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Purpose: To report the incidence, risk factors, clinical presentation, and outcome predictors of severe leptospirosis requiring intensive care unit (ICU) admission in a temperate zone., Methods: LEPTOREA was a retrospective multicentre study conducted in 79 ICUs in metropolitan France. Consecutive adults admitted to the ICU for proven severe leptospirosis from January 2012 to September 2016 were included. Multiple correspondence analysis (MCA) and hierarchical classification on principal components (HCPC) were performed to distinguish different clinical phenotypes., Results: The 160 included patients (0.04% of all ICU admissions) had median values of 54 years [38-65] for age, 40 [28-58] for the SAPSII, and 11 [8-14] for the SOFA score. Hospital mortality was 9% and was associated with older age; worse SOFA score and early need for endotracheal ventilation and/or renal replacement therapy; chronic alcohol abuse and worse hepatic dysfunction; confusion; and higher leucocyte count. Four phenotypes were identified: moderately severe leptospirosis (n = 34, 21%) with less organ failure and better outcomes; hepato-renal leptospirosis (n = 101, 63%) with prominent liver and kidney dysfunction; neurological leptospirosis (n = 8, 5%) with the most severe organ failures and highest mortality; and respiratory leptospirosis (n = 17, 11%) with pulmonary haemorrhage. The main risk factors for leptospirosis contamination were contact with animals, contact with river or lake water, and specific occupations., Conclusions: Severe leptospirosis was an uncommon reason for ICU admission in metropolitan France and carried a lower mortality rate than expected based on the high severity and organ-failure scores. The identification in our population of several clinical presentations may help clinicians establish an appropriate index of suspicion for severe leptospirosis.

The study aimed to compare two scores: the pediatric logistic organ dysfunction (PELOD) with its updated version (PELOD-2) in describing the severity of organ dysfunction in pediatric intensive care unit (PICU) and assess the performance of PELOD-2 in the Egyptian population. A prospective cohort study of 200 patients consecutively admitted to PICU between July 2015 and A 2016 was included. The median age was 6 months, and the male to female ratio was 1.04. The median length of PICU stay was 4 days. The overall predicted number of deaths using PELOD was 76 patients whereas, by PELOD-2, it was 50 patients. The observed mortality was 50 patients. The area under the receiving operating characteristic curve was excellent for both PELOD and PELOD-2 (0.93 and 0.91, respectively). The Hosmer and Lemeshow goodness-of-fit test showed good calibration of PELOD-2 (χ 2  = 9.9, p = 0.27), while PELOD showed poor calibration (χ 2  = 42, p = 0.000) in the same studied group., Conclusion: Both scores had excellent discrimination. PELOD-2 is reproducible and easier to perform and had better calibration compared to PELOD score. What is Known: • Pediatric logistic organ dysfunction (PELOD) score was developed 1999 and validated in 2003 to describe the organ dysfunction severity in pediatric intensive care units. • A new and easier version of (PELOD-2) was developed 2013 in France and Belgium to replace the old score. It is important to assess the performance of the new score in other population else than the original. What is New: In an Egyptian pediatric intensive care, the performance of the score revealed: • PELOD-2 was an excellent discriminatory score comparable to the original score. • PELOD-2 calibrated well in the Egyptian population while the old score had poor calibration.

Background: There is so far no information on how the third act on amendment of the German guardianship law from 29 July 2009 has affected dying processes of critically ill patients., Methods: This retrospective study analyzed the patterns of dying processes in postoperative critically ill patients treated from 2009 to 2012 (period II after the commencement of the German Living Will Act) and 10 years before (period I, 1999-2002). Independent associations were calculated by logistic regression., Results: In the observation period II (n = 137 dying patients) time until death significantly decreased to 19.3 days (95% CI 14.8-23.8, p = 0.008) vs. 29.2 days (95% CI 23.7-34.6) in period I (n = 163). In period II respect of the patient's will preceded death in 42.3% of the dying patients (period I: 8.6%, p < 0.001). Simultaneously, the frequency of patients with a severe preoperative comorbidity (failure of more than one organ) increased (26.8% of dying patients vs. 5.5% in period I, p = 0.001). The treatment during period II was, in addition to high age and a severe comorbidity, a significant independent predictor for the possibility that respect of the patient's will preceded death (odds ratio 7.42; 95% CI 3.77-14.60)., Conclusion: Independent of various covariables, treatment after the commencement of the German Living Will Act was associated with a broader and earlier respect of the patient's will, thereby shortening the time until death.

Background: Blast injuries are a rare cause of potentially life-threatening injuries in Germany. During the past 30 years such injuries were seldom the cause of mass casualties, therefore, knowledge and skills in dealing with this type of injury are not very extensive., Material and Methods: A retrospective identification of all patients in the TraumaRegister DGU® of the German Trauma Society (TR-DGU) who sustained blast injuries between January 1993 and November 2012 was carried out. The study involved a descriptive characterization of the collective as well as three additional collectives. The arithmetic mean, standard deviation and 95 % confidence interval of the arithmetic mean for different demographic parameters and figures for prehospital and in-hospital settings were calculated. A computation of prognostic scores, such as the Revised Injury Severity Classification (RISC) and the updated version RISC II (TR-DGU-Project-ID 2012-035) was performed., Results: A total of 137 patients with blast injuries could be identified in the dataset of the TR-DGU. Of the patients 90 % were male and 43 % were transported by the helicopter emergency service (HEMS) to the various trauma centres. The severely injured collective with a mean injury severity scale (ISS) of 18.0 (ISS ≥ 16 = 52 %) had stable vital signs. In none of the cases was it necessary to perform on-site emergency surgery but a very high proportion of patients (59 %) had to be surgically treated before admittance to the intensive care unit (ICU). Of the patients 27 % had severe soft tissue injuries with an Abbreviated Injury Scale (AIS) ≥ 3 and 90 % of these injuries were burns. The 24 h in-hospital fatality was very low (3 %) but the stay in the ICU tended to be longer than for other types of injury (mean 5.5 ventilation days and 10.7 days in the intensive care unit). Organ failure occurred in 36 % of the cases, multiorgan failure in 29 % and septic events in 14 %. Of the patients 16 % were transferred to another hospital during the first 48 h. The RISC and the updated RISC II tended to underestimate the severity of injuries and mortality (10.2 % vs. 6.8 % and 10.7 % vs. 7.5 %, respectively) and the trauma associated severe hemorrhage (TASH) score underestimated the probability for transfusion of more than 10 units of packed red blood cells (5.0 % vs. 12.5 %)., Conclusion: This article generates several hypotheses, which should be confirmed with additional investigations. Until then it has to be concluded that patients who suffer from accidental blast injuries in the civilian setting (excluding military operations and terrorist attacks) show a combination of classical severe trauma with blunt and penetrating injuries and additionally a high proportion of severe burns (combined thermomechanical injury). They stay longer in the ICU than other trauma patients and suffer more complications, such as sepsis and multiorgan failure. Established scores, such as RISC, RISC II and TASH tend to underestimate the severity of the underlying trauma.

