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Introduction Toxic megacolon is a rare but life-threatening disease and may be defined as the severe dilatation of the colon associated with colitis. The main causes are inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn’s disease. Toxic megacolon is one of the most serious complication of Clostridium difficile infection (CDI) [1]. The risk factors for CDI are: advanced age (persons > 65 years), inflammatory bowel diseases, immunodeficiency (human immunodeficiency virus infection, hematologic malignancies, chronic kidney disease) increased duration of hospitalization, exposure to antibiotics or chemotherapeutic agents, the use of proton pump inhibitors and upper gastro-intestinal tract surgery [2]. It has been shown that fulminant evolution of CDI results from toxin-induced proinflammatory cytokine released into the colon, followed by increased vascular permeability and host cell necrosis [3] and is associated with the hypervirulent 027 strain of Clostridium difficile [4]. Certain risk factors may precipitate the progression of CDI to toxic megacolon and include long-term antibiotic therapy, concurrent malignancy, chronic obstructive pulmonary disease, renal failure, immunosuppressive medication [5], exposure to prokinetic agents [6] or proton pump inhibitors [7, 8]. In critically ill patients, the severity of underlying disease, surgery procedures, length of hospitalization, multiple admissions, and one or more organs dysfunction, are also factors predisposing to a high risk of CDI [8].

suppressive medication [5], exposure to prokinetic agents [6] or proton pump inhibitors [7, 8]. In critically ill patients, the severity of underlying disease, surgery procedures, length of hospitalization, multiple admissions, and one or more organs dysfunction, are also factors predisposing to a high risk of CDI [8]. The incidence of toxic megacolon in patients with colitis induced by Clostridium difficile is low and ranges between 0.4% and 3% [9]. However, the mortality rate is very high, and varies from 38% to 80% [10]. The absence of diarrhea due to ileus, rapid abdominal distension, abdominal pain and tenderness, tachycardia and hypotension in patients diagnosed with CDI are important signs of a progression to toxic megacolon [9]. The diagnosis of toxic megacolon needs radiological proof of colonic dilatation in excess of 6 cm. CT scan findings, such as colonic wall thickening, distortion of haustral folds, and ascites are helpful in confirming the diagnosis of a toxic megacolon [10]. The treatment of toxic megacolon in CDI remain a challenge. Drug therapy remains controversial due to the frequently resultant poor results. In such cases, surgical treatment must be considered as an alternative approach [11]. Due to the increased mortality, which occurs in cases associated with colonic perforation, peritonitis, septic shock and multiple organ dysfunction, early diagnosis and treatment are crucial [2]. Three cases where the diagnosis was toxic megacolon caused by the CDI, and which were successfully treated by drug therapy alone, are presented.

Due to the increased mortality, which occurs in cases associated with colonic perforation, peritonitis, septic shock and multiple organ dysfunction, early diagnosis and treatment are crucial [2]. Three cases where the diagnosis was toxic megacolon caused by the CDI, and which were successfully treated by drug therapy alone, are presented. Cases presentation The three cases presented below were Caucasian female patients with severe CDI hospitalized in the Clinical Infectious Diseases Hospital, Constanta, between August 2014 and May 2016. They had prolonged hospitalizations before admission to the department of infectious diseases. The first patient had spent three weeks in the hematology department, where she received chemotherapy for a non-Hodgkin’s lymphoma and ten days of antibiotic treatment with ceftriaxone 1 g IV q12hrs, and ciprofloxacin 400 mg IV q12hrs, for an acute bacterial pneumonia. After discharge from hospital, diarrheal stools occurred and the patient received ambulatory symptomatic treatment for two weeks without any improvement of symptoms. The second patient was hospitalized for three weeks in the general surgery clinic, where she underwent surgery intervention for colon cancer. During hospitalization, she was diagnosed with a urinary tract infection with E. coli, for which she received a seven-day treatment with oral ciprofloxacin 500 mg PO q12hrs. Diarrheal stools occurred subsequently, at which point only symptomatic treatment was provided.

e underwent surgery intervention for colon cancer. During hospitalization, she was diagnosed with a urinary tract infection with E. coli, for which she received a seven-day treatment with oral ciprofloxacin 500 mg PO q12hrs. Diarrheal stools occurred subsequently, at which point only symptomatic treatment was provided. The third patient had surgery for a herniated disc. Two interventions were undertaken within three months in the neurosurgery clinic. During this time, the patient had a urinary catheter placed and had repeated urinary tract infections. Ciprofloxacin 500 mg PO q12hrs was prescribed, and continued for more than two weeks. None of the patients were known to have with chronic hepatitis B, HIV, tuberculosis or inflammatory bowel disease, or had received treatment with proton pump inhibitors in the last six months. Only one patient recently had been diagnosed with chronic viral C hepatitis, with a F3 fibrosis score. Another had been diagnosed with rheumatoid arthritis, but had not taken any specific medication for this within the last two years, except short courses of nonsteroidal anti-inflammatory drugs (seven-day courses of either meloxicam PO 15 mg/day, or ibuprofen 400 mg PO q12hrs). None of our patients was consuming alcohol or drugs, and all had a BMI greater than 30 kg/m2 (Table 1). Table 1 Patients’ characteristics – demographics and diseases history

None of the patients were known to have with chronic hepatitis B, HIV, tuberculosis or inflammatory bowel disease, or had received treatment with proton pump inhibitors in the last six months. Only one patient recently had been diagnosed with chronic viral C hepatitis, with a F3 fibrosis score. Another had been diagnosed with rheumatoid arthritis, but had not taken any specific medication for this within the last two years, except short courses of nonsteroidal anti-inflammatory drugs (seven-day courses of either meloxicam PO 15 mg/day, or ibuprofen 400 mg PO q12hrs). None of our patients was consuming alcohol or drugs, and all had a BMI greater than 30 kg/m2 (Table 1). Table 1 Patients’ characteristics – demographics and diseases history Case 1 Case 2 Case 3 Age (years) 67 75 59 Body mass index (BMI) (kg/m2) 30.5 30.1 32.3 Environmental origin Urban Rural Urban Chronic hepatitis B/C No/YES No/No No/No HIV/AIDS No No No Autoimmune diseases No No YES Inflammatory bowel disease (IBD) No No No Treatment with proton pump inhibitors No No No Alcohol consumption No No No Drug users No No No Pathological recent history Non-Hodgkin lymphoma chemotherapy Colon cancer surgery Neurosurgical intervention for a herniated disc Antibiotic treatment ceftriaxone + ciprofloxacin ciprofloxacin ciprofloxacin On admission, all patients were hemodynamically stable, presenting with a temperature in excess of 38.5° C, signs of dehydration, nausea, abdominal cramps, oliguria, peripheral edema, ascites. In two patients, there was evidence of bilateral pleural effusion (Table 2).

iaxone + ciprofloxacin ciprofloxacin ciprofloxacin On admission, all patients were hemodynamically stable, presenting with a temperature in excess of 38.5° C, signs of dehydration, nausea, abdominal cramps, oliguria, peripheral edema, ascites. In two patients, there was evidence of bilateral pleural effusion (Table 2). Table 2 Clinical and laboratory patients’ characteristics Case 1 Case 2 Case 3 Fever (max) 39.0°C 38.8°C 39.2°C Heart rate >90/minute, yes yes yes Respiratory rate >20/minute yes yes yes Peripheral edema yes yes yes Ascites yes yes yes Pleural effusion yes no yes Low diuresis yes yes yes Acute renal failure yes yes yes White cell count (109/L) 23.0 × 109/L 25.0 × 109/L 30.0 × 109/L C-reactive protein (mg/dL) 16.8 18.6 15.9 Blood urea nitrogen (mg/dL) 102 89 98 Serum albumin levels < 2.5 g/dL yes yes yes ATLAS score 6 7 6 Toxin test (A + B) positive positive positive Ribotype 027 yes yes yes Laboratory tests showed a marked leukocytosis (20.0×109/L) with neutrophilia, C-reactive protein greatly increased (>15 mg/dl), hypoalbuminemia and signs of acute renal failure associated with oliguria, increased blood urea nitrogen and serum creatinine. In all cases the toxin test (A+B) was positive, and ribotype 027 was present (Table 2). The ATLAS score was calculated which includes age, treatment with systemic antibiotics, leucocyte count, albumin, and serum creatinine. A white blood cell count in excess of 15 × 109/L, rising serum creatinine, temperature greater than 38.5° C and levels of serum albumin less than 2.5 mg/dL were considered predictors of severe CDI.

re was calculated which includes age, treatment with systemic antibiotics, leucocyte count, albumin, and serum creatinine. A white blood cell count in excess of 15 × 109/L, rising serum creatinine, temperature greater than 38.5° C and levels of serum albumin less than 2.5 mg/dL were considered predictors of severe CDI. For this reason, the patients received initial treatment with intravenous metronidazole, 1.5g / day divided into 3 doses, and oral vancomycin, 125 mg, four times daily as well as parenteral hydration and albumin infusions. After a period of 48-72 hours all three presented with increased temperature (>39.0° C), increased abdominal cramping, significant bloating of the abdomen and vomiting. Laboratory tests revealed marked leukocytosis (29.0 × 109/L, 32.0 × 109/L and 38.0 × 109/L, respectively). Abdominal CT examination, both without contrast medium (Figure 1A and B) and with intravenous contrast medium (Figure 2A and B), showed that the colon was significantly dilated, with marked thickening of the wall. This suggested a diagnosis of toxic megacolon. Fig.1A and B Colon significantly dilated, with marked thickening of the wall (without contrast medium) Fig. 2A and B Colon significantly dilated, with marked thickening of the wall (intravenous contrast medium) The APACHE II scores for each patient were 26 pts in the first case, 29 pts in the second and 24 pts in the third, with an estimated mortality of 56.9%, 67.2% and respectively 49.7%.

Fig.1A and B Colon significantly dilated, with marked thickening of the wall (without contrast medium) Fig. 2A and B Colon significantly dilated, with marked thickening of the wall (intravenous contrast medium) The APACHE II scores for each patient were 26 pts in the first case, 29 pts in the second and 24 pts in the third, with an estimated mortality of 56.9%, 67.2% and respectively 49.7%. Because severe CDI was considered possible, tigecycline therapy was started, 100 mg IV infusion, then 50 mg IV infusion q12hrs. In addition, intravenous metronidazole was administrated, 1.5 g/day divided into 3 doses and oral vancomycin, 1 g/day, divided into 4 doses. Supportive measures, including intravenous fluid resuscitation and electrolyte replacement were given to all patients and a nasogastric tube (NGT) was placed to assist with gastrointestinal decompression. In two patients, there was a rapid improvement in their condition. After three days, there was an absence of fever with an improvement in their clinical and para-clinical status, with declined leukocytosis (16.0 × 109/L and 19.0 × 109/L) and C-reactive protein (8.2 mg/dL and 8.9 mg/dL).

Because severe CDI was considered possible, tigecycline therapy was started, 100 mg IV infusion, then 50 mg IV infusion q12hrs. In addition, intravenous metronidazole was administrated, 1.5 g/day divided into 3 doses and oral vancomycin, 1 g/day, divided into 4 doses. Supportive measures, including intravenous fluid resuscitation and electrolyte replacement were given to all patients and a nasogastric tube (NGT) was placed to assist with gastrointestinal decompression. In two patients, there was a rapid improvement in their condition. After three days, there was an absence of fever with an improvement in their clinical and para-clinical status, with declined leukocytosis (16.0 × 109/L and 19.0 × 109/L) and C-reactive protein (8.2 mg/dL and 8.9 mg/dL). In the third case, the general condition was worsened. Her temperature rose to over 39.5° C, and she had considerable abdominal pain, pronounced abdominal distention and vomiting. The APACHE II score increased to 26 pts. For this reason, tigecycline was removed from the regimen, and the vancomycin dose was increased to 2 g/day orally, administered by nasogastric tube, divided into 4 doses plus vancomycin, 1 g/day in enema. After other two days, the patient’s general condition improved. All three patients received human albumin, depending on the amount of losses and hydro-electrolytic balance.

In the third case, the general condition was worsened. Her temperature rose to over 39.5° C, and she had considerable abdominal pain, pronounced abdominal distention and vomiting. The APACHE II score increased to 26 pts. For this reason, tigecycline was removed from the regimen, and the vancomycin dose was increased to 2 g/day orally, administered by nasogastric tube, divided into 4 doses plus vancomycin, 1 g/day in enema. After other two days, the patient’s general condition improved. All three patients received human albumin, depending on the amount of losses and hydro-electrolytic balance. After ten days of treatment all patients improved. Abdominal distension disappeared, there was no edema and ascites and feces were of normal appearance. The complete blood count (CBC) was within normal limits (leukocytes 8.9 x 109/L, 9.1 x 109/L and respectively 8.0 × 109/L), inflammatory markers were absent, C-reactive protein was less than 1 mg/dL. The erythrocyte sedimentation rate was 12 mm/h and serum albumin was normal. The hospitalization periods were between 14 to 21 days, and all three patients were discharged having good general condition. They were followed up for 6 months after hospital discharge, and no relapses were recorded. Discussions In the last four years, 220 cases with Clostridium difficile diarrhea were reported, but only three cases of toxic megacolon were registered (1.36% incidence).

The hospitalization periods were between 14 to 21 days, and all three patients were discharged having good general condition. They were followed up for 6 months after hospital discharge, and no relapses were recorded. Discussions In the last four years, 220 cases with Clostridium difficile diarrhea were reported, but only three cases of toxic megacolon were registered (1.36% incidence). Numerous studies have shown that there are certain risk factors favoring the evolution from mild diarrhea to toxic megacolon in patients with CDI including older age and underlying co-morbidities, significant leukocytosis, hypoalbuminemia and acute renal failure [10, 11, 12]. In our case, two of the three patients were older than 65 years, and all three had all the other risk factors listed above. Hypoalbuminemia (serum albumin levels < 2.0 g/dL) is caused by the inflammation of the bowel wall that allows leakage of albumin into the lumen, associated with an inadequate compensatory liver synthesis. Ascites and peripheral edema may be observed in these situations [11, 12]. Obesity was also considered as a risk factor in CDI. In a cohort of 196 patients with CDI hospitalized in a gastroenterology department, Mulki (2016) identify a statistically significant association between BMI and severe infection with Clostridium difficile. The authors’ conclusion was that BMI> 35kg/m2 was more frequently associated with severe CDI, compared to a BMI 20-35kg/m2 [13].

196 patients with CDI hospitalized in a gastroenterology department, Mulki (2016) identify a statistically significant association between BMI and severe infection with Clostridium difficile. The authors’ conclusion was that BMI> 35kg/m2 was more frequently associated with severe CDI, compared to a BMI 20-35kg/m2 [13]. Regarding the relationship between chronic viral hepatitis B or C and CDI, it is reported that there is an alteration of the gut microbiota in liver cirrhosis and thus a higher risk of CDI. But, it has not been demonstrated that chronic viral hepatitis B or C, regardless of the stage of fibrosis, is a risk factor for a severe form of CDI [14, 15]. The same thing can be said about CDI association with autoimmune diseases. It is known that there is a causal relationship between the presence of rheumatoid arthritis and CDI, rather between methotrexate therapy and CDI.Naimushin (2011) presents a case of CDI in a patient with rheumatoid arthritis under methotrexate therapy, in whom Clostridium difficile-associated colitis had developed without prior antibiotic treatment [16, 17]. Moreover, a change in gut microbiota in patients with rheumatoid arthritis could favor the occurrence of CDI [18]. In all three patients, the epidemic strain ribotype 027 was detected which is known to be associated with an increased severity of disease and high mortality [12, 19, 20]. However, the detection of toxin A and/or B in feces by EIA has not been established as a predictor of CDI severity [21].

Regarding the relationship between chronic viral hepatitis B or C and CDI, it is reported that there is an alteration of the gut microbiota in liver cirrhosis and thus a higher risk of CDI. But, it has not been demonstrated that chronic viral hepatitis B or C, regardless of the stage of fibrosis, is a risk factor for a severe form of CDI [14, 15]. The same thing can be said about CDI association with autoimmune diseases. It is known that there is a causal relationship between the presence of rheumatoid arthritis and CDI, rather between methotrexate therapy and CDI.Naimushin (2011) presents a case of CDI in a patient with rheumatoid arthritis under methotrexate therapy, in whom Clostridium difficile-associated colitis had developed without prior antibiotic treatment [16, 17]. Moreover, a change in gut microbiota in patients with rheumatoid arthritis could favor the occurrence of CDI [18]. In all three patients, the epidemic strain ribotype 027 was detected which is known to be associated with an increased severity of disease and high mortality [12, 19, 20]. However, the detection of toxin A and/or B in feces by EIA has not been established as a predictor of CDI severity [21]. Malignancies and chemotherapy are frequently associated with severe forms of CDI. Duberkke (2007) found that 57% patients who had various forms of cancer and chemotherapy developed severe CDI [22, 23].

In all three patients, the epidemic strain ribotype 027 was detected which is known to be associated with an increased severity of disease and high mortality [12, 19, 20]. However, the detection of toxin A and/or B in feces by EIA has not been established as a predictor of CDI severity [21]. Malignancies and chemotherapy are frequently associated with severe forms of CDI. Duberkke (2007) found that 57% patients who had various forms of cancer and chemotherapy developed severe CDI [22, 23]. Regarding therapy for patients with severe CDI who are unresponsive to metronidazole and vancomycin, several studies have reported good results after intracolonic administration of vancomycin. Akamine (2016), in a study of 696 patients with severe CDI, demonstrated that the intracolonic administration of vancomycin therapy was beneficial in unresponsive CDI patients [24]. In our patients, especially in patient number three, intracolonic vancomycin treatment improved the overall condition and helped in the remission of toxic megacolon. Tigecycline, a new glycylcycline, has been shown to have favorable activity against Clostridium difficile and is now recommended for the treatment of CDI, including severe cases refractory to other treatments, in combination with metronidazole and vancomycin [25, 26]. In our study, only two of the three patients progressed satisfactorily after administration of tigecycline. Both Larson KC (2011) and Britt (2014) reported an 85.7% clinical cure after therapy with metronidazole, oral vancomycin and intravenous tigecycline [27].

n combination with metronidazole and vancomycin [25, 26]. In our study, only two of the three patients progressed satisfactorily after administration of tigecycline. Both Larson KC (2011) and Britt (2014) reported an 85.7% clinical cure after therapy with metronidazole, oral vancomycin and intravenous tigecycline [27]. Conclusions Toxic megacolon occurred as a severe complication of Clostridium difficile infection in 1.36% of patients in the Clinical Infectious Diseases Hospital, Constanta. The risk factors for severe CDI evolution were: older age, obesity, significant leukocytosis, renal failure, marked hypoalbuminemia, malignancies, chemotherapy and ribotype 027. Tigecycline was successful for the treatment of severe CDI, together with intravenous metronidazole and oral vancomycin. The beneficial effect of intracolonic administration of vancomycin as treatment in unresponsive CDI patients was noted in the three presented cases, resulting in a better outcome, and without the need of surgical procedures. Acknowledgement This work has been supported by the grant EASME/ EMFF/2014/ 1.2.1.5/2/SI2. 707672 MSP LOT 1 BLACK SEA (MARSPLAN-BS), developed by Ovidius University of Constanţa as partner, and financed by the European Commission. Author Disclosure Statement: The authors report no conflicts of interest.

Introduction Due to an aging population, patients presenting for both elective and emergency surgery have more complex co-morbidities. Of these, heart disease represents the leading cause of death worldwide [1]. Nowadays, increasingly more elderly patients are treated with at least one antiplatelet drug concomitant with anticoagulants due to the high incidence of atrial fibrillation [2 and severe heart failure. These patients often miss their regular follow-up visits and so are at greater risk from oral anticoagulants misadministration and overdose compared to those that have regular follow-ups either with their general practitioner or cardiologist. It is not uncommon for such patients to present at a hospital with cerebral or gastrointestinal bleeding [3]. Reports on how to manage such patients have been extensively published recently [4, 5]. When facing such a scenario, the anaesthesiologist must consider an individualized approach to preserve haemostatic balance without inducing pathological thrombosis or bleeding.

spital with cerebral or gastrointestinal bleeding [3]. Reports on how to manage such patients have been extensively published recently [4, 5]. When facing such a scenario, the anaesthesiologist must consider an individualized approach to preserve haemostatic balance without inducing pathological thrombosis or bleeding. Case presentation The case of a 72-year-old male, weight 66 kg, height 185 cm, who presented to the emergency department with abdominal pain and constipation, is described. He complained of sharp pain, like ”being stabbed”, and that the symptoms had started four hours earlier. Physical examination showed a distended abdomen, tender, painful on palpation, especially in the mesogastric and hypogastric region, with a positive Blumberg sign, irregular tachycardic rhythm (115 beats/min), without increased blood pressure (138/65 mmHg) and tachypnea (30 breaths/min). The patient was mildly agitated, with a shallow breathing pattern, pale, sweating and with cold extremities. His medical history showed he had permanent atrial fibrillation and had suffered an acute myocardial infarction three months previously. This was treated percutaneously with two drug-eluting stents on the anterior descending coronary artery. After revascularization, the left anterior descending coronary artery had a TIMI II flow. The right coronary artery had an 80% occlusion and was left untreated. Since then the patient was treated with acenocumarol and dual antiplatelet therapy (aspirin 100 mg/day and clopidogrel 75 mg/day).

descending coronary artery. After revascularization, the left anterior descending coronary artery had a TIMI II flow. The right coronary artery had an 80% occlusion and was left untreated. Since then the patient was treated with acenocumarol and dual antiplatelet therapy (aspirin 100 mg/day and clopidogrel 75 mg/day). An emergency abdominal computer tomography was performed for the preoperative differential diagnosis of acute abdominal pain and revealed thickening of the intestinal mucosa, volvulus of the small intestine and haemoperitoneum. Laboratory tests showed good liver and kidney function, leukocytosis, normal platelet count but non-coagulable blood tests (Table 1). Also a drop in haematocrit from 45%, to 30% and in haemoglobin levels from 14.5 g/dL to 9.8 g/dL were noted compared with data taken at the time of the percutaneous coronary intervention. The patient confirmed that he was taking a tablet of acenocumarol daily without checking his INR and that he took both aspirin and clopidogrel on the day of hospital admission. A thromboelastogram (TEG 5000®, Haemoscope, Niles, IL) was performed. (Figure 1A). The results were interpreted as either severe clotting impairment due to anticoagulant overdose or hyperfibrinolysis. Due to the high risk of antifibrinolytic therapy in a patient with a recent myocardial infarction and severe coronary artery disease it was decided to administer thirty units/kg of prothrombin complex concentrate (Pronativ®, Octapharma, Manchester, UK). The TEG and standard coagulation tests were repeated (Figure 1B; Table 1) and showed near normal clotting activity with no signs of hyperfibrinolysis. Because of the risk of in-stent thrombosis and thromboembolic events the decision was taken to stop further administer of any pro-coagulant medication. Since the patient took both antiplatelet drugs that day an aggregometry (VerifyNow®, Accumetrics, San Diego, CA, USA) was performed. The results showed a 20% inhibition for clopidogrel compatible with the profile of a partial responder.

the decision was taken to stop further administer of any pro-coagulant medication. Since the patient took both antiplatelet drugs that day an aggregometry (VerifyNow®, Accumetrics, San Diego, CA, USA) was performed. The results showed a 20% inhibition for clopidogrel compatible with the profile of a partial responder. Fig. 1 Thromboelastogram at presentation (A) and after administration of 2000 U prothrombin complex (B).A: severe clotting impairment due to anticoagulation overdose (flat line); B: near normal clotting activity (partial reversal of anticoagulation) Table 1 Paraclinical results noted at presentation, after administration of prothrombin complex and 4 hours after surgery At presentation After PCC After surgery (4 hours) ALT (U/L) 21 NA 21 AST (U/L) 27 NA 27 Total bilirubin (mg/dL) 0.5 NA 0.5 Creatinine (mg/dL) 0.91 NA 43 Blood urea nitrogen (mg/dL) 40 NA 1.01 Troponin I (ng/mL) 0.002 NA NA NTproBNP (pg/mL) 2094 NA NA WBC (*103/μL) 12.56 15.84 16.78 Haemoglobin (g/dL) 9.8 8.7 8.2 Haematocrit (%) 30.7 27.1 26.0 Platelet count (*103/μL) 317 308 261 aPTT (sec) NC 56 41.4 PT (sec) NC 418 24.1 INR NC 2.54 2.21 Fibrinogen (mg/dL) 486 413 378 PCC – Prothrombin Complex Concentrate, ALT - Alanine Aminotransferase, AST - Aspartate Aminotransferase, WBC – White Blood Cells, aPTT – activated Partial Thromboplastin Time, PT – Prothrombin Time, INR – International Normalized Ratio, NA – Not Available, NC – Not Coagulable.

C 2.54 2.21 Fibrinogen (mg/dL) 486 413 378 PCC – Prothrombin Complex Concentrate, ALT - Alanine Aminotransferase, AST - Aspartate Aminotransferase, WBC – White Blood Cells, aPTT – activated Partial Thromboplastin Time, PT – Prothrombin Time, INR – International Normalized Ratio, NA – Not Available, NC – Not Coagulable. Echocardiography showed interventricular septum, anterior and lateral wall akinesis with an ejection fraction of 30%, which was unchanged compared to previous echocardiography that had been performed immediately after coronary re-vascularisation and a distended left atrium and grade III mitral regurgitation. Due to the severity of ischemic heart disease and the need for emergency surgery, the patient was classified as ASA IV E (American Society of Anaesthesiology Physical Status Classification). The patient was transferred to the surgical ward and emergency surgery was performed immediately.

grade III mitral regurgitation. Due to the severity of ischemic heart disease and the need for emergency surgery, the patient was classified as ASA IV E (American Society of Anaesthesiology Physical Status Classification). The patient was transferred to the surgical ward and emergency surgery was performed immediately. A rapid sequence induction was performed. Intraoperative monitoring consisted of standard 2-lead electrocardiogram, pulse oximetry, temperature, bispectral index, train of four and invasive hemodynamic monitoring of central venous pressure, blood pressure and cardiac output by transpulmonary thermodilution (arterial catheter on left femoural artery)– PiCCO Plus System®, Pulsion Medical Systems, Feldkirchen, Germany. Maintenance of anesthesia was achieved with Sevoflurane titered to a minimum alveolar concentration between 1 and 1.2. The lungs were mechanically ventilated in pressure control to target a tidal volume of 6 mL/kg. An end-expiratory positive pressure of 5 mmHg was applied. The fresh gas flow consisted of 50% oxygen in air at a rate of two L/min. Bolus doses of fentanyl were administered during surgery at the anaesthesiologist’s discretion and atracurium was used for neuro-muscular blockade. A cell salvage system and a rapid infusion system were prepared in case of massive blood loss.

ed. The fresh gas flow consisted of 50% oxygen in air at a rate of two L/min. Bolus doses of fentanyl were administered during surgery at the anaesthesiologist’s discretion and atracurium was used for neuro-muscular blockade. A cell salvage system and a rapid infusion system were prepared in case of massive blood loss. Opening of the abdomen confirmed the diagnosis of haemoperitoneum with the presence of approximately 1000 ml of fresh blood, and volvulus of the ileum. A venous mesenteric infarction associated with intestinal intramural hematomas as well as haematomas at the base of the mesentery were present. (Figure 2) Fig. 2 Intraoperative findings. Venous infarction of the small intestine (A), hematomas at the base of the mesentery (B, arrows) and intramural and submucosal hematomas (C)

Opening of the abdomen confirmed the diagnosis of haemoperitoneum with the presence of approximately 1000 ml of fresh blood, and volvulus of the ileum. A venous mesenteric infarction associated with intestinal intramural hematomas as well as haematomas at the base of the mesentery were present. (Figure 2) Fig. 2 Intraoperative findings. Venous infarction of the small intestine (A), hematomas at the base of the mesentery (B, arrows) and intramural and submucosal hematomas (C) During surgery normovolemia was maintained using 2500 ml of Ringer lactate and 1000 ml of Gelofusine®, in accordance with local protocol and PiCCO Plus data. There was no need for either vasopressor or inotropic support. No blood products were transfused during surgery. An enterectomy with terminal ileostomy was performed. On completion of surgery the trachea was safely extubated and the patient was transferred awake to the Postanaesthesia Care Unit. Postoperative anticoagulation was started six hours after surgery with unfractionated heparin to maintain an activated partial thromboplastin time between 50 and 70 sec and converted 24 hours later to 6000 IU of enoxaparin twice daily. Aspirin was re-started on postoperative Day One and Clopidogrel on postoperative Day Two. Routine echocardiography was performed on postoperative Day One and showed no changes compared with post re-vascularisation and preoperative assessments. Because the patient was only partially antiaggregated on clopidogrel a cardiologist was consulted who recommended maintenance of the previous dual-antiplatelet therapy and re-evaluation of therapy one week after surgery. Postoperative course was uneventful and the patient was transferred to the surgical ward forty-eight hours after surgery.

s only partially antiaggregated on clopidogrel a cardiologist was consulted who recommended maintenance of the previous dual-antiplatelet therapy and re-evaluation of therapy one week after surgery. Postoperative course was uneventful and the patient was transferred to the surgical ward forty-eight hours after surgery. Discussion The above case represents one of the most difficult clinical scenarios that an anaesthesiologist may encounter when managing haemostasis. Two major aspects must be considered. First, the risk of intraoperative massive blood loss in a patient that is actively bleeding and, second, the risk of perioperative myocardial infarction, stroke and in-stent thrombosis in a patient with a recent myocardial infarction and severe cardiovascular disease. On the other hand, the patient was intraoperatively diagnosed with mesenteric infarction that also required adequate anticoagulation. Hence, the particularity of this case relies on the association between venous mesenteric infarction, in a patient with coagulation deficit and bleeding status, and intestinal and mesenteric haematomas that needed emergency surgical intervention and intensive care management, to prevent both thrombotic and haemorrhagic complications.

icularity of this case relies on the association between venous mesenteric infarction, in a patient with coagulation deficit and bleeding status, and intestinal and mesenteric haematomas that needed emergency surgical intervention and intensive care management, to prevent both thrombotic and haemorrhagic complications. Standard coagulation tests can be used for both dose adjustment and treatment of vitamin K antagonist overdosing, but such tests are not precise enough for patients taking multiple anticoagulants and antiplatelet drugs [6]. High-risk patients, like the one presented, require fine tuning in order to optimize the haemostatic balance and prevent both bleeding and pathological thrombosis. Viscoelastic coagulation testing represents an alternative to standard coagulation tests and offers a better and faster understanding of the haemostatic status. [7]. Moreover, thromboelastography has been used for the assessment of platelet reactivity in patients taking clopidogrel [8]. We used a combined approach. First, vitamin K antagonist overdose was diagnosed by standard coagulation tests. Both thromboelastography and point-of-care platelet function testing (VerifyNow®) were used synchronously in order to assess the magnitude of oral anticoagulant overdose and antiaggregant activity. The 20% platelet inhibition by clopidogrel demonstrated that the major coagulation abnormality was due to acenocumarol overdose.

hromboelastography and point-of-care platelet function testing (VerifyNow®) were used synchronously in order to assess the magnitude of oral anticoagulant overdose and antiaggregant activity. The 20% platelet inhibition by clopidogrel demonstrated that the major coagulation abnormality was due to acenocumarol overdose. Fresh frozen plasma has been used for decades for oral anticoagulants overdose. This could not be applied in our case due to the high volume of fresh frozen plasma required. The administration of large volumes of plasma could have led to fluid overload and acute heart failure. Instead a prothrombin complex concentrate in accordance to recently published work was used [9]. The effects were assessed using thromboelastography. We aimed at achieving a partial reversal of anticoagulation (borderline normal) in order to prevent thrombotic complications. This approach was proven to be appropriate, both massive bleeding and thrombosis were avoided. Recent guidelines suggest the use of new oral anticoagulants for patients at high risk of thrombosis and thromboembolism [10].Monitoring of such anticoagulants is not necessary and overdose can be effectively treated by using reversal agents. Current research offers promising results and probably, in the near future, anaesthesiologists will encounter fewer patients, if any, using vitamin K antagonists.

k of thrombosis and thromboembolism [10].Monitoring of such anticoagulants is not necessary and overdose can be effectively treated by using reversal agents. Current research offers promising results and probably, in the near future, anaesthesiologists will encounter fewer patients, if any, using vitamin K antagonists. Patients with a coronary flow, only partially achieved after percutaneous coronary intervention, are at a high risk of major adverse cardiac events in the perioperative period [11]. In the case presented, the patient had low ejection heart failure, cardiac arrhythmia and TIMI II flow after re-vascularisation of a recent myocardial infarction. This, in conjunction with a severe bleeding (1000 ml haemoperitoneum), posed the possibility of a high risk of perioperative mortality. In conclusion, emergency surgery in patients taking oral anticoagulants and dual antiplatelet therapy remains one of the greatest challenges an anaesthesiologist can encounter. Management of such patients requires precise diagnostics and fine tuning of drug therapy, including the use of point-of-care tests and prothrombin complex concentrates as treatment options. Perioperative intensive care should be aimed at both preventing further blood loss and pathological thrombosis. Author Disclosure Statement: The authors report no conflicts of interest.

Introduction Toxic epidermal necrolysis (TEN) is still a controversial diagnosis in terms of classification and pathogenic mechanism [1, 2]. Major Erythema Multiforme (MEM), Stevens-Johnson Syndrome (SJS), or Toxic epidermal necrolysis (TEN) are terms that are used as variants of the same disease, although the aetiology and pathogenesis are different. [2] Clinically there are criteria that differentiate the three conditions, the main criterion being the affected body surface area (BSA), linked with the number of involved mucous membranes. According to this classification TEN is the most severe of the three variants, affecting over 10-30% of the BSA. [2] TEN is one of the major dermatological emergencies, needing rapid diagnosis and treatment in an intensive care unit (ICU) or major burns unit. The incidence of TEN worldwide is 1-2 cases per million per year. [2] TEN can occur at any age and is more common in women and the elderly. [1, 2] The drug known to cause adverse cutaneous reactions such as TEN are allopurinol, carbamazepine, lamotrigine, nevirapine, oxicam, NSAIDs, phenobarbital, phenitoin, sulfamethoxazole and other sulfur antibiotics, and sulfasalazine [1, 2, 3, 4].

The incidence of TEN worldwide is 1-2 cases per million per year. [2] TEN can occur at any age and is more common in women and the elderly. [1, 2] The drug known to cause adverse cutaneous reactions such as TEN are allopurinol, carbamazepine, lamotrigine, nevirapine, oxicam, NSAIDs, phenobarbital, phenitoin, sulfamethoxazole and other sulfur antibiotics, and sulfasalazine [1, 2, 3, 4]. It is a life-threatening condition, which commonly begins with prodromal flu-like symptoms, followed by the appearance of a muco-cutaneous morbilliform rash, initially located at acral areas, but spreading quickly over the body. [2, 3]. Flaccid blisters may occur as the condition progresses, bursting quickly, causing large areas of denudation. The skin is extremely fragile, with denudation or blister formation at pressure sites (Nikolsky sign). Associated with these initial events are the subsequent appearance of muco-cutaneous, ophthalmic, renal, gastrointestinal, lung involvement, major hydro-electrolytic imbalance and sepsis due to supra-infection of the muco-cutaneous lesions. These predispose to death in around 30% of patients. [1, 3] Survivors are prone to a risk of long term sequelae. The activation of cytotoxic T lymphocytes (CTLs) is the main pathogenic element of the keratinocyte apoptosis and necrosis. [1, 3, 4]

It is a life-threatening condition, which commonly begins with prodromal flu-like symptoms, followed by the appearance of a muco-cutaneous morbilliform rash, initially located at acral areas, but spreading quickly over the body. [2, 3]. Flaccid blisters may occur as the condition progresses, bursting quickly, causing large areas of denudation. The skin is extremely fragile, with denudation or blister formation at pressure sites (Nikolsky sign). Associated with these initial events are the subsequent appearance of muco-cutaneous, ophthalmic, renal, gastrointestinal, lung involvement, major hydro-electrolytic imbalance and sepsis due to supra-infection of the muco-cutaneous lesions. These predispose to death in around 30% of patients. [1, 3] Survivors are prone to a risk of long term sequelae. The activation of cytotoxic T lymphocytes (CTLs) is the main pathogenic element of the keratinocyte apoptosis and necrosis. [1, 3, 4] Case Presentation The present case is of a 66 year-old male patient from a rural area, transferred to the Dermatology Clinic, Emergency Hospital “St. Spiridon” Iassy, Romania, in April 2016 from the Dialysis Center, Hospital Parhon, Iassy, Romania, due to the appearance of a rash, represented by erythemato-violaceous macules and papules, some of them purpuric, isolated or grouped in plaques, located at acral areas and which were intensely itchy. These had occurred within the previous forty-eight hours. Associated with these were postblister erosions on the oral and nasal mucosa and genital areas with deep fissures, covered by haematic crusts on the lips. The patient complained of accompanying painful burning sensations. Prodromal flu-like symptoms of fever, fatigue, malaise, preceded the onset of skin lesions.

hours. Associated with these were postblister erosions on the oral and nasal mucosa and genital areas with deep fissures, covered by haematic crusts on the lips. The patient complained of accompanying painful burning sensations. Prodromal flu-like symptoms of fever, fatigue, malaise, preceded the onset of skin lesions. The patient’s medical history included a diagnoses of complicated diabetes mellitus type II, treated with insulin, chronic kidney disease Stage 5, chronic haemodialysis, obstructive nephropathy, and right nephrostomy, secondary renal hypertension which had existed for about 30 years, mixed decompensate toxic cirrhosis due to alcohool intake and hepatic encephalopathy, first reported in 2014. The patient was taking insulin 10 UI b.i.d., amlodipine 5 mg q.d. and carbamazepine 100 mg q.d. Event History The onset of illness was recorded 48 hours before admission to the Dermatology Clinic, when the patient was hospitalized for haemodialysis in the Nephrology Clinic. The clinical examination revealed a slightly itchy erythemato-papulous rash, on the face, hands, feet accompanied by prodromal flu-like symptoms of fever, fatigue, malaise. The patient’s condition was aggravated by the extension of the rash and the appearance of purpuric elements with a tendency to spread. The, appearance of flaccid blisters which quickly erupted, resulted in large areas of denudation.

ace, hands, feet accompanied by prodromal flu-like symptoms of fever, fatigue, malaise. The patient’s condition was aggravated by the extension of the rash and the appearance of purpuric elements with a tendency to spread. The, appearance of flaccid blisters which quickly erupted, resulted in large areas of denudation. Given the appearance and progression of the skin lesions a preliminary diagnosis of drug-induced allergic vasculitis was made and the patient was transferred to the Department of Dermatology, to confirm the diagnosis and to establish the therapeutic management. Clinical examination Clinical examination at admission revealed malaise, itchy rash with erythemato-violaceous, some purpuric macules and papules, isolated or conflated in patches (Fig. 1,2), disseminated on the trunk, upper and lower limbs and cephalic extremities. Flaccid blisters and erosions, resulting in large areas of denudation, covered over 10% of the skin of the trunk and legs. (Fig. 3) On the oral and nasal mucosa erosions there were deep fissures, some of them covered with haematic crusts. (Fig. 4) On genital mucosa erosions were covered with yellow-white exudates and balano-preputial folding. Fig. 1 Erythematous, purpuric macules and papules on the lower limb Fig. 2 Erythematous, purpuric macules and papules on the trunk Fig. 3 Extensive denudation on the trunk Fig. 4 Erosions on the oral mucosa, erythemato-crustous plaques on the face

Clinical examination Clinical examination at admission revealed malaise, itchy rash with erythemato-violaceous, some purpuric macules and papules, isolated or conflated in patches (Fig. 1,2), disseminated on the trunk, upper and lower limbs and cephalic extremities. Flaccid blisters and erosions, resulting in large areas of denudation, covered over 10% of the skin of the trunk and legs. (Fig. 3) On the oral and nasal mucosa erosions there were deep fissures, some of them covered with haematic crusts. (Fig. 4) On genital mucosa erosions were covered with yellow-white exudates and balano-preputial folding. Fig. 1 Erythematous, purpuric macules and papules on the lower limb Fig. 2 Erythematous, purpuric macules and papules on the trunk Fig. 3 Extensive denudation on the trunk Fig. 4 Erosions on the oral mucosa, erythemato-crustous plaques on the face The general examination identified high blood pressure (160/120 mmHg), an increased abdominal volume due to ascites fluid, collateral venous circulation on the abdominal wall, without neurological manifestations.

Fig. 3 Extensive denudation on the trunk Fig. 4 Erosions on the oral mucosa, erythemato-crustous plaques on the face The general examination identified high blood pressure (160/120 mmHg), an increased abdominal volume due to ascites fluid, collateral venous circulation on the abdominal wall, without neurological manifestations. Laboratory investigations At admission to the Dermatology Clinic laboratory investigations revealed marked anemia (RBC 2.22 x 106 / μL, Hb 7.6 g / dl, Ht 23.1%), leukocytosis (12.96 x 103 / μL) with neutrophilia (10.08 x 103 / μL), thrombocytopenia (67 x 103 / μL), inflammatory syndrome (ESR 28 mm / 1hr, fibrinogen 593 IU / ml, CRP 3.17 mg / dL), elevated ASLO titer (861 U / ml), elevated IgE (593UI / ml), nitrogen retention syndrome (urea 111 mg / dL, creatinine 4.7 mg / dL, clearance of creatinine 9,7-12 ml/min/1.73 sm, uric acid 9.1 mg / dL) and elevated blood sugar levels (129 mg /ml). Other changes were highlighted hydro-electrolyte imbalance (hypokalemia, low RA), abnormal liver function (GGT 334 U / L), reversing the albumin / globulin rate, and normal values for serum total proteins, INR. A Gram stain and culture from genital secretion and skin lesions, a nasal swab revealed the presence of a bacterial supra-infection with Klebsiella pneumoniae, multi-resistant to antibiotics, but sensitive to colistin, amikacin, ertapenem, imipenem, meropenem. The ascites fluid examination revealed numerous red blood and white blood cells, but the absence of pathogens.

skin lesions, a nasal swab revealed the presence of a bacterial supra-infection with Klebsiella pneumoniae, multi-resistant to antibiotics, but sensitive to colistin, amikacin, ertapenem, imipenem, meropenem. The ascites fluid examination revealed numerous red blood and white blood cells, but the absence of pathogens. Based on the clinical examination and laboratory investigations a diagnosis of toxic epidermal necrolysis was established in a patient with severe kidney disease, vascular decompensated cirrhosis, complicated diabetes mellitus type II. Considering the general pathology and the patient’s systemic medication, a drug reaction syndrome due to carbamazepine was suspected. Given the severity of the muco-cutaneous manifestations the immediate initiation of pulse-therapy with corticosteroid together with topical corticosteroids, topical antiseptics and antibiotics, hydro-electrolyte rebalancing in addition to basic medication for associated pathology was undertaken. Despite the slightly favorable progress of the skin lesions and the lack of appearance of new elements and a tendency of existing lesions to heal, there was a worsening condition of associated pathologies with high blood sugar values (499 mg / dl) due to systemic corticosteroid administration, worsening of nitrogenous retention (urea 179 mg / dl, creatinine 6.65 g / dL), low alkaline reserve (17.2 mmol / l) with hyponatremia, hypokalemia, associating an episode of upper gastrointestinal hemorrhage, without neurological changes. This resulted in the patient being transferred to an ICU for appropriate treatment.

rsening of nitrogenous retention (urea 179 mg / dl, creatinine 6.65 g / dL), low alkaline reserve (17.2 mmol / l) with hyponatremia, hypokalemia, associating an episode of upper gastrointestinal hemorrhage, without neurological changes. This resulted in the patient being transferred to an ICU for appropriate treatment. Treatment in the ICU resulted in the satisfactory resolution of the muco-cutaneous aspects, allowing reduction in corticosteroids after three days with complete discontinuation of systemic corticosteroid after ten days, resulting blood glucose levels returning to normal. Resumption of dialysis and electrolyte rebalancing led to normalization of renal function and acid-basic balance. The patient was discharged from the hospital 15 days after admission to the Dermatology Clinic, with the advice to stop carbamazepine and medically related drugs. Discussions Allergic drug induced reactions are one of the most common presentation in an emergency department, but not all of them are life threatening conditions. SJS and TEN are life threatening, usually drug induced severe muco-cutaneous reactions, [1] characterized by blistering and epithelial sloughing. SJS is the less severe and extensive and TEN the most severe and extensive form, and may present with a variety of systemic complications including multi-organ failure. [2].

SJS and TEN are life threatening, usually drug induced severe muco-cutaneous reactions, [1] characterized by blistering and epithelial sloughing. SJS is the less severe and extensive and TEN the most severe and extensive form, and may present with a variety of systemic complications including multi-organ failure. [2]. The key element of the pathogenic mechanism in TEN is the widespread keratinocyte apoptosis. [1] The pathophysiology of TEN is incompletely understood. Current theories connect apoptosis with a Fas-mediated mechanism, a granulysin-mediated apoptosis or the implication of reactive oxygen species. [4, 5] In the immunopathology of TEN, CD8+ T cells act as the major mediator of the keratinocyte death, these cells being found in the inflammatory infiltrate from the superficial dermis and in the liquid of the blisters. [1] Other cells of the immune system (CD4+ cells, CD3-CD56+ NK cells, mast cells, dendritic cells, monocytes, granulocytes and NK/T cells) also involved in the pathogenic mechanism of TEN. [1, 3, 4] Caproni et al. (2006), reported on a significant presence of CD40 ligand (CD40L) staining cells in the dermis and the epidermis. [6] CD40L is an important co-stimulator of dendritic cells, B cells, macrophages, epithelial cells, and stimulates the release of proinflammatory tumor necrosis factor-alfa (TNF-α), nitric oxid (NO), interleukin 8 (IL-8), and adhesion molecules. High levels of soluble CD40L (sCD40L) were found in patients’ sera, suggesting it as a possible marker for a positive diagnosis in the future. [2, 8]

hages, epithelial cells, and stimulates the release of proinflammatory tumor necrosis factor-alfa (TNF-α), nitric oxid (NO), interleukin 8 (IL-8), and adhesion molecules. High levels of soluble CD40L (sCD40L) were found in patients’ sera, suggesting it as a possible marker for a positive diagnosis in the future. [2, 8] Perforin/granzyme B and granulysin. Granulysin is considered to be linked with the keratinocyte apoptosis in TEN, are implicated in the mechanism of apoptosis in TEN. [1] Chung et al. (2008), found a 10-to 20-fold increased level of granulysin in the blister fluid of patients with TEN. [7] Studies conducted by Abe et al. (2009), found similar changes, suggesting that granulisyn is an inducer of apoptosis in TEN and could also be used as an early diagnostic marker. [8, 9]

sis in TEN. [1] Chung et al. (2008), found a 10-to 20-fold increased level of granulysin in the blister fluid of patients with TEN. [7] Studies conducted by Abe et al. (2009), found similar changes, suggesting that granulisyn is an inducer of apoptosis in TEN and could also be used as an early diagnostic marker. [8, 9] As there are no markers currently available for the early diagnosis of TEN, the clinical examination of the patient is the most important criteria for a positive diagnosis. Nearly all patients with TEN present major mucosal involvement: painful erosions, ulcerations, inflammation – oral (70-100%), genital (40-63%), ocular (50-78%) involvement [1, 2, 3, 4]. Systemic involvement is also described with acute renal failure (5%), adult respiratory distress syndrome, bronchiolitis obliterans (25%), anemia, leukopenia or hepatitis, worsening the prognosis of the disease [1, 2, 3, 4]. In our patient associated kidney failure, cirrhosis and diabetis mellitus were agravated by the systemic treatment with corticosteroids and by the fluid loss. Despite all of these systemic complications, infection is the most common cause of death in patients with TEN, and because of this, topical antibiotherapy were administered to the patient in this report. Bastuji-Garin et al. (2000), developed the SCORTEN score, a recognized and validate measure of disease severity, with the following seven clinical criteria (Table 1).[10]. Table 1 SCORTEN score: clinical criteria

As there are no markers currently available for the early diagnosis of TEN, the clinical examination of the patient is the most important criteria for a positive diagnosis. Nearly all patients with TEN present major mucosal involvement: painful erosions, ulcerations, inflammation – oral (70-100%), genital (40-63%), ocular (50-78%) involvement [1, 2, 3, 4]. Systemic involvement is also described with acute renal failure (5%), adult respiratory distress syndrome, bronchiolitis obliterans (25%), anemia, leukopenia or hepatitis, worsening the prognosis of the disease [1, 2, 3, 4]. In our patient associated kidney failure, cirrhosis and diabetis mellitus were agravated by the systemic treatment with corticosteroids and by the fluid loss. Despite all of these systemic complications, infection is the most common cause of death in patients with TEN, and because of this, topical antibiotherapy were administered to the patient in this report. Bastuji-Garin et al. (2000), developed the SCORTEN score, a recognized and validate measure of disease severity, with the following seven clinical criteria (Table 1).[10]. Table 1 SCORTEN score: clinical criteria Risk factor 0 1 Age < 40 years > 40 years Associated malignancy no yes Heart rate (beats/min) <120 >120 Serum BUN (mg/dL) <28 >28 Detached or compromised body surface <10% >10% Serum bicarbonate (mEq/L) >20 <20 Serum glucose (mg/dL) <252 >252 In our patient the SCORTEN was 4, indicating a high risk of mortality (58,3%) (Table 2) [11]. Table 2 The mortality rate corelated with SCORTEN score

Risk factor 0 1 Age < 40 years > 40 years Associated malignancy no yes Heart rate (beats/min) <120 >120 Serum BUN (mg/dL) <28 >28 Detached or compromised body surface <10% >10% Serum bicarbonate (mEq/L) >20 <20 Serum glucose (mg/dL) <252 >252 In our patient the SCORTEN was 4, indicating a high risk of mortality (58,3%) (Table 2) [11]. Table 2 The mortality rate corelated with SCORTEN score No of risk factors Mortality rate 0-1 3.2% 2 12.1% 3 35.3% 4 58.3% General management of TEN includes the early withdrawal of any potentially offending drug and the surveillance of the patient in an intensive care unit. Because of the immunological basis of TEN three important drugs are used in the systemic treatment of the acute phase, systemic corticosteroids, intravenous immunoglobulin (IVIg) and cyclosporine. [2, 3, 4, 12] Studies regarding the use of IVIg in the terapy of TEN show discordant results. The first meta-analysis conducted by Huang et al. (2012), on the efficacy of IV Ig therapy did not provide sufficient data regarding the proper dose and the benefit of IV Ig in TEN. [2, 3, 4, 13] Corticosteroids have been used in the treatment of patients with TEN for a long time, with mixed results, and with an increased risk of associated infections, increased duration of hospital stay, and mortality. Other studies suggest that pulse therapy with corticosteroid (1,5 mg/kg intravenous methylprednisolone or 100 mg intravenous dexamethasone) for three days is better than a long period of smaller doses of non-pulsed methylprednisolone. [2, 3, 4, 14] There is no consensus on the doses or regimen of corticosteroid use in TEN.

r studies suggest that pulse therapy with corticosteroid (1,5 mg/kg intravenous methylprednisolone or 100 mg intravenous dexamethasone) for three days is better than a long period of smaller doses of non-pulsed methylprednisolone. [2, 3, 4, 14] There is no consensus on the doses or regimen of corticosteroid use in TEN. Ciclosporine, plasmapheresis, both TNF-α inhibitors, have also been reported but there is no strong recommendation for their use. [2, 4] The presence of characteristic skin lesions made the diagnosis in the current case easier. Rapid initiation of systemic corticosteroid stopped the development of skin lesions, but upset kidney function and carbohydrate metabolism. Continued haemodialysis, electrolyte rebalancing, and decreasing corticosteroid doses led to the restoration of renal and liver function values, and blood glucose levels. Conclusion TEN is a rare but extremely severe, life threatening, drug induced muco-cutaneous disease, which needs to be recognized and immediately treated in special care units. The cessation of the causative drug is the most important step in the treatment of the disease. The patients need to be treated by a multidisciplinary team in an ICU or severe burns unit. Conflict of interest: Nothing to declare

Medical simulation-based teaching includes a variety of educational techniques used to complement actual patient experiences with true-to-life yet artificial tasks. This field is rapidly growing and is widely used in critical care graduate medical education programs, having teaching, learning and assessment roles. Its use is on the increase due to many factors including patient discontent with being “practiced on”, current considerations regarding patient safety, and the significance of early attainment of complex medical proficiencies. Simulation-based assessment (SBA) is advancing to the point where it can revolutionize the way clinical competence is assessed in residency training programs. A whole new professional vocabulary has developed in tandem with this type of teaching. We refer to “learning environments”, “regulatory expectations”, “micro and macro simulators”, “quality control”, “teaching tools” and” time courses” [1, 2]. Learning and acquiring clinical skills by simulator-based training is very much an educational tool still under scrutiny. A recent survey indicated that Canadian anaesthesiology residents reported that they were intimidated by the atmosphere of high fidelity simulator-based educational methods but valued it as a means of promoting safe practice and developing skills required in emergency situations [3].

cational tool still under scrutiny. A recent survey indicated that Canadian anaesthesiology residents reported that they were intimidated by the atmosphere of high fidelity simulator-based educational methods but valued it as a means of promoting safe practice and developing skills required in emergency situations [3]. Nevertheless, due to the practical impossibility of students to encounter and manage every important critical experience and scenario essential for the completion of a comprehensive medical training, simulator-based educational centres fill this gap. Simulator-based sessions are highly appreciated by medical students, as shown in a recent study analysing the degree of satisfaction of the students undertaking such courses in the University of Tirgu-Mures [4]. Medical conditions such as SARS (Severe Acute Respiratory Syndrome), a worrying condition associated with a high mortality, are now relatively common. High fidelity simulator-based educational programmes have been developed and have led to the implementation of an adapted cardiac arrest protocol for use in SARS. This proved to be crucial in the subsequent teaching of trainees in the use of unfamiliar protective equipment [6]. Simulator-based programs were successfully used to teach chest tube insertion. On completion of simulator-based training, those surgeons trained by this method were compared with doctors who had not be trained by this approach, and it was found that simulator-based taught surgeons exhibited more self-confidence and satisfaction than those taught in a more conventional manner [7].

tube insertion. On completion of simulator-based training, those surgeons trained by this method were compared with doctors who had not be trained by this approach, and it was found that simulator-based taught surgeons exhibited more self-confidence and satisfaction than those taught in a more conventional manner [7]. This issue of the Journal of Critical Care Medicine (JCCM) hosts an article on the perception of residents in anaesthesia and intensive care in four of the medical education centres in Romania, The Universities of Medicine in Cluj, Tirgu Mures, Iasi and Bucharest regarding simulator-based training [8]. Training in anaesthesia and intensive care comprises five years of study and concomitant practice. Submitting patients to the stress of demonstrating, learning and conducting medical and surgical procedures by junior doctors is not without an increased risk to these patients. This is why, despite the fact that simulator-based teaching centres are resource consuming, their introduction into the medical curriculum, is well worth the financial outlay. We recently carried out a 20 question survey on simulator-based teaching which was distributed to junior doctors completing their residency training. The overall attitude favoured the use of simulator-based teaching, with monthly training and assessment being most favoured. Interestingly, none of the residents participating in the survey had ever participated in a simulator-based teaching session. Thus their opinions were not being based on previous experience.

ing. The overall attitude favoured the use of simulator-based teaching, with monthly training and assessment being most favoured. Interestingly, none of the residents participating in the survey had ever participated in a simulator-based teaching session. Thus their opinions were not being based on previous experience. The thought of undertaking simulator-based procedures such as difficult airway management, cardiac life support and various anaesthesia techniques and clinical scenarios were reported to be as stressful as in real life. This makes sense since the majority of the responders were junior trainees and the contemplation of not being able to intubate and ventilate is very distressing at this stage of their training. The fact that resuscitation skills along with anaesthesia techniques scored equally as second high preferences for inclusion in a simulator-based training program, also reflects the junior state of the residents. Robotic surgery and medical simulation-based training have much in common and both technologies are experiencing rapid adoption and are viewed as modalities that allow physicians to perform increasingly complex minimally invasive procedures while enhancing patient safety. A review of the literature and industry developments concludes that medical simulation-based training can be useful tools in determining a young doctors understanding and use of best practices, management of patient complications, appropriate use of instruments and tools, and overall competence in performing procedures.

review of the literature and industry developments concludes that medical simulation-based training can be useful tools in determining a young doctors understanding and use of best practices, management of patient complications, appropriate use of instruments and tools, and overall competence in performing procedures. Future use of these systems depends on their impact on patient safety, procedure completion time and cost efficiency. Results will be timelier, and improved, the sooner simulation training can be introduced into medical education curricula. Continued studies are needed to identify and ensure the ongoing applicability of these systems for both training and certification. Moreover, if simulator-based teaching is perceived as an enjoyable experience for trainees, it will undoubtedly contribute to the eudemonia or the art of being happy when learning and practising medicine. [9]

Introduction Congenital heart defects (CHD) are among the more common categories of congenital malformations and an important cause of early childhood mortality [1, 2]. Globally each year, eight per 1000 live born infants are diagnosed with a form of CHD [3], and the incidence of critical CHD (CHD leading to death or needing major surgery during the first year of life is 3 per 1000 [4, 5, 6]. Although remarkable progress was made during the last 20 years concerning the diagnosis and treatment of CHD, there are still 25% [7] to 39% [8] infants diagnosed with this condition after leaving the maternity ward, at a mean age of 6 weeks. Prenatal diagnosis by ultrasonography can often detect major CHDs, but these defects are often missed in Romania, due to the lack of adherence of pregnant women to a program of prenatal visits to the obstetrician. Pulse oximetry is a useful, inexpensive, non-invasive method for routine monitoring of the neonate, and it can also be used for raising suspicion of CDHs. Pulse oximetry can detect hypoxemia, missed during a clinical examination before it becomes profound enough for cyanosis to be observed. Early detection of CHDs can significantly reduce the risk of sudden cardiovascular collapse [9, 10] and allows timely intervention, whether by palliation with prostaglandin E1, or by surgical repair. Moreover, monitoring of blood oxygen saturation during the first day can guide the physician towards the diagnosis of other conditions, mainly respiratory, but also infectious or metabolic.

Pulse oximetry is a useful, inexpensive, non-invasive method for routine monitoring of the neonate, and it can also be used for raising suspicion of CDHs. Pulse oximetry can detect hypoxemia, missed during a clinical examination before it becomes profound enough for cyanosis to be observed. Early detection of CHDs can significantly reduce the risk of sudden cardiovascular collapse [9, 10] and allows timely intervention, whether by palliation with prostaglandin E1, or by surgical repair. Moreover, monitoring of blood oxygen saturation during the first day can guide the physician towards the diagnosis of other conditions, mainly respiratory, but also infectious or metabolic. The American Academy of Pediatrics recommends pulse oximetry screening for CHD between 24 and 72 hours postpartum [11]. We aimed to ascertain whether an even earlier diagnosis can be made with a low risk of false-positive results. The purpose of this study was to examine the use of peripheral blood oxygen saturation monitoring in neonates during the first hour postpartum and at 24 hours of life, as a means of the early diagnosis of CHD.

We aimed to ascertain whether an even earlier diagnosis can be made with a low risk of false-positive results. The purpose of this study was to examine the use of peripheral blood oxygen saturation monitoring in neonates during the first hour postpartum and at 24 hours of life, as a means of the early diagnosis of CHD. Material and Methods A prospective study of neonates born in the “Cuza Voda” Clinical Hospital of Obstetrics and Gynecology from December 1, 2012, to December 31, 2013, was undertaken. Preductal pulse oximetry was carried out on all newborns, in the delivery room, by placing the sensor on the right hand or wrist. Blood oxygen saturation was monitored throughout the first hour postpartum and logged at 1, 5, 15, 30 and 60 minutes. The values provided by Dawson et al [12]. were used as the reference range. Values of 95% or higher at one hour were considered normal. Values of less than 95% mandated further investigations. Postductal blood oxygen saturation was recorded at 24 hours, with the sensor being attached to the foot of the infant until a stable reading was obtained. If values of less than 95% were recorded, an echocardiogram was performed, regardless of any clinical signs. The entire process of monitoring was conducted using Nellcor™ (Covidien, Ireland) or Masimo™ (Masimo, Switzerland) pulse oximeters. Collected data were analyzed with the purpose of designing the receiver operator characteristic (ROC) curve for pulse oximetry as a screening test for CHD.

Material and Methods A prospective study of neonates born in the “Cuza Voda” Clinical Hospital of Obstetrics and Gynecology from December 1, 2012, to December 31, 2013, was undertaken. Preductal pulse oximetry was carried out on all newborns, in the delivery room, by placing the sensor on the right hand or wrist. Blood oxygen saturation was monitored throughout the first hour postpartum and logged at 1, 5, 15, 30 and 60 minutes. The values provided by Dawson et al [12]. were used as the reference range. Values of 95% or higher at one hour were considered normal. Values of less than 95% mandated further investigations. Postductal blood oxygen saturation was recorded at 24 hours, with the sensor being attached to the foot of the infant until a stable reading was obtained. If values of less than 95% were recorded, an echocardiogram was performed, regardless of any clinical signs. The entire process of monitoring was conducted using Nellcor™ (Covidien, Ireland) or Masimo™ (Masimo, Switzerland) pulse oximeters. Collected data were analyzed with the purpose of designing the receiver operator characteristic (ROC) curve for pulse oximetry as a screening test for CHD. Critical CHDs were defined as, D-transposition of the great arteries, coarctation of the aorta, Tetralogy of Fallot, hypoplastic left heart syndrome, pulmonary stenosis, aortic stenosis, and truncus arteriosus. Other defects, such as persistent foramen ovale or isolated ventricular septal defect, were considered non-critical CHDs.

s were defined as, D-transposition of the great arteries, coarctation of the aorta, Tetralogy of Fallot, hypoplastic left heart syndrome, pulmonary stenosis, aortic stenosis, and truncus arteriosus. Other defects, such as persistent foramen ovale or isolated ventricular septal defect, were considered non-critical CHDs. The prediction of SpO2 for CHD was studied through the assessment of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), as well as through the design of the ROC curve and the analysis of the area under the curve (AUC), as a reference parameter for the strength of prediction. To assess its discriminative capability to detect CHD, the sensitivity and specificity of pulse oximetry was estimated when used as a diagnostic tool. PPV and NPV were used to describe the accuracy of pulse oximetry. The ROC curve conveyed the relationship between sensitivity and specificity for pulse oximetry. All calculations were made using SPSS for Windows, version 20.0.0, Chicago, Illinois. Statistical significance was set α = 0.05. The study was approved by the “Cuza Voda” Hospital’s Ethics Committee. Results During the 13-month study period, there were 5406 infants born in the “Cuza Voda” Maternity Hospital. The infants had gestational ages between 24 and 43 weeks, with a mean of 38.2 ± 2.0 SD and birth weights between 600 and 5000 grams, with a mean of 3175 ± 590 SD. 608 (11.2%) of the infants were born preterm.

The study was approved by the “Cuza Voda” Hospital’s Ethics Committee. Results During the 13-month study period, there were 5406 infants born in the “Cuza Voda” Maternity Hospital. The infants had gestational ages between 24 and 43 weeks, with a mean of 38.2 ± 2.0 SD and birth weights between 600 and 5000 grams, with a mean of 3175 ± 590 SD. 608 (11.2%) of the infants were born preterm. Apgar scores at 1 minute were between 1 and 10, with a median value of 9. At 5 minutes, Apgar scores were between 2 and 10 and at 10 minutes, they were between 3 and 10. Both at 5 and 10 minutes, median values for the Apgar score were 9 (Table 1). Table 1 Characteristics of the patients Mean value SD Min Max Gestational age (wk) 38.2 2.0 24 43 Birth weight (g) 3175 590 600 5600 Apgar 1min 8.4 1.1 1 10 Apgar 5min 8.5 1.2 2 10 Apgar 10min 8.7 1.0 3 10 87.7% of the newborns required no resuscitation in the delivery room, 10.7% needed simple methods of resuscitation such as tactile stimulation and free-flow oxygen, and 1.6% needed complicated resuscitation, including positive-pressure ventilation, chest compressions and medication. At one minute postpartum, median blood oxygen saturation was 65% (IQR 62-70%). At one hour, blood oxygen saturation was 100% (98-100%), and at 24 hours, values of 100% (99-100%) were detected (Table 2). Median values at 5 and 15 minutes were slightly lower than expected (81% and 94%, respectively). Table 2 Oxygen saturation values at different times after birth

At one minute postpartum, median blood oxygen saturation was 65% (IQR 62-70%). At one hour, blood oxygen saturation was 100% (98-100%), and at 24 hours, values of 100% (99-100%) were detected (Table 2). Median values at 5 and 15 minutes were slightly lower than expected (81% and 94%, respectively). Table 2 Oxygen saturation values at different times after birth Mean SpO2 SD Min Max preductal SpO2_1’ 65.6 7.0 30 90 SpO2_5’ 80.0 8.1 40 99 SpO2_15’ 92.5 4.9 55 100 SpO2_30’ 97.0 2.5 70 100 SpO2_1h 98.8 1.6 74 100 postductal SpO2_24h 99.5 1.1 75 100 According to gestational age, median preductal blood oxygen saturation values at 1 minute were 66% (64-70%) in term and post-term infants, whereas in preterm newborn were 61% (55-67%). At 24 hours of age, term infants had postductal oximetry values of 100% (99-100%) and preterm infants had blood oxygen saturation of 98% (98-100%) (Table 3). Table 3 Oxygen saturation values in term or post-term vs. preterm newborns Means SpO2 SD Min Max Term/post-term preductal 1’ 66.4 6.3 34 90 5’ 80.8 7.4 55 99 15’ 92.9 4.3 70 100 30’ 97.2 2.2 82 100 1h 99.0 1.4 88 100 postductal 24h 99.6 0.9 90 100 Preterm preductal 1’ 60.1 9.5 30 83 5’ 74.2 10.3 40 98 15’ 88.7 7.6 55 100 30’ 95.3 3.6 70 100 1h 97.8 2.6 74 100 postductal 24h 98.6 1.9 75 100 Following pulse oximetry readings and echocardiography, a total of 87 CHDs (1.6%), 62 in term newborns and 25 in preterms, were identified. (Fig. 1). Fig. 1 Presence and type of CHD in infants born in a 13-months period

Preterm preductal 1’ 60.1 9.5 30 83 5’ 74.2 10.3 40 98 15’ 88.7 7.6 55 100 30’ 95.3 3.6 70 100 1h 97.8 2.6 74 100 postductal 24h 98.6 1.9 75 100 Following pulse oximetry readings and echocardiography, a total of 87 CHDs (1.6%), 62 in term newborns and 25 in preterms, were identified. (Fig. 1). Fig. 1 Presence and type of CHD in infants born in a 13-months period Blood oxygen saturation values are significantly lower in neonates with CHD at all times in the first 24 hours, compared to those without CHD, regardless of gestational age. 84% of CHDs (73 cases) were categorized as noncritical and 16% (14 cases) as critical. Critical CHD were: 3 cases of pulmonary stenosis, 2 cases each of Tetralogy of Fallot, D-transposition of the great arteries, coarctation of the aorta and truncus arteriosus, and 1 case each of hypoplastic left heart syndrome, single ventricle, and aortic stenosis. We did not find in our study atrioventricular defects, total anomalous pulmonary venous return, or pulmonary atresia with an intact interventricular septum. Of the 4736 term newborns, 98.7% had no CHD, 1.1% (52) had non-critical CHD and 0.2% [10] had critical CHD. Of the 583 preterm infants, 95.9% had no CHD, 3.4% [21] were found to have non-critical CHD and 0.7% [4] had critical CHD.

84% of CHDs (73 cases) were categorized as noncritical and 16% (14 cases) as critical. Critical CHD were: 3 cases of pulmonary stenosis, 2 cases each of Tetralogy of Fallot, D-transposition of the great arteries, coarctation of the aorta and truncus arteriosus, and 1 case each of hypoplastic left heart syndrome, single ventricle, and aortic stenosis. We did not find in our study atrioventricular defects, total anomalous pulmonary venous return, or pulmonary atresia with an intact interventricular septum. Of the 4736 term newborns, 98.7% had no CHD, 1.1% (52) had non-critical CHD and 0.2% [10] had critical CHD. Of the 583 preterm infants, 95.9% had no CHD, 3.4% [21] were found to have non-critical CHD and 0.7% [4] had critical CHD. Blood oxygen saturation values differed significantly among the three groups. In the group without CHD, blood oxygen saturation was 100% (98-100%) at 1 hour and 24 hours, and in the group with non-critical disease, oximetry values were 98% (97-100%) at 1 hour and 100% (98-100%) at 24 hours, whereas in infants with critical CHD, lower values were recorded at both 1 and 24 hours - 92% (88-98%) and 94% (90-98%), respectively (Fig. 2). Fig. 2 Oximetry values in infants with critical CHD vs. noncritical CHD vs. no CHD Preterm infants, regardless of the presence or absence of heart defects, had significantly lower blood oxygen saturation, both when compared to normal ranges and the values of term infants. Also, preterm infants with CHD had lower values compared to their peers without CHD at all times.

Fig. 2 Oximetry values in infants with critical CHD vs. noncritical CHD vs. no CHD Preterm infants, regardless of the presence or absence of heart defects, had significantly lower blood oxygen saturation, both when compared to normal ranges and the values of term infants. Also, preterm infants with CHD had lower values compared to their peers without CHD at all times. The results of the analysis showed good sensitivity and specificity at 1 hour (Se=87.5%, Sp=95.5%) and 24 hours (Se=92.5%, Sp=97.4%) (Fig. 3). Whereas the NPV was high at all time periods (80.6%-98.9%), PPV was low during the first 30 minutes, but rose to 70% at 1 hour and peaked at 77.5% at 24 hours. (Fig. 4). Fig. 3 Positive and negative predictive values of pulse oximetry Fig. 4 Sensitivity and specificity of pulse oximetry We found significant AUCs throughout the examined time periods (0.71-0.86), with a good compromise between sensitivity and specificity, thus ascertaining that, both during the first hour and at 24 hours of life, pulse oximetry is accurate enough as an indicator of CHD (Fig. 5). Fig. 5 The ROC curve for neonatal pulse oximetry According to our calculations, preductal pulse oximetry at 1 hour and postductal pulse oximetry at 24 hours are useful discriminative parameters for the presence of CHD and, thus, can be used for the postnatal screening for CHD.

We found significant AUCs throughout the examined time periods (0.71-0.86), with a good compromise between sensitivity and specificity, thus ascertaining that, both during the first hour and at 24 hours of life, pulse oximetry is accurate enough as an indicator of CHD (Fig. 5). Fig. 5 The ROC curve for neonatal pulse oximetry According to our calculations, preductal pulse oximetry at 1 hour and postductal pulse oximetry at 24 hours are useful discriminative parameters for the presence of CHD and, thus, can be used for the postnatal screening for CHD. Discussion Congenital heart defects (CHD) have a substantial impact on infant mortality and childhood morbidity, accounting for more than 3% of all infant deaths and leaving long-term sequelae in survivors. Prenatal diagnosis of CHD, as well as a diagnosis in the neonatal period, can often be missed. In 2009, the American Heart Association and the American Academy of Pediatrics issued a joint statement recommending routine pulse oximetry for all newborns before hospital discharge, but not in the first 24 hours, to improve the rate of detection of critical CHDs [6].

