscious and oriented, and looked very unwell. His pulse rate was 110 beats/minute and his blood pressure was 70/30 mmHg. Examination of the respiratory system was unremarkable. Cardivascularly he was in shock. The oxygen saturation was 90% with pulse oximetry at atmospheric temperature and air. We began aggressively resuscitating the patient. Two peripheral lines for resuscitation were inserted and gastric lavage conducted with saline. Vasopressor norepinephrine was administered as per the standard dosage and one liter of normal saline was infused within one hour. On the first day, investigations showed a HG of 12 gm%, total white cell count of 7000/cumm and a normal ABG. Serum total calcium was 9.2 mg/dl, serum magnesium was 2.33 mg/dl, serum sodium 143 meq/L, serum potassium 5.3 meq/L and serum bicarbonate was 20 mmol/L. Blood urea, serum creatinine and LFTs were normal. After two hours of gastric lavage we gave coconut oil through Ryle's tube. ECG recorded on arrival showed a broad QRS complex with ST elevation in mainly the inferior oriented leads mimicking inferior wall myocardial infarction [Figure 1]. Serum CPKMB was very high (290 U/L).

rea, serum creatinine and LFTs were normal. After two hours of gastric lavage we gave coconut oil through Ryle's tube. ECG recorded on arrival showed a broad QRS complex with ST elevation in mainly the inferior oriented leads mimicking inferior wall myocardial infarction [Figure 1]. Serum CPKMB was very high (290 U/L). Figure 1 Showing ST elevation in inferior oriented leads mimicking inferior wall myocardial infraction

rea, serum creatinine and LFTs were normal. After two hours of gastric lavage we gave coconut oil through Ryle's tube. ECG recorded on arrival showed a broad QRS complex with ST elevation in mainly the inferior oriented leads mimicking inferior wall myocardial infarction [Figure 1]. Serum CPKMB was very high (290 U/L). Figure 1 Showing ST elevation in inferior oriented leads mimicking inferior wall myocardial infraction Over the next few hours the patient's blood pressure continued to fall despite being on maximum doses of norepinephrine infusion, we therefore started the patient on a dopamine infusion as per standard recommended doses. Over the next six hours of aggressive supportive measures, the patient continued to deteriorate. An ECG six hours after admission resembled myocardial infarction or pericarditis [Figure 2]. Electrolytes after six hours were normal except for a mild decrease in serum magnesium and hence, we started IV Magnesium therapy in the recommended dosage. On day 2, the patient was drowsy and could not maintain his saturation (80% saturation with oxygen) and therefore, the patient was intubated and ventilatory support was initiated. Blood pressure on the 2nd day was 70/30 mm Hg and did not improve despite the maximum dose of dopamine and norepinephrine. ECG on the 2nd day was suggestive of severe myocardial injury. Electrolytes were normal except for serum magnesium which was 3 mg/dl. We therefore stopped the magnesium infusion. Despite 48 hours of maximal resuscitative measures, the patient died. We conducted a post mortem examination. On autopsy the heart appeared to be normal on gross examination. The heart was removed for histopathological examination. Figures 3 and 4 show striking changes in the myocardial muscles. Histopathological findings showed that both the left and right ventricles as well as the interventricular septum were involved. Sections from both the apex and base of the heart showed changes. The right ventricle showed minimal changes and the interventricular septum was the worst affected. The changes comprised of areas of mild to severe myocyte vacuolation and areas of myoctyloysis and degeneration. There were areas of increased waviness of myocardial fibers.

the apex and base of the heart showed changes. The right ventricle showed minimal changes and the interventricular septum was the worst affected. The changes comprised of areas of mild to severe myocyte vacuolation and areas of myoctyloysis and degeneration. There were areas of increased waviness of myocardial fibers. Figure 2 Showing ST elevation with broad QRS complex mimicking anterior wall myocardial infarction with bundle branch block Figure 3 Severe degree of vacuolation in myocytes. (H and E, ×40) Figure 4 Necrosis and myocytolysis in many of the myocardial fibers. (H and E, ×40) Discussion Aluminium phosphide (ALP) is used as a rodenticide and is a common agent used in suicide attempts in India. Most of the cases in India are reported from northern India.[23] Refractory myocardial depression from ALP toxicity is not uncommon and carries a mortality of up to 77% (37–100%).[14] Easy availability and no antidote makes it an ideal suicidal poison. Upon exposure to moisture, it liberates phosphine gas, which is absorbed rapidly by inhalation or through the cutaneous or enteral routes. Phosphine resembles cyanide in that it inhibits cytochrome oxidase and thereby hampers cellular oxygen utilization.[5]

vailability and no antidote makes it an ideal suicidal poison. Upon exposure to moisture, it liberates phosphine gas, which is absorbed rapidly by inhalation or through the cutaneous or enteral routes. Phosphine resembles cyanide in that it inhibits cytochrome oxidase and thereby hampers cellular oxygen utilization.[5] The classical presentation of ALP is epigastric pain, nausea and cardiogenic shock reflected as severe refractory hypotension and is described in many case reports;[1–367] however, severe myocardial depression predominated in our case. There are a few case reports of survival in case of ALP poisoning when patients were treated with vegetable oils particularly with coconut oil and hence, we tried the same.[89]

as severe refractory hypotension and is described in many case reports;[1–367] however, severe myocardial depression predominated in our case. There are a few case reports of survival in case of ALP poisoning when patients were treated with vegetable oils particularly with coconut oil and hence, we tried the same.[89] Our patient had severe myocardial depression which could be correlated with serial ECG changes resembling myocardial infarction/ myocarditis or pericarditis. [Figure 1] in the initial hours resembles inferior wall myocardial infarction and later resembles extensive anterior wall myocardial infarction. We feel that the initially liberated phosphine may be absorbed through the stomach and diaphragm and affect the inferior wall first which rests on diaphragm and later the entire heart.(authors need to provide evidence of this mechanism being described before) ECG changes have been studied in detail in various studies[10–13] and include atrial fibrillation, supraventricular and ventricular tachycardia, ST-T changes, bundle branch blocks and AV conduction disturbances. We did not encounter any such ECG changes in our patient except ST-T changes and broad QRS complexes [Figures 1 and 2]. Broad QRS complex, ST-T changes along with raised cardiac marker CK-MB point to severe myocardial damage. Controversies exist about the magnesium level and prognosis of poisoning.[14] There was no magnesium imbalance or any electrolyte disturbance seen in our patient though we administered magnesium to avoid hypomagnesemia induced arrhythmias and death.

Our patient had severe myocardial depression which could be correlated with serial ECG changes resembling myocardial infarction/ myocarditis or pericarditis. [Figure 1] in the initial hours resembles inferior wall myocardial infarction and later resembles extensive anterior wall myocardial infarction. We feel that the initially liberated phosphine may be absorbed through the stomach and diaphragm and affect the inferior wall first which rests on diaphragm and later the entire heart.(authors need to provide evidence of this mechanism being described before) ECG changes have been studied in detail in various studies[10–13] and include atrial fibrillation, supraventricular and ventricular tachycardia, ST-T changes, bundle branch blocks and AV conduction disturbances. We did not encounter any such ECG changes in our patient except ST-T changes and broad QRS complexes [Figures 1 and 2]. Broad QRS complex, ST-T changes along with raised cardiac marker CK-MB point to severe myocardial damage. Controversies exist about the magnesium level and prognosis of poisoning.[14] There was no magnesium imbalance or any electrolyte disturbance seen in our patient though we administered magnesium to avoid hypomagnesemia induced arrhythmias and death. As the heart was the predominant organ affected in our case, we studied the histology of the heart in detail to correlate the clinical and histological findings. Histopathological findings of myocyte vacuolation and myoctyloysis and degeneration are both suggestive of myocardial injury. The areas of increased waviness of myocardial fibers indicate an episode of myocardial infarction. Cellular infiltration as reported in some articles was minimal in our case and could be due to the fact that the full blown infarct occurred only some time before the patient succumbed.[15]

uggestive of myocardial injury. The areas of increased waviness of myocardial fibers indicate an episode of myocardial infarction. Cellular infiltration as reported in some articles was minimal in our case and could be due to the fact that the full blown infarct occurred only some time before the patient succumbed.[15] Source of Support: Nil Conflict of Interest: None declared.

Dual lumen hemodialysis catheters are usually inserted via the right internal jugular vein (IJV). Subclavian vein (SCV) is generally avoided to prevent thrombosis or narrowing.[1] The site of stenosis caused by SCV catheter is usually near the junction of the SCV and IJV.[2] A 30-year-old female, suffering from endstage renal disease, was in the operating room for insertion of a hemodialysis catheter. She had undergone right IJV catheterization about 45 days back. The previous catheter had remained in situ for about 15 days. The exact cause of catheter removal was not documented. As she had no clinical signs or symptoms in the upper limb or the neck suggesting any complication, it was decided to cannulate the right IJV again. After instituting monitoring with lead II electrocardiogram, noninvasive blood pressure, and a pulse oximeter, a 12.5 Fr hemodialysis catheter (Soft-cell® PC kit, Bard Access Systems, Utah, USA) was placed uneventfully via the right IJV under local anesthesia with full aseptic precautions. Free aspiration of blood via both the lumens was attained through a 5-ml syringe. A chest radiograph was obtained postprocedure and haemodialysis was started without inspecting the X-ray film. However, a satisfactory blood flow through the hemodialysis machine could not be obtained. Gentle manipulation of the catheter and change in patient position made no difference to the flow. Meanwhile, the X-ray film revealed catheter misplacement into the ipsilateral SCV [Figure 1]. Figure 1 Chest X-ray showing the misplacement of right internal jugular hemodialysis catheter

After instituting monitoring with lead II electrocardiogram, noninvasive blood pressure, and a pulse oximeter, a 12.5 Fr hemodialysis catheter (Soft-cell® PC kit, Bard Access Systems, Utah, USA) was placed uneventfully via the right IJV under local anesthesia with full aseptic precautions. Free aspiration of blood via both the lumens was attained through a 5-ml syringe. A chest radiograph was obtained postprocedure and haemodialysis was started without inspecting the X-ray film. However, a satisfactory blood flow through the hemodialysis machine could not be obtained. Gentle manipulation of the catheter and change in patient position made no difference to the flow. Meanwhile, the X-ray film revealed catheter misplacement into the ipsilateral SCV [Figure 1]. Figure 1 Chest X-ray showing the misplacement of right internal jugular hemodialysis catheter The patient was transferred back to the operating room and the catheter was partially withdrawn over a guidewire using an image intensifier. At that time it became difficult to pass the guidewire beyond the junction of right IJV and SCV. Everytime an attempt was made the guidewire was deflected into the SCV. After gentle manipulations, the guidewire entered medially into the brachiocephalic vein but the catheter could not be advanced over it. The guidewire along with the catheter was partially withdrawn and the catheter was repositioned keeping its tip proximal to the site of the suspected stenosis. The catheter was used for hemodialysis without any complication.

entered medially into the brachiocephalic vein but the catheter could not be advanced over it. The guidewire along with the catheter was partially withdrawn and the catheter was repositioned keeping its tip proximal to the site of the suspected stenosis. The catheter was used for hemodialysis without any complication. Postcatheterization stenosis following long-term right IJV catheterization is not unknown. The prevalence of stenosis following SCV cannulation has been found to be 40–50% and stenosis resulting from cannulation of IJV 0–10%.[3] Anatomic narrowing can be present without clinical consequences,[4] as was seen in this patient. Stenosis has been defined as 50% or greater diameter reduction in the vein with or without collateral vessels. This patient had a previous catheter in situ for only 15 days, so it was thought that a reinsertion would be safe on the same side. But this was enough to cause a stenosis at the site described. Probably the lateral pressure caused by the catheter movement on the vein wall at the junction of IJV and SCV led to this stenosis. This suspected stenosis deflected the guidewire laterally into the SCV. The lower tapered part of the catheter entered the SCV following the guidewire in a lateral direction. Blood could be aspirated freely through a syringe as probably the kin k was not enough to occlude blood flow at low pressure. Fortunately there was no trauma leading to further complications.

e laterally into the SCV. The lower tapered part of the catheter entered the SCV following the guidewire in a lateral direction. Blood could be aspirated freely through a syringe as probably the kin k was not enough to occlude blood flow at low pressure. Fortunately there was no trauma leading to further complications. It has been recommended to use ultrasound examination prior to IJV catheterization, especially in patients with previous temporary or tunneled catheters.[5] The authors found IJV stenosis in five out of 100 such patients. Significantly, catheter could be placed through four of these five stenotic lesions. It is known that ultrasound cannot visualize and directly evaluate the brachiocephalic vein and superior vena cava, and Doppler waveform analysis should be added to detect any stenosis.[5] Such a device could have suspected a stenosis in this patient even in the absence of collaterals.

Introduction In the practice of critical care, ‘the care of a severely brain injured patient ’ is one of the toughest challenges for a critical care physician. Initial therapy provided for patients with severe brain injury or insult, is directed towards preservation and restoration of neuronal function. When this primary treatment is unsuccessful and the patient's condition evolves to brain death, the critical care physician has the responsibility to diagnose brain death with certainty and to offer the patient's family the opportunity to donate organs and / or tissues. There is a clear difference between severe brain damage and brain death. The physician must understand this difference, as brain death means that life support is futile, and brain death is the principal prerequisite for the donation of organs for transplantation. This review focuses on the clinical determination of brain death in adults and children, including the potential confounding factors, and provides an overview of valid confirmatory tests

There is a clear difference between severe brain damage and brain death. The physician must understand this difference, as brain death means that life support is futile, and brain death is the principal prerequisite for the donation of organs for transplantation. This review focuses on the clinical determination of brain death in adults and children, including the potential confounding factors, and provides an overview of valid confirmatory tests Evolution of the criteria for brain death Historically death was defined by the presence of putrefaction or decapitation, failure to respond to painful stimuli, or the apparent loss of observable cardio respiratory action. The widespread use of mechanical ventilators that prevent respiratory arrest has transformed the course of terminal neurologic disorders. Vital functions can now be maintained artificially after the brain has ceased to function. In 1968, an ad hoc committee at Harvard Medical School reexamined the definition of brain death and defined irreversible coma, or brain death, as unresponsiveness and lack of receptivity, the absence of movement and breathing, the absence of brain-stem reflexes, and coma whose cause has been identified.

ed to function. In 1968, an ad hoc committee at Harvard Medical School reexamined the definition of brain death and defined irreversible coma, or brain death, as unresponsiveness and lack of receptivity, the absence of movement and breathing, the absence of brain-stem reflexes, and coma whose cause has been identified. Definition Brain death is defined as the irreversible loss of all functions of the brain, including the brainstem. The three essential findings in brain death are coma, absence of brainstem reflexes, and apnoea. An evaluation for brain death should be considered in patients who have suffered a massive, irreversible brain injury of identifiable cause. A patient determined to be brain dead is legally and clinically dead. The diagnosis of brain death is primarily clinical. No other tests are required if the full clinical examination, including each of two assessments of brain stem reflexes and a single apnoea test, are conclusively performed. Determination of brain death The process for brain death certification includes Identification of history or physical examination findings that provide a clear etiology of brain dysfunction. The determination of brain death requires the identification of the proximate cause and irreversibility of coma. Severe head injury, hypertensive intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, hypoxic-ischemic brain insults and fulminant hepatic failure are potential causes of irreversible loss of brain function.

mination of brain death requires the identification of the proximate cause and irreversibility of coma. Severe head injury, hypertensive intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, hypoxic-ischemic brain insults and fulminant hepatic failure are potential causes of irreversible loss of brain function. The evaluation of a potentially irreversible coma should include, as may be appropriate to the particular case; clinical or neuro-imaging evidence of an acute CNS catastrophe that is compatible with the clinical diagnosis of brain death; Exclusion of any condition that might confound the subsequent examination of cortical or brain stem function. The conditions that may confound clinical diagnosis of brain death are: Shock/ hypotension Hypothermia -temperature < 32°C Drugs known to alter neurologic, neuromuscular function and electroencephalographic testing, like anaesthetic agents, neuroparalytic drugs, methaqualone, barbiturates, benzodiazepines, high dose bretylium, amitryptiline, meprobamate, trichloroethylene, alcohols. Brain stem encephalitis. Guillain- Barre' syndrome. Encephlopathy associated with hepatic failure, uraemia and hyperosmolar coma Severe hypophosphatemia. Performance of a complete neurological examination. Components of a complete neurological examination are: Examination of the patient-absence of spontaneous movement, decerebrate or decorticate posturing, seizures, shivering, response to verbal stimuli, and response to noxious stimuli administered through a cranial nerve path way. During the examination spinal reflexes may be present.