Introduction: Sepsis is a devastating condition that is generally treated as a single disease. Identification of meaningfully distinct clusters may improve research, treatment and prognostication among septic patients. We therefore sought to identify clusters among patients with severe sepsis or septic shock., Methods: We retrospectively studied all patients with severe sepsis or septic shock admitted directly from the emergency department to the intensive care units (ICUs) of three hospitals, 2006-2013. Using age and Sequential Organ Failure Assessment (SOFA) subscores, we defined clusters utilizing self-organizing maps, a method for representing multidimensional data in intuitive two-dimensional grids to facilitate cluster identification., Results: We identified 2533 patients with severe sepsis or septic shock. Overall mortality was 17 %, with a mean APACHE II score of 24, mean SOFA score of 8 and a mean ICU stay of 5.4 days. Four distinct clusters were identified; (1) shock with elevated creatinine, (2) minimal multi-organ dysfunction syndrome (MODS), (3) shock with hypoxemia and altered mental status, and (4) hepatic disease. Mortality (95 % confidence intervals) for these clusters was 11 (8-14), 12 (11-14), 28 (25-32), and 21 (16-26) %, respectively (p < 0.0001). Regression modeling demonstrated that the clusters differed in the association between clinical outcomes and predictors, including APACHE II score., Conclusions: We identified four distinct clusters of MODS among patients with severe sepsis or septic shock. These clusters may reflect underlying pathophysiological differences and could potentially facilitate tailored treatments or directed research.

Background: In the intensive care unit (ICU), the outcomes of patients with acute mesenteric ischemia (AMI) are poorly documented. This study aimed to determine the risk factors for death in ICU patients with AMI., Methods: A retrospective, observational, non-interventional, multicenter study was conducted in 43 ICUs of 38 public institutions in France. From January 2008 to December 2013, all adult patients with a diagnosis of AMI during their hospitalization in ICU were included in a database. The diagnosis was confirmed by at least one of three procedures (computed tomography scan, gastrointestinal endoscopy, or upon surgery). To determine factors associated with ICU death, we established a logistic regression model. Recursive partitioning analysis was applied to construct a decision tree regarding risk factors and their interactions most critical to determining outcomes., Results: The death rate of the 780 included patients was 58 %. Being older, having a higher sequential organ failure assessment (SOFA) severity score at diagnosis, and a plasma lactate concentration over 2.7 mmol/l at diagnosis were independent risk factors of ICU mortality. In contrast, having a prior history of peripheral vascular disease or an initial surgical treatment were independent protective factors against ICU mortality. Using age and SOFA severity score, we established an ICU mortality score at diagnosis based on the cutoffs provided by recursive partitioning analysis. Probability of survival was statistically different (p < 0.001) between patients with a score from 0 to 2 and those with a score of 3 and 4., Conclusion: Acute mesenteric ischemia in ICU patients was associated with a 58 % ICU death rate. Age and SOFA severity score at diagnosis were risk factors for mortality. Plasma lactate concentration over 2.7 mmol/l was also an independent risk factor, but values in the normal range did not exclude the diagnosis of AMI.

Sepsis remains a critical problem in virtually all fields of clinical medicine. Despite intensive scientific and clinical efforts no significant progress has emerged in the fight against sepsis mortality. Solely the algorithm of the "surviving sepsis campaign" has proven to result in significantly enhanced survival of sepsis patients when consequently adopted. Novel research in the field of the complex immunological alterations in sepsis suggests that ongoing immunosuppression is the critical determinant underlying sepsis mortality. Therefore, it was proposed that immunostimulation might be a successful approach to improve outcome in individually selected patients. Others favor a different view on the pathophysiology of sepsis and support the notion that the manifestation of organ failure may be the dominant therapeutic target. Due to the fact that breakdown of the microcirculation and disruption of the microvascular barrier are critical events preceding organ failure, experimental therapeutic efforts to address these events led to promising results. Taken together, in view of the many initially promising experimental data and the failure to translate them into successful clinical therapies, a different view on the pathophysiology of sepsis is warranted to obtain the key for novel therapeutic options.

The cutaneous radiation syndrome includes all deterministic effects on the skin and visible parts of the mucosa from ionizing radiation. The Intensity and duration of radiation-induced skin symptoms depend on the kind and quality of ionizing radiation. The aim of this study was the investigation of the importance of the time of the development of radiation induced-skin effects on the prognosis of radiation accident victims. Clinical data about radiation accident victims from the database SEARCH were used. 211 cases with good documentation regarding radiation-induced skin effects were selected. From these 211 patients, 166 survived the acute phase of the acute radiation syndrome, while 45 died during the acute phase. Among those patients who did not survive the acute phase, 82.2 % showed their first documented radiation-induced skin symptoms during the first 3 days after radiation exposure. Of those patients whose first documented radiation-induced skin symptoms appeared on or after day four, 94.2 % survived the acute phase. The time to the occurrence of the first radiation-induced skin effects is diagnostically significant. The skin plays an important role in the clinical course of radiation syndromes and in the development of radiation-induced multi-organ failure. In a retrospective data analysis like this, the quality of data might be a limitation.

After severe multiple injuries (first hit) a two-phase immunological response with early hyperinflammation followed by immunosuppression can be observed. This process involves a variety of humoral and cellular factors. Depending on the individual predisposition, overall injury severity and injury pattern, both reactions can lead to sepsis and multiorgan failure. Various clinical and intensive care parameters indicate stabilization of specific organ functions. The clinical course can be positively influenced by adequate intensive care therapy, avoiding iatrogenic second hits by non-emergency surgical interventions during a phase of immunological dysregulation. Important decision parameters besides time to initial trauma include adequate oxygenation, no coagulopathy, declining inflammatory mediators and normalized serum lactate.

Purpose: Children with Down syndrome (DS) have several genetic anomalies within chromosome 21 which may influence their response to critical illness. We compared the intensive care course and outcome of children with DS versus those without., Methods: Retrospective cohort study in four English paediatric intensive care units (ICUs) (2003-2009, n = 33,485). We examined, via a competing risks model, whether risk (subhazard) for ICU mortality differed for children with DS, after adjusting for important confounders., Results: DS patients exhibited lower disease severity at ICU admission but subsequently required a higher proportion of cardiovascular support, and similar renal support to non-DS patients. Children with DS (n = 1,278) had lower crude mortality than those without (4.2 versus 6.2 %, p = 0.003). This was not significant when expressed as standardized mortality ratio: 0.83 [95 % confidence interval (CI) 0.63-1.09] versus 0.90 (95 % CI 0.86-0.94). However, the competing risks model showed that mortality risk was influenced by length of ICU stay. At admission, DS patients exhibited a subhazard for mortality of 0.63 (95 % CI 0.46-0.85), which increased to 1.00 by day 10 of admission, and continued rising above that of non-DS children thereafter., Conclusions: Children with DS require a higher proportion of organ support than expected by disease severity at ICU admission. In addition, the mortality risk for children with DS is dependent upon length of ICU stay. These findings could reflect differences in case mix, but are also compatible with different response to critical illness in this group.