Discussion Congenital heart defects (CHD) have a substantial impact on infant mortality and childhood morbidity, accounting for more than 3% of all infant deaths and leaving long-term sequelae in survivors. Prenatal diagnosis of CHD, as well as a diagnosis in the neonatal period, can often be missed. In 2009, the American Heart Association and the American Academy of Pediatrics issued a joint statement recommending routine pulse oximetry for all newborns before hospital discharge, but not in the first 24 hours, to improve the rate of detection of critical CHDs [6]. Oximetry values, documented during the first hour of life, can be influenced by multiple factors such as mode of delivery, gestational age, placement of the sensor, type of pulse oximeter used, or the administration of oxygen during resuscitation [13]. Preterm infants seem to take longer to establish a peripheral capillary oxygen saturation (SpO2) greater than 90% [14], which was in accordance with the results of the present study. While term newborns have a mean SpO2 of 93% at 15 minutes, preterm infants have a mean SpO2 of 89%. Detection of CHD by pulse oximetry in the delivery room is confounded by the possibility of persistent ductus arteriosus and thus of overlooking ductal-dependent CHD. Oximetry in the first 24 hours also has a slightly higher incidence of false positive results due to transient pulmonary hypertension or retention of lung fluid [10]. On the other hand, postductal pulse oximetry assessed at 24 hours or later has been shown to be accurate in detecting CHD [15, 16, 17].

al-dependent CHD. Oximetry in the first 24 hours also has a slightly higher incidence of false positive results due to transient pulmonary hypertension or retention of lung fluid [10]. On the other hand, postductal pulse oximetry assessed at 24 hours or later has been shown to be accurate in detecting CHD [15, 16, 17]. A pulse oximetry screening study for congenital heart defects in newborn infants found a sensitivity of 72-75% in the first 12 hours, specificity of 99% throughout the first day and an excellent negative predictive value, similar to prenatal ultrasound [18]. Sendelbach et al. found that pulse oximetry screening at four hours postpartum did not improve detection of critical CHD beyond clinical assessment, and they did not endorse routine pulse oximetry in otherwise healthy neonates [19]. The major difference between this study and the others was the time of SpO2 readings, four hours postpartum in their study compared to 24 hours or longer in other reported studies.

e detection of critical CHD beyond clinical assessment, and they did not endorse routine pulse oximetry in otherwise healthy neonates [19]. The major difference between this study and the others was the time of SpO2 readings, four hours postpartum in their study compared to 24 hours or longer in other reported studies. Our study proved excellent sensitivity and specificity throughout the periods of evaluation. To convey the relationship between sensitivity and specificity we elaborated the ROC curve and we expressed the global specificity of pulse oximetry by the area under the curve (AUC). The larger the AUC, the more precise is the test. In a meta-analysis, Thangaratinam et al [20]. found a similar ROC curve to the one obtained in the current study, with high sensitivity and specificity, but reported a lower rate of false-positive results if the pulse oximetry was performed after 24 hours of age. Indeed, in our study, the PPV was low at 30 minutes (conveying a high probability of false positive results), but was already 70% at one hour and higher at 24 hours. Pulse oximetry can be of limited value in infants with poor peripheral perfusion, cardiac arrhythmias or environmental factors. The main limitation of pulse oximetry as a screening method of CHD is the risk of false negative results. The use of preductal and postductal blood oxygen saturation difference may further improve the detection of critical CHDs [21].

infants with poor peripheral perfusion, cardiac arrhythmias or environmental factors. The main limitation of pulse oximetry as a screening method of CHD is the risk of false negative results. The use of preductal and postductal blood oxygen saturation difference may further improve the detection of critical CHDs [21]. Conclusions Pulse oximetry has been proven to be a feasible assessment for all levels of maternity hospitals, as it is inexpensive, easy to use with minimal training and acceptable to both parents and caregivers [3, 9, 22]. Pulse oximetry during the first 24 hours postpartum can be considered indicative of CHD, thus allowing early diagnosis and timely therapeutic intervention. The sensitivity and specificity of pulse oximetry, as well as its low cost and high compliance by both parents and health care personnel, warrant its use as a screening method for the identification of CHD. Author Disclosure Statement: The authors report no conflicts of interest.

Introduction Elevated intraabdominal pressure (IAP) is known to have an impact on renal function through the pressure transmitted from the abdominal cavity to the vasculature responsible for the renal blood flow [1]. Intraabdominal hypertension (IAH) is frequently encountered in intensive care patients and it was proposed to be responsible for AKI - acute kidney injury in these patients [2]. Intraabdominal pressure is found to be also a predictor of mortality [3]. Intraabdominal high pressure is an entity that can have serious impact on intensive care patients, studies concluding that if this condition progresses to abdominal compartment syndrome mortality is as high as 80% [4]. In 2013 the World Society of the Abdominal Compartment Syndrome modified some of the definitions of the intraabdominal pressure and abdominal compartment syndrome, and defined 4 grades of abdominal pressure [5]: Grade I, IAP 12–15 mmHg Grade II, IAP 16–20 mmHg Grade III, IAP 21–25 mmHg Grade IV, IAP > 25 mmHg High intraabdominal pressure can interfere with the normal function of cardiovascular system, pulmonary system and renal system [6, 7]. Because it has such high interferences it is important not only to detect the high intraabdominal pressure but also to understand and evaluate its effects on the other systems of the body. The renal system is one of the affected systems and its proper function is vital for critically ill patients. This is why the need to recognize the possible malfunctions caused by intraabdominal increased pressure.

intraabdominal pressure but also to understand and evaluate its effects on the other systems of the body. The renal system is one of the affected systems and its proper function is vital for critically ill patients. This is why the need to recognize the possible malfunctions caused by intraabdominal increased pressure. It is known that increased abdominal pressure can reduce the abdominal perfusion pressure which further affects the end organs and tissues. Renal artery and renal veins are affected in the presence of intraabdominal high pressure, and renal injury appears due to ischemia and congestion due to low renal perfusion [8]. Neutrophil gelatinase-associated lipocalin (NGAL) is produced in the distal nephron and its production is increased when an injury appears at this level. Serum concentrations of NGAL increase before those of creatinine. Creatinine and NGAL could be used in determining kidney problems for both patients without known renal disease and for monitoring known disease [9].

) is produced in the distal nephron and its production is increased when an injury appears at this level. Serum concentrations of NGAL increase before those of creatinine. Creatinine and NGAL could be used in determining kidney problems for both patients without known renal disease and for monitoring known disease [9]. There are several methods to determine the renal injury in the context of intraabdominal pressure increase: ultrasound flow probes, which is invasive, CEUS (contrast enhanced ultrasound), which is a non-invasive blood flow measurement but necessitates a special designed ultrasound machine and medical skills [10]. These are direct measurements, but the renal state can be indirectly assessed by measuring some renal products such as urine, urinary creatinine. From these products, with the help of some special designed formulas, the renal activity can be graded. The glomerular filtration rate is considered by Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group to be the best index of kidney function [11]. Objective The aim of this study was to assess any correlation between NGAL and increased intraabdominal pressure. A secondary objective of the study was to evaluate the correlations existing between GFR, creatinine clearance and intraabdominal pressure.

There are several methods to determine the renal injury in the context of intraabdominal pressure increase: ultrasound flow probes, which is invasive, CEUS (contrast enhanced ultrasound), which is a non-invasive blood flow measurement but necessitates a special designed ultrasound machine and medical skills [10]. These are direct measurements, but the renal state can be indirectly assessed by measuring some renal products such as urine, urinary creatinine. From these products, with the help of some special designed formulas, the renal activity can be graded. The glomerular filtration rate is considered by Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group to be the best index of kidney function [11]. Objective The aim of this study was to assess any correlation between NGAL and increased intraabdominal pressure. A secondary objective of the study was to evaluate the correlations existing between GFR, creatinine clearance and intraabdominal pressure. Material and Method The study enrolled 30 critically ill patients admitted in the Intensive Care Unit of SCJU T îrgu Mures between November 2015 and August 2016. The Ethics Committee of the Hospital approved the conduction of this study and patients or their legal representatives were asked for their written approval to enter the study. The inclusion criteria were: adult aged patients admitted in intensive critical care, hemodynamically stable - defined by a normal blood pressure maintained without any vasopressor or inotropic support, invasive monitoring using PICCO device and abdominal pressure monitoring.

Material and Method The study enrolled 30 critically ill patients admitted in the Intensive Care Unit of SCJU T îrgu Mures between November 2015 and August 2016. The Ethics Committee of the Hospital approved the conduction of this study and patients or their legal representatives were asked for their written approval to enter the study. The inclusion criteria were: adult aged patients admitted in intensive critical care, hemodynamically stable - defined by a normal blood pressure maintained without any vasopressor or inotropic support, invasive monitoring using PICCO device and abdominal pressure monitoring. Exclusion criteria: chronic renal failure. Study protocol: after patient admission in the intensive care unit, the hemodynamic stability was assessed, the anthropometric parameters were registered, the intraabdominal pressure was measured and renal function was assessed by obtaining the values of serum creatinine, N-GAL. The 24-hour diuresis was recorded. These values were registered for each day the patient stayed in the intensive care unit and were noted in a specially designed sheet. For the variables measurement we used the following: The intraabdominal pressure was measured with the AbViser (ConvaTec, Salt Lake City, USA) device – the measurement was done with the help of a urethra-vesical catheter. A value of > 12mmHg was considered high intraabdominal pressure. The NGAL value was measured using the Alere Triage NGAL tests with the Alere Triage Meter-Pro device ( Alere Inc. USA). Normal values of serum NGAL are between 40–100 ng/ml.

The intraabdominal pressure was measured with the AbViser (ConvaTec, Salt Lake City, USA) device – the measurement was done with the help of a urethra-vesical catheter. A value of > 12mmHg was considered high intraabdominal pressure. The NGAL value was measured using the Alere Triage NGAL tests with the Alere Triage Meter-Pro device ( Alere Inc. USA). Normal values of serum NGAL are between 40–100 ng/ml. The creatinine serum value was determined by blood sampling and was processed using routine laboratory tests For glomerular filtration ratio calculation we used the Cockroft Gault formula GFR for males= (140-age) x weight (kg)/72x serum creatinine GFR for females= GFR for males x 0.85 The study enrolled 30 patients from which we obtained data sheets with the listed parameters. No patients were excluded from the study. The patients were divided in two groups, based on the value of intraabdominal pressure. The first group included the patients with normal value of the intraabdominal pressure – NP, 52 values, and the second group included the patients with increased value of the intraabdominal pressure – IP, 35 values.

The study enrolled 30 patients from which we obtained data sheets with the listed parameters. No patients were excluded from the study. The patients were divided in two groups, based on the value of intraabdominal pressure. The first group included the patients with normal value of the intraabdominal pressure – NP, 52 values, and the second group included the patients with increased value of the intraabdominal pressure – IP, 35 values. The data were collected using Microsoft Excel (Microsoft, Washington, USA) and statistically processed using the programs GraphPad (GraphPad Software, Inc., California, USA) and MedCalc (MedCalc Software, Ostend, Belgium). We used an alpha significance of 0.05 and statistic tests for non-paired data, parametric and non-parametric tests: Man Whitney, Student’s t test for equality of means, and Levene’s test for equality of variances. Data series distribution normality was assessed using Kolmogorov-Smirnov goodness-of-fit test. Results We enrolled a total of 30 patients who spent in the ICU a minimum of one day and maximum of 12 days. The measured parameters of the entire group of 30 patients are presented in table 1. Inferential statistics for the two formed groups, showed no statistical significance between them in respect of 24 hour diuresis, creatinine clearance and age. Table 1 Measured parameters of the enrolled patients

Results We enrolled a total of 30 patients who spent in the ICU a minimum of one day and maximum of 12 days. The measured parameters of the entire group of 30 patients are presented in table 1. Inferential statistics for the two formed groups, showed no statistical significance between them in respect of 24 hour diuresis, creatinine clearance and age. Table 1 Measured parameters of the enrolled patients Variable Minimum Maximum Median Age (yrs) 39 84 74 NGAL(ng/ml) 36 1300 316 IAP(cmH2O) 5 51 10 24 hr diuresis (ml) 100 7800 2700 GFR (ml/hr) 9 103 47.5 The groups are significantly different when compared in the light of NGAL values and GFR values. The detailed results are shown in table 2. Table 2 Group statistics for the two studied groups Intraabdominal pressure N Mean Std. Deviation Std. Error Mean P value /Test used Diuresis Normal 49 2709.18 1470.03 210.005 0.65 / T test Increased 35 2861.42 1661.06 280.77 Creatinine clearance Normal 44 70.61 42.48 6.40 Increased 33 61.34 31.18 5.42 0.27 / T test NGAL Normal 26 324.11 299.05 58.64 Increased 19 571.73 411.61 94.43 0.02 / T test GFR Normal 50 63.49 41.78 5.90 Increased 33 46.30 24.92 4.33 0.02 / Mann-Whitney Age Normal 52 68.23 13.99 1.94 Increased 35 69.31 6.69 1.13 0.6 / T test We performed Spearman correlation between 24 our diuresis, glomerular filtration rate, NGAL value and intraabdominal pressure. The results are presented in the table 3. Table 3 Correlation matrix -Spearman r

Intraabdominal pressure N Mean Std. Deviation Std. Error Mean P value /Test used Diuresis Normal 49 2709.18 1470.03 210.005 0.65 / T test Increased 35 2861.42 1661.06 280.77 Creatinine clearance Normal 44 70.61 42.48 6.40 Increased 33 61.34 31.18 5.42 0.27 / T test NGAL Normal 26 324.11 299.05 58.64 Increased 19 571.73 411.61 94.43 0.02 / T test GFR Normal 50 63.49 41.78 5.90 Increased 33 46.30 24.92 4.33 0.02 / Mann-Whitney Age Normal 52 68.23 13.99 1.94 Increased 35 69.31 6.69 1.13 0.6 / T test We performed Spearman correlation between 24 our diuresis, glomerular filtration rate, NGAL value and intraabdominal pressure. The results are presented in the table 3. Table 3 Correlation matrix -Spearman r 24h diuresis Creatinine clearance NGAL GFR 24h Diuresis 0.05 (p=0.63) -0.39 (p=0.004) 0.14 (p=0.15) Creatinine clearance 0.05 (p=0.63) -0.14 (p=0.35) 0.92 (p= 1.5) NGAL -0.39 (p=0.004) -0.14 (p=0.35) -0.10 (p= 0.47) GFR 0.14 (p=0.15) 0.92 (p= 1.5) -0.10 (p= 0.47) We obtained a statistically significant correlation between NGAL value and 24-hour diuresis. No other significant correlations were encountered between the studied items. Discussions Our study shows an inverse significant correlation between NGAL and 24-hour urine output, which can guide the medical approach towards a thorough evaluation of renal function. Also, in this respect we obtained another significant result when we compared the increased intraabdominal pressure and the value of this biomarker.

study shows an inverse significant correlation between NGAL and 24-hour urine output, which can guide the medical approach towards a thorough evaluation of renal function. Also, in this respect we obtained another significant result when we compared the increased intraabdominal pressure and the value of this biomarker. The effects of increased intraabdominal pressure on the renal system are among the most frequently encountered in the above condition [12]. Neutrophil gelatinase-associated lipocalin (NGAL) is a molecule that is released by polymorphonuclear granulocytes in context of inflammation and its source is the endothelial cells of nephrons for urinary secretion and later reabsorption into bloodstream [13]. A low amount of NGAL circulates in the bloodstream and is freely filtered by the glomerulus. Normal values are between 40–100 ng/ml. [14] Serum NGAL is secreted under stress conditions from epithelial cells, tumor cells, liver, and kidney [15]. Recent developments in the field of biomarkers pointed out the NGAL as an indicator of kidney injury in the context of increased intraabdominal pressure. In correlation with this, several studies suggest that whole blood NGAL is not as sensitive as a marker for renal injury as urinary NGAL [16, 17]. Whole blood NGAL may not be superior to RIFLE criteria for predicting mortality for renal injury in critically ill patients [18].

Recent developments in the field of biomarkers pointed out the NGAL as an indicator of kidney injury in the context of increased intraabdominal pressure. In correlation with this, several studies suggest that whole blood NGAL is not as sensitive as a marker for renal injury as urinary NGAL [16, 17]. Whole blood NGAL may not be superior to RIFLE criteria for predicting mortality for renal injury in critically ill patients [18]. The need for this new rapid determination of kidney impairment in case of increased intraabdominal pressure came to meet the need of more prompt actions of reducing intraabdominal pressure for the secondary lesions to have a lower occurrence, and the patient’s prognostic to be improved [19]. The results resemble the ones obtained by other authors, but in experimental studies on mice [20]. We did not find and significant correlations between this biomarker and creatinine clearance or the glomerular filtration rate, but the literature that studied urinary NGAL showed positive correlations between creatinine clearance and glomerular filtration rate [21]. In the subgroup analysis we had two significant differences between the compared groups and those were related to NGAL and GFR. Regarding the NGAL values, in the group with increased pressure we found significantly higher values of this biomarker than in the one with normal intraabdominal pressure. Also, in the group with increased intraabdominal pressure the GFR is significantly reduced compared to that from the normal intraabdominal pressure.

Regarding the NGAL values, in the group with increased pressure we found significantly higher values of this biomarker than in the one with normal intraabdominal pressure. Also, in the group with increased intraabdominal pressure the GFR is significantly reduced compared to that from the normal intraabdominal pressure. The literature on this matter is comprised of a multitude of studies which cannot conclude the exact utility for this marker but which can conclude that it could be useful in guiding the therapeutic conduct [20, 22]. Although the literature is inconclusive about this marker, in critically ill patients with increased intraabdominal pressure it could be a good detector of renal injury, especially because the glomerular filtration rate is also decreased in this group of patients. This points out the pressure effects on the renal blood flow, and early detection of renal injury may improve patient recovery. Conclusions NGAL values are increased in patients with high intraabdominal pressure which may suggest its utility in patients with increased intraabdominal pressure. There is a significantly decreased GFR in patients with elevated intraabdominal pressure, observation that can help in early detection of renal injury in patients due to high intraabdominal pressure. No correlation was found between creatinine clearance and increased intraabdominal pressure. Conflict of interest: None declared.

Death represents a biological state which appears at the end of life and can be defined by the halting of all life-sustaining biological functions. Medically speaking, death represents the irreversible loss of consciousness associated with the irreversible loss of breathing [1]. Throughout its history, humanity has been interested by the mystery surrounding the end of life, and especially of finding out precise means of diagnosis. But how can we medically diagnose the phenomenon of death? Currently there are three means of diagnosis [1]: Somatic diagnosis - it focuses on external signs, visible on inspection (rigor mortis, decapitation, decomposition); Cardiovascular diagnosis - entails a diagnosis of irreversible cardio-respiratory arrest - the most used in hospital environments, including ICUs. The diagnosis will be made after 5 minutes of ECG asystole [2]. For these criteria to be certain, they must be preceded by brain death.

Somatic diagnosis - it focuses on external signs, visible on inspection (rigor mortis, decapitation, decomposition); Cardiovascular diagnosis - entails a diagnosis of irreversible cardio-respiratory arrest - the most used in hospital environments, including ICUs. The diagnosis will be made after 5 minutes of ECG asystole [2]. For these criteria to be certain, they must be preceded by brain death. Neurologic diagnosis – it first appeared in the middle of the XX century, after the appearance of organ transplant and the development of life support techniques in ICU (mechanical ventilation, vasoactive medication). It also brings a new dimension to the concept of death in saying that the organ responsible for integrating all bodily functions as well as modulating its relationship with the surrounding environment is the brain. Naturally, if all brain functions come to an end, especially at the level of the brainstem, irreversible loss of consciousness, loss of relation to the surrounding environment, cardio-respiratory arrest and finally disintegration of the entirely organism will follow. Even if it is considered as the death of the whole brain (whole brain death) - North America criteria [3], or just of the brainstem (brainstem death) - U.K. criteria [4], the diagnosis of brain death raises many discussions.

Neurologic diagnosis – it first appeared in the middle of the XX century, after the appearance of organ transplant and the development of life support techniques in ICU (mechanical ventilation, vasoactive medication). It also brings a new dimension to the concept of death in saying that the organ responsible for integrating all bodily functions as well as modulating its relationship with the surrounding environment is the brain. Naturally, if all brain functions come to an end, especially at the level of the brainstem, irreversible loss of consciousness, loss of relation to the surrounding environment, cardio-respiratory arrest and finally disintegration of the entirely organism will follow. Even if it is considered as the death of the whole brain (whole brain death) - North America criteria [3], or just of the brainstem (brainstem death) - U.K. criteria [4], the diagnosis of brain death raises many discussions. In reality, not all the brain functions will be simultaneously shut down. Although some subcortical integrated systems remain working for a brief period of time, such as ADH secretion, and even if some time there is a minimal activity in some isolated cerebral centres, these do not modify the brain death diagnosis. Moreover, the integration of some structures of the entire organism such as: Elimination, detoxification and recycling of cellular wastes throughout the body; energy balance, involving interactions among liver, endocrine systems, muscle and fat; successful gestation of a foetus in a (brain-dead) pregnant woman etc. can still function for some time even if the person is brain dead. Their presence will not be able to change the diagnosis but will produce confusion. This is why, for a better clarification of the neurological situation, in the bioethics board president report, the preferred name for brain death is “total brain failure” [5].

ll function for some time even if the person is brain dead. Their presence will not be able to change the diagnosis but will produce confusion. This is why, for a better clarification of the neurological situation, in the bioethics board president report, the preferred name for brain death is “total brain failure” [5]. The brain death concept considers a patient that is taken as dead, but whose organs that are sustained with the help of mechanical ventilation and hemodynamic maintaining techniques, are viable and can be transplanted (“patient already dead” or “heart-beating cadaver”). Actually, this situation is that of a cadaver that instead of being buried is artificially kept in an ICU bed. With some exceptions, this situation is unacceptable for the patient and disconnection from the artificially life supporting machines is recommended. Of great importance is the irreversibility of ending the neurological functions [6]. Which could be the effects of the neurological brain death diagnosis for ICU patients? Organ harvesting for transplant; Interrupting the life support and futile therapeutically measures to patients that are not included in the transplant program [7].

Actually, this situation is that of a cadaver that instead of being buried is artificially kept in an ICU bed. With some exceptions, this situation is unacceptable for the patient and disconnection from the artificially life supporting machines is recommended. Of great importance is the irreversibility of ending the neurological functions [6]. Which could be the effects of the neurological brain death diagnosis for ICU patients? Organ harvesting for transplant; Interrupting the life support and futile therapeutically measures to patients that are not included in the transplant program [7]. Both situations have raised numerous controversies related to ethics and correct management of the patient. Nowadays, the deontological conduct, as well as the medical one, especially related to the irreversibility of ending the neurological functions, is well defined in the case of organ transplantation. However, not the same can be said for a brain-dead patient or for the one with an untreatable disease, and who is kept alive only with cardiopulmonary resuscitation devices. Conduct in a brain-dead parent not submitted to organ transplant or beyond therapeutical resources Nowadays the death diagnosis in the ICU is made on cardio-pulmonary criteria, with the brain death diagnosis being a secondary one. The brain death diagnosis must follow a rigorous protocol and is generally done only for organ harvesting. In the absence of this situation the brain death diagnosis is only a simple clinical diagnosis.

eath diagnosis in the ICU is made on cardio-pulmonary criteria, with the brain death diagnosis being a secondary one. The brain death diagnosis must follow a rigorous protocol and is generally done only for organ harvesting. In the absence of this situation the brain death diagnosis is only a simple clinical diagnosis. Although theoretically it represents a diagnosis of death that allows for organ harvesting, it is not as efficient in solving other situations such as the “do-not-resuscitate” order (DNR), of ending an already started treatment (Withdrawing-Wd); to not start or enlarge the treatment (Withholding-Wh). The DNR order implies letting the heartbeat and respiration stopping without any intervention of the medical staff. In case of a severe prognostic, in patients beyond therapeutically manageable situations, this is a usual order [7]. In some cases the continuity of useless treatment can harm the patient. In these situations, most authors agree that life support can be withdrawn. In a French study, 777 (14%) of 5589 patients admitted in the ICU, and 584 (52%) of 1132 patients dying in the ICU had their treatment Wh or Wd [8]. These decisions must take into consideration, apart from the medical responsibility, some ethical rules: The action will always be done for the good and interest of the patient, for his/her right to a decent life. A clinical treatment is useless when, in the evolution of the disease, it is: Ineffective - unable to change the natural evolution of a disease or its trajectory towards death;

These decisions must take into consideration, apart from the medical responsibility, some ethical rules: The action will always be done for the good and interest of the patient, for his/her right to a decent life. A clinical treatment is useless when, in the evolution of the disease, it is: Ineffective - unable to change the natural evolution of a disease or its trajectory towards death; Non-beneficial - unable to satisfy any good or value perceived by the patient or his or her surrogate; Disproportionately burdensome to the patient, physically, psychologically, or financially [9]. The desire of the patient is mandatory (if it can be obtained). Some studies show that in only 23% of the cases it is practically achievable [8]. The diagnosis must be clear and certain. The prerequisite of the brain death diagnosis is for the patient to be unconscious, apnoeic and mechanically ventilated; there must be no suspicion related to the irreversible neurological damage as aetiology. If the primary diagnosis remains unclear, the patient observation time must be prolonged before deciding the diagnosis [10].

te of the brain death diagnosis is for the patient to be unconscious, apnoeic and mechanically ventilated; there must be no suspicion related to the irreversible neurological damage as aetiology. If the primary diagnosis remains unclear, the patient observation time must be prolonged before deciding the diagnosis [10]. There must be a permanent communication with the patient’s family, in the spirit of honesty and transparency. We must consider that the family will be suspicious, sceptical or even will fear possible diagnosis errors [11]. An alternative is to not ask for the family’s consent but for it to only be informed. This way, confusion and emotional distress of the family can be avoided. Also, the information that patients and their families have related to what will happen is many times wrong and based on the myth that if you wish for something long enough it will also happen, an idea taken from movies and books which in reality has no support [12, 13]. Maybe it is better to stop the ventilator despite the objections of the family [14]. This behaviour is, however, debatable because the family needs a gradual preparation in time and a complete information to accept the situation. The legislation must be very precise. A medical committee formed out of doctors from the same section must agree with the withdrawal or the withholding of the futile treatment.

There must be a permanent communication with the patient’s family, in the spirit of honesty and transparency. We must consider that the family will be suspicious, sceptical or even will fear possible diagnosis errors [11]. An alternative is to not ask for the family’s consent but for it to only be informed. This way, confusion and emotional distress of the family can be avoided. Also, the information that patients and their families have related to what will happen is many times wrong and based on the myth that if you wish for something long enough it will also happen, an idea taken from movies and books which in reality has no support [12, 13]. Maybe it is better to stop the ventilator despite the objections of the family [14]. This behaviour is, however, debatable because the family needs a gradual preparation in time and a complete information to accept the situation. The legislation must be very precise. A medical committee formed out of doctors from the same section must agree with the withdrawal or the withholding of the futile treatment. In many countries the legislation accepts the use of such measures for ending the patient’s life. Romanian legislation is ambiguous and there is no legal support for utilising these medical measures. The health law 95/2006 and the patients’ rights law 46/2003 have not included the situation in which the patient has an acute unfavourable evolution towards death. Excepting the situation of organ transplantation, where the law is clear and synchronised with international laws, other situations of acute death are not regulated. In these cases, the death diagnosis lies on cardio-pulmonary arrest. Article 13 from the 46/2003 law only specifies that the patient has the right to refuse or stop a medical intervention, accepting in writing the consequences of his/her decision [15]. These legislative directives are not directly related to the terminal or brain-dead patient from the ICU in whom there is the question of not initiating or stopping the supporting therapy. This could damage the terminally ill patient and the limited resources of the unit. Moreover, the ICU doctor who acts according to the best interest of the patient and within the international guidelines is not protected by the legislation and can be accused of murder [15].

nitiating or stopping the supporting therapy. This could damage the terminally ill patient and the limited resources of the unit. Moreover, the ICU doctor who acts according to the best interest of the patient and within the international guidelines is not protected by the legislation and can be accused of murder [15]. Maybe if the neurological brain death diagnosis would be given not only to the patients that are potential donors, but also in other medical situations, it will allow for the stopping futile treatments in the interest of the patient. In the particular conditions of our country, the population should be prepared first for this. Although the French system does not ask the family for permission, only communicates them the decision of the medical staff, we believe that we must permanently discuss and communicate the patient’s status with the family, maybe even before radical measures are taken. All patients must have the possibility (when they are conscious) to express their desire also regarding the possibility of unfavourable evolution. In conclusion, we consider that a revision of the Health Law to take into account the possibility of an unfavourable evolution of the patient, as well as the recognition of brain death also in non-donor patients as a real death diagnosis, is absolutely needed. At the same time, it is necessary to implement guidelines similar to those used in organ transplantation, that should be strongly anchored in today’s realities and that will allow the ICU doctor to take the necessary measures for the good of the patient.

n-donor patients as a real death diagnosis, is absolutely needed. At the same time, it is necessary to implement guidelines similar to those used in organ transplantation, that should be strongly anchored in today’s realities and that will allow the ICU doctor to take the necessary measures for the good of the patient. Conflict of interest: None declared.

Introduction Myxomas are the most common primary heart tumours most of which occur sporadically. In 90% of cases it is a solitary tumour, and in 75-90% of cases, it is localised in the left atrium [1]. The tumour is usually benign and malignant forms of myxomas are very rarely reported [2]. The clinical manifestation of a myxoma depends on its localisation, size and fragility. In the majority of cases, nonspecific systemic symptoms precede from several months up to years before a diagnosis is made. These symptoms are probably caused by the production of interleukin-6 by tumour cells [3]. Additional possible clinical manifestations such as fatigue, exertional dyspnoea up to pulmonary oedema, vertigo, atrial fibrillation and syncope, following from the obstruction of the mitral orifice and systemic embolisms. Embolisms are described in about one-third of the patients [4]. Right atrial myxomas can cause right-sided heart failure and pulmonary embolism or a paradoxical systemic embolism in case of patent foramen ovale (PFO). Coronary artery embolism is one of the less frequent clinical manifestations of the tumour. Case study A 67 years old man with no significant medical history called an ambulance following a sudden onset of chest pain and shortness of breath which lasted for 20 minutes.

The clinical manifestation of a myxoma depends on its localisation, size and fragility. In the majority of cases, nonspecific systemic symptoms precede from several months up to years before a diagnosis is made. These symptoms are probably caused by the production of interleukin-6 by tumour cells [3]. Additional possible clinical manifestations such as fatigue, exertional dyspnoea up to pulmonary oedema, vertigo, atrial fibrillation and syncope, following from the obstruction of the mitral orifice and systemic embolisms. Embolisms are described in about one-third of the patients [4]. Right atrial myxomas can cause right-sided heart failure and pulmonary embolism or a paradoxical systemic embolism in case of patent foramen ovale (PFO). Coronary artery embolism is one of the less frequent clinical manifestations of the tumour. Case study A 67 years old man with no significant medical history called an ambulance following a sudden onset of chest pain and shortness of breath which lasted for 20 minutes. An ECG showed myocardial infarction with ST elevations in the anterolateral leads. The patient was treated with acetylsalicylic acid 250 mg and heparin 5.000 IU intravenously and transferred for an urgent coronary angiogram. These procedures were started fifty minutes after the onset of chest pain. Embolic occlusions of several branches of the left coronary artery were demonstrated in the periphery of the left an terior descending artery (LAD), the second diagonal artery (D2) and the proximal part of the first obtuse marginal artery (OM1). (Figure 1) There was no pathology relating to the right coronary artery. No signs of pathological vascularization were present. Percutaneous coronary intervention on OM1 was attempted. The occlusion was easily crossed with Runthrough® NS Floppy PTCA guidewire (Terumo, Japan). Repetitive usage of ProntoV4 and Pronto LP extraction catheters (Vascular Solutions, Inc., USA) was unsuccessful, and also dilatations in the site of the occlusion and intracoronary administration of eptifibatide did not lead to the artery recanalization. The only result was a slight movement of embolic mass distally to OM1. (Figure 2) Because there was a clear embolic possibility and minimal effect resulting from aspirations and balloon dilatations in OM1, other occluded coronary artery branches were not percutaneously treated. The patient continued to experience mild chest pain and shortness of breath following the procedure, and he was admitted to the Coronary Care Unit for further therapy.

y and minimal effect resulting from aspirations and balloon dilatations in OM1, other occluded coronary artery branches were not percutaneously treated. The patient continued to experience mild chest pain and shortness of breath following the procedure, and he was admitted to the Coronary Care Unit for further therapy. Fig. 1 Embolic occlusion of periphery of LAD, D2, proximal OM1 (arrow) Fig. 2 Result in OM after multiple aspirations and balloon dilatations (arrow)

y and minimal effect resulting from aspirations and balloon dilatations in OM1, other occluded coronary artery branches were not percutaneously treated. The patient continued to experience mild chest pain and shortness of breath following the procedure, and he was admitted to the Coronary Care Unit for further therapy. Fig. 1 Embolic occlusion of periphery of LAD, D2, proximal OM1 (arrow) Fig. 2 Result in OM after multiple aspirations and balloon dilatations (arrow) Transthoracic echocardiography showed a non-dilated left ventricle with akinesia of the apex, lateral wall and part of the inferior wall. Systolic function of the the left ventricle (LV) was moderately impaired with a left ventricle ejection fraction (LVEF) of 40%. The second degree of diastolic LV dysfunction, pseudonormal filling pattern, mild mitral and tricuspid regurgitation, was observed. Other than a mildly enlarged left atrium, no other pathology was found. The right ventricle was not dilated, which showed a well preserved systolic function. Transoesophageal echocardiography was performed subsequently to find the source of the coronary embolism. A 25 x 20mm villous tumour in the left atrium, arising from the interatrial septum, presenting with the echocardiographic features of a cardiac myxoma, was detected. (Figures 3-4) The tumour did not cause an obstruction of the mitral orifice, and the mitral annulus was not dilated. Furthermore, the PFO was recorded as having an insignificant left-to-right shunt. Dilatation of the tricuspid annulus to 47mm and moderate tricuspid regurgitation were the other findings. Blood tests showed significant leukocytosis (20 x 109/l) with mild neutrophilia, C-reactive protein was increased (113 mg/l). However, procalcitonin levels were within the normal range (0.12 μg/l). The maximum value of creatine kinase CK was 68 μkat/l and troponin T 5451 ng/l.

pid regurgitation were the other findings. Blood tests showed significant leukocytosis (20 x 109/l) with mild neutrophilia, C-reactive protein was increased (113 mg/l). However, procalcitonin levels were within the normal range (0.12 μg/l). The maximum value of creatine kinase CK was 68 μkat/l and troponin T 5451 ng/l. Fig. 3 Left atrial myxoma arising from fossa ovalis area, permanent foramen ovale. 2D TOE view. (arrow) Fig. 4 Villous left atrial myxoma. 3D TOE view At a multidisciplinary team meeting, it was agreed to proceed to with surgery. A standard pre-assessment was completed and all no contradictory results reported. Neurological examination, including computed tomography (CT) of the brain, excluded embolisms in the intracranial arteries. The patient was treated with intravenous furosemide 120 mg i.v. daily before surgery and also with levosimendan 0,1 μg/kg/min infusion for 30 hours immediately postoperatively due to the development of acute heart failure. Surgical resection of the tumour was performed the third day after the admission. After the opening of the left atrium, a villous myxoma was removed including the adjacent part of the interatrial septum. (Figures 5-6) The resultant septal defect was closed by direct suturing. Suturing of the PFO and an annuloplasty of the dilated tricuspid annulus was carried out using an Edwards MC3 Tricuspid Annuloplasty Ring (Edwards Lifesciences, USA). Fig. 5 Surgical view into the left atrium with myxoma arising from interatrial septum Fig. 6 Myxoma extirpated with adjacent atrial septum

Surgical resection of the tumour was performed the third day after the admission. After the opening of the left atrium, a villous myxoma was removed including the adjacent part of the interatrial septum. (Figures 5-6) The resultant septal defect was closed by direct suturing. Suturing of the PFO and an annuloplasty of the dilated tricuspid annulus was carried out using an Edwards MC3 Tricuspid Annuloplasty Ring (Edwards Lifesciences, USA). Fig. 5 Surgical view into the left atrium with myxoma arising from interatrial septum Fig. 6 Myxoma extirpated with adjacent atrial septum After the surgery, the patient required increased ventilation support and extubation was postponed. There were no other postoperative issues. Histology confirmed the diagnosis of a left atrial myxoma (Figures 7-8) with typical findings of stellate cells with eosinophilic cytoplasm in a myxoid stroma, extravasated erythrocytes and hemosiderin depositions. Because of the positive histology, no other immunohistochemical methods were used. Fig. 7 Histopathological specimen showing myxoma tissue with reactive and regresive changes. H&E 20x Fig 8 Histopathological specimen showing a border between myxoma tissue and myocardium. H&E 100x

Histology confirmed the diagnosis of a left atrial myxoma (Figures 7-8) with typical findings of stellate cells with eosinophilic cytoplasm in a myxoid stroma, extravasated erythrocytes and hemosiderin depositions. Because of the positive histology, no other immunohistochemical methods were used. Fig. 7 Histopathological specimen showing myxoma tissue with reactive and regresive changes. H&E 20x Fig 8 Histopathological specimen showing a border between myxoma tissue and myocardium. H&E 100x Postoperative echocardiography did not show any residual tricuspid regurgitation and improvement of the left ventricular systolic function with LVEF of 50% was observed. This probably followed the fast resorption of myxomatous emboli in the coronary circulation. The patient was discharged ten days after surgery, and a follow up in a cardiology outpatient clinic, was arranged. Echocardiographic screening of the first degree relatives has been organised.

on with LVEF of 50% was observed. This probably followed the fast resorption of myxomatous emboli in the coronary circulation. The patient was discharged ten days after surgery, and a follow up in a cardiology outpatient clinic, was arranged. Echocardiographic screening of the first degree relatives has been organised. Discussion Heart tumours are rare with an estimated incidence of 0.002-0.02%. They are benign in 75% of cases. Myxomas, first described by Virchow, are the most common benign heart tumours typically manifested in the 3rd to 6th decade of life, more often in women [5]. This type of tumour is considered to arise from multipotent mesenchymal cells which have persisted in the heart since the embryonal development period [6, 7]. Cardiomyocyte progenitor cells and other poorly differentiated cells are another possible source. These cells are very often localised in the fossa ovalis area of the interatrial septum [8, 9]. In 85% of cases, the tumour grows on the fibrovascular stalk attaching to the sub-endothelial base towards the left atrium. In 10% of patients, the myxoma grows towards the right atrium, and in the remaining 5% of patients, it is localised in the cavity of heart ventricles. Most commonly, myxomas are of a jelly consistency and 3-8 cm when diagnosed. Calcifications of left atrial myxomas are rarely reported, though they are described in more than fifty percent of right atrial myxomas [10]. Furthermore, focal haemorrhages are common. Approximately half of the myxomas have a smooth surface. The other half of myxomas have a fragile villous surface which has a greater potential to form embolisms. The embolic potential of myxoma is not proportional to its size but rather to it is related histological characteristics. Low fibrotic myxomas with a large myxoid intracellular mass, have a high embolic risk. On the other hand, highly fibrotic myxomas, more commonly found in elderly patients, have a lower rate of embolic complications [6].

of myxoma is not proportional to its size but rather to it is related histological characteristics. Low fibrotic myxomas with a large myxoid intracellular mass, have a high embolic risk. On the other hand, highly fibrotic myxomas, more commonly found in elderly patients, have a lower rate of embolic complications [6]. In this reported case, the patient had a relatively small myxoma of little haemodynamic significance but with a high embolic potential because of its fragile villous surface. Histological examination showed a lot of myxoid intercellular matrix and regressive changes with haemorrhages and low grade of fibrillization. In 4-10% of patients, myxomas are seen as a part of Carney complex [11]. Autosomal dominant inherited mutations in genes for PRKAR 1A and MYH9 synthesis are the probable cause. The other possible manifestations of the Carney complex are extracardiac myxomas and other tumours such as testicular tumours, schwannomas, pituitary adenomas and thyroid gland tumours as well as skin hyperpigmentation and endocrine disorders. Cardiac myxomas are often multiple and commonly atypically localised [12]. Regarding the risk of a familial transfer, routine echocardiographic screening for the first-degree relatives of patients with myxoma is recommended, particularly in young patients who have multiple or rightsided tumours. Ninety percent of myxomas are visible on transthoracic echocardiography. An overall evaluation of the haemodynamic significance of myxoma especially interference with valvular apparatus is an important part of the examination.

Regarding the risk of a familial transfer, routine echocardiographic screening for the first-degree relatives of patients with myxoma is recommended, particularly in young patients who have multiple or rightsided tumours. Ninety percent of myxomas are visible on transthoracic echocardiography. An overall evaluation of the haemodynamic significance of myxoma especially interference with valvular apparatus is an important part of the examination. Transesophageal echocardiography increases the sensitivity of myxoma detection up to 97% especially in cases of small myxomas, right atrial myxomas, or when a poor transthoracic window exists [13]. Other imaging modalities are indicated when the findings are unclear or atypical. Cardiac CT scan offers the advantage of a fast performance with an excellent three-dimensional resolution (0.4-0.6mm). In a differential diagnosis, a CT scan compared to echocardiography is more reliable in excluding invasive growths of other malignant tumours into the cardiac or surrounding tissues [14, 15]. A radiation burden is a disadvantage. A typical CT image of a myxoma is a spherical or ovoid heterogeneous tumour with a signal density lower than that of the myocardium. Less often, the signal density is the same but never higher than that of the myocardium [10]. Cardiovascular magnetic resonance (CMR) is another excellent diagnostic modality in the differential diagnostics of cardiac tumours [16]. It provides the advantages of best soft tissue resolution and absence of the radiation burden, but this is offset by the time required.

never higher than that of the myocardium [10]. Cardiovascular magnetic resonance (CMR) is another excellent diagnostic modality in the differential diagnostics of cardiac tumours [16]. It provides the advantages of best soft tissue resolution and absence of the radiation burden, but this is offset by the time required. A myxoma is most often of a heterogeneous texture with lower signal intensity than blood in SSFP sequences on CMR imaging. Late gadolinium enhancement (LGE) is usually positive and often of a spotted character [17].

never higher than that of the myocardium [10]. Cardiovascular magnetic resonance (CMR) is another excellent diagnostic modality in the differential diagnostics of cardiac tumours [16]. It provides the advantages of best soft tissue resolution and absence of the radiation burden, but this is offset by the time required. A myxoma is most often of a heterogeneous texture with lower signal intensity than blood in SSFP sequences on CMR imaging. Late gadolinium enhancement (LGE) is usually positive and often of a spotted character [17]. Clinical manifestation of a myxoma varies from being completely asymptomatic in 20% of cases, to a fully expressed triad of symptoms such as constitutional symptoms, signs of intracavitary heart obstruction and embolic complications which are reported in 30-45% patients [4]. Fragments of a myxoma in the left heart and adhering blood clots can embolize anywhere in the systemic circulation and cause an infarction and eventually local haemorrhage. Half of myxoma embolisms from in the left heart are directed into cerebral arteries and are responsible for 0.5% of cerebrovascular accidents [18], and it is, therefore, necessary to exclude myxoma in cases of multiple cerebral artery emboli. Late development of vascular aneurysms at the site of adherent emboli is an associated unwanted risk of rupture and haemorrhage. Propagation of tumour cells in the vasa vasorum with destruction of the architecture of the arterial wall similarly to mycotic aneurysms is a possible explanation [19]. A direct tumour cell extension through the endothelium is another possible mechanism in the development of aneurysms.

risk of rupture and haemorrhage. Propagation of tumour cells in the vasa vasorum with destruction of the architecture of the arterial wall similarly to mycotic aneurysms is a possible explanation [19]. A direct tumour cell extension through the endothelium is another possible mechanism in the development of aneurysms. Individual cases of embolisms into coronary arteries, retinal arteries, visceral arteries, aorta and peripheral arteries are also described in the literature. Coronary artery embolisms are rare complications with an incidence of 0.06%. The perpendicular direction of the coronary arteries ostia from the aorta is a possible explanation for this [20, 21]. Embolisms into the right coronary artery are more often described in the literature, in comparison with the left coronary artery. Patients typically present with STEMI rather than NSTEMI, but cases of sudden cardiac death have also been reported [22, 23]. In reality, the number of embolisms into coronary arteries may be higher because of the possibility of insufficient examination of all the patients with myocardial infarction or enduring sudden cardiac death. Embolism into an otherwise smooth coronary artery is a typical finding on coronary angiograms, though in about 25% of patients with proven embolic myocardial infarction, a standard angiogram is obtained and this may be explained by a fast resorption characteristic of the tumour in coronary arteries [24]. Pathological neovascularization of the myxoma on coronary angiogram is rarely observed [25].

nary angiograms, though in about 25% of patients with proven embolic myocardial infarction, a standard angiogram is obtained and this may be explained by a fast resorption characteristic of the tumour in coronary arteries [24]. Pathological neovascularization of the myxoma on coronary angiogram is rarely observed [25]. The treatment of patients with an embolic acute myocardial infarction consists of the aspirations with catheters and balloon catheter dilatation if needed to achieve an opened artery. Thrombolytic therapy in patients with myxoma embolism is accompanied by a high risk of local bleeding [26, 27, 28]. Surgical extirpation is the only curative treatment possibility and is coupled with excellent results. Perioperative mortality is reported between 0-4% [29, 30]. A median sternotomy approach with extracorporeal circulation is common. Another possibility is a less invasive approach through a right mini-thoracotomy or partial hemi-sternotomy [31]. Complete extirpation of a myxoma with its fibrovascular stalk and the adjacent interatrial septum or the cardiac wall should be performed to prevent a local recurrence. The septal defect is then closed with a direct suture or with an autologous pericardium or synthetic patch. Surgical correction of other significant valvular pathology is then performed if necessary.

ascular stalk and the adjacent interatrial septum or the cardiac wall should be performed to prevent a local recurrence. The septal defect is then closed with a direct suture or with an autologous pericardium or synthetic patch. Surgical correction of other significant valvular pathology is then performed if necessary. The long term prognosis following a successful surgery is excellent. Supraventricular tachyarrhythmias or a higher degree of atrioventricular block related to surgery can occur in some patients. A recurrence rate of 3% is reported, most often occurring in the first four years after the surgery [2, 10, 30]. Rare cases of extracardiac myxoma recurrences in the brain, lungs, kidneys, skeleton and skin, whose origins were probably from previous embolisms, have been reported [32, 33]. Conclusion Embolism into the coronary artery from a left atrial myxoma is a rare cause of an acute myocardial infarction. Transesophageal echocardiography is indicated in all patients with an unclear source of coronary artery embolism. If a myxoma is found, early surgical resection is indicated. The surgery is of a curative nature with excellent long-time results. Appropriate dispensary care of patients after the surgery is necessary regarding the risk of possible myxoma recurrence. Conflict of Interest: None to declare.

Introduction Sepsis is a clinical syndrome whose incidence and mortality rate has increased over the last thirty years, [1] as a consequence of patients’ advanced age, immunosuppressive diseases and therapies or infections with multi-drug resistant bacteria [2]. It remains the leading cause of death in non-coronary intensive care units worldwide, with a mortality rate estimated at 30% in sepsis and 80% in septic shock in the USA [3] and at 12.8% in sepsis and 45.7% in septic shock in Europe [4]. Reduced rates of reporting may affect estimations in developing countries. The concept of sepsis, defined for the first time at the beginning of the 90’s and updated in 2001 [5], refers to the presence of an infectious systemic inflammatory response syndrome (SIRS). The definition was reanalysed and modified in 2016 relating it to a severe organ dysfunction, caused by an inadequate response of the organism to an infectious agent [6]. The prognosis and the rate of mortality are now estimated using the SOFA score (The Sequential Organ Failure Assessment score). This definition, nevertheless, does not offer clear criteria for sepsis diagnosis. In this context, sepsis raises multiple problems of diagnosis and prognosis, and further studies are necessary to identify useful criteria for establishing a rapid and correct diagnosis and quick and effective treatment.

sessment score). This definition, nevertheless, does not offer clear criteria for sepsis diagnosis. In this context, sepsis raises multiple problems of diagnosis and prognosis, and further studies are necessary to identify useful criteria for establishing a rapid and correct diagnosis and quick and effective treatment. Several inflammatory biomarkers have been evaluated with the aim of identifying those with the highest sensitivity, specificity, positive and negative predictive values for sepsis diagnosis. Another problem is the assessment of the septic patient outcome during treatment as currently used clinical and biological criteria are undefined and inadequate for this purpose. Previously published studies have investigated the use of inflammatory biomarkers in assessing the severity and outcome of the disease treated under defined antimicrobial therapy. They tend to offer little precise results due to group heterogeneity and the inclusion of patients with various comorbidities.

Several inflammatory biomarkers have been evaluated with the aim of identifying those with the highest sensitivity, specificity, positive and negative predictive values for sepsis diagnosis. Another problem is the assessment of the septic patient outcome during treatment as currently used clinical and biological criteria are undefined and inadequate for this purpose. Previously published studies have investigated the use of inflammatory biomarkers in assessing the severity and outcome of the disease treated under defined antimicrobial therapy. They tend to offer little precise results due to group heterogeneity and the inclusion of patients with various comorbidities. Search criteria There is an extensive literature regarding inflammatory biomarkers in sepsis. These include haemogram indicators like Neutrophil/Lymphocyte Count Ratio (NLCR), Mean Platelet Volume (MPV), Red Blood Cells Distribution Width (RDW), and continue with the classic inflammatory tests such as fibrinogen, C-reactive protein (CRP) and go on with the discovery of procalcitonin (PCT), soluble-CD14 subtype (sCD14-ST, presepsin), pro-adrenomedullin (pro-ADM), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), interleukin-6 (IL6), interleukin-8 (IL8), interleukin-27 (IL27), soluble urokinase-type plasminogen activator receptor (suPAR). To date, no inflammatory biomarker has been identified which exhibits a high degree of sensitivity and specificity which would permit the identification of patients who need rapid antibiotic therapy.

Search criteria There is an extensive literature regarding inflammatory biomarkers in sepsis. These include haemogram indicators like Neutrophil/Lymphocyte Count Ratio (NLCR), Mean Platelet Volume (MPV), Red Blood Cells Distribution Width (RDW), and continue with the classic inflammatory tests such as fibrinogen, C-reactive protein (CRP) and go on with the discovery of procalcitonin (PCT), soluble-CD14 subtype (sCD14-ST, presepsin), pro-adrenomedullin (pro-ADM), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), interleukin-6 (IL6), interleukin-8 (IL8), interleukin-27 (IL27), soluble urokinase-type plasminogen activator receptor (suPAR). To date, no inflammatory biomarker has been identified which exhibits a high degree of sensitivity and specificity which would permit the identification of patients who need rapid antibiotic therapy. The literature focuses on NLCR, MPV and RDW, i.e., the three haemogram parameters which are easy to evaluate, and which do not incur additional costs to routine analysis. Literature review Neutrophil/lymphocytes count ratio (NLCR) has been the focus of several recent studies published as it is accessible, cheap and readily determined. The importance of this parameter is related to the pathophysiological mechanism of SIRS, which is characterised by an increased number of circulating leucocytes, due to the increased number of neutrophils, the first line of antimicrobial defence. On the other hand, lymphocytopenia appears as a consequence of lymphocyte margination and redistribution in the lymphatic system, with accelerated apoptosis [7].

which is characterised by an increased number of circulating leucocytes, due to the increased number of neutrophils, the first line of antimicrobial defence. On the other hand, lymphocytopenia appears as a consequence of lymphocyte margination and redistribution in the lymphatic system, with accelerated apoptosis [7]. The predictive role of NLCR has been evaluated not only in septic patients but also in patients with tumours, cardiovascular diseases or intestinal inflammatory diseases. The initial value of this indicator was correlated with the outcome and with the survival rate in patients with different types of cancers: pulmonary, breast, prostatic, pancreatic, oesophageal [8], colorectal [9] or hepatocellular carcinoma followed by liver transplant [10]. Several studies, published in cardiovascular medicine domain, showed the prognostic role of NLCR in patients with an acute coronary syndrome, aortocoronary bypass or congestive heart failure [11, 12]. Moreover, Ertas et al. (2013) indicated that NLCR was useful in the prognosis of patients with thromboembolic stroke [13]. On the other hand, a high correlation between NLCR and the outcome of patients with gangrenous appendicitis was demonstrated, and was shown to be superior to other parameters like fever, CRP, Leucocytes number or the Glasgow scale [14].

that NLCR was useful in the prognosis of patients with thromboembolic stroke [13]. On the other hand, a high correlation between NLCR and the outcome of patients with gangrenous appendicitis was demonstrated, and was shown to be superior to other parameters like fever, CRP, Leucocytes number or the Glasgow scale [14]. Moreover, NLCR is considered to be superior to other biomarkers such as CRP, leukocytes count or neutrophils count, as a predictor for bacteraemia in patients admitted to emergency or intensive care units [15]. In a study of 40 patients with severe sepsis, Okashah et al. (2014) highlighted NLCR superiority regarding sensitivity, specificity, positive and negative predictive values to other parameters like lactate, CRP, neutrophils count, lymphocytes count, or leucocytes count. [16] The same study showed the usefulness of NLCR in prognostic evaluation by highlighting the statistically significant correlation with two severity scores, Acute Physiology and Chronic Health Evaluation (APACHE) II (p=0.01) and SOFA (p=0.01).

e lactate, CRP, neutrophils count, lymphocytes count, or leucocytes count. [16] The same study showed the usefulness of NLCR in prognostic evaluation by highlighting the statistically significant correlation with two severity scores, Acute Physiology and Chronic Health Evaluation (APACHE) II (p=0.01) and SOFA (p=0.01). Other studies attempted to establish threshold values for NLCR to predict the severity and outcome of the disease. A retrospective study, which included 2311 patients with bacteraemia concluded that a value of NLCR over seven on admission, represented an independent increased mortality rate risk factor [17]. A more recent study showed that an initial value of NLCR over ten could be correlated with an unfavourable prognosis, as assessed by the number of SIRS criteria, the presence of organ failures or septic metastasis at admission. Despite the low number of investigated patients, this study tended to substantiate the prognostic role of NLCR in sepsis through the statistically significant correlations with APACHE IV (p=0.01) and APS (p=0.01) scores and with the estimated rate of mortality (p=0.01) [18].

failures or septic metastasis at admission. Despite the low number of investigated patients, this study tended to substantiate the prognostic role of NLCR in sepsis through the statistically significant correlations with APACHE IV (p=0.01) and APS (p=0.01) scores and with the estimated rate of mortality (p=0.01) [18]. Mean platelet volume (MPV) is another haemogram parameter which has gained importance in the management of septic patients. Sepsis induces multiple changes in the organism systems, including the haemostasis, platelets activation including excessive aggregation and destruction, with consequences on their number and dimension. Platelet activation is caused by endothelial injuries triggered by the infectious agent. In this context, an increased MPV and a reduced platelet count are associated with an unfavourable prognosis and with an elevated mortality risk [19]. Studies published in the early 80’s showed elevated values of MPV in about half of patients with systemic infection, in contradistinction to those with localised bacterial infections and negative blood cultures. In these cases, MPV values remained within normal limits, independent of platelet count. Same authors concluded that in patients who received effective antimicrobial therapy, MPV became normal within one week. Also, the increase of MPV in patients with localised infection was considered a signal for a generalised infection [20].

ases, MPV values remained within normal limits, independent of platelet count. Same authors concluded that in patients who received effective antimicrobial therapy, MPV became normal within one week. Also, the increase of MPV in patients with localised infection was considered a signal for a generalised infection [20]. The further discovery of other inflammatory biomarkers tests with a superior sensitivity such as fibrinogen, CRP or PCT, lead to MPV being marginalised form the core literature. However, recently, numerous cost-effective studies have been published which feature this accessible parameter. One study involving 183 septic patients revealed a correlation between MPV value at admission and the risk of death. Patients who died presented with a higher initial value of MPV (9.6 versus 9.19 fl, p=0.031) [21]. The relation between MPV and the disease severity as evaluated by APACHE IV, and APS scores, were also shown to be statistically significant (p=0.03, respective p=0.02) [22]. Establishing a threshold value for the diagnosis or prognosis of sepsis has been the target of several recent studies. A level of MPV over eight fl is associated with moderate sensitivity (53.47%) and excellent diagnostic specificity. Besides thrombocytopenia and elevated MPV, an increased platelet distribution width (PDW) was also registered in septic patients, and it was found that a value over 18% is associated with a higher risk of death [23].

PV over eight fl is associated with moderate sensitivity (53.47%) and excellent diagnostic specificity. Besides thrombocytopenia and elevated MPV, an increased platelet distribution width (PDW) was also registered in septic patients, and it was found that a value over 18% is associated with a higher risk of death [23]. The predictive value of MPV in appreciating the mortality risk was not demonstrated in patients with septic shock, in which MPV median was similar between the group of deceased patients and the survivor group (10.6 fl [±0.9] versus 10.5 fl [±0.9]. In this study, other parameters such as age, APACHE and SOFA scores and the platelet count indicated significant differences between the two groups of patients [24]. MPV was evaluated for neonatal sepsis prognosis in multiple studies in which a comparative analysis was made between patients with proven sepsis and a healthy control group. The evaluation of inflammatory biomarkers at admission revealed higher values of the leucocyte count, CRP, IL-6 and MPV in patients with sepsis (p=0.01, p<0.001, p<0.001, respectively p=0.001), compared to the control group. Furthermore, the CRP and MPV medians were significantly higher in patients with positive microbiological tests, comparative to patients with sepsis of unknown aetiology [25]. MPV proved a good predictor of the outcome of children with community acquired pneumonia, but with limited specificity and a negative predictive value and a high rate of false-negative results [26].

ly higher in patients with positive microbiological tests, comparative to patients with sepsis of unknown aetiology [25]. MPV proved a good predictor of the outcome of children with community acquired pneumonia, but with limited specificity and a negative predictive value and a high rate of false-negative results [26]. MPV has been shown to be useful in the prognosis of other non-infectious pathologies, such as ischemic heart disease [27] or stroke [28], as much as other markers of unspecific inflammation. Red cell distribution width (RDW) represents an indicator which can vary in sepsis, under the influence of pro-inflammatory cytokines (TNFα, IFNδ, IL-1β, IL-6) [29], released during the inflammatory process. These cytokines cause inefficient erythropoiesis resulting in structural and functional changes of erythrocytes, with volume variations and increased RDW. High values of this parameter can also appear in nutritional deficiencies such as iron deficiency anaemia, vitamin B12 or folate deficiency anaemia, or in blood transfusions [30]. As RDW is a marker of unspecific inflammation, it can increase in many other diseases such as heart failure, stroke, peripheral arterial disease or chronic pulmonary diseases [31].

ppear in nutritional deficiencies such as iron deficiency anaemia, vitamin B12 or folate deficiency anaemia, or in blood transfusions [30]. As RDW is a marker of unspecific inflammation, it can increase in many other diseases such as heart failure, stroke, peripheral arterial disease or chronic pulmonary diseases [31]. Recent studies have centred on evaluating RDW’s prognostic value and less for the diagnostic role in sepsis. A study, which enrolled 349 patients, revealed the function of RDW in appreciating septic patients’ outcome through the statistically significant association with APACHE II score and with hospital mortality rate. (p<0.0001). This study demonstrated that an RDW value over16% is concurrent with a higher APACHE value and risk of death [31]. Kim et al. (2015) evaluated the predictive role of RDW regarding the short and medium-term mortality in elderly patients with severe sepsis and septic shock and concluded that every one percent (1%) increase in RDW is equivalent to a 15% increase in the mortality rate in the first 30 days [32]. RDW was also considered a good predictor of the length of hospitalisation for septic patients admitted to intensive care units [33].

rly patients with severe sepsis and septic shock and concluded that every one percent (1%) increase in RDW is equivalent to a 15% increase in the mortality rate in the first 30 days [32]. RDW was also considered a good predictor of the length of hospitalisation for septic patients admitted to intensive care units [33]. This biomarker proved its usefulness as an outcome measure because an ascending trend of RDW in the first 72 hours of admission is associated with an unfavourable prognosis, even though the initial values were normal [34]. Chen et al. (2015) analysed almost 7000 adult patients with sepsis, with a mortality rate of 6.8%. In this study, patients who died had higher initial values of RDW than the survivors (15.7% versus 13.8%). There were also established threshold values; for RDW over than 15.6%, the risk of death was 16.7%, for RDW between 14 – 15.6% it was 7.3%, and for RDW under 13.1% the mortality rate was 1.6%. Thus, RDW was considered to be a superior mortality predictive factor to SIRS criteria, the MEDS (Mortality in Emergency Department Sepsis) or CURB65 scores [35]. Similar results were published by Lorente et al. (2014) showing that RDW is a low-cost procedure which should be routinely performed to identify the risk of death in sepsis. In this study, the prognostic value of RDW was compared with other biomarkers such as serum malondialdehyde and αTNF, with comparable results [36].

imilar results were published by Lorente et al. (2014) showing that RDW is a low-cost procedure which should be routinely performed to identify the risk of death in sepsis. In this study, the prognostic value of RDW was compared with other biomarkers such as serum malondialdehyde and αTNF, with comparable results [36]. Discussion Sepsis pathogenesis is complex, with heterogeneous pathophysiological and immunological variations related to the aetiology, primary septic focus, organ dysfunctions and pre-existent pathologies. Another problem is the differential diagnosis between an infectious and a non-infectious cause of SIRS because a delay in initiating antimicrobial therapy in a septic patient can significantly increase the risk of death. The microbiological examination remains the gold standard for the diagnosis of sepsis, and it is preferable because it identifies the incriminating bacterial pathogens and allows the administration of an appropriate antimicrobial regimen, according to an antibiogram. However, both the prognostic and monitoring role of microbiological tests are limited. On the other hand, it can be influenced by several factors such as the ability of the bacteria to grow in cultures, the site of the infectious focus, the antibiotics received before the tests or the equipment of each laboratory. Concerning the prognosis, sepsis is a life-threatening syndrome, responsible for multiple complications, several organ failures and high mortality rate.

ch as the ability of the bacteria to grow in cultures, the site of the infectious focus, the antibiotics received before the tests or the equipment of each laboratory. Concerning the prognosis, sepsis is a life-threatening syndrome, responsible for multiple complications, several organ failures and high mortality rate. Within this context, additional studies to identify parameters useful for the diagnosis and prognosis of septic patients are required. Current published data are controversial because they include multiple biomarkers with different sensitivity, specificity, positive or negative predictive values and have been studied using heterogeneous patient groups. Further research of these biomarkers may provide valuable data and suggest which markers can be used to establish a rapid positive and differential diagnosis between infectious and noninfectious SIRS, how these markers can be correlated with the severity of sepsis or how its dynamics can predict the septic patient outcome.

her research of these biomarkers may provide valuable data and suggest which markers can be used to establish a rapid positive and differential diagnosis between infectious and noninfectious SIRS, how these markers can be correlated with the severity of sepsis or how its dynamics can predict the septic patient outcome. At present biomarkers like CRP, IL-6 and PCT are frequently used in diagnosing and monitoring patients with sepsis. CRP is involved in innate immune system regulation and represents a highly sensitive acute phase reactant, but with limited specificity for infectious systemic inflammatory response syndrome. This biomarker is usually associated with chronic inflammatory processes such as autoimmune or rheumatological disorders, haematological diseases or tumours. Recent studies which evaluated different inflammatory biomarkers showed that CRP is inferior to PCT and NLCR, regarding sensitivity (80% versus 91.2% and 88% respectively), specificity (65% versus 82% and 75% respectively), positive (82% versus 90%and 87.5% respectively) and negative (66.5% versus 80% and 75% respectively) predictive values [16].

ed different inflammatory biomarkers showed that CRP is inferior to PCT and NLCR, regarding sensitivity (80% versus 91.2% and 88% respectively), specificity (65% versus 82% and 75% respectively), positive (82% versus 90%and 87.5% respectively) and negative (66.5% versus 80% and 75% respectively) predictive values [16]. IL-6, a cytokine released from the inflammatory process along with IL-1β or TNFα, represents another useful parameter to guide the clinician for the diagnosis and prognosis of sepsis. Jekarl et al. (2013) found that IL-6 is a better test than CRP and PCT in estimating bacterial sepsis severity. In this study, 86% of survivors registered a rapid decrease of IL-6 values in contrast with the others [37]. Klag et al. (2016) held the same opinion concerning the use of IL-6 in assessing the severity of the condition. In the first 24-48 hours, levels of IL-6 declined steeply in patients who survived contrary to non-survivors and had a higher sensitivity than other inflammatory markers [38]. Arguably, PCT is the most specific test for bacterial sepsis though it is only moderate with respect to sensitivity. Recent studies consider that PCT has higher specificity for sepsis than presepsin or other new sophisticated parameters [39]. Several authors concluded that in comparison to the other haemogram indicators reviewed in this article, PCT has superior sensitivity, specificity and predictive values, but with minor differences. For example, Zhang et al. (2016) indicated that PCT and NLCR have similar predictive values for sepsis [40].

ameters [39]. Several authors concluded that in comparison to the other haemogram indicators reviewed in this article, PCT has superior sensitivity, specificity and predictive values, but with minor differences. For example, Zhang et al. (2016) indicated that PCT and NLCR have similar predictive values for sepsis [40]. Whereas some authors are interested in the discovery of new cytokines which can be used as inflammatory biomarkers, numerous recent studies have focused on the seeing afresh older inexpensive tests. This literature review emphasises the importance of three haemogram parameters (NLCR, MPV, RDW) which can help the clinician to arrive at a prompt diagnosis and to monitor septic patients’ outcome. Authors’ contributions statement: The authors have equally contributed to the writing of this work. Conflicts of interest: The authors declare no conflicts of interest. Acknowledgment This paper is part of “Carol Davila” doctoral programme.

Introduction Transcranial Doppler (TCD) was developed originally to detect vasospasm after subarachnoid haemorrhage [1]. However, since its launch in 1982, its use has widened to include diagnosis of stenosis or occlusion of the main intracranial arteries, measurement of cerebrovascular reserve capacity, examination of autoregulation and neurovascular coupling, microembolus detection and thus diagnosis of right-to-left shunt, ultrasound enhanced thrombolysis, assessment of increased intracranial pressure (ICP), detection of stop of brain circulation in brain death, and monitoring of cerebral circulation during carotid surgery or stenting, as well as during heart surgery. Moreover, development of transcranial colour-coded duplex (TCCD) examination allows the investigation of the cerebral parenchyma, the size of brain ventricles, and a more precise analysis of blood flow in the intracranial arteries. TCD is now extensively used in neurological disorders requiring intensive therapy. The aim of this review is to summarise the potential applications of TCD and TCCD in intensive care units.

Introduction Transcranial Doppler (TCD) was developed originally to detect vasospasm after subarachnoid haemorrhage [1]. However, since its launch in 1982, its use has widened to include diagnosis of stenosis or occlusion of the main intracranial arteries, measurement of cerebrovascular reserve capacity, examination of autoregulation and neurovascular coupling, microembolus detection and thus diagnosis of right-to-left shunt, ultrasound enhanced thrombolysis, assessment of increased intracranial pressure (ICP), detection of stop of brain circulation in brain death, and monitoring of cerebral circulation during carotid surgery or stenting, as well as during heart surgery. Moreover, development of transcranial colour-coded duplex (TCCD) examination allows the investigation of the cerebral parenchyma, the size of brain ventricles, and a more precise analysis of blood flow in the intracranial arteries. TCD is now extensively used in neurological disorders requiring intensive therapy. The aim of this review is to summarise the potential applications of TCD and TCCD in intensive care units. The Basics of TCD TCD uses relatively low frequency (2.0-2.5 MHz) ultrasound, as ultrasound at this frequency penetrates through the thinner parts of the skull, known as “bone windows”. The ophthalmic artery and the carotid syphon can be viewed through the eye, the main intracranial arteries through the trans-temporal window, and the vertebral arteries and the basilar artery through the foramen magnum. The flow velocity in the extracranial part of the internal carotid artery used for calculation of the Lindegaard index in subarachnoid haemorrhage can be determined using a submandibular approach [2].

teries through the trans-temporal window, and the vertebral arteries and the basilar artery through the foramen magnum. The flow velocity in the extracranial part of the internal carotid artery used for calculation of the Lindegaard index in subarachnoid haemorrhage can be determined using a submandibular approach [2]. TCD examination allows the determination of flow velocity in the main vessels as well as the pulsatility index. It is important to emphasise that flow velocity in different individuals is not proportional to the blood flow, though flow velocity changes in one individual reflect the flow variations in the region of the insonated vessel [3, 4]. The pulsatility index (PI) is calculated using the ratio of the difference of peak systolic (PSV) and end-diastolic flow velocity (EDV) and the mean flow velocity (MV) i.e. PI = (PSV-EDV)/MV. [5] PI is a useful parameter for assessing the vascular resistance in the region of an insonated artery. With the use of head frames, TCD probes can be fixed to allow the continuous monitoring of flow parameters. Intracranial Pressure and TCD Since the brain is enclosed in a rigid cavity, increase in the volume of any intracranial element leads to increased intracranial pressure. TCD is suitable for assessing intracranial pressure reducing the need for invasive measurement.