Performance of a complete neurological examination. Components of a complete neurological examination are: Examination of the patient-absence of spontaneous movement, decerebrate or decorticate posturing, seizures, shivering, response to verbal stimuli, and response to noxious stimuli administered through a cranial nerve path way. During the examination spinal reflexes may be present. Absent pupillary reflex to direct and consensual light; pupils need not be equal or dilated. The pupillary reflex may be selectively altered by eye trauma, cataracts, high dose dopamine, glutethamide, scopolamine, atropine, bretilium or monoamine oxidase inhibitors. Absent corneal, oculocephalic, cough and gag reflexes. The corneal reflex may be altered as a result of facial weakness. Absent oculovestibular reflex when tested with 20 to 50 ml. Of ice water irrigated into an external auditory canal clear of cerumen, and after elevating the patients head 30'. Labyrinthine injury or disease, anticholinergics, anticonvulsants, tricyclic antidepressants, and some sedatives may alter response. Failure of the heart rate to increase by more than 5 beats per minute after 1- 2 mg. of atropine intravenously. This indicates absent function of the vagus nerve and nuclei. Absent respiratory efforts in the presence of hypercarbia. Generally, the apnoea test is performed after the second examination of brainstem reflexes. The apnoea test need only be performed once when its results are conclusive. Before performing the apnoea test, the physician must determine that the patient meets the following conditions:

Absent respiratory efforts in the presence of hypercarbia. Generally, the apnoea test is performed after the second examination of brainstem reflexes. The apnoea test need only be performed once when its results are conclusive. Before performing the apnoea test, the physician must determine that the patient meets the following conditions: Core temperature ≥ 36.5°C or 97.7°F Euvolemia. Option: positive fluid balance in the previous 6 hours Normal PCO2. Option: arterial PCO2 ≥ 40 mm Hg Normal PO2. Option: pre-oxygenation to arterial PO2 ≥ 200 mm Hg After determining that the patient meets the above prerequisites, the physician should conduct the apnoea test as follows: Connect a pulse oximeter and disconnect the ventilator. Deliver 100% O2, 6 l/min, into the trachea. Option: place a cannula at the level of the carina. Look closely for any respiratory movements (abdominal or chest excursions that produce adequate tidal volumes). Measure arterial PO2, PCO2, and pH after approximately 8 minutes and reconnect the ventilator. If respiratory movements are absent and arterial PCO2 is ≥ 60 mm Hg (option: 20 mm Hg increase in PCO2 over a baseline normal PCO2), the apnoea test result is positive (i.e. it supports the diagnosis of brain death). If respiratory movements are observed, the apnoea test result is negative (i.e. it does not support the clinical diagnosis of brain death). Connect the ventilator, if during testing the systolic blood pressure becomes < 90 mm Hg (or below age appropriate thresholds in children less than 18 years of age) or the pulse oximeter indicates significant oxygen desaturation, or cardiac arrhythmias develop;

If respiratory movements are observed, the apnoea test result is negative (i.e. it does not support the clinical diagnosis of brain death). Connect the ventilator, if during testing the systolic blood pressure becomes < 90 mm Hg (or below age appropriate thresholds in children less than 18 years of age) or the pulse oximeter indicates significant oxygen desaturation, or cardiac arrhythmias develop; Immediately draw an arterial blood sample and analyze arterial blood gas. If PCO2 is ≥ 60 mm Hg or PCO2 increase is ≥ 20 mm Hg over baseline normal PCO2, the apnoea test result is positive (it supports the clinical diagnosis of brain death). if PCO2 is < 60 mm Hg and PCO2 increase is < 20 mm Hg over baseline normal PCO2, the result is indeterminate and a confirmatory test can be considered. When appropriate a 10 min. apnoea test can be performed after preoxygenation for 10 minutes with an Fi02 of 1.0 and normalization of patients PaCO2 to 40 mmHG. Assessment of brainstem reflexes Pupils- no response to bright light Size: midposition (4 mm) to dilated (9 mm) (absent light reflex - cranial nerve II and III) Ocular movement- cranial nerve VIII, III and VI No oculocephalic reflex (testing only when no fracture or instability of the cervical spine or skull base is apparent) No deviation of the eyes to irrigation in each ear with 50 ml of cold water (tympanic membranes intact; allow 1 minute after injection and at least 5 minutes between testing on each side) Facial sensation and facial motor response No corneal reflex (cranial nerve V and VII) No jaw reflex (cranial nerve IX)

No oculocephalic reflex (testing only when no fracture or instability of the cervical spine or skull base is apparent) No deviation of the eyes to irrigation in each ear with 50 ml of cold water (tympanic membranes intact; allow 1 minute after injection and at least 5 minutes between testing on each side) Facial sensation and facial motor response No corneal reflex (cranial nerve V and VII) No jaw reflex (cranial nerve IX) No grimacing to deep pressure on nail bed, supraorbital ridge, or temporo-mandibular joint (afferent V and efferent VII) Pharyngeal and tracheal reflexes (cranial nerve IX and X) No response after stimulation of the posterior pharynx No cough response to tracheobronchial suctioning Clinical observations compatible with the diagnosis of brain death: The following manifestations are occasionally seen and should not be misinterpreted as evidence for brainstem function: spontaneous movements of limbs other than pathologic flexion or extension response respiratory-like movements (shoulder elevation and adduction, back arching, intercostal expansion without significant tidal volumes) sweating, flushing, tachycardia normal blood pressure without pharmacologic support or sudden increases in blood pressure absence of diabetes insipidus deep tendon reflexes; superficial abdominal reflexes; triple flexion response Babinski reflex

respiratory-like movements (shoulder elevation and adduction, back arching, intercostal expansion without significant tidal volumes) sweating, flushing, tachycardia normal blood pressure without pharmacologic support or sudden increases in blood pressure absence of diabetes insipidus deep tendon reflexes; superficial abdominal reflexes; triple flexion response Babinski reflex Responsibilities of Physicians Determining Brain Death The diagnosis of brain death is primarily clinical. No other tests are required if the full clinical examination, including each of two assessments of brain stem reflexes and a single apnoea test, is conclusively performed. In the absence of either complete clinical findings consistent with brain death, or confirmatory tests demonstrating brain death, brain death cannot be diagnosed and certified. These guidelines apply to patients one year of age or older. Notify Next of Kin The facility must make diligent efforts to notify the person closest to the patient that the process for determining brain death is underway. Consent need not be obtained but requests for reasonable accommodation based on religious or moral objections should be noted and referred to appropriate hospital staff. Where family members object to invasive confirmatory tests, physicians should rely on the guidance of hospital counsel and the ethics committee.

rway. Consent need not be obtained but requests for reasonable accommodation based on religious or moral objections should be noted and referred to appropriate hospital staff. Where family members object to invasive confirmatory tests, physicians should rely on the guidance of hospital counsel and the ethics committee. Interval Observation Period After the first clinical exam, the patient should be observed for a defined period of time for clinical manifestations that are inconsistent with the diagnosis of brain death. Most experts agree that a 6 hour observation period is sufficient and reasonable in adults and children over the age of 1 year. Longer intervals are advisable in young children. Repeat Clinical Assessment of Brain Stem Reflexes The examination as described above should be repeated in full and documented. When clinical circumstances prohibit completion of any steps in the clinical examination, these should be documented. Confirmatory Testing as Indicated When the full clinical examination, including both assessments of brain stem reflexes and the apnoea test, is conclusively performed, no additional testing is required to determine brain death. In some patients, skull or cervical injuries, cardiovascular instability, or other factors may make it impossible to complete parts of the assessment safely. In such circumstances, a confirmatory test verifying brain death is necessary. These tests may also be used to reassure family members and medical staff.

Confirmatory Testing as Indicated When the full clinical examination, including both assessments of brain stem reflexes and the apnoea test, is conclusively performed, no additional testing is required to determine brain death. In some patients, skull or cervical injuries, cardiovascular instability, or other factors may make it impossible to complete parts of the assessment safely. In such circumstances, a confirmatory test verifying brain death is necessary. These tests may also be used to reassure family members and medical staff. Any of the suggested tests may produce similar results in patients with catastrophic brain damage who do not fulfill the clinical criteria of brain death. The confirmatory tests are. Angiography (conventional, computerized tomographic, magnetic resonance, and radionuclide): Brain death confirmed by demonstrating the absence of intracerebral filling at the level of the carotid bifurcation or Circle of Willis. The external carotid circulation is patent, and filling of the superior sagittal sinus may be delayed. Radionuclide angiography (CRAG) does not adequately image vasculature of the posterior fossa. MRI angiography can be quite challenging in an ICU patient because of magnet incompatibility with lines, ventilator tubing and other hardware. Cerebral arteriography: This test is often difficult to perform in a critically ill, unstable patient.

Radionuclide angiography (CRAG) does not adequately image vasculature of the posterior fossa. MRI angiography can be quite challenging in an ICU patient because of magnet incompatibility with lines, ventilator tubing and other hardware. Cerebral arteriography: This test is often difficult to perform in a critically ill, unstable patient. Electroencephalography: Brain death confirmed by documenting the absence of electrical activity during at least 30 minutes of recording that adheres to the minimal technical criteria for EEG recording in suspected brain death as adopted by the American Electroencephalographic Society, including 16-channel EEG instruments. The ICU setting may result in false readings due to electronic background noise creating innumerable artifacts. Nuclear brain scanning: Brain death confirmed by absence of uptake of isotope in brain parenchyma and/or vasculature, depending on isotope and technique used. (“hollow skull phenomenon”). Somatosensory evoked potentials: Brain death confirmed by bilateral absence of N20-P22 response with median nerve stimulation. The recordings should adhere to the minimal technical criteria for somatosensory evoked potential recording in suspected brain death as adopted by the American Electroencephalographic Society. Transcranial doppler ultrasonography: Brain death confirmed by small systolic peaks in early systole without diastolic flow, or reverberating flow, indicating very high vascular resistance associated with greatly increased intracranial pressure.

Somatosensory evoked potentials: Brain death confirmed by bilateral absence of N20-P22 response with median nerve stimulation. The recordings should adhere to the minimal technical criteria for somatosensory evoked potential recording in suspected brain death as adopted by the American Electroencephalographic Society. Transcranial doppler ultrasonography: Brain death confirmed by small systolic peaks in early systole without diastolic flow, or reverberating flow, indicating very high vascular resistance associated with greatly increased intracranial pressure. Since as many as 10% of patients may not have temporal insonation windows because of skull thickness, the initial absence of Doppler signals cannot be interpreted as consistent with brain death. Certification of Brain Death Brain death can be certified by a single physician privileged to make brain death determinations. However, before a patient can become an organ donor, New York State law requires that the time of brain death must be certified by the physician who attends the donor at his death and one other physician, neither of whom shall participate in the process of transplantation. This requirement ensures that all evaluations meet accepted medical standards, and that all participants can have confidence that brain death determination has not been influenced by extraneous factors, including the needs of potential organ recipients.

ither of whom shall participate in the process of transplantation. This requirement ensures that all evaluations meet accepted medical standards, and that all participants can have confidence that brain death determination has not been influenced by extraneous factors, including the needs of potential organ recipients. When two physicians are required to certify the time of death, i.e., when organ donation is planned, both physicians should affirm that the clinical evaluation meets accepted medical standards, and that the data fully support the determination of brain death. Generally, both physicians should observe the patient, review the medical record, and note whether any additional information is required to make a definitive determination. Neither physician should certify brain death unless all aspects of the determination have been completed. Medical Record Documentation: All phases of the determination of brain death should be clearly documented in the medical record; The medical record must indicate: etiology and irreversibility of coma / unresponsiveness absence of motor response to pain absence of brainstem reflexes during two separate examinations separated by at least 6 hours absence of respiration with pCO2 ≥ 60 mm hg justification for, and result of, confirmatory tests if used

Medical Record Documentation: All phases of the determination of brain death should be clearly documented in the medical record; The medical record must indicate: etiology and irreversibility of coma / unresponsiveness absence of motor response to pain absence of brainstem reflexes during two separate examinations separated by at least 6 hours absence of respiration with pCO2 ≥ 60 mm hg justification for, and result of, confirmatory tests if used Withdraw cardio-respiratory support in accordance with hospital policies, including those for organ donation When a patient is certified as brain dead and the ventilator is to be disconnected, the family should be treated with sensitivity and respect. If family members wish, they may be offered the opportunity to attend while the ventilator is disconnected. However, family members should be prepared for the possibly disturbing clinical activity that they may witness when organ donation is contemplated, ventilatory support will conclude in the operating room and family attendance is not appropriate. Source of Support: Nil Conflict of Interest: None declared. Appendix: Determination of Brain Death in Children Less Than One Year of Age General Policy Statement. The brains of infants and young children have increased resistance to damage and may recover substantial functions even after exhibiting unresponsiveness on neurological examination for longer periods as compared to adults. When applying neurological criteria to determine death in children younger than one year, longer observation periods are required.

ildren have increased resistance to damage and may recover substantial functions even after exhibiting unresponsiveness on neurological examination for longer periods as compared to adults. When applying neurological criteria to determine death in children younger than one year, longer observation periods are required. The patient must not be significantly hypothermic or hypotensive for age. Observation Periods According to Age. The recommended observation period depends on the age of the patient and the laboratory tests utilized. It is assumed that the child was born at full term Between the ages of 2 months and 1 year, an interval of at least 24 hours should be used. Between the ages of 7 days and 2 months, the minimum interval should be 48 hours. Reliable criteria have not been established for the determination of brain death in children less than 7 days old. Seven days to two months: Two examinations and electroencephalograms (EEGs) should be separated by at least 48 hours. Two months to one year: Two examinations and EEGs should be separated by at least 24 hours. A repeat examination and EEG are not necessary if a concomitant radionuclide (CRAG) or other angiographic study demonstrates no visualization of cerebral arteries.

Introduction Liver transplantation is the treatment of choice in patients with acute or chronic end stage liver disease (ESLD), irresectable primary liver tumors, and metabolic disorders.[1] Orthotopic liver transplantation (OLT) is the replacement of a diseased liver with a healthy liver in the normal anatomic position. The operative procedure is extensive, complex, and technically challenging with multiple vascular transections and anastomoses.[2] In addition, OLT is associated with several hemostatic defects that contribute to a risk of massive blood loss.[2] The liver is an extremely vascular organ. The associated coagulopathy, anemia, malnutrition, and severe portal hypertension have made this procedure more daunting and the use of blood products is almost universal.[3] Hence, of all solid organ transplantations, OLT has placed the greatest demands on clinical transfusion services.[4] Although blood use has steadily declined with improved surgical and anesthesiological techniques, better graft preservation, better intraoperative monitoring of coagulation status, and pharmacologic treatment of fibrinolysis during the last decade, OLT still frequently demands transfusion equal to one blood volume (massive transfusion).[5] Because the transfusion needs during OLT are unpredictable, transfusion services must remain prepared to effectively deliver massive transfusion support. Liver transplant recipients present unique challenges, not only in terms of blood supply, but requirements of specialized blood components, serologic problems, and immunologic effects of transfusion on both the allograft and the recipient.[6] Studies have observed that increased blood requirements are associated with higher incidence of infections, drug overdose, prolonged stay in the ICU, serologic problems, and immunologic effects of transfusion on both the allograft and the recipient, graft rejection or graft death and patient death.[1–6] However, whether these differences in outcomes are related to the transfusion as an independent risk factor, or whether the transfusion is a marker for a technically more difficult surgery remains unclear.

cts of transfusion on both the allograft and the recipient, graft rejection or graft death and patient death.[1–6] However, whether these differences in outcomes are related to the transfusion as an independent risk factor, or whether the transfusion is a marker for a technically more difficult surgery remains unclear. Yet, bloodless liver transplantation has been achieved in Jehovah's witness patients.[2] This subset of patients has allowed us a distinctive opportunity to develop strategies towards a transfusion-free environment, with ultimate aim of being able to translate this practice to all general surgical procedures.[3] Donor leucocyte microchimerism is under active investigation as a mechanism to improve graft survival.[7] Starzl et al., proposed that the long-term presence of donor leucocytes may lead to tolerance of the graft.[7] Studies have shown that patients receiving cadaveric marrow stem cells at the time of liver transplantation had fewer rejection episodes and better graft survival than control patients.[7] Method of literature search: The name of topic is typed and searched in Google search. The name of topic is typed and searched in PubMed search; went through the related articles. Some standard books in Transfusion Medicine were also referred. Contributing factors to blood loss during liver transplantation can be categorized based on factors related to preoperative and intraoperative factors.

The name of topic is typed and searched in Google search. The name of topic is typed and searched in PubMed search; went through the related articles. Some standard books in Transfusion Medicine were also referred. Contributing factors to blood loss during liver transplantation can be categorized based on factors related to preoperative and intraoperative factors. Transfusion Predictors Preoperative factors Preoperative factors associated with blood loss during OLT include liver failure, cirrhosis, cholestasis, and splenomegaly.[2] The liver plays a central role in hemostasis. Many complex derangements of hemostasis are associated with ESLD which are shown in Table 1.[1] Table 1 Hemostatic abnormalities in liver disease

Transfusion Predictors Preoperative factors Preoperative factors associated with blood loss during OLT include liver failure, cirrhosis, cholestasis, and splenomegaly.[2] The liver plays a central role in hemostasis. Many complex derangements of hemostasis are associated with ESLD which are shown in Table 1.[1] Table 1 Hemostatic abnormalities in liver disease Hypocoagulability Deficiency of coagulation factors by impaired synthesis Synthesis of abnormal clotting proteins (dysfibrinogenemia) Impaired clearance of activated coagulation factors and degradated fibrin Vitamin K deficiency Hypercoagulability Decreased levels of antithrombin, protein C or protein S by impaired synthesis Enhanced fibrinolytic activity Increased levels of circulating t-PA by impaired hepatic clearance Reduced synthesis of fibrinolytic inhibitors Quantitative and qualitative platelet defects Splenomegaly caused by portal hypertension leads to platelet sequestration and destruction Thrombopoietin deficiency due to cirrhosis leads to low platelet production Disturbed platelet-vessel wall interaction Inhibition of GP IIb/IIIa by increased levels of fibrin degradation products Degraded platelet receptors by increase in plasmin levels Disseminated intravascular coagulation Consumption of coagulation factors and platelets Hyperfibrinolysis Impaired platelet function due to fibrin degradation products, secondary to hyperfibrinolysis Two scoring systems have been used to grade the severity of ESLD and prioritize the patients on waiting list for OLT.

ls Disseminated intravascular coagulation Consumption of coagulation factors and platelets Hyperfibrinolysis Impaired platelet function due to fibrin degradation products, secondary to hyperfibrinolysis Two scoring systems have been used to grade the severity of ESLD and prioritize the patients on waiting list for OLT. Child-Turcotte-Pugh Score CTP score is a measure of disease severity and is classified into CTP class A to C with a scoring system of 5 to 15.[2] Class A: 5-6 (less severe) Class B: 7-9 Class C: 10-15 (more severe) Model for end-stage liver disease MELD, a numerical scale, ranging from 6 (less ill) to 40 (gravely ill), used for liver transplant patients gives a score based on how urgently the patient needs a liver transplant within the next three months. Its impact on transfusion requirements can be translated directly to the timing of the transplantation. With longer waiting times the liver disease progresses, as reflected in higher Child-Pugh/MELD score and thereby increasing transfusion requirement. Etiology of liver disease Patients with chronic active hepatitis have more advanced disease and require more blood products than patients with primary biliary cirrhosis.[2] Preoperative hematological parameters A retrospective study of 300 liver transplants reported no correlation among preoperative platelet count, aPTT, PT, fibrinogen to that of intraoperative blood loss or transfusion requirements.[2] Blood transfusions in OLT should be based on clinical assessment and well established transfusion protocol rather than laboratory tests.[2]

study of 300 liver transplants reported no correlation among preoperative platelet count, aPTT, PT, fibrinogen to that of intraoperative blood loss or transfusion requirements.[2] Blood transfusions in OLT should be based on clinical assessment and well established transfusion protocol rather than laboratory tests.[2] Previous abdominal surgery Those with previous upper abdominal surgery tend to have vascularised adhesions which may render liver dissection hemorrhagic thereby increasing intraoperative transfusion requirement.[2] Transjugular intrahepatic porto systemic shunt TIPSS is done in patients with liver disease for intractable variceal bleed and refractory ascites. The benefits noted were that it decreases the bleeding during surgery by virtue of lowered portal pressures thereby decreasing blood requirements.[2] Preexisting coagulopathy It is associated with increased blood loss during surgery, thereby increasing blood transfusions.[2] Intra-operative factors Liver transplantation may be divided into three stages: Stage I (preanhepatic phase): Patient's diseased liver and its vessels are dissected free and ends with removal of the diseased organ. Blood loss occurs from transection of collaterals that develops from portal hypertension. Preexisting abnormalities of clotting, platelets, and fibrinolysis compound the problem.[4] Stage II (anhepatic phase): Begins with implantation of the donor liver and ends with graft reperfusion. This is a dangerous moment in the procedure when hemodynamic, metabolic, and hemostatic abnormalities can arise.[4]