Introduction: Corticosteroids have been proposed to decrease morbidity and mortality in patients with septic shock. An impact on morbidity should be anticipated to be earlier and more easily detected than the impact on mortality., Methods: Prospective, randomized, double-blind, placebo-controlled study of 28-day mortality in patients with septic shock for <72 h who underwent a short high-dose ACTH test in 52 centers in 9 European countries. Patients received 11-day treatment with hydrocortisone or placebo. Organ dysfunction/failure was quantified by the use of the sequential organ failure assessment (SOFA) score., Results: From March 2002 to November 2005, 499 patients were enrolled (hydrocortisone 251, placebo 248). Both groups presented a similar SOFA score at baseline (hydrocortisone 10.8 ± 3.2 vs. placebo 10.7 ± 3.1 points). There was no difference in 28-day mortality between the two treatment groups (hydrocortisone 34.3% vs. placebo 31.5%). There was a decrease in the SOFA score of hydrocortisone-treated patients from day 0 to day 7 compared to the placebo-treated patients (p = 0.0027), driven by an improvement in cardiovascular organ dysfunction/failure (p = 0.0005) and in liver failure (p < 0.0001) in the hydrocortisone-treated patients., Conclusion: Patients randomized to treatment with hydrocortisone demonstrated a faster decrease in total organ dysfunction/failure determined by the SOFA score, primarily driven by a faster improvement in cardiovascular organ dysfunction/failure. This organ dysfunction/failure improvement was not accompanied by a decreased mortality.

Background: Uncontrollable hemorrhaging after blunt trauma and the resulting hemorrhagic shock is still one of the main causes of death in trauma patients. Starting volume replacement before admission to hospital is one of the main pillars of immediate treatment. The statements concerning the quantity of the preclinically administered fluid are still controversial and have a low level of evidence in the literature. Massive abdominal trauma and unstable pelvic fractures belong to the most relevant causes of hemorrhagic shock. The aim of this study was to analyze the influence of the quantity of the preclinically administered fluid on the posttraumatic course of patients with massive abdominal and pelvic injuries., Patients and Methods: All patients of the trauma registry of the DGU (German Society for Trauma Surgery) who met the following criteria were included: injury severity score ≥16 points, primary admission to hospital, age ≥16 years, initial blood pressure <100 mmHg and transfusion of erythrocyte concentrate (EC). Out of this collective patients with an AIS abdomen ≥4 or an AIS pelvis ≥4 were analyzed. Both groups were divided into 4 subgroups subject to the preclinically infused volume (<1000 ml, 1000-2000 ml, 2001-3000 ml and >3000 ml)., Results: Of the 375 patients with abdominal trauma and 229 patients with pelvic trauma were consistent with the inclusion criteria. In both groups an increasing volume replacement was associated with an increased need for transfusion and a reduction of the coagulation ability (Quick 61% in the case of <1000 ml versus 49.1% in the case of >3000 ml). The rescue time had a relevant influence on the quantity of preclinically infused volume (62 min for <1000 ml versus 88 min for >3000 ml). On admission to hospital the blood pressure values were on average the same in all patients (~ 95 mmHg). With an increasing volume a slight elevation of lethality was found as well as a significant increase of the transfused erythrocyte concentrates, a significant deterioration of coagulation and an increase of patients with mass transfusions., Conclusion: In the case of a preclinical relevant bleeding after blunt pelvic or abdominal trauma moderate volume replacement (<1000 ml) results in an enhancement of the initial coagulation situation and in a reduction in the need for transfusion. The results of this study support the concept of a restrained volume therapy after massive trauma with and bleeding requiring transfusion.

Objective: To study the clinical course in children requiring continuous renal replacement therapy (CRRT) and to analyse factors associated with mortality., Design: Prospective observational study., Setting: Paediatric intensive care department of a tertiary university hospital., Patients: Critically ill children with CRRT were included in the study., Intervention: Continuous renal replacement therapy., Measurements and Results: Univariate and multivariate analyses were performed to analyse the influence of each factor on mortality. The ability of the PRISM, PIM II and PELOD severity of illness scores to predict mortality was tested using receiver-operating characteristic curve statistics. A total of 174 children aged between 1 month and 22 years were treated with CRRT. Mortality was 35.6%, and multiorgan failure and haemodynamic disturbances were the principal causes of death. Mortality was higher in children less than 12 months of age (44.7%; P = 0.037) and in patients with a diagnosis of sepsis (44.1%; P = 0.001). Haemodynamic disturbances at the time of starting CRRT (hypotension or need for adrenaline >0.6 microg/kg/min) and the presence of multiorgan failure were the factors associated with an increased risk of mortality. The PRISM scale was the severity score with the best predictive capacity, although all three scales underestimated the actual mortality., Conclusions: Mortality in children who require CRRT is high. Haemodynamic disturbances and the presence of multiorgan failure at the time of starting the technique are the factors associated with a higher mortality. The clinical severity scores underestimate mortality in children requiring CRRT.

Purpose: Multiple organ failure is a leading cause of death in critically ill patients and could be secondary to early gut ischemia. Plasma citrulline is a biomarker of enterocyte mass, and critically ill patients may have enterocyte mass reduction. The objectives of this study were to assess plasma citrulline kinetics and its prognostic value in critically ill patients., Methods: This prospective observational study included adults without small bowel disease and without chronic renal failure consecutively admitted to a single intensive care unit. Prognostic variables as well as plasma citrulline concentrations were studied at admission, 12, 24, 48 h, and the 7th day after admission. Univariate and multivariate analyses including plasma citrulline (0-10, 11-20, and >20 micromol l(-1)) and other variables were performed., Results: Sixty-seven patients were included, and the 28-day mortality was 34%. During the 1st day mean plasma citrulline decreased from 18.8 to 13.5 micromol l(-1). Low plasma citrulline at 24 h was associated with low plasma glutamine and arginine (p = 0.01 and 0.04), and high plasma CRP concentration, nosocomial infection rate, and 28-day mortality (p = 0.008, 0.03, and 0.02, respectively). In multivariate analysis plasma citrulline < or = 10 micromol l(-1) at 24 h and SOFA score > or =8 at 24 h were associated with 28-day mortality(odds ratios 8.70 and 15.08)., Conclusions: In critically ill patients, low plasma citrulline at 24 h is an independent factor of mortality and could be a marker of acute intestinal failure.

Objective: External validation of the paediatric logistic organ dysfunction (PELOD) score in two paediatric intensive care units (PICU) in South America., Methods: Prospective observational cohort study including all PICU admissions from July 2003 to December 2004 in Porto Alegre, Brazil, and from January 2004 to December 2004 in Buenos Aires, Argentina. The data collected included demographic variables, diagnosis, need for mechanical ventilation, length of PICU stay and mortality, and the 12 variables in the PELOD score. For each PELOD score variable, the worst daily value and the worst value of the whole PICU stay were used for the daily PELOD (dPELOD) and PELOD scores, respectively., Results: A total of 1,476 admissions (51.3% from Argentina and 48.7% from Brazil) were analysed. Observed and predicted mortality were, respectively, 4.7% and 6.6%, with a standardized mortality ratio of 0.72. The score showed excellent discrimination capacity, with an area under the receiver operator characteristic (ROC) curve of 0.93 (0.88-0.98). The dPELOD score on days 1-5 also showed good discrimination capacities, with areas under the ROC curve >0.85. However, PELOD and dPELOD scores showed poor calibration with the Hosmer-Lemeshow test (chi-square 72.3, p < 0.001). This poor calibration was explained by a deficiency in the PELOD score where it fails to identify two risk intervals; 3.1-16.2% and 40-80%., Conclusions: The PELOD score is reproducible, has excellent discrimination, but over-predicts mortality and has poor calibration. Although the lack of calibration may not invalidate the score, the PELOD score is a discontinuous variable and we advise careful consideration when using it as a surrogate endpoint in clinical trials.