TCD examination allows the determination of flow velocity in the main vessels as well as the pulsatility index. It is important to emphasise that flow velocity in different individuals is not proportional to the blood flow, though flow velocity changes in one individual reflect the flow variations in the region of the insonated vessel [3, 4]. The pulsatility index (PI) is calculated using the ratio of the difference of peak systolic (PSV) and end-diastolic flow velocity (EDV) and the mean flow velocity (MV) i.e. PI = (PSV-EDV)/MV. [5] PI is a useful parameter for assessing the vascular resistance in the region of an insonated artery. With the use of head frames, TCD probes can be fixed to allow the continuous monitoring of flow parameters. Intracranial Pressure and TCD Since the brain is enclosed in a rigid cavity, increase in the volume of any intracranial element leads to increased intracranial pressure. TCD is suitable for assessing intracranial pressure reducing the need for invasive measurement. Increased intracranial pressure can be caused by cytotoxic or vasogenic oedema, tumors, hydrocephalus, and cerebral haemorrhage. An increase in intracranial pressure, more than the venous pressure, results in compression of veins and thus decreased venous outflow. Increase in ICP is accompanied by an increase in PI due to a decrease in diastolic and mean velocities [6].

otoxic or vasogenic oedema, tumors, hydrocephalus, and cerebral haemorrhage. An increase in intracranial pressure, more than the venous pressure, results in compression of veins and thus decreased venous outflow. Increase in ICP is accompanied by an increase in PI due to a decrease in diastolic and mean velocities [6]. PI larger than 1.26 was shown to be associated with an intracranial pressure more than 20 cm H2O (sensitivity 81.1%, specificity 96.3% [7]. Bouzat et al. (2011) showed that low end-diastolic flow velocity (<25 cm/s; sensitivity 92%, specificity 76%) and high PI (>1.25; sensitivity 90%, specificity 91%) indicated increased risk of secondary neurological deterioration in patients with mild to moderate traumatic brain injury with no severe brain lesions on CT [8]. Despite these data, pulsatility index alone does not seem to be a reliable predictor for intracranial pressure, but there is evidence that the autoregulatory index (Mx) derived from blood flow velocity and arterial blood pressure measured non-invasively, is a useful parameter for assessing increased intracranial pressure in traumatic brain injury. Although more sophisticated analysis is necessary for assessment of dynamic cerebral autoregulation, poorer autoregulation was proven to be associated with poorer outcome and greater mortality in traumatic brain injury. Sorrentino et al. (2011) found that an autoregulation index (Mx) of more than 0.3 clearly indicated disturbed autoregulation [9].

nalysis is necessary for assessment of dynamic cerebral autoregulation, poorer autoregulation was proven to be associated with poorer outcome and greater mortality in traumatic brain injury. Sorrentino et al. (2011) found that an autoregulation index (Mx) of more than 0.3 clearly indicated disturbed autoregulation [9]. A significant correlation was shown between PI and ICP (CC = 0.938). Regression statistics revealed that the ICP value could be determined from the PI (ICP = 11.1 x PI – 1.43) with an error of ±4.2 mmHg compared to the actual ICP measured by an invasive method. ICP of more than 20 mmHg was established with 89% sensitivity and 92% specificity [10]. In another study, a PI ≥1.56 in patients with traumatic brain injury predicted a poor outcome at six months, while a PI ≤1 identified patients with a favourable outcome [11]. At present, changes in pulsatility index values rather than absolute values can be used to assess an increase in ICP. Monitoring of flow parameters by TCD allows changes in PI to be monitored and a 1 mmHg change in ICP was shown to equate to a PI change of 2.4% [12]. Optic nerve sheath diameter and increased intracranial pressure In addition to flow parameters and auto-regulatory index, a more reliable indicator of increased intracranial pressure, namely the optic nerve sheath diameter (ONSD) has been widely used in the last decade. Although measurement of ONSD is based on B-mode ultrasound, and not on TCD, we consider it is important to describe this technique briefly.

ters and auto-regulatory index, a more reliable indicator of increased intracranial pressure, namely the optic nerve sheath diameter (ONSD) has been widely used in the last decade. Although measurement of ONSD is based on B-mode ultrasound, and not on TCD, we consider it is important to describe this technique briefly. The subarachnoid space surrounds the optic nerve and is bounded by the optic nerve sheath that is an anatomical extension of the dura mater. It is well known that an increase in the intracranial pressure results in swelling of the optic disc, i.e. papilla-oedema. However, development of papilla-oedema takes time, as is, therefore, a delayed indicator of increased intracranial pressure. Dilatation of the optic nerve sheath has been described as an early manifestation of a rise in intracranial pressure (Figure 1). [13, 14, 15] The optic nerve sheath can be examined by B-mode ultrasound with use of 7-11 MHz. ultrasound probe. The cut-off value for normal ONSD, measured at three mm posterior to the eye, ranges from 5.2 to 5.9 mm [15]. Although there is a relatively wide variation in the optimal cut-off values for normal ONSD [16, 17], it seems to be a sensitive test for predicting elevated ICP. During the examination, the mechanical index has to decrease as little as possible, and the probe has to be placed lightly on the eyelids. The method cannot be used in patients with eye trauma or glaucoma [18]. Moreover, ONSD should not be considered in isolation, but must form part of a holistic approach towards the management of a patient with possible intracranial hypertension.

little as possible, and the probe has to be placed lightly on the eyelids. The method cannot be used in patients with eye trauma or glaucoma [18]. Moreover, ONSD should not be considered in isolation, but must form part of a holistic approach towards the management of a patient with possible intracranial hypertension. Fig. 1 The subarachnoid space surrounds the optic nerve and is bounded by the optic nerve sheath that is an anatomical extension of the dura mater around the nerve. In case of increased intracranial pressure (ICP), the optic nerve sheath is dilated due to the elevated cerebrospinal fluid (CSF) pressure. TCD in brain death Brain death is defined as an irreversible cessation of brain stem functions that is associated with cerebral circulatory arrest caused by increased intracranial pressure. TCD is used as a confirmatory test to authenticate lack of cerebral blood flow. With increasing ICP, TCD waveform shows highresistance profiles. At first, the diastolic flow velocity decreases then becomes zero, and if the intracranial pressure increases further, flow reversal occurs during diastole [19]. As cerebral perfusion pressure approaches zero, oscillating flow and small systolic spikes may appear (Figure 2), and finally no signal is detected [19, 20]. Oscillating MCA flow pattern is characterised by equal systolic forward flow and diastolic reversed flow, i.e. net zero flow, indicating raised ICP and brain death. Systolic spikes of <200 ms duration and <50 cm/s PSV with no diastolic flow, as well as lack of flow, proves lack of cerebral circulation.

tected [19, 20]. Oscillating MCA flow pattern is characterised by equal systolic forward flow and diastolic reversed flow, i.e. net zero flow, indicating raised ICP and brain death. Systolic spikes of <200 ms duration and <50 cm/s PSV with no diastolic flow, as well as lack of flow, proves lack of cerebral circulation. Fig. 2 Systolic spikes detected in the right MCA in brain death. Once oscillating flow is identified, it should be present in both MCAs and the basilar artery and should be registered at two different time points, with a time interval of 30 minutes, to exclude effects of a transient increase in intracranial pressure. TCD alone is not suitable for diagnosing brain death but may shorten the duration of the observation period.

ould be present in both MCAs and the basilar artery and should be registered at two different time points, with a time interval of 30 minutes, to exclude effects of a transient increase in intracranial pressure. TCD alone is not suitable for diagnosing brain death but may shorten the duration of the observation period. TCD detection of vasospasm caused by subarachnoid haemorrhage (SAH) In non-traumatic SAH due to a ruptured intracranial aneurysm, the primary causes of morbidity are rebleeding and cerebral vasospasm [21, 22, 23]. Vasospasm is caused by the release of haemoglobin and its breakdown products into the CSF [24, 25]. Vasoconstriction of the main intracranial arteries, leading to delayed ischemic damage, was shown to have a significant effect on mortality and morbidity [26]. Vasospasm following SAH most commonly develops after the second day and reaches a maximum at the end of the second week [27, 28, 29]. Daily TCD is recommended in all cases of SAH, 3-10 days after the onset of the disease. Serial TCD measurements can be stopped two weeks after the beginning of SAH, if vasospasm does not develop in this period. Otherwise, daily TCD measurements should be performed until the vasospasm resolves. The aim of TCD is to identify early development of a significant vasospasm and to start appropriate treatment to avoid delayed ischemic deficits.

topped two weeks after the beginning of SAH, if vasospasm does not develop in this period. Otherwise, daily TCD measurements should be performed until the vasospasm resolves. The aim of TCD is to identify early development of a significant vasospasm and to start appropriate treatment to avoid delayed ischemic deficits. Vasospasm results in increased flow velocity in the affected artery. However, increase in MFV might also be caused by stenosis or hyperaemia. Increased flow velocity due to stenosis usually affects smaller segments of the artery, while vasospasm results in flow velocity increase in longer arterial segments. The Lindegaard ratio, defined as MFV in MCA / MFV in extracranial ICA, differentiates between hyperaemic flow and vasospasm [30]. While hyperaemic flow is associated with higher ICA and MCA flow velocities, vasospasm due to SAH results in flow velocity increase only in intracranial, but not in extracranial arteries, meaning that hyperaemic flow does not influence the Lindegaard ratio significantly. However, in vasospasm, an increase in the Lindegaard ratio is expected. MFV and the Lindegaard ratio are suitable to grade the severity of vasospasm. Criteria for vasospasm in SAH were established for MCA and BA (Table 1), but are less reliable for ACA and PCA. Table 1 Grading of severity of the vasospasm in the MCA and BA (Aaslid et al., 1984; Lindegaard et al., 1986; Lindegaard et al., 1988; Sviri et al., 2006)

Vasospasm results in increased flow velocity in the affected artery. However, increase in MFV might also be caused by stenosis or hyperaemia. Increased flow velocity due to stenosis usually affects smaller segments of the artery, while vasospasm results in flow velocity increase in longer arterial segments. The Lindegaard ratio, defined as MFV in MCA / MFV in extracranial ICA, differentiates between hyperaemic flow and vasospasm [30]. While hyperaemic flow is associated with higher ICA and MCA flow velocities, vasospasm due to SAH results in flow velocity increase only in intracranial, but not in extracranial arteries, meaning that hyperaemic flow does not influence the Lindegaard ratio significantly. However, in vasospasm, an increase in the Lindegaard ratio is expected. MFV and the Lindegaard ratio are suitable to grade the severity of vasospasm. Criteria for vasospasm in SAH were established for MCA and BA (Table 1), but are less reliable for ACA and PCA. Table 1 Grading of severity of the vasospasm in the MCA and BA (Aaslid et al., 1984; Lindegaard et al., 1986; Lindegaard et al., 1988; Sviri et al., 2006) Degree of vasospasm in the MCA MFV and LR Mild (<25%) 120-149 cm/s 3-6 Moderate (25.50%) 150-199 cm/s 3-6 Severe (>50%) >200 cm/s >6 Degree of vasospasm in the BA MFV and LR Mild (may represent vasospasm) 70-85 cm/s 2.00-2.49 Moderate (25–50%) >85 cm/s 2.50-2.99 Severe (>50%) >85 cm/s ≥3 MCA: middle cerebral artery, BA: basilar artery, MFV: mean flow velocity; LR: Lindegaard ratio

m/s 3-6 Moderate (25.50%) 150-199 cm/s 3-6 Severe (>50%) >200 cm/s >6 Degree of vasospasm in the BA MFV and LR Mild (may represent vasospasm) 70-85 cm/s 2.00-2.49 Moderate (25–50%) >85 cm/s 2.50-2.99 Severe (>50%) >85 cm/s ≥3 MCA: middle cerebral artery, BA: basilar artery, MFV: mean flow velocity; LR: Lindegaard ratio Thrombolysis and TCD TCD and TCCD are useful tools for diagnosing the occlusion of main intracranial arteries. Moreover, TCD with monitoring probes fixed by a headband is suitable for monitor spontaneous or treatment-induced recanalization [31, 32]. Ultrasound was shown to loosen fibrin bridges resulting in thrombi being dissolved [33]. Although smaller studies suggested that insonation with TCD may augment the lytic effect of the rt-PA [32, 34], the CLOTBUST trial failed to confirm a significant clinical benefit, measured at 90 days, of rt-PA treatment and the additional use of low power ultrasound compared to the rt-PA treatment alone [35]. Stenosis of the main intracranial arteries caused by sickle cell disease Circulating sickled cells and their adherence to the endothelial cells increase the risk of stenosis and occlusion of the main intracranial arteries, including ICA, MCA and ACA [36]. Because the time-averaged mean of the maximum velocity above 170-200 cm/s in the middle cerebral artery was associated with an increased risk of stroke [37], and beneficial effect of blood transfusion could reduce the risk of stroke significantly [38], TCD screening is extremely useful in children with sickle cell disease.

use the time-averaged mean of the maximum velocity above 170-200 cm/s in the middle cerebral artery was associated with an increased risk of stroke [37], and beneficial effect of blood transfusion could reduce the risk of stroke significantly [38], TCD screening is extremely useful in children with sickle cell disease. Monitoring of MCA flow during carotid endarterectomy During carotid endarterectomy, the CCA on the side of the surgery is clamped for the period of disobliteration. However, in case of poor collateral circulation, this type of artificial occlusion of the CCA may result in significant hypoperfusion and stroke. There are several methods to monitor the safety of CCA clamping, including local anaesthesia, somatosensory evoked potential and TCD monitoring. At least 30% decrease of MCA MFV after clamping of CCA indicates a significant reduction in cerebral flow. Lack of normalisation of the MCA MFV within 1-2 minutes suggests reduced collateral cerebral circulation and the need for shunting during carotid endarterectomy [39, 32]. Acknowledgment This work was supported by the Hungarian National Brain Research Program, NAP_13-1-2013-0001. Conflict of interest: None to declare.

Introduction Lower respiratory tract infections are a leading cause of death for approximately 3.9 million people per year worldwide, and of these, 1.8 million deaths occur in children under the age of five years [1]. Pulmonary abscess is an infectious condition which destroys the lung parenchyma leading to cavitations and central necrosis in localised areas, formed by thick-walled purulent material, and can primary or secondary [2]. Primary lung abscesses develop in previously healthy children without any known underlying conditions, being usually solitary, while secondary ones occur in children with underlying or predisposing disorders and these can be multiple [2]. Most frequently, lung abscess is a local complication of pneumonia. The clinical manifestations of lung abscess in children include a cough, fever, tachypnea, dyspnea, chest pain, vomiting, sputum production, weight loss and haemoptysis. The diagnosis is usually established by chest radiography or a CT scan in selected cases, the later being able to indicate the location, size and anatomic characteristics of a lesion [2].

bscess in children include a cough, fever, tachypnea, dyspnea, chest pain, vomiting, sputum production, weight loss and haemoptysis. The diagnosis is usually established by chest radiography or a CT scan in selected cases, the later being able to indicate the location, size and anatomic characteristics of a lesion [2]. The aetiology of lung abscess can be bacterial including (a) aerobic Streptococcus spp., Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, or very rarely Mycoplasma pneumoniae, (b) anaerobic such as Bacteroides spp., Fusobacterium spp., and Peptostreptococcus spp. or (c) fungal in immunocompromised patients [2]. Though lung abscess can occur at any age, it seems that paediatric pulmonary abscess morbidity is lower than in adults. Nevertheless, there are only a few reported studies reported regarding the prevalence and clinical outcome of this condition in children [3, 4]. However the development of antimicrobial therapy over the last decades has improved the outcome of lung abscess, the data from 1969 to 2005 reported mortality rates, ranging from 2% to 38.2% [5].

are only a few reported studies reported regarding the prevalence and clinical outcome of this condition in children [3, 4]. However the development of antimicrobial therapy over the last decades has improved the outcome of lung abscess, the data from 1969 to 2005 reported mortality rates, ranging from 2% to 38.2% [5]. The treatment of lung abscess can be conservative or surgical, with most physicians preferring conservative treatment as the treatment of choice. Conservative treatment involves parenteral antibiotics for two to three weeks, followed by a course of oral antibiotics for four to six weeks, concurrently with vital function support [2]. In severe cases, where there is little or no improvement after seven to ten days of therapy, surgical intervention is the appropriate therapeutic option [2].

olves parenteral antibiotics for two to three weeks, followed by a course of oral antibiotics for four to six weeks, concurrently with vital function support [2]. In severe cases, where there is little or no improvement after seven to ten days of therapy, surgical intervention is the appropriate therapeutic option [2]. Case report Medical history and presenting concerns The case is presented of a one year and 5-month-old male child admitted to Paediatric Clinic 1, Tg. Mureş, with fever, loss of appetite and altered general status. Neither the family nor his personal history revealed any pathological elements. The onset of the disease occurred approximately ten days before admission, with a raised temperature of 39°C in spite of the administration of antipyretics. Therefore, the mother consulted a paediatrician who recommended antibiotic treatment (Cefuroxime suspension 125 mg/5 ml; 5 ml 2 times/ day). No improvement in the child’s condition resulted and he was admitted to the territorial hospital where thoracic radiography revealed a massive right pneumonia with pleural effusion. The child was transferred to the Paediatrics Clinic 1 Tg. Mureş, Romania, for further investigations and treatment. Clinical findings The clinical examination on admission showed an altered general status, ringed face, pallor, cryptic and hyperaemic tonsils, hyperaemic pharynx, respiratory distress, abdominal breathing, vesicular murmur absent on the right lung, peripheral oxygen saturation 94%, heart rate 134 beats/minute. The patient weighed 10 kilogrammes, and his height was 95 centimetres.

an altered general status, ringed face, pallor, cryptic and hyperaemic tonsils, hyperaemic pharynx, respiratory distress, abdominal breathing, vesicular murmur absent on the right lung, peripheral oxygen saturation 94%, heart rate 134 beats/minute. The patient weighed 10 kilogrammes, and his height was 95 centimetres. Diagnostic focus and assessment The laboratory tests performed on the day of admission revealed a severe inflammatory syndrome with increased inflammatory biomarkers. C-reactive protein (CRP) 299 mg/L, erythrocyte sedimentation rate (ESR) 130 mm/h; leukocytosis (Leu 24 550/μL) with neutrophilia (Neu 16 680/μL), thrombocytosis (Plt 883/μL), anemia (Hb 7.3 g/dL, Htc 23.2%, MEV 66.9fL, MEH 21 pg), low serum iron (3.21 μmol/l), and an increased level of lactate dehydrogenase (LDH 398 U/L). A blood smear indicated 1% myelocyte, 3% non-segmented cells, 69% segmented cells, 11% monocytes, 16% lymphocytes with hypochromic, microcytic red blood cells, increased number of platelets, hyper granulated and hyper segmented polymorphonuclear cells. A blood culture was negative. A chest X-ray showed a massive right pneumonia with pleural effusions. (Fig. 1) Fig. 1 Radiological aspect of the right lung on the day of admission

A blood smear indicated 1% myelocyte, 3% non-segmented cells, 69% segmented cells, 11% monocytes, 16% lymphocytes with hypochromic, microcytic red blood cells, increased number of platelets, hyper granulated and hyper segmented polymorphonuclear cells. A blood culture was negative. A chest X-ray showed a massive right pneumonia with pleural effusions. (Fig. 1) Fig. 1 Radiological aspect of the right lung on the day of admission Therapeutic focus and assessment Based on the clinical, laboratory and radiological findings a diagnosis was a diagnosis was made of staphylococcal pleural-pneumonia. Antibiotic treatment with meropenem (200 mg 3 times a daily for 7 days) and vancomycin (100 mg 4 times daily for 7 days) together with oxygen by mask during the first three days of admission, electrolytes (sodium chloride and potasium chloride) and glucose solutions by vein during the first week of admission depeding on the oral intake and symptomatic treatment (antipyretics – paracetamol 125 mg/dose up to 600 mg/day, inhaled bronchodilator therapy with salbutamol sulphate 5mg/ml 0,5 ml up to 1 ml/dose). We initiated the treatment with antipyretics followed by inhaled bronchodilator therapy with salbutamol and rehydration therapy. At the same time we administrated the above mentioned antibiotherapy.

mol 125 mg/dose up to 600 mg/day, inhaled bronchodilator therapy with salbutamol sulphate 5mg/ml 0,5 ml up to 1 ml/dose). We initiated the treatment with antipyretics followed by inhaled bronchodilator therapy with salbutamol and rehydration therapy. At the same time we administrated the above mentioned antibiotherapy. Unfortunately, after one week of the above mentioned antibiotic treatment, the fever persisted, and the patient developed bilateral lower limbs oedema. Subsequent laboratory tests showed approximately the same level of inflammatory biomarkers (CRP 291 mg/L, ESR 120 mm/h), decreasing level of Hb (6.1 g/dL), and low level of albumin and total proteins (Alb 2.14 g/dL, TP 5.05 g/dL) as previously recorded. A chest X-ray showed a massive fluid cavity with air inclusions in the upper and middle right lobes associated with right pleural effusion compressing the mediastinum. (Fig. 2) Fig. 2 Radiological aspect of the lung abscess

Unfortunately, after one week of the above mentioned antibiotic treatment, the fever persisted, and the patient developed bilateral lower limbs oedema. Subsequent laboratory tests showed approximately the same level of inflammatory biomarkers (CRP 291 mg/L, ESR 120 mm/h), decreasing level of Hb (6.1 g/dL), and low level of albumin and total proteins (Alb 2.14 g/dL, TP 5.05 g/dL) as previously recorded. A chest X-ray showed a massive fluid cavity with air inclusions in the upper and middle right lobes associated with right pleural effusion compressing the mediastinum. (Fig. 2) Fig. 2 Radiological aspect of the lung abscess A thoracic CT established the diagnosis of a massive lung abscess, partially evacuated, with a cranial-caudal diameter of approximately 74 mm, and secluded pleural effusion. The paediatric surgeon refused surgical treatment based on the patient’s relatively good general status without signs of respiratory distress. An infectious diseases specialist recommended the following antibiotic regimen: meropenem 200 mg 3 times daily, metronidazole 60 mg 3 times daily, amikacin 75 mg 2 times daily, and levofloxacin 50 mg 2 times daily for one week. Human albumin 10 g per day for three days, blood transfusion 100 ml once, and immunoglobulin 5 g a day for five days parenterally, were also administered, resulting in a favourable clinical evolution after three days of treatment.

s daily, amikacin 75 mg 2 times daily, and levofloxacin 50 mg 2 times daily for one week. Human albumin 10 g per day for three days, blood transfusion 100 ml once, and immunoglobulin 5 g a day for five days parenterally, were also administered, resulting in a favourable clinical evolution after three days of treatment. Laboratory tests were repeated one week after the commencement of the new antibiotic regimen and showed that the inflammatory biomarkers remained elevated. A second CT was taken which revealed right fluid-pneumothorax compressing the mediastinum and causing the collapse of the right superior lobe, and an air cavity of approximately 49 mm diameter with a fluid content of approximately 19 mm axial diameter. The patient was transferred to the Paediatric Surgery and Orthopedic Clinic Tg Mureş where a right pleurostomy was carried out. Afterwards, he was admitted to the Paediatric Intensive Care Unit for three days. A bronchoscopy indicated an atelectasis of the superior right lobe due to purulent secretions. The amount of drained purulent secretions was approximately 40-50 ml per day. A culture from the drained fluid, as well as a specific bacteriological culture, were both negative for Koch bacillus. Treatment was continued with meropenem 200 mg 3 times daily and levofloxacin 50 mg 2 times daily for another three weeks to cover both Gram positive and negative bacteria and anaerobic bacteria. The pleurostomy was suppressed after two weeks, and the patient was discharged soon after.

The patient was transferred to the Paediatric Surgery and Orthopedic Clinic Tg Mureş where a right pleurostomy was carried out. Afterwards, he was admitted to the Paediatric Intensive Care Unit for three days. A bronchoscopy indicated an atelectasis of the superior right lobe due to purulent secretions. The amount of drained purulent secretions was approximately 40-50 ml per day. A culture from the drained fluid, as well as a specific bacteriological culture, were both negative for Koch bacillus. Treatment was continued with meropenem 200 mg 3 times daily and levofloxacin 50 mg 2 times daily for another three weeks to cover both Gram positive and negative bacteria and anaerobic bacteria. The pleurostomy was suppressed after two weeks, and the patient was discharged soon after. Discussion Lung abscess in children is very rare, accounting for approximately 0.7 per 100 000 admissions per year [6] with a continuing decrease in their incidence due to major pharmacological developments. Most cases of paediatric lung abscess arise due to a complication of bacterial pneumonia [7]. There are, however, other predisposing factors that can lead to this condition in children such as immunodeficiency syndromes or immunosuppression states due to viral infections, severe systemic disorders and neurological conditions which can lead to aspiration lung disease [8].

complication of bacterial pneumonia [7]. There are, however, other predisposing factors that can lead to this condition in children such as immunodeficiency syndromes or immunosuppression states due to viral infections, severe systemic disorders and neurological conditions which can lead to aspiration lung disease [8]. Even though in the present case the lung abscess was the result of pneumonia, no predisposing factors or underlying conditions were identified that could have led to this condition. One of the most severe and common complications of lung abscess is sepsis, a critical condition with a wide spectrum of aetiologies, but which usually carries a good prognosis in children [9, 10]. The most common aetiological agents of lung abscess in paediatric patients are Gram-positive cocci including Staphylococcus aureus and Streptococcus pneumonia and anaerobic bacteria. In immunocompromised or aspiration patients, several Gram-negative bacteria have been identified, such as Pseudomonas aeruginosa and Klebsiella pneumoniae [3]. Nevertheless, other rare aetiologies can be encountered such as that identified by Ruffini et al., (2014) who showed that a Mycoplasma pneumoniae infection might predispose to severe infections caused by typical respiratory pathogens [11]. Though we did not identify the precise aetiology in our case, it was most likely that the condition was caused by Gram-positive cocci, probably Staphylococcus aureus.

Even though in the present case the lung abscess was the result of pneumonia, no predisposing factors or underlying conditions were identified that could have led to this condition. One of the most severe and common complications of lung abscess is sepsis, a critical condition with a wide spectrum of aetiologies, but which usually carries a good prognosis in children [9, 10]. The most common aetiological agents of lung abscess in paediatric patients are Gram-positive cocci including Staphylococcus aureus and Streptococcus pneumonia and anaerobic bacteria. In immunocompromised or aspiration patients, several Gram-negative bacteria have been identified, such as Pseudomonas aeruginosa and Klebsiella pneumoniae [3]. Nevertheless, other rare aetiologies can be encountered such as that identified by Ruffini et al., (2014) who showed that a Mycoplasma pneumoniae infection might predispose to severe infections caused by typical respiratory pathogens [11]. Though we did not identify the precise aetiology in our case, it was most likely that the condition was caused by Gram-positive cocci, probably Staphylococcus aureus. The diagnosis of lung abscess is usually established radiologically, but in certain cases, it can be difficult to differentiate between empyema and a lung abscess, based solely on a chest radiography. In such cases, it is necessary to perform a CT scan to confirm a diagnosis [12].

Though we did not identify the precise aetiology in our case, it was most likely that the condition was caused by Gram-positive cocci, probably Staphylococcus aureus. The diagnosis of lung abscess is usually established radiologically, but in certain cases, it can be difficult to differentiate between empyema and a lung abscess, based solely on a chest radiography. In such cases, it is necessary to perform a CT scan to confirm a diagnosis [12]. The first step in the management of a lung abscess is by parenteral antibiotics together with physiotherapy to facilitate postural drainage [13]. In most cases, due to the difficulties in establishing the aetiology in paediatric patients, antibiotic therapy is administered empirically [14]. Surgical drainage or percutaneous drainage should be limited to those cases which are refractory to medical therapy or who develop complications like bronchopleural fistula [15].

The first step in the management of a lung abscess is by parenteral antibiotics together with physiotherapy to facilitate postural drainage [13]. In most cases, due to the difficulties in establishing the aetiology in paediatric patients, antibiotic therapy is administered empirically [14]. Surgical drainage or percutaneous drainage should be limited to those cases which are refractory to medical therapy or who develop complications like bronchopleural fistula [15]. Our case was refractory to medical therapy and developed a right fluid-pneumothorax compressing the mediastinum and collapse of the right superior lobe. It, therefore, required surgical drainage. The consensus opinion is that in cases of children under the age of seven years, lung abscess does not respond readliy to medical therapy and does not drain spontaneously [13], and it follows that up to 21% of patients diagnosed with lung abscess, who do not respond to antibiotics, are likely to need surgical or percutaneous drainage [16]. Even though lung abscesses in paediatric patients are rare conditions, our case proves that they can develop despite the early administration of wide-spectrum antibiotics in children without any predisposing factors or underlying conditions, probably due to the bacterial strain involved and its pathogenicity.

age [16]. Even though lung abscesses in paediatric patients are rare conditions, our case proves that they can develop despite the early administration of wide-spectrum antibiotics in children without any predisposing factors or underlying conditions, probably due to the bacterial strain involved and its pathogenicity. Conclusions Lung abscess infrequently occurs in paediatric patients and is commonly a complication of bacterial pneumonia. Despite the fact that we initiated wide-spectrum antibiotics and vital functional support from the first day of admission, our patient developed a massive lung abscess with multiple complications eventually requiring surgical drainage. The eventual outcome and prognosis for the patient were favourable. Conflict of interest: None to declare. Abbreviations Albalbumin CRPC-reactive protein ESRerythrocyte sedimentation rate Hbhaemoglobin Htchematocrit MEHmedium erythrocyte haemoglobin MEVmedium erythrocyte volume LDHlactate dehydrogenase Leuleukocytes Neuneutrophils Pltplatelets TPtotal proteins

Introduction Although uncommon, acute-on-chronic subdural haematoma (ACSDH) is not rare. Lee et al. (2004) found that 8% of chronic subdural haematomas (CSDH) were actually ACSDHs, [1, 2] although there are few cases reported in medical literature. Chronic haematomas develop by the pooling of blood caused by tears in the bridging vessels in the subdural space. Old age, repeated trauma and brain atrophy are the main risk factors. Unlike acute subdural haematomas, which may be life-threatening, chronic haemorrhages have a better prognosis. Some chronic subdural haematomas remain asymptomatic, but a mild injury or brain trauma may lead to the subdural reoccurrence of bleeding. Case Report A 60-year-old man was admitted to hospital following a mild traumatic head injury. He was lethargic and stuporous. His wife reported that six months before, he had accidentally fallen and hit his head and had been admitted to hospital.

Introduction Although uncommon, acute-on-chronic subdural haematoma (ACSDH) is not rare. Lee et al. (2004) found that 8% of chronic subdural haematomas (CSDH) were actually ACSDHs, [1, 2] although there are few cases reported in medical literature. Chronic haematomas develop by the pooling of blood caused by tears in the bridging vessels in the subdural space. Old age, repeated trauma and brain atrophy are the main risk factors. Unlike acute subdural haematomas, which may be life-threatening, chronic haemorrhages have a better prognosis. Some chronic subdural haematomas remain asymptomatic, but a mild injury or brain trauma may lead to the subdural reoccurrence of bleeding. Case Report A 60-year-old man was admitted to hospital following a mild traumatic head injury. He was lethargic and stuporous. His wife reported that six months before, he had accidentally fallen and hit his head and had been admitted to hospital. At that visit, he had no neurological symptoms, except for headache and nausea. No lower or upper limbs paresis were present. A brain CT was performed, and the definitive diagnosis was an acute left frontoparietal subdural haematoma. Given it was small in size and the lack of severe symptoms after 48 hours of observation, the supervising clinicians decided to manage the case with careful monitoring over time. In accordance with this policy, a second brain CT scan was carried out several weeks later, which did not show any changes compared to the previous CT scan (Figure 1). This, together with the fact that the patient had been asymptomatic since the initial admission to hospital, led to a diagnosis of chronic subdural haematoma.

ordance with this policy, a second brain CT scan was carried out several weeks later, which did not show any changes compared to the previous CT scan (Figure 1). This, together with the fact that the patient had been asymptomatic since the initial admission to hospital, led to a diagnosis of chronic subdural haematoma. Fig. 1 A: Axial slide of a brain CT scan, showing a chronic subdural haematoma (white arrow), 13 mm thick and mild midline shift to the right (8 mm). B: The current CT scan showed an acute crescent-shaped haematoma, 21 mm thick, causing mass-effect with raised intracranial pressure and midline shift to the right (12 mm). Chronic haematoma is hypodense, whereas acute (or acute-on-chronic) haematoma is hyperdense. At the time of his second admission to hospital, he was assessed in the Emergency Medicine Department. His relatives claimed that the trauma to his head had been mild, explaining that he had taken a nap and had rolled over and fallen off the couch. After a few minutes, he showed decreased alertness and was unable to follow simple commands or speak. On physical examination, his pupils were normal, but right hemiparesis was present. The patient was not on any drug treatment, nor was he taking any vitamin K antagonists or antiplatelet agents. The patient then underwent a brain CT scan, which showed acute reoccurrence of bleeding of the previous chronic subdural haematoma (Figure 1). The patient was referred to the Neurosurgery Department to undergo surgical drainage, after which he fully recovered.

On physical examination, his pupils were normal, but right hemiparesis was present. The patient was not on any drug treatment, nor was he taking any vitamin K antagonists or antiplatelet agents. The patient then underwent a brain CT scan, which showed acute reoccurrence of bleeding of the previous chronic subdural haematoma (Figure 1). The patient was referred to the Neurosurgery Department to undergo surgical drainage, after which he fully recovered. Discussion Chronic haematomas are a mixture of liquefied blood and a semisolid clot pooling between the dura mater and the arachnoid mater [1, 3]. Although the pathophysiology of ACSDH is complex and incompletely understood, it appears that rotational forces accompanying movement of the skull exert tensile strain and rupture of bridging veins leading to acute haemorrhaging into the subdural space [4]. When acute onset occurs, subdural haematomas can be life-threatening though some chronic haematomas remain asymptomatic and have a good prognosis. Brain atrophy after a traumatic brain injury is considered to be one of the underlying conditions that leads to the development of chronic haematomas. Elderly and alcoholic patients, with a history of repeated trauma or receiving treatment such as antiplatelet agents or warfarin, are more likely to develop this kind of haematoma. A chronic subdural haematoma leads to an excessive local activation of coagulation and fibrinolytic events, and a new onset haematoma would not necessarily form a solid clot [2].

history of repeated trauma or receiving treatment such as antiplatelet agents or warfarin, are more likely to develop this kind of haematoma. A chronic subdural haematoma leads to an excessive local activation of coagulation and fibrinolytic events, and a new onset haematoma would not necessarily form a solid clot [2]. Nevertheless, acute-on-chronic haematomas are not very common, representing about 8% of chronic subdural haematomas [5,6]. Removal of the lesion may relieve the pressure on the brain and resolve the midline shift. Conclusions Underlying conditions leading to a chronic subdural haematoma are old age, repeated trauma and brain atrophy. However, repetitive trauma can cause a reoccurrence of bleeding of a chronic haematoma even after a mild traumatic brain injury. This case highlights the fact that acute bleeding over a chronic subdural haematoma may be identified by the onset of acute symptoms. Conflicts of interest: The author has no competing interests in the manuscript. Acknowledgement I would like to thank Jacqueline Lamb for her great support, suggestions and encouragement in the making of this manuscript.

Introduction Infection with Raoultella ornithinolytica is rare and this Gram-negative, oxidase-negative, non-motile, capsulated facultative anaerobic bacillus of the enterobacteriaceae family is normally found in aquatic environments, fish and insects [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]. Raoultella ornithinolytica occurs mainly in patients with underlying malignancies or chronic diseases, trauma, nosocomial infection and invasive procedures and is a risk factor for a poor outcome [1, 4, 8, 9, 12]. The bacterium was originally named Klebsiella ornithinolytica but was subsequently reclassified as Raoultella ornithinolytica. It is an important histamine-producing bacterium associated with distinctive cutaneous signs consisting of flushing or a maculopapular rash [3, 6, 7, 10, 11, 12, 13]. Raoultella ornithinolytica is a rarely reported hospital-acquired infection [9]. It is occasionally isolated from bronchial lavage or other deep respiratory samples and should never be considered simply a saprophytic bacterium. It shows a high resistance to antimicrobial resistance [9, 10] and it has been reported that it may cause a fatal neonatal infection, especially in preterm infants [12]. The present report concerns a patient in a neurointensive care unit who had been diagnosed with the colonization of the trachea by Raoultella ornithinolytica and who recovered without antibiotic treatment. Written informed consent to publish this report was received from the patient and her husband.

Raoultella ornithinolytica is a rarely reported hospital-acquired infection [9]. It is occasionally isolated from bronchial lavage or other deep respiratory samples and should never be considered simply a saprophytic bacterium. It shows a high resistance to antimicrobial resistance [9, 10] and it has been reported that it may cause a fatal neonatal infection, especially in preterm infants [12]. The present report concerns a patient in a neurointensive care unit who had been diagnosed with the colonization of the trachea by Raoultella ornithinolytica and who recovered without antibiotic treatment. Written informed consent to publish this report was received from the patient and her husband. Case Report A 48-year-old woman with hypertension was admitted to the emergency department in Odense University Hospital, Odense, Denmark, with subarachnoid haemorrhage associated with the internal carotid artery. She was treated with a stent and coiling technique. After a period of rehabilitation in hospital, she made significant progress and was discharged.

rtension was admitted to the emergency department in Odense University Hospital, Odense, Denmark, with subarachnoid haemorrhage associated with the internal carotid artery. She was treated with a stent and coiling technique. After a period of rehabilitation in hospital, she made significant progress and was discharged. Two months later she suffered a second subarachnoid hemorrhage with bleeding into the brain ventricles and hydrocephalus due to a dissection of an aneurysm in the internal carotid artery. She was treated using the endovascular coiling technique. She was admitted to the Department of Neuro-intensive Care in the same hospital and sedated with propofol 9 ml/h (20 mg/ml). Later this treatment was changed and she was sedated with sodium thiopental 7 ml/h (25 mg/ml), fentanyl 6 ml/h (50 mcg/ml) and midazolam 10 ml/h (50 mg/ml). An external ventricular drain was placed together with a Camino® Micro Ventricular Bolt Intracranial Pressure Temperature Monitoring Kit (Integra Camino, San Diego, USA). Endovascular coiling was undertaken and twenty-five days after readmission she underwent a percutaneous dilatational tracheostomy to provide a long-term route for mechanical ventilation. The sedation procedure was reduced over time and she slowly made progress. Maintaining normal blood pressure was a challenge but otherwise she had no other organ dysfunctions.

enty-five days after readmission she underwent a percutaneous dilatational tracheostomy to provide a long-term route for mechanical ventilation. The sedation procedure was reduced over time and she slowly made progress. Maintaining normal blood pressure was a challenge but otherwise she had no other organ dysfunctions. Four days after the tracheostomy, a positive test was obtained for multi-resistant Pseudomonas from samples from her trachea. A decision was taken to change the tracheostomy tube and to isolate the patient as part of the infection control regime. Furthermore, it was elected only to prescribe antibiotics if symptoms of infection occurred. The tracheostomy tube was changed to a Bivona® Adult TTS™ tracheotomy size 7.0 with cuff (Smiths Medical, Kent, UK).

was taken to change the tracheostomy tube and to isolate the patient as part of the infection control regime. Furthermore, it was elected only to prescribe antibiotics if symptoms of infection occurred. The tracheostomy tube was changed to a Bivona® Adult TTS™ tracheotomy size 7.0 with cuff (Smiths Medical, Kent, UK). On day thirty-seven after readmission, and nine days after the change of the tracheostomy tube, the patient became febrile. There was no evidence of flushing or rash. A blood transfusion had not been given and the laboratory data revealed a C-reactive protein level of 15 mg/L and a white blood cell count of 17.5 x 109/L (Table 1, Laboratory data). However, Gram-negative bacilli were cultured from the patient’s trachea, along with Pseudomonas.The hospital’s clinical department of microbiology identified these as Raoultella ornithinolytica using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) (Bruker Daltronics Biotyper 3.1). Microbe identification and antibiotic susceptibility tests were performed by disk diffusion and the organism was shown to be sensitive to cefuroxime, gentamicin and ciprofloxacin but resistant to ampicillin. The next day a new sample was sent to the microbiology department and Raoultella ornithinolytica was identified for the second time, still together with a high number of Pseudomonas. This time they were resistant to ampicillin and piperacillin/ tazobactam. The recommendation was to start treatment with antibiotics only if she showed symptoms of infection. In accordance with this advice, antibiotics were withheld and on day three and four after the first test result with Raoultella ornithinolytica, tracheal swabs were found to be negative.

in and piperacillin/ tazobactam. The recommendation was to start treatment with antibiotics only if she showed symptoms of infection. In accordance with this advice, antibiotics were withheld and on day three and four after the first test result with Raoultella ornithinolytica, tracheal swabs were found to be negative. Table 1 Laboratory data from the department of clinical biochemistry and clinical microbiology Date 14/4 15/4 16/4 17/4 18/4 19/4 C-reactive Protein mg/L 9.5 13 15 28 14 18 White blood cell × 109/L 9.0 14.0 17.5 9.0 8.7 12.6 Temperature °C 36.9 37.2 37.5 37.8 37.4 37.0 Raoultella ornithinolytica Negative Negative Positive Positive Negative Negative Forty-nine days after the second subarachnoid hemorrhage and eleven days after the identification of Raoultella ornithinolytica, the patient was able to breathe spontaneously. The tracheostomy tube was removed and she was discharged from the intensive care unit to a general ward. The patient made slow but continuous progress. She was paralyzed on the left side of her body, suffered from nausea and headaches, found it difficult to concentrate and spoke only a few words. Later she was discharged to a neurological rehabilitation clinic where she had regained almost all of her neurocognitive functions although she still had memory problems. At the end of the rehabilitation program she was discharged to her home. Discussion Most case reports of Raoultella ornithinolytica concern patients with serious comorbidities. In one study, the mortality rate related to infection was found to be 5% [10].

Date 14/4 15/4 16/4 17/4 18/4 19/4 C-reactive Protein mg/L 9.5 13 15 28 14 18 White blood cell × 109/L 9.0 14.0 17.5 9.0 8.7 12.6 Temperature °C 36.9 37.2 37.5 37.8 37.4 37.0 Raoultella ornithinolytica Negative Negative Positive Positive Negative Negative Forty-nine days after the second subarachnoid hemorrhage and eleven days after the identification of Raoultella ornithinolytica, the patient was able to breathe spontaneously. The tracheostomy tube was removed and she was discharged from the intensive care unit to a general ward. The patient made slow but continuous progress. She was paralyzed on the left side of her body, suffered from nausea and headaches, found it difficult to concentrate and spoke only a few words. Later she was discharged to a neurological rehabilitation clinic where she had regained almost all of her neurocognitive functions although she still had memory problems. At the end of the rehabilitation program she was discharged to her home. Discussion Most case reports of Raoultella ornithinolytica concern patients with serious comorbidities. In one study, the mortality rate related to infection was found to be 5% [10]. The patient in the present case had a previous history of arterial hypertension but no malignancies or other chronic diseases and was otherwise in good physical condition, fit and non-smoking. This differs from the descriptions of patients reported to be infected with Raoultella ornithinolytica [3, 5, 7, 8, 9, 10, 11, 12, 13], though in a case report concerning a 21-day-old boy, the patient was healthy except for having a sinus venous type atrial septal defect [12].

d physical condition, fit and non-smoking. This differs from the descriptions of patients reported to be infected with Raoultella ornithinolytica [3, 5, 7, 8, 9, 10, 11, 12, 13], though in a case report concerning a 21-day-old boy, the patient was healthy except for having a sinus venous type atrial septal defect [12]. In other case reports patients received antibiotics, unlike the present case where the patient was not treated with antibiotics but nevertheless recovered [3, 5, 7, 8, 9, 10, 11, 12, 13]. Details of this watch-and-wait policy have not been found in the literature. In a previous study [10], Raoultella ornithinolytica pneumonia was observed in twenty patients over a ninety-one-month period. Half of these cases had hospital-acquired pneumonia and three had ventilator associated pneumonia. The patients diagnosed with Raoultella ornithinolytica presented a medical history of solid cancer, immunodeficiency, diabetes mellitus or chronic alcoholics [10]. This seems to be different from the woman in the present case report. Identification of Raoultella species is difficult due to its phenotypic similarity to Klebsiella species [1, 9, 10, 11]. The MALDI-TOF MS technique, used to identify the bacterium in this case, has a high sensitivity and specificity for Raoultella ornithinolytica. The technique has been used to correctly and rapid identify of various microorganisms, including Raoultella ornithinolytica which often do not need confirmation by molecular procedures [9, 10].

technique, used to identify the bacterium in this case, has a high sensitivity and specificity for Raoultella ornithinolytica. The technique has been used to correctly and rapid identify of various microorganisms, including Raoultella ornithinolytica which often do not need confirmation by molecular procedures [9, 10]. Accurate identification of Raoultella ornithinolytica and determination of antibiotics susceptibility are necessary to determine appropriate patient care. Normally Raoultella ornithinolytica strains are sensitive to at least two or three different antibiotics [5], but one report has described that a strain was resistant to all antibiotics except tigecycline and colistin [14]. Raoultella species have the potential for multi-drug resistance [4]. The consensus recommendation is that a Raoultella ornithinolytica infection should be treated with antibiotics e.g. amoxicillin plus clavulanic acid for 10-14 days [6]. Conclusion This is a case report concerning a patient in the neurointensive care who was infected with Raoultella ornithinolytica and the distinctive feature in this case was that the patient was successfully treated without antibiotics, suggestive of the advantage offered by a “watch-and-wait policy”. Raoultella ornithinolytica is a pathogen with potent virulence. It is very rare but should be dealt with attention. Raoultella ornithinolytica may have fatal outcome in patients with severe comorbidities.

Conclusion This is a case report concerning a patient in the neurointensive care who was infected with Raoultella ornithinolytica and the distinctive feature in this case was that the patient was successfully treated without antibiotics, suggestive of the advantage offered by a “watch-and-wait policy”. Raoultella ornithinolytica is a pathogen with potent virulence. It is very rare but should be dealt with attention. Raoultella ornithinolytica may have fatal outcome in patients with severe comorbidities. The prevalence of Raoultella ornithinolytica may be an underreported, emerging hospital-acquired infection and early recognition and proper infection control measures are important. Physicians should be aware of the possibility of medical and surgical device-associated Raoultella ornithinolytica infections and the risk of antimicrobial resistance. Conflict of interest: None declared.

Background Fusobacterium is an anaerobic gram-negative bacteria which is often involved in the development of Lemierres syndrome[1], although other bacteria, such as other fusobacteria or Streptococcus, can also be related to this syndrome[2]. The most common species isolated within this genus are F. nucleatum and F. necrophorum. Fusobacterium are usually found as part of the normal oral, gastrointestinal and genital flora, but may induce septic thrombophlebitis in the neighboring neck vessels when the infection is associated with an oropharyngeal abscess. The clinical spectrum may be wide, including abscess formation, bacteremia, puerperal infections, and septic shock[2, 3, 4, 5, 6]. Some reliable studies on Fusobacterium[7, 8] revealed an overall incidence of bacteremia of 0.55 cases per 100,000 population per year, and a wide spectrum of clinical features. Nohrström et al.[8] categorized the infections into 4 types: Lemierre’s syndrome, sepsis in healthy patients, puerperal infections and sepsis in patients with underlying conditions, in an attempt to identify risk factors, comorbidities and predisposing conditions for favorable outcomes. They reported that some comorbid conditions, such as chronic kidney disease, dementia, cardiovascular disease, diabetes, and ICU admission, may be considered as risk factors for poor outcomes. Our aim was to characterize and analyze the clinical features and outcomes of patients with Fusobacterium infections, as well as predisposing diseases, and determine which variables were able to predict favorable or poor outcomes.

isease, diabetes, and ICU admission, may be considered as risk factors for poor outcomes. Our aim was to characterize and analyze the clinical features and outcomes of patients with Fusobacterium infections, as well as predisposing diseases, and determine which variables were able to predict favorable or poor outcomes. Methods Study design We conducted a retrospective cohort study at the Mostoles University Hospital in Madrid, a second-level general hospital serving a high variety of patients, and a teaching hospital for specializing postgraduates. The cohort was enrolled among patients cared for at the hospital between 2007 and 2016 (9.4 years), and they were evaluated retrospectively. All patients with an isolation of Fusobacterium species were identified in that timeframe through our Clinical Microbiology Laboratory, which is the only laboratory processing the clinical specimens in our area. We considered the patient to be suitable for entering the study if, along with the isolation of the fusobacteria, he/she exhibited clinical characteristics of an ongoing systemic infection. Thanks to our electronic record system, we were able to collect data regarding demographic features such as age and gender, clinical characteristics such as comorbidities, malignancy or immunocompromised status, hospital stay, medical or surgical management, and outcome. Sepsis was defined according to The Third International Consensus Definitions for Sepsis and Septic Shock[9]. Therefore, organ dysfunction was identified as an acute change in total SOFA (Sequential [Sepsis-Related] Organ Failure Assessment) score ≥2 points consequent to the infection caused by Fusobacterium species. Sepsis diagnosis was established if the patient met the organ dysfunction criteria and qSOFA (quick SOFA) score ≥2 of the following items: alteration in mental status, systolic blood pressure ≥100 mm Hg, or respiratory rate ≥22/min[10, 9].

nt) score ≥2 points consequent to the infection caused by Fusobacterium species. Sepsis diagnosis was established if the patient met the organ dysfunction criteria and qSOFA (quick SOFA) score ≥2 of the following items: alteration in mental status, systolic blood pressure ≥100 mm Hg, or respiratory rate ≥22/min[10, 9]. Septic shock was defined by the presence of sepsis with persisting hypotension requiring vasopressors to maintain mean arterial pressure ≥65 mm Hg and having a serum lactate level >2 mmol/L (18mg/dL) despite adequate fluid resuscitation. We defined severe infection as sepsis, need for ICU admission, bacteremia, peritonitis, disseminated intravascular coagulation, pelvic inflammatory disease, and septic shock. We were able to identify the source of infection thanks to the electronic records, imaging studies and microbiological isolations within the tissues. Microbiological identification Species-level identification was performed from positive cultures by manual methods, by means of the commercial system of multi-substrate analytical profile index, API 20A, that determines the phenotypical characteristics for anaerobic bacteria identification, both gram-negative and gram-positive. First isolations in our cohort were identified by automated methods—i. e. mass spectrometry Matrix-Assisted Laser Desorption Ionization Time Of Flight (MALDI-TOF MS)[11, 12].

ile index, API 20A, that determines the phenotypical characteristics for anaerobic bacteria identification, both gram-negative and gram-positive. First isolations in our cohort were identified by automated methods—i. e. mass spectrometry Matrix-Assisted Laser Desorption Ionization Time Of Flight (MALDI-TOF MS)[11, 12]. Statistical analysis We performed a normality test for continuous variables using the Shapiro-Wilk test to assess the shape of the distribution of the continuous variables. Data are reported as the median, interquartile range (IQR) and percentage. We used either the Chi-square test or Fisher’s exact test to assess the comparison between categorical variables, the Mann-Whitney-Wilcoxon test to establish comparisons between continuous and categorical variables, and Spearman’s correlations to compare 2 continuous variables. Statistical analysis was performed using R version 3.3.2 (2016-10-31)[13]. For statistical comparison, a p-value of 0.05 was considered significant.

ables, the Mann-Whitney-Wilcoxon test to establish comparisons between continuous and categorical variables, and Spearman’s correlations to compare 2 continuous variables. Statistical analysis was performed using R version 3.3.2 (2016-10-31)[13]. For statistical comparison, a p-value of 0.05 was considered significant. Results Demographic characteristics We collected clinical records and microbiological data for 26 patients, of whom 9 were women (34.6%) and 17 were men (65.4%). The demographic features are summarized in Table 1. The median age was 46.5 years (IQR, 20.5 years). Four patients (15.4%) were active smokers. In terms of comorbidities, 4 patients (15.4%) had respiratory diseases (asthma or chronic obstructive pulmonary disease), and 4 patients (15.4%) had colorectal cancer, either prior to the Fusobacterium infection or diagnosed during the workup. Only 2 patients were considered to have immunocompromised status, due to either active HIV infection or chemotherapy treatment. Table 1 Demographic and clinical features, and outcomes of the studied population

Results Demographic characteristics We collected clinical records and microbiological data for 26 patients, of whom 9 were women (34.6%) and 17 were men (65.4%). The demographic features are summarized in Table 1. The median age was 46.5 years (IQR, 20.5 years). Four patients (15.4%) were active smokers. In terms of comorbidities, 4 patients (15.4%) had respiratory diseases (asthma or chronic obstructive pulmonary disease), and 4 patients (15.4%) had colorectal cancer, either prior to the Fusobacterium infection or diagnosed during the workup. Only 2 patients were considered to have immunocompromised status, due to either active HIV infection or chemotherapy treatment. Table 1 Demographic and clinical features, and outcomes of the studied population Characteristics Patients Total Patients 26 Age (years) 46.5 (20.5) Gender (female) 9 (34.6%) Gender (male) 17 (65.4%) Asthma/COPD 4 (15.4%) Smoking habit 4 (15.4%) Colorectal cancer 4 (15.4%) Immunocompromised status 2 (7.7%) Clinical features Sepsis 9 (34.6%) Sources of infection Peritonsillar abscess 6 (23.1%) Perforated acute appendicitis 3 (11.5%) Liver abscess 2 (7.7%) Ovarian abscess 2 (7.7%) Chorioamnionitis 2 (7.7%) Empyema 3 (11.5%) Sigmoid colon abscess 3 (11.5%) Sinusitis 2 (7.7%) Other complications 4 (15.4%) ICU admission 7 (26.9%) Surgical treatment 18 (69.2%) Date are given in number and percentages, except for age, which is given in median and interquartile range. COPD: chronic obstrutive pulmonary disease. Other complications: peritonitis, disseminated intravascular coagulation and pelvic inflammatory disease.

(15.4%) ICU admission 7 (26.9%) Surgical treatment 18 (69.2%) Date are given in number and percentages, except for age, which is given in median and interquartile range. COPD: chronic obstrutive pulmonary disease. Other complications: peritonitis, disseminated intravascular coagulation and pelvic inflammatory disease. Presentation, sources of infection and outcome Clinical characteristics and outcomes are shown in Table 1. Sepsis was present in 9 patients (34.6%). Only 4 patients (15.4%) developed severe complications: peritonitis (2 patients), disseminated intravascular coagulation (1 patient), and pelvic inflammatory disease (1 patient). However, septic shock could not be identified in any patient. An intra-abdominal source of the infection was identified in 12 patients (46.1%), while an upper respiratory tract source was identified in 5 patients (19.2%), and a lower respiratory tract source in 2 patients (7.7%). None of the patients presented with Lemierre’s syndrome. All 3 sigmoid colon abscesses were related to colorectal cancer, while 19 (73.1%) out of 26 patients were diagnosed with an abscess of any origin. Surgical management, whether open surgery, drainage or aspiration, was required in 18 patients (69.2%). While most of the patients stayed at the hospitalization ward, only 7 patients (26.9%) had to be admitted to the Intensive Care Unit (ICU). The median length of hospital stay was 11.5 days (IQR, 21 days). All 26 patients survived the Fusobacterium infection. Those who died months or years later could not be attributable to bacterial infections.

stayed at the hospitalization ward, only 7 patients (26.9%) had to be admitted to the Intensive Care Unit (ICU). The median length of hospital stay was 11.5 days (IQR, 21 days). All 26 patients survived the Fusobacterium infection. Those who died months or years later could not be attributable to bacterial infections. Microbiological features Sample specimens were obtained from exudate (57.7%), blood (30.8%) and tissue (11.5%). Data regarding microbiological characteristics are summarized in Table 2. Fusobacterium necrophorum and F. nucleatum were the most frequent isolations (92.3%). One case of F. mortiferum was identified, and only one Fusobacterium strain could not be identified. The annual incidence of fusobacterial infection was 1.78 per 100,000 population. Although the median age was very similar in both F. nucleatum (median 49.5 years, IQR 18.25) and F. necrophorum (median 40.5 years, IQR 35.25), the incidence follows a pattern in which F. necrophorum affects a younger population (Figure 1). Fig. 1 Boxplot showing age distribution by Fusobacterium species Table 2 Microbiological characteristics of the studied population

Microbiological features Sample specimens were obtained from exudate (57.7%), blood (30.8%) and tissue (11.5%). Data regarding microbiological characteristics are summarized in Table 2. Fusobacterium necrophorum and F. nucleatum were the most frequent isolations (92.3%). One case of F. mortiferum was identified, and only one Fusobacterium strain could not be identified. The annual incidence of fusobacterial infection was 1.78 per 100,000 population. Although the median age was very similar in both F. nucleatum (median 49.5 years, IQR 18.25) and F. necrophorum (median 40.5 years, IQR 35.25), the incidence follows a pattern in which F. necrophorum affects a younger population (Figure 1). Fig. 1 Boxplot showing age distribution by Fusobacterium species Table 2 Microbiological characteristics of the studied population Sample features Sample size (percentage) Exudate sample (%) 15 (57.7%) Blood sample (%) 8 (30.8%) Tissue sample (%) 3 (11.5%) Species isolated Fusobacterium mortiferum 1 (3.8%) Fusobacterium necrophorum 10 (38.5%) Fusobacterium nucleatum 14 (53.8%) Fusobacterium sp 1 (3.8%) Isolation in pure culture 21 (80.8%) The isolation of bacteria in pure culture was more frequent (80.8%) than in the polymicrobial culture (19.2%). Strains of Bacteroides fragilis, Escherichia coli, Klebsiella pneumoniae and Enterococcus faecium were identified in the polymicrobial cultures.

) Fusobacterium sp 1 (3.8%) Isolation in pure culture 21 (80.8%) The isolation of bacteria in pure culture was more frequent (80.8%) than in the polymicrobial culture (19.2%). Strains of Bacteroides fragilis, Escherichia coli, Klebsiella pneumoniae and Enterococcus faecium were identified in the polymicrobial cultures. Antimicrobial susceptibility testing Data regarding antimicrobial susceptibility were available in all 26 patients. All strains were susceptible to metronidazole, clindamycin, piperacillin/tazobactam and carbapenems. Resistance to penicillin was present in 16 isolates (9 cases of F. nucleatum and 7 cases of F. necrophorum). Risk factors for severe disease The univariate analysis of the risk factors for severe infection is shown in Table 3. We found no significant differences in terms of gender, age, isolated species, presence of an abscess, immunosuppression status, presence of a tumor or respiratory disease between the patients presenting with severe infection and those with non-severe features. However, bacteremia (Chi-squared = 6.1553, df = 1, p-value = 0.0073) was statistically significant. When included in a linear regression analysis, bacteremia could be considered as an independent risk factor for severe infection (OR 0.611, 95% CI 0.240 - 0.981, p=0.002). Table 3 Univariate analysis of the risk factors for severe infection

Risk factors for severe disease The univariate analysis of the risk factors for severe infection is shown in Table 3. We found no significant differences in terms of gender, age, isolated species, presence of an abscess, immunosuppression status, presence of a tumor or respiratory disease between the patients presenting with severe infection and those with non-severe features. However, bacteremia (Chi-squared = 6.1553, df = 1, p-value = 0.0073) was statistically significant. When included in a linear regression analysis, bacteremia could be considered as an independent risk factor for severe infection (OR 0.611, 95% CI 0.240 - 0.981, p=0.002). Table 3 Univariate analysis of the risk factors for severe infection Variable Severe infection (n=15) Non-severe infection (n=11) p-value Gender (male) 10 (66.7%) 7 (46.69%) 1 Age (years) 49 +/- 22 42 +/- 15.9 0.420 F. nucleatum 8 (53.36%) 6 (40.02%) 1 F. necrophorum 7 (46.69%) 3 (20.01%) 0.551 Bacteremia 8 (53.36%) 0 0.007 Abscess 10 (66.7%) 9 (60.93%) 0.679 Immunosuppression 3 (20.01%) 0 0.238 Cancer 3 (20.01%) 1 (6.67%) 0.613 Respiratory disease 1 (6.67%) 3 (20.01%) 0.374 Risk factors for length of hospital stay After performing a univariate analysis of the risk factor for longer hospital stay, we could not find significant differences for length of hospital stay with regard to gender, age, Fusobacterium species, bacteremia, presence of an abscess, immunosuppression condition, malignant tumor, or respiratory disease.

ital stay After performing a univariate analysis of the risk factor for longer hospital stay, we could not find significant differences for length of hospital stay with regard to gender, age, Fusobacterium species, bacteremia, presence of an abscess, immunosuppression condition, malignant tumor, or respiratory disease. Discussion The main findings in our case series showed the wide spectrum of clinical presentations caused by Fusobacterium infections, ranging from local pharyngeal or upper respiratory tract infections, such as sinusitis, to life-threatening infections that require ICU admission. Despite the severe infection, after appropriate management with antibiotic therapy or surgical procedures if required, patients were successfully discharged. Fusobacterium is an anaerobic pathogen usually involved in the development of Lemierre’s syndrome[1], although other bacteria may also cause this complication of pharyngitis. Typical manifestations of Lemierre’s syndrome include the development of a pyogenic thrombosis of the internal jugular vein, and septic emboli to the lungs, brain, and liver[2]. However, in our series we found no cases of Lemierre’s syndrome, unlike some other case series which did identify the syndrome. Nevertheless, Lemierre’s syndrome is an uncommon infection[2], with an annual incidence of between 0.05 and 0.09 per 100,000 population[2, 8], and like ours, there are other case series which did not find any cases presenting this syndrome[14].

’s syndrome, unlike some other case series which did identify the syndrome. Nevertheless, Lemierre’s syndrome is an uncommon infection[2], with an annual incidence of between 0.05 and 0.09 per 100,000 population[2, 8], and like ours, there are other case series which did not find any cases presenting this syndrome[14]. Fusobacterium infections, whether soft-tissue or bacteremic infections, are uncommon. During the 10-year period of observation, we found 26 cases of fusobacterial infections in a population of 155,000 inhabitants. The annual incidence, according to our retrospective study, was 1.78 per 100,000 population, and the incidence of bacteremia was 0.53 per 100,000 population, which is very similar to other retrospective studies: Nohrström et al.[8] reported an annual incidence of bacteremia of 0.55 per 100,000 population, and the series by Afra et al.[7] also reported an incidence of 0.55 per 100,000 per year. Pett et al.[15] reported an incidence of 0.76 cases per 100,000 per year.

lation, which is very similar to other retrospective studies: Nohrström et al.[8] reported an annual incidence of bacteremia of 0.55 per 100,000 population, and the series by Afra et al.[7] also reported an incidence of 0.55 per 100,000 per year. Pett et al.[15] reported an incidence of 0.76 cases per 100,000 per year. An interesting feature was the preference F. necrophorum showed for healthy, younger patients. F. nucleatum cases had a median age of 49.5 years (IQR 18.25), while F. necrophorum had a median of 40.5 years (IQR 35.25). Although the median only differs by 9 years, Figure 1 shows that F. nucleatum did not affect individuals under 40 years of age, while F. necrophorum affected individuals up to 18 years of age. Other studies are more consistent with these findings, such as that by Afra et al.[7], who reported an obvious pattern between F. necrophorum (median of 21 years) and F. nucleatum (median of 53.5 years), and Pett et al.[15], who reported that F. necrophorum affected patients under 47 years of age. We also observed a male predominance (65.4%) versus female infections (34.6%). These findings were consistent with other publications[7, 15]. F. necrophorum and F. nucleatum were the most common isolated species in our study (24 out of 26 patients), consistent with other retrospective studies[2, 7, 15]. We only reported one strain of F. mortiferum, and one strain of unidentified Fusobacterium. Other studies, however, reported the isolation of F. varium and F. gonidiaformans [15].

nucleatum were the most common isolated species in our study (24 out of 26 patients), consistent with other retrospective studies[2, 7, 15]. We only reported one strain of F. mortiferum, and one strain of unidentified Fusobacterium. Other studies, however, reported the isolation of F. varium and F. gonidiaformans [15]. In addition to the above-mentioned low likelihood of causing bacteremic infections, Fusobacterium species tend to involve abscess formation (17 patients out of our 26 reported cases), perhaps due to an attempt to protect an anaerobic environment from the oxidative conditions of the host. In our series, not all abscesses required surgical treatment: one patient presenting with a liver abscess was managed with antibiotic therapy only, with a good outcome at discharge. In our study, all abscesses were considered to arise from primary infections, except the 2 cases of liver abscesses, the primary source of which was probably the disruption of the mucosal colonic barriers related to colorectal cancer. However, some publications have reported liver abscessation related to periodontal disease [6] without Lemierre’s syndrome, or after a dental procedure[16] (dental cleaning in an otherwise healthy patient). Colorectal tumors, diverticular disease and even a recent colonoscopy[17] may be the potential source of Fusobacterium infection. A recent publication reported a liver abscess in an immunocompetent patient with no recognizable risk factors for Fusobacterium infection[18].

ntal cleaning in an otherwise healthy patient). Colorectal tumors, diverticular disease and even a recent colonoscopy[17] may be the potential source of Fusobacterium infection. A recent publication reported a liver abscess in an immunocompetent patient with no recognizable risk factors for Fusobacterium infection[18]. The liver is the most common visceral organ in which abscesses can be found, but very few cases of Fusobacterium as a causative pathogen have been reported. With regard to Lemierre’s syndrome, about 2-4% of cases develop liver abscesses when metastatic emboli occur[2]. Liver abscesses are often polymicrobial, due to a complication of peritonitis, spreading from a biliary infection or via hematogenous spread in the context of a systemic infection.[5] Other risk factors for a liver abscess include underlying gastrointestinal neoplasm, such as colorectal or hepatobiliary carcinoma, pancreatic abscesses, diabetes and a certain degree of immunosuppression[3]. Although the liver is the most common site of metastatic visceral abscesses, the presence of septic emboli involving this organ is uncommon. With no evidence of pharyngeal infection, it is less common to diagnose a liver abscess in an immunocompetent patient, and a workup should therefore be performed in order to identify the primary focus of the infection[5, 7].

metastatic visceral abscesses, the presence of septic emboli involving this organ is uncommon. With no evidence of pharyngeal infection, it is less common to diagnose a liver abscess in an immunocompetent patient, and a workup should therefore be performed in order to identify the primary focus of the infection[5, 7]. In our series, malignancy, in the form of colorectal cancer, was found in 4 patients (15.4%), associated with F. nucleatum in 2 patients, and F. necrophorum in the other 2 cases. Three patients with this underlying condition showed features of severe infection, and the need for ICU admission. Only one patient presented with a solitary liver abscess, and the malignancy was diagnosed in the ensuing workup. Several studies have reported the association between malignancy and Fusobacterium infections[7, 8, 14, 19], although other comorbidities such as diabetes, dementia, respiratory disease, and heart disease may also be risk factors[7]. In our study, however, despite the fact that malignancy, chronic obstructive pulmonary disease, and immunosuppressed status were encoded in our electronic dataset, we could not find any statistical association between these risk factors and the likelihood of severe infection. The only identifiable risk factor for a severe infection (sepsis or ICU admission) was the presence of bacteremia.

ctive pulmonary disease, and immunosuppressed status were encoded in our electronic dataset, we could not find any statistical association between these risk factors and the likelihood of severe infection. The only identifiable risk factor for a severe infection (sepsis or ICU admission) was the presence of bacteremia. Regarding the outcomes, we were able to report a low mortality due to Fusobacterium infections since we did not record any deaths attributable to this pathogen. These data are not consistent with those obtained by other publications, which report a mortality rate of 1%,[20] 11%,[7] or even 47.4%[21]. Our study has a number of limitations. Although patient data were available, given the uncommon nature of these infections, even in a 10-year observation period, the size of our cohort remained small (26 patients), in contrast with other aforementioned publications. For this reason, we believe our results regarding risk factors lack statistical significance. With further studies, researchers should be able to shed light on the mechanisms of infection, underlying conditions, and the risk factors involving Fusobacterium infections.

in contrast with other aforementioned publications. For this reason, we believe our results regarding risk factors lack statistical significance. With further studies, researchers should be able to shed light on the mechanisms of infection, underlying conditions, and the risk factors involving Fusobacterium infections. Conclusions Fusobacterium species are the causative pathogen of uncommon infections. The overall incidence found in our study is consistent with other publications. F. necrophorum tends to cause infection in younger individuals, while F. nucleatum has a preference for older patients. The clinical spectrum is wide, ranging from upper respiratory tract infections, such as sinusitis or pharyngitis, to abscess formation and septic shock. Until sample cultures can yield any definitive results, empirical treatment with broad-spectrum antibiotics, such as metronidazole or carbapenems, should be initiated. This treatment should be corrected according to sensitivities and drug resistances. The elective treatment for an abscess is usually percutaneous or surgical drainage, although in some cases, broad-spectrum, systemic antibiotics and medical management may be enough to achieve the complete resolution of the abscess. Conflict of interest: The authors declare that they have no conflict of interest.

Conclusions Fusobacterium species are the causative pathogen of uncommon infections. The overall incidence found in our study is consistent with other publications. F. necrophorum tends to cause infection in younger individuals, while F. nucleatum has a preference for older patients. The clinical spectrum is wide, ranging from upper respiratory tract infections, such as sinusitis or pharyngitis, to abscess formation and septic shock. Until sample cultures can yield any definitive results, empirical treatment with broad-spectrum antibiotics, such as metronidazole or carbapenems, should be initiated. This treatment should be corrected according to sensitivities and drug resistances. The elective treatment for an abscess is usually percutaneous or surgical drainage, although in some cases, broad-spectrum, systemic antibiotics and medical management may be enough to achieve the complete resolution of the abscess. Conflict of interest: The authors declare that they have no conflict of interest. Acknowledgments Authors would like to thank Jacqueline Lamb for her invaluable advice and tips for English grammar and spelling, and Blanca San Jose Montano, the Health Science Librarian-Documentalist of our institution, for her great support, suggestions and encouragement in the making of this manuscript.

Conflict of interest: The authors declare that they have no conflict of interest. Acknowledgments Authors would like to thank Jacqueline Lamb for her invaluable advice and tips for English grammar and spelling, and Blanca San Jose Montano, the Health Science Librarian-Documentalist of our institution, for her great support, suggestions and encouragement in the making of this manuscript. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: For this type of study formal consent is not required.

Introduction The most frequent aetiology of acute pharyngitis is represented by respiratory viruses that usually cause symptoms like conjunctival hyperaemia, rhinorrhoea, sore throat, laryngitis or cough. Exudative pharyngitis is not common in viral infections, except for the Epstein-Barr virus (EBV) infection. Streptococcus pyogenes is the most common bacterial agent involved in exudative pharyngitis, being responsible for 5%-30% of all cases of acute tonsillitis, especially in children [1]. Streptococcal pharyngitis can be associated with multiple complications such as toxin-mediated (TMC), septic or allergic complications. TMC due to streptococcal infections are rarely reported in the literature, but when reported, any organ can be affected, causing arthritis, nephritis, hepatitis, haematological or cardiac disorders or even toxic shock [2, 3]. Several cases of haematological disorders [4] or ECG abnormalities [5] due to streptococcal infection have been reported in the medical literature, though none can be traced regarding the association between T-wave inversion and neutropenia. Case presentation A 31-year-old woman, without a medical history of streptococcal tonsillitis, was admitted, presenting with fever, headache, sore throat, tachycardia and fatigue. The onset of the disease had occurred three days before the admission. The patient had, prior to admission, cefuroxime 500 mg twice a day without improvement.

A 31-year-old woman, without a medical history of streptococcal tonsillitis, was admitted, presenting with fever, headache, sore throat, tachycardia and fatigue. The onset of the disease had occurred three days before the admission. The patient had, prior to admission, cefuroxime 500 mg twice a day without improvement. On admission, the patient’s temperature was recorded as 39.5°C. Clinical exam showed enlarged tonsils with extended white spots on both tonsils and submandibular lymphadenopathy. ECG, complete blood count (CBC), markers of inflammation, biochemistry (renal, liver and metabolic tests), urinalysis, a throat swab and a rapid test for streptococcal infection were carried out. The patient was hospitalized having presented with a leukocyte count of 1800 leukocyte/mm3, a neutrophil count of 300 neutrophils/mm3, inverted T waves in leads V1-4 (Figure 1) and negative “rapid strep test”. After that, we completed the investigations as follows: Fig. 1 The ECG at admission – transaminases, electrolytes, lactate dehydrogenase (LDH), creatin kinase-MB (CK-MB) and troponin; all the mentioned tests were within normal values; – antistreptolysin O test (ASLO) below 200 IU/ ml; – blood smear with leukopenia and neutropenia, without blast cells; – inflammatory syndrome (C reactive protein 123 mg/L, fibrinogen 8.18 g/L); – procalcitonin level under 0.05 ng/ml; – viral capsid antigen (VCA) IgM for EBV - negative, with positive IgG; – thyroid tests within normal limits; – transthoracic echocardiography without signs of pericarditis.

– blood smear with leukopenia and neutropenia, without blast cells; – inflammatory syndrome (C reactive protein 123 mg/L, fibrinogen 8.18 g/L); – procalcitonin level under 0.05 ng/ml; – viral capsid antigen (VCA) IgM for EBV - negative, with positive IgG; – thyroid tests within normal limits; – transthoracic echocardiography without signs of pericarditis. From the beginning, four possible scenarios were taken into consideration for the differential diagnosis: a streptococcal infection, a viral infection, a bacterial tonsillitis of other aetiology and a haematological disorder. Streptococcal infection A streptococcal pharyngitis is the most frequent aetiology of exudative tonsillitis. Moreover, the TMC during a streptococcal infection can include cardiac or haematological toxicity. The severe inflammatory syndrome on admission and the increasing value of ASLO at discharge sustain this supposition. The rapid strep test and the cultures were negative, but can be explained by the fact that the patient received antimicrobial therapy active on Streptococcus pyogenes prior to admission. A viral infection A viral infection, especially an infectious mononucleosis, the most common cause of viral exudative tonsillitis, was excluded because the patient was previously infected with EBV (positive anti VCA IgG for EBV). Furthermore, we did not find generalized lymphadenopathy, hepatosplenomegaly, increased transaminases which are suggestive elements for EBV primary infection.

cleosis, the most common cause of viral exudative tonsillitis, was excluded because the patient was previously infected with EBV (positive anti VCA IgG for EBV). Furthermore, we did not find generalized lymphadenopathy, hepatosplenomegaly, increased transaminases which are suggestive elements for EBV primary infection. Bacterial tonsillitis of other aetiology Bacterial tonsillitis of other aetiology, especially a staphylococcal infection; the TMC of staphylococcal infection involves especially skin disorders and it is unusual to associate leukopenia and ECG changes. Diphtheria has been eradicated in Romania and therefore was ruled out. Moreover, the symptomatology was not suggestive for this aetiology. A haematological disorder This was excluded after haematological evaluation, including a blood smear. The haematologist did not consider necessary a bone aspiration or biopsy. The conclusion was that the most probable aetiology was Streptococcus pyogenes. The patient received intravenous Penicillin G (1 million units every 6 hours) in association with oral slow-releasing clarithromycin (500 mg/day) and dexamethasone (4mg twice a day).