Stage I (preanhepatic phase): Patient's diseased liver and its vessels are dissected free and ends with removal of the diseased organ. Blood loss occurs from transection of collaterals that develops from portal hypertension. Preexisting abnormalities of clotting, platelets, and fibrinolysis compound the problem.[4] Stage II (anhepatic phase): Begins with implantation of the donor liver and ends with graft reperfusion. This is a dangerous moment in the procedure when hemodynamic, metabolic, and hemostatic abnormalities can arise.[4] Stage III (postreperfusion phase): Begins with reperfusion of the grafted liver, creating hepatic arterial anastamosis, preparing a form of biliary drainage for the new liver, obtaining good surgical hemostasis and closing.[4] During surgery, marked changes in coagulation can occur. These may result from hemodilution, platelet consumption, disordered thrombin regulation, and fibrinolysis. Some patients develop severe coagulopathy, during the anhepatic and early reperfusion phase of OLT.[4] Transplantation of a healthy liver restores the patient's clotting function. However, a dysfunctional graft may not immediately produce clotting factors, thereby leading to coagulopathy mandating massive transfusions.[2]

e patients develop severe coagulopathy, during the anhepatic and early reperfusion phase of OLT.[4] Transplantation of a healthy liver restores the patient's clotting function. However, a dysfunctional graft may not immediately produce clotting factors, thereby leading to coagulopathy mandating massive transfusions.[2] Thromboelastography: Besides standard coagulation tests (i.e., PT, aPTT, fibrinogen levels), TEG is a measurement technique allowing rapid on-site assessment of the functional clotting status.[8] TEG findings have been correlated with intraoperative hemorrhage and coagulopathy and can assist anesthesiologists in treating intraoperative bleeding by identifying the cause.[2] In combination with clinical bleeding assessment, it facilitates selective use of component therapy and specific drug treatment.[8] Graft quality: Steatosis increases cold ischemic injury and reduces the rate of hepatic regeneration.[9] The risk of primary nonfunction after transplantation of cadaveric graft increases proportionately with the degree of steatosis.[9] Marcos et al., suggested that steatosis reduces the percentage of the functioning liver.[9] Increased risk of graft dysfunction is observed in fatty infiltration of >30%, abnormal liver tests and other donor risk factors such as high inotrope administration and donor stay in the intensive care unit (>five days).[10] Graft dysfunction further necessitates massive transfusions.

tage of the functioning liver.[9] Increased risk of graft dysfunction is observed in fatty infiltration of >30%, abnormal liver tests and other donor risk factors such as high inotrope administration and donor stay in the intensive care unit (>five days).[10] Graft dysfunction further necessitates massive transfusions. Older donors (>60 years) are vulnerable to prolonged cold ischemia and high inotrope levels, give rise to early graft dysfunction and prolonged cholestasis.[10] Such recipients are vulnerable to receive massive transfusions. Graft-recipient body weight ratio: GRWR <0.8% in partial graft transplants (living donor liver transplants and split cadaveric transplants) leads to small-for-size syndrome (SFSS) which results in lower graft survival.[10] Such small-for size grafts depend on appropriate blood component therapy until the graft regenerates. A GRWR ratio of 1% is accepted to be a graft of good size.[9] Graft preservation: University of Wisconsin (UW) solution and Histidine-tryptophan-ketogluterate (HTK) solution are used as the primary preservation solution for liver allograft.[11] Improper and suboptimal graft preservation leads to graft dysfunction and to severe post transplant bleeding because of failure to synthesize coagulation factors which accelerates massive and multiple blood transfusions.

ketogluterate (HTK) solution are used as the primary preservation solution for liver allograft.[11] Improper and suboptimal graft preservation leads to graft dysfunction and to severe post transplant bleeding because of failure to synthesize coagulation factors which accelerates massive and multiple blood transfusions. Cold ischemia time: Length of CIT is the length of time an organ is preserved between procurement (organ recovery) and transplantation. Prolonged CIT continues to have a negative effect on liver transplant outcomes.[12] CIT had a significant effect on short-term graft failure.[12] CIT should be kept as short as possible to reduce the intraoperative RBC transfusion requirement as prolonged CIT has a negative effect on perioperative RBC transfusion requirement.[13]

IT continues to have a negative effect on liver transplant outcomes.[12] CIT had a significant effect on short-term graft failure.[12] CIT should be kept as short as possible to reduce the intraoperative RBC transfusion requirement as prolonged CIT has a negative effect on perioperative RBC transfusion requirement.[13] Surgical technique: OLT involves explantation of native liver and replacement with the donor liver. This is done by piggyback transplantation, whereby the inferior vena cava is preserved and venovenous bypass is avoided.[2] Portosystemic shunting is done in patients with liver failure in order to decrease preoperative complications associated with portal hypertension (for example, bleeding varices, ascites, sepsis). This decreases blood requirement and operative time.[2] The experience of the surgical and anaesthesiology team, impacts blood loss and transfusion requirement. Additionally, modifications in surgical technique, including use of electrocautery, argon beam coagulation and use of fibrin glue, minimizes blood loss thereby minimizing transfusions.[2] Meticulous surgical technique and securing hemostasis on the operating table remains a priority for the surgeon, and indeed long operating times translate into higher transfusion requirement.

g use of electrocautery, argon beam coagulation and use of fibrin glue, minimizes blood loss thereby minimizing transfusions.[2] Meticulous surgical technique and securing hemostasis on the operating table remains a priority for the surgeon, and indeed long operating times translate into higher transfusion requirement. Blood loss: Blood loss is directly proportional to the duration of surgery. Consumption of banked blood (number of RBC units) reflects the degree of blood loss. Based on the consumption of RBC units, patients are categorized into High Blood Loss (HBL) group (>6 RBC units transfused) and Low Blood Loss (LBL) group (<6 RBC units transfused).[14] Intraoperative bleeding remains a significant problem affecting the immediate outcome after transplantation of liver.[15] Preoperative parameters cannot predict operative bleeding accurately and the mainstay to prevent bleeding is a meticulous surgical technique during the hepatectomy and correction of coagulation abnormalities throughout the procedure.[15]

ficant problem affecting the immediate outcome after transplantation of liver.[15] Preoperative parameters cannot predict operative bleeding accurately and the mainstay to prevent bleeding is a meticulous surgical technique during the hepatectomy and correction of coagulation abnormalities throughout the procedure.[15] Hemodynamics: Central venous pressure (CVP) monitoring is an important aspect of OLT. Patients undergo volume expansion prior to hepatic resection to prevent bleeding complications, but expansion increases CVP. Deliberate lowering of the CVP during liver resection assists in bleeding control by decreasing the blood pressure gradient over which bleeding occurs during dissection.[2] Massicotte et al. showed that maintenance of a low CVP prior to the anhepatic phase, avoidance of plasma transfusions and restricting volume replacement during OLT was associated with a decrease in RBC transfusions during OLT.[16]

y decreasing the blood pressure gradient over which bleeding occurs during dissection.[2] Massicotte et al. showed that maintenance of a low CVP prior to the anhepatic phase, avoidance of plasma transfusions and restricting volume replacement during OLT was associated with a decrease in RBC transfusions during OLT.[16] Cell salvage: The use of cell salvage to collect and reinfuse shed, autologous blood is common practice in OLT, when high blood loss is anticipated.[2] Autologous blood transfusion reduces the risks associated with allogenic transfusions. Cell salvage is not indicated in the presence of sepsis and hepatocellular carcinoma (HCC).[2] Large volume transfusion of salvaged blood can cause postoperative hypofibrinogenemia, thrombocytopenia, prolonged prothrombin and partial thromboplastin time and elevated fibrin split products.[17] This cell saver induced coagulopathy can be prevented by simultaneous platelet and cryoprecipitate transfusions along with reinfusion of salvaged blood, as salvaged blood does not provide platelets and fibrinogen.[1718] Saline washing of red cells increases sodium levels and decreases potassium and calcium levels. Hence, supplementation of potassium and calcium is done during cell salvage. Postoperative factors Primary nonfunction of graft or delayed graft function Failure of graft to function contributes to postoperative bleeding, causing coagulopathy.[2] Appropriate blood component therapy is given to these patients.

Cell salvage: The use of cell salvage to collect and reinfuse shed, autologous blood is common practice in OLT, when high blood loss is anticipated.[2] Autologous blood transfusion reduces the risks associated with allogenic transfusions. Cell salvage is not indicated in the presence of sepsis and hepatocellular carcinoma (HCC).[2] Large volume transfusion of salvaged blood can cause postoperative hypofibrinogenemia, thrombocytopenia, prolonged prothrombin and partial thromboplastin time and elevated fibrin split products.[17] This cell saver induced coagulopathy can be prevented by simultaneous platelet and cryoprecipitate transfusions along with reinfusion of salvaged blood, as salvaged blood does not provide platelets and fibrinogen.[1718] Saline washing of red cells increases sodium levels and decreases potassium and calcium levels. Hence, supplementation of potassium and calcium is done during cell salvage. Postoperative factors Primary nonfunction of graft or delayed graft function Failure of graft to function contributes to postoperative bleeding, causing coagulopathy.[2] Appropriate blood component therapy is given to these patients. Leaks at anastomosis Leaks at vascular suture lines or bleeding from the cut surfaces at bowel anastomoses due to technical failures, result in postoperative bleeding which may require re-intervention and blood transfusions.[2]

Failure of graft to function contributes to postoperative bleeding, causing coagulopathy.[2] Appropriate blood component therapy is given to these patients. Leaks at anastomosis Leaks at vascular suture lines or bleeding from the cut surfaces at bowel anastomoses due to technical failures, result in postoperative bleeding which may require re-intervention and blood transfusions.[2] Graft versus-host disease GVHD can occur from transfer of donor-derived passenger lymphocytes and manifests as hemolysis during 7-14 days after transplantation.[6] This is controlled by transfusion of donor-specific RBCs.[6] Sepsis: Sepsis also results in multiple blood transfusions during the post-operative period. Thrombocytopenia It causes bleeding which is associated with platelet consumption, platelet-associated IgM and IgA antibody production, sequestration, thrombin generation, viral infection and ABO-incompatible GVHD.[2] This further necessitates platelet transfusions.

Sepsis: Sepsis also results in multiple blood transfusions during the post-operative period. Thrombocytopenia It causes bleeding which is associated with platelet consumption, platelet-associated IgM and IgA antibody production, sequestration, thrombin generation, viral infection and ABO-incompatible GVHD.[2] This further necessitates platelet transfusions. Drugs that Minimize Blood Loss Antifibrinolytics: Increased fibrinolysis is observed in some patients during the second and third phases of OLT. Various antifibrinolytic agents like aprotinin (AP), tranexamic acid (TA) and epsilon amino caproic acid (EACA) have been used to counter this accelerated fibrinolysis.[2] Prophylactic inhibition of hyperfibrinolysis with the biological serine protease inhibitor AP or the synthetic lysine analog TA is common clinical practice in OLT.[19] Aprotinin has been shown to significantly decrease blood loss, transfusion of RBC units, FFPs, platelets and cryoprecipitate and duration of surgery.[20] It also has an effect on platelet function, anti inflammatory properties and the need for intraoperative ionotropes.[2021] Tranexamic acid also decreases transfusion requirements in some but not all studies.[2]

crease blood loss, transfusion of RBC units, FFPs, platelets and cryoprecipitate and duration of surgery.[20] It also has an effect on platelet function, anti inflammatory properties and the need for intraoperative ionotropes.[2021] Tranexamic acid also decreases transfusion requirements in some but not all studies.[2] Recombinant factor VIIa (rFVIIa) has been shown to improve hemostasis during liver transplantation.[5] A single dose of 80 mcg/kg rFVIIa significantly reduced transfusion requirements during OLT.[522] A study was done where rFVIIa was given as a bolus just before surgery to patients with preoperative risk of high intraoperative blood loss, including severe uncorrected coagulopathy.[2] There was immediate correction of coagulation after administration of rFVIIa and these patients were adjusted to normal risk group without an increased risk for thrombotic complications.[2] Conjugated estrogen administered in a dose of 100 mg prior to surgery and just after graft perfusion has shown to decrease blood loss and transfusion requirement.[2] Frenette et al. reported statistical decrease in the use of blood products when conjugated estrogen was used instead of placebo during OLT.[23] Clonidine, a centrally acting alpha2-adrenergic receptor agonist, significantly decreased transfusion and fluid requirements in a small prospective, randomized controlled trial.[2]

Conjugated estrogen administered in a dose of 100 mg prior to surgery and just after graft perfusion has shown to decrease blood loss and transfusion requirement.[2] Frenette et al. reported statistical decrease in the use of blood products when conjugated estrogen was used instead of placebo during OLT.[23] Clonidine, a centrally acting alpha2-adrenergic receptor agonist, significantly decreased transfusion and fluid requirements in a small prospective, randomized controlled trial.[2] Orthotopic liver transplantation without transfusion The literature includes cases of OLT performed without transfusion of any blood products and OLT performed safely without additional blood products if blood loss is limited to 1,600-3,400 ml.[2] Reports have described OLT in Jehovah's witness patients (for religious reasons, Jehovah's witnesses refuse transfusion of blood products), who received no blood products.[2] Jabbour and colleagues continue to lead the field in performing OLT without the use of blood products. They reported favourable results in 27 consecutive patients who underwent transfusion-free liver transplantation.[23] This team used a combination of preoperative stimulation of red cell production using recombinant human erythropoietin and iron and intraoperative hemodilution, cell salvage, and tolerance to moderate anemia.[3] They reported successful use of rFVIIa in 10 patients, just prior to the incision.[3] Another team led by Olivier Detry reported successful transfusion-free liver transplantation in 9 Jehovah's witnesses.[24]

man erythropoietin and iron and intraoperative hemodilution, cell salvage, and tolerance to moderate anemia.[3] They reported successful use of rFVIIa in 10 patients, just prior to the incision.[3] Another team led by Olivier Detry reported successful transfusion-free liver transplantation in 9 Jehovah's witnesses.[24] Transfusion support ABO grouping: Liver transplants must be ABO compatible, because of the complement-fixing effect of ABO antibodies on endothelial cells.[6] Efforts to cross the traditional ABO barrier fall into three categories: (i) neonatal recipients (ii) A2 organs (iii) fully ABO-incompatible organs.[7] Major ABO-incompatible liver transplants do not undergo hyperacute rejection, but their short-term graft survival is significantly reduced. These protocols utilize plasmapheresis, multiple immunosuppressive agents, and sometimes splenectomy.[7] An error in ABO compatibility for organs can be life threatening for the patient. Hence, the United Network for Organ Sharing (UNOS) instituted new requirements for additional clerical verification of correct ABO types for transplant donors and recipients.[7] UNOS also proposed new policies requiring the performance of two separate ABO typings of each organ donor and recipient.[7] Selection of compatible blood components ABO blood-type selection[6]: Group A or B patients: Group A or B are managed with type-specific blood and switched to group O blood, if necessary

An error in ABO compatibility for organs can be life threatening for the patient. Hence, the United Network for Organ Sharing (UNOS) instituted new requirements for additional clerical verification of correct ABO types for transplant donors and recipients.[7] UNOS also proposed new policies requiring the performance of two separate ABO typings of each organ donor and recipient.[7] Selection of compatible blood components ABO blood-type selection[6]: Group A or B patients: Group A or B are managed with type-specific blood and switched to group O blood, if necessary Group AB patients: Can receive RBCs of any group. ‘AB’ RBCs available through outdating should first be used, then switched to group ‘A’ RBCs. After transfusing 10 units of group ‘A’ RBCs, patient can be switched to group ‘A’ plasma. Group O patients: Only group ‘O’ RBCs can be used in these patients, they can receive any ABO group plasma.