Purpose: To describe outcome and changes in clotting and inflammatory parameters in an uncontrolled case series of consecutive patients with severe sepsis who received protein C concentrate soon after cardiac surgery., Methods: From January 2007 to January 2008 nine consecutive adult patients with severe sepsis or septic shock and two or more organ failure after cardiac surgery received protein C concentrate, 50 IU/kg as a bolus followed by continuous infusion of 3 IU/kg per hour for 72 h., Results: The increase in protein C levels was accompanied by an early drop in interleukins and near-normalization of prothrombin time, activated partial thromboplastin time, antithrombin and thrombin-antithrombin complex levels (p < or = 0.03). No patient experienced drug-related side effects. Thirty-day mortality was 11% (1 patient) compared to the expected mortality of 68%., Conclusions: In this pilot, uncontrolled study of nine patients with sepsis-induced double organ failure following cardiac surgery, treatment with protein C concentrate was associated with significant improvement in clinical, inflammatory and clotting parameters, no bleeding and low 30-day mortality.

Purpose: To describe the course of early organ dysfunction in a cohort of patients admitted in ICU suffering classic heatstroke., Methods: Prospective observational single-centre cohort study with a 1-year follow-up., Interventions: None., Measurements and Main Results: Clinical and biological data of 22 patients were analysed. Median body temperature on admission was 41.1 degrees C. Respiratory, circulatory, haematological, hepatic and renal function all deteriorated within the first 24 h of admission. ICU-mortality was 63.6%. Cooling time, serum lactate, serum cardiac troponin I and creatinine were significantly higher in non-survivors. Early ICU-mortality (within 7 days of ICU stay) was due to multiple organ failure. Late ICU-mortality was due to neurological disability., Conclusions: Classic heat stroke may demonstrate a rapidly worsening organ dysfunction course leading to death even though cooling procedures and intensive care management are promptly started.

Objective: To compare the time course of organ dysfunction/failure, mortality and cause of death in patients with severe sepsis (SS) and patients with severe non-infectious systemic inflammatory response syndrome (SNISIRS)., Design: Secondary analysis of a multi-centre inception cohort study., Setting: Twenty-three multidisciplinary intensive care units (ICUs) in Australia and New Zealand., Patients and Participants: 3,543 ICU admissions > or = 48 h or <48 h if SIRS and organ dysfunction present., Interventions: None., Measurements and Results: ICU prevalence of SS and SNISIRS was 20% (707/3,543) and 28% (980/3,543), respectively. ICU mortality was similar in patients with SNISIRS and with SS (25 vs. 27%, P = 0.40). Central nervous system (CNS) failure occurred more frequently in patients with SNISIRS (33 vs. 22%, P < 0.001) and resulted in death more commonly than in SS (relative risk = 1.6, 95% confidence interval 1.4-1.7, P < 0.001). The time to peak organ dysfunction (0.67 vs. 0.91 days, P = 0.004), overall episode length (3.6 vs. 5.6 days, P < 0.001) and ICU stay (geometric mean: 4.1 vs. 5.8 days, P < 0.001) were significantly shorter in patients with SNISIRS., Conclusions: Whilst SNISIRS and SS have similarities, including their crude mortality rate, important differences exist. SNISIRS is more common on admission to the ICU, and is more commonly coupled with CNS dysfunction and death from neurological failure., Descriptors: SIRS/sepsis: clinical studies.

Chen et al. found that the CA haplotype of protein C -1654C/T and -1641G/A was associated with increased risk of death and organ dysfunction in Chinese Han patients with severe sepsis (Hum Genet 123:281-287, 2008). We similarly tested for association of the C allele of protein C 673 T/C (rs2069912) (linkage disequilibrium with the CA haplotype, D' = 100%) in a cohort of 100 North American East Asians with severe sepsis. The C allele was associated with increased mortality and organ dysfunction, consistent with Chen et al.

Objective: To study the predictive value of high mobility group box-1 protein (HMGB1) and hospital mortality in adult patients with severe sepsis., Study Design: Prospective observational cohort study in 24 ICUs in Finland., Patients: Two hundred and forty-seven adult patients with severe sepsis., Measurements and Main Results: Blood samples for HMGB1 analyses were drawn from 247 patients at baseline and from 210 patients 72 h later. The mean APACHE II and SAPS II scores were 24 (SD 9) and 44 (SD 17), respectively. The hospital mortality was 26%. The serum HMGB1 concentrations were measured first by semi-quantitative Western immunoblotting (WB) analysis. The median HMGB1 concentration on day 0 was 108% (IQR 98.5-119) and after 72 h 107% (IQR 98.8-120), which differed from healthy controls (97.5%, IQR 91.3-106.5; p=0.028 and 0.019, respectively). The samples were re-analysed by ELISA (in a subgroup of 170 patients) to confirm the results by WB. The median concentration in healthy controls was 0.65 ng/ml (IQR 0.51-1.0). This was lower than in patients with severe sepsis (3.6 ng/ml, IQR 1.9-6.5, p< 0.001). HMGB1 concentrations (WB and ELISA) did not differ between hospital survivors and non-survivors. In ROC analyses for HMGB1 levels (WB) on day 0 and 72 h with respect to hospital mortality, the areas under the curve were 0.51 and 0.56 (95% CI 0.40-0.61 and 0.47-0.65)., Conclusions: Serum HMGB1 concentrations were elevated in patients with severe sepsis, but did not differ between survivors and non-survivors and did not predict hospital mortality.

Objective: To assess the temporal relationship between ICU-acquired infection (IAI) and the prevalence and severity of organ dysfunction or failure (OD/F)., Design and Setting: Observational, single center study in a mixed intensive care unit of a university hospital., Patients: We analyzed 1,191 patients hospitalized for more than 2 days during a 2-year observation period: 845 did not acquire IAI, 306 of whom had infection on admission (IOA); 346 did acquire IAI, 125 of whom had IOA., Measurements and Results: The SOFA score was calculated daily, both SOFAmax, the sum of the worst OD/F during the ICU stay, and SOFApreinf, the sum of the worst OD/F existing before the occurrence of the first IAI. The SAPS II and SOFA score of the first 24 h were significantly higher in patients with than in those without IAI. SOFApreinf of IAI patients was also higher than the SOFAmax of patients without IAI both in patients with (12.1+/-4.6 vs. 8.9+/-4.7) and those without IOA (9.2+/-4.0 vs. 6.7+/-3.5). SOFApreinf represented 85.7% of the value of SOFAmax in patients with IAI. SOFApreinf increased significantly with the occurrence of sepsis, severe sepsis, or septic shock during ICU stay. Severe sepsis and septic shock during ICU stay as well as SOFApreinf were part of the factors associated with hospital mortality., Conclusions: IAI is significantly associated with hospital mortality; however, its contribution to OD/F is minor. Moreover, severity of IAI seems to be related to previous health status.