A haematological disorder This was excluded after haematological evaluation, including a blood smear. The haematologist did not consider necessary a bone aspiration or biopsy. The conclusion was that the most probable aetiology was Streptococcus pyogenes. The patient received intravenous Penicillin G (1 million units every 6 hours) in association with oral slow-releasing clarithromycin (500 mg/day) and dexamethasone (4mg twice a day). The clinical outcome was good, but after 24 hours the leucocyte count decreased to 1100/mm3 with 200 neutrophils/mm3. After 48 hours, the leucocyte count was 4600/mm3 with normal neutrophil count. The ECG was repeated after 48 hours and it showed normal sinus rhythm and cardiac axis (+30 degrees), but with bradycardia (55/minute) and the persistence of T-wave inversion in leads V1-3, with almost normal T waves in V5-6 (Figure 2). The biological markers for myocardial necrosis (troponin, LDH, CK-MB) remained normal after 48 hours. We stopped clarithromycin after 2 days because a staphylococcal infection was excluded. In day 3 of admission, the clinical exam showed the decrease of tonsils volume without any exudate at this level. The submandibular lymphadenopathy has also decreased in volume. After 96 hours, the ECG revealed T waves with favourable outcome, with inverted T waves only in leads V1-2, prolonged QT interval and persistent bradycardia (Figure 3). The cardiologist did not consider necessary to perform any supplementary evaluation. The leucocyte count increased to 12000/mm3 and we stopped the dexamethasone. We discharged the patient after 6 days, with normal leucocyte count and inflammatory biomarkers. ASLO titre increased 3 fold.

rsistent bradycardia (Figure 3). The cardiologist did not consider necessary to perform any supplementary evaluation. The leucocyte count increased to 12000/mm3 and we stopped the dexamethasone. We discharged the patient after 6 days, with normal leucocyte count and inflammatory biomarkers. ASLO titre increased 3 fold. Fig. 2 The ECG after 48 hours Fig. 3 The ECG after 96 hours Oral penicillin 1 million units every 6 hours for another 4 days was prescribed. One week after discharge, the ECG showed normal heart rate, inverted T waves only in V1-2 and a normal QT interval. Discussions In this case report, we describe the TMC of streptococcal tonsillitis such as T-wave inversion syndrome and severe leukopenia and neutropenia in a patient without any history of recurrent streptococcal infection and also without cardiac or haematological antecedents. Streptococcus pyogenes is the most common aetiology of exudative pharyngitis and in more rare cases, some viruses or other bacteria can be involved. This is the main reason why swabbing the throat should be performed from the beginning, before starting the antimicrobial therapy, to identify the pathogen agent. The pathogenesis of streptococcal infections involves multiple toxins or virulence factors such as exotoxins A, B, C, F, streptococcal superantigens released into the circulation in the acute phase of infection. A high number of T-lymphocytes is activated, which is responsible for releasing inflammatory cytokines into the blood, causing several organic dysfunctions [6].

s multiple toxins or virulence factors such as exotoxins A, B, C, F, streptococcal superantigens released into the circulation in the acute phase of infection. A high number of T-lymphocytes is activated, which is responsible for releasing inflammatory cytokines into the blood, causing several organic dysfunctions [6]. Myocarditis related to streptococcal infection is usually associated with rheumatic fever, 7-10 days after an acute episode of tonsillitis. The mechanism is probably a cross-reaction between streptococcal M proteins and cardiac myosin [7]. The first case of myocarditis unrelated to rheumatic fever was reported in 1947 [8]. Since then, several other cases, usually describing young patients without a history of cardiac pathologies, have been published, with previously unspecified clinical signs or symptoms and ECG changes in the acute phase of a streptococcal tonsillitis [9, 10]. The most frequent ECG finding in streptococcal myocarditis is a diffuse T-wave inversion [11]. It is mandatory to differentiate between a normal variant, which is more frequent in young women than in men [12], an acute coronary syndrome and a transient T-wave inversion related to a streptococcal infection. Because the patient had previously normal ECG and cardiac enzymes and the ECG improved under antimicrobial therapy during hospitalization, we concluded that the T-wave inversion was infection-related.

men than in men [12], an acute coronary syndrome and a transient T-wave inversion related to a streptococcal infection. Because the patient had previously normal ECG and cardiac enzymes and the ECG improved under antimicrobial therapy during hospitalization, we concluded that the T-wave inversion was infection-related. Concerning the haematological disorders, streptococcal infections are associated with leucocytosis with a high number of neutrophils, due to the intense activation of the immune system. In rare cases, leukopenia can occur and this is thought to be a toxin-mediated complication during acute tonsillitis. Other haematological disorders have also been associated with acute streptococcal infection, such as haemolytic anemia or thrombocytopenia. The haemolytic anemia can appear as an effect of the haemolytic enzymes contained by the bacteria [4]. Regarding the thrombocytopenia, it can be caused by M proteins’ property to stimulate platelets activation [13]. A low number of cases reporting either T-wave inversion or neutropenia as TMC of streptococcal infections have been reported in the literature [14]. Our case is probably the first one reported until present regarding this association in a patient without previous cardiac or haematological disorders.

Concerning the haematological disorders, streptococcal infections are associated with leucocytosis with a high number of neutrophils, due to the intense activation of the immune system. In rare cases, leukopenia can occur and this is thought to be a toxin-mediated complication during acute tonsillitis. Other haematological disorders have also been associated with acute streptococcal infection, such as haemolytic anemia or thrombocytopenia. The haemolytic anemia can appear as an effect of the haemolytic enzymes contained by the bacteria [4]. Regarding the thrombocytopenia, it can be caused by M proteins’ property to stimulate platelets activation [13]. A low number of cases reporting either T-wave inversion or neutropenia as TMC of streptococcal infections have been reported in the literature [14]. Our case is probably the first one reported until present regarding this association in a patient without previous cardiac or haematological disorders. The sudden onset and the rapid recovery following antimicrobial therapy to combat Streptococcus pyogenes, sustains a toxic pathogenesis hypothesis. If ECG disturbances in such situation are accompanied by suggestive symptomatology or increased cardiac enzymes, further investigations as cardiac MRI may be necessary [15]. Unfortunately, in the absence of symptoms, the TMC of streptococcal infections remain under-recognized and under-reported.

athogenesis hypothesis. If ECG disturbances in such situation are accompanied by suggestive symptomatology or increased cardiac enzymes, further investigations as cardiac MRI may be necessary [15]. Unfortunately, in the absence of symptoms, the TMC of streptococcal infections remain under-recognized and under-reported. Conclusions It is important to perform an ECG in order to early diagnose a myocarditis when confronted by a patient with exudative tonsillitis, even though the patient does not have cardiac symptomatology. Further investigations are necessary if a myocarditis is suspected. Leukopenia with neutropenia, in a patient with exudative tonsillitis and an inflammatory syndrome, may also suggest a TMC related to a streptococcal infection. Authors’ contributions statement: The authors have equally contributed to this paper. All the authors treated the patient, contributed to the writing of the draft and approved the final manuscript. Conflict of interest:The authors declare no conflicts of interest. Acknowledgements Written informed consent was obtained from the patient to publish the clinical details and images in this article. We thank Bogdana Manu, our cardiologist. This work is part of “Carol Davila” doctoral programme.

Introduction Victims of domestic fire usually present with co-existing skin and respiratory lesions [1, 2]. In many cases, upper airway lesions are often ignored. All good medical practice reports recommend that all fire victims should be systematically evaluated by bronchoscopy [3, 4]. Criteria for bronchoscopy assessment, to standardise the severity of respiratory lesions in domestic fire cases, have been published [5]. Bronchoscopy is considered to be the “gold standard” for early evaluation of upper airway injury in burns patients for predicting acute pulmonary lesions and treating these injuries [3, 6]. The current case reports the experience of using repeated bronchoscopies as a treatment tool in a case of severe respiratory failure due to bronchial obstruction by secretions and soot deposits in a burns patient. The patient was a victim of a domestic closed space fire who presented with 1-3-degree skin burns on 10% of the total body surface. Forty-eight hours from admission, he developed severe respiratory failure, requiring repeated bronchial lavages to remove secretions and soot deposits. Case report A 23-year-old man, victim of a closed space house fire, was first admitted to the Roman County Hospital, Romania and two days later was transferred to the Emergency County Clinic Hospital Iasi, Romania.

The current case reports the experience of using repeated bronchoscopies as a treatment tool in a case of severe respiratory failure due to bronchial obstruction by secretions and soot deposits in a burns patient. The patient was a victim of a domestic closed space fire who presented with 1-3-degree skin burns on 10% of the total body surface. Forty-eight hours from admission, he developed severe respiratory failure, requiring repeated bronchial lavages to remove secretions and soot deposits. Case report A 23-year-old man, victim of a closed space house fire, was first admitted to the Roman County Hospital, Romania and two days later was transferred to the Emergency County Clinic Hospital Iasi, Romania. On admission, the physical examination revealed an overweight patient with a body mass index of 28.7 kg/m2, with 1-3-degree skin burns on 10% of the total body surface involving areas of the face, left shoulder, arm and forearm, and both hands. He was conscious and haemodynamically stable. He had dyspnoea with polypnea (25 breaths/min), productive cough with yellow grey sputum, and bilateral rhonchi were detected on pulmonary auscultation. Chest X-rays revealed an area of pulmonary condensation in the superior lobe of the left lung, while the right lung area appeared radiologically normal. Arterial blood gases analysis while breathing room air showed pO2 120 mmHg, pCO2 60 mmHg, SaO2 94%, pH 7.32.

bilateral rhonchi were detected on pulmonary auscultation. Chest X-rays revealed an area of pulmonary condensation in the superior lobe of the left lung, while the right lung area appeared radiologically normal. Arterial blood gases analysis while breathing room air showed pO2 120 mmHg, pCO2 60 mmHg, SaO2 94%, pH 7.32. Laboratory tests showed marked leucocytosis (34,100/mm3) with neutrophilia, increased ASAT (73 U/l), CK (1868 U/l) and LDH (1161 U/l), increased lactate level (1.3 mmol/l), and glycaemia - 119 mg/dl. Bronchoscopy was delayed due to unforeseen technical difficulties. Local treatment of the skin burns consisting of mechanical and chemical washing was commenced on the first day of admission along with broad spectrum antibiotic therapy with intravenous amoxicillin/clavulanate potassium 1000 mg/200 mg, every 8 hours for 14 days. Forty-eight hours after admission, despite receiving supplemental oxygen via nasal cannula, the patient developed progressively severe dyspnoea and tachypnoea with a respiratory rate of 32/minute, peripheral cyanosis and agitation, tachycardia (134/min), blood pressure (40/80 mmHg) and decreased oxygen saturation (70%). Arterial blood gas analysis showed pO2, 41 mmHg; pCO2, 98 mmHg; pH = 7.18, and PaO2/FiO2 = 102, which were consistent with the diagnosis of respiratory failure. The patient was promptly intubated and mechanically ventilated. A bedside chest X-ray showed bilateral confluent multiple nodular lesions similar to those described in moderate acute respiratory distress syndrome (ARDS).

g; pH = 7.18, and PaO2/FiO2 = 102, which were consistent with the diagnosis of respiratory failure. The patient was promptly intubated and mechanically ventilated. A bedside chest X-ray showed bilateral confluent multiple nodular lesions similar to those described in moderate acute respiratory distress syndrome (ARDS). Despite repeated attempts to correct ventilation, only a limited improvement of arterial gases, was achieved. Mechanical ventilation using BiPAP mode with FiO2 100% which was progressively increased 5 to 7 cm water PEEP, improved the oxygen saturation to 86% and pO2 to 54 mmHg. The change of inspiratory pressure (Pi) from 25 to 35 cm water failed to improve the tidal volume, which remained at 350 ml. It was considered necessary to increase the respiratory rate to 16-18 breaths/min to correct hypoventilation and to decrease pCO2. At this point, it was suspected that an obstruction of the superior airway had occurred, and an emergency endoscopy was requested. This showed a grade 2 inhalation injury, numerous white-grey secretions and soot deposits which had formed bronchial casts causing severe airway obstruction (Fig. 1). Fig. 1 Endoscopic appearance of the airways: A. Secretions and deposits of soot; B. Organized bronchial casts; C. Removal using bronchial forceps; D. Revealing a normal bronchial mucosa underneath the secretions.

Introduction Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) improves the prognosis in selected patients with peritoneal surface malignancies [1]. It is an extensive procedure with significant hemodynamic, metabolic, hematological unbalances predisposing to major complications. A recent manuscript highlighted that diabetes predicted significant more major complications and increased mortality following CRS/HIPEC [2]. Among them renal toxicity was reported to occur with a frequency ranged between 1.9-5.7%, depending on chemotherapy [3, 4, 5]. Severe renal insufficiency is considered a contraindication for this complex procedure [6]. Scare literature data address a debate regarding the peri-operative anesthetic management of patients with moderate renal insufficiency related to diabetes mellitus that are considered for CRS with HIPEC. We present a patient with diabetic nephropathy and chronic renal failure stage 3 Kidney Disease Outcomes Quality Initiative (KDOQI 3) and peritoneal metastasis from sigmoid adenocarcinoma with a good clinical outcome after CRS with HIPEC, highlighting the anesthetic precautions considered for this particular clinical case.

At this point, it was suspected that an obstruction of the superior airway had occurred, and an emergency endoscopy was requested. This showed a grade 2 inhalation injury, numerous white-grey secretions and soot deposits which had formed bronchial casts causing severe airway obstruction (Fig. 1). Fig. 1 Endoscopic appearance of the airways: A. Secretions and deposits of soot; B. Organized bronchial casts; C. Removal using bronchial forceps; D. Revealing a normal bronchial mucosa underneath the secretions. The removal of the bronchial casts required the use of biopsy forceps to detach the pseudo membranes and when completed, revealed a normal bronchial mucosa underneath. The respiratory status of the patient, as well as the parameters of arterial blood gases, improved after daily bronchial endoscopic lavages. Bronchoscopy was necessary for eight days to clean all bronchial secretions and soot deposits efficiently. Extubation was possible ten days after the development of the severe respiratory failure. The serial direct microscopic exam of the samples collected daily revealed an inflammatory reaction, with neutrophils and fibrin. No bacterial growths were obtained from repeated culture of broncho alveolar specimens. The skin burns and lesions of the upper airway responded favourably to supportive therapy, broad spectrum antibiotherapy and analgesia with remifentanil 0.075-1 mcg/kg/min, continuous infusion for 8 days. The bronchoscopy performed just before discharge revealed no secretions, no luminal obstructions and no fistulas. The patient was released from the hospital after 24 days.

The skin burns and lesions of the upper airway responded favourably to supportive therapy, broad spectrum antibiotherapy and analgesia with remifentanil 0.075-1 mcg/kg/min, continuous infusion for 8 days. The bronchoscopy performed just before discharge revealed no secretions, no luminal obstructions and no fistulas. The patient was released from the hospital after 24 days. Discussion Severe airways obstruction due to secretions and deposits of soot organised as bronchial casts was treated by repeated bronchial endoscopic examination. This proved to be an effective therapeutic method for removing bronchial soot casts, resulting in improved ventilator function and patient condition. As reported in the literature on domestic fire victims with inhalational smoke injuries, upper airway lesions are often ignored. Pulmonary lesions usually cause problems which commence a few days following the fire and lead to worsening of the patient’s vital prognosis. Serial bronchoscopies with lavage have been reported to be useful for clearing of mucus plugs. [1, 2, 5, 7, 8, 9]. There are contradictory opinions regarding serial fibre-optic bronchoscopies in patients with smoke inhalational injuries, because of the lack of prospective or interventional studies. [10] However, a study performed on 624 patients with smoke inhalational injuries showed a trend toward shorter hospitalisation in patients who underwent more than one bronchoscopy procedure [11].

c bronchoscopies in patients with smoke inhalational injuries, because of the lack of prospective or interventional studies. [10] However, a study performed on 624 patients with smoke inhalational injuries showed a trend toward shorter hospitalisation in patients who underwent more than one bronchoscopy procedure [11]. Although there are multiple causes, in addition to smoke inhalation, which contribute to lung injury, such as systemic inflammation in response to burns, ventilator-induced injury or pulmonary infections [1], only smoke inhalation and systemic inflammation were considered to be responsible for the bronchial lesions. Scoring systems have been formulated to identify patients with a poor prognosis, The Abbreviated Injury Score grading scale is one of them and is correlated with increased mortality in burns victims [12]. In the current case, bronchoscopy revealed a moderate inhalation injury. The patient developed a severe respiratory failure that could not be treated only by mechanical ventilation, and repeated bronchoscopies were required to separate and remove bronchial secretions and soot deposits before their organisation in bronchial casts. There are two types of respiratory injuries that appear in domestic fire victims, injuries related to smoke inhalation and injuries related to the heat generated by a fire [1, 9]. Patients with respiratory injuries have a poor prognosis and a mortality rate of up to 20% [1]. When there are associated pulmonary infections, the mortality rate can reach 40% [1, 8].

that appear in domestic fire victims, injuries related to smoke inhalation and injuries related to the heat generated by a fire [1, 9]. Patients with respiratory injuries have a poor prognosis and a mortality rate of up to 20% [1]. When there are associated pulmonary infections, the mortality rate can reach 40% [1, 8]. The negative bronchial cultures obtained in the present case were probably accounted for by the broad spectrum antibiotic therapy initiated on admission. Following the experience of using multiple bronchoscopies in this reported case, a bronchial endoscopy investigation protocol was implemented for all domestic fire victims admitted to the Burns Department of Iasi Clinical Emergency County Hospital. From January 2004 to December 2013, a total of 1759 cases of burnt patients were admitted to the Burns Department and flexible bronchoscopy was performed on all admitted patients. In most cases, mild to moderately severe lesions, graded 5 and 8 on the Jones’ system of grading, were detected [5]. Conclusions Daily flexible bronchoscopies and airway washings for the treatment of respiratory failure from bronchial plugs secondary to lung injury after exposure to domestic fires lesions contributed to patient progress, which was not responding to treatment with mechanical ventilation alone. Conflict of interest: None to declare

resent a patient with diabetic nephropathy and chronic renal failure stage 3 Kidney Disease Outcomes Quality Initiative (KDOQI 3) and peritoneal metastasis from sigmoid adenocarcinoma with a good clinical outcome after CRS with HIPEC, highlighting the anesthetic precautions considered for this particular clinical case. Case Report A 64-year-old ASA II (American Society of Anesthesiologists) patient known with sigmoid adenocarcinoma pT4bN0M0L0V0R0 treated with sigmoid resection and chemotherapy was proposed for CRS with HIPEC considering the development of peritoneal metastases 10 months later. His past medical history was significant for blood hypertension, diabetes mellitus treated with insulin, hypertensive and diabetic nephropathy with renal insufficiency KDOQI 3. At admittance in hospital the clinical examination revealed an obese patient with BMI of 34.5 with controlled blood pressure and diuresis of 1500 ml daily. Blood analyses revealed, a blood glucose level of 165mg/dl, a creatinine level of 2.25mg/dl corresponding to a GFR of 49.98. The CRS with HIPEC procedure was performed in general anesthesia. Anesthesia was induced with fentanyl 3μg/kg and propofol 2mg/kg, intubation being facilitated with atracurium 0.5 mg/kg. Anesthesia was maintained with isoflurane and supplemented with intravenous fentanyl or epidural bupivacaine according to the patient’s individual needs.

rocedure was performed in general anesthesia. Anesthesia was induced with fentanyl 3μg/kg and propofol 2mg/kg, intubation being facilitated with atracurium 0.5 mg/kg. Anesthesia was maintained with isoflurane and supplemented with intravenous fentanyl or epidural bupivacaine according to the patient’s individual needs. The cytoreductive phase consisted in extensive peritoneal resections together with segmental colonic and ileal resections, reestablishing digestive continuity through L-L ileo-transverso-colonic anastomosis. After cytoreduction before initiation of HIPEC, we ensured that fluid warmers and warming blankets were turned off. HIPEC was performed using an open technique (COLISEUM). For HIPEC phase oxaliplatin at 41-43°C for 30 min was used, being associated with intravenous administration of 5-fluorouracil and leucovirin. We monitored the core body temperature that was maintained by using warming blankets and infusing warm fluids. The duration of the whole procedures was 720 min with 100ml blood loss. The main purpose during the procedure was to maintain hemodynamic stability (MAP≥65 mmHg) and euvolemia (CVP between 3 and 5 mmHg). Hemodynamic stability was achieved by continuous infusion of low dose of noradrenaline (0,03-0,05 μg/kg/min).

The cytoreductive phase consisted in extensive peritoneal resections together with segmental colonic and ileal resections, reestablishing digestive continuity through L-L ileo-transverso-colonic anastomosis. After cytoreduction before initiation of HIPEC, we ensured that fluid warmers and warming blankets were turned off. HIPEC was performed using an open technique (COLISEUM). For HIPEC phase oxaliplatin at 41-43°C for 30 min was used, being associated with intravenous administration of 5-fluorouracil and leucovirin. We monitored the core body temperature that was maintained by using warming blankets and infusing warm fluids. The duration of the whole procedures was 720 min with 100ml blood loss. The main purpose during the procedure was to maintain hemodynamic stability (MAP≥65 mmHg) and euvolemia (CVP between 3 and 5 mmHg). Hemodynamic stability was achieved by continuous infusion of low dose of noradrenaline (0,03-0,05 μg/kg/min). Crystalloids at the rate of 10-15 ml/kg/h were infused and urine output (62.5 ml/15 min) was used as a guide for fluids administration. It was noticed a brief metabolic acidosis and a transient increase in arterial lactate levels (ph = 7.2, lactate = 1.8mmol/l). Calcium, potassium, sodium and magnesium were also checked intraoperatively and the values were normal.

infused and urine output (62.5 ml/15 min) was used as a guide for fluids administration. It was noticed a brief metabolic acidosis and a transient increase in arterial lactate levels (ph = 7.2, lactate = 1.8mmol/l). Calcium, potassium, sodium and magnesium were also checked intraoperatively and the values were normal. The patient was monitored in intensive care unit for 5 days without any significant complications. We focused on the renal function, the diuresis being approximately 2500 ml daily, and creatinine level dropped at 1.3 mg/dl in the 5th day after surgery and then stabilizes at 1.6 mg/dl at discharge from hospital [Fig 1-Fig 3]. He was discharged from hospital 10 days after the procedure in good clinical condition. Fig 1 Creatinine values in postoperative period Fig 2 Blood urea nitrogen values in postoperative period Fig 3 GFR values in postoperative period At 6 months follow-up there were no signs of tumor recurrence and the creatinine level was similar with the basal values of the patient. Discussions CRS with HIPEC is an extensive procedure with significant hemodynamic, metabolic, hematologic alterations that predispose patients to a wide variety of postoperative complications. Among them renal toxicity was reported to occur with a frequency ranged between 1.9-5.7%, depending on the type of chemotherapy [3, 4, 5]. Severe renal insufficiency is considered a contraindication for this complex procedure [6]. Diabetes pre-disposes to significantly more major complications and increased mortality following CRS/HIPEC [2].

ty was reported to occur with a frequency ranged between 1.9-5.7%, depending on the type of chemotherapy [3, 4, 5]. Severe renal insufficiency is considered a contraindication for this complex procedure [6]. Diabetes pre-disposes to significantly more major complications and increased mortality following CRS/HIPEC [2]. Literature data are lacking in protocols regarding the peri-operative anesthetic management of patients with moderate renal insufficiency related to diabetes mellitus that are considered for CRS with HIPEC. We report for the first time a case of renal insufficiency KDOQI 3 in a diabetic patient who tolerated well a 12-hour intervention of CRS with HIPEC for peritoneal metastasis from sigmoid adenocarcinoma, highlighting the anesthetic precautions considered for this particular clinical case. The risk factors for renal failure after CRS with HIPEC are: chemotherapy, surgical technique, hemodynamic instability, fluid losses and temperature. Oxaliplatin is a chemotherapeutic agent that affects renal function by direct toxicity, or through hemolytic mechanism [7]. The closed technique of CRS with HIPEC can affect the renal function by raising the intra-abdominal pressure (IAP). It was showed that there is a signicantly decreased GFR in patients with elevated intraabdominal pressure (8).

Oxaliplatin is a chemotherapeutic agent that affects renal function by direct toxicity, or through hemolytic mechanism [7]. The closed technique of CRS with HIPEC can affect the renal function by raising the intra-abdominal pressure (IAP). It was showed that there is a signicantly decreased GFR in patients with elevated intraabdominal pressure (8). HIPEC produces a hyperdynamic vasodilated state leading to increase in heart rate and increase in intra-abdominal pressure, especially in the closed technique with reduction in the cardiac output [9, 10]. Considering the extent of this type of intervention large fluid shifts can explain the renal impairment. Hyperthermia may cause consumptive coagulopathies, arrhythmias, liver/renal injury, peripheral neuropathies, and seizures [10, 11]. Our intraanesthetic management to prevent further renal function deterioration consisted of achieving hemodynamic stability by continuous infusion of low dose of noradrenaline, maintaining euvolemia by crystalloid infusion (10-15 ml/kg/h). For this patient we preferred the open technique to prevent the increase in intra-abdominal pressure. In the HIPEC phase we monitored the urinary output and try to achieve a flow of 50-70-ml/15 min using crystalloids and loop and osmotic diuretics. We also used anesthetic drugs with low impact on the renal function. The total amount of crystalloid used was 11000ml/12h and we obtained a diuresis of 3000ml/12h.

pressure. In the HIPEC phase we monitored the urinary output and try to achieve a flow of 50-70-ml/15 min using crystalloids and loop and osmotic diuretics. We also used anesthetic drugs with low impact on the renal function. The total amount of crystalloid used was 11000ml/12h and we obtained a diuresis of 3000ml/12h. There is a debate in literature regarding the use of furosemide to enhance urine output to clear as much chemotherapeutic agent as possible [9, 12, 13, 14]. Forced diuresis by the use of high dose loop-diuretics is still considered “standard of care” during chemotherapy with compound derived from platinum, even without definitive evidence. Corbella et al highlighted the role of invasive monitoring of euvolemia, as drug clearance is mainly linked to renal blood flow and not to plain urine output; this approach permitted the use of loop diuretics in accordance with maintaining euvolemia [9]. Our management was similar as we used only 80 mg of Furosemide administered bolus in the first 3 postoperative days. Postoperative management was also focused on maintaining euvolemia (CVP between 3 and 7 mmHg) and an adequate diuresis using loop and osmotic diuretics (100mg mannitol 20% in the first 3 postoperative days) that were gradually stopped as the renal function stabilized (creatinine level dropped from 2.26mg/dl to 1.3mg/dl in the 5th day and stabilized to 1.6 mg/dl at discharge from hospital). At 6 months follow up there were no signs of tumor recurrence and the creatinine level was similar with the basal values of the patient.

at were gradually stopped as the renal function stabilized (creatinine level dropped from 2.26mg/dl to 1.3mg/dl in the 5th day and stabilized to 1.6 mg/dl at discharge from hospital). At 6 months follow up there were no signs of tumor recurrence and the creatinine level was similar with the basal values of the patient. Conclusion In patients with renal failure that need CRS with HIPEC we recommend that intraoperative management should be focused on maintaining euvolemia by measuring parameters that give information about it (lactate, SVV, CVP) and maintenance of hemodynamic stability (MAP> 65 mmHg) using vasopressors. We also recommend the administration of diuretics (loop diuretics and osmotics) both intraoperatively during the HIPEC phase of the procedure and in the first 3 days postoperatively. With this management CRS (open technique) with HIPEC can be performed safely to patients with renal failure KADOQI 3 related to diabetes mellitus. Conflict of Interest: None declared.

Introduction Aetiology of stroke in elderly patients can be difficult to diagnose. One of the unusual etiologies of stroke is meningovascular neurosyphilis, which is frequently overlooked in the diagnosis process. We report a case of an elderly with uncharacteristic neurologic and cognitive symptoms, suspected of ischemic stroke, which required an extensive assessment in the departments of neurology and internal medicine. The patient fully recovered after antibiotic therapy. Case presentation An 84 years old woman presented to the emergency department with dysarthria, weakness in her right arm, headache, dizziness, with the inability to maintain orthostatic posture. The symptoms appeared six months previously but had increased in severity in the last month. The patient had been diagnosed with hypertension several years earlier. She was undertaking chronic antihypertensive therapy with enalapril 20 mg/day and nifedipine 20 mg/day. She was first admitted to a county hospital, and at family’s request, she was transferred to “Sf. Spiridon” Clinical County Emergency Hospital. On admission, she had gait difficulties. She could not maintain an orthostatic position for more than seven minutes. Neurologic examination revealed: central vestibular syndrome (vertigo, nystagmus, with static and dynamic balance impairment), right incomplete hemiparesis, dysphasia, diffuse headache without meningeal irritation signs, and neuropsychiatric syndrome (insomnia, poor concentration, a deficit in attention, memory loss).

Neurologic examination revealed: central vestibular syndrome (vertigo, nystagmus, with static and dynamic balance impairment), right incomplete hemiparesis, dysphasia, diffuse headache without meningeal irritation signs, and neuropsychiatric syndrome (insomnia, poor concentration, a deficit in attention, memory loss). She had an area of nasal and malar hyperemia very similar to a “butterfly rash”. On the nose and right retro-auricular region, she had a postoperative scar. The rest of the physical exam was normal. The patient reported a 4-5 months’ history of intermittent fever, worsening headache, dizziness, loss of appetite, and insomnia. She said she had difficulty in concentration, short-term memory loss and sometimes slurred speech. Two months previously she had had a surgical intervention for skin tumours in the right nasal region and right retro-auricular area. She could not explain the type of tumours that had been excised. She did not report any other diseases in her past medical history. The initial CT scan of the brain excluded stroke, or cerebral vascular malformation and showed only microangiopathy-like lesions that were interpreted as secondary to poorly controlled hypertension. Blood tests were normal as were renal function and hepatic function tests, complete blood count, fasting blood glucose, electrolytes and thyroid function tests. The ESR was 69 mm /1 hour. To exclude vasculitis, immunological tests are necessary for a patient with neurological symptoms and hypertension. All markers of vasculitis were negative.

Blood tests were normal as were renal function and hepatic function tests, complete blood count, fasting blood glucose, electrolytes and thyroid function tests. The ESR was 69 mm /1 hour. To exclude vasculitis, immunological tests are necessary for a patient with neurological symptoms and hypertension. All markers of vasculitis were negative. The level of VDRL was 1:128 and Treponema pallidum particle agglutination assay (TPPA) was more than 1:800. Cerebrospinal fluid (CSF) examination showed a protein level of 99 mg/dl, 29 leukocytes /mm3 and a glucose level of 40 mg/dl. At the time of admission, it was technically impossible to determine VDRL in the CSF. A later result was negative. An MRI of the brain showed multiple lacunar ischemic lesions in the basal ganglia, enhancement of the leptomeningeal vessels in the left frontoparietal area, mild T2 and FLAIR signal hyperintensity in the left frontoparietal subcortical area. (Figure 1) Fig. 1 A. Multiple lacunar ischemic lesions in basal ganglia, dilatation of the Virchow-Robin spaces. B. Enhancement of the leptomeningeal vessels in left frontoparietal area. C. Enhancement of the leptomeningeal vessels in left frontoparietal area, mild T2 and FLAIR signal hyperintensity in left frontoparietal subcortical area. Based on clinical signs, laboratory data and the brain MRI, neurosyphilis was diagnosed. Penicillin G was started, 24 million IU infusion/day, divided into four doses, for 14 days. After that intramuscular benzathine penicillin, 2.4 million units once per week was administered by intramuscular injection and continued for three weeks.

Based on clinical signs, laboratory data and the brain MRI, neurosyphilis was diagnosed. Penicillin G was started, 24 million IU infusion/day, divided into four doses, for 14 days. After that intramuscular benzathine penicillin, 2.4 million units once per week was administered by intramuscular injection and continued for three weeks. At follow-up, six months later, she had no symptoms, and serological tests were negative. Discussion Neurosyphilis is a neurologic disease underdiagnosed especially because of its atypical, and sometimes bizarre clinical features [1, 2, 3]. Osler stated in 1892 that “syphilis simulates all other diseases” and called it “the great imitator” [4]. In the elderly, neurosyphilis is often overlooked in the diagnostic algorithm of an ischemic stroke [1, 3, 4, 5]. Frequently, the onset can appear to be an ischemic stroke, dementia, or psychosis [1, 2, 3, 6, 7, 8, 9]. Neurosyphilis is determined by Treponema pallidum infection of the brain, meninges and spinal cord, affecting approximately 25-40% of untreated infected patients [6, 7, 8, 9]. It is caused by an infection with Treponema pallidum, appearing in the secondary or tertiary phase of the disease[3, 8, 9, 10]. In the majority of cases, it occurs 10-20 years after the initial infection, [1, 5, 7] although it may appear after a shorter period [8, 9]. The most common known clinical features of neurosyphilis are neuropsychic changes (psychosis, dementia, delirium), strokes, ophthalmologic features (uveitis, optic neuritis), myelopathies, seizures, brainstem or cranial nerves involvement [2, 3, 6, 8, 9, 10].

In the majority of cases, it occurs 10-20 years after the initial infection, [1, 5, 7] although it may appear after a shorter period [8, 9]. The most common known clinical features of neurosyphilis are neuropsychic changes (psychosis, dementia, delirium), strokes, ophthalmologic features (uveitis, optic neuritis), myelopathies, seizures, brainstem or cranial nerves involvement [2, 3, 6, 8, 9, 10]. Neurosyphilis represents a diagnostic problem because of its nonspecific clinical features and given the recurrence of the disease both in young and elderly patients whether they are immunocompromised or not [1, 2, 8, 9]. There are many reported cases of delayed diagnosis of neurosyphilis, explained by its atypical clinical features [1, 2, 3, 4, 5, 6, 7]. The patient reported in this instance had skin lesions, most probably syphilitic gummas, which had not been diagnosed as such, and the interpretation of the cerebral lesions as shown on the CT scan of the brain as being secondary to untreated hypertension resulted in a delayed diagnosis. Establishing an accurate diagnostic was possible only after multiple investigations regarding the aetiology of an ischemic stroke. It was impossible, for technical reasons, to determine VDRL in the CSF upon admission, and a later result was negative. However, the VDRL in the CSF is reactive in only 70-75% of cases [1], and a negative result does not exclude the diagnosis of neurosyphilis [11]. If the VDRL in the CSF is negative, a white blood cell count more than five cells/mm3 or a protein level more than 46 mg/dl are suggestive of neurosyphilis [12].

as negative. However, the VDRL in the CSF is reactive in only 70-75% of cases [1], and a negative result does not exclude the diagnosis of neurosyphilis [11]. If the VDRL in the CSF is negative, a white blood cell count more than five cells/mm3 or a protein level more than 46 mg/dl are suggestive of neurosyphilis [12]. The standard therapy for neurosyphilis is intravenous Penicillin G, 12-24 million units continuous IV infusion for 10-14 days followed by Benzathine penicillin, 2.4 million units intramuscular once per week for up to three weeks [1, 11]. An alternative treatment is by intramuscular Penicillin G procaine, 2.4 million units qd, plus Probenecid 500 mg orally four times a day for 10-14 days. After treatment, follow-up clinical and CSF examination should be scheduled at 3-6 months [8, 11]. Recognising and diagnosing neurosyphilis can be difficult even for an experienced physician. Because of the increasing incidence of syphilis in the last decade, consideration should be given to a diagnosis of neurosyphilis in every patient presenting with an ischemic stroke [13]. According to the literature, the common situations in clinical practice, when neurosyphilis should be considered as a possible diagnosis are young patients with ischemic stroke, elderly patients with multiple ischemic strokes despite a correct therapy, patients with progressive cognitive deterioration and patients with clinical features suggestive of neurosyphilis [3, 8, 9, 10].

l practice, when neurosyphilis should be considered as a possible diagnosis are young patients with ischemic stroke, elderly patients with multiple ischemic strokes despite a correct therapy, patients with progressive cognitive deterioration and patients with clinical features suggestive of neurosyphilis [3, 8, 9, 10]. Conclusions Neurosyphilis is a disease overlooked because of its atypical, and sometimes bizarre clinical features. Classical presentation suggestive of neurosyphilis is represented by neuropsychiatric changes (psychosis, dementia, delirium), strokes, ophthalmologic features (uveitis, optic neuritis), myelopathies, seizures, brainstem or cranial nerves involvement. Elderly patients with uncharacteristic neurologic and cognitive symptoms need extensive assessment to identify the aetiology of an ischemic stroke. In every patient with an ischemic stroke, the possible presence of a neurosyphilis should be considered, and appropriate treatment should be administered. Specific antibiotic therapy can resolve the neurologic and cognitive symptoms completely. Conflict of interest: None declared.

Introduction Vitamin K antagonists are widely used drugs. However, they have a narrow therapeutic range. Below the lower limit, the patient is not anticoagulated; above the upper limit, there is an increased risk of major bleeding. Diagnosing bleeding can be challenging, especially when haemorrhage is not evident. In patients who have been overdosed with anti-coagulants, serious consequences may arise, making an early and accurate diagnosis essential. In patients needing a rapid reversal of these drugs, the effects of vitamin K antagonists can be reversed with oral vitamin K or prothrombin complex concentrate, depending on the severity of the case.

Introduction Vitamin K antagonists are widely used drugs. However, they have a narrow therapeutic range. Below the lower limit, the patient is not anticoagulated; above the upper limit, there is an increased risk of major bleeding. Diagnosing bleeding can be challenging, especially when haemorrhage is not evident. In patients who have been overdosed with anti-coagulants, serious consequences may arise, making an early and accurate diagnosis essential. In patients needing a rapid reversal of these drugs, the effects of vitamin K antagonists can be reversed with oral vitamin K or prothrombin complex concentrate, depending on the severity of the case. Case Description Case 1 A 75-year-old man, giving a five-month history of dizziness, light-headedness, muscular weakness, blurred vision and feeling faint. He was admitted to hospital due to a sudden loss of consciousness. He reported no prodromal symptoms and the relatives who were present when he fainted, said that the syncope was of a short duration. Shortly afterwards, he recovered spontaneously with no neurological symptoms. The patient had fallen, hitting his head and chest. Since he had atrial fibrillation and was taking the vitamin K antagonist, acenocoumarol, his relatives were concerned about the risk of bleeding after the fall. The patient had a history of Type 2 diabetes, right internal carotid artery stenosis. He suffered from chronic kidney disease, reported as Stage 3B, with a glomerular filtration rate of 40 ml/min/1.73 m2. He was taking aspirin 100 mg daily, losartan 100 mg daily, atorvastatin 20 mg daily, amlodipine 10 mg daily, insulin glargine 16 IU daily and acenocoumarol 9 mg weekly, taken daily at the same time of day, but adjusted every three weeks according to response.

3B, with a glomerular filtration rate of 40 ml/min/1.73 m2. He was taking aspirin 100 mg daily, losartan 100 mg daily, atorvastatin 20 mg daily, amlodipine 10 mg daily, insulin glargine 16 IU daily and acenocoumarol 9 mg weekly, taken daily at the same time of day, but adjusted every three weeks according to response. On physical examination, he had a mild bleeding head injury and bruises on the left side of the face. His blood pressure was 139/51, heart rate was 65 bpm and oxygen saturation was 95% in room air. On auscultation, heart sounds were arrhythmical, with no murmurs. Breath sounds were diminished on the left side, with hypoventilation in the basal and middle fields. Otherwise, the examination was normal. On admission, routine blood tests showed a white blood cell count of 10,100/μl, a haemoglobin level of 12.7 g/dl and a platelet count of 132,000/μl. The International Normalized Ratio (INR) was 5.1. The remaining blood tests were normal. A chest X-ray revealed left-sided pleural effusion (Figure 1), with no rib fracture, and CT scan showed no subdural or epidural haematomas. Fig. 1 A: The chest X-ray shows the left pleural effusion. B: The chest CT scan (without intravenous contrast) shows the left pleural effusion (arrows), the left lower lobe collapse and a small right pleural effusion. His doctor decided a thoracentesis should be performed, but since the pleural effusion was not causing dyspnoea or discomfort, it was considered appropriate to postpone this until the INR was normal. Acenocoumarol was withdrawn, and the patient was hospitalised.

Fig. 1 A: The chest X-ray shows the left pleural effusion. B: The chest CT scan (without intravenous contrast) shows the left pleural effusion (arrows), the left lower lobe collapse and a small right pleural effusion. His doctor decided a thoracentesis should be performed, but since the pleural effusion was not causing dyspnoea or discomfort, it was considered appropriate to postpone this until the INR was normal. Acenocoumarol was withdrawn, and the patient was hospitalised. Twenty-four hours after admission, further blood tests were performed, which revealed a haemoglobin level of 10.4 g/dl. It was noticed that the haemoglobin level had been 13.5 g/dl a week earlier suggesting there was haemorrhagic pleural effusion. Prothrombin complex concentrate was immediately prescribed to reverse the effects of acenocoumarol. When the INR was normal, a diagnostic thoracentesis revealed a haemothorax, and the decision was taken to drain this through a pleural tube. A total amount of 1,800 ccs of fluid were drained. Over the following days, the haemothorax resolved. When the patient was discharged, he was referred to the Vascular Surgery Department (Alcorcon University Hospital, Madrid, Spain) for assessment of his previously known carotid stenosis, which was considered to be the most likely cause of the syncope.

Twenty-four hours after admission, further blood tests were performed, which revealed a haemoglobin level of 10.4 g/dl. It was noticed that the haemoglobin level had been 13.5 g/dl a week earlier suggesting there was haemorrhagic pleural effusion. Prothrombin complex concentrate was immediately prescribed to reverse the effects of acenocoumarol. When the INR was normal, a diagnostic thoracentesis revealed a haemothorax, and the decision was taken to drain this through a pleural tube. A total amount of 1,800 ccs of fluid were drained. Over the following days, the haemothorax resolved. When the patient was discharged, he was referred to the Vascular Surgery Department (Alcorcon University Hospital, Madrid, Spain) for assessment of his previously known carotid stenosis, which was considered to be the most likely cause of the syncope. Case 2 An 89-year-old man was admitted to hospital presenting with pain, swelling, redness and warmness in his left thigh. Two weeks before admission, he had tripped and fallen due to a defect in the pavement, hitting his left thigh. The patient had a medical history of atrial fibrillation and was taking acenocoumarol, 12 mg weekly, taken daily at the same hour, but adjusted every three weeks, and amlodipine, 5 mg daily. His blood pressure was 155/93 mmHg, and heart rate was 58 bpm. His left thigh was enlarged compared to the right one, was warmer and appeared red and swollen. Otherwise, the examination was normal.

Case 2 An 89-year-old man was admitted to hospital presenting with pain, swelling, redness and warmness in his left thigh. Two weeks before admission, he had tripped and fallen due to a defect in the pavement, hitting his left thigh. The patient had a medical history of atrial fibrillation and was taking acenocoumarol, 12 mg weekly, taken daily at the same hour, but adjusted every three weeks, and amlodipine, 5 mg daily. His blood pressure was 155/93 mmHg, and heart rate was 58 bpm. His left thigh was enlarged compared to the right one, was warmer and appeared red and swollen. Otherwise, the examination was normal. Initial laboratory tests showed a white blood cell count of 6,840/μl, a haemoglobin level of 7.1 g/dl and a platelet count of 162,000/μl. The INR was 4.9. The remainder of the routine blood tests, including liver and kidney panels, and as C-reactive protein were normal. His doctor diagnosed cellulitis and prescribed amoxicillin/clavulanate 1 g every 8 hours. The patient was then admitted to hospital. In the hospital, the case was taken over another doctor. A haematoma on the thigh was suspected and considered to be the cause of the severe anaemia. Prothrombin complex concentrate and two packed red blood cells transfusion were immediately prescribed. The patient underwent a CT scan (Figure 2), which showed a ruptured popliteal artery aneurysm, resulting in a nine cm haematoma on the left thigh.

h was suspected and considered to be the cause of the severe anaemia. Prothrombin complex concentrate and two packed red blood cells transfusion were immediately prescribed. The patient underwent a CT scan (Figure 2), which showed a ruptured popliteal artery aneurysm, resulting in a nine cm haematoma on the left thigh. Fig. 2 A: CT scout view of both lower limbs, showing the enlargement of the left leg, compared to the right one. The increased size of the leg is even more apparent in the left thigh. B: CT of lower limbs (without intravenous contrast), showing the left haematoma (arrows). Note the atheromatous plaques in both popliteal arteries, and how the plaques draw an outline of the ruptured aneurysm. The patient was referred to the Vascular Surgery Department (Alcorcon University Hospital, Madrid, Spain) where a metallic stent graft was inserted through the arteries of the left leg and deployed across an aneurysm (Figure 3). The patient was discharged four days later. Fig. 3 A: Angiogram showing the catheterisation of the popliteal artery. B: Active extravasation of arterial contrast, outlining the haematoma. C: Covered stent placed to repair an aneurysm. D: The angiogram shows the lack of contrast leakage from the stent graft.

The patient was referred to the Vascular Surgery Department (Alcorcon University Hospital, Madrid, Spain) where a metallic stent graft was inserted through the arteries of the left leg and deployed across an aneurysm (Figure 3). The patient was discharged four days later. Fig. 3 A: Angiogram showing the catheterisation of the popliteal artery. B: Active extravasation of arterial contrast, outlining the haematoma. C: Covered stent placed to repair an aneurysm. D: The angiogram shows the lack of contrast leakage from the stent graft. Discussion Vitamin K antagonists, such as warfarin and acenocoumarol, are widely used drugs for long-term anticoagulation therapy [1, 2]. The use of these drugs should be undertaken with caution, given their narrow therapeutic range. The major side effect of vitamin K antagonist use is bleeding. The risk of bleeding is increased if the INR is out of normal range [2, 3]. Clinicians should be aware of the subtle balance between bleeding complications and an insufficient anticoagulation status [4]. Major bleeding can be life-threatening [2], but bleeding is not always obvious. Bleeding wounds, skin bruises, gastrointestinal bleeding and brain haemorrhages can be easily noticed. However, retroperitoneal haemorrhages, post-traumatic haematomas and unnoticed rupture of an arterial aneurysm are a few examples of occult bleeding. In both cases described, initial diagnoses were inaccurate. The first patient was admitted to hospital because of a syncope.

Major bleeding can be life-threatening [2], but bleeding is not always obvious. Bleeding wounds, skin bruises, gastrointestinal bleeding and brain haemorrhages can be easily noticed. However, retroperitoneal haemorrhages, post-traumatic haematomas and unnoticed rupture of an arterial aneurysm are a few examples of occult bleeding. In both cases described, initial diagnoses were inaccurate. The first patient was admitted to hospital because of a syncope. The main risk of a patient on acenocoumarol therapy is intracranial bleeding, which was why the patient underwent a brain CT scan. The patient was properly managed, but the clinician overlooked other conditions related to internal bleeding. On the other hand, pleural effusion must be assessed if the aetiology is uncertain [5], and thoracentesis should not have been delayed. The only treatment was the withdrawal of acenocoumarol while waiting for the INR to drop to normal limits. The possibility of post-traumatic haemorrhagic pleural effusion in an anticoagulated patient was not considered. The patient was stabilised, but since the INR was out of the normal range, it would have been reasonable to believe that the haemorrhagic pleural effusion could worsen.

for the INR to drop to normal limits. The possibility of post-traumatic haemorrhagic pleural effusion in an anticoagulated patient was not considered. The patient was stabilised, but since the INR was out of the normal range, it would have been reasonable to believe that the haemorrhagic pleural effusion could worsen. The diagnoses of head injury and pleural effusion of unknown origin were proposed. Unfortunately proper management, comprising the infusion of prothrombin complex concentrate before inserting a drainage intercostal tube, was delayed for twenty-four hours. Haemothorax is a risk factor for the development of complications such as empyema and fibrothorax, and the delay in proscribing the above must be viewed as a diagnostic error [6]. The second patient presented with severe anaemia, yet had a good tolerance. This tolerance may have been a confounding factor, despite the INR being out of the normal range. The initial diagnosis, that of cellulitis of the left thigh, was inaccurate. Peripheral pulses were weak but present and symmetrical. However, the clinical course of the anaemia had been progressive, and this was not linked to the trauma to the swollen leg. Therefore, two different diagnoses, cellulitis of the left thigh and chronic anaemia of unknown origin, were established.

, was inaccurate. Peripheral pulses were weak but present and symmetrical. However, the clinical course of the anaemia had been progressive, and this was not linked to the trauma to the swollen leg. Therefore, two different diagnoses, cellulitis of the left thigh and chronic anaemia of unknown origin, were established. On admission to hospital, the patient was put under the care of another doctor. The patient underwent a CT that confirmed the primary suspicion of post-traumatic internal bleeding. After two packed red blood cells and prothrombin complex concentrate had been administered, a vascular surgeon over saw the treatment of the ruptured arterial aneurysm. (Figure 3). Conclusions Clinicians must be aware of the main side effects of vitamin K antagonists, especially when the INR is above the upper normal limit. Some internal bleeding can go unnoticed. Students, interns and residents must be taught to link symptoms, signs and tests to establish a proper, accurate diagnose when managing the risk of bleeding in an anticoagulated patient. Major bleeding in an anticoagulated patient can be life-threatening or leave serious sequelae. It is, therefore, critical to diagnose the origin of the bleeding. Anaemia, empyema, fibrothorax and infected haematomas are some of the possible complications of unobserved bleeding. We believe that these two cases have a noteworthy educational value as they highlight the relationship between vitamin K antagonists and the risk of undetected bleeding. Conflict of interest: The author has not any competing interests in the manuscript.

Syphilis is a consequence of a symbiotic relationship between Treponema pallidum and humankind. The spirochete is nowadays well characterized in shape and in length, and its entire genome is sequenced. Despite all these, confirmation of infection is based on serologic tests. The diagnosis of nervous system disease heavily depends on examination of the cerebrospinal fluid [1, 2, 3, 4]. Neurologic involvement is generally dichotomized into early/secondary (acute meningitis, cranial nerves involvement) or late/tertiary (all the rest of the manifestations) [1]. In the current issue of Journal of Critical Care Medicine, Bologa et al. present the utility of having meningovascular syphilis in mind as a possible diagnosis, in an apparent average case of an 84-year-old patient diagnosed with stroke [5]. The obliterative endarteritis that involves the intracranial arteries causes stroke. Symptomatic involvement of the central nervous system (CNS) is scarce, found in 4-6% of neglected patients. Among neurosyphilis cases, this type of CNS involvement occurs in approximately a forth of untreated patients [1, 2].

roke [5]. The obliterative endarteritis that involves the intracranial arteries causes stroke. Symptomatic involvement of the central nervous system (CNS) is scarce, found in 4-6% of neglected patients. Among neurosyphilis cases, this type of CNS involvement occurs in approximately a forth of untreated patients [1, 2]. The spirochetal infections of the nervous system have two main actors: Treponema Pallidum and Borrelia Burgdorferi sensu lato. There are numerous similarities between these 2 infections, due to biologic characteristics of spirochetes: a wide mythology, both being called the great imitator; after 1950 the types of central nervous system (CNS) involvement were described in a scientific manner; both are chronic; the immune reaction can be demonstrated by the presence of antibodies against major epitopes (a small number of surface antigens are expressed on the spirochete’s surface but the expressed epitopes might be changed during the infestation); a close contact with a vector is required for spirochetal spreading, demonstrating the lability of this organism in vitro; the infestation is marked by impressive painless (probably secondary to poor host immune response) cutaneous involvement; a good motility and adherence to cell-surface molecules allows spirochetes to penetrate the blood-brain barrier and disseminate into the CNS; a various but atypical CNS pathology is produced (an approach based on phenomenology instead of pathophysiology) but fortunately only a small number of patients become clinically manifest; a diagnosis of later CNS disease demand advanced techniques for cerebrospinal fluid assay; luckily, both spirochetes are sensitive to the same family of antibiotics [1, 3, 6].

uced (an approach based on phenomenology instead of pathophysiology) but fortunately only a small number of patients become clinically manifest; a diagnosis of later CNS disease demand advanced techniques for cerebrospinal fluid assay; luckily, both spirochetes are sensitive to the same family of antibiotics [1, 3, 6]. An interesting discussion is that cranial syphilitic vasculitis differs from other cerebrovascular disease through the site of damage and not the mechanism. Prodromal manifestations are more frequently found in meningovascular syphilis (headaches, mental status change, meningismus) compared with classical stroke cases. The percentages of the symptoms as described in specialized literature are: headache 10%, dizziness 10%. The arterial territory most frequently affected is the middle cerebral artery territory. It is still unknown which factors lead to the development and evolution of this chronic tertiary syphilis. The vascular lesions are due to an endarteritis with perivascular inflammation that obliterates vasa vasorum. The endarteritis consists in an intimal fibroblastic proliferation, decreasing the media thickness, and in the periphery plasma cells and lymphocytes infiltrate the adventitia [1, 2, 3].

onic tertiary syphilis. The vascular lesions are due to an endarteritis with perivascular inflammation that obliterates vasa vasorum. The endarteritis consists in an intimal fibroblastic proliferation, decreasing the media thickness, and in the periphery plasma cells and lymphocytes infiltrate the adventitia [1, 2, 3]. The old tertiary syphilis classification comprised 3 types: cardiovascular syphilis, neurosyphilis, and late benign also known as gummatous syphilis. Lately, researchers have gathered clinical and laboratory data from neurosyphilis cases and compiled them into 6 different diagnostic types: first category – neuropsychiatric (most frequently found) disorders such as dementia, delirium, psychosis; second category – ischemic stroke with an acute onset of a focal neurological deficit; third category, with ocular involvement which amounts to optic nerve dysfunction followed sometimes by visual loss or uveitis; fourth category, where tabes dorsalis is included, with myelopathy of various types of onset i.e. acute, subacute, or chronic spinal cord syndromes; fifth category – the epileptic type, presenting partial seizures or myoclonus; sixth category, involving the brain stem and the cranial nerves. The 84-year-old patient reported in the article under discussion can be classified in the second category. All the prodromal symptoms of the patient were of CNS origin (dizziness, memory loss, insomnia, headache). In a previous publication from 2014, we reported the case of a 64 year-old patient that presented hints of meningovascular syphilis, syphilitic amyotrophy and general paralysis maybe a seventh category of tertiary syphilis [1, 2, 3, 4].

oms of the patient were of CNS origin (dizziness, memory loss, insomnia, headache). In a previous publication from 2014, we reported the case of a 64 year-old patient that presented hints of meningovascular syphilis, syphilitic amyotrophy and general paralysis maybe a seventh category of tertiary syphilis [1, 2, 3, 4]. Regarding the risk of neurosyphilis, Caucasians are 2-3 times more predisposed than the rest of populations, and it is more frequent in males than in females. The case presented was a female that, like other referred-to cases, contracted the infection most probably long before the disease expressed clinically, placing this pathology among progressive chronic infections.

2-3 times more predisposed than the rest of populations, and it is more frequent in males than in females. The case presented was a female that, like other referred-to cases, contracted the infection most probably long before the disease expressed clinically, placing this pathology among progressive chronic infections. Spirochetal infection diagnosis in the tertiary stage is exclusively done by serologic tests. We must not forget that patients infected with spirochetes frequently have elevated titers of anticardiolipin antibodies (a possible explanation would be the putative interaction of the host’s lipoproteins with the spirochete). Diagnostic tests (that are very sensitive but lack specificity) from this group of “reaginic” antibodies are: Venereal Disease Research Laboratory (VDRL), rapid plasma reagin, Wassermann test, Hinton tests. A further test in positive patients to these reaginic tests is needed: microhemagglutination for Treponema Pallidum, Fluorescent treponemal antibody. The importance of the VDRL test remains when evaluating the response to a certain antibiotic. An infection of the CNS requires the thorough examination of the CSF: CSF VDRL is reliable (a positive result is perceived as part of the diagnosis). A slight increase of CSF leukocytes was found in the case reported by Bologa et al., similar to the ones found in the specialized literature. From the theoretical point of view, it is still highly debatable whether the antibodies against Treponema pallidum are generated inside the CNS [3, 7, 8].

part of the diagnosis). A slight increase of CSF leukocytes was found in the case reported by Bologa et al., similar to the ones found in the specialized literature. From the theoretical point of view, it is still highly debatable whether the antibodies against Treponema pallidum are generated inside the CNS [3, 7, 8]. Lately, due to the increase of syphilis infection even in the most unlikely patients, screening for spirochetal infection is advisable, although interpreting the tests might be a source of problematic false-positive or falsenegative results [4, 6]. The diagnosis is equally important since neurosyphilis has a curative treatment which is easy to administer, generally without any adverse events or significant costs [7]. This is also the case of the reported 84-year-old patient. At first glance, stroke pathology in an 84-year-old woman is a common occurrence, as well as syphilis vascular involvement of the CNS. The importance of case reports resembling the one currently under discussion consists of the different final image compared to each trivial scattered piece. The discussion of the pathophysiology mechanism of CNS involvement by an infection first described in 1530 remains still open in 2017. Disclosure The author reports no disclosure relevant for this manuscript.

Introduction Recently developed immunotherapeutic agents, such as check point inhibitors and antibodies against programmed cell death 1 (PD-1), open up new horizons in cancer therapy. The PD-1 antibody nivolumab has been approved for the treatment of malignant melanoma and lung cancer by the European Medicines Agency (EMA) since 2015. Serious adverse events are comparably rare [1]. Today the use of extracorporeal membrane oxygenation (ECMO) is a worldwide established method for treating severe lung failure [2]. We report the successful use of extracorporeal membrane oxygenation (ECMO) in pneumonitis with ARDS-pattern associated with the use of PD-1 antibody nivolumab. Case presentation A 74-year-old man with a body mass index (BMI) of 27.7 kg/m2), was admitted to the emergency department of the Barmherzige Brueder Hospital in Munich, Germany. He presented with acute dyspnoea, muscle weakness, tiredness but no fever. Prehospital treatment with antibiotics had not resulted in any improvement in his condition. His medical history showed he had had a deep vein thrombosis and a pulmonary embolism one year previously. Two years earlier he had been diagnosed with a stage IV melanoma. He had received immunotherapy, first with ipilimumab and sequentially with pembrolizumab. Due to the advancement of his condition he received nivolumab, 3 mg/kg every two weeks for six cycles. The last cycle was received thirteen days before admission to the hospital.

ier he had been diagnosed with a stage IV melanoma. He had received immunotherapy, first with ipilimumab and sequentially with pembrolizumab. Due to the advancement of his condition he received nivolumab, 3 mg/kg every two weeks for six cycles. The last cycle was received thirteen days before admission to the hospital. Clinical findings Breathing rate was 23/min, SpO2 76%, FiO2 0.21, heartrate 97 bpm, blood pressure 150/80 mmHg, and temperature 36.8 °C. Blood gas: SaO2 92%, with 8 l/min supplementary oxygen, pO2 64 mmHg, pCO2 24 mmHg, lactate 4.7 mmol/l, pH 7.40 and BE -8.2 mmol/l. Relevant laboratory results Leukocytes 15.4x103/μl, CRP 76mg/l, troponin T 0.0 7ng/ml, D-dimer 4052 μg/l, ALAT 232 U/l, creatinine 1.85 mg/dl, GFR 38 ml/min. An initial differential diagnosis of a severe community-acquired pneumonia or an acute pulmonary embolism was considered. The echocardiography showed a Grade 1 mitral valve insufficiency, and diastolic dysfunction. There was no evidence from the CT of a pulmonary embolism, but diffuse bilateral infiltrations with consolidations and enlarged mediastinal lymph nodes were seen (Figure 1). Fig. 1 CT-Scan, with contrast agent, on admission (left side) and high-resolution computer tomography during treatment (right side). The therapeutic interventions and course is presented in Figure 2. Fig. 2 Diagnostic and therapeutic interventions during treatment. BAL: bronchoalveolar lavage, ECMO: extracorporeal membrane oxygenation, NIV: non-invasive ventilation.

Fig. 1 CT-Scan, with contrast agent, on admission (left side) and high-resolution computer tomography during treatment (right side). The therapeutic interventions and course is presented in Figure 2. Fig. 2 Diagnostic and therapeutic interventions during treatment. BAL: bronchoalveolar lavage, ECMO: extracorporeal membrane oxygenation, NIV: non-invasive ventilation. After collecting blood cultures, calculated empiric antibiotic therapy with piperacillin-tazobactam (4.5g, 3 x per day) and clarithromycin (500mg 2 x per day) was initiated. The patient was transferred to the intensive care unit (ICU) in a stable cardio-circulatory condition, but with a serious respiratory failure and the need for immediate non-invasive ventilation. Twenty-four hours after his admission to the hospital, the patient’s condition deteriorated due to exhaustion and intubation with mechanical ventilation was required. He quickly developed a severe ARDS, with a recorded oxygenation index of 75 mmHg, compliance of 18 ml/100Pa, and a peak inspiratory pressure of 4 kPa. These conditions led to the decision to initiate a venovenous extracorporeal membrane oxygenation using an ILA-activve® system (Novalung, Heilbronn, Germany). Cannulas were placed in the right femoral vein (French 23) and the right internal jugular vein (French 19). The ECMO circuit was set at blood flow 4l/minutes, and oxygen flow 9 l/minutes and this allowed the mechanical ventilation to be reduced to an ultra protective level.

tivve® system (Novalung, Heilbronn, Germany). Cannulas were placed in the right femoral vein (French 23) and the right internal jugular vein (French 19). The ECMO circuit was set at blood flow 4l/minutes, and oxygen flow 9 l/minutes and this allowed the mechanical ventilation to be reduced to an ultra protective level. Due to possible MRSA colonisation, the antibiotic regimen was intensified with the addition of linezolide, 600 mg every 12 hours by intravenous infusion over 30–120 minutes. Haemodynamic monitoring was performed with PiCCO® (Pulsion Medical Systems SE, Feldkirchen, Germany). Initially, the infectious parameters slightly increased but rapidly decreased over the following few days of therapy. (Figure 3). There was no bacterial, fungal or viral growth from repeated broncho-alveolar lavage or blood cultures. The patient’s temperature was never recorded as being higher than 38.5 °C. Fig. 3 Important parameters in the course of treatment: C-reactive peptide (CRP), procalcitonin (PCT), extravascular Lung water index (ELWI)

Haemodynamic monitoring was performed with PiCCO® (Pulsion Medical Systems SE, Feldkirchen, Germany). Initially, the infectious parameters slightly increased but rapidly decreased over the following few days of therapy. (Figure 3). There was no bacterial, fungal or viral growth from repeated broncho-alveolar lavage or blood cultures. The patient’s temperature was never recorded as being higher than 38.5 °C. Fig. 3 Important parameters in the course of treatment: C-reactive peptide (CRP), procalcitonin (PCT), extravascular Lung water index (ELWI) Considering the patient had nivolumab induced pneumonitis, it was decided, after four days of mechanical ventilation, to start an immunosuppressive therapy with methylprednisolone, 2mg/kg/day together with pneumocystis pneumonia prophylaxis with cotrimoxazole, 960mg twice a week. Nine days after intubation, a dilative tracheostomy was performed. After thirteen days, the pulmonary gas exchange had improved to the extent that it was possible to end ECMO therapy. Complications associated with ECMO therapy did not occur. At day seventeen, a high-resolution CT showed a slight improvement in the pulmonary infiltration though there remained a diffuse bilateral ground glass opacity with consolidations in the lower lobes and bronchial thickening. (Figure 1)

sible to end ECMO therapy. Complications associated with ECMO therapy did not occur. At day seventeen, a high-resolution CT showed a slight improvement in the pulmonary infiltration though there remained a diffuse bilateral ground glass opacity with consolidations in the lower lobes and bronchial thickening. (Figure 1) During the following weaning period, prolonged wake-up trials and daily physiotherapy were given resulting in the oxygen supply being reduced. Eight days later the patient was in a good cognitive and cardiopulmonary condition, and one day before he was discharged from the ICU, the tracheostomy tube was removed. After three weeks of rehabilitation, he went home, without impairments besides a slight weakness. He gave written consent in publishing this case.

ed. Eight days later the patient was in a good cognitive and cardiopulmonary condition, and one day before he was discharged from the ICU, the tracheostomy tube was removed. After three weeks of rehabilitation, he went home, without impairments besides a slight weakness. He gave written consent in publishing this case. Discussion The promising ratio between benefit and adverse events, as well as a widening range of indications, are likely to result in an increasing use of new immunotherapeutic agents like ipilimumab, nivolumab or pembrolizumab. However, it is perceived that a growing number of people will report with moderate or severe adverse events related to these drugs. In a recent study [3], 50% of the patients treated with the CTLA-4 inhibitor, ipilimumab, experienced Grade 3 adverse events requiring admission to a hospital or Grade 4 life threatening events. Severe adverse reactions with nivolumab seem to occur less often [4]. The data suggests a better therapeutic outcome when sequential therapy with ipilimumab followed by nivolumab is prescribed for the treatment of malignant melanoma [5]. The incidence of nivolumab associated pneumonitis is 2.2-6%, and pneumonitis associated mortality is 0.7% [6]. There are positive reports to treat Grade 3 and 4 adverse events with 2-4mg/kg prednisolone. If there is no response, another immunosuppressant such as infliximab can be administered [7, 8].

Discussion The promising ratio between benefit and adverse events, as well as a widening range of indications, are likely to result in an increasing use of new immunotherapeutic agents like ipilimumab, nivolumab or pembrolizumab. However, it is perceived that a growing number of people will report with moderate or severe adverse events related to these drugs. In a recent study [3], 50% of the patients treated with the CTLA-4 inhibitor, ipilimumab, experienced Grade 3 adverse events requiring admission to a hospital or Grade 4 life threatening events. Severe adverse reactions with nivolumab seem to occur less often [4]. The data suggests a better therapeutic outcome when sequential therapy with ipilimumab followed by nivolumab is prescribed for the treatment of malignant melanoma [5]. The incidence of nivolumab associated pneumonitis is 2.2-6%, and pneumonitis associated mortality is 0.7% [6]. There are positive reports to treat Grade 3 and 4 adverse events with 2-4mg/kg prednisolone. If there is no response, another immunosuppressant such as infliximab can be administered [7, 8]. The use of ECMO is now an established method for the treatment of severe lung failure. In the present case, ECMO was used to allow the prednisolone therapy to improve lung function and to allow an ultra-protective mechanical ventilation level and the avoidance of further ventilator-induced lung injury [9]. Jugular or femoral veins large enough to ensure a sufficient blood flow are essential, as is a team experienced in ECMO therapy and possible complications. Common complications are haemolysis, haemorrhage, infection, pump failure and dislocation of an ECMO-cannula. Those complications occur much more frequently in veno-arterial than in veno-venous ECMO therapy [2], and for this reason, the latter can be considered somewhat safer. Also, it is superior in treating an isolated lung failure compared to veno-arterial-ECMO, because pre-oxygenated blood in the pulmonary artery reduces the right ventricular afterload caused by hypoxic pulmonary vasoconstriction. Furthermore, selective hypoxemia of the coronary arteries and the cerebral vessels cannot occur.

it is superior in treating an isolated lung failure compared to veno-arterial-ECMO, because pre-oxygenated blood in the pulmonary artery reduces the right ventricular afterload caused by hypoxic pulmonary vasoconstriction. Furthermore, selective hypoxemia of the coronary arteries and the cerebral vessels cannot occur. ECMO therapy in patients with malignancy is associated with a higher mortality rate, compared to patients without malignancy [10] due to the underlying disease and inherent complications. ECMO therapy should not be considered if the patient’s health status is already impaired and improvement or maintenance of quality-of-life seems unlikely. Taking into account that the risks of serious complications under veno-venous ECMO are less frequent, the decision whether to perform ECMO or not can be more liberal when dealing with an isolated lung failure. In our case, the patient presented with a one organ failure but his general health was otherwise good. The patient retrospectively confirmed that he was grateful for the decision to use ECMO. Conclusion It is our opinion that, in general, patients with malignancies should not be excluded from ECMO therapy. Decisions, established on a case by case basis and considering all benefits and risks, should clarify which patients are likely to benefit from ECMO. It should be borne in mind that the newer immunotherapeutic agents can cause life-threatening pneumonitis, but when identified promptly, can be successfully treated.

Conclusion It is our opinion that, in general, patients with malignancies should not be excluded from ECMO therapy. Decisions, established on a case by case basis and considering all benefits and risks, should clarify which patients are likely to benefit from ECMO. It should be borne in mind that the newer immunotherapeutic agents can cause life-threatening pneumonitis, but when identified promptly, can be successfully treated. Acknowledgment CT-Scans by courtesy of the Department of Diagnostic and Interventional Radiology, Krankenhaus Barmherzige Brueder, Munich Conflict of interest: All authors declare that there are no conflicts of interest.

Introduction Elizabethkingia meningoseptica, assigned to the phyllum Bacteroidaeota, family Flavobacteriaceae, are Gram-negative aerobe rod, nonfermentative, nonmotile, nonspore-forming bacteria, which can be cultivated on blood and chocolate agar at 370C, and give positive reactions to catalase, oxidase and urease [1, 2]. The bacterial genus Elizabethkingia has been known as such since 2005 and was named after the American bacteriologist Elisabeth O. King, who in 1959 discovered Flavobacterium meningoseptica, which, until 1994, had been the previous name for Elizabethkingia meningoseptica. It was reclassified into the genus Chryseobacterium (1994-2005), due to its production of a yellow pigment [3]. The genus Elizabethkingia includes four species: E. anophelis, E. endophityca, E. miricola and E. meningoseptica [4]. Based on genome sequence analysis, a recent report indicates the greater ability of Elizabethkingia meningoseptica to form biofilm, compared to other species [5]. Elizabethkingia meningoseptica are commonly found in soil and water, although it is also involved in hospital emergent infections related to contaminated medical equipment, especially in neonatal wards [3,6]. Elderly, newborns and immunocompromised patients are most susceptible to this infection, with recorded case-fatality rates of over 50% [7]. The diagnosis of Elizabethkingia infection is based on cultures from sterile sites, mostly from blood samples, although the prevalence of infection may be underestimated by misidentification. The Clinical and Laboratory Standards Institute does not have clinical breakpoints for Elizabethkingia meningoseptica [8]. New microbiological techniques, such as pulsed-field gel electrophoresis, the mass spectrometry method matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-ToF) and optical mapping of the bacterial genome should improve bacterial diagnostics [9]. As the infection is prone to multidrug resistance, it is difficult to standardize treatment of Elizabethkingia meningoseptica infection.

y method matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-ToF) and optical mapping of the bacterial genome should improve bacterial diagnostics [9]. As the infection is prone to multidrug resistance, it is difficult to standardize treatment of Elizabethkingia meningoseptica infection. A review of medical literature confirms frequent inappropriate antibiotic use in Elizabethkingia meningoseptica infections and its subsequent influence on mortality risk [10,11]. Case report A premature female infant born at 33 weeks’ gestational age was admitted to the Neonatal Intensive Care Unit in the Pediatric Emergency Clinical Hospital in Galați, Romania, having been transferred from a secondary hospital when she was 2 weeks of age. The onset was marked by fever, in the 5th day after birth, while in the Neonatal Intensive Care Unit. Despite having antibiotic treatment with Ampicillin and Gentamicin, the clinical condition progressively worsened, as the patient presented with psychomotor agitation, food refusal and diarrhea. The infant’s history was unusual in that there was no medical control during the mother’s pregnancy, there was a vaginal premature delivery, with a weight at birth of 2100 g, and an Apgar-Score of 9. Sociodemographic characteristics of the mother were as follows: from a rural area, minor age, minimal formal education, unemployed and unmarried.

unusual in that there was no medical control during the mother’s pregnancy, there was a vaginal premature delivery, with a weight at birth of 2100 g, and an Apgar-Score of 9. Sociodemographic characteristics of the mother were as follows: from a rural area, minor age, minimal formal education, unemployed and unmarried. The clinical examination at admission revealed: poor clinical condition, fever 40°C, bulging fontanelle, general hypertonia with opisthotonus, abnormal Moro reflex, cardiac rate 170/min, respiratory rate 35-45/ min, systolic murmur II-III, arterial blood pressure 75/40 mmHg, blood oxygen saturation 92%, chest wall retractions during respiratory movements. Significant biological findings revealed leukocytosis with neutrophilia, anemia, thrombocytosis, positive D-Dimer, elevation of inflammatory markers and serum lactate dehydrogenase. Chest X-ray, transfontanellar and abdominal ultrasound were normal. Clinical suspicion of neonatal sepsis with meningoencephalitis was confirmed by the biochemical and cytological findings of the cerebrospinal fluid (CSF) (Table 1). Table 1 Successive Characteristics of Biological Data in a neonate sepsis with E. meningoseptica

The clinical examination at admission revealed: poor clinical condition, fever 40°C, bulging fontanelle, general hypertonia with opisthotonus, abnormal Moro reflex, cardiac rate 170/min, respiratory rate 35-45/ min, systolic murmur II-III, arterial blood pressure 75/40 mmHg, blood oxygen saturation 92%, chest wall retractions during respiratory movements. Significant biological findings revealed leukocytosis with neutrophilia, anemia, thrombocytosis, positive D-Dimer, elevation of inflammatory markers and serum lactate dehydrogenase. Chest X-ray, transfontanellar and abdominal ultrasound were normal. Clinical suspicion of neonatal sepsis with meningoencephalitis was confirmed by the biochemical and cytological findings of the cerebrospinal fluid (CSF) (Table 1). Table 1 Successive Characteristics of Biological Data in a neonate sepsis with E. meningoseptica Paediatric Clinic Hospital Galati Normal Day 1 Day 14 Day 21 Day 28 Day 42 Cerebrospinal fluid Appearance clear deposits turbid turbid clear clear Leukocyte [/mm3] 1-10 605 96 218 34 8 PMN [%] 0 95 60 58 10 0 Proteins [mg/dl] 12-60 620 178 218 114 67 Glucose [mg/dl] 40-70 <20 21.8 <20 35.3 45 Chloride [mg/dl] 7.15-7.45 6.31 7.08 6.73 7.19 7.20 Blood WBC [x103/mm3] 6-17 20300 21000 20200 9900 8300 Neutrophils [%] 20-40 53 66 54 25.4 22.4 Thrombocytes [x103/mm3] 220-520 953 784 605 482 473 Fibrinogen [mg/dl] 150-400 1600 848 724 337.5 296 Glycemia [mg/dl] 65-110 109.8 82.3 60.9 73 81 ALT [IU/l] 14-36 30 154 44 76 49 AST [IU/l] 9-52 26 111 46 39 28 LDH [IU/l] 225-600 783 1034 1009 842 640 A strain of Elizabethkingia meningoseptica was isolated in the CSF and in the blood culture by a VITEK 2 system. In vitro antibiotic activity testing found: Vancomycin-sensitive, Rifampicin -sensitive and Clarithromycin - sensitive, Ciprofloxacin - low resistance, Ampicillin - resistant, Cephepime - resistant, Ceftazidime - resistant, Cefuroxime - resistant, Trimethoprim -Sulphamethoxazol - resistant, Penicillin G - resistant, Methicillin - resistant. Neonatal bacterial meningitis with probable nosocomial origin showed an apparent clinical and CSF improvement during the first two weeks, under antibiotic treatment with Vancomycin and Meropenem. However, several “spikes” in the temperature chart, less than 390C, had been recorded and regression of CSF pathological changes were sub-optimal in the 14th day (Table 1, Table 2).

igin showed an apparent clinical and CSF improvement during the first two weeks, under antibiotic treatment with Vancomycin and Meropenem. However, several “spikes” in the temperature chart, less than 390C, had been recorded and regression of CSF pathological changes were sub-optimal in the 14th day (Table 1, Table 2). Table 2 Sequential antibiotic treatment Antibiotic treatment Week 1 Week 2 Week 3 Week 4 Week 5 Week 2 Ampicillin +Gentamicine ⇩ Meropenem ⇩ ⇩ Vancomycine ⇩ ⇩ ⇩ ⇩ ⇩ Rifampicine ⇩ ⇩ ⇩ ⇩ Piperacillin/Tazobactam ⇩ ⇩ ⇩ Alerts were generated for poor outcomes, and antibiotic treatment was adjusted by replacing Meropenem with Rifampicin, while continuing Vancomycin. Piperacillin/tazobactam was added on the 21st day, due to recrudescence of CSF pathological changes. Periventriculitis and tetraventricular hydrocephaly were revealed on the 4th week by transfontanellar ultrasound and were confirmed by magnetic resonance imaging. The cerebrospinal fluid normalized in 6 weeks, suggesting a positive response from Piperacillin/tazobactam. The infant was referred to a neurosurgeon for CSF drainage and required neuropsychiatric monitoring for late complications. Epidemiological investigation classified the infection as an isolated case. No source of infection was identified. Additional specific intensive care interventions contributed to case management, including supplemental oxygen with high-flow nasal cannula, intravenous hydrocortisone infusion, fluid and electrolyte therapy, albumin therapy, diuretics, antiplatelet aggregation with dipyridamole.