Group AB patients: Can receive RBCs of any group. ‘AB’ RBCs available through outdating should first be used, then switched to group ‘A’ RBCs. After transfusing 10 units of group ‘A’ RBCs, patient can be switched to group ‘A’ plasma. Group O patients: Only group ‘O’ RBCs can be used in these patients, they can receive any ABO group plasma. Rho (D) selection[67]: Rh-negative patients should be provided with D- RBCs to avoid sensitization to D. When transfusion requirements become excessive, D-women over child bearing age, and adult men may be switched to D + RBCs, provided anti-D is not detected before transfusion. Effort should be made to maintain D-women of child bearing age and children on D-blood, although the risk of D alloimmunization in OLT is low perhaps due to postoperative immunosuppression. Such patients should be given Rh immunoglobulin (RhIg) after administration of Rh-positive blood components. A case of severe anti-D mediated hemolysis resulting from liver transplantation in a O Rh + man who received an O Rh- liver allograft is reported.[25] The female O Rh – donor had alloantibodies against D,C, and K. This patient required two red blood cell exchanges and intermittent red cell transfusions negative for D, C, and K. A normalization of hemoglobin levels and decrease in serum bilirubin occurred after a splenectomy on postop Day 321.[25]

aft is reported.[25] The female O Rh – donor had alloantibodies against D,C, and K. This patient required two red blood cell exchanges and intermittent red cell transfusions negative for D, C, and K. A normalization of hemoglobin levels and decrease in serum bilirubin occurred after a splenectomy on postop Day 321.[25] Selection of red cell units in patients with clinically significant allo-antibodies Clinically significant allo-antibodies are present in 6% of liver transplant patients, due to sensitization through previous blood transfusions.[6] To minimize the risk of hemolysis, these patients are managed by using antigen-negative units for the first 5-10 units, switching to antigen unscreened and/or partially matched units in the middle of the case, and then switching back to antigen-negative units for the last 5-10 units to prevent postoperative hemolysis.[6] This strategy requires close co-operation between anesthesiologist and transfusion services. An additional strategy would be to use preoperative plasmapheresis to remove clinically significant low-titer antibodies.[7] Use of Autologous Blood: Pre-operative autologous blood deposit, perioperative isovolemic hemodilution, and reinfusion of salvaged blood by cell saver during surgery minimizes allogenic transfusions.[7]

Selection of red cell units in patients with clinically significant allo-antibodies Clinically significant allo-antibodies are present in 6% of liver transplant patients, due to sensitization through previous blood transfusions.[6] To minimize the risk of hemolysis, these patients are managed by using antigen-negative units for the first 5-10 units, switching to antigen unscreened and/or partially matched units in the middle of the case, and then switching back to antigen-negative units for the last 5-10 units to prevent postoperative hemolysis.[6] This strategy requires close co-operation between anesthesiologist and transfusion services. An additional strategy would be to use preoperative plasmapheresis to remove clinically significant low-titer antibodies.[7] Use of Autologous Blood: Pre-operative autologous blood deposit, perioperative isovolemic hemodilution, and reinfusion of salvaged blood by cell saver during surgery minimizes allogenic transfusions.[7] Specialised blood components CMV reduced risk components: As a result of immunosuppression, liver transplant recipients are more susceptible to some transfusion complications such as cytomegalovirus (CMV) infection.[6] Steps should be taken to prevent transmission of CMV through blood transfusions to liver transplant recipients who have not been previously infected (i.e., CMV-seronegative recipients of seronegative donors).[26] Prevention can be achieved by leucocyte reduction of the cellular components, by selection of blood from CMV-seronegative donors, or both.[26]

ansmission of CMV through blood transfusions to liver transplant recipients who have not been previously infected (i.e., CMV-seronegative recipients of seronegative donors).[26] Prevention can be achieved by leucocyte reduction of the cellular components, by selection of blood from CMV-seronegative donors, or both.[26] Leucocyte-reduced blood components: Transfusions before, during, and after transplant surgery should be leucocyte reduced to reduce the risk of developing HLA alloimmunization.[26] If HLA antibodies develop in patients waiting for an organ transplant, the risk of rejecting the transplanted organ increases and the chance of finding a compatible organ decreases.[26] Irradiated blood components: Graft versus-host disease (GVHD) is a rare complication of organ transplantation and is almost always due to donor organ. These few cases do not support a policy of routine irradiation of cellular blood components for solid organ transplant recipients.[6] ‘Male only plasma’: The strategy to issue plasma from male donors for transfusion is an effort to reduce the incidence of Transfusion Related Acute Lung Injury (TRALI), as plasma components linked to female donors (parous women) with neutrophilic antibodies are responsible for the majority of probable TRALI cases.[27]

Irradiated blood components: Graft versus-host disease (GVHD) is a rare complication of organ transplantation and is almost always due to donor organ. These few cases do not support a policy of routine irradiation of cellular blood components for solid organ transplant recipients.[6] ‘Male only plasma’: The strategy to issue plasma from male donors for transfusion is an effort to reduce the incidence of Transfusion Related Acute Lung Injury (TRALI), as plasma components linked to female donors (parous women) with neutrophilic antibodies are responsible for the majority of probable TRALI cases.[27] Minor ABO-incompatible transplants: When group O allografts are transplanted to nongroup-O patients/nongroup-AB allografts are transplanted to group AB patients, donor passenger lymphocytes are transferred with the organ at the time of transplantation and produce alloantibodies against host antigens in the recipient causing delayed hemolysis.[7] Clinically significant hemolysis caused by anti-Jk(a), produced by passenger lymphocytes transferred from the donor's liver to the recipient has been reported.[6] These donor derived antibodies(DDAb) develop 7-14 days after transplantation and is heralded by the development of positive direct antiglobulin test (DAT).[6] Serum antibody is predominantly IgG. DDAb are short lived antibodies that persist for 2-3 weeks. Ramsey reported the incidence of DDAb and hemolysis in OLT as 40% and 29%.[6] Hemolysis is usually mild and self limiting. This is more likely in group A recipients of group O livers who receive cyclosporin or tacrolimus immunosuppression.[6] In most cases the hemolysis associated with DDAb is mild and can be treated with transfusions.[6] Several cases of hemolysis-induced acute renal failure have been reported. In fulminant cases, red cell exchange with donor ABO group or group O red cells, or plasma exchange, has been performed.[6]

s immunosuppression.[6] In most cases the hemolysis associated with DDAb is mild and can be treated with transfusions.[6] Several cases of hemolysis-induced acute renal failure have been reported. In fulminant cases, red cell exchange with donor ABO group or group O red cells, or plasma exchange, has been performed.[6] Transfusion protocol in minor ABO mismatched liver transplants Transfusing exclusively donor group red blood cells(RBCs) from the beginning of surgery.[67] Transfusing recipient ABO group of red cells at the beginning of surgery, but switching to donor ABO group of red cells after early reperfusion phase up to six weeks in postoperative period. This replaces susceptible red cells with cells that will not be hemolyzed. Plasma products are transfused based on recipient ABO group to reduce the risk of hemolysis by providing soluble ABO antigen capable of neutralizing DDAb. After six weeks, if DAT and anti-A/anti-B antibodies are negative, red cells are switched over to recipient's ABO group.[67] Transfusing recipient group RBCs, but performing postoperative DAT and switching to donor group RBCs if DAT is positive.[67] Transfusing recipient group RBCs until incompatibility is noted in a crossmatch.[67] Transfusion Protocol During Liver Transplantation Clinical protocol[4]: RBCs, fresh frozen plasm (FFP), and crystalloid are given in the rapid transfusion device and in the intravenous lines as per following ratio:

Transfusing recipient group RBCs, but performing postoperative DAT and switching to donor group RBCs if DAT is positive.[67] Transfusing recipient group RBCs until incompatibility is noted in a crossmatch.[67] Transfusion Protocol During Liver Transplantation Clinical protocol[4]: RBCs, fresh frozen plasm (FFP), and crystalloid are given in the rapid transfusion device and in the intravenous lines as per following ratio: 2 units of RBCs (banked + salvaged) + 1 unit of FFP 1 + 200 ml of crystalloid. This mixture will generate hematocrit (Hct) >30%, prothrombin time (PT) in the range of 14-18 seconds, and fibrinogen >100 mg/dl. Each salvaged unit counts as a unit of RBCs. Switch from crystalloid to a mixture of crystalloid and 5% albumin, if the patient requires a cumulative total of 125 ml/kg crystalloid from all sources. FFP: In the presence of active fibrinolysis and fibrinogen <80 mg/dl, the PT/aPTT will overestimate the degree of hemodilution. Mild to moderate prolongations of the PT need not be corrected. In the absence of active fibrinolysis or a surgical bleeder, an INR <2.5 is adequate. Platelet concentrate: The platelet count will halve from dilution with each blood volume transfused. In nonrefractory patients, maintain platelet count >75 × 103/mm3 for patients without severe splenomegaly and >50 × 103/mm3 for those with splenomegaly. For refractory patients, do not transfuse for numbers.

FFP: In the presence of active fibrinolysis and fibrinogen <80 mg/dl, the PT/aPTT will overestimate the degree of hemodilution. Mild to moderate prolongations of the PT need not be corrected. In the absence of active fibrinolysis or a surgical bleeder, an INR <2.5 is adequate. Platelet concentrate: The platelet count will halve from dilution with each blood volume transfused. In nonrefractory patients, maintain platelet count >75 × 103/mm3 for patients without severe splenomegaly and >50 × 103/mm3 for those with splenomegaly. For refractory patients, do not transfuse for numbers. Cryoprecipitate and aminocaproic acid: Most patients do not require cryoprecipitate. For fibrinolysis (fibrinogen < 100 mg/dl) with bleeding, give 5 g intravenous aminocaproic acid infusion. If lysis continues after 1 hour, reload aminocaproic acid, and begin drip of 1 g/h. Transfuse 10 units cryoprecipitate. Another protocol Criteria for replacement of blood products are as follows: Administration of red cell units to maintain Hemoglobin (Hb) levels at 8 gm%; FFP (1 unit/20 kg) in case of hemorrhage associated with International normalized ratio (INR) >2.0; apheresed platelets to maintain platelet count >50 × 103/mm3 (>80 × 103/mm3 in massive transfusion) and cryoprecipitate (1 unit/10 kg) for fibrinogen levels <100 mg/dl in case of ongoing bleed (<120 mg/dl in massive transfusion).[1428]

kg) in case of hemorrhage associated with International normalized ratio (INR) >2.0; apheresed platelets to maintain platelet count >50 × 103/mm3 (>80 × 103/mm3 in massive transfusion) and cryoprecipitate (1 unit/10 kg) for fibrinogen levels <100 mg/dl in case of ongoing bleed (<120 mg/dl in massive transfusion).[1428] Hourly laboratory monitoring of hemoglobin (Hb), platelet count (PT), and fibrinogen are done throughout the surgery. Cell saver is used to salvage blood for autologous transfusion. In case of massive blood loss, rapid infusion pump is used to facilitate fluid resuscitation and transfusions are given in a blood warmer. Air-warming blankets are used to maintain body temperature. In OLT, there is institutional variability in transfusion practice, which mandates reassessment of the rational use of blood products.[29] Massive transfusion When transfusions exceed more than one blood volume within 24 hours, it is considered as massive transfusion.[18] Patients are grouped into three categories according to intraoperative blood volume transfused:[30] Group A: 1.5 or less blood volume transfused Group B: >1.5 and <3 volumes used Group C: 3 or more volumes given Complications of massive transfusions Dilutional coagulopathy: Volume replacement with crystalloids and colloids and temperature control are initial resuscitation measures. This is followed by transfusion of red cells, coagulation factors and platelets, and DIC requires treatment.[31]

Group B: >1.5 and <3 volumes used Group C: 3 or more volumes given Complications of massive transfusions Dilutional coagulopathy: Volume replacement with crystalloids and colloids and temperature control are initial resuscitation measures. This is followed by transfusion of red cells, coagulation factors and platelets, and DIC requires treatment.[31] Dilutional thrombocytopenia: It has been shown that at least 1.5 times blood volume must be replaced for this to become a clinical problem. It can occur following smaller transfusions, if DIC occurs or there is preexisting thrombocytopenia.[31] DIC: There is association of hemostatic defects related to the exaggerated generation of thrombin and fibrin and the excessive consumption of platelets and coagulation factors which is one of the causes for massive bleed in postanhepatic phase. DIC has been correlated with ischemic damage of the graft liver.[2] Citrate toxicity and hypocalcemia: Each unit of blood contains 3 grams of citrate, which binds calcium. Healthy liver metabolises 3 grams of citrate every 5 minutes. Transfusion at rates higher than one unit every 5 minutes or impaired liver function leads to citrate toxicity, hypocalcemia, and hypomagnesemia. Calcium should be given if there is biochemical, clinical or ECG evidence of hypocalcemia.[31] Hyperkalemia: Hyperkalemia is not a problem unless very large amounts of blood are given quickly. Hypokalemia is more common as red cells begin active metabolism and intracellular uptake of potassium restarts.[31]

Citrate toxicity and hypocalcemia: Each unit of blood contains 3 grams of citrate, which binds calcium. Healthy liver metabolises 3 grams of citrate every 5 minutes. Transfusion at rates higher than one unit every 5 minutes or impaired liver function leads to citrate toxicity, hypocalcemia, and hypomagnesemia. Calcium should be given if there is biochemical, clinical or ECG evidence of hypocalcemia.[31] Hyperkalemia: Hyperkalemia is not a problem unless very large amounts of blood are given quickly. Hypokalemia is more common as red cells begin active metabolism and intracellular uptake of potassium restarts.[31] Acid/base disturbances: Lactic acid levels in a blood pack give an acid load of up to 30-40 mmol/l. This along with citric acid is usually metabolized rapidly. Citrate is metabolized to bicarbonate, and a profound metabolic alkalosis may ensue.[31] Hypothermia: Hypothermia leads to reduction in citrate and lactate metabolism (leading to hypocalcemia and metabolic acidosis), increase in affinity of Hb for oxygen, impairment of red cell deformability, platelet dysfunction and an increased tendency for cardiac dysrhythmias.[31] Immunosuppression: Large volumes of allogenic blood transfusion results in the infusion into the recipient of large amounts of foreign antigens in both soluble and cell-associated forms, the persistence of these antigens in the circulation of the recipient is considered to result in immune downregulation.[14]

Hypothermia: Hypothermia leads to reduction in citrate and lactate metabolism (leading to hypocalcemia and metabolic acidosis), increase in affinity of Hb for oxygen, impairment of red cell deformability, platelet dysfunction and an increased tendency for cardiac dysrhythmias.[31] Immunosuppression: Large volumes of allogenic blood transfusion results in the infusion into the recipient of large amounts of foreign antigens in both soluble and cell-associated forms, the persistence of these antigens in the circulation of the recipient is considered to result in immune downregulation.[14] Immunomodulation: Numerous retrospective and prospective studies have observed a significant association between allogenic blood transfusion and immune suppression, including graft survival, recurrence after surgery of a variety of malignancies, impaired cell-mediated cell and natural killer cell activity, and deterioration in liver regeneration.[14] Sepsis: Large transfusion requirements, i.e., excessive blood loss during OLT are correlated with reduced graft survival (graft dysfunction) and increased septic episodes, prolonged intensive care unit stay and morbidity and mortality.[14] Reintervention: Intraoperative red cell transfusion requirement was the main determinant of early in-hospital surgical reintervention after liver transplantation.[32]

Sepsis: Large transfusion requirements, i.e., excessive blood loss during OLT are correlated with reduced graft survival (graft dysfunction) and increased septic episodes, prolonged intensive care unit stay and morbidity and mortality.[14] Reintervention: Intraoperative red cell transfusion requirement was the main determinant of early in-hospital surgical reintervention after liver transplantation.[32] Acute respiratory distress syndrome: ARDS is a serious multifactorial complication after OLT with a high mortality and fatality. The most likely cause is fluid overload from crystalloid liquid infusion or massive transfusion. Other factors such as TRALI and reperfusion syndrome of the newly implanted liver may also contribute.[33] Intracerebral hemorrhage: Intracerebral hemorrhage is one of the most disastrous complication after OLT.[34] Intraoperative hypotension, massive intraoperative transfusion and coagulopathy may be correlated with this complication.[34]

Acute respiratory distress syndrome: ARDS is a serious multifactorial complication after OLT with a high mortality and fatality. The most likely cause is fluid overload from crystalloid liquid infusion or massive transfusion. Other factors such as TRALI and reperfusion syndrome of the newly implanted liver may also contribute.[33] Intracerebral hemorrhage: Intracerebral hemorrhage is one of the most disastrous complication after OLT.[34] Intraoperative hypotension, massive intraoperative transfusion and coagulopathy may be correlated with this complication.[34] Conclusion Multi disciplinary approach Proper patient selection, better preservation of graft, short CIT, meticulous surgical technique, skilled anesthesia practice, intraoperative auto transfusion, use of antifibrinolytic drugs and rFVIIa during surgery, use of TEG, and administration of appropriate components, optimal use of available new technologies, and drugs, minimizes transfusions during OLT. Efforts to reduce intraoperative bleeding leading to limitation of the amount of blood used are therefore desirable not only to improve results but also to control costs, preserve the blood pool for other emergency or routine surgeries and to decrease the program's dependence on blood availability. Goal should be to develop strategies towards a transfusion free environment. Source of Support: Nil Conflict of Interest: None declared.

Introduction Critical Care Services in modern medicine play a vital role in delivering prompt, appropriate and adequate care to acutely ill patients. Acutely ill patients present with diverse pathophysiological derangements that require constant monitoring with rapid and repetitive interventions. These interventions often involve complex multi-modal approaches, all of which need to be seamlessly integrated in order to optimize outcome. Whilst some of these interventions/activities would be planned activities, others would include both initiated and reactive activities.[1] Planned activities could be scheduled routine (checklist) activities (bed position, deep venous thrombosis (DVT) and gastrointestinal (GI) prophylaxis) or standing orders unique to each patient (administration of a drug, replacement of fluid). Initiated activities are those that are not an integral part of routine treatment (e.g. placement of an arterial line) whilst reactive activities include activities in direct response to changes in the patients' clinical status.[1] It has been observed that, on an average, 178 such patient activities occur in a 24-h period for every patient in an intensive care unit (ICU). Of these, 84% of activities are performed by a single nurse, whilst only a small proportion is directly performed by physicians.[1] The sheer magnitude of tasks that need to be performed in a complex environment such as the ICU along with the amount of data that needs to be integrated and interpreted place the environment at considerable risk for errors.

ormed by a single nurse, whilst only a small proportion is directly performed by physicians.[1] The sheer magnitude of tasks that need to be performed in a complex environment such as the ICU along with the amount of data that needs to be integrated and interpreted place the environment at considerable risk for errors. Computerized systems have been gradually integrated into medical practice over the last few decades.[2] Systems termed as “Clinical Information Systems” (CISs) have been developed[3–6] in order to improve the quality of delivered services. These systems vary from those which provide basic functions to more complex and sophisticated “decision support systems”.[7] In a systematic review of 68 controlled trials of decision support systems published between 1974 and 1992, computer-based clinical decision support systems improved physician performance in 66%, particularly for drug dosing and preventive care but not for diagnosis.[8] In a more recent systematic review of 70 studies, decision support systems again significantly improved clinical practice in 68% of trials.[9] Some of the randomized trials included in this review[9] included computer-generated reminders for specific examination (e.g. breast examination) or tests (e.g. fecal occult blood test, cervical smear, mammography). A larger systematic review[10] incorporating 100 studies again found that such CISs improved practitioner performance in 64% of the studies with higher (P = 0.02) success rates with systems that automatically prompted users compared with those that required users to activate the system (73% vs. 47%).[10] These systematic reviews included studies predominantly in primary healthcare.