Background: The prognosis of multiple injured patients is mainly limited by initial severe hemorrhage causing hemorrhagic shock, subsequent sepsis and multiple organ failure (MOF). Although mechanisms of altered microcirculation, cytokine release etc. have been intensively investigated, little is known about the relevance of severe liver trauma as an independent predictive outcome factor in these patients. This study aimed to clarify the impact of severe liver trauma in one of the largest trauma databases., Patients and Methods: The study was based on data from the German trauma register within the German Society for Trauma Surgery (DGU) and 24,711 patients from 113 hospitals were collected for retrospective analysis between 1993 and 2005. Patients with an injury severity score (ISS) >16, no isolated head injury and primary admission to a trauma center were included. Data were allocated according to the injury pattern into I liver group (severe damage of the liver, AIS>3 and AIS abdomen <3), II Abdomen group (severe abdominal trauma AIS>3, AIS liver <3) and III Control group (liver and/or abdominal trauma AIS<3, other trauma AIS>3)., Results: Out of 24,771 multiple injured patients from 113 trauma centers, 321 individuals were identified which matched the criteria of the liver group. Another 574 patients were allocated to the abdomen group while the majority of patients formed the trauma group (9574). Severe injury of the liver is associated with excessive demands for volume resuscitation and induces a significantly increased risk for sepsis and MOF compared to both other groups (sepsis 19.9% vs 11%; MOF 32.7% vs 16.6%). Furthermore, deleterious outcome is more frequent associated with patients with severe liver trauma (lethality 34.9%) compared to severe abdominal trauma (12%) and the control group (19.5%)., Conclusions: Severe liver trauma is an independent predictor for severe hemorrhage with a substantial increased risk of sepsis, MOF and trauma-related death. While conservative treatment of patients with severe liver trauma but no hemorrhage is effective, patients with hemodynamic instability seem to form a subgroup where contemporary treatment modalities are not yet sufficient.

Objective: The insertion/deletion (I/D) of a 289 base pair Alu repeat sequence polymorphism in the angiotensin-converting enzyme gene (ACE) has been shown to predict susceptibility and outcome in the acute respiratory distress syndrome (ARDS). We hypothesized that the I/D polymorphism also confers susceptibility to sepsis and is a predisposing factor for morbidity and mortality of patients with severe sepsis., Design and Setting: Case-control study including 212 consecutive patients fulfilling criteria for severe sepsis admitted to a Spanish network of postsurgical and critical care units, and 364 population-based controls. Susceptibility to severe sepsis was evaluated as primary outcome; mortality in severe sepsis, susceptibility to sepsis-induced ARDS, and mortality in sepsis-induced ARDS were examined as secondary outcomes. An additive model of inheritance in which patients were classified into three genotype groups (II, ID, and DD) was used for association testing., Measurements and Results: Genotype and allele frequencies of I/D were distributed similarly in all septic, ARDS, and non-ARDS patients and in population-based controls. ACE I/D polymorphism was not associated with severe sepsis susceptibility or mortality. The ACE I/D polymorphism was associated neither with sepsis-induced ARDS susceptibility (p=0.895) or mortality (p=0.950). These results remained nonsignificant when adjusted for other covariates using multiple logistic regression analysis or Kaplan-Meier estimates of 28-day survival., Conclusions: Our data do not support an association of the ACE gene I/D polymorphism with susceptibility or mortality in severe sepsis or with sepsis-induced ARDS in Spanish patients.

Objective: To empirically test, based on a large multicenter, multinational database, whether a modified PIRO (predisposition, insult, response, and organ dysfunction) concept could be applied to predict mortality in patients with infection and sepsis., Design: Substudy of a multicenter multinational cohort study (SAPS 3)., Patients: A total of 2,628 patients with signs of infection or sepsis who stayed in the ICU for >48 h. Three boxes of variables were defined, according to the PIRO concept. Box 1 (Predisposition) contained information about the patient's condition before ICU admission. Box 2 (Injury) contained information about the infection at ICU admission. Box 3 (Response) was defined as the response to the infection, expressed as a Sequential Organ Failure Assessment score after 48 h., Interventions: None., Main Measurements and Results: Most of the infections were community acquired (59.6%); 32.5% were hospital acquired. The median age of the patients was 65 (50-75) years, and 41.1% were female. About 22% (n=576) of the patients presented with infection only, 36.3% (n=953) with signs of sepsis, 23.6% (n=619) with severe sepsis, and 18.3% (n=480) with septic shock. Hospital mortality was 40.6% overall, greater in those with septic shock (52.5%) than in those with infection (34.7%). Several factors related to predisposition, infection and response were associated with hospital mortality., Conclusion: The proposed three-level system, by using objectively defined criteria for risk of mortality in sepsis, could be used by physicians to stratify patients at ICU admission or shortly thereafter, contributing to a better selection of management according to the risk of death.

Objective: Inadequate cortisol levels and adrenal dysfunction may play a role in the pathophysiology of severe acute pancreatitis. This study aimed to analyse the incidence of relative adrenal insufficiency (RAI) in these patients, to identify factors associated with RAI and to describe how adrenal responsiveness affects outcome., Design: Prospective observational multicenter study., Patients: Twenty-five patients with severe acute pancreatitis., Interventions: A short Synacthen test (SST) was performed within 5 days after admission to the hospital. The incidence of RAI, defined as an increment after SST of less than 9 microg/dl was the primary endpoint of the study. Serum cortisol was measured at baseline and at 30 and 60 min after administration of 250 microg adrenocorticotropic hormone., Measurements and Results: Median baseline cortisol level was 26.6 microg/dl, and increased to 43.2 microg/dl and 48.8 microg/dl after 30 min and 60 min respectively. RAI was found in 16% of all patients and in 27% of patients with organ dysfunction. Patients with RAI were more severely ill and had higher SOFA scores from days 4 to 7 after admission. All patients with RAI developed pancreatic necrosis, and all of them needed surgical intervention. Twenty-eight-day mortality was significantly higher in patients with RAI (75% vs. 5%, p =0.007). Patients who died had a lower increment in cortisol levels after the SST than patients who survived., Conclusion: RAI is frequent in patients with severe acute pancreatitis and organ dysfunction. It occurs in patients with more severe pancreatitis and is associated with increased mortality.

Objective: To investigate the concentration of cell-free plasma DNA and its association with organ dysfunction and hospital mortality in intensive care unit patients., Design and Setting: Prospective cohort study in a medical and two medical-surgical intensive care units in a university hospital., Patients: 228 critically ill patients admitted to the ICUs between January 2004 and July 2005., Measurements and Results: Blood samples were collected as soon as possible after ICU admission, the following morning, and 48[Symbol: see text]h after the second sample. The cell-free plasma DNA was measured by real-time quantitative PCR assay for the beta-globin gene. Physiological and mortality data were collected to the clinical database. Hospital mortality rate and SOFA scores were primary outcome measures. The maximum plasma DNA concentrations were correlated significantly with APACHE II points and with maximum SOFA scores. Cell-free plasma DNA concentrations were higher in hospital non-survivors than in survivors (median 9,366 vs. 6,506 GE/ml). Using logistic regression analysis, the maximum plasma DNA was an independent predictor of hospital mortality., Conclusions: The maximum plasma DNA concentration measured during the first 96[Symbol: see text]h of intensive care is associated with the degree of organ dysfunction and disease severity. Moreover, the maximum DNA concentration is independently associated with hospital mortality.