The infant was referred to a neurosurgeon for CSF drainage and required neuropsychiatric monitoring for late complications. Epidemiological investigation classified the infection as an isolated case. No source of infection was identified. Additional specific intensive care interventions contributed to case management, including supplemental oxygen with high-flow nasal cannula, intravenous hydrocortisone infusion, fluid and electrolyte therapy, albumin therapy, diuretics, antiplatelet aggregation with dipyridamole. Discussion The main clinical characteristic of neonatal bacterial meningitis is the high frequency of nonspecific symptoms, including irritability, poor feeding, hypertonia and concomitant septic shock in more than 25% of cases, as we have found in the presented case study [12]. The most common pathogens related to neonatal meningitis are Streptococcus agalactiae and Escherichia coli, appearing in two thirds of cases [12,13]. The antibiotic combination therapy of Ampicillin plus Cefotaxime or Ampicillin plus an aminoglycoside is recommended as empirical treatment for neonatal meningitis and was considered the first-line antibiotic therapy while the patient was in our Neonatal Intensive Care Unit [12,13,14].

g in two thirds of cases [12,13]. The antibiotic combination therapy of Ampicillin plus Cefotaxime or Ampicillin plus an aminoglycoside is recommended as empirical treatment for neonatal meningitis and was considered the first-line antibiotic therapy while the patient was in our Neonatal Intensive Care Unit [12,13,14]. Elizabethkingia meningoseptica is a rare cause of meningitis in newborns, mostly associated with premature birth. However, meningitis is the most common infection associated with Elizabethkingia meningoseptica. Cases of endocarditis, pneumonia, cellulitis, wound infections, bacteremia following burns, abdominal abscesses, dialysis-associated peritonitis or endophthalmitis, especially in immunocompromised patients, have also been reported [15,16,17,18]. The impact of Elizabethkingia meningoseptica in susceptible hosts, whether by simple colonization or invasive infections, suggests the influence of the immune response on a variety of pathogenic mechanisms [16]. The sources of infection could not be accurately identified in most reported symptomatic cases, although nosocomial transmission was usually presumed [16,17].

sceptible hosts, whether by simple colonization or invasive infections, suggests the influence of the immune response on a variety of pathogenic mechanisms [16]. The sources of infection could not be accurately identified in most reported symptomatic cases, although nosocomial transmission was usually presumed [16,17]. The antibiotic profile of Elizabethkingia meningoseptica is different from other Gram-negative rods. Namely, the bacterium is characterized by its inherent resistance to aminoglycosides, β-lactam agents, Chloramphenicol and carbapenems, but also by its susceptibility to Rifampicin, Ciprofloxacin, Vancomycin and Trimethoprim–Sulfamethoxazole [17,19]. The significance of Elizabethkingia meningoseptica antibiotic susceptibility is limited, as there are no available validated susceptibility testing methods or antimicrobial treatment guidelines [20]. Our bacterial isolate was sensitive to Vancomycin, but the clinical and CSF outcomes were below expectations. According to a review of medical literature, Vancomycin has been recommended for the treatment of meningitis with Elizabethkingia meningoseptica, but the efficacy has been questioned in several recent studies, with regards to the high minimum inhibitory concentration [19,21]. Additionally, successful use of Piperacillin/tazobactam was documented by clinical reports [1, 21]. Considering these arguments, we decided to escalate the antibiotic treatment by adding rifampicin and Piperacillin/tazobactam, although Piperacillin was not considered in our antibiotic testing.

ry concentration [19,21]. Additionally, successful use of Piperacillin/tazobactam was documented by clinical reports [1, 21]. Considering these arguments, we decided to escalate the antibiotic treatment by adding rifampicin and Piperacillin/tazobactam, although Piperacillin was not considered in our antibiotic testing. The latest studies demonstrated the benefit of fluoroquinolone, which can be explained by the superior pharmacokinetics as compared to hydrophilic antimicrobials, such as beta-lactams [22]. The fluoroquinolones are lipophilic agents, with better penetration through the blood-brain barrier, and are not as significantly affected by the variation of volume distribution during sepsis [22,23]. Piperacillin/tazobactam has a lower concentration in the cerebrospinal fluid compared to levofloxacin [24]. However, we avoided fluoroquinolone because of the low susceptibility for Ciprofloxacin of our Elizabethkingia meningoseptica strain, as well as the relative lack of data available on the safety and efficacy of levofloxacin in neonates [25]. Normalization of CSF was achieved in the present case after six weeks, but hydrocephaly developed, and other late neuropsychological complications are possible over the next several years. This outcome is confirmed in the literature review which showed 57% mortality rate and 69% hydrocephaly rate in survivors [21,26,27].

Normalization of CSF was achieved in the present case after six weeks, but hydrocephaly developed, and other late neuropsychological complications are possible over the next several years. This outcome is confirmed in the literature review which showed 57% mortality rate and 69% hydrocephaly rate in survivors [21,26,27]. Conclusions Elizabethkingia meningoseptica is an emerging infection and a nosocomial threat, with high risk for complications and mortality in premature neonates. The improvement of accuracy in bacterial identification and standardization of antibiotic susceptibility tests are essential for early diagnostic and etiologic treatment, in order to reduce mortality and neurological complications. Intensive care procedures and multidisciplinary interventions are crucial for case management. Active infection control in hospital environments, especially of water sources, is necessary to prevent Elizabethkingia meningoseptica epidemics. Conflict of interest None to declare.

Planning for a disaster must anticipate how demands imposed by a disaster equate with the capacity of the available facilities. Resources must be organized before an event occurs so that they are best prepared in every way to treat as many victims as possible. The actual number of victims is less relevant than the extent receiving facility can be adjusted to meet the appropriate requirements of victims. Multiple casualty incidents (MCIs) are defined as a large number of casualties generated over a short period that are appropriately managed with existing or extended resources. Mass casualty events (MCEs), in contrast, are major medical disasters that erode organized community support mechanisms and result in casualty numbers which overwhelm resources [1]. Due to the increased frequency and impact of disasters, including natural disasters, pandemics and terrorism, the concept of disaster resilience is accepted as being of increasing importance. The notion of resilience can be defined as the capacity to adapt to unexpected challenges and the flexibility to revert to normality. Additionally, the issues learned from the experience should be incorporated into protocols which would allow for better preparedness for future challenges [2,3]. Another definition, linked to disaster management, describes resilience as the capability of a medical facility to withstand the event, while being able to maintain and expand their medical capacity and to respond to sudden and significant increases in patient demand [4,5].

The notion of resilience can be defined as the capacity to adapt to unexpected challenges and the flexibility to revert to normality. Additionally, the issues learned from the experience should be incorporated into protocols which would allow for better preparedness for future challenges [2,3]. Another definition, linked to disaster management, describes resilience as the capability of a medical facility to withstand the event, while being able to maintain and expand their medical capacity and to respond to sudden and significant increases in patient demand [4,5]. Hospital disaster resilience refers to a hospital’s ability to withstand, absorb, and respond to disasters while maintaining critical functions, and then to recover to its original state or adapt to a new one. Understanding the status of a hospital’s disaster resilience is the first step in planning to enhance effective emergency response services [6]. Healthcare resilience, especially hospital resilience, is essential as it provides “lifeline” services for minimising the impact of disasters on the community and achieving higher community resilience [2,3]. The role of hospitals in response to disasters has significantly increased over the last twenty years due to the concomitant escalation in numbers of large-scale emergencies and natural, technological or terrorist-related disasters. Hospital design and preparedness must be sufficient to deal with and recover from all types of emergencies and disasters [7].

isasters has significantly increased over the last twenty years due to the concomitant escalation in numbers of large-scale emergencies and natural, technological or terrorist-related disasters. Hospital design and preparedness must be sufficient to deal with and recover from all types of emergencies and disasters [7]. Resilience can be achieved through the “PPRR” management strategy of prevention and mitigation (P), preparation and planning (P), response and relief (R), and recovery (R) [8]. The strategies should be comprehensive, including structural components (e.g. infrastructural safety), non-structural components (e.g. staff capability), emergency medical functions (e.g. critical care, on-site rescue, and surge capacity), and disaster management mechanisms (e.g. plans, crisis communication, and cooperation) [9,10]. All these components can influence or determine the performance of hospitals following a disaster and ultimately influence a community’s health outcomes [3]. Given the critical role of hospitals, the model of “safe and resilient hospitals” was promoted as a key component of disaster risk reduction planning in the healthcare sector during the 2005 World Conference on Disaster Reduction. This conference endorsed policies that would ensure “that all new hospitals are built with a level of resilience that strengthens their capacity to remain functional in disaster situations” [11,12].

nent of disaster risk reduction planning in the healthcare sector during the 2005 World Conference on Disaster Reduction. This conference endorsed policies that would ensure “that all new hospitals are built with a level of resilience that strengthens their capacity to remain functional in disaster situations” [11,12]. Albanese et al. showed that the concept of „safe and resilient hospitals” hospitals must encompass and address infrastructure and cross-cutting themes of hospital disaster preparedness including institutional capacity building, education and training, project implementation, facilitating local and regional cooperation, information sharing, networking and knowledge management, and the provision of subject matter expertise. Safe and resilient hospitals represent facilities where urgent medical care can be dispensed in an environment which is functioning at full capacity or can operate as a sufficiency-of-care facility. These healthcare units should be capable of providing the reassurance and medical leadership needed by the general public in times of crisis and develop structured relationships that establish an interface among local and regional entities involved in community-wide disaster response. The establishment of “safe and resilient” hospitals is needed to validate the hospitals’ importance as a community asset and maximize their integration within a community-wide disaster response [13].

elationships that establish an interface among local and regional entities involved in community-wide disaster response. The establishment of “safe and resilient” hospitals is needed to validate the hospitals’ importance as a community asset and maximize their integration within a community-wide disaster response [13]. There is little consensus regarding a framework for evaluating hospital resilience, and this has led to confusion in disaster health management research, making it difficult either to evaluate hospitals comprehensively or to identify their prioritized actions for confronting future disasters. Zhong et al. developed a comprehensive framework which integrates key indicators of hospital disaster resilience. The framework provides a starting point for broad agreement regarding the key components of hospital resilience. According to this framework the most critical indicators of hospital disaster resilience are related to emergency critical care capabilities, such as on-site rescue, referral of patients with complex needs, emergency medical treatment, surge capacity, hospital mass casualty triage, and the factors that guarantee it: disaster committee, disaster plan, stockpile and management of medications. Hospital resilience can also be improved through putting in place a wide variety of flexible plans, such as cooperation with other facilities, strategies to prioritize and maintain critical care functions, and strategies to surge emergency resources, medications, and staff [14].

stockpile and management of medications. Hospital resilience can also be improved through putting in place a wide variety of flexible plans, such as cooperation with other facilities, strategies to prioritize and maintain critical care functions, and strategies to surge emergency resources, medications, and staff [14]. A conceptual understanding of hospital resilience is essential to provide an intellectual basis for an integrated approach to system development. Developing the concept of “hospital resilience” will provide a starting point for agreement about what it comprises and how to measure it. The new concept links these key components with an achievable goal to improve hospital pre-event robustness as well as rapidity to recover and adapt for disasters [15]. Further consensus on key measures of hospital resilience would improve the consistency of a hospital’s emergency practices and position it with an improved ability to cope with disasters of all kinds. Conflict of interest None to declare

Introduction For decades patients with End-Stage Liver Disease (ESLD) have been considered be naturally anti-coagulated and they were consecutively treated in order to normalize standard coagulation tests. Recent studies [1] have demonstrated a rebalanced haemostasis in which pro-haemostatic and anti-haemostatic systems complemented each other [2]. Moreover, many cirrhotic patients who suffered from thrombotic complications such as portal vein thrombosis could be attributed to local endothelial factors and liver inflammation [3]. Because of these findings, the exact threshold for blood products transfusion and administration of both pro- and anti- coagulant therapies became a challenge [4]. Rotational thromboelastometry (ROTEM) is currently consider the method of choice in guiding haemostatic management in acute care settings in cirrhotic patients [5]. Different algorithms have been developed for the management of severe bleeding in liver transplantation [6] and variceal bleeding [7]. Despite this, fine tuning of haemostasis in non-urgent situations remains debatable. The aim of the present study was to assess the impact of fibrinogen levels and platelet count on ROTEM parameters and to determine the cut-off value below which severe coagulopathy develops. Materials and Methods The ethical approval for the present study was provided by the Ethical Committee of Fundeni Clinical Institute, Bucharest, Romania.

The aim of the present study was to assess the impact of fibrinogen levels and platelet count on ROTEM parameters and to determine the cut-off value below which severe coagulopathy develops. Materials and Methods The ethical approval for the present study was provided by the Ethical Committee of Fundeni Clinical Institute, Bucharest, Romania. Patient inclusion We prospectively included 260 patients with ESLD admitted to the Intensive Care Unit (ICU) prior to liver transplantation between March 2013 and March 2016. Exclusion criteria consisted of: age under 18 years, diagnosis of hepatocellular carcinoma, portal vein thrombosis, use of anticoagulant or anti-thrombotic therapy within the last 7 days, use of pro-haemostatic therapy within the last 7 days, systemic infection or sepsis and splenectomy performed prior to inclusion.

6. Exclusion criteria consisted of: age under 18 years, diagnosis of hepatocellular carcinoma, portal vein thrombosis, use of anticoagulant or anti-thrombotic therapy within the last 7 days, use of pro-haemostatic therapy within the last 7 days, systemic infection or sepsis and splenectomy performed prior to inclusion. Collected data Patient demographic data, aetiology of liver disease, severity scores (Model for End-Stage Liver Disease – MELD and MELD-Sodium), liver function tests (total bilirubin, conjugated bilirubin, serum transaminases), renal function test (serum creatinine and urea), standard coagulation tests (Fibrinogen level, aPTT – activated partial thromboplastin time, PT- prothrombin time, International Normalized Ratio - INR), ROTEM parameters, platelet count and spleen size were recorded. All tests were performed from venous blood collected by a single puncture needle system. Biochemical tests (liver and renal functional tests), standard coagulation tests and platelet count were performed in the central laboratory in accordance with our institutional protocol. Fibrinogen levels were determined using the Claus method. Spleen size was determined echographically by a senior radiologist as the longest diameter between the spleen poles.

nal tests), standard coagulation tests and platelet count were performed in the central laboratory in accordance with our institutional protocol. Fibrinogen levels were determined using the Claus method. Spleen size was determined echographically by a senior radiologist as the longest diameter between the spleen poles. ROTEM (ROTEM®, Tem Innovations GmbH, Germany) assay was performed using whole blood (collected on standard citrated tubes) as a point-of-care test in the ICU. The following ROTEM tests were used: ExTEM, InTEM, ApTEM, FibTEM and the following parameters were recorded: CT – clotting time, CFT – clot formation time, MCF – maximum clot firmness, ML – maximum lysis. Derived parameters were recorded from the ROTEM ExTEM assay: alpha angle, TPI – thrombin potential index, MaxV - maximum velocity of clot formation (MaxV), MaxVt - time to MaxV, MCE- maximum clot elasticity and AUC - area under the curve. Results were recorded after 10 minutes running time and at the end of the assay (one hour and 30 minutes). A graphic representation of the results was printed, and a senior anaesthesiologist reviewed the results. If the results were considered inappropriate due to external factors (e.g. machine malfunction), the test was repeated.

recorded after 10 minutes running time and at the end of the assay (one hour and 30 minutes). A graphic representation of the results was printed, and a senior anaesthesiologist reviewed the results. If the results were considered inappropriate due to external factors (e.g. machine malfunction), the test was repeated. Statistical analysis Statistical analyses were performed using SPSS 19.0 (SPSS Inc®, Chicago, IL, USA). Data are presented as mean ± standard deviation of the mean, median (minimum, maximum), otherwise percentage. Data distribution was assessed in order to insure the proper statistical examination. Categorical variables were analysed with Chi-square test and quantitative data were analysed with independent samples t-test. Mann-Whitney test was used when the analysed data did not follow a normal distribution. All P values are two-tailed and a P value of less than 0.05 was considered statistically significant. Results After applying exclusion criteria, 176 patients were included in the final analysis. Demographic data, ESLD severity scores, spleen size and standard coagulation tests are presented in table 1. Table 1 Demographic data, severity scores and standard coagulation tests of patients included

Statistical analysis Statistical analyses were performed using SPSS 19.0 (SPSS Inc®, Chicago, IL, USA). Data are presented as mean ± standard deviation of the mean, median (minimum, maximum), otherwise percentage. Data distribution was assessed in order to insure the proper statistical examination. Categorical variables were analysed with Chi-square test and quantitative data were analysed with independent samples t-test. Mann-Whitney test was used when the analysed data did not follow a normal distribution. All P values are two-tailed and a P value of less than 0.05 was considered statistically significant. Results After applying exclusion criteria, 176 patients were included in the final analysis. Demographic data, ESLD severity scores, spleen size and standard coagulation tests are presented in table 1. Table 1 Demographic data, severity scores and standard coagulation tests of patients included Parameter Age (years) 50.5 ± 12.5 Aetiology of liver disease HBV liver cirrhosis 36.9 % (n=65) HCV liver cirrhosis 34.2 % (n=60) Alcoholic liver cirrhosis 28.9 % (n=51) MELD score 19.3 ± 6.1 MELD-sodium score 23.2 ± 6.3 Spleen size (mm) 159 ± 33 INR 1.6 ± 0.4 aPTT (sec) 39.2 ± 10.5 PT (sec) 17.8 ± 5.2 Fibrinogen (mg/dL) 184 ± 97 Platelet count (/mm3) 91347 [12000 - 434000] Thrombocytopenia was associated with higher MELD scores (correlation coefficient: -0.422, p=0.004) and spleen size (correlation coefficient: -443, p=0.003). There was no statistically significant correlation between aetiology of liver disease and platelet count.

dL) 184 ± 97 Platelet count (/mm3) 91347 [12000 - 434000] Thrombocytopenia was associated with higher MELD scores (correlation coefficient: -0.422, p=0.004) and spleen size (correlation coefficient: -443, p=0.003). There was no statistically significant correlation between aetiology of liver disease and platelet count. From the univariate analysis, platelet count correlated with ExTEM MCF (p<0.01), ExTEM TPI (p<0.01), ExTEM MaxV (p<0.01), ExTEM AUC (p=0.037) and ExTEM MCE (p<0.01). Fibrinogen levels correlated significantly with ExTEM CFT (p=0.036), ExTEM MCF (p<0.01), ExTEM TPI (p<0.01), ExTEM MaxV (p<0.01) and ExTEM MCE (p<0.01). Except for a significant linear correlation between fibrinogen levels and FibTEM MCF (p=0.01), no other significant correlations were found between either platelet count or fibrinogen levels and InTEM or ApTEM parameters. Further analysis revealed a linear correlation between platelet count and ExTEM TPI (R2 linear =0.494), ExTEM MaxV (R2 linear =0.253), ExTEM MCE (R2 linear = 0.351) and ExTEM MCF (R2 linear = 0.498) – Figure 1. Fibrinogen levels correlated linearly with ExTEM MCF (R2 linear = 0.426), ExTEM TPI (R2 linear = 0.544), ExTEM MaxV (R2 linear = 0.332), ExTEM MCE (R2 linear = 0.395) and non-linearly with ExTEM CFT (R2 cubic = 0.475) – Figure 2. Fig. 1 Correlation between platelet count and ROTEM parameters: ExTEM TPI (A), ExTEM MaxV (B), ExTEM MCE (C) and ExTEM MCF (D). Fig. 2 Correlation between fibrinogen levels and ROTEM parmeters: ExTEM MCF (A), ExTEM TPI (B), ExTEM MaxV (C), ExTEM MCE (D) and ExTEM CFT (E).

Further analysis revealed a linear correlation between platelet count and ExTEM TPI (R2 linear =0.494), ExTEM MaxV (R2 linear =0.253), ExTEM MCE (R2 linear = 0.351) and ExTEM MCF (R2 linear = 0.498) – Figure 1. Fibrinogen levels correlated linearly with ExTEM MCF (R2 linear = 0.426), ExTEM TPI (R2 linear = 0.544), ExTEM MaxV (R2 linear = 0.332), ExTEM MCE (R2 linear = 0.395) and non-linearly with ExTEM CFT (R2 cubic = 0.475) – Figure 2. Fig. 1 Correlation between platelet count and ROTEM parameters: ExTEM TPI (A), ExTEM MaxV (B), ExTEM MCE (C) and ExTEM MCF (D). Fig. 2 Correlation between fibrinogen levels and ROTEM parmeters: ExTEM MCF (A), ExTEM TPI (B), ExTEM MaxV (C), ExTEM MCE (D) and ExTEM CFT (E). For non-linear correlations, we determined a cut-off value for fibrinogen of 200 mg /dL that corresponds to an ExTEM CFT of 160 s and a maximum inflection point for ExTEM CFT of 320 s that corresponds to a fibrinogen level of 115 mg/dL. For platelet count we determined a cut-off value of 23000/mm3 that corresponds to an ExTEM MCF of 72 mm and a maximum inflection point for ExTEM MCF of 38 mm that corresponds to a platelet count of 57000/mm3.

For non-linear correlations, we determined a cut-off value for fibrinogen of 200 mg /dL that corresponds to an ExTEM CFT of 160 s and a maximum inflection point for ExTEM CFT of 320 s that corresponds to a fibrinogen level of 115 mg/dL. For platelet count we determined a cut-off value of 23000/mm3 that corresponds to an ExTEM MCF of 72 mm and a maximum inflection point for ExTEM MCF of 38 mm that corresponds to a platelet count of 57000/mm3. Discussions The main results of our study show that both platelet counts and fibrinogen levels significantly impacted whole blood haemostasis as assessed by ROTEM. We found a linear correlation between platelet counts, fibrinogen levels, extrinsically activated thrombin potential index, maximum clot velocity and maximum clot elasticity. Moreover, we determined a cut-off value of 200 mg/dL for fibrinogen and 57000/mm3 for platelet counts below which coagulopathy developed and another cut-off value of 115 mg/dL for fibrinogen and 23000/mm3 below which severe coagulopathy developed. The main disadvantage of our study is represented by its observational nature. Although from a rational point of view, the thresholds determined corresponded to the development of coagulopathy we did not evaluate their impact on blood loss or transfusion in acute bleeding situations. Therefore, the exact clinical value of our data must be further assessed in randomized clinical trials.

al nature. Although from a rational point of view, the thresholds determined corresponded to the development of coagulopathy we did not evaluate their impact on blood loss or transfusion in acute bleeding situations. Therefore, the exact clinical value of our data must be further assessed in randomized clinical trials. In a study performed by Jeong et al. [8], the authors demonstrated that maximum clot firmness could be used for the prediction of intra-operative blood loss in liver transplantation and recently Dotsch et al [9] showed that FibTEM MCF correlated significantly with postoperative bleeding in liver transplantation. Further studies demonstrated that fibrinogen levels but not platelet counts correlated with excessive transfusion [10]. On the other hand, Seo et al. [11] demonstrated that FibTEM assay did not correlate with fibrinogen levels in severe hypo-fibrinogenemia during liver transplantation. Furthermore, Lentschener et al. [12] stipulated that the use of viscoelastic testing in guiding pro-haemostatic interventions could lead to unnecessary transfusion. Our results show that both fibrinogen levels and platelet counts had a significant impact on whole blood coagulation. We found that as platelet counts fell in a linear model below 57000/mm3, so did clot firmness, elasticity and clot kinetics. At a platelet count below 23000/mm3 , blood viscosity was detrimentally affected to a point that could not sustain clot formation.

elet counts had a significant impact on whole blood coagulation. We found that as platelet counts fell in a linear model below 57000/mm3, so did clot firmness, elasticity and clot kinetics. At a platelet count below 23000/mm3 , blood viscosity was detrimentally affected to a point that could not sustain clot formation. To our knowledge, few studies have shown the utility of derived ROTEM parameters in assessing coagulation kinetics. These parameters are beginning to be used in septic patients with multiple system organ failure with promising results [13]. Solomon et al. [14] demonstrated that clot elasticity and clot firmness did not follow a linear correlation and that the use of clot elasticity could prove to offer a more significant insight into clot strength. Also, platelet counts are more importantly reflected by clot elasticity compared to clot firmness and so a more precise decision can be made in regard to platelet transfusion in cases of massive bleeding.

correlation and that the use of clot elasticity could prove to offer a more significant insight into clot strength. Also, platelet counts are more importantly reflected by clot elasticity compared to clot firmness and so a more precise decision can be made in regard to platelet transfusion in cases of massive bleeding. Viscoelastic tests have become the method of choice in assessing coagulopathy and guiding transfusion in patients with ESLD with a decrease in blood product administration, costs and an overall improved outcome [15]. We consider that the next logical step will be to use derived ROTEM parameters that are able to provide new insights into coagulation kinetics. Thrombin potential index and maximum clot velocity represent the most significant parameters associated with coagulation kinetics and the magnitude of platelet counts and fibrinogen levels on these parameters are able to assess the haemostatic reserve in cirrhotic patients. Furthermore, clot elasticity, as measured by ExTEM MCE, is a marker of clot stability. The combination of these parameters may be able to offer a better picture and form the basis for fine tuning in the management of cirrhotic coagulopathy. In conclusion, both platelet counts and fibrinogen levels have significant effects on clot kinetics and clot strength in patients with ESLD. The cut-off values of both fibrinogen and platelet count we determined need further investigation in clinical studies and should be adjusted so that fine tuning of haemostasis can be performed without the risk of either over- or under- correction of coagulopathy.

n clot kinetics and clot strength in patients with ESLD. The cut-off values of both fibrinogen and platelet count we determined need further investigation in clinical studies and should be adjusted so that fine tuning of haemostasis can be performed without the risk of either over- or under- correction of coagulopathy. Conflict of interest No conflict of interests to declare. This article did not benefit from any support in the form of grants, equipment or drugs.

Introduction Thrombophilia is defined as a tendency towards excessive blood clotting [1]. The inherited types of thrombophilia include prothrombin (PT) gene (G20210A) mutation, factor V Leiden (FVL) mutation, protein C (PC) deficiency, protein S (PS) deficiency, and antithrombin III (ARIII) deficiency [2]. This hypercoagulable state, either acquired or inherited, increases the risk of developing venous thromboembolism (VTE) [2]. Other frequent causes that may lead to VTE in pediatric patients are vascular malformation or sepsis [3, 4, 5]. VTE, which comprises deep vein thrombosis (DVT) and its life-threatening complication, acute pulmonary embolism (PE), represents a significant worldwide health problem which can result in death. The annual incidence of VTE ranges between 75 and 269 cases per 100,000 individuals, as shown by global studies in Western Europe, North America, Australia, and southern Latin America [6,7]. In the United States, PE is a relatively common disease, with an incidence ranging from 60 to 112 per 100,000 inhabitants [8].

h. The annual incidence of VTE ranges between 75 and 269 cases per 100,000 individuals, as shown by global studies in Western Europe, North America, Australia, and southern Latin America [6,7]. In the United States, PE is a relatively common disease, with an incidence ranging from 60 to 112 per 100,000 inhabitants [8]. Recent studies using CT pulmonary angiography have proved a high incidence (14–15.5%) of PE in children [9]. PE in the pediatric population is rare, but evidence suggests it often goes undetected and seldom considered, as part of a differential diagnosis, by physicians. Predisposing risk factors for PE in children include obesity, immobility, central venous catheter, malignancy, congenital heart disease, systemic lupus erythematosus, nephrotic syndrome, surgery, trauma, and prolonged total parenteral nutrition [10]. The early diagnosis and treatment of PE are essential, while failure to diagnose the condition can have severe consequences. Mortality rates of PE in childhood are reported to be up to 10%, in a Canadian registry [10,11].

erythematosus, nephrotic syndrome, surgery, trauma, and prolonged total parenteral nutrition [10]. The early diagnosis and treatment of PE are essential, while failure to diagnose the condition can have severe consequences. Mortality rates of PE in childhood are reported to be up to 10%, in a Canadian registry [10,11]. Pregnancy is a physiological state that predisposes to thrombosis due to hormonal changes that involve blood flow (venous stasis), the vascular wall (hypotonia, endothelial lesion), coagulation factors (increased levels of factor VII, factor VIII, factor X, von Willebrand factor) and decreased activity levels of natural anticoagulants (protein C, protein S) [12]. Also, in some cases, this physiological hypercoagulable state can be augmented by hereditary or acquired ‘defects’ in anticoagulant mechanisms. [12,13] VTE during pregnancy has an incidence of 1/1000 births. The risk of developing VTE is 4.5 times higher in pregnant compared to non-pregnant women. 75-80% of VTEs related to pregnancy are deep DVTs and 20-25% are Eps. [12, 13, 14] Thrombophilia is a common cause of recurrent pregnancy loss representing up to 40-50% of cases. [1]

g pregnancy has an incidence of 1/1000 births. The risk of developing VTE is 4.5 times higher in pregnant compared to non-pregnant women. 75-80% of VTEs related to pregnancy are deep DVTs and 20-25% are Eps. [12, 13, 14] Thrombophilia is a common cause of recurrent pregnancy loss representing up to 40-50% of cases. [1] Case report Medical history The case describes a 16-year-old girl, admitted to the Pediatrics Clinic, for dyspnea, sudden onset chest pains and one episode of loss of consciousness. Her medical history revealed two orthopedic surgical interventions in infancy for inferior limb inequality, two pregnancies, one spontaneous miscarriage one year before this admission. One week before this current admission, she had undergone a caesarian section at 20 weeks of gestation for the premature detachment of a normally situated placenta associated with a deceased fetus. The patient is a non-smoker, does not consume alcohol or other drugs, and has not used oral contraceptives. Her family history did not reveal any relevant pathological elements. Clinical findings On admission, the clinical examination showed the following pathological elements: altered general health status, ringed face, pallor, sweaty skin, tachycardia, a post-cesarean scar in the lower abdominal quadrant, inferior limb inequality with the right inferior limb shorter by 8-10 centimeters. Examination of the respiratory tract revealed symmetrically disseminated sibilant rales and an O2 saturation in hemoglobin (SaO2) of 94%. Weight 59 kg, height 164 cm, and a body mass index of 22.01.

scar in the lower abdominal quadrant, inferior limb inequality with the right inferior limb shorter by 8-10 centimeters. Examination of the respiratory tract revealed symmetrically disseminated sibilant rales and an O2 saturation in hemoglobin (SaO2) of 94%. Weight 59 kg, height 164 cm, and a body mass index of 22.01. Diagnosis The pathological elements of the laboratory tests consisted of low activated partial thromboplastin time (APTT) 21.9 seconds. The international normalized ratio (INR) was 1.01. An angio-CT was performed which showed multiple filling defects in both pulmonary arteries, mixed thrombi, both floating and parietal, positioned in the area of pulmonary artery dichotomy with extension in the bilateral lower lobar artery and bilaterally in the lower lobe segmental arteries. The right arterial lumen was completely obstructed and the left arterial lumen partially obstructed (Figure 1,2). Laboratory tests were performed in order to diagnose a possible thrombophilia. The results indicated antithrombin III 30%, repeated 16.7%, C protein 107.7%, S protein 78.6%, and homocysteine 10.14 μmol/l. Genetic testing revealed no mutation of factor V Leiden (A506G) or factor II (prothrombin gene G20210A). Antiphospholipid syndrome was ruled based on lupus anticoagulant, anti-cardiolipin antibodies and beta2-glycoprotein I Ig M, IgG, that were within normal ranges. Based on these data, a diagnosis of PE and thrombophilia (antithrombin III deficiency) was made. Fig. 1 CT-scan: Thrombus in the left pulmonary artery Fig. 2 CT-scan: Partial obliteration of both pulmonary arteries

Diagnosis The pathological elements of the laboratory tests consisted of low activated partial thromboplastin time (APTT) 21.9 seconds. The international normalized ratio (INR) was 1.01. An angio-CT was performed which showed multiple filling defects in both pulmonary arteries, mixed thrombi, both floating and parietal, positioned in the area of pulmonary artery dichotomy with extension in the bilateral lower lobar artery and bilaterally in the lower lobe segmental arteries. The right arterial lumen was completely obstructed and the left arterial lumen partially obstructed (Figure 1,2). Laboratory tests were performed in order to diagnose a possible thrombophilia. The results indicated antithrombin III 30%, repeated 16.7%, C protein 107.7%, S protein 78.6%, and homocysteine 10.14 μmol/l. Genetic testing revealed no mutation of factor V Leiden (A506G) or factor II (prothrombin gene G20210A). Antiphospholipid syndrome was ruled based on lupus anticoagulant, anti-cardiolipin antibodies and beta2-glycoprotein I Ig M, IgG, that were within normal ranges. Based on these data, a diagnosis of PE and thrombophilia (antithrombin III deficiency) was made. Fig. 1 CT-scan: Thrombus in the left pulmonary artery Fig. 2 CT-scan: Partial obliteration of both pulmonary arteries Therapy Anticoagulant therapy with 5000 UI unfractionated heparin as a bolus, followed by 20 000 UI in perfusion, with close monitoring of the coagulation parameters was prescribed. The treatment was continued for five days with 50 000 UI unfractionated heparin. Antibiotic therapy with amikacin (2x500 mg/day, intra venous, 9 days) and ceftazidime (3x1 g/day, intra venous, 13 days) was prescribed. Subsequently, the patient received low molecular weight heparin 0,6 ml (100UI/kg) subcutaneously for three months. This approach was taken because the patient refused INR monitoring. Unfortunately, she developed an exanthema with pruritus after the administration of Fraxiparine, which was considered as a potential allergic reaction to the therapy. Therefore, the subcutaneous anticoagulant treatment was replaced with acenocoumarol (3 mg/day, oral, life-long) and close monitoring of INR.

monitoring. Unfortunately, she developed an exanthema with pruritus after the administration of Fraxiparine, which was considered as a potential allergic reaction to the therapy. Therefore, the subcutaneous anticoagulant treatment was replaced with acenocoumarol (3 mg/day, oral, life-long) and close monitoring of INR. Discussion PE is a difficult to diagnose, life-threatening condition presenting with non-specific signs and symptoms. [8] Mortality rates of PE during childhood are reported to reach approximately 10%. A recent study found the incidence of clinically relevant PE to be of 25 cases per 100 000 admissions. [10]. Despite known predisposing risk factors and associated signs, and symptoms, the diagnosis of PE is still often delayed because the presenting disorders may overlap with other conditions.[10] VTE is a major cause of maternal morbidity and mortality during pregnancy or early after delivery, and remains a diagnostic and therapeutic challenge in both circumstances. [15] The incidence of pregnancy-associated VTE has been reported to be between 1 in 1,000 and 1 in 2,000 deliveries. Also, it was found that 20% of these episodes are due to arterial events, while 80% are venous. VTE episodes are 4–5-fold higher during pregnancy than in a non-pregnant status. Moreover, it was proved that VTE risk is higher in the postpartum than the antepartum period. A 20- to 80-fold higher VTE risk has been reported within the first six weeks following delivery, being 100-fold higher in the first week after delivery [15].

are 4–5-fold higher during pregnancy than in a non-pregnant status. Moreover, it was proved that VTE risk is higher in the postpartum than the antepartum period. A 20- to 80-fold higher VTE risk has been reported within the first six weeks following delivery, being 100-fold higher in the first week after delivery [15]. The most common clinical indicators of PE in pregnancy include shortness of breath, pleuritic chest pain, hypoxemia, and tachycardia. Among the less frequently reported symptoms are tachypnea, hemoptysis, syncope, cough, unexplained hypotension, and other types of chest pain. [16] The patient in this reported case presented with several of the signs mentioned above i.e. sudden onset chest pain and one episode of syncope. Pregnancy impairs the hemostatic system leading to a state of hypercoagulability which increases in severity during pregnancy and reaches the maximum point around term. These peri-partum changes in the hemostatic system may lead to maternal and fetal complications during pregnancy. The mother is at risk from the time of conception until the postnatal period, with recent data suggesting that the risk extends to at least 12 weeks postpartum. The fetal risks include pre-eclampsia, placental abruption, fetal growth restriction, late and recurrent early miscarriage, intrauterine death and stillbirth. [17]

mother is at risk from the time of conception until the postnatal period, with recent data suggesting that the risk extends to at least 12 weeks postpartum. The fetal risks include pre-eclampsia, placental abruption, fetal growth restriction, late and recurrent early miscarriage, intrauterine death and stillbirth. [17] Beyond the specific pregnancy-related increased hemostatic activation, congenital or acquired thrombophilia are frequently encountered, accounting for approximately 15% of all thrombophilic conditions in western countries and up to 50% of VTE cases during pregnancy or the postpartum period. [15,10] There is a paucity of strong evidence associated with adverse pregnancy outcomes and thrombophilia in pregnancy. These problems include both early and late placental vascular-mediated problems. [17, 18, 19] Clinical studies suggest that hyper coagulation is the primary underlying pathophysiological mechanism which leads to uteroplacental insufficiency and, subsequent miscarriage. It is considered that thrombophilia impairs the placental function by causing arterial and venous thrombosis at the maternal-fetal interface. [1,19] Similarly, in the current case, there was one miscarriage and a recent caesarian section at the gestational age of 20 weeks.

tal insufficiency and, subsequent miscarriage. It is considered that thrombophilia impairs the placental function by causing arterial and venous thrombosis at the maternal-fetal interface. [1,19] Similarly, in the current case, there was one miscarriage and a recent caesarian section at the gestational age of 20 weeks. Conclusions Thrombophilia is a disorder of hemostasis that predisposes a person to a thrombotic event. The association between thrombophilia and recurrent pregnancy loss has become an undisputed fact. VTE has an increased incidence among pregnant women, but the highest risk is observed postpartum. The case presented above emphasized a female teenager associated with an increased number of risk factors which contributed to PE development. The importance of ruling out thrombophilia in all cases of repeated miscarriage is emphasized as this hypercoagulable state representing a critical risk factor for PE. Conflict of interest None to declare

Introduction Nosocomial infections represent a major health care problem associated with high mortality and increased costs. Medical device-related infections represent almost one fourth of nosocomial infections [1]. Researchers devote extensive work in order to discover efficient prevention and treatment strategies. The most common type is nosocomial pneumonia with a reported incidence of 6.8-27% [1, 2]. Nosocomial pneumonia is a hospital-acquired life-threatening infection. Critically ill patients requiring mechanical ventilation in intensive care unit (ICU) is the group at the highest risk to develop the most severe form, ventilator-associated pneumonia (VAP). VAP is defined as a nosocomial pneumonia occurring in a patient after 48 hours of mechanical ventilation via an endotracheal tube (ET) or tracheostomy tube [3] and it is the most common infectious complication in critically ill patients [4]. VAP prevalence varies between 9-65% [5, 6], mortality rates are high (15-76%), ICU- and hospital-length of stay are increased (by 5-7 ICU days, respectively by 2-3 folds), with significantly increased costs per patient [6, 7]. Endotracheal tube and risk of ventilator-associated pneumonia Although mechanical ventilation is a life-saving procedure, the use of endotracheal intubation has its risks. The ET provides an ideal opportunity for bacterial and fungal adhesion and biofilm formation on both its inner luminal and outer surface [8]. Being recognized as an independent risk factor for pulmonary infection in intubated patients [9], ET increases this risk by 6-10 times [10].

ndotracheal intubation has its risks. The ET provides an ideal opportunity for bacterial and fungal adhesion and biofilm formation on both its inner luminal and outer surface [8]. Being recognized as an independent risk factor for pulmonary infection in intubated patients [9], ET increases this risk by 6-10 times [10]. While necessary to facilitate mechanical ventilation, the ET results in several host-device interactions described to be involved in VAP pathogenesis. ET has direct effects, which impair host’s local defense mechanisms: it keeps the epiglottis open altering the cough reflex and muco-ciliary clearance; it modifies the phenotype of trachea-bronchial cells promoting the bacterial binding; low airway tract inoculation with the endogenous oropharyngeal flora and airway injury during intubation can also create bacterial binding sites; the ET surface is a nest for bacterial biofilm formation [7, 11, 12]. In addition, it was proven that the accumulation of contaminated secretions from the oropharynx or gastro-intestinal tract in the subglottic space above the inflated ET cuff is a source of microaspiration leading to ET and airway colonization and VAP [3].

T surface is a nest for bacterial biofilm formation [7, 11, 12]. In addition, it was proven that the accumulation of contaminated secretions from the oropharynx or gastro-intestinal tract in the subglottic space above the inflated ET cuff is a source of microaspiration leading to ET and airway colonization and VAP [3]. It is also presumed that apart from interfering with respiratory tract defense, the ET presence causes an imbalance in the lung microbiome [13]. The use of culture-independent techniques proves that bacteria exist in normal individuals even in the lower airway tract and this microbial population is termed lung microbiota [14]. In never-smokers these bacterial communities are very few and composed of different types of bacteria [15]. The lung microbiota is a biological defense barrier of the respiratory tract. Changes of its composition promote pathogen invasion and occurrence and progression of lung infections and acute exacerbation of chronic diseases [16]. Such changes are enhanced in intubated patients [13].

of different types of bacteria [15]. The lung microbiota is a biological defense barrier of the respiratory tract. Changes of its composition promote pathogen invasion and occurrence and progression of lung infections and acute exacerbation of chronic diseases [16]. Such changes are enhanced in intubated patients [13]. Biofilms – definition and formation 80% of human bacterial infections are biofilm-related [17]. It is known that ET acts as a reservoir for infecting microorganisms. Soon after intubation a mixed biofilm harboring microbial pathogens is formed on the ET [18], especially lining in the interior of the tube distal third [3]. In 1967 Redman and Lockey were the first to demonstrate ET bacterial colonization by culturing the distal end of the ET and in 1986 Sottile et al. were the first to use scanning microscopy to demonstrate biofilm presence on the inner surface of polyvinylchloride ETs [19, 20].

the interior of the tube distal third [3]. In 1967 Redman and Lockey were the first to demonstrate ET bacterial colonization by culturing the distal end of the ET and in 1986 Sottile et al. were the first to use scanning microscopy to demonstrate biofilm presence on the inner surface of polyvinylchloride ETs [19, 20]. Microorganisms can exist as planktonic organism – individual cells freely suspended in a liquid medium, or as a sessile community into biofilms [biofilm]. A microbial biofilm is a three-dimensional structured aggregate of microbial cells surrounded by a self-produced polymer matrix, which protects it from the hostile environment [21]. The matrix-enclosed bacterial populations are adherent to each other and to inert or living surfaces [11]. Consequently, the hosted microorganisms can survive in a dormant state in these protected communities [22]. These metabolically inactive persister cells are a small part of the biofilm, which survive in this state because of a slowed down metabolism, where they are less sensitive to the effects of antimicrobials [23]. Biofilm formation is a dynamic process. There are several described stages of biofilm formation: adhesion stage, aggregation stage, maturation stage, mature biofilm stage and dispersion stage [23]. After attachment bacteria have to mature into a differentiated biofilm and they secrete signaling molecules to determine if there are enough bacteria to initiate the expression of a particular phenotype (“quorum sensing”). Then the sessile forms of the bacteria coating the biofilm can give rise to planktonic bacteria, which may also generate biofilm and disperse into the environment [11].

and they secrete signaling molecules to determine if there are enough bacteria to initiate the expression of a particular phenotype (“quorum sensing”). Then the sessile forms of the bacteria coating the biofilm can give rise to planktonic bacteria, which may also generate biofilm and disperse into the environment [11]. Endotracheal tube sheltered biofilm The ET is rapidly, within hours after insertion, colonized by microorganisms that form a biofilm on its surface [24]. The sequence of colonization with pathogenic bacteria in mechanically ventilated patients was firstly reported by Feldman et al.: the oropharynx (within 36 hours), the stomach (within 36-60 hours), the lower respiratory tract (within 60-84 hours) and thereafter the ET (within 60-96 hours) [25]. Yan et al. assessed by scanning electron microscopy patchy biofilms on the ET surface after 2-7 days of ventilation initiation, 87.5% of ETs being covered by biofilms after 7-10 days. Day 10 was the breakpoint when all the ETs housed biofilms on their surfaces [26]. In fact, ET colonization occurs much earlier and the capacity to demonstrate this fact depends on the assessment methods. Perkins et al. showed ET colonization by quantitative polymerase chain reaction (PCR) even after 24 hours of intubation [27]. Gil-Perotin et al. showed the same by electron microscopy and culture [12].

In fact, ET colonization occurs much earlier and the capacity to demonstrate this fact depends on the assessment methods. Perkins et al. showed ET colonization by quantitative polymerase chain reaction (PCR) even after 24 hours of intubation [27]. Gil-Perotin et al. showed the same by electron microscopy and culture [12]. New data show that ET biofilm contains multiple bacterial populations. Usually the composition of ET biofilms is often misrepresented due to the fact that the gold standard assessment method is the traditional culture analysis. 99% of bacteria in the natural environment cannot be cultured [8]. Taking into account that ET biofilm flora may originate in the oral cavity it is important to know that 50% of the oral microflora is considered to be unculturable – difficult to culture or have not yet been cultured [28]. Culture identification results are at best available 48 hours after sampling and the interpretation is often difficult. Also, some loss of microbial viability between the time of patient’s ET removal and it’s processing for culture is likely to be responsible for the incomplete biofilm characterization [7]. Vandecandelaere et al. suggest that using combined surveillance cultures (throat swab, nose swab and sputum samples) may increase the sensitivity but decrease specificity to identify ET biofilm flora [18]. Ferreira et al. compare tracheal aspiration culture versus ET originated biofilm germ identification through sonication technique in 27 pediatric patients, proving the benefit of the later technique [10].

e swab and sputum samples) may increase the sensitivity but decrease specificity to identify ET biofilm flora [18]. Ferreira et al. compare tracheal aspiration culture versus ET originated biofilm germ identification through sonication technique in 27 pediatric patients, proving the benefit of the later technique [10]. In time numerous culture-independent approaches became available in order to analyze these microbial communities [7], which usually consist of a wide variety of bacteria [9]. Meligy et al. identifies biofilms in 20 ET mechanically ventilated patients by biofilm electronic microscopy and culture analysis [29]. Pan et al. uses 16S ribosomal RNA gene polymerase chain reaction, denaturing gradient gel electrophoresis (DGGE), cloning and sequencing in 15 pediatric VAP to compare throat swabs and tracheal aspirates versus ET biofilm samples [30]. Cairns et al. also uses DGGE and PCR in order to characterize microbial biofilms on the inner lumen of 24 extubated ETs from ICU patients [7]. All of them conclude that a combination of culture and different molecular methods should be used to obtain a complete picture of the bacterial diversity of ET biofilms. Endotracheal tube biofilms and ventilator-associated pneumonia Several mechanisms are responsible for ET biofilm involvement in VAP pathogenesis: biofilm pieces dispersed and passively moved towards the lung, biofilm cells aerosolized and aspirated into the lungs due to gas flow during artificial ventilation and individual cells can be dislodged by liquids and transferred deep into the lungs [24, 30].

e responsible for ET biofilm involvement in VAP pathogenesis: biofilm pieces dispersed and passively moved towards the lung, biofilm cells aerosolized and aspirated into the lungs due to gas flow during artificial ventilation and individual cells can be dislodged by liquids and transferred deep into the lungs [24, 30]. VAP diagnosis has its limits due to definition and currently available diagnostic methods. Its etiology is poly-microbial with a considerable inter-patient and intra-patient diversity [7, 31], and unfortunately, often the causative agent is not known at the time of VAP suspicion [18]. The differentiation colonization versus infection is very important [32], but also very difficult. It is the clinician’s responsibility to decide if the ET biofilm flora is either the primary source of infection or a concomitant colonization site [10]. The multidrug resistant ESKAPE pathogens (Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) play a dominant role in VAP etiology, and these organisms were frequently identified in ET biofilms. Members of the normal oral flora were also identified but considered to initiate ET biofilm formation and not to be directly involved in VAP development [33]. It is supposed that an indicator of VAP is the enrichment of pathogen strains in the biofilm [27] and a change in the prevalence of detectable organisms identified by molecular methods [8].

lora were also identified but considered to initiate ET biofilm formation and not to be directly involved in VAP development [33]. It is supposed that an indicator of VAP is the enrichment of pathogen strains in the biofilm [27] and a change in the prevalence of detectable organisms identified by molecular methods [8]. Adair et al. reported that 70% of VAP patients have identical pathogens present in the ET biofilm and in the lung, suggesting that the biofilm represents a significant and persistent source of pathogenic bacteria [7]. Bardes et al. found using 16S ribosomal RNA gene analysis a maximum 87 different bacterial species on 20 ET biofilms with a mean number of 16±9 identified species [9]. This huge variety is greater in smokers, but similar in patients with or without pneumonia [9].

ficant and persistent source of pathogenic bacteria [7]. Bardes et al. found using 16S ribosomal RNA gene analysis a maximum 87 different bacterial species on 20 ET biofilms with a mean number of 16±9 identified species [9]. This huge variety is greater in smokers, but similar in patients with or without pneumonia [9]. Despite the early presence of ET biofilm and despite its bacterial diversity, VAP occurs later. Perkins et al. demonstrated that longer intubation period increases the opportunity for the potentially pathogenic bacteria to proliferate [27] and De Souza et al. showed that an intubation period of more than 8 days represents a risk factor for developing VAP [34]. Wilson et al. prove that advanced biofilm stage (maturation or mature stage) is associated with pneumonia, while duration of intubation, patient age and hospital stay are not related and cannot predict the biofilm stage [35]. Bardes et al. and Cairns et al. also showed that there was no relationship between duration of intubation and number of identified bacterial species [7, 9]. Researchers even demonstrate that ET biofilm might always be present in intubated patients, whatever the duration of intubation and cannot be removed by rinsing due to strong adhesion [36]. It seems that VAP might be more related to the ET presence than to the mechanical ventilation per se. In 2009 Pneumatikos et al. suggested the replacement of the term „ventilator-associated pneumonia” with the term “endotracheal tube-associated pneumonia” in order to better describe its pathogenesis [3].

Despite the early presence of ET biofilm and despite its bacterial diversity, VAP occurs later. Perkins et al. demonstrated that longer intubation period increases the opportunity for the potentially pathogenic bacteria to proliferate [27] and De Souza et al. showed that an intubation period of more than 8 days represents a risk factor for developing VAP [34]. Wilson et al. prove that advanced biofilm stage (maturation or mature stage) is associated with pneumonia, while duration of intubation, patient age and hospital stay are not related and cannot predict the biofilm stage [35]. Bardes et al. and Cairns et al. also showed that there was no relationship between duration of intubation and number of identified bacterial species [7, 9]. Researchers even demonstrate that ET biofilm might always be present in intubated patients, whatever the duration of intubation and cannot be removed by rinsing due to strong adhesion [36]. It seems that VAP might be more related to the ET presence than to the mechanical ventilation per se. In 2009 Pneumatikos et al. suggested the replacement of the term „ventilator-associated pneumonia” with the term “endotracheal tube-associated pneumonia” in order to better describe its pathogenesis [3]. Antibiotic resistance of biofilms Biofilms represent a persistent source of organisms causing recurrent infections [11, 25]. Moreover, it was proven that these microorganisms exhibit significantly greater antibiotic resistance then their tracheal counterparts [37]. There are three mechanisms described to be responsible of decreased antibiotic susceptibility: the biofilm resides in an air-filled lumen with no host defense mechanisms, it protects the sessile forms so that the antibiotic cannot penetrate or deactivate them due to impaired diffusion and also offers slow growing or dormant state to the sessile bacteria [11].

e responsible of decreased antibiotic susceptibility: the biofilm resides in an air-filled lumen with no host defense mechanisms, it protects the sessile forms so that the antibiotic cannot penetrate or deactivate them due to impaired diffusion and also offers slow growing or dormant state to the sessile bacteria [11]. Due to the temporal biofilm dynamics VAP developing within the first 2-5 days after intubation is more likely to be caused by antibiotic-sensitive bacteria as methicillin-sensitive Stapylococcus aureus, with a better prognosis, later occurring VAP (5 or more days after initiation of mechanical ventilation) involving frequently multidrug resistant pathogen like methicillin-resistant Stapylococcus aureus, Pseudomonas aeruginosa and extended spectrum β-lactamase producing Enterobacteriaceae, with higher morbidity and mortality [24]. In subjects who experienced a successfully treated episode of VAP, the responsible bacteria were still present in the biofilm [36, 25]. Gordon Sahuquillo et al. even observed on a small sample of patients, that neither the use of systemic nor inhaled antibiotics influenced the persistence of variable and potentially infectious microorganisms in ET biofilm after VAP [4]. This resistance frequently implies the necessity of device withdrawal in order to achieve clinical and microbiological cure [7], but usually the elective ET change during mechanical ventilation is not recommended [18, 38].

he persistence of variable and potentially infectious microorganisms in ET biofilm after VAP [4]. This resistance frequently implies the necessity of device withdrawal in order to achieve clinical and microbiological cure [7], but usually the elective ET change during mechanical ventilation is not recommended [18, 38]. Prevention and treatment of biofilm formation Due to the high prevalence of ET biofilm in mechanically ventilated patients and the microbial dynamic link between airway colonization, biofilm formation and VAP development, biofilm-directed interventions seem to be a high priority [12]. In order to prevent ET biofilm formation, knowledge of the source of involved microorganisms is important [7]. Respiratory pathogens are not usually found in the oral microbiota of healthy people, but hospitalized patients are susceptible to oral biofilm colonization by these microorganisms [39]. Improved oral hygiene has been proven to be an effective strategy of VAP prevention, taking into consideration that normal oral microflora may represent pioneering colonizing species and potential respiratory pathogen may be isolated from dental plaque’s biofilm [7, 39]. Chemical control of oral pathogens seems to be more effective than mechanical removal [39].

an effective strategy of VAP prevention, taking into consideration that normal oral microflora may represent pioneering colonizing species and potential respiratory pathogen may be isolated from dental plaque’s biofilm [7, 39]. Chemical control of oral pathogens seems to be more effective than mechanical removal [39]. Biofilm formation prevention on the ET surface can be also achieved by the use of specific antiseptic (silver-coated, chlorhexidine, gendine) or antibiotic (sulfadia-zine) impregnated ET. Care must be taken to the fact that, although long-term use of antimicrobial-impregnated central venous catheters has shown no selection of bacterial resistance, biofilm formation has been associated with antibiotic-resistant pathogen and lack of antimicrobial penetrability into ET biofilm [40]. Another mechanical removal technique of ET biofilm is the mucus shaver. It consists of an inflatable silicone rubber (introduced into the ET in a deflated and extracted in an inflated status), which extracts the accumulated material on its inner surface. Published studies report encouraging results and it is recommended by VAP prevention guidelines [3, 38]. One recently described non-invasive treatment method is the photodynamic therapy. In vitro models, which used spraying of small amounts of a photosensitizer solution into the ET lumen followed by light exposure, resulted in reduced number of biofilm microorganisms after a single treatment [41].

Another mechanical removal technique of ET biofilm is the mucus shaver. It consists of an inflatable silicone rubber (introduced into the ET in a deflated and extracted in an inflated status), which extracts the accumulated material on its inner surface. Published studies report encouraging results and it is recommended by VAP prevention guidelines [3, 38]. One recently described non-invasive treatment method is the photodynamic therapy. In vitro models, which used spraying of small amounts of a photosensitizer solution into the ET lumen followed by light exposure, resulted in reduced number of biofilm microorganisms after a single treatment [41]. There are a lot of guidelines recommended strategies for VAP prevention. Some of them avoid or diminish the ET biofilm consequences. One recommended prevention strategy is to avoid the use of ET if possible. The use of noninvasive ventilation can decrease the tracheal intubation rates and even mortality, the available evidence suggesting a clear benefit in terms of a lower VAP risk [3]. Early extubation policies should be a standard procedure and implemented in all the hospitals. Some researchers suggest that a solution to overcoming the disadvantages of ET long-term use can be early tracheostomy, which significantly reduces the duration of mechanical ventilation and length of ICU stay. But biofilms can also form on the surface of tracheostomy tubes, even though the cleaning and maintenance methods are easier, with several disinfecting solutions available [42].

ages of ET long-term use can be early tracheostomy, which significantly reduces the duration of mechanical ventilation and length of ICU stay. But biofilms can also form on the surface of tracheostomy tubes, even though the cleaning and maintenance methods are easier, with several disinfecting solutions available [42]. Conclusions Ventilator-associated pneumonia (VAP) is a common and major nosocomial infection in mechanically ventilated patients. Two major mechanisms involved in airway colonization lead to VAP development: microaspiration and ET biofilm formation. Oral and ET biofilms play a major role in lung infection development, promotion of treatment resistance and infection recurrence in mechanically ventilated patients. As a result, biofilm formation control, either on the ET or in the oropharyngeal cavity is an important strategy for VAP prophylaxis. Will the term “ET-associated pneumonia” soon be transformed into “biofilm-associated pneumonia”? Further studies on larger populations need to be conducted to better characterize the biofilm-associated microorganisms, their origins, the timeline of biofilm formation and prevention strategies. Conflict of interest None to declare.

Background One of the challenges faced by physicians is to deal with undifferentiated and systemic diseases, such as systemic inflammatory response, anorexia, weight loss and fatigue observed in certain conditions, mainly malignancy and autoimmune diseases. This cluster of symptoms is non-specific and can often be misleading. The differential diagnosis includes cardiac myxoma, an uncommon cause of this cluster of symptoms. However, among a variety of clinical manifestations, systemic inflammatory symptoms can account for up to 30% of clinical features, thus mimicking malignancy or autoimmune-related problems. These unusual symptoms may complicate the diagnostic procedure. Case Presentation A 68-year-old man was admitted to hospital following the diagnosis of non-iron deficiency anaemia by his general practitioner. The patient reported fatigue, with a feeling of intense weakness. He also stated a weight loss of approximately 8 kg over the last year and low-grade fever. In the previous few months, he had experienced episodes of Raynaud syndrome triggered by low temperatures. He had COPD and type 2 diabetes mellitus, and was taking tiotropium bromide and glibenclamide, prescribed by his general practitioner. On physical examination, the only finding was a soft systolic murmur. Otherwise, the investigations revealed no untoward medical issues.

Raynaud syndrome triggered by low temperatures. He had COPD and type 2 diabetes mellitus, and was taking tiotropium bromide and glibenclamide, prescribed by his general practitioner. On physical examination, the only finding was a soft systolic murmur. Otherwise, the investigations revealed no untoward medical issues. On admission, the patient had a white cell count of 6.1 x 103/uL, haemoglobin of 11 g/dL, and a platelet count of 310 x 103/uL. Kidney and liver function were normal, and his INR was 0.9. However, the erythrocyte sedimentation rate (ESR) was 99 mm/hour, and C-reactive protein (CRP) was 99 mg/ L Antinuclear antibodies (ANAs) were positive, and indirect fluorescent antibody (IFA) was 1:160 with a homogenous pattern. Anti-SSA (Ro), anti-SSB (La), anti-dsDNA and anticentromere antibodies, and ENA panel were all negative. Investigations The positive ANA test result, the high levels of CRP and ESR, the low-grade fever, the weakness and the persistent fatigue were suggestive of an autoimmune disease. Indeed, the anaemia could be explained as being chronic-disease related. However, the patient did not have muscle pain, rash, arthritis or skin sensitivity to light. Analytical findings were subtle and non-specific, making it difficult to establish the diagnosis of an autoimmune disease.

stive of an autoimmune disease. Indeed, the anaemia could be explained as being chronic-disease related. However, the patient did not have muscle pain, rash, arthritis or skin sensitivity to light. Analytical findings were subtle and non-specific, making it difficult to establish the diagnosis of an autoimmune disease. Given the wasting syndrome, the constitutional symptoms and the malaise, it was decided to perform an abdominal ultrasound, and a chest CT scan, to rule out an occult neoplasm. The ultrasound results were normal; however, the CT scan revealed a large left atrial mass that passed through the mitral valve into the left ventricle. Its radiological features could not rule out a left atrial tumour, though the first choice was a large free-floating atrial thrombus (Figure 1). He was referred, therefore, to the intensive care unit (ICU) for close monitoring. Fig. 1 The CT scan with intravenous contrast medium administration showed a large left atrial mass that passed through the mitral valve into the left ventricle, in both slides: horizontal plane (A) and sagittal plane (B). Radiologists could not rule out an intracardiac thrombus (big white arrow). RV: right ventricle. LV: left ventricle. LA: left auricle.

contrast medium administration showed a large left atrial mass that passed through the mitral valve into the left ventricle, in both slides: horizontal plane (A) and sagittal plane (B). Radiologists could not rule out an intracardiac thrombus (big white arrow). RV: right ventricle. LV: left ventricle. LA: left auricle. Transthoracic echocardiography showed an 8.8 x 3.5-cm floating mass, which originated from the left atrial ceiling. It passed through the mitral valve and reached the centre of the left ventricle. The systolic function was normal, with an ejection fraction of 65%, but there was moderate mitral stenosis (Figure 2). Further trans-esophageal echocardiography confirmed the findings mentioned above: the mass originated from the interatrial septum, near the drainage of the right superior pulmonary vein. Fig. 2 Echocardiography revealed a floating mass (white arrow), which originated from the interatrial septum, near the drainage of the right superior pulmonary vein. Slide A (systole) shows the mass within the left auricle (LA). However, the mass prolapsed through the mitral valve and reached the centre of the left ventricle (LV) in diastole (slide B). Treatment and follow-up The patient was referred to our Cardiac Surgery Department to undergo surgical resection of the left atrial mass within 72 hours of the diagnosis being made. It turned out to be a sizeable reddish mass with fibroelastic consistency. Histopathology revealed eosinophilic spindle cells on a myxoid background and multiple small vessels. The mass stained positive with calretinin.

t to undergo surgical resection of the left atrial mass within 72 hours of the diagnosis being made. It turned out to be a sizeable reddish mass with fibroelastic consistency. Histopathology revealed eosinophilic spindle cells on a myxoid background and multiple small vessels. The mass stained positive with calretinin. The post-operative period was uneventful. The patient did not develop severe, respiratory or infectious complications. He recovered, was discharged, and resume normal activity. He had periodic follow-ups to monitor his symptoms and to detect possible complications. After an eighteen-month monitoring period, the patient had gained weight, and the fatigue and weakness had disappeared. Laboratory test abnormalities had improved, the ESR and CRP were normal at 15 mm/hour and 7 mg/L, respectively, and his haemoglobin level was 14.7 g/dL. The patient had experienced no further episodes of Raynaud syndrome, which we considered as primary since it did not occur in association with other autoimmune diseases. Discussion The three most common differential diagnoses, regarding cardiac masses, are large vegetations, intracardiac thrombi and tumours, and although echocardiography plays an essential role in detecting these masses, identifying their nature is difficult. Cardiac tumours represent 0.2% of all human tumours and can be primary or metastatic. Primary tumours are uncommon, representing less than 0.1%, and about 50-75% are benign tumours, i.e., cardiac myxomas.[1]

hough echocardiography plays an essential role in detecting these masses, identifying their nature is difficult. Cardiac tumours represent 0.2% of all human tumours and can be primary or metastatic. Primary tumours are uncommon, representing less than 0.1%, and about 50-75% are benign tumours, i.e., cardiac myxomas.[1] Intracardiac masses can have a broad clinical spectrum. Cardiac symptoms such as fatigue, exertional dyspnoea, valve dysfunction or arrhythmias can be present. Peripheral and cerebral embolic events, or systemic manifestations such as low-grade fever, weight loss and weakness, are also included in the cluster of symptoms.[2] The patient’s symptoms, although subtle and nonspecific, were suggestive of a systemic inflammatory disorder, often seen in malignancy and autoimmune diseases. The early analytical findings were in line with the likelihood of an autoimmune disease. However, he did not have any skin, muscle or joint manifestation. Since a connective tissue disease diagnosis was not definite, we decided to perform a full-body CT scan which would aid in the detection of malignancy as a potential cause of his symptoms. The main finding was an unexpected intracardiac mass, which later turned out to be a left atrial myxoma.

le or joint manifestation. Since a connective tissue disease diagnosis was not definite, we decided to perform a full-body CT scan which would aid in the detection of malignancy as a potential cause of his symptoms. The main finding was an unexpected intracardiac mass, which later turned out to be a left atrial myxoma. Cardiac myxomas are uncommon tumours. They can originate in any cardiac chamber, even in valves, but they are usually found as a pedunculated mass arising from the left atrium, near the fossa ovalis.[1] The extensive clinical spectrum which is presented in association with these cases can make the diagnosis complicated, and it can only be established by the clinical team systematically considering every possibility. Many case-series studies have identified heart failure, peripheral or central embolisms as the main spectrum of clinically significant complications due to atrial myxomas.[2,3] Some recently published case reports have highlighted unusual or uncommon symptoms, such as arrhythmias,[4] fever of unknown origin,[5] brachial artery embolism,[6] subclavian artery embolism,[7] central retinal artery occlusion[8] and multiple cerebral infarctions.[9] These acute presentations contrast with systemic symptoms such as malaise and weight loss, as reported in recent papers.[10,11] The clinical signs and symptoms found in our patient, as well as the analytical features, led us to consider either an autoimmune disease or an occult neoplasm. Left atrial myxoma was an unexpected finding that could explain not only the manifestations but also the analytical abnormalities.

ted in recent papers.[10,11] The clinical signs and symptoms found in our patient, as well as the analytical features, led us to consider either an autoimmune disease or an occult neoplasm. Left atrial myxoma was an unexpected finding that could explain not only the manifestations but also the analytical abnormalities. We would like to clarify a point regarding the patient’s ANA result as we believe it was misleading. Positive ANAs must be interpreted in the context of other laboratory studies and clinical features, and a single positive ANAs need not, on its own, mean that the patient has an autoimmune disease. A dilution of 1:160 could be considered a mild positive result, and could be the result of another condition, such as leukaemia or septic arthritis. Furthermore, a low ANA titre should be ignored in patients with no systemic disease or other manifestations of autoimmune disease.[12] It is worth noting the study by Mendoza et al. [13] in which interleukin-6 (IL-6) was overproduced by cardiac myxomas, and this may have a significant role in the presence of constitutional symptoms and immunologic abnormalities observed in patients presenting with cardiac myxomas. More recently, Kiechl[14] reported the case of a patient with a 3-year history of an unclassified rheumatic disease and elevated IL-6, who suffered multiple ischemic strokes, and whose final diagnosis was a left atrial myxoma. Finally, Pinede et al. [2] emphasised the importance of the classical presentation of constitutional symptoms of fever, and weight loss, suggestive of a connective tissue disease, due to IL-6 production. Thus, constitutional signs may be used for monitoring these cardiac tumours. These symptoms usually disappear after removal of the cardiac myxoma, although prolonged elevation of ANA has been noted.[15]

constitutional symptoms of fever, and weight loss, suggestive of a connective tissue disease, due to IL-6 production. Thus, constitutional signs may be used for monitoring these cardiac tumours. These symptoms usually disappear after removal of the cardiac myxoma, although prolonged elevation of ANA has been noted.[15] Learning points Although uncommon, atrial myxomas should be considered in the differential diagnosis of an atrial mass. However, in the first instance consideration should be given to the presence of a large thrombus or metastatic tumours. In the absence of further complications such as emboli, arrhythmia, etc., atrial myxomas have an excellent prognosis if promptly treated. Sometimes a diagnosis is difficult to achieve if the symptoms are paucisymptomatic. Non-specific, constitutional symptoms may be misleading and make the diagnosis difficult. The final diagnosis of autoimmune disease should be established only after exhaustive diagnostic procedures in patients with highly suggestive signs and symptoms. The role of IL-6 and its involvement in the presence of constitutional symptoms resembling an autoimmune disease should be noted. Conflict of interest disclosure The author declares that there is no conflict of interest regarding the publication of this paper.

Introduction Nonbacterial thrombotic endocarditis (NBTE) is part of the clinical manifestation spectrum characterising paraneoplastic hypercoagulability. In NBTE cases, vegetations of platelets and fibrin accumulate on the cardiac valves. These vegetations are fragile and have a high embolic potential. Approximately half of NBTE patients have systemic embolic events, most commonly affecting the cerebral circulation. In NBTE, these systemic embolic events are the main cause of mortality among patients. [1,2,3]. NBTE is a rare condition and a frequently underdiagnosed cause of ischemic stroke. Elucidating the cause of ischemic stroke in young patients without accompanying cardiovascular risk factors is a challenge for neurologists. If atherothrombotic pathology and cardiac arrhythmias have been excluded, consideration should be given to the possibility of cardiac disease such as endocarditis. [2]. The fatal case of a young patient with NBTE causing multiple arterial infarctions in the brain, lungs, spleen and kidneys, which was proved to be the initial manifestation of an occult gastric adenocarcinoma, is presented in this paper.