ound that such CISs improved practitioner performance in 64% of the studies with higher (P = 0.02) success rates with systems that automatically prompted users compared with those that required users to activate the system (73% vs. 47%).[10] These systematic reviews included studies predominantly in primary healthcare. The use of such systems in the critical care environment is probably more relevant. In a simple approach, errors, particularly omissions, can be minimized in the complex ICU environment by the use of checklists,[1112] that could remind the intensivist of routine tasks (e.g. DVT prophylaxis, GI prophylaxis, etc). These could be done manually, as a paper check or by electronic alerts at specified times (at admission or at a specified time each day). Capture of monitored data (pulse, blood pressure, respiration) directly on to electronic documentation sheets could potentially decrease the time spent by ICU nurses on paper documentation and channel the time to direct patient care.[13] Further, ICUs maintain a huge amount of data in several domains (cardiovascular, respiratory, neurological, etc) and employing a hybrid approach of case-based reasoning and rule-based reasoning could enhance patient care.[14] Benefits also include significant reductions in the rates of medication, intravenous therapy and ventilator incidents.[7]

ge amount of data in several domains (cardiovascular, respiratory, neurological, etc) and employing a hybrid approach of case-based reasoning and rule-based reasoning could enhance patient care.[14] Benefits also include significant reductions in the rates of medication, intravenous therapy and ventilator incidents.[7] However, the development of such integrated systems is challenging given the need for interaction between technologies and organizations.[15] Several systems which are developed have not been used clinically as they are not user-friendly and are primarily developed from an engineering perspective.[16] Thus, clinician involvement is crucial in the development of CISs to ensure a user-friendly system that is applicable to several clinical settings and situations. In this study, we present an integrated system that was designed to incorporate functions of recording, reminding, alerting, checklists and diagnostic alerts for common conditions encountered in critical care practice. This joint project, developed by intensivists and computer software students and teachers as a project, has been given the acronym - CARDAMOM (Computer-Assisted Recording, Diagnosis and Management of the Medically-ill).

rting, checklists and diagnostic alerts for common conditions encountered in critical care practice. This joint project, developed by intensivists and computer software students and teachers as a project, has been given the acronym - CARDAMOM (Computer-Assisted Recording, Diagnosis and Management of the Medically-ill). Materials and Methods This project was carried out at the Christian Medical College Hospital, Vellore, a tertiary care teaching hospital in South India, in collaboration with the Computer Science Department, Vellore Institute of Technology over a six-month period (June-November 2008). The project was designed and developed in four phases. In each of the phases, a detailed discussion occurred between the intensivists and the computer software developers on the requirements in the critical care environment. We did not use any predefined or previously published system approach as we were aware of the inherent problems and difficulties in adapting such systems to local needs and practice. The approach was purely driven by clinical requirements and these requirements were expressed to the information technology (IT) students and professionals at each stage of the development. In the first week of the project, the computer software students spent several hours in the critical care unit trying to understand how data was collected and recorded in the monitoring sheets that are presently used in the ICU.

he information technology (IT) students and professionals at each stage of the development. In the first week of the project, the computer software students spent several hours in the critical care unit trying to understand how data was collected and recorded in the monitoring sheets that are presently used in the ICU. Following this, in the first phase, monitoring and medication sheets were designed and developed and several terminologies were defined. The second phase was devoted to the development of diagnostics as well as the intervention bundle. The third phase (still being tested at the time of submission of article) was real-time testing. The final phase of the study will involve interfacing the investigations and radiology images (PACS) available on our Hospital Information System (HIS) with the CARDAMOM system as well as capturing real-time monitoring data from the bedside monitors automatically. Phase 1 - Monitoring and medication sheets; definitions The system was programmed such that data could be entered only after the hospital number specific to a patient and the length of the patient were entered. The length of the patient was mandatory as several calculations such as the tidal volume are based on the length. The user interface was designed to have the following modules:

Phase 1 - Monitoring and medication sheets; definitions The system was programmed such that data could be entered only after the hospital number specific to a patient and the length of the patient were entered. The length of the patient was mandatory as several calculations such as the tidal volume are based on the length. The user interface was designed to have the following modules: Vital signs chart that contained temperature, heart rate, respiratory rate, oxygen saturation (SpO2) and blood pressure. The blood pressures were recorded as systolic and diastolic pressures and the system calculated the mean arterial pressure. These parameters were entered on a time (at least hourly) basis. Results for these were displayed graphically. Ventilatory parameters such as FiO2, tidal volume, peak airway pressures and positive end-expiratory pressure (PEEP) settings were included for ventilated patients. Fluid balance chart that included hourly intake and output. The system calculated the total at 12 and 24 h along with cumulative fluid balance over the entire period of admission [Figure 1]. Investigation sheet wherein all investigations (biochemical, hematological, microbiological and serological) pertaining to the patient could be entered manually. Refinement of this, to be done subsequently, would be to capture the data automatically from the Hospital Information System (see Phase 4).

Fluid balance chart that included hourly intake and output. The system calculated the total at 12 and 24 h along with cumulative fluid balance over the entire period of admission [Figure 1]. Investigation sheet wherein all investigations (biochemical, hematological, microbiological and serological) pertaining to the patient could be entered manually. Refinement of this, to be done subsequently, would be to capture the data automatically from the Hospital Information System (see Phase 4). Medication chart containing medications at predefined intervals, infusions, fluids as well as STAT and PRN medications [Figure 2]. When the medications were entered along with the frequency, the time of administration of the drug was automatically generated based on predefined rules of drug administration (e.g. once daily drug at 8 am in the morning, subsequent medications on a regular basis over the 24-h period). Figure 1 Picture showing hourly fluid balance chart Figure 2 List of medications and the timing when it is to be administered

Medication chart containing medications at predefined intervals, infusions, fluids as well as STAT and PRN medications [Figure 2]. When the medications were entered along with the frequency, the time of administration of the drug was automatically generated based on predefined rules of drug administration (e.g. once daily drug at 8 am in the morning, subsequent medications on a regular basis over the 24-h period). Figure 1 Picture showing hourly fluid balance chart Figure 2 List of medications and the timing when it is to be administered Several terminologies were also defined during the first phase. Checklists were defined to be a list of interventions that pop up at defined times for all patients. This was not patient-specific. For example, for all ICU patients, a checklist would remind of GI bleed prophylaxis, DVT prophylaxis, propping up the patient at 30° head elevation etc [Figure 3]. On the other hand, reminders were time-based, unique to each patient and were entered by the treating intensivist. For example, a reminder would pop up about 15 min prior to a scheduled serum potassium level check. Alerts were categorized as time-based (as in the reminder above) or value-based, wherein an alert comes up when a predefined maximum or minimum value is crossed (e.g. when the SpO2 decreases to 80% a LO alert would come up). Trend-based alerts were defined for wide changes within the total bandwidth of the alert. For example, an increase or decrease from a previous value by 25% within the total bandwidth would trigger a trend-based alarm. An alarm specifies how the alert is displayed (either visually or by sound or a combination of both). A diagnosis was defined as a condition in which two or more criteria were fulfilled. An intervention was defined as a bundle of actions that were specific to a diagnosis.

al bandwidth would trigger a trend-based alarm. An alarm specifies how the alert is displayed (either visually or by sound or a combination of both). A diagnosis was defined as a condition in which two or more criteria were fulfilled. An intervention was defined as a bundle of actions that were specific to a diagnosis. Figure 3 Checklist. For example, a checklist will pop up on the screen every day at 8 am and will remain on screen till each of the events are ticked off. For new patients, the same checklist will appear and each aspect needs to be acknowledged

al bandwidth would trigger a trend-based alarm. An alarm specifies how the alert is displayed (either visually or by sound or a combination of both). A diagnosis was defined as a condition in which two or more criteria were fulfilled. An intervention was defined as a bundle of actions that were specific to a diagnosis. Figure 3 Checklist. For example, a checklist will pop up on the screen every day at 8 am and will remain on screen till each of the events are ticked off. For new patients, the same checklist will appear and each aspect needs to be acknowledged Several problems encountered during this phase merit mention here. The first was the need for several meetings with the IT students and teachers to help understand medical terminologies as well as diagnostic possibilities. The second major problem was to define thresholds for alarms, based not only on absolute values but also on trends. It is well recognized that significant changes in vital parameters, occurring over a short period of time, even within the “normal range” may be of clinical importance. For example, a sudden increase in the heart rate from a baseline 60 beats/min to 100 beats/min may signify the onset of an infection, volume loss or other major catastrophe. However, when only a value-based alert is placed (alert outside of the normal range of 60 to 100), then such change within the normal range would not result in an alert. Thus, a trend-based alert was described. Third, the initial confusion about the difference between a reminder and a checklist was sorted out by precise definitions as stated in the text above.

placed (alert outside of the normal range of 60 to 100), then such change within the normal range would not result in an alert. Thus, a trend-based alert was described. Third, the initial confusion about the difference between a reminder and a checklist was sorted out by precise definitions as stated in the text above. Information technology platform Decisions regarding the types of IT platforms were taken. Windows XP and ORACLE 10 g were chosen to be the operating system and the database system respectively, since these are the existing platforms used in the hospital. After discussion, Java, JSP and HTML were the languages used and Apache Tomcat 5.5 was the web server.

ions regarding the types of IT platforms were taken. Windows XP and ORACLE 10 g were chosen to be the operating system and the database system respectively, since these are the existing platforms used in the hospital. After discussion, Java, JSP and HTML were the languages used and Apache Tomcat 5.5 was the web server. Phase 2 - Diagnostics and intervention bundle The diagnostics was developed to provide the intensivist a list of possible diagnoses when two or more parameters were beyond acceptable limits. The diagnostic list contained only those entities that could be reasonably diagnosed based on parameters in the modules. For example, the diagnostic list does not include encephalitis, but includes shock and pulmonary embolism. The list of diagnoses that were included is summarized in Table 1. The intervention bundle consisted of a series of actions specific to the diagnosis [Figure 4]. The display of this bundle is triggered by the diagnosis. For example, in a patient with a diagnostic alert of “systemic inflammatory response syndrome (SIRS),” the intervention bundle would suggest to take appropriate cultures, check central venous pressure and consider fluid resuscitation or start vasoactive agents. These specific interventions were listed following a consensus by four intensivists and based on the best available evidence with available resources. Table 1 List of common intensive care unit diagnoses included in the diagnostic bundle

Phase 2 - Diagnostics and intervention bundle The diagnostics was developed to provide the intensivist a list of possible diagnoses when two or more parameters were beyond acceptable limits. The diagnostic list contained only those entities that could be reasonably diagnosed based on parameters in the modules. For example, the diagnostic list does not include encephalitis, but includes shock and pulmonary embolism. The list of diagnoses that were included is summarized in Table 1. The intervention bundle consisted of a series of actions specific to the diagnosis [Figure 4]. The display of this bundle is triggered by the diagnosis. For example, in a patient with a diagnostic alert of “systemic inflammatory response syndrome (SIRS),” the intervention bundle would suggest to take appropriate cultures, check central venous pressure and consider fluid resuscitation or start vasoactive agents. These specific interventions were listed following a consensus by four intensivists and based on the best available evidence with available resources. Table 1 List of common intensive care unit diagnoses included in the diagnostic bundle Acute fluid loss Systemic inflammatory response syndrome Acute blood loss Sepsis Acute lung injury Severe sepsis/Septic shock Acute respiratory distress syndrome Shock, including cardiogenic shock Obstructive airways disease Fluid overload Atelectasis/Collapse Left heart failure Pulmonary embolism Disseminated intravascular coagulation Pneumothorax Thrombotic thrombocytopenic purpura Deteriorating Glasgow coma score Hemolytic uremic syndrome Acute Kidney Injury RIFLE Class Heparin-induced thrombocytopenia Figure 4 Example of a diagnostic and intervention bundle. A diagnostic bundle (left boxes) would be activated if certain conditions are fulfilled. For the intervention bundle, a set of interventions would pop up. These interventions were decided by a panel of intensivists after several discussions

uced thrombocytopenia Figure 4 Example of a diagnostic and intervention bundle. A diagnostic bundle (left boxes) would be activated if certain conditions are fulfilled. For the intervention bundle, a set of interventions would pop up. These interventions were decided by a panel of intensivists after several discussions There was an in-depth discussion regarding the number of criteria that needed to be met in order to trigger a diagnostic possibility. Although we initially felt that even a single criterion should trigger a diagnostic possibility, we subsequently realized that such a threshold would continuously raise numerous diagnostic possibilities in the critical care environment where physiological derangements are the norm. We thus modified the diagnostic list to be triggered when two or more criteria were met. Each diagnostic list, triggered by a set of parameters, was carefully scrutinized to ensure that it was inclusive rather than exclusive and also listed in order of relevance (see results below). The intervention bundles specific to each of these diagnoses were worked out independently by each intensivist and subsequently pooled to ensure that all aspects of intervention were included.

ly scrutinized to ensure that it was inclusive rather than exclusive and also listed in order of relevance (see results below). The intervention bundles specific to each of these diagnoses were worked out independently by each intensivist and subsequently pooled to ensure that all aspects of intervention were included. Phase 3 - Testing of software The third phase of the project was testing the software. Testing of the software was conducted in two phases-the alpha and beta testing.[1718] The alpha test is the process of testing the product amongst the team to confirm that the product works. This was performed by the use of six scenarios written by intensivists on the regular ICU monitoring sheets. The problems pertaining to documentation, checklists, diagnostics or intervention were evaluated. Some modifications were made to ensure that all diagnostic possibilities that were trigged by a set of parameters were listed. Other problems encountered during this phase are discussed in the results section below. The beta test consisted of real-time testing in the ICU on patients actually admitted to the unit. Only the alpha testing was part of this initial study. The beta testing and interfacing of investigations were in progress at the time of submission.

Phase 3 - Testing of software The third phase of the project was testing the software. Testing of the software was conducted in two phases-the alpha and beta testing.[1718] The alpha test is the process of testing the product amongst the team to confirm that the product works. This was performed by the use of six scenarios written by intensivists on the regular ICU monitoring sheets. The problems pertaining to documentation, checklists, diagnostics or intervention were evaluated. Some modifications were made to ensure that all diagnostic possibilities that were trigged by a set of parameters were listed. Other problems encountered during this phase are discussed in the results section below. The beta test consisted of real-time testing in the ICU on patients actually admitted to the unit. Only the alpha testing was part of this initial study. The beta testing and interfacing of investigations were in progress at the time of submission. Phase 4 - Interfacing of investigations and monitoring data Interfacing of investigations that are available online on the HIS with the CARDAMOM software would be the final phase of the project (Proposed). The investigations would include hematology, pathology and biochemical tests, microbiology, images as well as arterial blood gas estimations. In addition, during this phase, real-time monitoring data from the bedside monitors would also be captured directly and integrated with the CARDAMOM software.

project (Proposed). The investigations would include hematology, pathology and biochemical tests, microbiology, images as well as arterial blood gas estimations. In addition, during this phase, real-time monitoring data from the bedside monitors would also be captured directly and integrated with the CARDAMOM software. Results Alpha testing was done in two stages. In the first stage, two case scenarios were constructed by an intensivist and this was analyzed by the CARDAMOM software. Feedback regarding the performance in terms of accuracy and reliability was given and modifications were made to the software before the second stage of alpha testing with four more case scenarios. It was observed that the alerts and reminders occurred appropriately in real-time. However, it was noted, after the first two scenarios, that there was a problem in the diagnostic list in that the differential diagnoses were not presented in the appropriate order (with the most likely diagnosis being the first). It appeared that for every diagnostic category, the main positive features were matched against the clinical presentation. For example, if diagnosis A needed four positive criteria (M, O, P, Q) for a perfect match but only three of the four criteria were met, a 75% probability was assigned to this diagnosis. However, if diagnosis B consisted of only two positive criteria (M, O) but other negative criteria (R, S, T) were not incorporated into the rule-based diagnosis, a 100% positive match (M and O present) put diagnosis B above diagnosis A.

ee of the four criteria were met, a 75% probability was assigned to this diagnosis. However, if diagnosis B consisted of only two positive criteria (M, O) but other negative criteria (R, S, T) were not incorporated into the rule-based diagnosis, a 100% positive match (M and O present) put diagnosis B above diagnosis A. In order to circumvent this problem, both positive as well as negative criteria were incorporated into the algorithm such that the list of differential diagnoses was narrowed down and the list generated was in a more clinically appropriate order. An example of such an interaction is summarized in the example in Figure 5. Figure 5 Interaction of positive and negative criteria in clinical scenarios. The most likely diagnosis for Scenario 1 is pneumonia and for Scenario 2 it is pneumothorax. There will be (and should be) other possibilities which are less matched but still to be considered in a lower order After completion of all the six scenarios, a written feedback was provided to the software developers and the program was fine-tuned. This is now followed by beta-testing of the software in real-time in the ICU for a period of six months. This is currently under way.