Objective: To determine the incidence and outcome of severe sepsis in the adult Finnish population and to evaluate how treatment guidelines in severe sepsis are applied in clinical practice., Study Design: A prospective study in 24 closed multidisciplinary ICUs in 21 hospitals (4 university and 17 tertiary hospitals) in Finland., Patients: All 4,500 consecutive ICU admission episodes were screened for severe sepsis during a 4-month period (1 November 2004 - 28 February 2005). The referral population was 3,743,225., Results: The severe sepsis criteria were fulfilled in 470 patients, who had 472 septic episodes. The incidence of severe sepsis in the ICUs in Finland was 0.38/1000 in the adult population (95% confidence interval 0.34-0.41). The mean ICU length of stay was 8.2+/-8.1 days. ICU, hospital, and 1-year mortality rates were 15.5%, 28.3%, and 40.9%, respectively. Respiratory failure requiring ventilation support was the most common organ failure (86.2%); septic shock was present in 77% and acute renal failure in 20.6% of cases. Activated protein C was given to only 15 of the 55 patients with indication (27%) and low-dose corticosteroids to 150 of 366 (41%) patients with septic shock., Conclusions: This prospective study found the incidence of ICU-treated severe sepsis in Finland to be 0.38 per 1,000 of the population. The ICU and hospital mortalities were also lower than earlier reported in United States or Australia. Evidence-based sepsis therapies were not used as often as recommended.

Objective: To determine serum concentrations of the soluble forms of vascular cell adhesion molecule 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), and E-selectin in ventilated neonatal and pediatric intensive care patients with varying severity of multiorgan dysfunction syndrome (MODS) with or without infection-triggered organ failure., Design and Setting: Prospective pilot study, a level III neonatal and pediatric intensive care unit at a University children's Hospital., Patients: We studied 22 ventilated pediatric (n=15) and neonatal (n=7) intensive care patients (aged 3 days-16 years). Inclusion criteria were mechanical ventilation and signs of at least one additional organ dysfunction (cardiovascular, respiratory, neurological, hematological, or renal)., Measurements and Results: Serum concentrations of the adhesion molecules were analyzed on the day of maximum organ dysfunction score and were quantitated by a sandwich ELISA technique. The overall mortality rate was 36% (8/22). Dysfunction of three or more organ systems was defined as MODS and was associated with a significant increase in VCAM-1 serum levels relative to dysfunction of three or fewer organ systems [median 1239 ng/ml (IQR 928-1615) vs. 766 ng/ml (644-915)]. A significant difference in E-selectin serum levels was found between organ failure of infectious (median 131 ng/ml, IQR 112-146) and noninfectious origin (68 ng/ml 49-105)., Conclusions: Determination of adhesion molecules in pediatric intensive care patients raises the possibility of more specific pathophysiological understanding. E-selectin showed significantly different serum levels between infectious and noninfectious causes of organ failure.

Objective: Most pediatric studies on multiple organ dysfunction syndrome derive from developed countries. There is little information regarding the etiologies and outcomes of multiple organ dysfunction syndrome in critically ill children from developing countries. The objective of this study was to examine the differences in epidemiology of multiple organ dysfunction syndrome and the relationship of the Organ Failure Index (OFI) to outcomes from multiple organ dysfunction syndrome in critically ill children from a developing country., Design: Prospective observational study., Setting: A 10-bed tertiary pediatric intensive care unit., Patients: A total of 1722 children (1 month to 16 years of age) admitted to a pediatric intensive care unit during the study period from January 1998 to June 2003., Interventions: None., Measurements and Main Results: Of all the patients admitted to the pediatric intensive care unit, 184 patients (10.6%) had persistent multiple organ dysfunction syndrome. During the study period 136 deaths (7.9%) occurred in the ICU. Multiple organ dysfunction syndrome was associated with nearly half of these deaths, 67/136 (49.2%). Overall survival of all patients with persistent multiple organ dysfunction syndrome was 64% (117/184). In addition to sepsis, falciparum malaria, fulminant hepatic failure, dengue shock syndrome, severe poisonings, post cardiopulmonary bypass, and post cardiac arrest were significant antecedents of multiple organ dysfunction syndrome . Patients with OFI scores of 2, 3, 4-5, and >5 exhibited mortalities of 9%, 29%, 58%, and 100% respectively., Conclusions: In addition to "traditional" sepsis, common etiologies of multiple organ dysfunction syndrome included falciparum malaria, fulminant hepatic failure, and dengue shock syndrome. In developing countries like India, multiple organ dysfunction syndrome carries a significant risk of mortality which is directly related to the OFI.

Objective: The multiple organ dysfunction syndrome (MODS) is the sequential failure of several organ systems after a trigger event, such as sepsis, pneumonia or cardiogenic shock. Even today, mortality is high. Statin therapy is associated with reduction of inflammation and subsequent rates of severe sepsis and ICU admission of patients admitted to hospital with presumed or documented acute bacterial infection. Our study aimed to characterize a potential survival benefit by statin therapy in MODS patients., Design: Retrospective cohort study., Setting: Twelve-bed medical intensive care unit in a university center., Patients: Forty score-defined MODS patients under statin treatment and 80 age- and sex-matched score-defined MODS patients without statin treatment. Inclusion criterion was an APACHE II score > or = 20 at admission to ICU., Interventions: Assessment of statin treatment and calculation of disease severity by scoring. The patients were followed up for 28-day mortality as well as for hospital mortality., Measurements and Results: The MODS severity was equally pronounced in both groups. There were 42/80 deaths in the group without statin treatment and 13/40 deaths in the statin group (28-day mortality 53% vs. 33%, p = 0.03). Cox proportional hazard analysis revealed a hazard ratio of 0.53 (95% CI 0.29-0.99, p = 0.04). Hospital mortality was calculated at 72% (non-statin group) vs. 35% (statin group; chi-square = 15.6, p < 0.0001). The overall hospital mortality was 60%., Conclusions: Patients under statin treatment developing MODS might have a better outcome than patients without statin therapy, probably by reduction of inflammatory responses and increase of vagal activity in MODS.

Background: For critically ill medical patients until the year 2000, increases in patient age and severity of disease but also acute prognosis have been described. Since then, further improvement appears possible. Several controlled studies have recently demonstrated that acute mortality may be further lowered by new adjuvant therapies such as aggressive glycemic control. However, it is still unknown whether demographic changes and progress in intensive care can be reproduced in surgical critically ill patients outside of a controlled trial setting., Methods: We performed a retrospective, observational cohort study using data prospectively collected from the surgical intensive care unit (ICU) of the LMU Department of Surgery in Munich, Germany, Grosshadern Campus, from March 1 1993 through February 28 2005. Since 1999 we have successively introduced a variety of new therapies to daily routine. A cohort of 5,495 patients was analysed., Results: We identified reduced ICU mortality during the observation period, although age rose simultaneously and disease severity remained constant. Results from multivariate analysis suggest that improvements in prognosis essentially result from the implementation of new therapies after 2001. After adjusting for more than 20 covariables, treatment received after 2001 was identified as an independent factor linked with reduced risk of death., Conclusions: General demographic trends and progress in intensive care can be demonstrated also in unselected surgical cohorts. Furthermore, the results here confirm the efficacy of new therapeutic modifications in routine therapy.