NBTE is a rare condition and a frequently underdiagnosed cause of ischemic stroke. Elucidating the cause of ischemic stroke in young patients without accompanying cardiovascular risk factors is a challenge for neurologists. If atherothrombotic pathology and cardiac arrhythmias have been excluded, consideration should be given to the possibility of cardiac disease such as endocarditis. [2]. The fatal case of a young patient with NBTE causing multiple arterial infarctions in the brain, lungs, spleen and kidneys, which was proved to be the initial manifestation of an occult gastric adenocarcinoma, is presented in this paper. Case report The case is presented of a 47-year-old male patient in apparently good health, suffered increasing weight loss during a 6-weeks-period. He was admitted to the emergency department of the Emergency County Hospital Targu Mures, Romania, presenting with sudden onset of dyspnoea, chest pain, micro haemoptysis, low-grade fever and fatigue. Physical examination revealed fever, skin paleness, mild tachycardia and laterocervical lymphadenopathy. All other physical and neurological findings were normal. An ECG revealed sinus tachycardia, right bundle branch block and negative T waves in V1-V4, DIII and aVF. The chest-abdomen-pelvis CT showed pulmonary, renal and splenic infarctions and the presence of bilateral pulmonary thromboembolism (Figure 1). Fig. 1 Abdominal CT scan showing multi-organ infarcts

Case report The case is presented of a 47-year-old male patient in apparently good health, suffered increasing weight loss during a 6-weeks-period. He was admitted to the emergency department of the Emergency County Hospital Targu Mures, Romania, presenting with sudden onset of dyspnoea, chest pain, micro haemoptysis, low-grade fever and fatigue. Physical examination revealed fever, skin paleness, mild tachycardia and laterocervical lymphadenopathy. All other physical and neurological findings were normal. An ECG revealed sinus tachycardia, right bundle branch block and negative T waves in V1-V4, DIII and aVF. The chest-abdomen-pelvis CT showed pulmonary, renal and splenic infarctions and the presence of bilateral pulmonary thromboembolism (Figure 1). Fig. 1 Abdominal CT scan showing multi-organ infarcts The brain-computer tomography found a hypodense lesion in the right parietal lobe. Transthoracic (TTE) and transesophageal echocardiography (TEE) revealed a mobile echogenic mass of 0,8 x 0,9 cm on the mitral valve (Figure 2). Fig. 2 Transthoracic echocardiography showed a mobile echogenic mass on the mitral valve

Fig. 1 Abdominal CT scan showing multi-organ infarcts The brain-computer tomography found a hypodense lesion in the right parietal lobe. Transthoracic (TTE) and transesophageal echocardiography (TEE) revealed a mobile echogenic mass of 0,8 x 0,9 cm on the mitral valve (Figure 2). Fig. 2 Transthoracic echocardiography showed a mobile echogenic mass on the mitral valve Vascular Doppler ultrasonography showed no signs of deep vein thrombosis in the lower limbs. Bacterial endocarditis was suspected at this point, and the patient was admitted to the Department of Cardiology Emergency County Hospital Targu Mures. The initial laboratory examination results (complete blood count, erythrocyte sedimentation rate, procalcitonin level, C-Reactive Protein, blood ion levels, coagulation tests, amylase, urea, creatinine) were all normal. The transaminase levels were three times above the normal range, and D-dimers were above 35 mg/L Repeated aerobic, anaerobic, and fungal blood cultures were all negative. The patient was treated with intravenous broad-spectrum antibiotics, cefuroxime 1.5 g and gentamicin 80 mg every 12 hours, and low-molecular-weight heparin (LMWH), enoxaparin 1 mg/kg every 12 hours, subcutaneously. After eight days of hospitalisation, he developed right-sided hemiparesis, graded as 4/5 on the Medical Research Council scale, and severe motor aphasia. Brain MRI revealed multiple lesions in hypersignal on T2-weighted images, suggestive of embolic infarctions in the left frontotemporal and the right parietal lobes. (Figure 3).

t days of hospitalisation, he developed right-sided hemiparesis, graded as 4/5 on the Medical Research Council scale, and severe motor aphasia. Brain MRI revealed multiple lesions in hypersignal on T2-weighted images, suggestive of embolic infarctions in the left frontotemporal and the right parietal lobes. (Figure 3). Fig. 3 Areas of hyperintensity on T2-weighted MRI sequences in the left frontal lobe and the right parietal lobe. Carotid Doppler ultrasound was normal. Repeated TEE showed a vegetation with an uneven surface, measuring 0,3 x 0,51 cm on the atrial surface of the mitral valve. There was no, mitral stenosis or regurgitation. As repeated blood cultures were negative and the patient showed no clinical signs of an infectious syndrome, the possibility of an aseptic marantic endocarditis was considered. His hereditary thrombophilia panel, antithrombin III, protein C, protein S, Factor V Leiden, methylenetetrahydrofolate reductase mutation screening, as well as the autoimmune panel, anti- cardiolipin IgG and IgM, antinuclear antibodies, lupus anticoagulant, were analysed. All results were within normal limits. In an attempt to detect a neoplastic process, tumour markers were taken. Alpha-fetoprotein, carcinoembryonic antigen, prostate-specific antigen were all within the normal range. The marker Cyfra 21-1, recorded as 5.9 ng/ml, was out with the normal range.

icoagulant, were analysed. All results were within normal limits. In an attempt to detect a neoplastic process, tumour markers were taken. Alpha-fetoprotein, carcinoembryonic antigen, prostate-specific antigen were all within the normal range. The marker Cyfra 21-1, recorded as 5.9 ng/ml, was out with the normal range. After 14 days of hospitalisation, the patient presented with a normochromic, normocytic anaemia with a progressive decrease in haemoglobin to 6.5 g/dl. The haematocrit values decreased to 19.5%. Gastroscopy revealed an ulcerated tumour at the gastric angle, which extended from the antrum to the subcardial region, measuring 4x6 cm and presenting diffuse bleeding. A biopsy was taken, and the pathology report indicated an infiltrative, poorly differentiated gastric adenocarcinoma. In spite of parenteral anticoagulant, antiplatelet, antibiotic, gastric antisecretory therapy and red blood cell transfusion, the patient’s neurological status worsened, and he developed tetraparesis with left hemiplegia. A cerebral CT examination was repeated and revealed a new infarction in the right sylvian artery. (Figure 4.) Fig. 4 Cerebral CT scan with acute right middle cerebral artery infarction Due to the patient`s impaired level of consciousness and respiratory failure, he was transferred to the intensive care unit where he required supportive care measures. The patient’s neurological condition worsened with progressive deterioration in consciousness, increased intracranial pressure, and transtentorial brain herniation. Death ensued four weeks after his initial admission to the hospital.

was transferred to the intensive care unit where he required supportive care measures. The patient’s neurological condition worsened with progressive deterioration in consciousness, increased intracranial pressure, and transtentorial brain herniation. Death ensued four weeks after his initial admission to the hospital. Discussions NBTE is a rare condition which, before echocardiography, had been diagnosed only following a post-mortem examination. It is clinically suspected if iterative and consecutive embolic events occur in several arterial areas. [1,2,3]. Post-mortem studies show that the incidence of NBTE is approximately 1% of the general population but increases by times five in patients with cancer. [4,5]. Neoplasia is associated with a pronounced prothrombotic status, which increases the risk of thromboembolic events by a factor of five. NBTE is part of the clinical manifestations’ spectrum characterising paraneoplastic hypercoagulability, along with deep vein thrombosis, pulmonary embolism, disseminated intravascular coagulation and thrombotic microangiopathy. [6].

rombotic status, which increases the risk of thromboembolic events by a factor of five. NBTE is part of the clinical manifestations’ spectrum characterising paraneoplastic hypercoagulability, along with deep vein thrombosis, pulmonary embolism, disseminated intravascular coagulation and thrombotic microangiopathy. [6]. The pathogenesis of the prothrombotic status in patients with gastric adenocarcinomas is linked to a release of procoagulant molecules by tumour cells, the most well-known being tissue factor and cancer procoagulant. This leads to an excessive generation of thrombin via the extrinsic pathway. Digestive adenocarcinomas can also accelerate the formation of thrombi by secreting a highly adherent glycoprotein called mucin, which is secreted directly into the blood, aggravating the hypercoagulability. This is an accepted characteristic for neoplasia. In the endothelial cells, platelets and lymphocytes, the mucin interacts with certain cell adhesion proteins, causing the formation of platelet-rich thrombi. [7,8,9,10]

oprotein called mucin, which is secreted directly into the blood, aggravating the hypercoagulability. This is an accepted characteristic for neoplasia. In the endothelial cells, platelets and lymphocytes, the mucin interacts with certain cell adhesion proteins, causing the formation of platelet-rich thrombi. [7,8,9,10] NBTE is a sterile endocarditis, affecting intact aortic and mitral valves. Fibrin and platelets are deposited in areas with increased blood flow. Frequently, NBTE is detected only by necropsy, as the cardiac vegetation is small, fragile, with an embolization tendency. It is usually too small to be seen with a transthoracic echocardiography. TEE has a much higher sensitivity in detecting NBTE. Taccone et al. (2008) observed that NBTE was the main aetiopathogenic cause of an ischemic stroke in patients with systemic cancer, especially in case of adenocarcinomas. [1,2,4,11,12]. Embolization occurs most commonly in the cerebral, renal, splenic, coronary and mesenteric vessels, multiple infarctions being the primary cause of morbidity and mortality in these patients. Cerebral infarctions due to paraneoplastic hypercoagulability and NBTE are usually multiple, extensive and have a poor prognosis. Sixty-seven percent of patients with stroke and neoplasia have multiple cerebral infarctions. [1,13,14,15].

infarctions being the primary cause of morbidity and mortality in these patients. Cerebral infarctions due to paraneoplastic hypercoagulability and NBTE are usually multiple, extensive and have a poor prognosis. Sixty-seven percent of patients with stroke and neoplasia have multiple cerebral infarctions. [1,13,14,15]. Coagulation testing is required if a paraneoplastic hypercoagulability is suspected. In the present case, the prothrombin time and the activated partial thromboplastin time were both normal, but the level of fibrinogen/fibrin degradation products were increased. Thrombin activation is assessed by measuring D-dimers. Our patient showed an increased level of D-dimers. D-dimers cannot be used as a screening tool, but it has been noticed that neoplasia patients with associated cerebral infarctions, have elevated D-dimer levels compared to stroke patients without neoplasia. [16, 17]

hrombin activation is assessed by measuring D-dimers. Our patient showed an increased level of D-dimers. D-dimers cannot be used as a screening tool, but it has been noticed that neoplasia patients with associated cerebral infarctions, have elevated D-dimer levels compared to stroke patients without neoplasia. [16, 17] The treatment of a stroke patient with cancer and other arterial infarctions is complex requiring close collaboration between neurologists, oncologists and intensive care physicians. The use of parenteral anticoagulation by patients with paraneoplastic hypercoagulability and NBTE is overshadowed by the increased risk of the haemorrhagic transformation of the areas affected by cerebral infarction. [18] Compared to oral antivitamin K, anticoagulant treatment with LMWH has proved to be more efficient in preventing recurrent deep vein thrombosis in cancer patients.[19,20] In contrast, in patients with NBTE, it is not clear which systemic anticoagulant treatment is optimal for secondary embolism prevention. However, current guidelines [21] suggest that both LMWH and unfractionated heparin are equally effective in treating this pathology. In our case, under parenteral anticoagulant treatment with therapeutic-dose LMWH, the patient’s neurological condition worsened with a new cerebral embolization originating from the endocardial vegetation. This caused a malignant cerebral infarction followed by death. [19,20,21]. NBTE-prognosis is poor, due to its association with an incurable neoplastic disease, but also due to thromboembolic complications. [1]

In our case, under parenteral anticoagulant treatment with therapeutic-dose LMWH, the patient’s neurological condition worsened with a new cerebral embolization originating from the endocardial vegetation. This caused a malignant cerebral infarction followed by death. [19,20,21]. NBTE-prognosis is poor, due to its association with an incurable neoplastic disease, but also due to thromboembolic complications. [1] The present case report had an intriguing clinical picture of bilateral pulmonary thromboembolism and arterial infarctions in multiple vascular areas, as inaugural manifestations of a gastric adenocarcinoma. The peculiarity of this case lies in its development, which was initially favourable but was followed by the severe worsening of the patient’s neurological condition and finally by his death. This progression raises questions regarding the effectiveness of the LMWH therapy. Conclusion In case of patients with multiple arterial infarctions, one should consider the possibility of an NBTE, which is frequently associated with a detected or undetected neoplasm. Once NBTE has been diagnosed, it is essential to exclude an infectious endocarditis or a primary thrombophilia. Therefore, a detailed paraclinical examination should be performed to detect an occult neoplasia, especially an adenocarcinoma. Diagnosis and treatment of NBTE, in the context of a complex paraneoplastic pro-coagulant status, represents a challenge, involving a multidisciplinary approach, as the optimal anticoagulation treatment has not yet been established.

nation should be performed to detect an occult neoplasia, especially an adenocarcinoma. Diagnosis and treatment of NBTE, in the context of a complex paraneoplastic pro-coagulant status, represents a challenge, involving a multidisciplinary approach, as the optimal anticoagulation treatment has not yet been established. Informed consent The written informed consent to publish this case presentation and the related images was granted by the patient’s wife. A copy of this consent has been handed to the Chief Editor of the JCCM. Acknowledgement This study was supported by the internal research grant of the University of Medicine and Pharmacy Targu Mures, 18/2015

Mankind has been and still is constantly threatened by infectious diseases. Antimicrobials, used to treat infections, are considered one of the greatest discoveries of the 20th century because they saved millions of lives from diseases that had a high mortality rate. Mankind has been and is still constantly threatened by infectious diseases. Antimicrobials, used to treat infections, are considered one of the greatest discoveries of the 20th century because they saved millions of lives from diseases that had a high mortality rate. Current infectious pathology is worryingly extending due mainly to “globalization”, which confirms the current concept of “Infections Without Borders”. In this context, both the consumption of antimicrobial substances and, inherently, the resistance of the main pathogens involved have increased. Unfortunately, antimicrobials have become victims of their success because their abusive use in humans and animals has led to the emergence of resistance among clinically important pathogens. Each dose of antibiotic creates selective evolutionary pressures, resulting in pandemic spread of highly resistant bacterial clones. Resistance to antibiotics is one of the greatest threats to human health. A return to the pre-antibiotic era would not only make possible the development of epidemics caused by multidrug-resistant bacteria, a major threat to the population, but would also jeopardize some of the most valuable therapies in modern medicine, such as transplantation and immunosuppressive chemotherapy programmes –dependent on supportive antimicrobial treatments.

make possible the development of epidemics caused by multidrug-resistant bacteria, a major threat to the population, but would also jeopardize some of the most valuable therapies in modern medicine, such as transplantation and immunosuppressive chemotherapy programmes –dependent on supportive antimicrobial treatments. Antibiotics have been abusively used in both humans and animals because of their low cost, uncontrolled availability, poor understanding of their curative limits, and the interference of economic factors (the use of antibiotics as promoters of animal husbandry).[1] The more antibiotics used (even if this use is medically justified), the more likely the pathogenic bacteria will develop resistance. The situation in Romania, where multi-drug resistant bacteria have become a major threat to human health, is worrying because there are few antibiotics available against such highly resistant bacteria.[2] The World Health Organization (WHO) currently considers antibiotic resistance to be one of the “three major threats to human health” in the coming decades. Antibiotics, active and effective yet, often have major side effects, or are extremely expensive. More worrying are the occasional reports of resistance to these “last resort” antibiotics (such as carbapenems, tigecycline, linezolid, colistin and daptomycin). The resistance to some of these antibiotics has increased rapidly, selecting multiresistant germs, the most eloquent example being the emergence of multi drug-resistant Klebsiella pneumoniae in Southern European hospitals. [3]

t resort” antibiotics (such as carbapenems, tigecycline, linezolid, colistin and daptomycin). The resistance to some of these antibiotics has increased rapidly, selecting multiresistant germs, the most eloquent example being the emergence of multi drug-resistant Klebsiella pneumoniae in Southern European hospitals. [3] This phenomenon affects not only the pathogenic flora but also the commensal one. Recent researches suggest that the portage of commensal bacteria that have acquired resistance genes is increasing.[4] Even in areas where antibiotic use is non-existent or minimal, up to 50% of the population is resistant to multi-resistant E. coli.[5] Clearly, antibiotic-resistant bacteria have become so widespread on the planet that they have become a common resident of our body and can easily spread between individuals (for example, from mother to child or within a family). A slow pandemic spread of resistance clones is developing, and it may be unnoticed if there is no clear and transparent corrective action. Resistance to carbapenems is particularly worrying because these molecules, initially considered as “reserve” antibiotics, are currently commonly used in hospitals. Carbapenemases are enzymes that confer resistance to the class of carbapenemic antibiotics. Carbapenemase NDM-1 (an abbreviation of beta-lactamase-1 metal in New Delhi) has recently occurred but has expanded widely, and NDM-1G carbapenemase is al-

Resistance to carbapenems is particularly worrying because these molecules, initially considered as “reserve” antibiotics, are currently commonly used in hospitals. Carbapenemases are enzymes that confer resistance to the class of carbapenemic antibiotics. Carbapenemase NDM-1 (an abbreviation of beta-lactamase-1 metal in New Delhi) has recently occurred but has expanded widely, and NDM-1G carbapenemase is al- In this extremely complex context, which is the role of doctors? Physicians, both human and veterinary, are those who prescribe antimicrobial treatments. In the absence of coherent policies on the management strategy and control of antibiotic use at national level, as well as of modern and fast microbiological diagnostic tools, their administration is often insufficiently documented by evidence, “empirical” sometimes even “irrational”. Hospitals concentrate the largest number of such multi-resistant germs, with patients and care staff being exposed to varying degrees of risk of getting a healthcare associated infection.[6] These infections are very common (one in eighteen patients in European hospitals are affected by healthcare associated infections [7]) and can be life-threatening, especially when caused by bacteria resistant to different drugs.

f being exposed to varying degrees of risk of getting a healthcare associated infection.[6] These infections are very common (one in eighteen patients in European hospitals are affected by healthcare associated infections [7]) and can be life-threatening, especially when caused by bacteria resistant to different drugs. Among the most important antibiotic-resistant bacteria in hospitalized patients are the so-called “ESKAPE” pathogens. These are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and the Enterobacter species [8]. In addition to the ESKAPE pathogens, Escherichia coli (E. coli), which is present in the human intestine, remains the leading cause of mortality related to severe sepsis in hospitalized patients and Clostridium difficile is an important cause of antibiotic-associated diarrhea. They are often resistant to antibiotics and can cause life-threatening complications.

ichia coli (E. coli), which is present in the human intestine, remains the leading cause of mortality related to severe sepsis in hospitalized patients and Clostridium difficile is an important cause of antibiotic-associated diarrhea. They are often resistant to antibiotics and can cause life-threatening complications. The highest risk of infection is experienced by those admitted into the intensive care services, and especially by critically ill patients. A one-day prevalence study (May 8, 2007) showed that out of 13,796 patients in 1,256 intensive care units (ICUs), in seventy-five of them, 51% of patients in the ICU were found to be infected. The mortality due to infection of patients assisted in ICU was twice as high as that of patients hospitalized in other sections [8]. It is necessary to approach the critical patient with a multidisciplinary team, which necessarily includes, from the very beginning, a specialist in infectious diseases. His/her participation must be active in the initial assessment of the infectious risk, in the development of an individual plan for the prevention of health care-associated infections, in determining the appropriateness of establishing antimicrobial therapy and in the recommendation and management of anti-infective therapy.[6]

participation must be active in the initial assessment of the infectious risk, in the development of an individual plan for the prevention of health care-associated infections, in determining the appropriateness of establishing antimicrobial therapy and in the recommendation and management of anti-infective therapy.[6] Dramatically, most hospital-acquired infections are of endogenous origin, coming from the patient’s own microbiota [9]. An aging population and an increased prevalence of obesity and diabetes mellitus, which are global trends, will cause a significant increase in vulnerable patients, causing the greatest burden in terms of human morbidity and mortality. The global and multilateral problem of antimicrobial resistance (AMR) necessitates a comprehensive analysis and creative solutions that require action from several sectors of society. The “One Health” concept recognizes that human and animal health is closely linked to interactions through direct physical contact with farms and animals, the food chain and the environment. High levels of antibiotic-resistant microorganisms and antibiotic resistance genes are excreted in human and animal feces, which contaminate the environment and interact with the soil. Fecal contamination, dust and insects spread microorganisms and resistance genes from humans and animals to the environment [10], with significant ecotoxicological consequences for the microbiosphere.

resistance genes are excreted in human and animal feces, which contaminate the environment and interact with the soil. Fecal contamination, dust and insects spread microorganisms and resistance genes from humans and animals to the environment [10], with significant ecotoxicological consequences for the microbiosphere. The economic consequences of these phenomena are enormous. Various studies have attempted to evaluate the morbidity and mortality caused by germs resistant to antimicrobial therapy. ECDC/ EMEA (the European Centre for Disease Prevention and Control/European Medicines Agency) estimated that, in 2007, resistant strains in Europe caused about 400,000 infections, more than 25,000 additional deaths and 2.5 million additional days of hospitalization.[1]

aused by germs resistant to antimicrobial therapy. ECDC/ EMEA (the European Centre for Disease Prevention and Control/European Medicines Agency) estimated that, in 2007, resistant strains in Europe caused about 400,000 infections, more than 25,000 additional deaths and 2.5 million additional days of hospitalization.[1] It is a tremendous responsibility of all those involved to undertake concrete and effective actions in view of establishing the supervision and control of this threatening phenomenon. Research, which provides knowledge, will need to set clear targets for the synthesis of new antimicrobial molecules and alternatives to antibiotics (vaccines). The introduction of new antibiotics will be stimulated by the modernization of diagnostic microbiology, which should be able to quickly identify the causative agents of infections, allowing the predominant use of narrow-spectrum antibiotics. Several antibiotics developed in the past are no longer used due to pharmacokinetics, to pharmacodynamics or to side effects. Research could now “resuscitate” these antibiotics, in order to improve clinical efficacy and to reduce unwanted effects and reuse them as safe and effective antimicrobial drugs in modern clinical practice. Investigations are also needed to optimize consumption, dosage and delivery, to improve the antibacterial efficacy of existing antibiotics and to reduce their negative impact on the normal microbiota. In particular, the application of nanomedicine in the delivery of antibiotics (e.g. by coating or encapsulating antibiotics on or in nanoparticles or liposomes) shows great promise.

and delivery, to improve the antibacterial efficacy of existing antibiotics and to reduce their negative impact on the normal microbiota. In particular, the application of nanomedicine in the delivery of antibiotics (e.g. by coating or encapsulating antibiotics on or in nanoparticles or liposomes) shows great promise. Programs are needed to implement the monitorization of antibiotic resistance in patients, both in the hospital and in the community, as well as among the healthy population, which include both phenotypic and genotypic analyses, especially of bacterial clones associated with antibiotic resistance genes. There is a need for concrete action to determine whether food is an important vector for spreading antimicrobial resistance, the role of migration, that of tourism, that of various healthcare systems and the role of agriculture. The growth of global trade and travels are factors, which are certain to favor the spread of antimicrobial resistance between countries and continents. Knowledge on the exact role of different reservoirs in the environment (e.g. surface water, the soil, the air) in the emergence and diffusion of antimicrobial resistance needs to be deepened, to control and minimize the spread. Understanding the biological process underlying these phenomena will generate effective preventive measures and countermeasures, provided there is a global approach to the problem, with sector-specific measures.

Knowledge on the exact role of different reservoirs in the environment (e.g. surface water, the soil, the air) in the emergence and diffusion of antimicrobial resistance needs to be deepened, to control and minimize the spread. Understanding the biological process underlying these phenomena will generate effective preventive measures and countermeasures, provided there is a global approach to the problem, with sector-specific measures. Clearly, the initiatives of several international organizations addressing antibiotic resistance, such as the World Health Organization, the European Commission, the European Centre for Disease Prevention and Control (ECDC) and ReAct (Action on Antibiotic Resistance) have been very successful in raising the global level of awareness regarding the imminent dangers threatening humanity. Experts in the field must provide innovative approaches to ensure that we can successfully treat the bacterial infections of the 21st century. Conflict of interests None to declare

Introduction Cancer remains one of the leading causes of death in the United States of America (USA). Currently, intensive care units (ICU) play a significant role in the management of cancer patients. Recent studies reveal that patients with cancer account for 15% of total admissions to an ICU [1]. However, patients with malignancies are responsible for almost half of the total ICU bed-days [2]. Despite significant advances in the treatment of cancer, patients admitted to an ICU with malignancies still have a higher mortality rate than patients without malignancies. Knowledge of the factors that influence outcomes in these patients is pivotal in their management, as it will help significantly in making appropriate triage decisions. While several studies have been published on the outcome predictors in patients with cancer in general or those with hematologic malignancies, there are only a few in those with solid malignancies and controversies remain regarding outcome-predictors in these patients (3). Besides, there are limited data from the USA and a lack of data on racial differences on these predictors. The primary aim was to identify the general characteristics and outcomes of patients with solid malignancies who are admitted to the intensive care unit (ICU) of a tertiary medical center in the United States. The usefulness of different critical care scoring systems as prognostic tools as well as the and identification of factors associated with poor outcomes were also evaluated.

outcomes of patients with solid malignancies who are admitted to the intensive care unit (ICU) of a tertiary medical center in the United States. The usefulness of different critical care scoring systems as prognostic tools as well as the and identification of factors associated with poor outcomes were also evaluated. Methods This was a prospective cohort study in which patients were sequentially recruited over a two year period in an ICU of a tertiary medical center with a comprehensive cancer center, in Detroit, Michigan, USA. The Institutional Review Board (IRB) of Wayne State University in Detroit, Michigan approved the study. The principal investigator and his research associates screened all new admissions to the ICU on a daily basis. Patients were deemed eligible for enrollment in the study if they met the following inclusion criteria: they were 18 years of age or older, had an established diagnosis of malignancy that was under treatment or surveillance, and had a need for admission to the ICU due to life-threatening conditions during the study period. The exclusion criteria were: patients admitted under the surgical intensive care unit service, patients who were admitted to the ICU only for monitoring of chemotherapy, patients who were admitted for less than 24 hours and readmitted to the ICU within the study period.

e-threatening conditions during the study period. The exclusion criteria were: patients admitted under the surgical intensive care unit service, patients who were admitted to the ICU only for monitoring of chemotherapy, patients who were admitted for less than 24 hours and readmitted to the ICU within the study period. Once eligible patients were identified, baseline data including demographics, a detailed description of malignancy, the reason for admission to the ICU and several clinical and laboratory parameters at the time of ICU admission. Also included at the time of ICU admission were baseline performance status using ECOG (Eastern Cooperative Oncology Group) score. Additionally, the Charlson baseline comorbidity index was calculated. Data regarding the patient’s stage and type of malignancy were collected from patient notes. It was considered a “New Diagnosis” if the diagnosis was made within four weeks of admission to the ICU. The absence of evidence of an active primary malignancy was considered a case “in remission”. Patients with relapsing malignancy were considered as “relapsed”. The patients were then followed throughout their ICU stay to get updates on their ICU course until they were discharged from the ICU. Various scoring systems were used including the Acute Physiologic and Chronic Health Evaluation II (APACHE II), the APACHE III, the Simplified Acute Physiologic Score I, (SAPSI) SAPS II, Sepsis-related Organ Failure Assessment (SOFA), the Cancer Mortality Model (CMM), the Mortality Probability Model MPM) and the Logistic Organ Dysfunction Score (LODS). The patients were followed afterwards only to determine the total duration of their hospitalization, condition at the time of discharge and any readmission to the ICU. Six months after their ICU admission, the patient’s final outcome was determined. By reviewing the medical record, all other information was collected. No diagnostic interventions, including laboratory, work up, imaging studies and diagnostic procedure, were ordered for the sole purpose of the study. All diagnostic interventions were decided upon and ordered by the primary ICU team responsible for the patient, based on what they deemed clinically appropriate.

llected. No diagnostic interventions, including laboratory, work up, imaging studies and diagnostic procedure, were ordered for the sole purpose of the study. All diagnostic interventions were decided upon and ordered by the primary ICU team responsible for the patient, based on what they deemed clinically appropriate. Standard descriptive statistics were used to describe the study population. Continuous variables were reported using the mean and standard deviation. Categorical variables were reported using counts and percentages. Univariate and multivariate logistic regression models, adjusting for the different confounding factors, were used to determine factors that could be associated with poor outcome. Receiver operator curves were produced for various scoring systems and the area under the curves were determined.

ng counts and percentages. Univariate and multivariate logistic regression models, adjusting for the different confounding factors, were used to determine factors that could be associated with poor outcome. Receiver operator curves were produced for various scoring systems and the area under the curves were determined. Results Of the 252 patients with solid malignancy enrolled in the study, 142 (56.4%) with a mean age of 61.6 {SD±12.4} years were female. One hundred and thirty-three (53%) of the patients were African Americans. Urogenital cancers were the most frequently reported solid malignancies (66 patients;26.3%) followed by lung cancer (59;23.5%)while head and neck cancers were the least reported (26;10.4%). The cancer stage was I in 5% of patient, stage II in 6%, stage III in 10% and stage IV in 59% of patients. In 20% of cases, the cancer stage was unknown at the time of admission to the ICU. Eighty-five patients (34.4%) presented with a baseline performance status of 2. Most of the patients (147;58.3%) were in remission during their initial visit to the ICU. A significant majority of the patients (169; 67%) were smokers, on average most patients spent 2.3 days in the hospital before ICU admission. A lactic acid level of more than 2 was reported in 141(60%) of the patients. Major reasons for ICU admission included sepsis in 116(46%) of patients and respiratory failure in 130; 51.6% of the patients. Other minor reasons are shown in Table 1. Major ICU interventions included the use of mechanical ventilation 127(50.4%) and administration of antibiotics 189 (75%).

in 141(60%) of the patients. Major reasons for ICU admission included sepsis in 116(46%) of patients and respiratory failure in 130; 51.6% of the patients. Other minor reasons are shown in Table 1. Major ICU interventions included the use of mechanical ventilation 127(50.4%) and administration of antibiotics 189 (75%). Table 1 Baseline Characteristics on Intensive Care Unit Admission

in 141(60%) of the patients. Major reasons for ICU admission included sepsis in 116(46%) of patients and respiratory failure in 130; 51.6% of the patients. Other minor reasons are shown in Table 1. Major ICU interventions included the use of mechanical ventilation 127(50.4%) and administration of antibiotics 189 (75%). Table 1 Baseline Characteristics on Intensive Care Unit Admission Variable Mean±SD, n(%) Age (years) 61.6 ±12.4 Sex Male 110 (43.6) Female 142 (56.4) Race White 102(40.6) African American 134(53) Other 16(6.4) Underlying malignancy Lung 59(23.5) Breast 32(12.7) Urogenital 66(26.3) Head and Neck 26(10.4) GI 37(14.7) Other 32(12.7) Baseline Performance Status 0 20(8.1) 1 56(22.3) 2 87(34.4) 3 74(29.5) 4 15(5.7) Disease status at admission Remission 147(58.3) New diagnosis 47(18.7) Relapse 58(23) Smoking History Yes 169(67) No 73(29) Unknown 10(4) Days in a hospital before ICU admission 2.3±3.7 Absolute neutrophil count < 1000 22(8.7) Lactic acid level >2 141(60) Main reasons for ICU admission (patient may have more than one diagnosis) Sepsis 116(46) Respiratory failure 130(51.6) Pneumonia 76(30.2) Liver failure 10(3.97) Acute renal failure 45(17.9) Narcotic overdose 8(3.17) Following CPR 2(0.8) Cardiogenic pulmonary edema 16(6.35) In Receiver Operator Characteristic (ROC) analysis, an Area Under the Curve (AUC) greater than 0.7 was considered as a reasonable cutoff for predicting outcomes of the severity of illness. The SAPS III, Cancer Mortality Model, Mortality Probability Model II, APACHE II and APACHEIII were scores that met this cutoff, with the APACHE III being the highest, with an AUC of 0.72. The SOFA score had an AUC of 0.64 when 5.2 was used as the cutoff, as shown in Table 2.

dicting outcomes of the severity of illness. The SAPS III, Cancer Mortality Model, Mortality Probability Model II, APACHE II and APACHEIII were scores that met this cutoff, with the APACHE III being the highest, with an AUC of 0.72. The SOFA score had an AUC of 0.64 when 5.2 was used as the cutoff, as shown in Table 2. Table 2 Severity of illness scores on admission to the ICU Severity of illness Score Score Mean±SD ROC AUC value predict to Mortality SAPS II 42.7±13.8 0.69 SAPS III 70.2±16 0.71 SOFA 5.2±4 0.64 Cancer Mortality Model 0.5±0.25 0.72 Mortality Probability Model III 0.50±0.3 0.70 APACHE II 21.4±7.5 0.70 APACHE III 74.3±28.1 0.72 LODS 0.2±0.2 0.65 Charlson Comorbidity Index>7 7.8±2.8 0.59 The mean ICU length of stay was 5.5 days. There were 55 deaths reported in the ICU with an estimated ICU mortality of 21.8%. Hospital mortality was 34.3%, and the 6-month mortality was 38.4% (Table 3). One hundred and one patients (40%) were specified as “Do-Not-Resuscitate”. Of these, 52 were discharged alive from the ICU, and 29 were discharged alive from hospital. Fifty-one patients (20%) were withdrawn from aggressive care being provided with comfort measures only while in the ICU. Four of these patients were discharged alive from hospital. Table 3 ICU interventions and outcomes

Severity of illness Score Score Mean±SD ROC AUC value predict to Mortality SAPS II 42.7±13.8 0.69 SAPS III 70.2±16 0.71 SOFA 5.2±4 0.64 Cancer Mortality Model 0.5±0.25 0.72 Mortality Probability Model III 0.50±0.3 0.70 APACHE II 21.4±7.5 0.70 APACHE III 74.3±28.1 0.72 LODS 0.2±0.2 0.65 Charlson Comorbidity Index>7 7.8±2.8 0.59 The mean ICU length of stay was 5.5 days. There were 55 deaths reported in the ICU with an estimated ICU mortality of 21.8%. Hospital mortality was 34.3%, and the 6-month mortality was 38.4% (Table 3). One hundred and one patients (40%) were specified as “Do-Not-Resuscitate”. Of these, 52 were discharged alive from the ICU, and 29 were discharged alive from hospital. Fifty-one patients (20%) were withdrawn from aggressive care being provided with comfort measures only while in the ICU. Four of these patients were discharged alive from hospital. Table 3 ICU interventions and outcomes ICU interventions Number (%) Vasopressors 53(21) Antibiotics 189(75) Non-invasive ventilation 38(15) Mechanical Ventilation 127(50.4) Chemotherapy 6(2.4) Renal replacement therapy 16(6.6) Outcome data Length of stay in ICU, d 5.5±7.4 ICU mortality 55(21.8) Hospital mortality 86(34.3) 6 Month Mortality 97(38.4) Following univariate analysis of possible variables associated with hospital mortality, ten factors were statistically significant. These factors included Lactic acid >2 mg/dL, use of mechanical ventilation, acute kidney injury, use of vasopressors, liver failure, sepsis, ICU length of stay ≥5 days, ACLS in the ICU, respiratory failure and performance status ≥2. All the scoring

ed with hospital mortality, ten factors were statistically significant. These factors included Lactic acid >2 mg/dL, use of mechanical ventilation, acute kidney injury, use of vasopressors, liver failure, sepsis, ICU length of stay ≥5 days, ACLS in the ICU, respiratory failure and performance status ≥2. All the scoring systems used were statistically significant except for the Charlson comorbidity index when a cutoff of >7 was used (Table 4). During multivariable analysis, the severity of illness scores were not used in the model to avoid collinearity. Factors that were significantly associated with hospital mortality included acute kidney injury, OR 2.97, 95% CI 1.48-5.96 and P=0.002, use of mechanical ventilation, OR 3.13 95% CI 1.40 – 7.02 and P=0.006 and performance status of ≥2 with OR of 3.54, 95% CI of 1.64- 7.65 and P= 0.001 as seen in Table 5. The receiver operator curves for the above factors were determined. The area under the curve (AUC) for acute kidney injury was 0.65. For the use of mechanical ventilation the AUC was 0.63, and for performance status, it was 0.59. Table 4 Univariate analysis of possible predictors of hospital mortality

systems used were statistically significant except for the Charlson comorbidity index when a cutoff of >7 was used (Table 4). During multivariable analysis, the severity of illness scores were not used in the model to avoid collinearity. Factors that were significantly associated with hospital mortality included acute kidney injury, OR 2.97, 95% CI 1.48-5.96 and P=0.002, use of mechanical ventilation, OR 3.13 95% CI 1.40 – 7.02 and P=0.006 and performance status of ≥2 with OR of 3.54, 95% CI of 1.64- 7.65 and P= 0.001 as seen in Table 5. The receiver operator curves for the above factors were determined. The area under the curve (AUC) for acute kidney injury was 0.65. For the use of mechanical ventilation the AUC was 0.63, and for performance status, it was 0.59. Table 4 Univariate analysis of possible predictors of hospital mortality Variable Patient Cases Mortality OR 95% CI P- Value Neutrophil count <1000 22 12 1.68 0.69 – 4.05 0.25 Lactic acid>2 131 53 1.80 1.05 – 3.08 0.031 Mechanical Ventilation 126 58 3.00 1.72 – 5.21 0.001 Non-invasive ventilation 38 16 1.49 0.73 – 3.00 0.27 Acute kidney injury 52 31 3.79 2.15 – 6.70 0.001 Vasopressors 52 25 2.10 1.12 – 3.91 0.02 Liver failure 13 10 4.17 1.40 – 12.4 0.01 Sepsis 113 48 1.96 1.15 – 3.32 0.01 Pneumonia 75 28 1.21 0.68 – 2.13 0.50 APACHE II ≥ 20 148 65 3.13 1.74 – 5.64 <0.0001 APACHE III ≥ 75 115 57 3.69 2.12-6.41 <0.0001 SAPS II ≥ 40 150 65 2.98 1.65 -5.37 <0.0001 SAPS III ≥ 70 127 62 4.06 2.29 – 7.20 <0.0001 SOFA score≥5 85 54 2.20 1.28 – 3.77 0.004 Cancer Mortality Model ≥0.5 125 64 3.24 1.86 – 5.63 <0.0001 Mortality Probability Model III ≥0.5 115 56 3.40 1.96 – 5.90 <0.0001 ICU LOS ≥ 5 days 80 36 1.99 1.14 – 3.45 0.015 Charlson Comorbidity 175 68 2.09 1.12-3.9 0.02 Performance Status ≥2 173 70 2.72 1.43-5.16 0.002 Renal Replacement Therapy 16 7 1.48 0.53-4.14 0.45 Disease Status Remission 144 47 ---- New diagnosis 47 15 0.97 0.48-1.95 0.93 Relapse 57 23 1.40 0.74-2.63 0.30 Table 5 Multivariable analysis of predictors of hospital mortality

son Comorbidity 175 68 2.09 1.12-3.9 0.02 Performance Status ≥2 173 70 2.72 1.43-5.16 0.002 Renal Replacement Therapy 16 7 1.48 0.53-4.14 0.45 Disease Status Remission 144 47 ---- New diagnosis 47 15 0.97 0.48-1.95 0.93 Relapse 57 23 1.40 0.74-2.63 0.30 Table 5 Multivariable analysis of predictors of hospital mortality Covariate OR 95% CI P- Value Acute Kidney Injury 2.82 1.50 – 5.32 0.001 Mechanical Ventilation 2.67 1.37 – 5.19 0.004 ICU Length of Stay ≥5 days 1.11 0.56 – 2.20 0.76 Vasopressor use 0.89 0.40– 1.20 0.79 Liver failure 2.95 0.91 – 9.58 0.07 Sepsis 1.49 0.76 – 2.93 0.245 Performance status≥ 2 3.05 1.50– 6.20 0.002 Outcome measures were compared between African Americans and non-African Americans. ICU, hospital and six months mortality for African Americans were 21%, 34% and 40%, respectively compared to 24%, 33% and 37%, respectively in non-African Americans. There were no differences in factors associated with mortality between the two groups (Table 6). Table 6 Predictors of Hospital Mortality associated with Ethnicity

Covariate OR 95% CI P- Value Acute Kidney Injury 2.82 1.50 – 5.32 0.001 Mechanical Ventilation 2.67 1.37 – 5.19 0.004 ICU Length of Stay ≥5 days 1.11 0.56 – 2.20 0.76 Vasopressor use 0.89 0.40– 1.20 0.79 Liver failure 2.95 0.91 – 9.58 0.07 Sepsis 1.49 0.76 – 2.93 0.245 Performance status≥ 2 3.05 1.50– 6.20 0.002 Outcome measures were compared between African Americans and non-African Americans. ICU, hospital and six months mortality for African Americans were 21%, 34% and 40%, respectively compared to 24%, 33% and 37%, respectively in non-African Americans. There were no differences in factors associated with mortality between the two groups (Table 6). Table 6 Predictors of Hospital Mortality associated with Ethnicity Covariate OR for African Americans 95% CI P- Value OR for Non-African Americans 95% CI P- Value Acute Kidney Injury 1.21 0.70 - 1.99 0.90 0.52 0.14 - 1.99 0.35 Mechanical Ventilation 0.88 0.52 - 1.48 0.61 0.69 0.24 – 1.69 0.50 ICU Length of Stay ≥5 days 0.70 0.40 - 1.21 0.20 0.76 0.24 – 2.37 0.64 Vasopressor use 0.83 0.44 - 1.58 0.58 1.14 0.33– 3.89 0.83 Liver failure 0.76 0.24 - 2.42 0.64 1.07 0.12 – 0.14 0.95 Sepsis 0.71 0.42 - 1.20 0.20 0.42 0.13 – 1.29 0.13 Performance status≥ 2 1.30 0.74 - 2.27 0.36 1.50 0.45 - 5.00 0.51 Discussion In this prospective study to determine outcomes of patients with solid malignancy admitted to the ICU an ICU mortality of 21.8% and hospital mortality of 34.4% was reported. Similar results were reported in recent studies from Europe and South America [3]. In a prospective study in Brazil, Soares et al. (2010) reported an ICU mortality of 21% and hospital mortality of 30%, while in France, Mokart et al. (2012) reported an ICU mortality of 32% and hospital mortality of 41%[4,5]. In the latter study, a significant number of patients had a hematologic malignancy, and this was an essential difference between the two studies. Most of the patients in Mokart’s study (2012) died as a result of secondary viral infections. In the study by Soares (2010), a significant number of patients had a solid malignancy with only a small fraction having a hematologic malignancy, making the results more suitable to be compared with the current study. In a recent systematic review of the literature, Puxty et al. (2014) reported the survival in solid cancer patients following ICU admission indication that ICU mortality ranged from 4.5% to 85% with an average mortality of 31.2% [6]. The present study provides results from prospectively collected data exclusively from critically ill patients with a solid malignancy.

Puxty et al. (2014) reported the survival in solid cancer patients following ICU admission indication that ICU mortality ranged from 4.5% to 85% with an average mortality of 31.2% [6]. The present study provides results from prospectively collected data exclusively from critically ill patients with a solid malignancy. The improved outcome of critically ill patients with a solid malignancy is reasonably well established. , however, the primary challenge is identifying the factors that predict an outcome. Such factors may provide valuable information for patients, their families and physicians to avoid futile care and better management of resources. The current study showed that patients with performance status ≥2, requiring mechanical ventilation with acute renal failure had a worse prognosis. Taccone et al. (2009) in their study carried out in 198 participating European ICUs, showed that patients with more than three organ dysfunctions resulted in high mortality (58%) [1]. In another study, Soares et al. (2010) looked at the characteristics and outcome of cancer patients in Brazilian ICUs. They found that there is increased mortality in patients admitted for medical complications compared to patients admitted postoperatively. The presence of an active underlying malignancy in recurrence or progression, higher SOFA scores, poor performance status, the need for mechanical ventilation and the number of hospital days before ICU admission, were all predictors of a poor outcome. However, it is important to note that the majority of the patients in the study had solid tumors and were admitted to the ICU postoperatively [4]. Mendoza et al. (2008) reported that the presence of metastatic disease and use of vasopressor agents were predictors of a poor outcome [7]. Puxtry et al. (2014) reported that poor functional status, invasive mechanical ventilation in addition to poor physiological scores, were associated with a poor prognosis [6].

[4]. Mendoza et al. (2008) reported that the presence of metastatic disease and use of vasopressor agents were predictors of a poor outcome [7]. Puxtry et al. (2014) reported that poor functional status, invasive mechanical ventilation in addition to poor physiological scores, were associated with a poor prognosis [6]. The present study also addresses the value of the severity of illness and organ failure scores in predicting patient outcome. None of these scores (Table 2) accurately predicted the outcome of critically ill patients with a solid malignancy. Multiple studies evaluated one or more of these scores with variable results [8, 9, 10, 11, 12]. The current study is in accord with the overall impression that no one score system is better in predicting an outcome. Based on this conclusion, patients should not be denied admission to an ICU based on the severity of illness scores or severity of organ failure scores. Such patients should be given aggressive ICU care and then re-assessed. A better indicator of outcome, reported in some studies [3, 13], was the organ function status after an “ICU trial” for 3-5 days, whereas in the study by Lecuyer et al. (2007) the persistence or worsening of organ failure was stated to be a better outcome predictor [13]. In general, the outcome of cancer is worse in an African American population [14], however, the effect of race on the outcome of a critically ill patient remains controversial, with some studies suggesting worse outcomes in African Americans [15, 16, 17].

The present study also addresses the value of the severity of illness and organ failure scores in predicting patient outcome. None of these scores (Table 2) accurately predicted the outcome of critically ill patients with a solid malignancy. Multiple studies evaluated one or more of these scores with variable results [8, 9, 10, 11, 12]. The current study is in accord with the overall impression that no one score system is better in predicting an outcome. Based on this conclusion, patients should not be denied admission to an ICU based on the severity of illness scores or severity of organ failure scores. Such patients should be given aggressive ICU care and then re-assessed. A better indicator of outcome, reported in some studies [3, 13], was the organ function status after an “ICU trial” for 3-5 days, whereas in the study by Lecuyer et al. (2007) the persistence or worsening of organ failure was stated to be a better outcome predictor [13]. In general, the outcome of cancer is worse in an African American population [14], however, the effect of race on the outcome of a critically ill patient remains controversial, with some studies suggesting worse outcomes in African Americans [15, 16, 17]. An important finding of the present study is that the short-term mortality of critically ill patients with a solid malignancy was not different between African Americans and other races.

In general, the outcome of cancer is worse in an African American population [14], however, the effect of race on the outcome of a critically ill patient remains controversial, with some studies suggesting worse outcomes in African Americans [15, 16, 17]. An important finding of the present study is that the short-term mortality of critically ill patients with a solid malignancy was not different between African Americans and other races. The study has many strengths, being prospective with a relatively large number of enrolled diverse racial patients, reporting on only solid malignancies with purely medical indications for ICU admission. However, there are a few limitations including being a single center experience and the lack of comparison of outcomes in cancer-patients with non-cancer patients. It would be helpful to study changes in severity of illness scores after patients’ admission to the ICU and determine whether these can provide better outcome-predictions. Also, the study does not provide predictors of long-term outcomes in these patients. Further prospective multicenter studies are still needed to validate the current data. Conclusions The current study shows encouraging ICU, hospital and six months survival rates in patients with solid malignancies who are admitted to an ICU. There were no differences in outcome between races. The need for mechanical ventilation, acute renal failure and poor performance status were associated with worse outcomes. Conflict of interest None to declare

Background Despite significant developments and advancements in antibiotic therapy life-threatening complication of infective diseases cause hundreds of thousands of deaths in the USA and millions more worldwide [1, 2]. Sepsis is the body's overwhelming and life-threatening response to infection which can lead to multiple organ systems failure. It is the body's immune system overresponse to infection following the release of inflammatory mediators such as cytokines into the blood circulation [3, 4]. Pro-coagulation factors in endothelial cells are activated causing local damages which will lead to a systemic inflammatory response syndrome (SIRS), septic shock and multiple organ dysfunction syndrome (MOSF) [5]. During such severe inflammatory stages, patients are often sedated and intubated, and the collection of relevant data requires well-developed communication skills [6]. This paper updates matters of abdominal sepsis etiology and treatment in the light of the latest guidelines outlined by the Intraabdominal Infection (IAI) Consensus (2017) [7].

mmatory stages, patients are often sedated and intubated, and the collection of relevant data requires well-developed communication skills [6]. This paper updates matters of abdominal sepsis etiology and treatment in the light of the latest guidelines outlined by the Intraabdominal Infection (IAI) Consensus (2017) [7]. Prognostic scores A diversity of prognostic scores are currently used to assess the course of peritonitis and intra-abdominal infections according to age, sex, the origin of sepsis, the degree of peritonitis, the time between any perforation to an operation and the type of exudates. Their objective is the early classification of patients presenting with peritonitis and intra‐abdominal sepsis through an objective scoring system, to aid in patient select for specific treatment modalities as well as to compare the results of different treatment regimens (Table I) Unfortunately, none of the current scoring systems satisfies all prerequisites [8, 9, 10, 11, 12, 13, 14]. Table I Prognostic scores used to evaluate the prognostic of abdominal infection

Prognostic scores A diversity of prognostic scores are currently used to assess the course of peritonitis and intra-abdominal infections according to age, sex, the origin of sepsis, the degree of peritonitis, the time between any perforation to an operation and the type of exudates. Their objective is the early classification of patients presenting with peritonitis and intra‐abdominal sepsis through an objective scoring system, to aid in patient select for specific treatment modalities as well as to compare the results of different treatment regimens (Table I) Unfortunately, none of the current scoring systems satisfies all prerequisites [8, 9, 10, 11, 12, 13, 14]. Table I Prognostic scores used to evaluate the prognostic of abdominal infection Prognostic scores Etiology Peritonitis Severity Score (PSS) Left-sided colon perforation Boey Score Jabalpur Index Hacettepe Score Gastroduodenal ulcers perforations PULP Score Postoperative peritonitis Dutch leakage score P-POSSUM Score Mannheim Peritonitis Index (MPI) Peritonitis Index Altona (PIA) Peritonitis of all causes WSES complicated IAI score (WISS study) Peritonitis classification Peritonitis can be classified by the anatomical integrity of the abdominal cavity. Primary peritonitis is associated with undamaged intra-abdominal cavity organs. It is also known as spontaneous bacterial peritonitis and is treated without surgical intervention. The source of infection is often hard to establish and is usually found occurring in infants and cirrhotic patients. Secondary peritonitis is an infection of the peritoneal cavity after hollow viscus perforation, anastomotic leak, ischemic necrosis, or other injuries of the gastrointestinal tract.

urgical intervention. The source of infection is often hard to establish and is usually found occurring in infants and cirrhotic patients. Secondary peritonitis is an infection of the peritoneal cavity after hollow viscus perforation, anastomotic leak, ischemic necrosis, or other injuries of the gastrointestinal tract. Secondary peritonitis, a common occurrence in critical surgical patients, is defined as an infection of the peritoneal cavity resulting from hollow viscus perforation, anastomotic leak, ischemic necrosis, or other injuries of the gastrointestinal tract. Tertiary peritonitis is defined as a serious recurrent or persistent intra-abdominal infection after the ostensibly successful control of secondary peritonitis [15, 16, 17]. Medical treatment of abdominal sepsis Irrespective of the cause, several measures are available and accepted as improving the survival rate, the most important being the early recognition of IAI. Efforts to achieve fluid balance should be initiated immediately to replace any intravascular insufficiency. Vasoactive agents may be necessary to augment and assist fluid restoration [18]. The WISS study showed that sepsis significantly influences mortality rate, this being only 1.2% in the absence of sepsis, increasing to 4.4% when sepsis is present and 71.8% when septic shock occurs [19].

Medical treatment of abdominal sepsis Irrespective of the cause, several measures are available and accepted as improving the survival rate, the most important being the early recognition of IAI. Efforts to achieve fluid balance should be initiated immediately to replace any intravascular insufficiency. Vasoactive agents may be necessary to augment and assist fluid restoration [18]. The WISS study showed that sepsis significantly influences mortality rate, this being only 1.2% in the absence of sepsis, increasing to 4.4% when sepsis is present and 71.8% when septic shock occurs [19]. Associated Microorganisms Associated microorganisms differ according to the type of peritonitis and with the levels of perforation in secondary and tertiary peritonitis. When perforation is higher up in the alimentary tract, i.e. the stomach or the duodenum, bacterial contamination usually has less serious consequences whereas perforation of the colon and rectum leads to severe bacterial contamination which can be life-threatening and is the leading cause of sepsis and septic shock [20].

en perforation is higher up in the alimentary tract, i.e. the stomach or the duodenum, bacterial contamination usually has less serious consequences whereas perforation of the colon and rectum leads to severe bacterial contamination which can be life-threatening and is the leading cause of sepsis and septic shock [20]. Primary bacterial peritonitis is associated with gram-negative Enterobacteriaceae and, Streptococcus spp., whereas secondary bacterial peritonitis is mainly linked to a polymicrobial infection of gram-negative Enterobacteriaceae, gram-positive Enterococci and Staphylococci, or anaerobes and candida. Tertiary peritonitis has a similar poly-microbial infection to secondary peritonitis, with common organisms isolated from patients being Enterococcus, Candida, and Staphylococcus epidermidis and are more likely to involve antibiotic-resistant strains [20]. Antibiotic therapy The Study for Monitoring Antimicrobial Resistance Trends (SMART) monitored the patterns of clinical gram-negative bacilli to antimicrobial agents. It reported the prevalence of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae in the clinical setting, to be of significant importance and acknowledged it to be increasing worldwide. In addition to the expected increased resistance to beta-lactams, fluoroquinolone resistance in ESBL-positive Escherichia coli causing intra-abdominal infections, ranges from 60 to 93 % [21,22]. A comprehensive list of currently acceptable antibiotic therapy treatment related to peritonitis severity is given in Table II [23].

tion to the expected increased resistance to beta-lactams, fluoroquinolone resistance in ESBL-positive Escherichia coli causing intra-abdominal infections, ranges from 60 to 93 % [21,22]. A comprehensive list of currently acceptable antibiotic therapy treatment related to peritonitis severity is given in Table II [23]. Table II Currently acceptable antibiotic therapy treatment related to peritonitis severity Diagnosis Monotherapy Combination therapy Primary peritonitis Ampicillin/Sulbactam 2nd generation Cephalosporin Secondary peritonitis Ampicillin/Sulbactam 2nd generation Cephalosporin + Metronidazole low risk (localized peritonitis) Carbapenem 3rd generation Cephalosporin + Metronidazole Secondary peritonitis Ampicillin/Sulbactam 2nd generation fluoroquinolone + Metronidazole low risk (diffuse peritonitis) Piperacillin/Tazobactam Carbapenem (group 1/2) 3rd or 4th generation Cephalosporin + Metronidazole Fluoroquinolone 4th generation Tigecycline Secondary peritonitis Piperacillin/Tazobactam 4th generation Cephalosporin + Metronidazole high risk Carbapenem (group 1/2) Tigecycline Tertiary peritonitis According to resistance from microbiology Antifungal therapy in high-risk patients Surgical treatment of abdominal sepsis IAI guidelines have published graded guidelines, A, B, C, D, for the medical and surgical treatment of abdominal sepsis, A, is a strong recommendation and D, one that is less robust in its recommendation[7].

to resistance from microbiology Antifungal therapy in high-risk patients Surgical treatment of abdominal sepsis IAI guidelines have published graded guidelines, A, B, C, D, for the medical and surgical treatment of abdominal sepsis, A, is a strong recommendation and D, one that is less robust in its recommendation[7]. Laparoscopic appendectomy is the primary treatment modalities recommended for perforated appendicitis. Antibiotic-therapy is used to supplement surgery or to delay a surgical procedure, though, on its own, it does not usually control an intraperitoneal infection [7]. According to Kong (2015), following retractable septic shock, the median overall length of hospital stay was five days, and the mortality rate was 1% [24]. In left colic perforated diverticular disease associated with a small abscess, treatment is commenced with antibiotics, with percutaneous drainage undertaken in cases of large abscess formation. The Hartmann procedure is used in cases of diffuse peritonitis and when progression to sepsis has occurred [25, 26], and in perforated colonic carcinoma, the Hartmann procedure is the first option of surgical treatment [27]. When local conditions allow, perforation subsequent to colonoscopy should be treated immediately by primary suture, if not the resection of the large bowel containing the perforation may be necessary [28, 29]. In gastroduodenal ulcer perforations, primary suturing, with or without an omentum patch, performed open or laparoscopically, is the treatment of choice [30,31].

When local conditions allow, perforation subsequent to colonoscopy should be treated immediately by primary suture, if not the resection of the large bowel containing the perforation may be necessary [28, 29]. In gastroduodenal ulcer perforations, primary suturing, with or without an omentum patch, performed open or laparoscopically, is the treatment of choice [30,31]. In small bowel perforation, primary suturing is the first option, but if it is associated with a large perforation or with a local ischemic condition, segmental resection is mandatory [32,33]. Early cholecystectomy in acute cholecystitis is now recommended as being superior to the previously held opinion of delaying cholecystectomy, with a laparoscopic technique being the procedure of choice. The alternative, and considered to be the best option, especially when complications occurs, is a classical approach [34]. Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for biliary decompression in patients with moderate to severe acute cholangitis, failing which, percutaneous biliary drainage (PTBD) is the second option[35,36]. Ineffective control of the septic source is associated with significantly elevated mortality rates [37]. Pelvic inflammatory disease (PID) usually responds to antibiotic therapy, though surgical drainage is usually required in patients with a tubo-ovarian abscess [38,39].

Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for biliary decompression in patients with moderate to severe acute cholangitis, failing which, percutaneous biliary drainage (PTBD) is the second option[35,36]. Ineffective control of the septic source is associated with significantly elevated mortality rates [37]. Pelvic inflammatory disease (PID) usually responds to antibiotic therapy, though surgical drainage is usually required in patients with a tubo-ovarian abscess [38,39]. In cases of trauma accompanied by perforation, repair or anastomosis of the intestinal injuries should be considered in all cases. A colostomy is to be considered in colorectal injuries involving all layers when multiple injuries or comorbid conditions are present [40,41].

Pelvic inflammatory disease (PID) usually responds to antibiotic therapy, though surgical drainage is usually required in patients with a tubo-ovarian abscess [38,39]. In cases of trauma accompanied by perforation, repair or anastomosis of the intestinal injuries should be considered in all cases. A colostomy is to be considered in colorectal injuries involving all layers when multiple injuries or comorbid conditions are present [40,41]. Discussion Sepsis originates from infections caused by microorganisms such as bacteria, fungi, viruses or parasites. A clinical diagnosis of the source of infection, be it lung, cutaneous or kidney, or an abdominal abscess, or infection with or without neoplasia [42], is the initial step of identification of the causative agent [1]. Pathogenic agents have changed in recent years, due to the use of newer antibiotics [1]. The gram-negative bacteria, the Pseudomonas aeruginosa and gram-positive Staphylococcus aureus continue to be the most frequent pathogenic agent isolated from blood [1]. A recent increase in Candida albicans can be attributed to the use of antibiotic therapy and immunosuppressants [43]. Though extremely rare, sepsis caused by malaria-causing Plasmodium falciparum has been reported in the literature [44]. Stearns-Kurosawa (2011) outlined the pathogenesis of the severity of sepsis and septic shock and charted the criteria for the systemic inflammatory response syndrome (SIRS) [45]. SIRS may be induced by trauma, pulmonary emboli, or myocardial infarction [46].

Discussion Sepsis originates from infections caused by microorganisms such as bacteria, fungi, viruses or parasites. A clinical diagnosis of the source of infection, be it lung, cutaneous or kidney, or an abdominal abscess, or infection with or without neoplasia [42], is the initial step of identification of the causative agent [1]. Pathogenic agents have changed in recent years, due to the use of newer antibiotics [1]. The gram-negative bacteria, the Pseudomonas aeruginosa and gram-positive Staphylococcus aureus continue to be the most frequent pathogenic agent isolated from blood [1]. A recent increase in Candida albicans can be attributed to the use of antibiotic therapy and immunosuppressants [43]. Though extremely rare, sepsis caused by malaria-causing Plasmodium falciparum has been reported in the literature [44]. Stearns-Kurosawa (2011) outlined the pathogenesis of the severity of sepsis and septic shock and charted the criteria for the systemic inflammatory response syndrome (SIRS) [45]. SIRS may be induced by trauma, pulmonary emboli, or myocardial infarction [46]. Sepsis is considered to occur when SIRS is associated with an infection, and if sepsis progresses and there is resultant arterial hypotension, then septic shock ensues[47]. Sepsis by itself can lead to the development of secondary abdominal compartment syndrome, which severely compromises the patient’s progress [48,49].

Sepsis is considered to occur when SIRS is associated with an infection, and if sepsis progresses and there is resultant arterial hypotension, then septic shock ensues[47]. Sepsis by itself can lead to the development of secondary abdominal compartment syndrome, which severely compromises the patient’s progress [48,49]. The key relationship in the pathogenesis of sepsis is the gram-negative bacterial endotoxin lipopolysaccharide (LPS) being recognized as a marker for the detection of bacterial pathogen invasion and responsible for the development of an inflammatory response. Release of LPS into the circulation triggers a strong systemic pro-inflammatory response [43].

enesis of sepsis is the gram-negative bacterial endotoxin lipopolysaccharide (LPS) being recognized as a marker for the detection of bacterial pathogen invasion and responsible for the development of an inflammatory response. Release of LPS into the circulation triggers a strong systemic pro-inflammatory response [43]. Cytokines release also represents a response against aggression. Tumor necrosis factor-a (TNF-a) and IL-1b are very well known in sepsis and septic shock involvement [50]. A systemic inflammatory response syndrome is triggered by high blood levels of cytokines one of them being IL-6 , initially described as B-cell– stimulating factor. IL-6, encoded by a gene located in the chromosome 7p2 region, is a cytokine with an initial pro-inflammatory role in a systemic inflammatory response to infectious injuries [51]. The importance of IL6 as a prognostic factor has been studied with the development of IL6 inhibitors, such as monoclonal neutralizing antibodies against IL-6 and its gp80 receptor, as well as a soluble gp130 Fc fusion protein that inhibits IL-6/sIL-6R trans-signaling. As a result of multiple studies, tocilizumab, a monoclonal antibody that acts as an IL-6 receptor antagonist, has been approved for the treatment of rheumatoid arthritis [52].

tralizing antibodies against IL-6 and its gp80 receptor, as well as a soluble gp130 Fc fusion protein that inhibits IL-6/sIL-6R trans-signaling. As a result of multiple studies, tocilizumab, a monoclonal antibody that acts as an IL-6 receptor antagonist, has been approved for the treatment of rheumatoid arthritis [52]. Conclusions Abdominal cavity pathology is the second most common site of sepsis, with perforated appendicitis being the most frequent source of an abdominal infection. If it is not recognized, it can progress to septic shock with a 1% mortality rate. The intra-abdominal compartment syndrome is a complication of the progression of peritonitis. According to IAI guidelines, depending on the degree of the condition, antibiotic- therapy should be initiated as soon as possible. Conflict of interest None to declare.

Evidence-based practice is the first step in underpinning and shaping how the profession delivers patient care. The Oxford Dictionary defines evidence as: ‘the available body of facts or information indicating whether a belief or proposition is true or valid’. The majority of evidence, though not all, is provided by research studies published in professional journals. Best evidence should be of high quality and is thus founded on the status of publishing journals and the process by which journals, editors, and the editorial team separate out the “good” from both the “mediocre” and the “bad”. This is undertaken by the process of Peer reviewing or refereeing; it is the practice of critically examining an author’s submitted research manuscript by experts in the same field before a paper is accepted for publishing in a journal. When well done, it confers a stamp of approval to the substance, authenticity and value of articles and therefore is a crucial element, integral to scholarly research and the validation of published evidence.

mitted research manuscript by experts in the same field before a paper is accepted for publishing in a journal. When well done, it confers a stamp of approval to the substance, authenticity and value of articles and therefore is a crucial element, integral to scholarly research and the validation of published evidence. Medical journals must, by necessity, have a process in place which reduces the likelihood of poor or substandard papers being published. Once published, papers of poor quality, bad methodology or non-valid results can have far-reaching implications for individuals, patients and society. A journal’s editorial team has a significant and ethical role in preventing the dissemination of inadequately reviewed material and should ensure that there is, in place, an initial filter for checking the validity and value of a paper before publication. The peer review process is the means by which this is achieved and by which a decision is made as to whether a work should be accepted or rejected. Editorial teams must ensure the trustworthiness and dependability of their peer review process and so warrant that accepted and published articles are of quality. Moreover, the status of the publishing journal is predicated on publishing sound scholarly articles and therefore the peer review process is central to achieving and maintaining this status. Journals, with a built-in high-class critical peer review practice, initiate and support evidence-based practice. The process of peer review is necessarily time-consuming due to the involved detailed, systematic and comprehensive approach.

Editorial teams must ensure the trustworthiness and dependability of their peer review process and so warrant that accepted and published articles are of quality. Moreover, the status of the publishing journal is predicated on publishing sound scholarly articles and therefore the peer review process is central to achieving and maintaining this status. Journals, with a built-in high-class critical peer review practice, initiate and support evidence-based practice. The process of peer review is necessarily time-consuming due to the involved detailed, systematic and comprehensive approach. The editor makes a preliminary check to decide if the subject matter and content of a manuscript is suitable for the journal, and submitted in the format dictated by the journal in its “guide to authors”. Based on this initial decision, he determines whether the manuscript should be sent for peer review or be immediately rejected. If the manuscript is selected for peer review, the editor must source qualified experts in the same field. Most journals use at least two reviewers initially.

The editor makes a preliminary check to decide if the subject matter and content of a manuscript is suitable for the journal, and submitted in the format dictated by the journal in its “guide to authors”. Based on this initial decision, he determines whether the manuscript should be sent for peer review or be immediately rejected. If the manuscript is selected for peer review, the editor must source qualified experts in the same field. Most journals use at least two reviewers initially. Reviewers assess the editor’s preliminary view as to whether the manuscript topic is acceptable to the journal’s requirements, check whether a research question has been clearly stated, and decide if suitable methodology has been used to address the expressed scientific issues. Most journals provide reviewers with a checklist to help in this procedure. The methodology, including the employed statistical methods together with the originality of the research findings, are evaluated, as well as the ethical aspects of the study. An essential aspect of the reviewers’ function is to judge the author’s knowledge of the subject. The logicality of the stated hypothesis, the contemporaneousness of references and whether they are primary sourced and relevant, are given consideration; whether the conclusions are understandable and justifiable are assessed.

sential aspect of the reviewers’ function is to judge the author’s knowledge of the subject. The logicality of the stated hypothesis, the contemporaneousness of references and whether they are primary sourced and relevant, are given consideration; whether the conclusions are understandable and justifiable are assessed. On completing their evaluation, reviewers report back to the editor individually; they do not consult with each other before reporting their views. Based on these reports, the editor decides whether to accept a manuscript or to ask authors to make minor or major revisions before being accepted, or rejected. Rejection usually means that the journal will not accept another manuscript by the authors based on the original submission. A rejected manuscript does not inevitably mean the work is inadequate with regards to scholarly quality but may fall short of the high standards of originality and innovativeness expected by an elite journal.

On completing their evaluation, reviewers report back to the editor individually; they do not consult with each other before reporting their views. Based on these reports, the editor decides whether to accept a manuscript or to ask authors to make minor or major revisions before being accepted, or rejected. Rejection usually means that the journal will not accept another manuscript by the authors based on the original submission. A rejected manuscript does not inevitably mean the work is inadequate with regards to scholarly quality but may fall short of the high standards of originality and innovativeness expected by an elite journal. The peer review process has an education element, and customarily, journals send the views of all reviewers to the authors with useful advice on how their manuscript could be improved. Authors should heed any advice given by reviewers and in most cases integrate these into their manuscript. Despite an outright rejection, authors should follow the given advice, re-write the paper and submit the improved version it to a different journal. It follows that the peer review process not only helps to nurture the quality and integrity of submitted paper but is also key to a researcher’s training. It has an important educational component which should be appreciated by younger and inexperienced authors. By taking cognisance of reviewers’ advice and deliberating on these, authors will soon recognise common flaws in research papers, and use this to improve future submissions.

s also key to a researcher’s training. It has an important educational component which should be appreciated by younger and inexperienced authors. By taking cognisance of reviewers’ advice and deliberating on these, authors will soon recognise common flaws in research papers, and use this to improve future submissions. Peer review encourages keeping in touch with current research and sharpens critical analysis skills, all of which lead to an enhancement in the likelihood of being a successful published author. There are several different approaches to peer review used by different journals. Each journal will indicate, in its guide to authors, which practice it uses. In the single-blind review, the reviewers’ names are not made known to the author(s), but the authors’ names and institute may be known to the reviewers. This is the traditional review process and used by the majority of journals. In the double-blind review, neither the reviewers nor the author(s) are known to each other. In both single-blind and double-blind there are usually at least two reviewers, and neither reviewer is known to the other. A third or more reviewer may be asked to assess the manuscript when there is a difference of opinion expressed by the original reviewers. Additionally, journals may ask specialists in methodology or statistics to comment on these. In this electronic age, many journals now use anti-plagiarism software and check if illustrations are original and have not been acquired from other published sources or manipulated by sophisticated software.

A third or more reviewer may be asked to assess the manuscript when there is a difference of opinion expressed by the original reviewers. Additionally, journals may ask specialists in methodology or statistics to comment on these. In this electronic age, many journals now use anti-plagiarism software and check if illustrations are original and have not been acquired from other published sources or manipulated by sophisticated software. Authors should be acquainted of the fact that the editor will, in most cases, abide by the final collective suggestion of the reviewers, whether this is for acceptance, the requirement of minor or major modifications or rejection, and appeals by authors are not usually accepted. A third review process, the open review in which authors and reviewers are known to each other is used by a small number of journals. Each process has its advantages, conceived disadvantages and criticism. The review process should allow all authors equivalence in manuscript acceptance. Papers should be accepted solely on the basis of their academic worth and not on the authors, reputation, status or country of origin.

A third review process, the open review in which authors and reviewers are known to each other is used by a small number of journals. Each process has its advantages, conceived disadvantages and criticism. The review process should allow all authors equivalence in manuscript acceptance. Papers should be accepted solely on the basis of their academic worth and not on the authors, reputation, status or country of origin. The single-blind review, with reviewer anonymity, is said to prevent reviewers from being influenced by authors. However, as the authors are known to the reviewers, concerns have been raised that this may lead to unnecessarily harsh or unjustifiable criticism and even personality clashes, where a reviewer may take steps against the authors to prevent or delay acceptance of a manuscript. On the other hand, the double-blind review with author anonymity prevents such reviewer bias.

, concerns have been raised that this may lead to unnecessarily harsh or unjustifiable criticism and even personality clashes, where a reviewer may take steps against the authors to prevent or delay acceptance of a manuscript. On the other hand, the double-blind review with author anonymity prevents such reviewer bias. Recently, a novel alternative to the standard peer-review process, called open peer review, has been piloted to address, in part, the critics listed above. This model includes “crowd-sourced” peer review where articles are published either immediately or after superficial initial checks by the journal, leaving any definitive and authoritative assessment to the scientific community. The method is not without inherent problems, the principal being the difficulty in finding an appropriate number of experts who are capable of offering a professional assessment. An in-depth evaluation of open review is inappropriate within this article, but the overall consensus is that open peer review should be complementary to the existing peer review process rather than supplanting it.

iculty in finding an appropriate number of experts who are capable of offering a professional assessment. An in-depth evaluation of open review is inappropriate within this article, but the overall consensus is that open peer review should be complementary to the existing peer review process rather than supplanting it. Authors can derive significant benefit from practising their own critical appraisal or peer review before submitting manuscripts; it is necessarily a systematised process which can be learned and improved. By routinely involving oneself in a self-peer review process, an author will acquire self-assurance in manuscript writing and benefit from the process. Self-peer reviewing can become an important element in an author’s personal development plan and advancement as a researcher. In engaging in the process, critical analysis skills are honed, the individual is up-to-date and well-informed of current research, and well able to spot common flaws in research papers These attributes once acquired improve one’s chances of being a successful published author To achieve this end, authors should acquire a standard checklist, used by reviewers, and adopt a disciplined and systematically appraisal of their paper before journal submission.

ell able to spot common flaws in research papers These attributes once acquired improve one’s chances of being a successful published author To achieve this end, authors should acquire a standard checklist, used by reviewers, and adopt a disciplined and systematically appraisal of their paper before journal submission. Peer-reviewed articles provide an established and reliable form of exchange of scientific ideas and in general ensures quality requirements of scientific publications. Scientific knowledge is by its very nature incremental and accumulative, and the quality of the previously published material is particularly important. Unreliable studies should never be allowed to become the basis of ongoing research. The peer-reviewed process cannot always prevent this occurring or ensure that all published work is factually accurate or conclusive, but it does go a long way to meeting these requirements.

published material is particularly important. Unreliable studies should never be allowed to become the basis of ongoing research. The peer-reviewed process cannot always prevent this occurring or ensure that all published work is factually accurate or conclusive, but it does go a long way to meeting these requirements. The Journal of Critical Care Medicine is an international journal dedicated to publishing high-quality peer-reviewed articles about critical care medicine, emphasising publishing novel and high-quality research papers. The Journal aims to improve the international practice of medicine at clinician, research, and policy-making levels. It is proud of its rigorous peer review system and its team of internationally renowned reviewers who give of their valuable time to undertake this critical process. It acknowledges the educational elements inherent in the process and takes steps to encourage young and inexperienced colleagues in developing their writing skills. Above all, it is proud of its pivotal role in presenting robust evidence-based data endorsed by a stringent but fair peer review process. Conflict of interest None to declare.