Figure 5 Interaction of positive and negative criteria in clinical scenarios. The most likely diagnosis for Scenario 1 is pneumonia and for Scenario 2 it is pneumothorax. There will be (and should be) other possibilities which are less matched but still to be considered in a lower order After completion of all the six scenarios, a written feedback was provided to the software developers and the program was fine-tuned. This is now followed by beta-testing of the software in real-time in the ICU for a period of six months. This is currently under way. Discussion Expert systems are being increasingly recognized as an important tool for clinicians. Expert systems or knowledge-based systems use computer programs that contain some of the subject-specific knowledge of one or more experts.[14] These CISs support a wide range of tasks ranging from simple reminders regarding routine tests to the more complex decision support systems that have the potential to enhance the quality and efficiency of treatment.[714] Such systems may play a vital role in a critical care environment since a large volume of data related to a single patient needs to be integrated over time. The complexity of critical care and the enormity of tasks that need to be performed for each patient[1] place the environment at risk for errors and preventable mishaps. Decision support systems that incorporate both routine functions such as checklists, alerts and reminders as well as diagnostic possibilities and suitable interventions thus score over the more basic CISs that are widely used currently. It is envisaged that such systems would increase efficiency and improve quality of care and outcomes.

ystems that incorporate both routine functions such as checklists, alerts and reminders as well as diagnostic possibilities and suitable interventions thus score over the more basic CISs that are widely used currently. It is envisaged that such systems would increase efficiency and improve quality of care and outcomes. The development of user-friendly tools has been limited by the lack of ‘clinician’ involvement. This has been recognized by the American Informatics Association (AMIA) and also reported in the Royal Australasian College of Physicians' newsletter[16] as a cause for failed systems. Another possible reason cited for failure is the predominantly ‘administrative’ (business) model with minimal clinical functionality.[16] Our software program CARDAMOM has been developed by a team. Several meetings at regular intervals between the two groups of professionals occurred. Such discussions focused on the utility as well as applicability of the software not only in a tertiary level critical care environment but also at a secondary level hospital. At each stage of the development of the software the interface between computer experts and medical personnel ensured that the program was not only user-friendly but also clinically functional, catering to the needs of the Indian critical care patient.

l critical care environment but also at a secondary level hospital. At each stage of the development of the software the interface between computer experts and medical personnel ensured that the program was not only user-friendly but also clinically functional, catering to the needs of the Indian critical care patient. Some limitations merit mention here. Alpha testing was done on six case scenarios that were constructed by the intensivists. This has not been previously validated. We felt that further validation of the diagnostic bundle should be done at the beta phase of the testing when real patients' data are entered, rather than using more case scenarios. Although some refinements have been made to the software following these scenarios, it is likely that more refinements may be required to make the diagnostic bundles more inclusive. Secondly, at present the software has not been enabled to capture data directly from the bedside monitors. These are currently entered manually at present. The investigations also need to be entered manually. However, in Phase 4 of this project, it is hoped that both these could be seamlessly integrated by capturing data directly from the bedside monitors as well as from the Hospital Information System.

he bedside monitors. These are currently entered manually at present. The investigations also need to be entered manually. However, in Phase 4 of this project, it is hoped that both these could be seamlessly integrated by capturing data directly from the bedside monitors as well as from the Hospital Information System. The successful alpha testing of the software has resulted in the beta testing being initiated. The accuracy of the software to prompt real-time checklists, alerts and reminders is encouraging and would aid in initiating appropriate and timely treatment. It is hoped that the differential diagnoses lists that come up in relation to derangements in physiological parameters would alert the physician in training to the various clinical possibilities and serve as a learning tool and reduce errors. However, it must be remembered that when a diagnostic likelihood is based on the combination of positive and negative features, it may be impossible to derive an algorithm that will always accurately list diagnoses in the correct order. Thus, the software should necessarily provide an inclusive rather than an exclusive or prioritized list of differentials, that are relevant and of significance in a critical care setting, that would alert the physician to all diagnostic possibilities, particularly in times of intense stress when a diagnosis or a test might not be considered and missed out. It is with these objectives that this CARDAMOM software has been designed to “assist” the clinician and not “supplant” rational decision-making and prioritization by the physician.

to all diagnostic possibilities, particularly in times of intense stress when a diagnosis or a test might not be considered and missed out. It is with these objectives that this CARDAMOM software has been designed to “assist” the clinician and not “supplant” rational decision-making and prioritization by the physician. We acknowledge the support of the Principal, Christian Medical College and the Computer Science Department, Vellore Institute of Technology for this project. Source of Support: Nil Conflict of Interest: None declared.

Introduction Lower respiratory tract infections (LRTI) are the most common bacterial infections among patients in intensive care units (ICUs) occurring in 10-25% of all ICU patients and resulting in high overall mortality, which may range from 22-71%.[12] Most common bacterial agents of LRTI in the ICU are Pseudomonas, Acinetobacter, Klebsiella, Citrobacter, Escherichia coli.[3–5] In almost all cases, there is a need to initiate empirical antimicrobial treatment before obtaining the microbial results, but the situation is further complicated by the emergence of multiple beta lactamase producers and multidrug resistant pathogens. In a recent report, Infectious Disease Society of America, specifically addressed three categories of gram negative bacilli (GNB), namely extended spectrum beta lactamase (ESBL) producing Escherichia coli, and Klebsiella spp., Multidrug resistant (MDR) Pseudomonas, and carbapenem resistant Acinetobacter spp., as high priority bacterial pathogens.[6] All these major reports indicate the need for obtaining data on prevalent strains in the ICU along with the susceptibility pattern, to help in revising antibiotic policy and guiding clinicians for the better management of patients. Prevalent flora and antimicrobial resistance pattern may vary from region to region depending upon the antibiotic pressure in that locality. Therefore, the present study was designed to know the bacterial profile and determine the antimicrobial resistance pattern among the aerobic GNB isolated from LRT of patients admitted to the ICU of our institute.

resistance pattern may vary from region to region depending upon the antibiotic pressure in that locality. Therefore, the present study was designed to know the bacterial profile and determine the antimicrobial resistance pattern among the aerobic GNB isolated from LRT of patients admitted to the ICU of our institute. Materials and Methods The present retrospective study was conducted in the Microbiology department of a teaching tertiary care hospital during Jan-Dec 2007. Transtracheal or bronchoscopic aspirates collected aseptically from 207 patients of all age and sex groups requiring mechanical ventilation for at least three days were included in study. All samples were plated right after the collection and were further processed as per standard protocol.[7] Single or mixed growth (two or more than two isolates per specimen) isolated from all the eligible consecutive samples were identified by observing the colony characteristic on the blood, Mac-Conkey agar plate and biochemical reactions using standard microbiological methods.[7] Isolates from repeat culture of previously recruited patients and isolates identified as commensals or contaminants were excluded. Susceptibility testing was done by Disc diffusion method.[8] The following antibiotics (Hi-Media Disc in mcg) were tested: Amikacin(Ak) (30), ciprofloxacin(Cf) (5), ofloxacin (Of) (5), aztreonam (Ao) (30), netilmicin (Nt) (30), doxycycline (Do) (30), cotrimoxazole (co) (25), ceftazidime (Cz) (30), ceftizoxime (Ck) (30), meropenem (Mr) (10), amoxycillin/clavulanic acid (Ac) (20/10), piperacillin/tazobactum (TZP) (100/10). Zone diameter was measured and interpreted as per the Clinical and Laboratory Standards Institute (CLSI) guidelines. For quality control of disc diffusion tests ATCC control strains of E. coli ATCC 25922, S. aureus ATCC 25923 and P. aeruginosa ATCC 27853 strains were used.

0/10), piperacillin/tazobactum (TZP) (100/10). Zone diameter was measured and interpreted as per the Clinical and Laboratory Standards Institute (CLSI) guidelines. For quality control of disc diffusion tests ATCC control strains of E. coli ATCC 25922, S. aureus ATCC 25923 and P. aeruginosa ATCC 27853 strains were used. Statistical analysis For retrospective analysis, SPSS software was used for calculation of percentage resistance of 95% confidence interval (CI).

0/10), piperacillin/tazobactum (TZP) (100/10). Zone diameter was measured and interpreted as per the Clinical and Laboratory Standards Institute (CLSI) guidelines. For quality control of disc diffusion tests ATCC control strains of E. coli ATCC 25922, S. aureus ATCC 25923 and P. aeruginosa ATCC 27853 strains were used. Statistical analysis For retrospective analysis, SPSS software was used for calculation of percentage resistance of 95% confidence interval (CI). Results During the study period, laboratory data of 207 patients whose LRT specimens were received in our laboratory was evaluated. Male to female ratio was 1.8:1. Out of the 207 patients, 70 were from the surgical ward, 62 from urology, 35 from medicine, 28 from nephrology, 12 from neuromedicine. Out of 207 specimens, 144 (69.5%) were culture positive whereas, 63 (30.43%) specimens showed no growth. From the 144 culture positive specimens, 161 isolates were recovered. Out of 161 isolates, 154 (95.6%) were GNB, three (1.86%) were Candida spp., and four (2.4%) were Gram positive cocci. In 17 (11.0%) specimens, there were two isolates per specimen and 127 (82.4%) specimens showed growth of a single organism. Table 1 represents the distribution of micro organisms recovered from the LRT specimens of ICU patients. The most common GNB in order of frequency were P. aeruginosa (35%), Acinetobacter baumannii (23.6%) and Klebsiella pneumoniae (13.6%). Very high rate of resistance (60-100%) was observed among A. baumannii and K. pneumoniae isolates to ceftazidime, amoxyclav, ciprofloxacin, amikacin, and cotrimoxazole. Meropenem and doxycycline were the most effective in vitro drugs against A. baumannii, K. pneumoniae, and Enterobacter [Table 2]. P. aeruginosa isolates showed high rate of resistance to aztreonam (94.7%), netilmicin (70.2%), ceftazidime (68.4%), ceftizoxime (68.4%), and ofloxacin (68.4%) [Table 2]. Out of 57 isolates of P. aeruginosa, 23 (40%) were resistant to all the antibiotics used against P. aeruginosa in the panel. Meropenem was the most effective (77.2%) drug in vitro followed by piperacillin/ tazobactum combination (50.5%) [Table 2]. Bacterial resistance rates (%R 95% CI) to doxycycline for various isolates except P. aeruginosa are given in Table 3.

were resistant to all the antibiotics used against P. aeruginosa in the panel. Meropenem was the most effective (77.2%) drug in vitro followed by piperacillin/ tazobactum combination (50.5%) [Table 2]. Bacterial resistance rates (%R 95% CI) to doxycycline for various isolates except P. aeruginosa are given in Table 3. Discussion Pneumonia is a frequent complication in patients admitted to the ICU. It is frequently polymicrobial with predominently multi drug resistant GNB, such as A. baumannii, P. aeruginosa, K. pneumoniae, E. coli.[7910] In our study, 97.4% isolates were GNB. P. aeruginosa (35%) being the most common isolate followed by A. baumannii (23.6%) and K. pneumoniae. In 10.75% cases, two isolates were recovered from a single specimen, in contrast to the other study that reported two to three isolates per specimen in 16.3% cases.[5] Antibiotic resistance is a major problem in ICU admitted patients. We noticed 100%, 96.9%, and 68.4% resistance to ceftazidime against A. baumannii, Klebsiella spp. and P. aeruginosa, respectively. Similar observations were made by other investigators that reported 96-100% resistance;[1112] whereas, other workers have reported lower rate of resistance (37-67.5%) to ceftazidime.[1113] High rate of resistance at our center might be due to the selective influence of extensive usage of third generation cephalosporins. Carbapenems are frequently used as a last choice in treating serious infections caused by GNB. In our study, 25.6% isolates of Acinetobacter spp., 22.8% isolates of P. aeruginosa, and 9% isolates of Klebsiella spp., were resistant to meropenem in contrast to another study, where meropenem resistance was found in 14.2% isolates of A. baumannii and 12-42.5% isolates of P. aeruginosa, respectively.[414] Another study reported 100% sensitivity to meropenem against Klebsiella spp.[15] This finding suggests that meropenem should be used judiciously in ventilated patients to prevent any further increase in resistance to meropenem. Another important observation of our study was that doxycycline, an old drug not included in empirical treatment in ICUs, nowadays had shown good sensitivity against A. baumannii, Klebsiella spp., Enterobacter spp., E. coil, and Citrobacter spp. [Table 3]. Vila et al., reported 98% sensitivity to doxycycline among A. baumannii.[16] We observed that 33% isolates of A. baumannii were sensitive and 64.4% strains were intermediate sensitive (IS) to doxycycline.

good sensitivity against A. baumannii, Klebsiella spp., Enterobacter spp., E. coil, and Citrobacter spp. [Table 3]. Vila et al., reported 98% sensitivity to doxycycline among A. baumannii.[16] We observed that 33% isolates of A. baumannii were sensitive and 64.4% strains were intermediate sensitive (IS) to doxycycline. Intermediate sensitive strains are amenable to treatment when large doses of the drug are used.[17] We did not perform MIC of IS strains, since this is a retrospective analysis of laboratory data and strains were not preserved for further study. Further studies are required to evaluate the usefulness of doxycycline for ICU admitted patients. Table 1 Different microorganisms isolated from the lower respiratory tract specimen from intensive care unit patients Organism Bronchioalveolr lavage (%) Tracheal aspirate (%) Total (%) P. aeruginosa 13 44 57 (35) A. baumannii 1 37 38 (23.6) K. pneumoniae 1 21 22 (13.6) Enterobacter spp. 0 17 17 (10.5) E. coli 0 12 12 (7.4) C. freundii 0 8 8 (4.9) S. aureus 0 3 3 (1.8) Coagulase negative S. aureus 0 1 1 (0.6) Candida spp. 0 3 3 (1.8) Total 15 (9.3) 146 (90) 161 Table 2 Antimicrobial resistance rates (%) for the gram negative bacilli recovered from lower respiratory tract secretions of intensive care unit patients

.5) E. coli 0 12 12 (7.4) C. freundii 0 8 8 (4.9) S. aureus 0 3 3 (1.8) Coagulase negative S. aureus 0 1 1 (0.6) Candida spp. 0 3 3 (1.8) Total 15 (9.3) 146 (90) 161 Table 2 Antimicrobial resistance rates (%) for the gram negative bacilli recovered from lower respiratory tract secretions of intensive care unit patients Antimicrobials A. baumannii (38) K. pneumoniae (22) C. freundii (8) E. coli (12) Enterobacter (17) P. aeruginosa (57) Cotrimoxazole 79.5 90.9 100 100 100 ND* Doxycycline 2.6 9.1 0 0 0 ND Amikacin 87.2 63.6 75 41.7 72.2 61.4 Netilmicin ND ND ND ND ND 70.2 Ciprofloxacin 89.7 95.5 100 100 100 ND Ofloxacin ND ND ND ND ND 68.4 Ceftizoxime ND ND ND ND ND 68.4 Ceftazidime 100 96.9 87.5 91.7 100 68.4 Meropenam 25.6 9.1 12.5 0 11.1 22.8 Amoxyclav 97.4 100 100 91.7 100 ND Ticarcillin/Tazobactam ND ND ND ND ND 49.1 Aztreonam ND ND ND ND ND 94.7 * ND - Not Done Table 3 Bacterial resistance rates (%R 95%CI) to doxycycline for various isolates recovered from lower respiratory tract specimens Organism(n) %R* %IS** %S*** %R 95%CI A. baumannii (38) 2.6 64.1 33.3 0.1-15.1 C. freundii (8) 0 75 25 0.0-40.2 Enterobacter spp. (17) 0 94.4 5.6 0.0-21.9 E. coli (12) 0 83.3 16.7 0.0-30.1 K. pneumoniae (22) 9.1 77.7 13.6 1.6-30.6 * % R - Percentage resistance ** % IS - Percentage intermediate sensitive ***% S - Percentage sensitive Limits and outcome One of the potential limitations of this study is that epidemiologic analysis, ESBL phenotypic detection and MIC of doxycycline was not carried out. Despite this limitation our data can be used for local therapeutic choices.

Organism(n) %R* %IS** %S*** %R 95%CI A. baumannii (38) 2.6 64.1 33.3 0.1-15.1 C. freundii (8) 0 75 25 0.0-40.2 Enterobacter spp. (17) 0 94.4 5.6 0.0-21.9 E. coli (12) 0 83.3 16.7 0.0-30.1 K. pneumoniae (22) 9.1 77.7 13.6 1.6-30.6 * % R - Percentage resistance ** % IS - Percentage intermediate sensitive ***% S - Percentage sensitive Limits and outcome One of the potential limitations of this study is that epidemiologic analysis, ESBL phenotypic detection and MIC of doxycycline was not carried out. Despite this limitation our data can be used for local therapeutic choices. We conclude that nonfermenters are the most common etiological agents of LRTIs in ICU. There is an alarmingly high rate of resistance to cephalosporins, β lactam-β-lactamase inhibitors, and carbapenem against predominant organisms. We suggest that further studies should be carried out to evaluate the usefulness of doxycycline against the ICU pathogens. Judicious use of older and newer antimicrobial agents is essential to prevent the emergence of multi drug resistant bacteria in the ICU. Source of Support: Nil Conflict of Interest: None declared.

Introduction Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most important nosocomial pathogens and has emerged as a serious threat to public health world wide.[1] Because of their multiresistance properties, with intrinsic resistance to all β-lactam antibiotics, there remain limited choices of antimicrobial agents to treat many serious life-threatening infections caused by MRSA, leading to prolonged stay of such patients in the ICU and hospital, and increased cost of care. The emergence of these resistant strains represents a consequential response to selective pressures imposed by antimicrobial chemotherapy and once established, they are difficult to control and eradicate. The knowledge of prevalence of MRSA and their antibiotic sensitivity pattern in any environment becomes necessary for selection of appropriate treatment for these patients. The aim of this study is to determine the prevalence and antimicrobial susceptibility pattern of MRSA in a tertiary care hospital in Assam. Materials and Methods Staphylococcus aureus isolates from routine clinical specimens submitted at the microbiology laboratories from January 2007 to February 2008 were included in this study. All isolates were identified morphologically and biochemically by standard laboratory procedures.[2]

Introduction Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most important nosocomial pathogens and has emerged as a serious threat to public health world wide.[1] Because of their multiresistance properties, with intrinsic resistance to all β-lactam antibiotics, there remain limited choices of antimicrobial agents to treat many serious life-threatening infections caused by MRSA, leading to prolonged stay of such patients in the ICU and hospital, and increased cost of care. The emergence of these resistant strains represents a consequential response to selective pressures imposed by antimicrobial chemotherapy and once established, they are difficult to control and eradicate. The knowledge of prevalence of MRSA and their antibiotic sensitivity pattern in any environment becomes necessary for selection of appropriate treatment for these patients. The aim of this study is to determine the prevalence and antimicrobial susceptibility pattern of MRSA in a tertiary care hospital in Assam. Materials and Methods Staphylococcus aureus isolates from routine clinical specimens submitted at the microbiology laboratories from January 2007 to February 2008 were included in this study. All isolates were identified morphologically and biochemically by standard laboratory procedures.[2] The antibiotic susceptibility pattern was determined by modified Kirby Bauer disc diffusion method against the following antibiotics: Oxacillin (1 μg), penicillin (10 U), Cephalexin (30 μg), gentamicin (10 μg), amikacin (30 μg), trimethoprim/sulfamethoxazole (1.25/23.75 μg), ciprofloxacillin (5 μg), erythromycin (15 μg) and clindamycin (2 μg). The entire surface of the Mueller-Hinton agar (MHA) plate with 2% NaCl was covered with inoculums of S. aureus, turbidity matching 0.5 McFarland standard, by a sterile cotton swab stick and the plate was air-dried before antibiotics discs were laid on the surface. To determining inducible macrolids Lincosamides type B streptogramins (MLSB) resistance (D-test) erythromycin and clindamycin discs were placed 15-18 mm apart. A truncated or blunted clindamycin zone of inhibition (D-shape) indicated inducible resistance. All discs were obtained from Difco supplied by Becton Dickinson India Pvt. Ltd. S. aureus ATCC 25923 as sensitive and ATCC 43300 as oxacillin-resistant strain were used for standard control. The plates were incubated at 35°C for 24 hours. The diameter of the zone of inhibition was compared according to Clinical and Laboratory Standards Institute guidelines (CLSI).[3]

cton Dickinson India Pvt. Ltd. S. aureus ATCC 25923 as sensitive and ATCC 43300 as oxacillin-resistant strain were used for standard control. The plates were incubated at 35°C for 24 hours. The diameter of the zone of inhibition was compared according to Clinical and Laboratory Standards Institute guidelines (CLSI).[3] Results A total of 276 S. aureus strains were isolated from various clinical specimens. Of 276 isolates, 96 (34.78%) were found to be methicillin-resistant. Maximum isolation of MRSA was from pus/wound swabs (46.67%) followed by sputum/throat swab (42.86%). Table 1 depicts the antibiotic susceptibility data for all the S. aureus isolates. None of the MRSA isolates was found to be sensitive to penicillin and Cephalexin, while 10.56% and 25% of methicillin-sensitive S. aureus (MSSA) were sensitive to these antibiotics, respectively. MSSA isolates also revealed higher susceptibility to trimethoprim/sulfamethoxazole (38.89% vs. 3.12%), gentamicin (27.22% vs. 12.5%), amikacin (61.1% vs. 21.88%), ciprofloxacillin (48.33% vs. 12.5%), erythromycin (75% vs. 18.75%) and clindamycin (90.56% vs. 43.75%) as compared with MRSA. In MRSA isolates, 50% had constitutive resistance (resistance to both erythromycin and clindamycin), 9.38% had the inducible MLSB resistance (flattening of the clindamycin zone adjacent to the erythromycin disc) and 18.75% had the MS phenotype (resistance to erythromycin and sensitive to clindamycin). In MSSA, 5% and 3.3% isolates were found to have the constitutive and inducible MLSB resistance phenotypes respectively, while 23.33% exhibited the MS phenotype.