Background: For the treatment of peritonitis or abdominal compartment syndrome, an open abdomen can be required. Because of the high complication rate associated with this method, different technical modifications were developed that are now being applied. Abdominal vacuum-assisted closure is increasingly favoured. We analyse our experience with this device in a distinct group of patients from gastrointestinal cancer surgery., Patients and Method: From June 2003 to December 2005, 36 patients were treated with 151 double-layer abdominal vacuum devices. Indications for applying this device were peritonitis (n = 22), abdominal compartment syndrome (n = 11), and necrotising fasciitis (n = 3). Thirty-four patients gave anamneses of malignoma., Results: Overall, the vacuum therapy treatment lasted a median of 13 days (range 3-48). With it, four enteric fistulas (11%) and four abdominal wall bleedings (11%) occurred. In our patient group, no new intra-abdominal abscesses were observed. Four patients died during treatment with the vacuum-assisted device and four afterward because of multiple organ failure in acute sepsis (in-hospital mortality 22%). Twenty-six patients (72%) underwent direct fascial closure after a median treatment duration of 10 days. Six patients (17%) required synthetic mesh for fascial closure. After a median follow-up of 100 days, two patients developed ventral hernias and two others showed ossification of the scar., Conclusion: Compared with other methods of temporary abdominal closure, our experience with the vacuum-assisted device demonstrates its advantages concerning clinical feasibility and the relatively low complication rate. The high rate of direct fascial closure with an acceptable rate of ventral hernias following vacuum-assisted abdominal closure are further benefits of this technique.

Background: Multiple organ dysfunction syndrome is the commonest reason for sepsis-associated mortality., Discussion: In the 40 years since it was first described understanding of its pathophysiology has improved, and novel methodologies for monitoring and severity of illness scoring have emerged. These, together with the development of systematic strategies for managing organ dysfunction in sepsis, and potentially effective new therapeutic interventions, should assist in reducing sepsis-associated mortality., Conclusion: These historical developments are discussed, and the reader is directed to these references for further guidance.

Objective: This study examined the incidence and mortality of multiple organ dysfunction syndrome (MODS) in intensive care units, evaluated the limitation of life support in these patients, and determined whether daily measurement of the Sequential Organ Failure Assessment (SOFA) is useful for decision making., Design and Setting: Prospective, observational study in 79 intensive care units., Patients and Participants: Of the 7,615 patients admitted during a 2-month period we found 1,340 patients to have MODS., Measurements and Results: We recorded mortality and length of stay in the intensive care unit and the hospital and the maximum and minimum total SOFA scores during MODS. Limitation of life support in MODS patients was also evaluated. Stepwise logistic regression was used to determine the factors predicting mortality. The in-hospital mortality rate in patients with MODS was 44.6%, and some type of limitation of life support was applied in 70.6% of the patients who died. The predictive model maximizing specificity included the following variables: maximum SOFA score, minimum SOFA score, trend of the SOFA for 5 consecutive days, and age over 60 years. The model diagnostic yield was: specificity 100%, sensitivity 7.2%, positive predictive value 100%, and negative predictive value 57.3%; the area under the receiver operating characteristic curve was 0.807., Conclusions: This model showed that in our population with MODS those older than 60 years and with SOFA score higher than 9 for at least 5 days were unlikely to survive.

Purpose: To Evaluate the MELD score as a predictor of 30-day mortality in patients undergoing elective TIPS procedures., Methods: This was a retrospective, IRB-approved study. The medical records of all patients who underwent a TIPS procedure between May 1, 1999 and June 1, 2003 in a single institution were reviewed. Patients who underwent elective TIPS were selected. Elective TIPS was performed in 119 patients with a mean age of 55.1 (+/- 9.6) years. The MELD and Child-Pugh scores before TIPS, etiology of cirrhosis, portosystemic gradients before and after TIPS, procedure time, and procedural complications were obtained from the medical records. The MELD and Child-Pugh scores before TIPS were compared between the survivor group (SG) and the early death (EDG) group. The early death rate was calculated for MELD score subgroups (1-10, 11-17, 18-24, and >24). Data were analyzed using the Fisher exact test, chi-square test and independent-sample t-test. A p value of less than 0.05 was considered significant., Results: Technical success rate was 100%. The early death rate was 10.9% (13/119). The mean MELD scores before TIPS were 19.4 (+/- 5.9) (EDG) and 14 (+/- 4.2) (SG) (p = 0.025). The early death rate was highest in the pre-TIPS MELD > 24 subgroup. The Child-Pugh scores were 9.0 (+/- 1.6) (SG) and 9.8 +/- 1.06 (EDG) (p = 0.08). The mean portosystemic gradients before TIPS were 20.5 (+/- 7.7) mmHg (EDG) and 22.7 (+/- 7.3) (SG) (p > 1) and the mean portosystemic gradients after TIPS were 6.5 (+/- 3.5) (EDG) and 6.9 (+/- 2.4) (SG) (p > 1). The mean procedural times were 95.6 (+/- 8.4) min (EDG) and 89.2 (+/- 7.5) min (SG) (p > 1). No early death was attributed to a fatal complication during TIPS., Conclusion: The MELD score is useful in identifying patients at a higher risk of early death after an elective TIPS. On th basis of our results, we do not endorse elective TIPS in patients with MELD scores > 24.

Objective: To evaluate whether the SOFA score can be used to develop a model to predict intensive care unit (ICU) mortality in different countries., Design and Setting: Analysis of a prospectively collected database. Patients with ICU stay longer than 2 days were studied to develop a mortality prediction model based on measurements of organ dysfunction., Patients: 748 patients from six countries., Measurements and Results: Two logistic regression models were constructed, one based on the SOFA maximum (SOFA Max model) and the other on variables identified by multivariate regression (SOFA Max-infection model). The H and C statistics had a p value above 0.05 for both models, but the D statistics showed a poor performance on the SOFA Max model when stratified for the presence of infection. Subsequent analysis was performed with SOFA Max-infection model. The area under the curve was 0.853. There were no statistically significant differences in observed and predicted mortalities except for one country which had a higher than predicted ICU mortality both in the overall population (28.3 vs. 19.1%) and in the noninfected patients (21.4 vs. 12.6%)., Conclusions: The SOFA Max adjusted for age and the presence of infection can predict mortality in this population, but in one country the ICU mortality was higher than expected. Our data do not allow us to determine the reasons behind these differences, and further studies to detect differences in mortality between countries and to elucidate the basis for these differences should be encouraged.