Introduction In the recent years, the need to enhance patient safety has become a priority as the majority of clinical errors (approximately 70%) are the results of human factors [1] and not technical in nature or due to the lack of knowledge (failure in team communication, situational awareness, resource utilization and leadership) [2]. Efforts are necessary to improve the quality of the medical care provided and the patient outcome, especially in high risk areas as emergency medicine, anesthesia, surgery and intensive care. How can we achieve this if just improving the knowledge is not enough? Steps were taken by adopting and adapting the Crises Resource Management (CRM) training, a tool that is oriented towards human factors and was initially developed by the aviation industry. CRM training is considered to be responsible for the decrease in aircraft accidents over the last four decades [3]. The primary objectives of CRM training are to improve team dynamics, to identify and help change mental models that create barriers in adopting effective communication, effective task management, healthy leadership and fellowship behaviors and an increasing awareness [4]. Anesthesia was one of the first specialties to adopt the CRM training and an improvement of team performance and a reduced risk of errors during medical and surgical crisis in the operating room has been shown [5]. Early interest in this type of training was demonstrated also by the emergency medicine specialty.

The primary objectives of CRM training are to improve team dynamics, to identify and help change mental models that create barriers in adopting effective communication, effective task management, healthy leadership and fellowship behaviors and an increasing awareness [4]. Anesthesia was one of the first specialties to adopt the CRM training and an improvement of team performance and a reduced risk of errors during medical and surgical crisis in the operating room has been shown [5]. Early interest in this type of training was demonstrated also by the emergency medicine specialty. Morey et al. (2002), in their evaluation of MedTeams Project’s results found that formal teamwork training was effective in improving team behaviors and in reducing errors in Emergency Departments (ED) [6]. Despite this, human factors training is not widely disseminated through professionals working in ED and most studies focused only on emergency medicine residents and interdisciplinary trauma teams. According to Chiniara (2003), simulation training is most suitable for low frequency high-risk situations that are potentially harmful for the patient [7]. These types of situations are those where crises arise, and CRM training may play an important role. As crises events are rare in real practice, the simulation room is an ideal setting for teaching CRM principles [7] and simulation-based CRM training was shown to be effective and relevant for the emergency medicine residents’ practice [2].

ions are those where crises arise, and CRM training may play an important role. As crises events are rare in real practice, the simulation room is an ideal setting for teaching CRM principles [7] and simulation-based CRM training was shown to be effective and relevant for the emergency medicine residents’ practice [2]. Different scales were developed to assess the nontechnical skills/behavioral performance and many studies reported on the reaction of participants toward the training, the acquisition of knowledge and the changes in attitude in non-clinical settings. Only a limited number of studies focused on transfer of the learning to the working place and even less measured the effect on patient outcomes [8]. As morbidity and mortality are indicators difficult to track in prospective studies, surrogates such as time to disposition, delays in achieving tasks in a timeframe, number of errors [9] have been used as well as checklists, to assess the clinical performance. This study is aimed at assessing whether a single day CRM oriented team training combining didactic and simulation sessions improves the clinical performance of interprofessional emergency medicine teams.

As morbidity and mortality are indicators difficult to track in prospective studies, surrogates such as time to disposition, delays in achieving tasks in a timeframe, number of errors [9] have been used as well as checklists, to assess the clinical performance. This study is aimed at assessing whether a single day CRM oriented team training combining didactic and simulation sessions improves the clinical performance of interprofessional emergency medicine teams. Methods Study design The study took place in the emergency department of the Tirgu-Mures Emergency Clinical County Hospital, Romania between March and July 2016. The hospital has an emergency medicine residency training program and is the site of an affiliated emergency and disaster medicine simulation center that focuses on multidisciplinary and inter-professional training. The emergency department’s annual census is around 77,000 patients, approximately 10% of them being “critically ill”. Emergency department clinical staff without prior CRM training were invited to participate. Residents with less than three months clinical experience in the emergency department were excluded. Twenty board-certified emergency medicine (EM) physicians, ten emergency medicine residents, and forty nurses volunteered for the study. The study protocol was approved by the Ethics Committee of the Tirgu-Mures Emergency Clinical County Hospital. Written informed consent was obtained from all study participants. Twenty mixed teams were constructed according to participants’ work schedules.

Emergency department clinical staff without prior CRM training were invited to participate. Residents with less than three months clinical experience in the emergency department were excluded. Twenty board-certified emergency medicine (EM) physicians, ten emergency medicine residents, and forty nurses volunteered for the study. The study protocol was approved by the Ethics Committee of the Tirgu-Mures Emergency Clinical County Hospital. Written informed consent was obtained from all study participants. Twenty mixed teams were constructed according to participants’ work schedules. Each team utilized an attending EM physician, an EM resident and two nurses, a structure we consider ideal for the management of a single critically ill patient in our ED. Because the number of eligible attending physicians was greater than the number of residents, each resident participated in two teams. Two sets of scenarios were designed, consisting of two scenarios each: a medical case and a trauma case. The first set consisted of: Medical patient A - A patient with an acute COPD exacerbation complicated by severe pneumonia, initially requiring noninvasive and subsequently invasive ventilation. Due to patient physiognomy as well as a history of prior tracheostomy, a difficult intubation needed to be anticipated. Trauma patient A - A trauma patient with severe brain injury complicated by hemorrhagic shock secondary to intra-abdominal bleeding requiring activation of the massive transfusion protocol and emergent surgery. The second set consisted of:

Medical patient A - A patient with an acute COPD exacerbation complicated by severe pneumonia, initially requiring noninvasive and subsequently invasive ventilation. Due to patient physiognomy as well as a history of prior tracheostomy, a difficult intubation needed to be anticipated. Trauma patient A - A trauma patient with severe brain injury complicated by hemorrhagic shock secondary to intra-abdominal bleeding requiring activation of the massive transfusion protocol and emergent surgery. The second set consisted of: Medical patient B - A patient with COPD now presenting with a pulmonary embolism necessitating thrombolysis due to clinical instability. Trauma patient B - A patient with a difficult airway, a severe, but surgically amenable intra-cranial injury, as well as long bones fractures, overall resulting in hypotension. Both medical cases had signs of β2 mimetics overuse (tremor, tachycardia, hypokalemia).

Medical patient B - A patient with COPD now presenting with a pulmonary embolism necessitating thrombolysis due to clinical instability. Trauma patient B - A patient with a difficult airway, a severe, but surgically amenable intra-cranial injury, as well as long bones fractures, overall resulting in hypotension. Both medical cases had signs of β2 mimetics overuse (tremor, tachycardia, hypokalemia). Sets were chosen pseudo-randomly, as participating residents were intended to be exposed to all cases and not to repeat scenarios. Simulations were performed in the ED resuscitation room during work hours. Scenarios utilized a high-fidelity manikin as well as the usual medical equipment and documentation forms from the resuscitation room. The role of different specialties doctors who were called for advice/help was played by one of the instructors, as well as the role of paramedics. The role of the radiologist was played by the radiologist on duty that day. Both a fixed camera, placed on the ceiling of the resuscitation room, as well as a mobile camera recorded all of the exercises. No debriefings took place after the assessment scenarios were completed.

ructors, as well as the role of paramedics. The role of the radiologist was played by the radiologist on duty that day. Both a fixed camera, placed on the ceiling of the resuscitation room, as well as a mobile camera recorded all of the exercises. No debriefings took place after the assessment scenarios were completed. We then held single day (6 to 7 hours) training sessions over a period of ten days. Participants chose the day for their training session at their convenience. Training sessions took place in a recreation of the ED resuscitation room in the simulation center. Each training session started with a lecture focusing on medical errors and CRM principles. No medical teaching was provided. After the lecture, participants had the opportunity to familiarize themselves with the manikin and the simulation setting. Each training session involved two multi-professional teams, each team consisting of one EM attending physician, one EM resident and two nurses. During the training sessions participants were permitted to change teams as long as the multi-professional composition remained the same. We utilized six critical patient scenarios (two trauma cases and four medical cases), different from those used in the initial assessment. One team completed a scenario while the other team observed the exercise remotely via a high-resolution real time video transmission system. Either as participants or observers, each team was exposed to all cases.

scenarios (two trauma cases and four medical cases), different from those used in the initial assessment. One team completed a scenario while the other team observed the exercise remotely via a high-resolution real time video transmission system. Either as participants or observers, each team was exposed to all cases. The simulation was run by two instructors (one doctor and one nurse) with CRM background training and one IT technician. Each scenario was followed by an instructor facilitated debriefing. Both technical and non-technical issues relating to team performance and team work were discussed. Identified clinical errors were addressed by either the participants or the instructors. Members of the team who had completed the scenario had priority in providing feedback, but both observers and participants were involved in debriefings. Two months after receiving training, a final assessment was performed consisting of the same scenarios, teams and setting used in the initial assessment. As in the initial assessment, the scenarios were video-recorded, and no briefing was provided. Objective measurement of clinical team performance was performed through a checklist that was designed for each scenario (Figure 1). The checklist included essential assessment items for the diagnosis and treatment of a critical patient, with the focus on key actions and decisions. The number of times a critical procedure was performed, as well as time to completion of the critical steps where appropriate, were recorded. Fig. 1 Example of a checklist used for the assessment of clinical performance

Objective measurement of clinical team performance was performed through a checklist that was designed for each scenario (Figure 1). The checklist included essential assessment items for the diagnosis and treatment of a critical patient, with the focus on key actions and decisions. The number of times a critical procedure was performed, as well as time to completion of the critical steps where appropriate, were recorded. Fig. 1 Example of a checklist used for the assessment of clinical performance The video recordings were analyzed, and the checklists completed by an assessor blinded to whether the scenarios analyzed were the initial or final assessment. Statistical analysis The collected data were organized into several SPSS data files. The variables obtained were binary type and continuous type. For binary data analysis, the likelihood ratio was used to assess the difference in proportions. Continuous variables were tested for normality using Kolmogorov-Smirnov test. Our data followed a non-gaussian distribution, therefore a non-parametric test was used to compare the central tendency for the data series. Wilcoxon signed rank test was used, since we analyzed paired data. The significance level used in all tests was 0.05.

bles were tested for normality using Kolmogorov-Smirnov test. Our data followed a non-gaussian distribution, therefore a non-parametric test was used to compare the central tendency for the data series. Wilcoxon signed rank test was used, since we analyzed paired data. The significance level used in all tests was 0.05. Results Seventy participants were enrolled in the study and 69 completed the study. One nurse participant resigned her position and she was not available for the final assessment scenario. She was replaced by another nurse who had attended the training. The initial nurse was excluded from the final analysis and the nurse who replaced her was analyzed only once with the team to whom she was allocated at the beginning of the study. The male: female ratio was 13:17 for doctors and 11:29 for nurses. Professional experience was variable (average 70 months, minimum 8 and maximum 300 months). A checklist was completed for each scenario and each team. A total of 40 checklists were collected, 20 for the initial assessment and 20 the for the final one.

Results Seventy participants were enrolled in the study and 69 completed the study. One nurse participant resigned her position and she was not available for the final assessment scenario. She was replaced by another nurse who had attended the training. The initial nurse was excluded from the final analysis and the nurse who replaced her was analyzed only once with the team to whom she was allocated at the beginning of the study. The male: female ratio was 13:17 for doctors and 11:29 for nurses. Professional experience was variable (average 70 months, minimum 8 and maximum 300 months). A checklist was completed for each scenario and each team. A total of 40 checklists were collected, 20 for the initial assessment and 20 the for the final one. For the medical case A, the patient with acute COPD exacerbation complicated by severe pneumonia, critical elements where considered: oxygen administration, sitting position, establishing an intravenous access, appropriate investigations- especially ECG and arterial blood gases, recognition of the need for non-invasive ventilation, recognition of β2 sympatico-mimetics overdose, appropriate antibiotic administration. Results are reported in table 1 and table 2. A trend towards improvement was seen for these elements. Concerning the time until the procedure was performed, a statistically significant value was reached only for intravenous access. In terms of number of procedures performed, β2 sympatico-mimetics overdose recognition and assessment of efficiency of NIV through repeated ABG 30 minutes after initiation of it, reached significance level.

ime until the procedure was performed, a statistically significant value was reached only for intravenous access. In terms of number of procedures performed, β2 sympatico-mimetics overdose recognition and assessment of efficiency of NIV through repeated ABG 30 minutes after initiation of it, reached significance level. Table 1 Checklist results for medical case A

ime until the procedure was performed, a statistically significant value was reached only for intravenous access. In terms of number of procedures performed, β2 sympatico-mimetics overdose recognition and assessment of efficiency of NIV through repeated ABG 30 minutes after initiation of it, reached significance level. Table 1 Checklist results for medical case A Element Number of teams “Yes”/initial Number of teams “Yes”/final Number of teams “No”/initial Number of teams “No”/final Likelihood Ratio* Consciousness 10 10 0 0 ABC evaluation < 2 minutes 10 10 0 0 Oxygen administration ** 10 10 0 0 Siting position ** 10 10 0 0 Monitoring Electrocardiogram 10 10 0 0 Blood pressure 10 10 0 0 Oxygen saturation 10 10 0 0 Temperature 8 9 2 1 0.528 Focused clinical Cardiac auscultation 1 2 9 1 0.528 examination Pulmonary auscultation 10 10 0 0 Jugular veins 0 1 10 9 Signs of PVT/edema 5 10 5 0 Focused history Anamnesis 10 10 0 0 Past medical history 10 10 0 0 Treatment 8 10 2 0 12-lead electrocardiogram ** 6 10 4 0 Intravenous line ** 10 10 0 0 Arterial blood gases (ABG) ** 10 10 0 0 Lab tests CBC, electrolytes, Renal &hepatic tests 9 10 1 0 C-reactive protein 1 0 9 10 NTproBNP 8 2 8 2 1.000 Troponin 2 4 8 6 0.326 D-dimers 6 8 4 2 0.326 Chest radiography 10 10 0 0 Cardiac ultrasound 1 1 9 9 1.000 Give β2mimetics 9 3 1 7 0.004 Noninvasive ventilation ** 10 10 0 0 Choose the mask 8 7 2 3 0.605 Set the ventilator correctly 8 9 2 1 0.528 Explain to the patient 8 10 2 0 0.112 Apply the mask 10 10 0 0 Observe for tolerance & synchronism 6 9 4 1 0.112 Observe the patient 9 9 1 1 1.000 Observe the ventilator 7 9 3 1 0.255 Repeat ABG after 30 minutes 4 9 6 1 0.015 Give appropriate antibiotic 8 10 2 0 Differential Exacerbation of COPD+ pneumonia 10 10 0 0 diagnosis Acute pulmonary edema 4 10 6 0 Acute coronary syndrome 0 3 10 7 Pulmonary embolism 7 10 3 0 Spontaneous pneumothorax 2 6 8 4 0.063 Correct diagnosis 10 10 0 0 Recognize β2mimetics overdose 1 7 9 3 0.004 * Chi-Square Tests; ** Time to achievement recorded; ABC- airway, breathing, circulation, PVT-profound venous thrombosis, CBC- complete blood count, NTproBNP- N-terminal pro b-type natriuretic peptide, COPD-chronic obstructive pulmonary disease

063 Correct diagnosis 10 10 0 0 Recognize β2mimetics overdose 1 7 9 3 0.004 * Chi-Square Tests; ** Time to achievement recorded; ABC- airway, breathing, circulation, PVT-profound venous thrombosis, CBC- complete blood count, NTproBNP- N-terminal pro b-type natriuretic peptide, COPD-chronic obstructive pulmonary disease Table 2 Results for medical case A – Time to achievement of critical steps Initial Final Time to…. (seconds) Median IQR Median IQR P value* Oxygen administration 65 80 39.5 63 0.203 Sitting position 17 113 6 18 0.074 12 leads electrocardiogram 56 121 136.5 111 0.463 Intravenous line 123.5 114 58.5 54 0.013 Arterial blood gases 142.5 99 70.5 99 0.169 Noninvasive ventilation 308 304 215.5 124 0.386 * Wilcoxon Signed Ranks Test

Median IQR Median IQR P value* Oxygen administration 65 80 39.5 63 0.203 Sitting position 17 113 6 18 0.074 12 leads electrocardiogram 56 121 136.5 111 0.463 Intravenous line 123.5 114 58.5 54 0.013 Arterial blood gases 142.5 99 70.5 99 0.169 Noninvasive ventilation 308 304 215.5 124 0.386 * Wilcoxon Signed Ranks Test For medical case B, the patient with COPD now presenting with a pulmonary embolism, critical elements where: oxygen administration, semi-sitting position, establishing an intravenous access, appropriate investigations- especially ECG, arterial blood gases, angioCT scan/ cardiac ultrasound, recognition of the need for and initiation of thrombolysis, request for cardiologic advice and recognition of β2 sympatico-mimetics overdose. Results are reported in table 3 and table 4. As for the medical case A, an improvement was seen for most of the elements. Significance level was reached in terms of number of procedures performed for cardiac ultrasound requested and β2 sympatico-mimetics overdose recognition. Concerning the time until the procedure was performed, significance level was reached for oxygen administration and sitting position. For time until a cardiac ultrasound was requested, the p value couldn’t be calculated as the test was requested during the initial assessment scenario only by two teams. Table 3 Checklist results for medical case B

For medical case B, the patient with COPD now presenting with a pulmonary embolism, critical elements where: oxygen administration, semi-sitting position, establishing an intravenous access, appropriate investigations- especially ECG, arterial blood gases, angioCT scan/ cardiac ultrasound, recognition of the need for and initiation of thrombolysis, request for cardiologic advice and recognition of β2 sympatico-mimetics overdose. Results are reported in table 3 and table 4. As for the medical case A, an improvement was seen for most of the elements. Significance level was reached in terms of number of procedures performed for cardiac ultrasound requested and β2 sympatico-mimetics overdose recognition. Concerning the time until the procedure was performed, significance level was reached for oxygen administration and sitting position. For time until a cardiac ultrasound was requested, the p value couldn’t be calculated as the test was requested during the initial assessment scenario only by two teams. Table 3 Checklist results for medical case B Element Number of teams “Yes”/initial Number of teams “Yes”/final Number of teams “No”/initial Number of teams “No”/final Likelihood Ratio* Consciousness 10 10 0 0 ABC evaluation < 2 minutes 10 10 0 0 Oxygen administration ** 10 10 0 0 Sitting position ** 9 10 1 0 Monitoring Electrocardiogram 10 10 0 0 Blood pressure 10 10 0 0 Oxygen saturation 10 10 0 0 Temperature 6 1 4 9 0.015 Focused clinical Cardiac auscultation 4 8 6 2 0.063 examination Pulmonary auscultation 9 8 1 2 0.528 Jugular veins 1 3 9 7 0.255 Signs of PVT/edema 9 10 1 0 Focused history Anamnesis 10 10 0 0 Past medical history 10 10 0 0 Treatment 10 10 0 0 12-lead electrocardiogram** 10 10 0 0 Intravenous line ** 10 10 0 0 Arterial blood gases (ABG) 10 10 0 0 Lab tests CBC, electrolytes, Renal &hepatic tests 10 10 0 0 CRP 0 0 10 10 NT-proBNP 8 9 2 1 0.528 Troponin 9 8 1 2 0.528 D-dimers 9 10 1 0 Chest radiography 6 4 4 6 0.369 Fluids bolus 2 9 8 1 0.001 Give β2mimetics 8 2 2 8 0.005 Request angioCT scan ** 10 8 0 2 Angio-CT scan performed 6 2 4 6 0.132 Request cardiac ultrasound ** 2 7 8 3 0.021 Request venous Doppler ultrasound 2 0 8 10 Decide to thrombolysis ** 9 10 1 0 Verify contraindications to thrombolysis 2 7 8 3 0.021 Start thrombolysis ** 9 10 1 0 Ask for cardiologic advise ** 10 10 0 0 Differential Exacerbation of COPD+ pneumonia 6 9 4 1 0.112 diagnosis Acute pulmonary edema 4 5 6 5 0.653 Acute coronary syndrome 5 10 5 0 Pulmonary embolism 10 10 0 0 Spontaneous pneumothorax 5 8 5 2 0.155 Correct diagnosis 10 10 0 0 Recognize β2mimetics overdose 2 8 8 2 0.005 * Chi-Square Test; ** Time to achievement recorded; ABC- airway, breathing, circulation, PVT-profound venous thrombosis, CBC- complete blood count, NT-proBNP- N-terminal pro b-type natriuretic peptide, COPD-chronic obstructive pulmonary disease

155 Correct diagnosis 10 10 0 0 Recognize β2mimetics overdose 2 8 8 2 0.005 * Chi-Square Test; ** Time to achievement recorded; ABC- airway, breathing, circulation, PVT-profound venous thrombosis, CBC- complete blood count, NT-proBNP- N-terminal pro b-type natriuretic peptide, COPD-chronic obstructive pulmonary disease Table 4 Results for medical case B – Time to achievement of critical steps Time to…. (seconds) Initial Final P value* Median IQR Median IQR Oxygen administration 76 81 51.5 29 0.022 Siting position 20 245 6.5 15 0.012 12 leads electrocardiogram 160 125 120 30 0.221 intravenous line 115 116 105 48 0.859 Arterial blood gases 159 73 128 144 0.767 AngioCT scan 345 369 501 NA NA Cardiac ultrasound 790 NA 520 450 NA Thrombolysis decision 515 233 510 394 0.515 Start thrombolysis 570 673 606.5 410 0.678 Request cardiologic advice 336 280 300 580 0.333 * Wilcoxon Signed Ranks Test; NA- not available Critical elements for the trauma case A, the patient with severe brain injury complicated by hemorrhagic shock secondary to intra-abdominal bleeding, were considered: 2 intravenous access, FAST ultrasound examination, administration of fluid bolus and O negative PRBCs, recognition of a shock patient requiring urgent surgery (request for surgeon advise early, transfer to the

h severe brain injury complicated by hemorrhagic shock secondary to intra-abdominal bleeding, were considered: 2 intravenous access, FAST ultrasound examination, administration of fluid bolus and O negative PRBCs, recognition of a shock patient requiring urgent surgery (request for surgeon advise early, transfer to the operating theatre), recognition of the need to intubate and anticipation of a difficult airway, recognition and initiation of treatment for increased ICP. Results are reported in table 5 and table 6. There was a trend towards improvement in all the elements, though not statistically significant, except for recognition and initiation of treatment of high ICP, and the time until airway was secured. Table 5 Checklist results for trauma case A

operating theatre), recognition of the need to intubate and anticipation of a difficult airway, recognition and initiation of treatment for increased ICP. Results are reported in table 5 and table 6. There was a trend towards improvement in all the elements, though not statistically significant, except for recognition and initiation of treatment of high ICP, and the time until airway was secured. Table 5 Checklist results for trauma case A Element Number of teams “Yes”/initial Number of teams “Yes”/final Number of teams “No”/initial Number of teams “No”/final Likelihood Ratio* Consciousness 10 10 0 0 A-airway 6 10 4 0 B-breathing 9 10 1 0 Primary survey C-circulation 9 10 1 0 (ABC < 2 minutes) D GCS 9 10 1 0 (DE < 5 minutes) Motor response 7 10 3 0 Pupillary exam 9 10 1 0 E-exposure 10 10 0 0 Oxygen administration 10 10 0 0 Electrocardiogram 10 10 0 0 Blood pressure 10 10 10 10 0 0 0 0 Monitoring Oxygen saturation 10 10 0 0 Temperature 1 5 9 5 0.044 Anamnesis 10 10 0 0 Past medical history 1 0 9 10 Allergies 0 0 10 10 Focused history Treatment 0 1 10 9 Mechanism of injury 7 10 3 0 Time from injury 0 7 10 3 Last meal 0 1 10 9 Insert an intravenous line ** 10 10 0 0 ABO+ Rhesus 10 10 0 0 Glucose level 2 1 8 9 0.528 CBC, electrolytes, renal &hepatic, coagulation tests, creatine kinase, arterial blood gases 10 10 0 0 Fluids bolus ** 7 10 3 0 FAST ultrasound exam ** 10 10 0 0 12-lead electrocardiogram ** 3 4 7 6 0.639 Insert a second intravenous line ** 10 10 0 0 Recognize signs of shock 10 10 0 0 Transfusion of O negative PRBCs 6 9 4 1 0.121 Recognize signs of increased ICP 6 10 4 0 Recognize the need for intubation ** 10 10 0 0 Anticipate a difficult airway 3 7 7 3 0.070 Airway secured ** 10 10 0 0 Request the surgeon advise ** 10 10 0 0 Request for a CT scan 3 3 7 7 1.000 Request the neurosurgeon advise 5 8 5 2 0.155 Treat high ICP 2 7 8 3 0.021 Immobilize the fracture 5 10 5 0 Perform the logroll 1 3 9 7 0.255 Perform a complete secondary survey 1 0 9 10 Transfer the patient to the operating room ** 9 10 1 0 IOT checklist completed verified 0 2 10 8 * Chi-Square Tests; ** Time to achievement recorded; D-disability, CBC-complete blood count, a FAST-focused assessment with Sonography in Trauma, PRBCs-packed red blood cells, ICP-intracranial pressure

ndary survey 1 0 9 10 Transfer the patient to the operating room ** 9 10 1 0 IOT checklist completed verified 0 2 10 8 * Chi-Square Tests; ** Time to achievement recorded; D-disability, CBC-complete blood count, a FAST-focused assessment with Sonography in Trauma, PRBCs-packed red blood cells, ICP-intracranial pressure Table 6 Results for trauma case A – Time to achievement of critical steps Time to…. (seconds) Initial Final P value* Median IQR Median IQR First intravenous line 65 49 43.5 45 0.139 Fluids bolus 208 258 116.5 114 0.128 FAST ultrasound exam 174 177 160.5 160 0.721 12 leads electrocardiogram 658 NA 114 52 0.109 Second intravenous line 174 352 158.5 190 0.646 Recognize the need for IOT 149 116 109 199 0.203 Airway secured 401 210 317 78 0.017 Request the surgeon advise 339.5 215 247.5 247 0.241 Transfer into the operating room 580 295 605 70 0.374 * Wilcoxon Signed Ranks Test; NA- not available; FAST-focused assessment with ultrasound in trauma, IOT-orotracheal intubation The trauma case B, the patient with a difficult airway, severe TBI and long bones fractures resulting in hypotension, had the following elements: intravenous access, administration of fluid bolus, FAST ultrasound examination, recognition of severe brain injury requiring urgent measures to decrease the ICP, performance of the CT scan and early involvement of the neurosurgeon, recognition of the need to intubate, anticipation of a difficult airway and management of a “cannot ventilate, cannot intubate “ situation (number of direct laryngoscopies, call for help, decide and perform a cricothyroidotomy).

to decrease the ICP, performance of the CT scan and early involvement of the neurosurgeon, recognition of the need to intubate, anticipation of a difficult airway and management of a “cannot ventilate, cannot intubate “ situation (number of direct laryngoscopies, call for help, decide and perform a cricothyroidotomy). Results are given in table 7 and table 8. An improvement was seen in most of the elements. Significant improvement was shown in the elements corelated with severe TBI and difficult airway management, in terms of number of procedures performed (recognition and treatment of increased ICP, anticipation of difficult airway) and time until procedure was completed (request for neurosurgeon advice, first attempt to intubate, decision for cricothyroidotomy, airway secured). Table 7 Checklist results for trauma case B

Results are given in table 7 and table 8. An improvement was seen in most of the elements. Significant improvement was shown in the elements corelated with severe TBI and difficult airway management, in terms of number of procedures performed (recognition and treatment of increased ICP, anticipation of difficult airway) and time until procedure was completed (request for neurosurgeon advice, first attempt to intubate, decision for cricothyroidotomy, airway secured). Table 7 Checklist results for trauma case B Element Number of teams “Yes”/initial Number of teams “Yes”/final Number of teams “No”/initial Number of teams “No”/final Likelihood Ratio* Consciousness 10 10 0 0 A-airway 9 10 1 0 B-breathing 9 10 1 0 Primary survey C-circulation 9 10 1 0 (ABC < 2 minutes) D GCS 8 10 2 0 (DE < 5 minutes) Motor response 7 10 3 0 Pupillary exam 8 10 2 0 E-exposure 10 10 0 0 Oxygen administration 8 10 2 0 Electrocardiogram 10 10 0 0 Blood pressure 10 10 0 0 Monitoring Oxygen saturation 10 10 0 0 Temperature 0 5 10 5 Anamnesis 10 10 0 0 Past medical history 1 5 9 5 0.044 Allergies 0 7 10 3 Focused history Treatment 0 1 10 9 Mechanism of injury 7 10 3 0 Time from injury 5 10 5 0 Last meal 0 0 10 10 Insert an intravenous line ** 10 10 0 0 ABO+ Rhesus 10 10 0 0 Glucose level 2 3 8 7 0.605 CBC, electrolytes, renal &hepatic& coagulation tests, creatine kinase, arterial blood gases 10 10 0 0 Fluids bolus ** 3 3 7 7 1.000 FAST ultrasound exam ** 5 7 5 3 0.359 12-lead electrocardiogram 1 4 9 6 0.112 Insert a second intravenous line ** 8 8 2 2 1.000 Request for CT scan 9 10 1 0 Request the neurosurgeon ** 9 10 1 0 Recognize signs of increased ICP 3 9 7 1 0.004 Recognize the need for intubation ** 10 10 0 0 Anticipate a difficult airway 5 9 5 1 0.044 Number of direct laryngoscopy atempts (more than two) 6 0 4 10 Ventilation achieved between intubation attempts 10 10 0 0 Ask for help ** 5 5 5 5 1.000 Use of alternative techniques for intubation 5 0 5 10 Decide for cricothyroidotomy ** 10 10 0 0 Airway secured ** 10 10 0 0 Treat high ICP 4 9 6 1 0.015 Immobilize the fracture 8 9 2 1 0.528 Give antibiotic 4 10 6 0 Perform the logroll 4 8 6 2 0.063 Perform a complete secondary survey 3 1 7 9 0.255 IOT checklist completed verified 0 2 10 8 * Chi-Square Test; ** Time to achievement recorded; D-disability, CBC-complete blood count, a FAST-focused assessment with Sonography in Trauma, ICP-intracranial pressure, IOT-orotracheal intubation

orm the logroll 4 8 6 2 0.063 Perform a complete secondary survey 3 1 7 9 0.255 IOT checklist completed verified 0 2 10 8 * Chi-Square Test; ** Time to achievement recorded; D-disability, CBC-complete blood count, a FAST-focused assessment with Sonography in Trauma, ICP-intracranial pressure, IOT-orotracheal intubation Table 8 Results for trauma case B – Time to achievement of critical steps Time to…. (seconds) Initial Final P value* Median IQR Median IQR First intravenous line 66 85 69.5 80 0.674 Fluids bolus 245 703 114 188 0.317 FAST ultrasound exam 170 875 240 510 0.715 Second intravenous line 150 207 195 552 0.917 Request for neurosurgeon 1200 338 580 465 0.008 Recognize the need for IOT 240 175 145 80 0.017 First IOT atempt 512 179 355 147 0.007 Call for help 682 356 520 186 0.655 Decide for cricothyroidotomy 790 195 446,5 262 0.005 Airway secured 1030 304 602 250 0.005 * Wilcoxon Signed Ranks Test; FAST-focused assessment with ultrasound in trauma, IOT-orotracheal intubation Discussion CRM trainings are addressing a set of nontechnical skills, “the cognitive, social and personal resource skills that complement technical skills, and contribute to safe and efficient task performance” [10]. These nontechnical skills can be divided into four domains essential for an effective team: teamwork, task management, decision making and situational awareness, all of them being linked by communication [11] The CRM key principles that act as a framework for teaching teamwork skills to emergency residents, according to GABA [5] and modified by Carne [12] are: Know your environment

Discussion CRM trainings are addressing a set of nontechnical skills, “the cognitive, social and personal resource skills that complement technical skills, and contribute to safe and efficient task performance” [10]. These nontechnical skills can be divided into four domains essential for an effective team: teamwork, task management, decision making and situational awareness, all of them being linked by communication [11] The CRM key principles that act as a framework for teaching teamwork skills to emergency residents, according to GABA [5] and modified by Carne [12] are: Know your environment Anticipate, share and review the plan Ensure leadership and role clarity Communicate effectively Call for help early Allocate attention wisely- avoid fixation Distribute the workload-monitor and support team members. In our study we assessed whether a single-day training on CRM principles combining didactic and high-fidelity simulated session may improve the clinical performance (objectively measured through a checklist) of an interprofessional emergency team. We found that most of the measured clinical parameters improved. We hypothesize this is due to an improvement of non-technical skills, as we didn’t teach the clinical skills in the simulation cases explicitly. Also, in each team we had an experienced attending physician, the mean experience for the EM attendings being 149 months (minimum 72 and maximum 300 months), so lack of knowledge was unlikely. Many of the clinical decisions as well as the evaluation of the patient include the correct usage of CRM principles.

In our study we assessed whether a single-day training on CRM principles combining didactic and high-fidelity simulated session may improve the clinical performance (objectively measured through a checklist) of an interprofessional emergency team. We found that most of the measured clinical parameters improved. We hypothesize this is due to an improvement of non-technical skills, as we didn’t teach the clinical skills in the simulation cases explicitly. Also, in each team we had an experienced attending physician, the mean experience for the EM attendings being 149 months (minimum 72 and maximum 300 months), so lack of knowledge was unlikely. Many of the clinical decisions as well as the evaluation of the patient include the correct usage of CRM principles. The cases were chosen in such a way that they were typical for an average acute ED patient, but still strongly dependent on correct application of CRM principles. E.g., when dealing with a difficult airway, in our case a “cannot ventilate cannot intubate” situation, the team should anticipate, share the same mental model, distribute the workload and plan ahead while staying alert for sudden changes of situation. All the required skills correspond to CRM principles and indeed improved significantly after the training as shown by the number of teams who anticipated the difficult airway (p=0.044), number of attempts to intubate by direct laryngoscopy, the time until decision to perform a cricothyroidotomy was taken and the airway was secured.

red skills correspond to CRM principles and indeed improved significantly after the training as shown by the number of teams who anticipated the difficult airway (p=0.044), number of attempts to intubate by direct laryngoscopy, the time until decision to perform a cricothyroidotomy was taken and the airway was secured. Managing a polytrauma patient with hemorrhagic shock, requiring damage control surgery and massive transfusion protocol activation, requires to: anticipate, share the plan, ensure leadership and role clarity, communicate effectively, distribute the workload, call for help early and maintain standards. An improvement was seen in the present study, reflected by number of teams that administrate fluids bolus and O negative PRBCs from the ED storage, monitored the temperature as hypothermia is one of the components of the lethal triad in bleeding patients [13], time until they insert the intravenous lines, gave the fluids bolus, performed the FAST exam, call for surgeon. Also, the recognition of a condition such as β2 sympatico-mimetics overdose, in a patient presenting with respiratory distress, where signs as tachycardia and agitation might have different causes, request situational awareness and wise allocation of attention. In both medical cases, a significant improvement was seen after the training (p=0.004 for case A and p=0.005 for case B). Avoiding fixation error was important in order to avoid a wrong diagnosis in medical cases as they had a similar history and almost the same clinical presentation, except for the blood pressure that was

Also, the recognition of a condition such as β2 sympatico-mimetics overdose, in a patient presenting with respiratory distress, where signs as tachycardia and agitation might have different causes, request situational awareness and wise allocation of attention. In both medical cases, a significant improvement was seen after the training (p=0.004 for case A and p=0.005 for case B). Avoiding fixation error was important in order to avoid a wrong diagnosis in medical cases as they had a similar history and almost the same clinical presentation, except for the blood pressure that was lower but still in normal range initially, for the patient with PE. Their final diagnosis was correct before and after the training, but more differential diagnoses were considered during the final assessment. The idea of team skills training being associated with better clinical performance and empirically with better patient outcome was already raised by Wright et al [14]. In their study on medical students, run in two settings: a classroom-based and a high-fidelity simulated environment, they found a strong correlation between team skills rating and objective performance measures within the high fidelity simulated environment, but no correlation on the classroom- based environment. Very few studies measured the impact of CRM training on patient outcome [8]. One of these found a significant decrease in mortality for in hospital pediatric cardiac arrest after simulation CRM training. [15].

The idea of team skills training being associated with better clinical performance and empirically with better patient outcome was already raised by Wright et al [14]. In their study on medical students, run in two settings: a classroom-based and a high-fidelity simulated environment, they found a strong correlation between team skills rating and objective performance measures within the high fidelity simulated environment, but no correlation on the classroom- based environment. Very few studies measured the impact of CRM training on patient outcome [8]. One of these found a significant decrease in mortality for in hospital pediatric cardiac arrest after simulation CRM training. [15]. A positive association between better teamwork, better nontechnical skills and disposition time and risk for delays to patient care was demonstrated by Pucher et al, on a study carried on fifty real trauma cases [9]. Similar to our study, the efficiency of a relatively brief (4 hours) teamwork training, including a one-hour web didactic session followed by a human patient simulator-based session, on clinical performance of an interdisciplinary trauma team was shown by Steinmann et al [16]. This improvement was seen on simulated cases as well as on real trauma cases. The effectiveness of teamwork training on clinical performance of an interprofessional team (surgeons, nurses), reflected by the decrease in time from arrival to CT scanner, endotracheal intubation and operating room, was demonstrated also by Capella et al [17]. As in the previously mentioned study, these results were obtained from real cases.

work training on clinical performance of an interprofessional team (surgeons, nurses), reflected by the decrease in time from arrival to CT scanner, endotracheal intubation and operating room, was demonstrated also by Capella et al [17]. As in the previously mentioned study, these results were obtained from real cases. The present study has several limitations. The study was run in a single center and this limited the number of participants. Due to the very small number of EM residents available during the study period, they were exposed twice to the initial and final assessment in two different teams. Although we used two sets of scenarios and we did not perform a debriefing afterwards, we cannot exclude that their experience with the first team influenced their performance with the second one. It is difficult to appreciate if this had an impact the team clinical performance. Participants were evaluated two months after the training. We did not assess them immediately after the training, so we do not know if their performance improved or declined over this time period. Ideally, after a CRM training the actual patient outcome would be measured. This was our initial intention when we implemented this study. Unfortunately, we encountered a technical problem when we tried to analyze real cases. The quality of the image returned by the fixed camera was good, but the quality of the sound was too poor to permit a proper evaluation.

atient outcome would be measured. This was our initial intention when we implemented this study. Unfortunately, we encountered a technical problem when we tried to analyze real cases. The quality of the image returned by the fixed camera was good, but the quality of the sound was too poor to permit a proper evaluation. Conclusion Our study supports the use of combined CRM training for improving clinical performance of an interprofessional emergency team. Empirically this may improve the patient outcome, but further research is necessary to establish the ideal length of the training, the real impact on patient outcome, the length of the decay phase and the optimal method and time for refresher training. Acknowledgements The authors thank all the participants in the study. Special thanks to Oana Mates, Andreea Soceanu and Bogdan Posteuca for their help in collecting the data. Conflict of Interest None to declare

To the Editor of JCCM, Regarding the article “Emerging Infection with Elizabethkingia meningoseptica in Neonate. A Case Report” by Arbune et al. (2018) [1], there are specific facts which need clarification regarding the reporting of this organism. First of all, Arbune reported the isolation of the organism from the cerebrospinal fluid (CSF) and blood culture of one case, and that no source of infection was identified. Elizabethkingia meningoseptica, although linked to meningitis and nosocomial infections, can be an environmental contaminant as well. Repeat cultures of the samples are mandatory for the confirmation of such unusual pathogens. Secondly, at present, no antibiotic sensitivity guidelines exist for this organism. Hence, the reporting of antibiotic susceptibilities must be done along with minimum inhibitory concentration (MIC) values of the tested antimicrobials rather than merely stating they are “sensitive” or “resistant”. MIC values of the tested antibiotics may help the clinicians in deciding the drug dosage. Additionally, they may contribute to the formulation of susceptibility guidelines in the future.

um inhibitory concentration (MIC) values of the tested antimicrobials rather than merely stating they are “sensitive” or “resistant”. MIC values of the tested antibiotics may help the clinicians in deciding the drug dosage. Additionally, they may contribute to the formulation of susceptibility guidelines in the future. Thirdly, and most importantly, accurate identification is the key issue for such rare isolates. Arbune used the Vitek 2 automated system to identify Elizabethkingia meningoseptica. However, discrepancies in identification by the Vitek2 system have been reported in the published literature. In a study by Carvalho et al. (2017) [2], an isolate of Chryseobacterium indologenes was misidentified as Elizabethkingia meningoseptica by a Vitek 2 system with 99 % certainty of identification. Lau et al. (2016 ) [3] reported seventeen isolates of Elizabethkingia anopheles and one isolate of E. miricola confirmed by 16S rRNA sequencing, all having been misidentified by Vitek 2 as E. meningoseptica. These included CSF isolates from three cases of neonatal meningitis. In a study by Lau et al. (2015) [4], three isolates including two CSF samples from neonatal meningitis cases that were later confirmed as E. anophelis by whole genome sequencing were initially misidentified as E. meningoseptica by the Vitek 2 system. Lo and Chang (2014) [5] also reported a 16S rRNA confirmed Chryseobacterium gleum isolate having been misidentified as E. meningoseptica by the Vitek 2 system.

l meningitis cases that were later confirmed as E. anophelis by whole genome sequencing were initially misidentified as E. meningoseptica by the Vitek 2 system. Lo and Chang (2014) [5] also reported a 16S rRNA confirmed Chryseobacterium gleum isolate having been misidentified as E. meningoseptica by the Vitek 2 system. The above data indicate that the Vitek 2 automated system has a high positive predictive value but also a variable number of false positives concerning the identification of Elizabethkingia meningoseptica. It can be concluded that the Vitek 2 system alone is not sufficient for confirmatory identification of this organism and more advanced techniques such as MALDI-TOF MS with its expanded database, as well as molecular techniques such as 16S rRNA gene sequencing and whole genome sequencing (WGS), should be considered for accurate identification. Further comparative studies of these molecular and microbiological techniques, with updated databases to prevent pseudo-identifications leading to false reporting of outbreaks and cases of this unusual pathogen, should be undertaken. Conflicts of interest None declared

Introduction Upper gastrointestinal bleeding can be a severe, life-threatening condition in children, depending on the source, degree and cause of the hemorrhage. The most frequent sources of hematemesis are varices and mucosal gastric and duodenal lesions, often caused by drug ingestion [1]. Moreover, a Romanian study performed on 103 children discovered that the most frequent cause of upper gastrointestinal bleeding was erosive gastritis, which accounted for a third of all cases [2]. According to Deerojanawong et al. (2019) gastrointestinal bleeding is not uncommon among intensive care patients [3], with mechanically ventilated children being at risk of developing gastrointestinal hemorrhage [4]. In children, inadequate nutrition and drugs are cited as more common etiological factors [2,5], compared to adults, where gastrointestinal tumors represent a major cause of digestive bleedings.

Introduction Upper gastrointestinal bleeding can be a severe, life-threatening condition in children, depending on the source, degree and cause of the hemorrhage. The most frequent sources of hematemesis are varices and mucosal gastric and duodenal lesions, often caused by drug ingestion [1]. Moreover, a Romanian study performed on 103 children discovered that the most frequent cause of upper gastrointestinal bleeding was erosive gastritis, which accounted for a third of all cases [2]. According to Deerojanawong et al. (2019) gastrointestinal bleeding is not uncommon among intensive care patients [3], with mechanically ventilated children being at risk of developing gastrointestinal hemorrhage [4]. In children, inadequate nutrition and drugs are cited as more common etiological factors [2,5], compared to adults, where gastrointestinal tumors represent a major cause of digestive bleedings. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for their therapeutic effects which include analgesia, inflammation inhibition and fever suppression [6]. Although NSAIDs can lead to gastrointestinal complications, they are frequently prescribed worldwide [7]. Their primary mechanism of action consists of cyclooxygenase (COX) enzymes inhibition, thus reducing the synthesis of prostaglandins, which play a crucial role in gastroprotective mucus secretion [8]. Therefore, NSAIDs use can lead to several adverse gastrointestinal effects, such as gastric or duodenal ulcer, hemorrhage or perforation [9,10]. These complications are more common in non-selective NSAIDs, which act both on COX1 and COX2, whereas COX2-selective inhibitors tend to lower the risk of gastrointestinal complications [8]. Although NSAIDs represent the most common class of drugs which can cause gastrointestinal tract complications, other substances can also damage the gastric mucosa in children, such as corticosteroids, valproic acid or chemotherapeutic drugs. A rare case of hemorrhagic gastritis induced by oral iron supplements in a teenager female has also been described in the literature [11].

ch can cause gastrointestinal tract complications, other substances can also damage the gastric mucosa in children, such as corticosteroids, valproic acid or chemotherapeutic drugs. A rare case of hemorrhagic gastritis induced by oral iron supplements in a teenager female has also been described in the literature [11]. Ibuprofen, a non-selective COX inhibitor, is commonly used in pediatric patients, not only for its analgesic and antipyretic properties but also for safety reasons, in comparison with other drugs from its class. The guidelines concerning its posology and intervals of administration should be strictly respected in order to avoid adverse gastrointestinal effects [6]. This case report aims to underline the potential severe side-effects related to inappropriate administration of ibuprofen in children. Informed written consent was obtained from the patient’s mother before the publication of this case report.

Ibuprofen, a non-selective COX inhibitor, is commonly used in pediatric patients, not only for its analgesic and antipyretic properties but also for safety reasons, in comparison with other drugs from its class. The guidelines concerning its posology and intervals of administration should be strictly respected in order to avoid adverse gastrointestinal effects [6]. This case report aims to underline the potential severe side-effects related to inappropriate administration of ibuprofen in children. Informed written consent was obtained from the patient’s mother before the publication of this case report. Case report Presenting concerns and case history The case of a 6-year-old-male child, with no significant personal history, admitted to the emergency department of Pediatric Clinic 1, Târgu Mureş, Romania for vomiting, abdominal pain and loss of appetite. At the time of initial admission to the emergency department, it was reported by the parents that the child had experienced ten episodes of vomiting, four of which contained a significant quantity of fresh blood and three of them had the appearance of 'coffee ground'. According to the mother, the patient received three doses of 100 mg ibuprofen, two hours apart from each other, followed by one dose of 190 mg ibuprofen, six hours later. The latter dose was administrated arbitrarily by the mother, in the form of an oral suspension.

three of them had the appearance of 'coffee ground'. According to the mother, the patient received three doses of 100 mg ibuprofen, two hours apart from each other, followed by one dose of 190 mg ibuprofen, six hours later. The latter dose was administrated arbitrarily by the mother, in the form of an oral suspension. Clinical findings The initial clinical examination indicated an altered general health status, pallor of the skin, productive cough, nasal obstruction, hyperemic pharynx and hypertrophic tonsils, mild abdominal tenderness in the epigastric area. The patient weighed 23 kg. Diagnostic focus and assessment The initial laboratory tests revealed the following pathological elements: neutrophilia (91.76%, 10850 cells/μl), lymphocytopenia (3.04%, 360 cells/μl), high levels of lactate dehydrogenase (269 U/l). The hemoglobin (12.7 g/dl) and hematocrit (36.7%) levels were within normal ranges. After a twenty-four-hour period, the hemoglobin levels decreased following parenteral rehydration therapy, reaching a value of 10.3 g/dl.

cells/μl), lymphocytopenia (3.04%, 360 cells/μl), high levels of lactate dehydrogenase (269 U/l). The hemoglobin (12.7 g/dl) and hematocrit (36.7%) levels were within normal ranges. After a twenty-four-hour period, the hemoglobin levels decreased following parenteral rehydration therapy, reaching a value of 10.3 g/dl. An upper digestive endoscopy was performed within the following twelve hours after the admission, which revealed an increased friability of the mucosa, a medium quantity of digested blood in the gastric corpus and fornix; no active bleeding site was identified. These data corresponded to a Forrest II B classification of upper gastrointestinal hemorrhage, (Fig.1 and 2) indicating that no endoscopic intervention was needed. The histopathological examination from the gastric biopsy showed an antral gastric mucosa with lymphoid aggregates and reactive modifications of the corporeal gastric mucosa. There was no evidence of Helicobacter pylori (H. pylori) infection after microscopic evaluation of the gastric biopsies. Fig. 1 The endoscopic aspect of digested blood in gastric corpus Fig. 2 The endoscopic aspect of digested blood in gastric corpus and fornix, but without an active bleeding site Based on these data, a final diagnosis was made of ibuprofen-induced hemorrhagic gastritis.

An upper digestive endoscopy was performed within the following twelve hours after the admission, which revealed an increased friability of the mucosa, a medium quantity of digested blood in the gastric corpus and fornix; no active bleeding site was identified. These data corresponded to a Forrest II B classification of upper gastrointestinal hemorrhage, (Fig.1 and 2) indicating that no endoscopic intervention was needed. The histopathological examination from the gastric biopsy showed an antral gastric mucosa with lymphoid aggregates and reactive modifications of the corporeal gastric mucosa. There was no evidence of Helicobacter pylori (H. pylori) infection after microscopic evaluation of the gastric biopsies. Fig. 1 The endoscopic aspect of digested blood in gastric corpus Fig. 2 The endoscopic aspect of digested blood in gastric corpus and fornix, but without an active bleeding site Based on these data, a final diagnosis was made of ibuprofen-induced hemorrhagic gastritis. Therapeutic focus and assessment Proton pump inhibitor therapy with Pantoprazol 20 mg (Takeda GmbH, Singen, Germany) was started intravenously immediately after admission in one daily dose and was maintained for five days. In order to compensate for the loss of fluids, perfusion with glucose and electrolytes was administered. The patient had two episodes of vomiting during the first night of hospitalization in which no signs of fresh or digested blood were detected. His evolution was favorable the next day, but his cough and rhinorrhea worsened towards the evening. Intravenous clindamycin (S.C. STADA M&D, Timişoara, Romania), 230 mg, three times a day, together with nebulization with acetylcysteine (ZAMBON S.p.A., Vicenza, Italy) and concentrated saline solution (NaCl 3%), lead to an improvement in respiratory symptoms. The patient’s condition slowly improved following this symptomatic treatment, though there was continuing persistent discomfort in the epigastric region accompanied by nausea. There was no recurrence of vomiting during the following two days.

ed saline solution (NaCl 3%), lead to an improvement in respiratory symptoms. The patient’s condition slowly improved following this symptomatic treatment, though there was continuing persistent discomfort in the epigastric region accompanied by nausea. There was no recurrence of vomiting during the following two days. The patient was discharged with the recommendation to continue with the clarithromycin 175 mg (BGP Products S.R.L., Roma, Italy), two times a day for four days together with probiotics – Lactobacillus reuteri (Ewopharma International, Gothenburg, Sweden). Oral proton-pump inhibitor therapy with 20 mg of esomeprazole (AstraZeneca, GmbH, Wedel, Germany), once a day, was prescribed for thirty days. The adherence to a gastritis diet low in: fats, processed foods, fried meals and smoked products was advised. Follow-up and outcome The patient presented for a check-up one week after discharge. He had an excellent general status without any gastrointestinal complaints in the past week. Laboratory tests were carried out and showed no abnormal changes, except for a mildly elevated erythrocyte sedimentation rate (ESR), of 17 mm/h. Continuation of the prescribed treatment and diet was recommended.

fter discharge. He had an excellent general status without any gastrointestinal complaints in the past week. Laboratory tests were carried out and showed no abnormal changes, except for a mildly elevated erythrocyte sedimentation rate (ESR), of 17 mm/h. Continuation of the prescribed treatment and diet was recommended. Discussions NSAIDs are generally considered safe drugs for fever management in pediatric cases if they are administered properly [12,13]. Ibuprofen is one of the most frequently used NSAIDs in pediatric cases due to its anti-inflammatory and antipyretic properties. The recommended posology for fever suppression is 5-10 mg/kg/ dose by mouth, every 6-8 hours, with a maximum total dose of 40 mg/kg/day [6]. In the above-described case, the patient had initially received three doses of ibuprofen, in lower amounts than the minimum recommended dose for fever control. However, the mother had not respected the intervals between the three initial doses, by administering oral ibuprofen every two hours. This could have been a risk factor for the adverse event that followed, although data in the literature describes several cases of gastrointestinal bleeding following intake of small doses of ibuprofen at appropriate intervals. Berezin et al. (2007) described a case series of four children, in which three of them received one dose of ibuprofen and one received two doses, and although the posology was appropriate, all of them developed hematemesis due to gastric antral ulcers [12]. Vaquero Sosa et al. (2013) reported on a study involving nine patients aged between 21 months and five years who had presented with upper gastrointestinal bleeding after two to four doses of ibuprofen. Only one of them had developed a superficial gastric ulcer, the others being diagnosed with acute hemorrhagic gastritis. Anemia or coagulopathies were not found in any of the children enrolled in the study, as was the case of our patient at the time of admission [14]. However, severe cases of gastrointestinal bleeding in children have also been published in the literature, Anyanwu et al. (2013) reported two cases of children presenting with melena associated with severe anemia. Both cases had a history of ibuprofen consumption in the past week, but with no precise quantification of the ingested doses. In one of the cases, a perforated ulcer was discovered, which required surgical intervention [15].

al. (2013) reported two cases of children presenting with melena associated with severe anemia. Both cases had a history of ibuprofen consumption in the past week, but with no precise quantification of the ingested doses. In one of the cases, a perforated ulcer was discovered, which required surgical intervention [15]. Additional risk factors can be associated with gastrointestinal bleeding in pediatric patients who had previously ingested NSAIDs, including a family history of peptic ulcers or H. pylori infection [9]. Genetic factors play in important role in children’s’ susceptibility to developing an H. Pylori infection, with various gene polymorphisms of interleukin 6, tumor necrosis factor-alpha and angiotensin-converting enzyme, all increasing the risk of acquiring this bacterium [16]. A single-center study involving 1332 Romanian children reported a unique association between H. pylori infection and acute hemorrhagic gastritis in eight cases [17]. Other recent reports in the literature describe the importance of H. pylori eradication in the evolution of patients with NSAIDs-induced acute hemorrhagic gastritis.[18] Histopathological examination did not identify the presence of H. pylori in the present case. The risk stratification scores for upper gastrointestinal bleedings in children are still under development, and therefore the management of this pathology remains a challenge for pediatricians [19].

Additional risk factors can be associated with gastrointestinal bleeding in pediatric patients who had previously ingested NSAIDs, including a family history of peptic ulcers or H. pylori infection [9]. Genetic factors play in important role in children’s’ susceptibility to developing an H. Pylori infection, with various gene polymorphisms of interleukin 6, tumor necrosis factor-alpha and angiotensin-converting enzyme, all increasing the risk of acquiring this bacterium [16]. A single-center study involving 1332 Romanian children reported a unique association between H. pylori infection and acute hemorrhagic gastritis in eight cases [17]. Other recent reports in the literature describe the importance of H. pylori eradication in the evolution of patients with NSAIDs-induced acute hemorrhagic gastritis.[18] Histopathological examination did not identify the presence of H. pylori in the present case. The risk stratification scores for upper gastrointestinal bleedings in children are still under development, and therefore the management of this pathology remains a challenge for pediatricians [19]. Conclusions Upper gastrointestinal bleeding is a possible adverse outcome of flawed NSAIDs administration. Short interval administration of NSAIDs should be avoided due to possible dose accumulation. Parents should steer clear of administering NSAIDs without consulting their pediatrician regarding posology and intervals of NSAIDs intake. Conflict of interest None to declare.

According to “The Burden of Stroke in Europe” report, Romania had, in 2015, the highest incidence and highest mortality due to stroke per 100,000 inhabitants [1]. Moreover, the Central and Eastern European Stroke Society Working group reported that, in 2015, in Romania, only about 1% of stroke patients had access to stroke units [2].

he Burden of Stroke in Europe” report, Romania had, in 2015, the highest incidence and highest mortality due to stroke per 100,000 inhabitants [1]. Moreover, the Central and Eastern European Stroke Society Working group reported that, in 2015, in Romania, only about 1% of stroke patients had access to stroke units [2]. Critical care professionals are familiar with the phrase “time is brain” and are well aware that even a couple of minutes delay in delivering thrombolytic intravenous treatment or endovascular thrombectomy can have an enormous impact on patients’ survival rates and the length of disability-free life [3,4]. While studies have observed significant improvement regarding the time from onset of stroke symptoms to up-to-date in-hospital therapy [5], access to treatment in specialized stroke units is far from optimal, and thrombolysis remains under-performed, especially in Eastern European countries [1]. Pre-hospital delay, particularly the time from the onset of symptoms to a decision to call the emergency medical services is considered a major cause of missing the therapeutic window of opportunity in the management of acute stroke [5, 6, 7]. Reported studies have identified a large range of reasons that influence pre-hospital delay time. These include socio-demographic characteristics, particular symptoms or their severity, and most importantly, the ability of patients’ or bystanders’ to recognize stroke symptoms at an early stage and promptly activate emergency intervention systems [8, 9, 10]. Both the European Stroke Organization and the American Stroke Association (ASA) strongly recommend the implementation of health education programs to raise the public’s awareness and level of knowledge and preparedness in cases of stroke [11,12], but neither make explicit reference to the internet, the most pervasively used source of health-related information.

he American Stroke Association (ASA) strongly recommend the implementation of health education programs to raise the public’s awareness and level of knowledge and preparedness in cases of stroke [11,12], but neither make explicit reference to the internet, the most pervasively used source of health-related information. In a systematic assessment of the quality of stroke-related information, derived from a sample of 50 Romanian and Hungarian websites, we checked how frequently the ASA’s basic stroke signs and recommendations (“F-A-S-T” acronym) were reported. While speech difficulties were mentioned on 92% of the websites as a sign that may signal the onset of stroke, arm weakness and facial drooping were reported on only 78% and 60% of the websites. Furthermore, only 60% of the websites have specified that stroke is a medical emergency and only 74% of them urged users to call the emergency service without delay. It is also worth mentioning that despite the recognition of medical hoaxes, rumors and frauds [13], only 22% of the websites warned users not to rely on diagnostic or treatment methods that are not scientifically validated.

medical emergency and only 74% of them urged users to call the emergency service without delay. It is also worth mentioning that despite the recognition of medical hoaxes, rumors and frauds [13], only 22% of the websites warned users not to rely on diagnostic or treatment methods that are not scientifically validated. Given that 71% of internet users in Europe have used the internet to gain health-related information [14], and that a correlation between using the internet for health information and stroke symptoms recognition has been reported [15], it would be wise to contribute as much as possible to the improvement of the quality of online stroke-related information and employ the vast educational potential of the electronic media to reduce pre-hospital delay time in the management of stroke. After all, good online stroke-related information is brain too. Acknowledgement We thank Sorin Săndulache MD, PhD, neurologist at Colentina Hospital, Bucharest, Romania for his valuable input in the development of the quality benchmark for stroke-related websites. Also, we thank Dalma Kasza, David Maior, and Alex-Otniel Popescu, medical students at the University of Medicine and Pharmacy of Tîrgu Mures, Romania for their contribution to data acquisition. Conflict of Interest None to declare

Introduction Since the early 2000s, Abdominal Compartment Syndrome (ACS) has been accepted as a well-defined clinical entity. Monitoring of intra-abdominal pressure (IAP) represents a necessity, particularly in critically ill patients in intensive care units [1]. Moreover, knowing the risk factors that could lead to an increase in intra-abdominal pressure and progression to ACS, IAP monitoring has made it possible to detect early signs of intra-abdominal hypertension (IAH) in patients being treated in intensive care, surgery, internal medicine and cardiology departments. Besides objective methods of measuring intra-abdominal pressure, detailed anamnesis as well as communication skills with the patients is an important factor in identifying possible risk factors [2]. Early detection of ACS is key to obtaining the best results in treating the syndrome [3]. In addition to IAP measuring, imaging methods such as ultrasound and computer tomography aid in flagging-up characteristic signs that may suggest an increase in IAP [4]. ACS treatment, as recommended by the World Society of Abdominal Compartment Syndrome (WSACS), has undergone several changes over time, and since 2006 both conservative therapy and surgical treatment have been added to their guidelines. This review reports on the multidisciplinary approach to ACS, from intensive care and surgical perspectives. The reviews aim is to identify gaps in knowledge and suggested guidelines regarding the diagnosis and treatment of ACS analyzing the results of published studies.

Introduction Since the early 2000s, Abdominal Compartment Syndrome (ACS) has been accepted as a well-defined clinical entity. Monitoring of intra-abdominal pressure (IAP) represents a necessity, particularly in critically ill patients in intensive care units [1]. Moreover, knowing the risk factors that could lead to an increase in intra-abdominal pressure and progression to ACS, IAP monitoring has made it possible to detect early signs of intra-abdominal hypertension (IAH) in patients being treated in intensive care, surgery, internal medicine and cardiology departments. Besides objective methods of measuring intra-abdominal pressure, detailed anamnesis as well as communication skills with the patients is an important factor in identifying possible risk factors [2]. Early detection of ACS is key to obtaining the best results in treating the syndrome [3]. In addition to IAP measuring, imaging methods such as ultrasound and computer tomography aid in flagging-up characteristic signs that may suggest an increase in IAP [4]. ACS treatment, as recommended by the World Society of Abdominal Compartment Syndrome (WSACS), has undergone several changes over time, and since 2006 both conservative therapy and surgical treatment have been added to their guidelines. This review reports on the multidisciplinary approach to ACS, from intensive care and surgical perspectives. The reviews aim is to identify gaps in knowledge and suggested guidelines regarding the diagnosis and treatment of ACS analyzing the results of published studies. Definitions In 2006, the WSACS published a series of definitions they are still valid today [5]. Within these definitions, ACS is defined as an elevated IAP of more than 25 mmHg associated with new organ failure. Trigger factors, located inside of the abdominal cavity, induce a primary ACS, whereas trigger factors, out with the abdomino-pelvic cavity, contribute to the development of a secondary ACS. When abdominal scars and adhesions exist, the IAP varies in different parts of peritoneal cavity, resulting in what is described as polyACS.

tors, located inside of the abdominal cavity, induce a primary ACS, whereas trigger factors, out with the abdomino-pelvic cavity, contribute to the development of a secondary ACS. When abdominal scars and adhesions exist, the IAP varies in different parts of peritoneal cavity, resulting in what is described as polyACS. In addition to well-established definitions, there are a number of recommendations and suggestions that have not been firmly endorsed, and further studies are required to accurately determine the level of implementation. They have been classified according to recommendation or suggestion in grades A to D; A - strongly recommended, D-poorly recommended, with subcategories occurring in each major grouping [5]. Risk factors A number of risk factors for the onset of ACS have been identified from studies, mainly performed in intensive care units. Thus, for primary ACS, the predominant predisposing factors are peritonitis, pancreatitis and abdominal trauma, and for secondary ACS, extra-abdominal sepsis is the major contributing factor (Table I) [5, 6, 7, 8, 9, 10]. Table I Risk factors for the occurrence of primary and secondary ACS

Risk factors A number of risk factors for the onset of ACS have been identified from studies, mainly performed in intensive care units. Thus, for primary ACS, the predominant predisposing factors are peritonitis, pancreatitis and abdominal trauma, and for secondary ACS, extra-abdominal sepsis is the major contributing factor (Table I) [5, 6, 7, 8, 9, 10]. Table I Risk factors for the occurrence of primary and secondary ACS Primary ACS Secondary ACS Severe intra-abdominal infection Sepsis Pancreatitis Large-volume fluid replacement Blunt/penetrating trauma Burns Ruptured abdominal aortic aneurysm Dialysis Postoperative bleeding Obesity Retroperitoneal hemorrhage Postoperative closure of the abdomen Undertension Ascites Ileus Pregnancy Pathophysiology The mechanisms of increased IAP are tissue edema, bowel and mesenteric edema, retroperitoneal space edema, and ascites after capillary leakage. IAH will lead to capillary compression which leads to intestinal ischemia [3,11]. Cardiovascular function is severely affected by the decreased preload due to inferior vena cava compression, which will lead to ischemia and hypoxia in all tissues [11,12]. A high position of the diaphragm and a decreased compliance of the thoracic wall will induce hypoxia, increased pleural pressure and accumulation of intrapleural fluid [13]. Compression on the inferior vena cava and renal veins leads to alterations of the glomerular filtration rate [11,12]. Liver function is also severely affected by ischemia, which will activate the Kupffer cells and release inflammatory mediators acting on hepatocytes and sinusoidal cells [14, 15, 16, 17]. In cases of abdominal trauma and ruptured aortic aneurisms, the high pressure from affected vessels will rapidly lead to the accumulation of blood inside of peritoneal cavity, and a rapid progression to ACS due to the rapid pressure changes of IAP [18,19].

rs acting on hepatocytes and sinusoidal cells [14, 15, 16, 17]. In cases of abdominal trauma and ruptured aortic aneurisms, the high pressure from affected vessels will rapidly lead to the accumulation of blood inside of peritoneal cavity, and a rapid progression to ACS due to the rapid pressure changes of IAP [18,19]. Diagnosis Measurement of IAP was recommended after recognition of severe effects of increased IAP and due to a low sensitivity of the whole series of clinical examinations tests [20]. The main variants of IAP measurement are presented in Table II [21]. Tabel II IAP measurements methods Direct IAP measurement methods Indirect IAP measurement methods Recording the values transmitted by an intraabdominal Urinary bladder pressure catheter Intragastric pressure Pressure inside the colon Intrautherine pressure Inferior vena cava pressure The direct method is the most sensitive in determining PIA values. It is an invasive one, not without complications [22]. Laparoscopy allows the direct recording of IAP throughout the surgical procedure and allows the pneumoperitoneum pressure to be controlled. Studies related to the negative impact of intra-abdominal hypertension on body systems have been correlated with establishing the standard value of pneumoperitoneum pressure commonly used in laparoscopic interventions at 12 mmHg - capillary perfusion pressure [23].

allows the pneumoperitoneum pressure to be controlled. Studies related to the negative impact of intra-abdominal hypertension on body systems have been correlated with establishing the standard value of pneumoperitoneum pressure commonly used in laparoscopic interventions at 12 mmHg - capillary perfusion pressure [23]. The gold standard of IAP’s indirect measurement is the monitoring of intravesical pressure, which is currently the most commonly used method [24,25]. There are several methods of measuring IAP by a transvesical approach. The first to be used was that described by Kron (1984) [22] in which the bladder wall was considered to be acting as a membrane pressure transducer. After the intravesical injection of 20 ml saline, the IAP is measured by a needle connected to a pressure manometer [26]`. Based on this technique, the continuous monitoring system of the IAP was developed. An easier but not so precise technique is the Harahill method, where the IAP values are read from a scale following the same principles as PVC measurement. The column of fluid elevated in a tube perpendicular to the body above the pubic symphysis and connected to the uretrovesical catheter represents the IAP value. In later studies it was concluded that the urinary bladder wall acts as a pressure transducer only when it contains 25 ml of liquid. Continuous monitoring of IAP using the transvesical approach involves the use of a three-way uretrovesical catheter, irrigating the urinary bladder continuously with a steady flow of 25 ml saline solution. The transducer between the urinary catheter and a monitor, displays real-time intravesical pressure [27].

liquid. Continuous monitoring of IAP using the transvesical approach involves the use of a three-way uretrovesical catheter, irrigating the urinary bladder continuously with a steady flow of 25 ml saline solution. The transducer between the urinary catheter and a monitor, displays real-time intravesical pressure [27]. Although theoretical use of the transurethral approach pathway could lead to urinary tract infections, Cheatman (2006) reported on 3108 critical patients of whom 122 had their IAP measured by a transvesical approach. It was found that the technique itself does not leads to the development of urinary infections in a higher proportion to those resulting from the simple catheterization of the bladder[28].

tract infections, Cheatman (2006) reported on 3108 critical patients of whom 122 had their IAP measured by a transvesical approach. It was found that the technique itself does not leads to the development of urinary infections in a higher proportion to those resulting from the simple catheterization of the bladder[28]. Early detection of ACS by imaging methods has also been reported as being satisfactory. Cavaliere et al. (2011) simulated intraabdominal hypertension in a group of sixteen healthy volunteers and evaluated ultrasonographically the size of the inferior cava vein, the flow through it and renal circulation. They concluded that IAH simulation was associated with decreased inferior vena cava cross-section area and an increased resistive index in renal arteries [29]. Pereira et al. (2017) reporting on a group of fifty critically ill patients who developed IAH, showed that the point of care ultrasound (POCUS) proved to be extremely useful in evaluation of bowel activity, identification of large intestinal contents, the identification of patients who would benefit from bowel evacuation as an adjuvant to lower IAP and the diagnosis of moderate to large amounts of free intra-abdominal fluid [30]. Echocardiography can detect indirect but non-specific signs of ACS, decreased preload as well as dysfunctions of systolic and diastolic ventricular functions [31]. Ignarra et al. (2011), after having performed a CT contrast scanning in fifty patients with IAH, observed some specific signs of elevated intraabdominal pressure. In eight patients there was elevation of the diaphragm, in five patients there was the “round belly sign”, in seven patients there was the presence of free fluid and air in the intraperitoneal and retroperitoneal spaces, in six patients there was collapse ot the inferior vena cava , in four patients there was hyperenhancement and thickening of the intestine bowel wall, an in another twenty, an elevated hepatic artery resistance index Color-Doppler with reversed diastolic flow [4].

air in the intraperitoneal and retroperitoneal spaces, in six patients there was collapse ot the inferior vena cava , in four patients there was hyperenhancement and thickening of the intestine bowel wall, an in another twenty, an elevated hepatic artery resistance index Color-Doppler with reversed diastolic flow [4]. Treatment Conservative treatment ACS conservative therapy should follow the WSACS Guidelines and must be initiated as soon as possible [32]. Reports on the incidence of ACS mortality indicate that without treatment the mortality is higher than 90%, and despite the administration of therapeutic measures, the mortality is between 25 and 75% [33]. The most important therapeutic measures are sedation, 0 or negative balance fluid resuscitation, nasogastric and rectal probe and neuromuscular blockade. Surgical treatment Decompressive laparotomy (DL) is of particular importance in the ACS, reducing the mortality by between 16% and 37% [11] (Table III) Table III The ACS mortality rates quoted by different authors in the specific literature after decompressive laparotomy [11,34-37]

Treatment Conservative treatment ACS conservative therapy should follow the WSACS Guidelines and must be initiated as soon as possible [32]. Reports on the incidence of ACS mortality indicate that without treatment the mortality is higher than 90%, and despite the administration of therapeutic measures, the mortality is between 25 and 75% [33]. The most important therapeutic measures are sedation, 0 or negative balance fluid resuscitation, nasogastric and rectal probe and neuromuscular blockade. Surgical treatment Decompressive laparotomy (DL) is of particular importance in the ACS, reducing the mortality by between 16% and 37% [11] (Table III) Table III The ACS mortality rates quoted by different authors in the specific literature after decompressive laparotomy [11,34-37] Author Year No. of patients Study type Mortality J.J De Waale 2006 250 Retrospective 49.2% J.J De Waale 2010 18 Retrospective 36% Davis et al 2013 45 Prospective 24% Divarci et al 2014 150 Prospective 16% Hwabejire et al 2015 122 Retrospective 37.7% J.J De Waale 2016 33 Prospective 36% Muresan et al 2016 66 Prospective 27.3% An “open abdomen” is a fraught and difficult solution in the treatment of ACS, both in terms of the temporary and the permanent closure. DL is part of the ACS treatment algorithm established by WSACS. [32] However, DL is rarely performed as conservative treatment shows good results in a proportion of patients developing ACS. In Cheatham’s study (2011) on 265 patients with ACS, only sixty-two needed DL, and thirty-one underwent percutaneous decompressive laparotomy (Table IV) [38].