attening of the clindamycin zone adjacent to the erythromycin disc) and 18.75% had the MS phenotype (resistance to erythromycin and sensitive to clindamycin). In MSSA, 5% and 3.3% isolates were found to have the constitutive and inducible MLSB resistance phenotypes respectively, while 23.33% exhibited the MS phenotype. Table 1 Antibiotic susceptibility pattern of 276 Staphylococcus aureus isolates from clinical specimens received at microbiology department, January 2007-February 2008 Antimicrobials Percentage of isolates sensitive

attening of the clindamycin zone adjacent to the erythromycin disc) and 18.75% had the MS phenotype (resistance to erythromycin and sensitive to clindamycin). In MSSA, 5% and 3.3% isolates were found to have the constitutive and inducible MLSB resistance phenotypes respectively, while 23.33% exhibited the MS phenotype. Table 1 Antibiotic susceptibility pattern of 276 Staphylococcus aureus isolates from clinical specimens received at microbiology department, January 2007-February 2008 Antimicrobials Percentage of isolates sensitive MSSA, n = 180 (65.21%) MRSA, n = 96 (34.78%) Oxacillin 100 0 Penicillin 10.56 0 Cephalexin 25 0 Trimethoprim/sulfamethoxazole 38.89 3.12 Gentamicin 27.22 12.5 Amikacin 61.1 21.88 Ciprofloxacillin 48.33 12.5 Erythromycin 75 18.75 Clindamycin 90.56 43.75 Discussion MRSA is a global phenomenon with a prevalence rate ranging from 2% in the Netherlands and Switzerland, to 70% in Japan and Hong Kong.[45] In this study, the prevalence of MRSA was found to be 34.78%, and this is higher than previous rates (23.6%) reported from the same institute.[6] A comparable prevalence rate of 31% and 38.56% were also reported from Tamil Nadu and Delhi, whereas in some studies the rate is comparatively low (19.56% in Nagpur) and in another study it was very high (80.89% in Indore).[7–10] Analysis from previous studies revealed a relationship between methicillin resistance and resistance to other antibiotics.[611] This study showed that all MRSA isolates were significantly less sensitive to antibiotics as compared with MSSA isolates. Many of the isolates (37.5%) were resistant to all antibiotics used. Anupurba et al. also observed that 32% of MRSA isolates are resistant to all commonly used antistaphylococcal agents except vancomycin.[12] Because of the resistance of MRSA to all commonly used antibiotics, it is necessary to test newer group of antibiotics such as vancomycin and teicoplanin routinely. Resistance to quinolones (ciprofloxacillin) was much higher (87.5%) in this study as compared with a previous study (22.8%) from the same institute.[6] The rapid emergence of ciprofloxacillin is probably due to the indiscriminate and empirical use of these drugs. Susceptibility to erythromycin and clindamycin were observed in 55.43% and 74.28%, respectively. MSSA isolates revealed higher susceptibility to erythromycin (75% vs. 18.75%) and clindamycin (90.56% vs. 43.75%) than MRSA. Both the constitutive (5% vs. 50%) and inducible resistance phenotypes (3.3% vs. 9.38%) were found to be significantly higher in MRSA isolates as compared with MSSA.

43% and 74.28%, respectively. MSSA isolates revealed higher susceptibility to erythromycin (75% vs. 18.75%) and clindamycin (90.56% vs. 43.75%) than MRSA. Both the constitutive (5% vs. 50%) and inducible resistance phenotypes (3.3% vs. 9.38%) were found to be significantly higher in MRSA isolates as compared with MSSA. A recent study in the All India Institute of Medical Science, New Delhi, observed that 10% of MSSA and 30% MRSA are D-test positive.[13] In our study, positive D-test was observed in 3.33% of MSSA and 9.38% in MRSA. A recent survey in South Africa observed inducible MLSB phenotype in 10.8% of MSSA and 82% of MRSA, whereas constitutive MLSB phenotype was identified in 1.4% of MSSA isolates but absent in all the MRSA.[14] Conclusions These observations indicate that the incidence of constitutive and inducible MLSB resistance in staphylococcal isolates varies by geographic region. The clinical microbiology laboratories should consider routine testing and reporting of inducible clindamycin resistance in S. aureus to prevent the possibility of clindamycin treatment failure. Because of the ability of these pathogens to acquire resistance to new classes of antimicrobial agents, surveillance on the antimicrobial susceptibility patterns is of utmost importance in understanding new and emerging resistance trends. Source of Support: Nil Conflict of Interest: None declared.

Sir, I read the recent publication by Jaiswal et al., on aluminium phosphide poisoning with great interest.[1] In their work,[1] correction of severe metabolic acidosis on patient outcome was studied. Jaiswal et al., noted that “there was significant improvement from 30.36% in the case when only half correction was done, as has been the common practice, to 57.5%, when full correction of metabolic acidosis was done.”[1] Indeed, aluminium phosphide poisoning is confirmed for induction of severe metabolic acidosis and relates to the high mortality. Khosla et al., noted that “severe metabolic acidosis was common and mortality was high (49%).”[2] The correction of metabolic acidosis seems to be the core therapeutic concept for aluminium phosphide poisoning. There is no doubt about the usefulness of this treatment. Several treatments are available at present, including gastric lavage with potassium permanganate solution, oral administration of charcoal and sorbitol suspension, intravenous administration of sodium bicarbonate, magnesium sulphate and calcium gluconate, and oral administration of sodium bicarbonate as well as alternative usage of oral administration of coconut oil.[3] No doubt that full correction of metabolic acidosis must be the aim of treatment since there is no reason to leave acidosis within the patient. Source of Support: Nil Conflict of Interest: None declared.

Foreword by Chair Intensive care has had a phenomenal growth since its inception during the Copenhagen Poliomyelitis outbreak in 1952. Few specialities have grown with that much pace as that of Intensive Care, in such a short period. True, it is a ‘capital intensive’ care, but it saves lives, which otherwise would not have been possible, and even contributes, with precision, to perception of the future course of the disease and therefore to instituting remedial measures well ahead of time; as these patients require critical care therapies. Target-oriented therapies and bundles are becoming the preferred modalities to improve outcomes and there are definite indications that such therapies are helpful. Intensive therapy outcomes have been constantly improving, notwithstanding the variations in deployment of processes, resources, drugs, consumables and techniques in different ICUs. While disease outcomes are relatively easy to appreciate and account for, intensive care outcomes are not so easy to appreciate and account for, because of the very nature of the units and the way we practice intensive care, particularly in our country with a large number of open, very few semi-closed and even fewer closed units. In order to develop the right kind of unit and practice optimum therapies to provide best quality treatment to our critically ill patients, we need to develop appropriate key performance indicators, which reflect the aspirations of patients, relatives and intensivists.

very few semi-closed and even fewer closed units. In order to develop the right kind of unit and practice optimum therapies to provide best quality treatment to our critically ill patients, we need to develop appropriate key performance indicators, which reflect the aspirations of patients, relatives and intensivists. Developing key performance indicators and monitoring, auditing and improving those parameters is a dynamic process which requires standardization, improvement and innovation – the three arms of any improvement process in industry or service scenario. While standardization means ‘removing the outliers,’ i.e. reducing the standard deviation, improvement denotes gradual bettering of a parameter from the previous level with a degree of irreversible consistency. Innovation is, however, sporadic and often requires a thinking cap, which while maintaining the speed of standardization and improvement, quickly takes the parameters to a new level. In Total Quality Management (TQM) parlance, the first two are a part or product of daily management and the last one is a part or product of policy management. While standardization and improvement come with all-round participation in the unit, the innovation comes from a particular individual or a section of the people connected with the unit.

t (TQM) parlance, the first two are a part or product of daily management and the last one is a part or product of policy management. While standardization and improvement come with all-round participation in the unit, the innovation comes from a particular individual or a section of the people connected with the unit. Small improvements through small group activities (SGAs), previously known as Quality Circles, are central to any improvement in a unit and bring about pride and involvement amongst the staff in ICU. While isolated improvement activities are important to engage members to start with, institutionalizing these activities is the ultimate goal of the unit for, only that will ensure a complete irreversibility of the process. The latter is possible if the problems are constantly identified in the process/procedure and improvement initiatives are taken to address those. Striving for results is extremely important and for that the team needs to identify and take care of the ‘vital few’ problems leaving the ‘trivial many;’ something like ‘triaging’ in mass casualty parlance.

oblems are constantly identified in the process/procedure and improvement initiatives are taken to address those. Striving for results is extremely important and for that the team needs to identify and take care of the ‘vital few’ problems leaving the ‘trivial many;’ something like ‘triaging’ in mass casualty parlance. Co-relating the improvement of the process/outcome parameter with the improvement activities is important; if it does not match, then either one has not chosen the parameter properly or the parameter needs further development in the form of precision and complexity or the ‘vital few’ problems have not been properly identified. A constant engagement with the improvement process is necessary on the part of the team. The parameter needs to be developed, validated and revalidated in the same unit and in different units among the similar and dissimilar case mix before it is finally accepted.

‘vital few’ problems have not been properly identified. A constant engagement with the improvement process is necessary on the part of the team. The parameter needs to be developed, validated and revalidated in the same unit and in different units among the similar and dissimilar case mix before it is finally accepted. Members' Details Dr B Ray: General Manager (Medical Services) Tata Main Hospital, Jamshedpur drbray@tatasteel.com; 09234510648 Dr D P Samaddar: HOD Anaesthesiology and Critical Care, Tata Main Hospital, Jamshedpur drdpsamaddar@tatasteel.com; 9234551849 Dr S K Todi: Head of Medicine and Critical Care, AMRI, Kolkata subhashtodi@vsnl.com; 09831202040 Dr George John: Professor of Medicine, Head division of Critical Care, CMC, Vellore yokavi@yahoo.com; 09443626986 Dr N Ramakrishnan: Director, Critical Care Services, Senior Consultant in Critical Care and Sleep Medicine, Apollo Hospital, Chennai icudoctor@gmail.com; 09840855115 Dr S Ramasubban: Director Critical Care, Apollo Gleaneagles Hospital, Kolkata drsuresh@hotmail.com; 09831740837 Preface Background: Efficiency of any healthcare unit is judged by its quality indicators. However in our country monitoring the outcome through quality indicators is not yet institutionalized because of many reasons including the fact that majority of ICUs in India are being run as open or semi closed units, with unaccountable custodians. Dependency on the key performance indicators practiced by the developed countries, therefore, becomes inevitable wherever some degree of total quality management system is being adhered to. It is generally seen that a few of the hospitals in India attempt to evolve their own parameters either taking ideas from the “established parameters” or from their experience in Indian hospitals. Some of the parameters, when pursued year after year, do not express or reflect the aspirations of the intensivists. Selecting definitive and sensitive quality indicators and forming a data base at national level, is therefore required. The executive committee of the Indian Society of Critical Care Medicine (ISCCM), took a decision in the year 2008 to evolve Quality Indicators for ICUs in India and a task force was constituted under the convener ship of Dr B Ray to give its report.

tors and forming a data base at national level, is therefore required. The executive committee of the Indian Society of Critical Care Medicine (ISCCM), took a decision in the year 2008 to evolve Quality Indicators for ICUs in India and a task force was constituted under the convener ship of Dr B Ray to give its report. Objective: The primary objective is to select suitable quality indicators for Indian intensive care units (ICUs). Development of national data base and meaningful utilization of this data base is the final objective. Parameters: Common performance parameters (nominators) along with certain basic parameters (denominators) have been selected to find out quality indicators. Each indicator has been explained for ease of understanding and uniformity of practice. Based on the selected parameters, the Dashboard has been developed to monitor the data. Dashboard: Dashboard includes the selected parameters which would be made available to participating institutions to report to a main body at pre-decided intervals. Caution and limitations: Very common parameters have been selected in this report. Acceptability and utility of these parameters in the Indian scenario will have to be assessed over a period of time. Accordingly, parameters will be modified and may be a few parameters have to be even discontinued if those parameters do not reflect the outcome directly or indirectly.

have been selected in this report. Acceptability and utility of these parameters in the Indian scenario will have to be assessed over a period of time. Accordingly, parameters will be modified and may be a few parameters have to be even discontinued if those parameters do not reflect the outcome directly or indirectly. Future steps: Addition and deletion of parameters, as per need, would be considered in future. This will be done in phases after proper evaluation of monitored parameters. National data base generated by this exercise can be released for public reporting at a later date. Institutions will also be in a position to compare their performance with the national data base. Approach by an Intensive Care Unit: These should be the guidelines and by no means a complete or closed list. Once the parameters are put in place, and monitored and audited at predetermined intervals, one would surely find some improvement in the key performance indicators (KPIs); but by no standards should that alone be construed as a successful exercise. The approach should be to minimize standard deviation (prevent “spikes” on either direction) while improving the KPIs. It will be clearly appreciated that the whole unit's involvement is essential to identify the bottlenecks in the process or functional areas of any parameter and take remedial action through small group activities (SGAs) and self initiated projects (SIPs). One would see a lot of Plan-Do-Check-Act (PDCAs) on the way to evolution of a parameter.

iated that the whole unit's involvement is essential to identify the bottlenecks in the process or functional areas of any parameter and take remedial action through small group activities (SGAs) and self initiated projects (SIPs). One would see a lot of Plan-Do-Check-Act (PDCAs) on the way to evolution of a parameter. Main Report Index Page no 1. Background (Introduction): 175 2. Gathering the Evidence: 175 3. Units 175 4. Objective 176 5. Parameters 176 6. Definition of Parameters 176 7. Dashboard 183 8. Limitations 183 9. Future Course of Action 183 10. Recommendations 184 11. List of Symbols 184 12. Acknowledgments 185 13. References (additional) 185 14. Annexure 185 14.1. Quality Indicators in Critical Care: An Overview 185 14.2. Quality Indicators in Critical Care: Patient Safety 192 14.3. Quality Indicators in Critical Care: Personnel Development 194 14.4. Quality Indicators for ICU: Process Parameters 196 14.5. Quality Indicators in Critical Care: Outcome Parameters 200 14.6. Quality Indicators: Infection Control 203 1. Background Quality orientation is an integral part of patient care. The best possible care at the institutional level is not considered adequate in the present competitive environment. It should be visible, appreciated and comparable. Total Quality Management therefore, is essential to judge the appropriateness and effectiveness of medical care. Quality of service offered, result of intervention and treatment, undesirable outcomes, and other managerial and treatment related processes can be analyzed to define the scope of improvement. Quality indicators help in achieving these objectives. Healthcare is becoming transparent and customer-focused. Patients and their relatives have the right to know the standard of care and its cost.

irable outcomes, and other managerial and treatment related processes can be analyzed to define the scope of improvement. Quality indicators help in achieving these objectives. Healthcare is becoming transparent and customer-focused. Patients and their relatives have the right to know the standard of care and its cost. It is therefore becoming more and more mandatory for an institution to monitor quality indicators/parameters, and compare their performance level with the national standard or international bench marks. It gives the individual institution an opportunity to improve its quality of care through standardization of processes, procedures and treatment protocols. Unfortunately, due to a variety of reasons, performance levels are not monitored in India and therefore a national data base does not exist for a meaningful comparison. Dependency on an international data base, even if not logical for Indian scenario, becomes inevitable in our strategic design and planning of the service. In 2008, the Indian Society of Critical Care Medicine (ISCCM) had taken the initiative, at its executive body meeting, to identify quality indicators for ICUs in India, which will help ICUs in India judge their performance levels and compare them with the national data base.

It is therefore becoming more and more mandatory for an institution to monitor quality indicators/parameters, and compare their performance level with the national standard or international bench marks. It gives the individual institution an opportunity to improve its quality of care through standardization of processes, procedures and treatment protocols. Unfortunately, due to a variety of reasons, performance levels are not monitored in India and therefore a national data base does not exist for a meaningful comparison. Dependency on an international data base, even if not logical for Indian scenario, becomes inevitable in our strategic design and planning of the service. In 2008, the Indian Society of Critical Care Medicine (ISCCM) had taken the initiative, at its executive body meeting, to identify quality indicators for ICUs in India, which will help ICUs in India judge their performance levels and compare them with the national data base. 2. Gathering Evidence Annexure: 1 Quality indicators in Critical Dr B Ray, Care: An overview Dr D P Samaddar 2 Patient safety Dr S K Todi 3 Personnel Development Dr Suresh 4 Quality of Processes Dr George John, Dr N Ramakrishnan 5 Outcome Parameters Dr George John, Dr N Ramakrishnan 6 Infection Control Dr D P Samaddar 3. Units This report focuses on adult mixed intensive care units, references have also been given (except Neonatal ICU) wherever possible, to benchmark other specified units). Abbreviations used for different specialized units are given in Table 1.

2. Gathering Evidence Annexure: 1 Quality indicators in Critical Dr B Ray, Care: An overview Dr D P Samaddar 2 Patient safety Dr S K Todi 3 Personnel Development Dr Suresh 4 Quality of Processes Dr George John, Dr N Ramakrishnan 5 Outcome Parameters Dr George John, Dr N Ramakrishnan 6 Infection Control Dr D P Samaddar 3. Units This report focuses on adult mixed intensive care units, references have also been given (except Neonatal ICU) wherever possible, to benchmark other specified units). Abbreviations used for different specialized units are given in Table 1. Table 1 Unit Abbreviation Burn BCU Coronary CCU Surgical cardiothoracic SCU Medical MICU Medical/surgical, major, teaching M-S ICU major teaching Medical/surgical, all others M- S ICU Pediatric medical/surgical PICU Neurological Neuro (Med) ICU Neurosurgical Neuro (Surg) ICU Surgical SICU Trauma TICU 4. Objective Select very common parameters mainly focusing on the Outcome (mortality and morbidity), process, infection, communication, human resource and safety. Generate national data base for comparison with international bench marks and provide data to participating institutions at national level for comparison with national data base.

Available at: http://www.qhc.on.ca/body.cfmid=565 Afessa B, Gajic O, Keegan MT. Keegan severity of illness and organ failure assessment in adult intensive care units. Crit Care Clin 2007;23:639-58. 6.2 Morbidity Parameters 6.2.1. Iatrogenic Pneumothorax Indicator Iatrogenic Pneumothorax Description Procedure related pneumothorax Rationality Associated mortality and morbidity, prolonged stay, cost implications Formula for calculation (Number of pneumothorax / Number of cases) X 1000 Patient population Intensive care Source of data Hospital record Type of parameter Morbidity, safety Bench mark 0.83per1000cases[1] 5% (interstitial emphysema/ pneumothorax /pneumomediastinum /subcutaneous emphysema)[2] References 1. AHRQ national average. Sharp health care. Malcolm Baldrige National Quality Award application, 2007. 2. Delgado MC, Pericas LC, Moreno JR, et al. Quality indicators in critically ill patients. SEMICYUC work groups. 1st ed. May 2005. ISBN 6095974. 6.2.2 Incidence of Acute Renal Failure in Noncoronary ICU Noncoronary ICU Indicator Incidence of severe Acute Renal Failure in noncoronary ICU Description Denovo acute renal failure requiring renal replacement therapy or when urine output is < 200 mL in 12 h and/or marked azotemia defined as a BUN level > 84 mg/dL) during patient's ICU stay.[1]

Table 1 Unit Abbreviation Burn BCU Coronary CCU Surgical cardiothoracic SCU Medical MICU Medical/surgical, major, teaching M-S ICU major teaching Medical/surgical, all others M- S ICU Pediatric medical/surgical PICU Neurological Neuro (Med) ICU Neurosurgical Neuro (Surg) ICU Surgical SICU Trauma TICU 4. Objective Select very common parameters mainly focusing on the Outcome (mortality and morbidity), process, infection, communication, human resource and safety. Generate national data base for comparison with international bench marks and provide data to participating institutions at national level for comparison with national data base. 5. Parameters Based on the objective of this report, common parameters with their international benchmarks have been selected to address different aspects of patient care, operational issues and human resource development. Certain basic data, which as such do not reflect patient care, but when used as denominators to the selected parameters, make the parameter more sensitive and meaningful. Examples of these denominators are: number of admissions, total patient days in the unit (occupancy), ventilatory days, central venous and arterial line days, urinary catheter days etc. In order to avoid confusion and ambiguity of interpretation, it is essential that purpose and usefulness of selected parameters must be understood by the care providers. All the selected parameters, therefore, are described under certain sub headings as given in the Table 2, along with explanations.

catheter days etc. In order to avoid confusion and ambiguity of interpretation, it is essential that purpose and usefulness of selected parameters must be understood by the care providers. All the selected parameters, therefore, are described under certain sub headings as given in the Table 2, along with explanations. Table 2 Indicator Explanation Description What does the parameter mean Rationality Why should it be monitored Formula for calculation How it should be calculated Patient population For whom the parameter is collected Source of data From where the input will be collected Type of parameter Linkage of parameter with the type of quality Bench mark Common national or international standard References Literature back up for the bench mark and background information for the selected parameter 6. Definition of Parameters 6.1 Mortality 6.1.1 Standardized Mortality Rate(SMR) Indicator Standardized mortality rate (SMR) or risk adjusted mortality rate Description Mortality rates are not often the indicators of performance even if those are often referred to. However, mortality rate related to prior prediction is a sensitive indicator for comparison. SMR allows comparison of actual performance of the institution with predicted performance, based on the average mortality as expressed by national or international data.

ators of performance even if those are often referred to. However, mortality rate related to prior prediction is a sensitive indicator for comparison. SMR allows comparison of actual performance of the institution with predicted performance, based on the average mortality as expressed by national or international data. Rationality Risk of death varies with severity of disease state, age, and co- morbid conditions. Crude mortality (overall mortality), therefore, is not a sensitive indicator. On the basis of influencing factors, SMR obviates limitation of crude mortality as data from a large pool of patients with similar diagnoses and risk factors are analyzed to get expected mortality for that group of patients. Data can be obtained from national records or international records. Mortality rate can be obtained from predictive models such as APACHE, SAPS, MPM etc.[2] The SMR is a very useful parameter, often used to compare outcomes in two or more groups under study. It also gives an opportunity to individual ICUs for improving the processes and techniques. Formula for calculation[1] Risk-adjusted Mortality 1 = (Observed Rate/Risk-adjusted expected Rate) X100 Observed rate = Actual death in ICU/institution. Risk adjusted expected rate = Predicted death rate by predictive Model Interpretation[1] Equal to 100 – hospital's mortality rate and the expected average rate are the same >100 – hospitals' mortality rate is higher than the expected average mortality rate <100 – hospitals mortality rate is lower than the expected average mortality rate

Formula for calculation[1] Risk-adjusted Mortality 1 = (Observed Rate/Risk-adjusted expected Rate) X100 Observed rate = Actual death in ICU/institution. Risk adjusted expected rate = Predicted death rate by predictive Model Interpretation[1] Equal to 100 – hospital's mortality rate and the expected average rate are the same >100 – hospitals' mortality rate is higher than the expected average mortality rate <100 – hospitals mortality rate is lower than the expected average mortality rate Higher SMR does not necessarily mean that the hospital is unsafe, as this is a snapshot method and simultaneous assessment of other quality indicators must be done to draw a logical conclusion. Single parameter-based judgment on performance level is not advocated.[2] Patient population All patients admitted to critical care units of different types Source of data Hospital record for the observed mortality (numerator) Type of parameter Outcome Bench mark If the 95% confidence interval of the SMR includes 1, the performance is considered average. If the 95% CI *does not include 1, SMRs less than 1 and more than 1 are considered to show good and poor performances respectively.[3] References Available at: http://www.mayoclinic.org/quality/adjustedmortality.html Available at: http://www.qhc.on.ca/body.cfmid=565 Afessa B, Gajic O, Keegan MT. Keegan severity of illness and organ failure assessment in adult intensive care units. Crit Care Clin 2007;23:639-58. 6.2 Morbidity Parameters 6.2.1. Iatrogenic Pneumothorax Indicator Iatrogenic Pneumothorax Description Procedure related pneumothorax

enal Failure in Noncoronary ICU Noncoronary ICU Indicator Incidence of severe Acute Renal Failure in noncoronary ICU Description Denovo acute renal failure requiring renal replacement therapy or when urine output is < 200 mL in 12 h and/or marked azotemia defined as a BUN level > 84 mg/dL) during patient's ICU stay.[1] Rationality Renal failure increases possibility of death (60.3%) notwithstanding whether renal replacement therapy has been initiated.[12] Even a modest increase in the serum creatinine level (0.3 to 0.4 mg per deciliter [26.5 to 35.4 ímol per liter]) increases risk of death by 70% when compared to normal creatinine levels. Formula for calculation Number developed severe renal failure/Number managed in ICU X 100 Patient population Nominator: Severe renal failure (GFR < 10 ml/min.)[4] developing in ICU (excluding chronic renal failure patients.) Denominator: Patient managed in ICU in a given time frame Source of data ICU record Type of parameter Outcome parameter Bench mark Severe ARF 5.7%[1] 10% patients develop ARF (including Severe ARF)[4] References Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813-8. Venkataraman R, Kellum JA. Prevention of Acute Renal Failure. Chest 2007;131:300-8. Chertow GM, Burdick E, Honour M, Bonventre JW, Bates DW. Acute kidney in jury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365-70.

References Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813-8. Venkataraman R, Kellum JA. Prevention of Acute Renal Failure. Chest 2007;131:300-8. Chertow GM, Burdick E, Honour M, Bonventre JW, Bates DW. Acute kidney in jury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365-70. Delgado MC, Pericas LC, Moreno JR, et al. Quality indicators in critically ill patients. SEMICYUC work groups. 1st ed. May ISBN; 2005. p. 609-5974. 6.2.3. Decubitus (Pressure) Ulcer: Indicator Decubitus (Pressure) ulcer Description Decubitus ulcer and pressure sore are synonyms. Decubitus is derived from the Latin word decumbere, means “to lie down”. Since pressure sore can develop from other positions, it is called “Pressure sore”. Prolonged uninterrupted pressure over bony prominences causes necrosis and ulceration. Depending upon tissue damage, ulcers are classified into four stages. Stage 1 indicates superficial color change, Stage 2 represents partial thickness skin loss, Stage 3: full thickness skin loss, and Stage 4 denotes deep and extensive tissue damage involving muscle, tendon or bone. Hip and buttock sores represent 67% of all pressure sores.[12] Rationality Annual cost of treatment in the US exceeds $1 billion Formula for calculation Number of pressure ulcers / Number of cases X 1000 Patient population Critically ill Source of data Hospital record Type of parameter Morbidity, Safety of patients Bench mark 3 – 11%[1] 22.71 / 1000 cases[3]

6.2.3. Decubitus (Pressure) Ulcer: Indicator Decubitus (Pressure) ulcer Description Decubitus ulcer and pressure sore are synonyms. Decubitus is derived from the Latin word decumbere, means “to lie down”. Since pressure sore can develop from other positions, it is called “Pressure sore”. Prolonged uninterrupted pressure over bony prominences causes necrosis and ulceration. Depending upon tissue damage, ulcers are classified into four stages. Stage 1 indicates superficial color change, Stage 2 represents partial thickness skin loss, Stage 3: full thickness skin loss, and Stage 4 denotes deep and extensive tissue damage involving muscle, tendon or bone. Hip and buttock sores represent 67% of all pressure sores.[12] Rationality Annual cost of treatment in the US exceeds $1 billion Formula for calculation Number of pressure ulcers / Number of cases X 1000 Patient population Critically ill Source of data Hospital record Type of parameter Morbidity, Safety of patients Bench mark 3 – 11%[1] 22.71 / 1000 cases[3] References Revis DR. Decubitus Ulcers. E Medicine October 25th, 2005. Pressure care for pressure ulcer and pain therapy. National Pressure Ulcer Advisory Panel (NPUAP). Available from: info@pressurecare.co.uk AHRQ national average. Sharphealth care 2007. Malcolm Baldrige National Quality Award application 2007. p. 34.

Bench mark 3 – 11%[1] 22.71 / 1000 cases[3] References Revis DR. Decubitus Ulcers. E Medicine October 25th, 2005. Pressure care for pressure ulcer and pain therapy. National Pressure Ulcer Advisory Panel (NPUAP). Available from: info@pressurecare.co.uk AHRQ national average. Sharphealth care 2007. Malcolm Baldrige National Quality Award application 2007. p. 34. 6.3 Operational or Process Parameters 6.3.1 Length of Stay Indicator Length of Stay (LOS) Description Total hours and days patients managed in the unit with midnight bed occupancy are more accurate than the number of calendar days a patient spends in the ICU. Arithmetic mean overestimates LOS, as outliers both ways influence the mean LOS very adversely. Median of LOS can circumvent this problem. LOS is also influenced by factors such as availability of intermediary care, discharge practices, and mortality rates. Appropriateness of using LOS as outcome measure is therefore being reconsidered by Joint Commission on Accreditation of Healthcare Organizations (JCACHO). LOS properly stratified on the basis of diseases and conditions and properly analyzed could be a sensitive parameter throwing up deficiency in process and technique in ICU. Rationality ICU beds are limited in any hospital. Rationalized use for needy patients therefore is necessary. LOS is, therefore, used to assess quality of care and resource utilization. Formula for calculation Total occupied bed days / number of patients in a given time frame (weekly/monthly /yearly) Patient population All admitted patients in the unit Source of data ICU data Type of parameter Outcome measure

Rationality ICU beds are limited in any hospital. Rationalized use for needy patients therefore is necessary. LOS is, therefore, used to assess quality of care and resource utilization. Formula for calculation Total occupied bed days / number of patients in a given time frame (weekly/monthly /yearly) Patient population All admitted patients in the unit Source of data ICU data Type of parameter Outcome measure Bench mark Average LOS in year 2001 Norfolk General Hospital[2] 4.36 days in general ICU; 2.43 days in vascular ICU References McMillan TR, Hyzy RC. Bringing quality improvement into the intensive care unit. Crit Care Med 2007;35:S59–65. Pronovost PJ. Accelerating Change Today (A.C.T.) for America's Health. Schoeni PQ, editor. © 2002 by the National Coalition on Health Care and the Institute for Healthcare Improvement. The Robert Wood Johnson Foundation supported report 6.3.2 Compliance to Protocol Indicator Compliance to protocol Description Selected guidelines, protocols, treatment bundles in the unit to improve patient care, resource utilization, and reduce iatrogenic complications. Rationality Compliance to protocols, guidelines and treatment bundles are expected to improve patient care. Compliance to protocol could be absolute or partial (Seventy percent correct compliance had been reported by McMillan et al.[1]) Formula for calculation Number of times followed/ number of times expected to follow × 100 Patient population All ICU patients Source of data Audit report Type of parameter Process parameter Bench mark 90%[2]

Rationality Compliance to protocols, guidelines and treatment bundles are expected to improve patient care. Compliance to protocol could be absolute or partial (Seventy percent correct compliance had been reported by McMillan et al.[1]) Formula for calculation Number of times followed/ number of times expected to follow × 100 Patient population All ICU patients Source of data Audit report Type of parameter Process parameter Bench mark 90%[2] References McMillan TR, Hyzy RC. Bringing quality improvement into the intensive care unit. Crit Care Med 2007;35:S59–65. Pronovost PJ. Accelerating Change Today (A.C.T.) for America's Health. Schoeni PQ, editor. © 2002 by the National Coalition on Health Care and the Institute for Healthcare Improvement. The Robert Wood Johnson Foundation supported report 6.3.3 ICU Readmission Rate Indicator ICU readmission rate Description Readmission to the ICU within 24 hrs of transfer during a single hospital stay. This is an indicator of post ICU care. Rationality A zero readmission rate reflects a more defensive approach by the ICU team, which increases LOS in ICU causing risk of nosocomial infection, iatrogenic complications, and nonavailability of beds for the deserving patients. A higher mortality rate of 1.5 to 10 times that of controls, and higher length of stay at least twice that of control patients had been documented. A higher readmission rate indicates premature decision to shift out patients Formula for calculation (Number of readmitted patients/ Total patients managed in ICU) × 100

Rationality A zero readmission rate reflects a more defensive approach by the ICU team, which increases LOS in ICU causing risk of nosocomial infection, iatrogenic complications, and nonavailability of beds for the deserving patients. A higher mortality rate of 1.5 to 10 times that of controls, and higher length of stay at least twice that of control patients had been documented. A higher readmission rate indicates premature decision to shift out patients Formula for calculation (Number of readmitted patients/ Total patients managed in ICU) × 100 Patient population All patients discharged from ICU in a time frame.(exclusion: death in CCU) Source of data Hospital record Type of parameter Process, Safety of patients Bench mark ICU readmission rates are around 5–6%[1] 4%[2] References 1. McMillan TR, Hyzy RC. Bringing quality improvement into the intensive care unit Crit Care Med 2007;35:S59–65. 2. Delgado MC, Pericas LC, Moreno JR, et al. Quality indicators in critically ill patients. SEMICYUC work groups. 1st ed. May 2005. ISBN 609- 5974 6.4 Error and Patient Safety Error is defined as “the failure of a planned action to be completed as intended, or the use of a wrong plan to achieve an aim”.[1] additional ref Culture of safety is important, considering the high number of preventable deaths (44000 to 98000/ annum medical error related deaths had been reported in USA).[2] additional ref Brochure released by society of Critical Care Medicine, USA in 2004 had quoted very high incidence of medication errors which caused more than 770,000 injuries and deaths per year.[3] additional ref

er of preventable deaths (44000 to 98000/ annum medical error related deaths had been reported in USA).[2] additional ref Brochure released by society of Critical Care Medicine, USA in 2004 had quoted very high incidence of medication errors which caused more than 770,000 injuries and deaths per year.[3] additional ref Both patient safety and staff safety are important. 6.4.1 Patients' Fall Rate Indicator Patients' Fall Rate Definition An untoward event, which results in the patient coming to rest unintentionally on the ground or another lower surface.[1] Rationality Fall could be accidental, anticipated physiological or unanticipated physiological. This is a safety issue for a patient in ICU. Accidental fall could lead to morbidity, prolonged stay and customer dissatisfaction. Formula for calculation[1] fall rate = (no. of falls/no. of bed days) × 1000 Patient population All patients Source of data ICU record Type of parameter Safety and morbidity Bench mark[23] 8.46 falls per thousand bed days with an injury rate of 12.85% in 2000-01[2] Norton Hospital USA, 2008 Norton Healthcare statistics per 1000 in patient days of the unit.[3] Without injury With injury ICU 2.10 0.22 Medical surgical 2.23 0.74 Medical 2.62 0.70 Surgical 2.02 0.37 References Barnett K. Reducing patient falls in an acute general hospital. In: Shaw T, Sanders K, editors. Foundation of Nursing Studies Dissemination Series. Vol. 1. 2002. Barnett K. Mid Yorkshire Hospitals NHS Trust. Reducing patients falls project. 2001-02 Norton hospital USA2008 Norton Healthcare. Available from: http://www.erlanger.org/quality/PatientSafety.asp