Author Year No. of patients Study type Mortality J.J De Waale 2006 250 Retrospective 49.2% J.J De Waale 2010 18 Retrospective 36% Davis et al 2013 45 Prospective 24% Divarci et al 2014 150 Prospective 16% Hwabejire et al 2015 122 Retrospective 37.7% J.J De Waale 2016 33 Prospective 36% Muresan et al 2016 66 Prospective 27.3% An “open abdomen” is a fraught and difficult solution in the treatment of ACS, both in terms of the temporary and the permanent closure. DL is part of the ACS treatment algorithm established by WSACS. [32] However, DL is rarely performed as conservative treatment shows good results in a proportion of patients developing ACS. In Cheatham’s study (2011) on 265 patients with ACS, only sixty-two needed DL, and thirty-one underwent percutaneous decompressive laparotomy (Table IV) [38]. Table IV The main indications for open abdomen [33, 39, 40]

Author Year No. of patients Study type Mortality J.J De Waale 2006 250 Retrospective 49.2% J.J De Waale 2010 18 Retrospective 36% Davis et al 2013 45 Prospective 24% Divarci et al 2014 150 Prospective 16% Hwabejire et al 2015 122 Retrospective 37.7% J.J De Waale 2016 33 Prospective 36% Muresan et al 2016 66 Prospective 27.3% An “open abdomen” is a fraught and difficult solution in the treatment of ACS, both in terms of the temporary and the permanent closure. DL is part of the ACS treatment algorithm established by WSACS. [32] However, DL is rarely performed as conservative treatment shows good results in a proportion of patients developing ACS. In Cheatham’s study (2011) on 265 patients with ACS, only sixty-two needed DL, and thirty-one underwent percutaneous decompressive laparotomy (Table IV) [38]. Table IV The main indications for open abdomen [33, 39, 40] General condition Open abdomen strong indication Trauma Prevention and treatment of IAH/ACS Need for a “second look” operation Post-injury septic abdomen Loss of abdominal wall Abdominal sepsis Peritonitis after perforations Peritonitis after anastomotic fistulas Severe acute pancreatitis Necrotizing pancreatitis Infected necrotizing pancreatitis Hemorrhagic necrotizing pancreatitis Abdominal Compartment Syndrome (ACS) Primary ACS Secondary ACS Recurrent ACS Severe ileus High fixation in frozen abdomen The solutions preventing complications of open abdomen (OA) surgery are diverse and have developed concomitantly with the evolution of this new therapeutic concept. Among the many surgery variants for Temporary Abdominal Closure (TAC), only a few have been incorporated into standard medical practice and include closing the skin over the bowels and omentum with clamps, use of a Bogota bag and the Whitman technique [41, 42, 43]. The method of wound aspiration by creating negative pressure has been proven to have the best results, accomplishing several of the goals of TAC management. Based on the technique of Brock and Barker (1995) the development of dedicated vacuum therapy kits was introduced. [44,45] The TAC approach using negative pressure wound therapy (NPWT) technique conforms with 1B WSACS recommendation of OA management [32]. The final closure is related to the formerly used TAC. If visceral protection with epiploon can be performed, or if the granulation tissue is sufficiently well developed after NPWT, polypropylene meshes can be applied over granulated tissue. Safe alternatives are dual meshes, sutured to the aponeurotic edges and applied over the viscera [46,47]. Biological materials offer a possible solution, but they are laborious and can give rise to postoperative complications due to graft necrosis. Modern cross-linked and non-cross-linked meshes, manufactured in the laboratory, are very expensive at present [48, 49, 50].

neurotic edges and applied over the viscera [46,47]. Biological materials offer a possible solution, but they are laborious and can give rise to postoperative complications due to graft necrosis. Modern cross-linked and non-cross-linked meshes, manufactured in the laboratory, are very expensive at present [48, 49, 50]. Conclusions Despite the new therapeutic protocols recently introduced, ACS remains an entity resulting in a high mortality. Primary ACS occurs most often after the contamination of the abdominal cavity. Decompressive laparotomy is a necessary therapeutic solution in the complex treatment of ACS, improving the prognosis. DL aims both to release the intra-abdominal pressure, and to treat the underlying disease. The open abdomen management is based on eliminating secretions, protecting the viscera and avoiding lateral musculoaponeurotic retraction. Vacuum-assisted wound therapy encounters all above requirements (grade 1B) according with WSACS Guidelines of 2013. Conflict of interest None to declare. Abbreviations ACS: Abdominal Compartment Syndrome IAP: Intra-Abdominal Pressure IAH: Intra-Abdominal Hypertension WSACS: World Society of Abdominal Compartment Syndrome DL: Decompressive Laparotomy OA:Open Abdomen

Introduction Lung protective mechanical ventilation (LPV) even in patients with healthy lungs is associated with a lower incidence of postoperative pulmonary complications (PPC), resulting in better outcomes, shorter length of hospital stay, and lower healthcare-associated costs [1,2]. The multifactorial pathophysiology of ventilator-induced lung injury (VILI), the surgery, the anaesthesia and the patient-related risk factors of PPCs have been widely reported in the literature [3, 4, 5, 6, 7]. Based on this, the concept of perioperative lung protective management emerged, including preoperative breathing physiotherapy, positive pressure respiratory support, prophylactic perioperative positive pressure ventilation (POP-ventilation), continuous positive airway pressure (CPAP), non-invasive ventilation (NIV), intraoperative LPV, applying low tidal volumes, moderate levels of positive end-expiratory pressure (PEEP) and regular ARM has been elaborated [8,9,10]. Despite the well-known advantages, Schultz MJ et al. (2017) concluded that intraoperative LPV is still not widely implemented in everyday anaesthesia practice even in high-risk surgical patients and it has been suggested that much more attention should be given to the use of lung protective strategies during general anaesthesia [11,12].

nown advantages, Schultz MJ et al. (2017) concluded that intraoperative LPV is still not widely implemented in everyday anaesthesia practice even in high-risk surgical patients and it has been suggested that much more attention should be given to the use of lung protective strategies during general anaesthesia [11,12]. Several differences are known to exist between Eastern and Western Europe health care systems and patient management[13]. As no data exists from Eastern Europe, including Hungary, a decision was made to survey members of the Hungarian Society of Anaesthesiology and Intensive Therapy (HSAIT) regarding the routine anaesthetic care, awareness and adherence to the LPV concept during major abdominal surgery. Materials and Methods A questionnaire of thirty-six “mandatory-to-answer” multiple-choice questions divided into five sections had been prepared and tested on a pilot sample of three expert anaesthesiologists to check the clarity and validity of the questions and to estimate the completion time of the survey. Agreement of any ethics committee was not necessary as the questionnaire was about the professional practice of anaesthesiologists, and participation was voluntary and anonymous. There were no exclusion criteria and the study complied with the survey-reporting list.

ns and to estimate the completion time of the survey. Agreement of any ethics committee was not necessary as the questionnaire was about the professional practice of anaesthesiologists, and participation was voluntary and anonymous. There were no exclusion criteria and the study complied with the survey-reporting list. After the questionnaire was considered appropriate, Hungarian anaesthesiologists were invited by email and by a newsletter, to participate in an online survey between January 1st to March 31st, 2018, using the public e-mail database of the Hungarian Hospital Federation (Magyar Kórházszövetség). A cover letter containing the investigators’ names and contact details, the objectives, aims and methodology of the study was attached. The online questionnaire was published using Google Forms (Google Inc., Mountain View, CA).

ng the public e-mail database of the Hungarian Hospital Federation (Magyar Kórházszövetség). A cover letter containing the investigators’ names and contact details, the objectives, aims and methodology of the study was attached. The online questionnaire was published using Google Forms (Google Inc., Mountain View, CA). Demographic data of respondents, routine preoperative, intraoperative and postoperative pulmonary management and opinions of participants about the risk factors of PPCs were evaluated in different sections. The primary endpoint was the frequency of consistent application of the three basic elements of LPV: low tidal volume (TV) ≤ 6 ml/kg ideal body weight (IBW), PEEP of 6 cmH2O at least and regular ARMs. Secondary endpoints were the respiratory rate, application of permissive hypercapnia [end tidal carbon dioxide tension (EtCO2) 35-40 mmHg], low plateau pressure (Pplat < 25 cmH2O) and low driving pressure (ᐃPaw < 20 cmH2O), use of neuromuscular blocking agent antagonists (NMBA-A) and prevalence of perioperative pulmonary management protocols. The tertiary endpoint was the opinion of respondents about the risk factors of PPCs. The difference, if any, in the way trainees and specialists practised and the difference in the standard of care between university hospitals and other hospitals was assessed. Statistical analysis Data are expressed as the number and percentage of survey respondents with associated 95% confidence interval (CI). Odds ratios (OR) were calculated and the level of significance set at α =0.05.

The difference, if any, in the way trainees and specialists practised and the difference in the standard of care between university hospitals and other hospitals was assessed. Statistical analysis Data are expressed as the number and percentage of survey respondents with associated 95% confidence interval (CI). Odds ratios (OR) were calculated and the level of significance set at α =0.05. MedCalc Statistical Software v14.8.1 (MedCalc Software bvba, Ostend, Belgium) was used for statistical analysis. Results Demographic Data Ten institutions from the 117 hospitals stated that they do not perform major abdominal surgery. In total, 111 anaesthesiologists completed the survey, 25 (22.5%) after the first e-mail and 86 (77.5%) after the newsletter published on the website. The survey population’s professional details and demographic characteristics are summarised in Table 1. Most of the anaesthesiologists worked in hospitals with significant patient turnover [> 300 major abdominal surgeries annually, 72 (64.9%)]. 24 (21.6%) of the respondents worked in university medical centres of which 89 (80.2%) were specialists. 70 (63.1%) of these had more ten years of surgical experience. Table 1 Demographic data and respondents’ professional details

The survey population’s professional details and demographic characteristics are summarised in Table 1. Most of the anaesthesiologists worked in hospitals with significant patient turnover [> 300 major abdominal surgeries annually, 72 (64.9%)]. 24 (21.6%) of the respondents worked in university medical centres of which 89 (80.2%) were specialists. 70 (63.1%) of these had more ten years of surgical experience. Table 1 Demographic data and respondents’ professional details n (=111) % Type of institution University medical centre 24 21.6 Hospital in capital 30 27.1 County hospital 44 39.6 Other hospitals 13 11.7 Respondents’ post Specialist candidate (trainees) 22 19.8 Specialist 58 52.3 Chief medical officer 31 27.9 Length of practice in anaesthesia < 5 yrs 20 18.0 5 – 10 yrs 21 18.9 > 10 yrs 70 63.1 The annual number of major abdominal surgery per centre < 100 6 5.4 100 – 200 11 9.9 200 – 300 22 19.8 300 – 400 12 10.8 > 400 60 54.1 Data are expressed as the number and percentage of respondents Primary Endpoint 61 (54.9%) (95% CI 48.7 – 78.4) of the anaesthesiologists applied low tidal volume (TV) of less than 6 ml/kg) and 67 (60.4%) [95% CI 51.9 – 85.1] used ideal body weight (IBW) to determine the appropriate TV (Figure 1).

n (=111) % Type of institution University medical centre 24 21.6 Hospital in capital 30 27.1 County hospital 44 39.6 Other hospitals 13 11.7 Respondents’ post Specialist candidate (trainees) 22 19.8 Specialist 58 52.3 Chief medical officer 31 27.9 Length of practice in anaesthesia < 5 yrs 20 18.0 5 – 10 yrs 21 18.9 > 10 yrs 70 63.1 The annual number of major abdominal surgery per centre < 100 6 5.4 100 – 200 11 9.9 200 – 300 22 19.8 300 – 400 12 10.8 > 400 60 54.1 Data are expressed as the number and percentage of respondents Primary Endpoint 61 (54.9%) (95% CI 48.7 – 78.4) of the anaesthesiologists applied low tidal volume (TV) of less than 6 ml/kg) and 67 (60.4%) [95% CI 51.9 – 85.1] used ideal body weight (IBW) to determine the appropriate TV (Figure 1). Fig. 1 Use of low tidal volume (TV) and ideal body weight (IBW) to determine the appropriate TV are common: 54.9% of respondents apply a low TV of 6 ml/kg or less and 60% of them use IBW. However, applying a TV of 7 ml/kg is also frequent and 38% of respondents use actual or estimated body weight to determine the appropriate TV and 2% of them do not take the patient’s weight into account (RBW). None of the respondents used zero PEEP, 54 [48.6% (95% CI 40.6 – 70.5)] always used lower levels of PEEP and 58(52.3%) [95% CI 44.0 – 74.9] never performed a PEEP titration procedure to determine the optimal levels of PEEP. Higher (6-10 cmH2O) or individually titrated levels of PEEP were more common during anaesthesia in obese patients with a BMI greater than 30 kg/m2 (Figure 2).

– 70.5)] always used lower levels of PEEP and 58(52.3%) [95% CI 44.0 – 74.9] never performed a PEEP titration procedure to determine the optimal levels of PEEP. Higher (6-10 cmH2O) or individually titrated levels of PEEP were more common during anaesthesia in obese patients with a BMI greater than 30 kg/m2 (Figure 2). Fig. 2 None of the respondents apply zero positive end-expiratory pressure (PEEP) during mechanical ventilation. Half of the respondents commonly use lower levels of PEEP (48.6%), and only 36.1% apply an individually optimal level of PEEP determined during a PEEP titration procedure. In contrast to these results, presumably based on pathophysiological rationality, both moderate (6-10 cmH2O, 37.8%) and individually titrated levels of PEEP (40.5%) are commonly considered appropriate for obese patients (body mass index greater than 30 kg/m2). The most commonly used PEEP titration procedure, used by 32 (28.8%) of respondents, was the “pressure-volume curve determined method” and the “fraction of inspired oxygen” (FiO2) adapted PEEP was by 20 (18%). Neither Electrical Impedance Tomography (EIT) nor oesophageal pressure monitoring were available during anaesthetic care according to respondents. The use of ARMs after induction of anaesthesia and endotracheal intubation during general anaesthesia and before the removal of the endotracheal tube is summarised in Figure 3.

The most commonly used PEEP titration procedure, used by 32 (28.8%) of respondents, was the “pressure-volume curve determined method” and the “fraction of inspired oxygen” (FiO2) adapted PEEP was by 20 (18%). Neither Electrical Impedance Tomography (EIT) nor oesophageal pressure monitoring were available during anaesthetic care according to respondents. The use of ARMs after induction of anaesthesia and endotracheal intubation during general anaesthesia and before the removal of the endotracheal tube is summarised in Figure 3. Fig. 3 Routine and regular use of alveolar recruitment manoeuvres (ARM) is rare after endotracheal intubation (8.1%), during general anaesthesia (10.8%) and prior to extubation procedure (10.8%). Based on our data ARM is a procedure for high-risk patients (33.3%) and usually used during anaesthesia when a decreasing oxygen saturation is detected (32.4%). Approximately 20-30% of respondents never use ARM during any phase of general anaesthesia. 30 (27%) [95% CI 20.2 – 42.8)] of all the anaesthesiologists applied the three basic elements of LPV, but only 6(5.4%) [95% CI 2.2 – 13.1] applied ARMs regularly every 30 or 60 minutes. Although there were obvious practice variations between doctors and institutes, there were no statistically significant differences neither in the intraoperative pulmonary management practice of trainees and specialists nor in the practice of university centres and other hospitals. Results are summarised in Table 2 and Figure 4.

here were obvious practice variations between doctors and institutes, there were no statistically significant differences neither in the intraoperative pulmonary management practice of trainees and specialists nor in the practice of university centres and other hospitals. Results are summarised in Table 2 and Figure 4. Fig. 4 Forest plot for the application of the basic elements of lung-protective ventilation. Differences between groups with P values less than 0.05 were considered significant. Despite obvious practice variations were evaluated between trainees and specialist, these differences were not significant statistically. Table 2 Use of the basic elements of lung protective ventilation

Fig. 4 Forest plot for the application of the basic elements of lung-protective ventilation. Differences between groups with P values less than 0.05 were considered significant. Despite obvious practice variations were evaluated between trainees and specialist, these differences were not significant statistically. Table 2 Use of the basic elements of lung protective ventilation Trainees Specialists n (=22) % n (=89) % OR (95% CI) p Low TV (≤ 6 mL/kg) 8 36.4 53 59.6 2.58 (0.98 – 6.77) 0.0549 Applies IBW 11 50.0 56 62.9 1.70 (0.66 – 4.34) 0.2701 PEEP < 6 cmH2O 12 54.5 42 47.2 0.74 (0.29 – 1.90) 0.5374 Never applies a PEEP titration procedure 12 54.5 45 50.6 0.85 (0.33 – 2.17) 0.7380 Never applies ARM after intubation 4 18.2 21 23.6 1.39 (0.42 – 4.56) 0.5874 Never applies ARM during anaesthesia 4 18.2 18 20.2 1.14 (0.34 – 3.79) 0.8297 Never applies ARM before extubation 8 36.4 27 30.3 0.76 (0.29 – 2.03) 0.5866 Applies ARM regularly during anaesthesia 2 9.1 10 11.2 1.27 (0.26 – 6.24) 0.7721 Targeted ARM (if SpO2 < 96%) during anaesthesia 8 36.4 28 31.5 0.80 (0.30 – 2.13) 0.6604 Applies the entire LPV concept 6 27.3 24 26.9 1.01 (0.36 – 2.89) 0.9769 TV = tidal volume, IBW = ideal body weight, PEEP = positive end-expiratory pressure, ARM = alveolar recruitment manoeuvres, SpO2 = oxygen saturation, LPV = lung protective ventilation, OR = odds ratio, 95% CI = 95% confidence intervals

2.13) 0.6604 Applies the entire LPV concept 6 27.3 24 26.9 1.01 (0.36 – 2.89) 0.9769 TV = tidal volume, IBW = ideal body weight, PEEP = positive end-expiratory pressure, ARM = alveolar recruitment manoeuvres, SpO2 = oxygen saturation, LPV = lung protective ventilation, OR = odds ratio, 95% CI = 95% confidence intervals Secondary Endpoints More than half of respondents. 66(59.5%) [95% CI 51.0 – 83.9] applied permissive hypercapnia (EtCO2 = 35-40 mmHg) during surgery and the great majority, 86 (77.5%) [95% CI 68.8 – 106.2] determined the appropriate respiratory rate based on capnography. Application of low plateau pressure (Pplat) and low ᐃPaw were 40.5% [45 (95% CI 32.8 – 60.2)] and the difference in the application of these two parameters between trainees and specialists was statistically significant [OR: 4.81 (95% CI 1.51 – 15.36) p=0.0079; OR: 4.50 (95% CI 1.69 – 11.99) p=0.0026] (Table 3 and Figure 5). Most patients, 93.7% [95% CI 84.9 – 126.0] were extubated in the operating theatre. The use of nondepolarizing neuromuscular blocking agents (NMBA-As) nondepolarizing neuromuscular blocking agents Fig. 5 Forest plot for the application of the other elements of lung-protective ventilation. Differences between groups with P values less than 0.05 were considered significant. Differences in the application of low Pplat and low dPaw between trainees and specialists was statistically significant. Application of these two target parameters are more common among specialists. Table 3 Use of other elements of lung protective ventilation

Fig. 5 Forest plot for the application of the other elements of lung-protective ventilation. Differences between groups with P values less than 0.05 were considered significant. Differences in the application of low Pplat and low dPaw between trainees and specialists was statistically significant. Application of these two target parameters are more common among specialists. Table 3 Use of other elements of lung protective ventilation Trainees Specialists n (=22) % n (=89) % OR (95% CI) p Use of permissive hypercapnia 14 63.6 52 58.4 0.80 (0.31 – 2.11) 0.6562 Appropriate RR based on EtCO2 17 77.3 69 77.5 1.01 (0.33 – 3.09) 0.9795 Pplat < 25 cmH2O 4 18.2 46 51.7 4,81 (1.51 – 15.36) 0.0079 dPaw < 20 cmH2O 4 18.2 25 28.1 4,50 (1.69 – 11.99) 0.0026 RR = respiratory rate, EtCO2 = end-tidal carbon dioxide tension, Pplat = plateau pressure, dPaw = driving pressure, OR = odds ratio, 95% CI = 95% confidence intervals (NMBA-As) was common, but only 19 [17.1% (95% CI 11.4 – 29.7)] respondents considered the necessity of these agents based on neuromuscular transmission monitoring (NMT). Also, 8.1% of respondents considered “head lifting test” to be appropriate.

Trainees Specialists n (=22) % n (=89) % OR (95% CI) p Use of permissive hypercapnia 14 63.6 52 58.4 0.80 (0.31 – 2.11) 0.6562 Appropriate RR based on EtCO2 17 77.3 69 77.5 1.01 (0.33 – 3.09) 0.9795 Pplat < 25 cmH2O 4 18.2 46 51.7 4,81 (1.51 – 15.36) 0.0079 dPaw < 20 cmH2O 4 18.2 25 28.1 4,50 (1.69 – 11.99) 0.0026 RR = respiratory rate, EtCO2 = end-tidal carbon dioxide tension, Pplat = plateau pressure, dPaw = driving pressure, OR = odds ratio, 95% CI = 95% confidence intervals (NMBA-As) was common, but only 19 [17.1% (95% CI 11.4 – 29.7)] respondents considered the necessity of these agents based on neuromuscular transmission monitoring (NMT). Also, 8.1% of respondents considered “head lifting test” to be appropriate. On the one hand, during the preoperative assessment, a large number of examinations such as chest X-ray, spirometry and arterial blood gas analysis (ABGA), were carried out, mainly in high-risk patients. On the other hand, substantive interventions such as breathing physiotherapy and positive pressure ventilatory support (CPAP) and non-invasive ventilation (NIV) were not reported in the survey. (Table 4). The same holds for postoperative care. Table 4 Preoperative assessment: examinations and prescribed interventions

On the one hand, during the preoperative assessment, a large number of examinations such as chest X-ray, spirometry and arterial blood gas analysis (ABGA), were carried out, mainly in high-risk patients. On the other hand, substantive interventions such as breathing physiotherapy and positive pressure ventilatory support (CPAP) and non-invasive ventilation (NIV) were not reported in the survey. (Table 4). The same holds for postoperative care. Table 4 Preoperative assessment: examinations and prescribed interventions Physiotherapy Chest X-ray Spirometry ABGA PPPVS Always 3 (2.7) 46 (41.1) 0 (0) 7 (6.3) 0 (0) In patients with COPD 49 (43.8) 44 (39.3) 101 (90.2) 63 (56.3) 8 (7.1) In patients with bronchial asthma 25 (22.3) 30 (26.8) 84 (75.0) 22 (19.6) 3 (2.7) Inactive smokers 18 (16.1) 22 (19.6) 18 (16.1) 10 (8.9) 0 (0) In case of actual intermittent respiratory disease 11 (9.8) 38 (33.9) 30 (26.8) 25 (22.3) 5 (4.5) In patients with abnormal chest X-ray or lung CT scan 17 (15.2) n/a 47 (42.0) 24 (21.4) 2 (1.8) If low SpO2 (< 96%) is observed during an assessment 20 (17.9) 41 (36.6) 46 (41.1) 63 (56.3) 7 (6.3) Prior to acute or vital surgery n/a 16 (14.3) n/a 45 (40.2) 7 (6.3) Never prescribed 56 (50) 9 (8) 6 (5.4) 9 (8.0) 96 (85.7) Data are expressed as the number (and percentage) of answers. COPD = chronic obstructive pulmonary disease, CT = computer tomography, SpO2 = oxygen saturation, ABGA = arterial blood gas analysis, PPPVS = perioperative positive pressure ventilatory support

7 (6.3) Never prescribed 56 (50) 9 (8) 6 (5.4) 9 (8.0) 96 (85.7) Data are expressed as the number (and percentage) of answers. COPD = chronic obstructive pulmonary disease, CT = computer tomography, SpO2 = oxygen saturation, ABGA = arterial blood gas analysis, PPPVS = perioperative positive pressure ventilatory support Written institutional perioperative pulmonary management protocols general were unavailable, regardless of the type of institution (Table 5). Neither CPAP nor NIV were available 24 hours a day in several hospitals, resulting in 45 (40.5%) [95% CI 32.8 – 60.2] of respondents never use POP. Table 5 Availability of perioperative breathing and intraoperative LPV protocols Other hospitals University Medical Centres n (=87) % n (=24) % OR (95% CI) p Availability of perioperative breathing protocols 10 11.5 8 33.3 0.39 (0.14 – 1.10) 0.0747 The absence of perioperative breathing protocols 79 90.8 18 75.0 0.42 (0.14 – 1.28) 0.1262 Availability of intraoperative LPV protocols 6 6.9 2 8.3 0.82 (0.15 – 4.32) 0.8099 The absence of intraoperative LPV protocols 81 93.1 22 91.7 1.22 (0.25 – 6.07) 0.8062 LPV = lung protective ventilation, OR = odds ratio, 95% CI = 95% confidence intervals

ive breathing protocols 79 90.8 18 75.0 0.42 (0.14 – 1.28) 0.1262 Availability of intraoperative LPV protocols 6 6.9 2 8.3 0.82 (0.15 – 4.32) 0.8099 The absence of intraoperative LPV protocols 81 93.1 22 91.7 1.22 (0.25 – 6.07) 0.8062 LPV = lung protective ventilation, OR = odds ratio, 95% CI = 95% confidence intervals Tertiary Endpoints Regarding knowledge about the surgical factors, anaesthetic issues and patient-related risk factors of PPCs, respondents considered that the most critical risk factors are: thoracic and major abdominal surgery, COPD, obesity and residual neuromuscular blockade after surgery. In contrast transplant and intracranial surgery, chronic malnutrition, anaemia and prolonged use of nasogastric tube after surgery were considered negligible risk factors (Table 6). These last three results indicated the lack of early recovery after surgery (ERAS) approach. Table 6 Opinions about the risk factors of postoperative pulmonary complications

Tertiary Endpoints Regarding knowledge about the surgical factors, anaesthetic issues and patient-related risk factors of PPCs, respondents considered that the most critical risk factors are: thoracic and major abdominal surgery, COPD, obesity and residual neuromuscular blockade after surgery. In contrast transplant and intracranial surgery, chronic malnutrition, anaemia and prolonged use of nasogastric tube after surgery were considered negligible risk factors (Table 6). These last three results indicated the lack of early recovery after surgery (ERAS) approach. Table 6 Opinions about the risk factors of postoperative pulmonary complications Risk factors of PPC Considered as important RF n (=111) % 95% CI Thoracic surgery 103 92.8 84.1 – 124.9 Major abdominal surgery 100 90.1 81.4 – 121.6 COPD 109 98.9 90.4 – 132.6 Obesity 97 87.4 78.7 – 118.3 Residual neuromuscular blockade after surgery 106 95.5 86.8 – 128.2 Transplant surgery 42 37.8 30.3 – 56.8 Intracranial surgery 38 33.3 26.1 – 51.0 Chronic malnutrition 39 35.8 28.6 – 54.5 Anaemia 37 33.7 23.5 – 47.5 Prolonged use of NGT after surgery 28 25.3 17.8 – 39.3 PPC = postoperative pulmonary complications, RF = risk factor, COPD = chronic obstructive pulmonary disease, NGT = nasogastric tube, 95% CI = 95% confidence intervals Discussion The questionnaire was designed to evaluate the routine perioperative pulmonary management practice during major abdominal surgery in Hungary. The reporting list described by Story et al., (2017) was used to obtain consistency, clarity, reproducibility and validity of the survey report [14].

Risk factors of PPC Considered as important RF n (=111) % 95% CI Thoracic surgery 103 92.8 84.1 – 124.9 Major abdominal surgery 100 90.1 81.4 – 121.6 COPD 109 98.9 90.4 – 132.6 Obesity 97 87.4 78.7 – 118.3 Residual neuromuscular blockade after surgery 106 95.5 86.8 – 128.2 Transplant surgery 42 37.8 30.3 – 56.8 Intracranial surgery 38 33.3 26.1 – 51.0 Chronic malnutrition 39 35.8 28.6 – 54.5 Anaemia 37 33.7 23.5 – 47.5 Prolonged use of NGT after surgery 28 25.3 17.8 – 39.3 PPC = postoperative pulmonary complications, RF = risk factor, COPD = chronic obstructive pulmonary disease, NGT = nasogastric tube, 95% CI = 95% confidence intervals Discussion The questionnaire was designed to evaluate the routine perioperative pulmonary management practice during major abdominal surgery in Hungary. The reporting list described by Story et al., (2017) was used to obtain consistency, clarity, reproducibility and validity of the survey report [14]. Major abdominal surgery is considered a high-risk intervention associated with the risk of development of PPCs [6,15]. Furthermore, it is often an urgent or vital procedure performed in high-risk patients with serious comorbidities such as cardiovascular and chronic pulmonary diseases, life-threatening intraabdominal infections or malignancies leading to chronic malnutrition. Applying LPV during major abdominal surgery is considered rational or even appropriate.

Major abdominal surgery is considered a high-risk intervention associated with the risk of development of PPCs [6,15]. Furthermore, it is often an urgent or vital procedure performed in high-risk patients with serious comorbidities such as cardiovascular and chronic pulmonary diseases, life-threatening intraabdominal infections or malignancies leading to chronic malnutrition. Applying LPV during major abdominal surgery is considered rational or even appropriate. Advantages of LPV in patients with acute respiratory distress syndrome (ARDS) were described in the early ‘90s leading to intensive research [16, 17, 18]. Amato et al. (1998) found significantly better survival rates in the LPV group than in the conventional ventilatory group, and this finding was strengthened by the investigators of the Acute Respiratory Distress Network (2000) [19,20].

(ARDS) were described in the early ‘90s leading to intensive research [16, 17, 18]. Amato et al. (1998) found significantly better survival rates in the LPV group than in the conventional ventilatory group, and this finding was strengthened by the investigators of the Acute Respiratory Distress Network (2000) [19,20]. Results of the study by Futier et al. (2013) emphasised that LPV during abdominal surgery, even in patients with healthy lungs, is associated with a lower incidence of PPCs, resulted in improved outcomes, shorter length of stay in a hospital and reduced health care utilisation.[1] These findings were confirmed and the multifactorial pathophysiology of VILI and the risk factors of PPCs had been thoroughly evaluated. [2,3,4, 9,10]. Based on this knowledge and the pathophysiological rationale, Futier et al. (2014) established a new integrated approach called “perioperative positive pressure ventilation” (POP concept) to improve pulmonary care [8]. Despite existing evidence, the work of Fischer et al. (2016) indicated that ventilatory management practice in cardiac surgery varied markedly between anaesthesiologists [21]. Colinet et al. (2017) were of the opinion that the use of protective ventilation during anaesthetic care is still not used frequently enough. This may be due to lack of knowledge and therefore indicates an urgent need for education and regular training [22]. Schultz et al. (2017) opined that intraoperative LPV is still not widely implemented in everyday anaesthesia practice even in high-risk surgical patients, further suggesting that attention should be given to the use of lung protective strategies during general anaesthesia [11].

for education and regular training [22]. Schultz et al. (2017) opined that intraoperative LPV is still not widely implemented in everyday anaesthesia practice even in high-risk surgical patients, further suggesting that attention should be given to the use of lung protective strategies during general anaesthesia [11]. The present results indicate that applying low TV based on IBW is common and it is implemented in everyday anaesthesia practice, although the use of moderate levels of PEEP and even more regular ARMs are usually ignored, not to mention that individually titrated levels of PEEP are seldom employed. In patients with a BMI greater than 30 kg/m2, slightly higher levels of PEEP are accepted, and PEEP titration procedures seem to be employed more commonly in this patient group. Based on this survey, ARM is a procedure used when a decreasing oxygen saturation (SpO2) is detected. Application of permissive hypercapnia and determination of appropriate respiratory rate based on capnography are common during general anaesthesia, but somewhat more sophisticated elements such as low Pplat and ᐃPaw are used only by experts, which may be due to the low availability rate of written intraoperative ventilatory protocols or the shortcomings of regular education and training sessions. A significant number of examinations such as chest X-ray, spirometry and ABGA are carried out during the preoperative assessment, especially in the high-risk patient groups with chronic obstructive pulmonary disease (COPD), patients with actual respiratory diseases or patients with decreased SpO2.

nd training sessions. A significant number of examinations such as chest X-ray, spirometry and ABGA are carried out during the preoperative assessment, especially in the high-risk patient groups with chronic obstructive pulmonary disease (COPD), patients with actual respiratory diseases or patients with decreased SpO2. However, perioperative pulmonary care, the socalled POP concept, is not generally used according to the survey findings. It is also important to note that constant access to CPAP or NIV devices is limited in several institutions. These findings altogether explain that consistent and entire application of LPV and POP concepts are rare, resulting markedly, but insignificant differences between anaesthesiologists and institutions. The main risk factors of PPCs are well-known, but some issues such as chronic malnutrition or prolonged use of nasogastric tube after surgery as negligible factors indicate the absence of an ERAS approach, maybe due to reasons such as the absence of written protocols or the shortcomings of regular education, described earlier.

risk factors of PPCs are well-known, but some issues such as chronic malnutrition or prolonged use of nasogastric tube after surgery as negligible factors indicate the absence of an ERAS approach, maybe due to reasons such as the absence of written protocols or the shortcomings of regular education, described earlier. The survey suffers from some limitations. First, the survey was declarative, and the response rate was relatively low with only approximately 15% of all anaesthesiologists responding. Secondly, to maintain anonymity, sensitive personal or institutional data were not collected; therefore, neither the exact number of participating institutions nor regional distribution were evaluated. Thirdly, the anchoring effect may have influenced the answers to the subsequent questions. Randomising the order of questions could have eliminated this problem, however, this approach could have affected the coherence of the survey significantly. Conclusions The results of a nationwide survey are very similar to that of earlier international surveys and reports, indicating that variations in practice of perioperative respiratory management occur nationally and worldwide. More attention should be given to the use of lung protective strategies during general anaesthesia. Implementation of recent guidelines, developing local institutional protocols and continuous, high-quality education and regular training sessions are essential to improve postoperative outcomes in high-risk patients undergoing major abdominal surgery.

o the use of lung protective strategies during general anaesthesia. Implementation of recent guidelines, developing local institutional protocols and continuous, high-quality education and regular training sessions are essential to improve postoperative outcomes in high-risk patients undergoing major abdominal surgery. Acknowledgements The authors extend thanks to everyone who participated in the survey and especially to Professor Ákos Csomós, former President of HSAIT, for editing a newsletter for members of HSAIT. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest The authors declare that they did not get any funding source supporting the manuscript and the submitted work. The authors disclose any commercial and noncommercial affiliations that are or may be perceived to be a conflict of interest with the work. The authors declare that they did not use or demand any other consultancies.

Introduction Primary hyperparathyroidism (PHPT) is ranked second in frequency amongst endocrine diseases, being caused in more than 80% of cases by a solitary parathyroid adenoma. Other, less frequent causes are multiple parathyroid hyperplasia, double adenomas and parathyroid cancer [1]. A hypercalcaemic crisis, also called para thyrotoxicosis, hyper parathyroid crisis or parathyroid storm, is a complication of PHPT and an endocrinology emergency that can have dramatic or even fatal consequences if it is not recognised and treated in time expeditiously [2,3]. A diagnosis is established in the biochemical context of hyperparathyroidism when there is an elevated serum intact parathyroid hormone level (iPth) together with a substantial increase in the serum calcium level more than 14 mg/dL, associated with an acute onset of symptoms. Symptoms include dehydration, anorexia and vomiting, mental alteration, cardiac arrhythmia, impaired cardiac and renal function and finally death [3,4], and the severity of the of symptoms tends to be proportional to the level of hypercalcaemia. In such cases, emergency hospitalisation and the rapid establishment of intensive care measures to restore calcium levels to within normal limits is mandatory. In most instances, surgical treatment, consisting of the excision of the parathyroid adenoma, is required.

ds to be proportional to the level of hypercalcaemia. In such cases, emergency hospitalisation and the rapid establishment of intensive care measures to restore calcium levels to within normal limits is mandatory. In most instances, surgical treatment, consisting of the excision of the parathyroid adenoma, is required. Two cases which presented in the emergency department of Emergency County Hospital Targu Mures, Romania with hypercalcaemic symptoms and a severe elevation of serum calcium and parathyroid hormone levels, consistent with a hypercalcaemic crisis of hyperparathyroidism origin are reported.

ds to be proportional to the level of hypercalcaemia. In such cases, emergency hospitalisation and the rapid establishment of intensive care measures to restore calcium levels to within normal limits is mandatory. In most instances, surgical treatment, consisting of the excision of the parathyroid adenoma, is required. Two cases which presented in the emergency department of Emergency County Hospital Targu Mures, Romania with hypercalcaemic symptoms and a severe elevation of serum calcium and parathyroid hormone levels, consistent with a hypercalcaemic crisis of hyperparathyroidism origin are reported. Case 1 A 16-year-old female patient, body mass index (BMI) of 24 kg/ m2, was admitted to the hospital’s endocrinology department, complaining of nausea, vomiting, dehydration and slight alteration of mental status, having experienced confusion over the three preceding days. Biochemical tests showed severe hypercalcaemia a serum calcium level of 14.9 mg/dL, [normal value (NV) 9-11 mg/dL], a serum phosphorus level of 1.8 mg/dL [NV:2.7-4.5 mg/dL] ) and a serum iPth level of 184 pg/mL [NV:20-65 pg/mL]. The patient was known to have had repeated admissions for bilateral renal lithiasis, including a left ureterolithotomy for an obstructive calculus and secondary hydronephrosis. Her medical records showed a steadily elevated value ​of iPth and serum calcium in the period preceding hospital admission. On admission, initial treatment consisted of oral and parenteral hydration, 3-3.5 L/day, and furosemide (Zentiva SA, Bucharest, Romania), 10 mg, 2-3 times/day, disodium pamidronate (Dr Reddy Laboratories Ltd. India), intravenously (IV) 30 mg/day was also given to reduce serum calcium levels. In the days following the emergency hospitalisation, calcium levels fell but constantly remained above the normal upper limit of 12.89 mg/dL.

A, Bucharest, Romania), 10 mg, 2-3 times/day, disodium pamidronate (Dr Reddy Laboratories Ltd. India), intravenously (IV) 30 mg/day was also given to reduce serum calcium levels. In the days following the emergency hospitalisation, calcium levels fell but constantly remained above the normal upper limit of 12.89 mg/dL. A cervical ultrasound showed a round-oval hypoechoic mass, 0.54x0.77x1.54, on the lower part of the right thyroid lobe, clearly delimited and of a moderate colour, according to the Doppler vascular signal. Parathyroid scintigraphy with Tc 99m-Sestamibi highlighted an increased capture of the radiotracer on early and late acquisition, at one hour and 30 minutes post-injection. A mass located on the lower part of the right inferior thyroid lobe was detected, indicative of a parathyroid adenoma (Figure 1 and 2). Fig. 1 Cervical ultrasonography indicating an hypoechogenic mass, corresponding to the right inferior parathyroid adenoma. Fig. 2 Parathyroid scintigraphy with Tc 99m-sestamibi showing uptake in the right inferior parathyroid gland The patient was referred for emergency surgical treatment and considering the imaging data that highlighted a parathyroid adenoma below the right inferior thyroid lobe, open minimally invasive parathyroidectomy (OMIP) was carried out. Intraoperatively, a friable reddish-brown tumour of about 1.5x1 cm was excised below the right thyroid lobe, and the histopathological report confirmed parathyroid tissue hyperplasia. (Figure 3). Fig. 3 Right open minimally invasive parathyroidectomy (OMIP)- the right inferior parathyroid adenoma.

The patient was referred for emergency surgical treatment and considering the imaging data that highlighted a parathyroid adenoma below the right inferior thyroid lobe, open minimally invasive parathyroidectomy (OMIP) was carried out. Intraoperatively, a friable reddish-brown tumour of about 1.5x1 cm was excised below the right thyroid lobe, and the histopathological report confirmed parathyroid tissue hyperplasia. (Figure 3). Fig. 3 Right open minimally invasive parathyroidectomy (OMIP)- the right inferior parathyroid adenoma. Postoperatively, serum calcium levels were strictly monitored and high doses of IV calcium, 6-8 g/day, was given to keep the calcium value within the normal range. The patient’s recovery was uneventful, and she was discharged three days postoperatively. Oral calcium supplements, 2-4 g/day, and vitamin D, 0.5-1μg/day, to be taken for one month after the operation, were prescribed. The patient’s condition continued to improve in the following period. The serum calcium level reached 9.6 mg/dL and the parathyroid hormone level 31.5 pg/mL after one month. At the three month follow-up, the patient was asymptomatic, with a total serum calcium level of 9.5 mg/dL and a normal parathyroid hormone level of 21.2 pg/mL, these values being achieved without medication.

period. The serum calcium level reached 9.6 mg/dL and the parathyroid hormone level 31.5 pg/mL after one month. At the three month follow-up, the patient was asymptomatic, with a total serum calcium level of 9.5 mg/dL and a normal parathyroid hormone level of 21.2 pg/mL, these values being achieved without medication. Case 2 A 35-year-old man, BMI of 29 kg/m2, was admitted to the emergency department of Emergency Mures County Hospital, complaining of abdominal pain, poor appetite, nausea, vomiting and generalised weakness that had started two weeks earlier. The patient had a history of a perforated gastric ulcer, ten years earlier, and several episodes of bilateral renal lithiasis. Upon admission, initial tests excluded an acute abdomen. However, the abdominal pain was refractory to symptomatic treatment. Laboratory tests revealed a serum calcium level of 15.2 mg/dL, a serum phosphate level of 2.6 mg/dL and a serum potassium level of 2.9 mmol/L, indicative of severe hypercalcaemia, hypophosphatemia and hypopotassaemia respectively. A hyperparathyroid crisis and primary hyperparathyroidism were suspected, which were subsequently confirmed by an increased serum iPth level of 295 pg/mL. Initial emergency treatment included aggressive fluid resuscitation of 4-4.5 L/day, furosemide (Zentiva SA, Bucharest, Romania), 10 mg, 2-3 times/day, calcitonin (Novartis Pharma Stein AG., Switzerland) 5 UI/kg IV twice a day and disodium pamidronate (Dr Reddy Laboratories Ltd. India) 30 mg/day IV, to reduce calcium levels.

al emergency treatment included aggressive fluid resuscitation of 4-4.5 L/day, furosemide (Zentiva SA, Bucharest, Romania), 10 mg, 2-3 times/day, calcitonin (Novartis Pharma Stein AG., Switzerland) 5 UI/kg IV twice a day and disodium pamidronate (Dr Reddy Laboratories Ltd. India) 30 mg/day IV, to reduce calcium levels. A cervical ultrasound revealed an imprecise hypoechogenic mass of 5x7x6 mm, below the left thyroid lobe. Parathyroid scintigraphy with Tc 99m-Sestamibi revealed an area of ​late tardive capture of radiotracer below the right thyroid lobe, compared to no alteration on the left parathyroid area, suggestive of a right inferior parathyroid adenoma. Five days after admission the patient was still symptomatic with a serum calcium level of 13.1 mg/dL. He was referred for an urgent parathyroidectomy. Given the lack of targeting, parathyroidectomy was performed through a standard cervicotomy with the bilateral exploration of parathyroid areas. Two parathyroid adenomas were excised, a left inferior adenoma of 1x1 cm and a right inferior adenoma of 1x0.5 cm. The histopathological report confirmed parathyroid tissue hyperplasia.

lack of targeting, parathyroidectomy was performed through a standard cervicotomy with the bilateral exploration of parathyroid areas. Two parathyroid adenomas were excised, a left inferior adenoma of 1x1 cm and a right inferior adenoma of 1x0.5 cm. The histopathological report confirmed parathyroid tissue hyperplasia. Immediately after surgery, the iPth value was recorded at 51.2 pg/mL. However, the patient developed a severe postoperative hypocalcaemia with a serum calcium level of 7.1 mg/dL. This was treated with high doses of IV calcium, 8-10 gr/day, for the next four post-operative days. Normal calcium levels were established, and he was discharged after one week. Oral calcium supplements, 2-4 gr/day and vitamin D, 0.5-1 μgr/day, were prescribed, to be taken for one month postoperatively. The patient was reviewed after three months and then intermittently for three years postoperatively during which time calcium and serum phosphorus values remained within normal limits with the late iPth value of 41.6 pg/mL. Discussion Primary hyperthyroidism is listed alongside malignancy as the primary cause of hypercalcaemia [1,4,5]. A hypercalcaemia crisis does not have a clear definition in the literature, but markedly elevated serum calcium values above 14 mg/dL, accompanied by the signs and symptoms of hypercalcaemia are recognised as relevant diagnostic criteria [2,3]. Also called a parathyroid crisis or parathyrotoxicosis, Hanes first described it in 1939, has a prevalence of 1-2% and is recognised as an endocrine emergency, invariably fatal in the absence of optimal treatment [6].

nied by the signs and symptoms of hypercalcaemia are recognised as relevant diagnostic criteria [2,3]. Also called a parathyroid crisis or parathyrotoxicosis, Hanes first described it in 1939, has a prevalence of 1-2% and is recognised as an endocrine emergency, invariably fatal in the absence of optimal treatment [6]. The symptoms of PHPT are heterogeneous, including neuromuscular, digestive, bone and kidney symptoms. The classic indicative aphoristic mnemonic “stones, bones, abdominal moans and groans psychic” is rarely seen these days, especially in western countries, where the disease usually progresses in an oligosymptomatic manner [7]. However, there are geographical areas, especially in less developed countries, where severe manifestations of PHPT are still commonly encountered, and where the disease frequently goes undiagnosed with treatment often commencing at a later than optimum time [8]. This is also the case in Romania, where symptomatic cases, such as those presented, are often encountered. Both patients were diagnosed in a difficult phase of the disease. In Case 1, a 16-year-old teenager, the disease caused bilateral renal lithiasis, the patient having to undergo surgery for this condition. The patient In Case 2, the patient had had a perforated ulcer at 18 years of age, probably because of undiagnosed PHPT. Irregular digestive symptoms persisted, and an episode of acute pancreatitis occurred. The emergency admission to hospital for a hypercalcaemic crisis was also due to continuous abnormal digestive symptoms.

tient In Case 2, the patient had had a perforated ulcer at 18 years of age, probably because of undiagnosed PHPT. Irregular digestive symptoms persisted, and an episode of acute pancreatitis occurred. The emergency admission to hospital for a hypercalcaemic crisis was also due to continuous abnormal digestive symptoms. Surprisingly, in Romania, situations are frequently observed where PHPT is diagnosed only when cervical tumours are discovered during routine ultrasound examinations in patients with long-standing heterogeneous symptoms. In such cases, it is not a rare event that large parathyroid adenomas are found intraoperatively [8]. The diagnosis of PHPT and implicitly of a hypercalcaemic crisis frequently depends on the results of biochemical tests. Measurements of the total serum calcium are frequently inaccurate and corrected total serum calcium on albumin, or ionic calcium are more useful in diagnosis. An increased serum level of iPth usually confirms a diagnosis of PHPT.

licitly of a hypercalcaemic crisis frequently depends on the results of biochemical tests. Measurements of the total serum calcium are frequently inaccurate and corrected total serum calcium on albumin, or ionic calcium are more useful in diagnosis. An increased serum level of iPth usually confirms a diagnosis of PHPT. Imagistics is not a diagnostic criterion in PHPT but helps the surgeon to locate an adenoma or adenomas and to target the appropriate surgical area [9]. In most PHPT cases a single adenoma is being dealt with, and targeting is an advantageous technique which allows minimally-invasive interventions. Case1 represents this well. Scintigraphy with Tc 99m-Sestamibi and a cervical ultrasound confirmed the location of the adenoma and allowed its targeted excision. A meta-analysis of several studies showed that sensitivity of scintigraphy with Tc 99m-Sestamibi compared to the high-resolution US was 88% versus 78% for single adenomas, and the combination of the two methods provides the best sensitivity for targeting the operation site [10]. The sensitivity of these methods decreases significantly in the case of double adenomas and especially in the case of four-gland hyperplasia [10]. The second case is indicative of these views. In Case 2, there was no correlation between the scintigraphy and ultrasonography, and so a bilateral exploration of the neck was opted for, revealing two parathyroid adenomas. Apparently, in this situation, a targeted operation would have been followed by persistent hyperparathyroidism. A solution not yet available in the clinic, but which would allow a better targeting, would be intraoperative parathyroid hormone assay. Indeed, it appears that a decrease of more than 50% over the baseline parathyroid hormone value at 10-15 minutes after resection, is suggestive of a single adenoma. In the absence of such a decrease over baseline parathyroid hormone values, it is more likely that a bilateral mass or four-gland hyperplasia exists and the procedural approach of a minimally invasive operation would be converted to one which allowed for exploration of other additional sites [11].

of a single adenoma. In the absence of such a decrease over baseline parathyroid hormone values, it is more likely that a bilateral mass or four-gland hyperplasia exists and the procedural approach of a minimally invasive operation would be converted to one which allowed for exploration of other additional sites [11]. Even though the mortality rate gradually declined in recent decades due to earlier diagnosis and improved medical treatment, the diagnosis of a hyperparathyroid crisis still demands emergency measures as it is a critical condition with high mortality in the absence of therapeutic intervention [12]. Initial treatment of moderate and severe hypercalcaemia consists of IV hydration and afterwards loop diuretics, carried out with 2-4 L/ day of saline solution for two-three days depending on calcaemia, the degree of dehydration and patient’s tolerance to rehydration.

ity in the absence of therapeutic intervention [12]. Initial treatment of moderate and severe hypercalcaemia consists of IV hydration and afterwards loop diuretics, carried out with 2-4 L/ day of saline solution for two-three days depending on calcaemia, the degree of dehydration and patient’s tolerance to rehydration. A repeated dose of diuretics can be useful after rehydration which will prevent overloading. Patients who do not tolerate rapid IV rehydration, particularly those presenting with renal or cardiac diseases, may require dialysis. In the cases presented, although the values ​of the calcaemia at admission were high, both patients responded favourably to rehydration and administration of furosemide, 10mg, 2-3 times daily. In recent years, calcitonin and bisphosphonate have been used to treat a parathyroid crisis due to their effect of inhibiting calcium bone resorption, though reports suggest that the results were not as good as expected [13,14]. However, it has been suggested that they might be used in moderate and severe hypercalcaemia as a bridge therapy to parathyroidectomy, when rapid rehydration is contraindicated [12].

due to their effect of inhibiting calcium bone resorption, though reports suggest that the results were not as good as expected [13,14]. However, it has been suggested that they might be used in moderate and severe hypercalcaemia as a bridge therapy to parathyroidectomy, when rapid rehydration is contraindicated [12]. Rehydration, stimulation of diuresis and daily as well as the inhibition of bone resorption are all emergency therapeutic measures useful in treating the critically ill hypercalcaemic patient, though surgery remains the definitive and pathogenic treatment of a parathyrotoxic crisis [6]. As shown in both the reported cases, parathyroidectomy succeeds by rapidly and substantially reducing the serum iPth level, to break the pathogenic chain in PHPT and HC crisis. IPth serum values ​rapidly normalised in both cases and serum calcium values ​ decreased gradually over the following few days.

xic crisis [6]. As shown in both the reported cases, parathyroidectomy succeeds by rapidly and substantially reducing the serum iPth level, to break the pathogenic chain in PHPT and HC crisis. IPth serum values ​rapidly normalised in both cases and serum calcium values ​ decreased gradually over the following few days. One should be mindful that in such patients there is a risk of postoperative hungry bone syndrome (HBS), its severity depending on preoperative serum calcium levels ​and bone damage secondary to hyperparathyroidism. HBS is not specific to PHPT, being also found in patients with secondary hyperparathyroidism (SHPT) of renal origin. In these cases, the pathogenic mechanism is more complex, and the treatment has particularities related to chronic dialysis [15]. A rapid reduction in postoperative calcaemia is not desirable in patients with high preoperative serum calcium levels. In contrast to post-thyroidectomy hypocalcaemia, usually transient, subclinical and secondary to incidental parathyroidectomy [16], hypocalcaemia after the resection of a parathyroid adenoma may be severe and responsible for fatal cardiac complications. For this reason, several authors have recommended that IV calcium substitution is initiated immediately postoperatively [17]. In both cases, serum calcium values were continuously monitored, and high doses of IV calcium were administered to keep the calcium levels within normal limits. Finally, both patients were discharged with normal calcium levels with oral calcium and vitamin D substitution.

is initiated immediately postoperatively [17]. In both cases, serum calcium values were continuously monitored, and high doses of IV calcium were administered to keep the calcium levels within normal limits. Finally, both patients were discharged with normal calcium levels with oral calcium and vitamin D substitution. The development of imaging techniques has enabled parathyroidectomy to be targeted. Different RCTs have demonstrated the benefits of a minimally invasive approach which result in reduced postoperative pain, shorter operative time, earlier discharge and better cosmetic results [18]. A minimally invasive approach was preferred this in Case 1. In any other situation, when the diagnosis of localisation is not certain, or there is suspicion of double or multiple masses, the only surgical solution remains bilateral cervical exploration with subtotal excision of the parathyroid hyperplasic parenchyma and maintenance of auto implantation in the cervical or distal region. This is illustrated by Case 2, where a discordance between the two imagistic investigations was noted. Indeed, intraoperative bilateral exploration revealed double diseased sites and allowed the excision of both parathyroid adenomas. Symptom resolution, normalisation of calcium levels, and maintaining iPth within normal limits during follow-up confirmed a successful outcome for both patients.

c investigations was noted. Indeed, intraoperative bilateral exploration revealed double diseased sites and allowed the excision of both parathyroid adenomas. Symptom resolution, normalisation of calcium levels, and maintaining iPth within normal limits during follow-up confirmed a successful outcome for both patients. Conclusion Primary hyperparathyroidism and its hypercalcaemic complication are frequently misdiagnosed due to atypical symptomatology. Emergency conservative treatment, including aggressive fluid resuscitation, diuretics, calcitonin and bisphosphonates may help to stabilise the critically ill patient providing time for further imagistic investigations. The current reports support the evidence that surgery remains the best approach for patients with a hypercalcaemic crisis of hyperparathyroidism origin, ensuring the rapid improvement of both the symptomatology and biochemical alterations of this disease. Conflict of interest None to declare.

There is a complex relationship between potential authors, especially those with limited experience in submitting manuscripts, medical journals, editors and the reviewers who participate in the peer review system. There is growing pressure on young graduates undertaking PhD and Master programs to publish papers, as the regulations for the completion of these degrees from many universities require papers to be published before the awarding of these degrees. The pressure to publish is nonetheless high, as colleagues proceed through their career pathway, with publications often dictating successful advancement or promotion. This paper highlights this complex relationship and discusses the responsibilities of all stakeholders, both ethically and professionally. An essential feature of a medical career includes sharing clinical practices and research outcomes with the broader medical community. At a recent symposium, a speaker posed the question “Why do we do research?”. The audience’s consensus opinion was “because we are curious and wish to share what we find”[1]. This may be partly true, but a questioner does not always get an answer representative of the whole truth, especially in a public forum. How many young professionals, at the start of their career, would admit, in public, that they only do research and subsequently share this through publications, only in order to satisfy prerequisites degree specifications? This is undoubtedly the case in many instances, and when it is so, can lead to some unwelcome, if not dangerous consequences.

, at the start of their career, would admit, in public, that they only do research and subsequently share this through publications, only in order to satisfy prerequisites degree specifications? This is undoubtedly the case in many instances, and when it is so, can lead to some unwelcome, if not dangerous consequences. When publication becomes mandatory, quality often suffers. This lack of quality research is evident in the many and ever increasing number of medical journals.

, at the start of their career, would admit, in public, that they only do research and subsequently share this through publications, only in order to satisfy prerequisites degree specifications? This is undoubtedly the case in many instances, and when it is so, can lead to some unwelcome, if not dangerous consequences. When publication becomes mandatory, quality often suffers. This lack of quality research is evident in the many and ever increasing number of medical journals. Authors, inexperienced or otherwise, have a professional and ethical duty to undertake high-quality research based on sound clinical or laboratory methodology and submit significant and quality manuscripts for publication. Their responsibilities commence long before the writing, submission and eventual publication of a study paper, originating in the planning and execution of the study on which papers will be based. Sound clinical or laboratory methodology should be predicated on a thorough acquisition of knowledge and finishing with complex decision making. Circumvention or nonconformity with standard practices in conducting research or inappropriate management leading to biased results is unacceptable, and their avoidance is the responsibility of all members of a research team and all the authors of a resultant manuscript. Timely and proper statistical tests, power calculations and analyses should be considered early in the study design, to ensure that, as far as possible, conclusions can be effective and, hopefully, efficient. Plagiarism must be deemed as totally insupportable, as is the misrepresentation of data by avoiding “outliers” and outcome measures that do not fit in with a preconceived hypothesis. Falsehood, suppression, and a disingenuous commentary is equivalent to scientific dishonesty, which has a serious detrimental impact on the general research community and possible future clinical recommendations, standards and strategies.

outliers” and outcome measures that do not fit in with a preconceived hypothesis. Falsehood, suppression, and a disingenuous commentary is equivalent to scientific dishonesty, which has a serious detrimental impact on the general research community and possible future clinical recommendations, standards and strategies. It is imperative that authors give proper attention to the sources quoted in their papers. Concerns result from improper citations may have both personal and far-reaching consequences with doubt being levied at the authors academic status, his or her academic honesty and the validity of the study and the resulting conclusions. Accurate referencing will throw out all of these potential questions [2]. It is imperative that authors appreciate what journal editors expect in submitted manuscripts. A central remit of an editor, especially of journals of high standing, is to enhance the status of their journal and a consequence is that they are interested mainly in original high-quality research of significant clinical relevance. They demand manuscripts that are written in clear and concise English. This goes beyond just proper spelling and grammar but instead that manuscripts clearly and effectively communicate the authors’ ideas and findings. Finally, all journals must follow a set of publication policies and ethical standards to ensure that the research they publish is of the highest quality.

d concise English. This goes beyond just proper spelling and grammar but instead that manuscripts clearly and effectively communicate the authors’ ideas and findings. Finally, all journals must follow a set of publication policies and ethical standards to ensure that the research they publish is of the highest quality. Medical journals aspire to select, through peer review, papers which communicate scientific evidence of the highest quality. To achieve this end, the peer review and publication process must be objective, systematic, and impartial. Editors, reviewers, authors, researchers, patients, readers, funding agencies, and health policy commissioners, must believe and have a deep conviction that this is so. Without this, a journal’s reputations will be diminished. It is therefore incumbent, if not mandatory, that journals describe their policies as clearly and straightforwardly as possible, in order to guarantee the ethical management of participants in the publication procedure. Each of the above stakeholders has individual and collective responsibilities. Medical editors or editors in chief as they are sometimes known, are responsible for the trustworthiness of published papers. The dependability of published works can influence professional performance, future patient care and ethics. Editors will make reliable and impartial decisions, selecting or rejecting submitted manuscripts solely on merit. Editors should be unbiased in their choice of reviewers, editorial decisions, or in editorial statements.

ndability of published works can influence professional performance, future patient care and ethics. Editors will make reliable and impartial decisions, selecting or rejecting submitted manuscripts solely on merit. Editors should be unbiased in their choice of reviewers, editorial decisions, or in editorial statements. By being creative and thoughtful in predicting the future of their speciality they have the opportunity and potential to recognise what authors and readers need and make the most of such a privileged position to benefit the practice and delivery of medicine. The concern of the peer review process is to identify and suggest for publication, manuscripts that are authoritative and contribute to the advancement of medical practice. In turn, these papers become the foundation for further research and the basis of day-to-day medical practices. It is central to medical research in that it appraises studies for competence, importance, and innovation by experienced experts in a particular field of study. The process is frequently an essential determinant of an author’s academic development, and because of the nature of the process, authors’ concerns often include long delays in publication. A robust peer review system identifies scientific transgression, plagiarism and irrelevant replication of topics.

field of study. The process is frequently an essential determinant of an author’s academic development, and because of the nature of the process, authors’ concerns often include long delays in publication. A robust peer review system identifies scientific transgression, plagiarism and irrelevant replication of topics. It can, however, fall short of ideal when editors or reviewers do not fully appreciate the matters reported and discussed in the submitted manuscript. In such cases, this can result in significant flaws in study design, assessment and discussion, going undetected before publication, with essential and significant errors becoming “published facts”. Notwithstanding its limitations [3], the peer review process is broadly favoured by the medical and scientific community. A relevant, transparent peer review is necessary to assist and expedite ongoing medical science [4].

It can, however, fall short of ideal when editors or reviewers do not fully appreciate the matters reported and discussed in the submitted manuscript. In such cases, this can result in significant flaws in study design, assessment and discussion, going undetected before publication, with essential and significant errors becoming “published facts”. Notwithstanding its limitations [3], the peer review process is broadly favoured by the medical and scientific community. A relevant, transparent peer review is necessary to assist and expedite ongoing medical science [4]. The role and definition of authorship in medical journals have become progressively complex. Due to modern technology, many studies are conducted by collaboration between colleagues in different parts of the world, a colleague who participated significantly to any part of a project, such as the theory or hypothesis development, data analysis or literature reviewing may be considered to have authorship eligibility. However, the inclusion of ghost authors is objectionable and should be rigorously avoided. The International Committee of Medical Journal Editors (ICMJE) [5] gives revised authorship criteria that should be followed in most cases. Some researchers opine that these guidelines are too strict, but nevertheless acknowledge that they safeguard the understanding that nominated authorship denotes responsibility to the scientific integrity of the paper. Authors have a responsibility to give attention to detail at all levels of his/her research; this fosters scientific thought and analysis and makes for better research. Errors of omission frequently are the cause of a reviewer not accepting a manuscript for publication. Failing to cite a critical or well-known paper may give the impression that authors have not undertaken an extensive literature review or having inadequate knowledge of their subject. It may even lead a reviewer to consider that the work is, in part, plagiarised.

f a reviewer not accepting a manuscript for publication. Failing to cite a critical or well-known paper may give the impression that authors have not undertaken an extensive literature review or having inadequate knowledge of their subject. It may even lead a reviewer to consider that the work is, in part, plagiarised. The responsibility to avoid plagiarism is self-evident. It is one of the most common causes of compromising the academic integrity of the author. Authors referencing all primary sources can avoid this inference. The question of plagiarism is firmly eliminated by proper referencing. The corresponding author takes primary responsibility for any prepublication communication with the journal during the manuscript submission and peer review process. This places an uncompromising responsibility on him/her to ensure that all the above issues have been considered and appropriately dealt with, and all authors agree to the final manuscript.

ary responsibility for any prepublication communication with the journal during the manuscript submission and peer review process. This places an uncompromising responsibility on him/her to ensure that all the above issues have been considered and appropriately dealt with, and all authors agree to the final manuscript. The editorial team of the Journal of Critical Care Medicine are aware of the complex symbiotic relationship between authors, Editors and the peer review system. The particular needs of potential authors, especially those with limited experience in submitting manuscripts, who are not fully conversant or indeed understand the complex issues characteristic of the system have been noted and identified. The JCCM editorial team have taken steps to help these colleagues in having papers of an appropriate standard, accepted and published. The educational nature of a medical journal starts with the authors receiving a report by reviewers. This is often given even when the manuscript has been rejected. The JCCM wishes to extend this educational quality, and to this end will publish occasional articles detailing the fitting structure and appropriate detail required of papers submitted to high standard international journals such as the JCCM. These articles will be published occasionally under the heading “Spotlight On…”. The first of these papers, “Spotlight on how to Write a Case Report”, will be published in the next issue of JCCM. Conflict of interest None to declare

Introduction The pyruvate dehydrogenase complex (PDC) is a multienzyme complex located in the mitochondrial matrix, which serves as a catalyst for oxidative decarboxylation of pyruvate to acetyl CoA, the rate-limiting step in the Krebs cycle [1]. Pyruvate dehydrogenase complex deficiency (PDCD) is a rare genetic, potentially life-threatening mitochondrial disorder commonly associated with lactic acidosis, and progressive neurological and neuromuscular degeneration. Patients with PDCD usually present with hypotonia, lethargy and developmental delay. Definitive diagnosis is usually made by genetic testing. Structural abnormalities of the brain are quite common in PDCD. A case of a patient with a late-onset diagnosis of PDCD with proximal muscle weakness, lactic acidosis and a normal brain magnetic resonance imaging (MRI) with an unusual presentation is presented.

. Definitive diagnosis is usually made by genetic testing. Structural abnormalities of the brain are quite common in PDCD. A case of a patient with a late-onset diagnosis of PDCD with proximal muscle weakness, lactic acidosis and a normal brain magnetic resonance imaging (MRI) with an unusual presentation is presented. Case Report A 20-month-old boy with a past medical history of developmental delay, hypotonia and feeding difficulty, presented to the emergency department (ED) with runny nose, cough, and increased work of breathing for five days. Birth history was insignificant. However, his developmental history was significant indicating he was unable to stand or crawl. He had just started to sit with support. Work up including audiology screen, fluorescent in-situ hybridisation, comparative genomic hybridisation microarray, and specific genetic testing for conditions like Prader-Willi syndrome as well as spinal muscular atrophy were normal. Neuroimaging included a brain MRI which was normal, except for an incidental finding of a small developmental venous anomaly in the right occipital lobe.

, comparative genomic hybridisation microarray, and specific genetic testing for conditions like Prader-Willi syndrome as well as spinal muscular atrophy were normal. Neuroimaging included a brain MRI which was normal, except for an incidental finding of a small developmental venous anomaly in the right occipital lobe. In the ED, vital signs revealed a temperature of 100.6° F (38.10C),a respiratory rate of 62 breaths per minute, heart rate 162 beats per min, blood pressure 111/60 mmHg, and 85% oxygen saturation at room air. On physical examination, he was in moderate respiratory distress with intercostal retractions, and coarse bilateral breath sounds with good perfusion. He received a fluid bolus and was placed on six litres high-flow nasal cannula which resulted in an improvement in his oxygen saturation. A chest radiograph was obtained which showed pulmonary hyper-expansion with bilateral streaky peripheral densities suggestive of viral lower airway disease (Figure 1). He was diagnosed with viral bronchiolitis and subsequently admitted for respiratory support. On day four after admission, his hypoxia worsened, raising the suspicion of a secondary pneumonia and intravenous (IV) Ampicillin (Athenex, Schaumburg, IL, USA) was started. Given his worsening respiratory status, he was made “nil per os” (NPO) and placed on IV fluids for hydration. Fig. 1 Chest radiograph on admission. The image shows pulmonary hyperexpansion with interstitial prominence and areas of patchy density which may be due to a viral airway disease with areas of atelectasis.

In the ED, vital signs revealed a temperature of 100.6° F (38.10C),a respiratory rate of 62 breaths per minute, heart rate 162 beats per min, blood pressure 111/60 mmHg, and 85% oxygen saturation at room air. On physical examination, he was in moderate respiratory distress with intercostal retractions, and coarse bilateral breath sounds with good perfusion. He received a fluid bolus and was placed on six litres high-flow nasal cannula which resulted in an improvement in his oxygen saturation. A chest radiograph was obtained which showed pulmonary hyper-expansion with bilateral streaky peripheral densities suggestive of viral lower airway disease (Figure 1). He was diagnosed with viral bronchiolitis and subsequently admitted for respiratory support. On day four after admission, his hypoxia worsened, raising the suspicion of a secondary pneumonia and intravenous (IV) Ampicillin (Athenex, Schaumburg, IL, USA) was started. Given his worsening respiratory status, he was made “nil per os” (NPO) and placed on IV fluids for hydration. Fig. 1 Chest radiograph on admission. The image shows pulmonary hyperexpansion with interstitial prominence and areas of patchy density which may be due to a viral airway disease with areas of atelectasis. His respiratory status improved on day five after admission, and he was restarted on enteral nutrition with PediaSure®. IV fluids were discontinued. Within forty-eight hours of starting feeds with PediaSure®, his respiratory and mental status worsened. He was difficult to arouse and developed respiratory arrest requiring emergent intubation and subsequent transfer

ter admission, and he was restarted on enteral nutrition with PediaSure®. IV fluids were discontinued. Within forty-eight hours of starting feeds with PediaSure®, his respiratory and mental status worsened. He was difficult to arouse and developed respiratory arrest requiring emergent intubation and subsequent transfer to the paediatric intensive care unit (PICU). His capillary blood gas before arrest revealed a metabolic acidosis with respiratory compensation (Table 1). He had a significantly elevated lactic acid level of 8.9 mmol/L despite normal haemodynamics. A viral respiratory panel (VRP) and blood cultures were obtained, and antibiotics were switched to IV Piperacillin/Tazobactam (Fresenius Kabi, Lake Zurich, IL, USA) and Vancomycin (Hospira, Lake Forest, IL, USA) to cover a broader spectrum of organisms for an intended duration of ten days. His VRP came back positive for Metapneumovirus, which was thought to be the cause of his respiratory illness. Table 1 Pertinent laboratory results of the patient Labs Values Time of collection pH pCO2 (mmHg) pO2 (mmHg) HCO3 (mmol/L) Serum lactate (mmol/L) 2 hours prior to respiratory arrest (Hospital Day 6) (Capillary gas) 7.42 22 81 14.2 8.9 Blood 1 hour after respiratory arrest (Hospital Day 6) (Capillary gas) 7.12 41.5 125 13.5 8.1 gases 36 hours after initiation of Pediasure® (Hospital Day 8) (Venous gas) 7.31 51.1 45.7 25.4 9.3 After development of ARDS (Hospital Day 13) (Arterial gas) 7.42 52 55 33.5 1.3 Serum pyruvate level (mg/dL) 2.42 (Reference range: 0.3-1.5) Blood lactate to pyruvate ratio 14.87

Labs Values Time of collection pH pCO2 (mmHg) pO2 (mmHg) HCO3 (mmol/L) Serum lactate (mmol/L) 2 hours prior to respiratory arrest (Hospital Day 6) (Capillary gas) 7.42 22 81 14.2 8.9 Blood 1 hour after respiratory arrest (Hospital Day 6) (Capillary gas) 7.12 41.5 125 13.5 8.1 gases 36 hours after initiation of Pediasure® (Hospital Day 8) (Venous gas) 7.31 51.1 45.7 25.4 9.3 After development of ARDS (Hospital Day 13) (Arterial gas) 7.42 52 55 33.5 1.3 Serum pyruvate level (mg/dL) 2.42 (Reference range: 0.3-1.5) Blood lactate to pyruvate ratio 14.87 Activated PDC level (nmol/min/mg protein) 0.35 (Reference range: 1.2-6.52) Skeletal muscle biopsy PDC/E3 ratio 0.4 (Reference range: 0.82-4.54) Pyruvate dehydrogenase and mitochondrial complex panel Positive for pyruvate dehydrogenase alpha 1 (PDHA1) gene mutation In the PICU, he was again made NPO until he was stabilised. His repeat blood gases normalised over twelve hours and his lactate results improved. Feeding with PediaSure® was restarted two days after PICU admission. A rise in arterial lactate from 2.9 to 9.3 mmol/L after restarting enteral nutrition was noted (Figure 2). He was subsequently made NPO again. Fig. 2 Change in lactate associated with introduction of feeds. The figure describes an increase in lactate after each time the patient is started on PediaSure® feeds. The level decreased to normal after discontinuation of PediaSure®. The figure also describes no change in lactate level after starting the patient on KetoCal® feeds.

in lactate associated with introduction of feeds. The figure describes an increase in lactate after each time the patient is started on PediaSure® feeds. The level decreased to normal after discontinuation of PediaSure®. The figure also describes no change in lactate level after starting the patient on KetoCal® feeds. Further trials of enteral administration of PediaSure® were unsuccessful, secondary to recurrent episodes of lactic acidosis (Figure 2). A geneticist was consulted due to concerns regarding the patient’s hypotonia and persistent lactic acidosis despite good perfusion. A metabolic workup that included a funduscopic examination, plasma amino acids, acylcarnitine, carnitine, urine organic acids and pyruvate level was recommended. Also recommended was obtaining a whole exome sequencing and a myotonia congenita panel. All results were normal except for an elevated pyruvate level with a blood lactate to pyruvate ratio of 14.87. This was suggestive of pyruvate dehydrogenase complex deficiency (PDCD) (Table 1). A skeletal muscle biopsy showed low levels of activated PDC and PDC/E3 ratio (Table 1) as well as a pyruvate dehydrogenase and mitochondrial complex panel testing positive for pyruvate dehydrogenase alpha 1 (PDHA1) gene mutation confirming the diagnosis of PDCD.