This study addressed the question of whether thaliporphine, a phenolic aporphine alkaloid obtained from Chinese herbs and possessing antioxidant and alpha-1 adrenoceptor antagonistic activity, has protective effects in endotoxaemic rats and we attempted to elucidate the mechanisms contributing to such protective effects. Injection of rats with endotoxin (E. coli lipopolysaccharide, LPS) induced severe hypotension and tachycardia as well as vascular hyporeactivity to noradrenaline. Pretreatment of LPS-treated rats with thaliporphine attenuated the delayed hypotension significantly whilst only a higher dose (1 mg/kg) of thaliporphine decreased LPS-induced tachycardia. LPS significantly increased nitric oxide (NO.) and superoxide anion (O(2).(-)) levels, a response that was reduced by pretreatment with 1 mg/kg thaliporphine. Endotoxaemia for 240 min resulted in a bell-shaped time course for the change of serum tumour necrosis factor-alpha (TNF-alpha) level with a peak at 60 min. Pretreatment of LPS-treated rats with 1 mg/kg thaliporphine significantly reduced the serum TNF-alpha level at 60 min. In addition, LPS caused a biphasic change in blood glucose and thaliporphine attenuated the late-phase decrease in blood glucose. Endotoxaemia induced multiple organ injury in the liver, kidney and heart, as indicated by increases of aspartate aminotransferase (GOT), alanine aminotransferase (GPT), creatinine (CRE), lactate dehydrogenase (LDH) and creatine phosphate kinase muscle-brain (CKMB) levels in serum. These increases of biochemical markers and inflammatory cell infiltration into injured tissues were reduced significantly by treatment with thaliporphine. In addition, thaliporphine increased the survival rate of LPS-treated mice dose-dependently. In conclusion, our results suggest that thaliporphine could be a novel agent for attenuating endotoxin-induced circulatory failure and multiple organ injury and may increase the survival rate. These beneficial effects of thaliporphine may be attributed to the suppression of TNF-alpha, NO. and O(2).(-) production.

Background: Existing intensive care unit (ICU) prediction tools forecast single outcomes, (e.g., risk of death) and do not provide information on timing., Objective: To build a model that predicts the temporal patterns of multiple outcomes, such as survival, organ dysfunction, and ICU length of stay, from the profile of organ dysfunction observed on admission., Design: Dynamic microsimulation of a cohort of ICU patients., Setting: 49Forty-nine ICUs in 11 countries., Patients: One thousand four hundred and forty-nine patients admitted to the ICU in May 1995., Interventions: None. MODEL CONSTRUCTION: We developed the model on all patients (n=989) from 37 randomly-selected ICUs using daily Sequential Organ Function Assessment (SOFA) scores. We validated the model on all patients (n=460) from the remaining 12 ICUs, comparing predicted-to-actual ICU mortality, SOFA scores, and ICU length of stay (LOS)., Main Results: In the validation cohort, the predicted and actual mortality were 20.1% (95%CI: 16.2%-24.0%) and 19.9% at 30 days. The predicted and actual mean ICU LOS were 7.7 (7.0-8.3) and 8.1 (7.4-8.8) days, leading to a 5.5% underestimation of total ICU bed-days. The predicted and actual cumulative SOFA scores per patient were 45.2 (39.8-50.6) and 48.2 (41.6-54.8). Predicted and actual mean daily SOFA scores were close (5.1 vs 5.5, P=0.32). Several organ-organ interactions were significant. Cardiovascular dysfunction was most, and neurological dysfunction was least, linked to scores in other organ systems., Conclusions: Dynamic microsimulation can predict the time course of multiple short-term outcomes in cohorts of critical illness from the profile of organ dysfunction observed on admission. Such a technique may prove practical as a prediction tool that evaluates ICU performance on additional dimensions besides the risk of death.

Objective: To determine the mode of death in patients admitted to an intensive care unit (ICU) after cardiac arrest who died before hospital discharge., Design: Prospectively defined retrospective review of a database and individual patient medical records and ICU charts., Setting: Eleven-bed multidisciplinary intensive care unit in a general hospital in the United Kingdom., Patients and Participants: All patients admitted to ICU between February 1998 and July 2003 after a cardiac arrest in the previous 24 h., Measurements and Results: The outcome at hospital discharge and mode of death in non-survivors were recorded. Based on the mode of death, non-survivors were placed in one of three groups: multiple organ failure death, neurological death or cardiovascular death. Two hundred and five patients were admitted to ICU after a cardiac arrest; 113 (55.1%) after out-of-hospital cardiac arrest and 92 (44.9%) after in-hospital cardiac arrest. One hundred and twenty-six (61.5%) patients died before hospital discharge and of these 58 (46.0%) died due to neurological injury. After cardiac arrest, 22.9% of the in-hospital patients and 67.7% of the out-of-hospital patients died due to neurological injury, irrespective of the primary cardiac arrest arrhythmia., Conclusions: Two-thirds of the patients dying after out-of-hospital cardiac arrest died due to neurological injury and this proportion was approximately the same for ventricular fibrillation/ventricular tachycardia and pulseless electrical activity/asystole. Approximately a quarter of the patients dying after in-hospital cardiac arrest died due to neurological injury.

Objective: To determine the incidence of body temperature (BT) alterations in critically ill patients, and their relationship with infection and outcome., Design: Prospective, observational study. SETTING. Thirty-one bed, medico-surgical department of intensive care., Patients: Adult patients admitted consecutively to the ICU for at least 24 h, during 6 summer months., Interventions: None., Results: Fever (BT > or =38.3 degrees C) occurred in 139 (28.2%) patients and hypothermia (BT< or =36 degrees C) in 45 (9.1%) patients, at some time during the ICU stay. Fever was present in 52 of 100 (52.0%) infected patients without septic shock, and in 24 of 38 (63.2%) patients with septic shock. Hypothermia occurred in 5 of 100 (5.0%) infected patients without septic shock and in 5 of 38 (13.1%) patients with septic shock. Patients with hypothermia and fever had higher Sequential Organ Failure Assessment (SOFA) scores on admission (6.3+/-3.7 and 6.4+/-3.3 vs 4.6+/-3.2; p<0.01), maximum SOFA scores during ICU stay (7.6+/-5.2 and 8.2+/-4.7 vs 5.4+/-3.8; p<0.01) and mortality rates (33.3 and 35.3% vs 10.3%; p<0.01). The length of stay (LOS) was longer in febrile patients than in hypothermic and normothermic (36 degrees C

Objective: To validate the Multiple Organ Dysfunction (MOD) score externally., Design: Prospective observational cohort study., Setting: Mixed medical/surgical ICU in a tertiary referral university hospital., Patients and Participants: Thousand eight hundred and nine patients admitted to ICU for more than 24 h over a 3-year period., Interventions: None., Measurements and Results: The MOD score was calculated daily for all patients. The criterion validity of the individual organ scores, the maximal MOD score and the change in MOD score were assessed by examining the relationship between increasing scores and ICU mortality. Increased maximal MOD scores and each of the six individual organ scores, and change in MOD scores were associated with increased mortality., Conclusions: Maximal and individual organ scores have criterion validity when tested in a different ICU from that in which the scores were derived, indicating that the scoring systems are reproducible. The association of change in MOD score with mortality indicates that the score is responsive. These data, combined with previous data establishing concept and content validity, indicate that the MOD score is a valid measure of multi-organ dysfunction.

Objective: Antipyrine metabolism is a "gold standard" measure of mixed cytochrome P450 (CYP) mediated drug metabolism in humans. Cytokines (e.g., interleukin-6) and nitric oxide reduce CYP 450 activity in vitro and in vivo. Because interleukin-6 and nitric oxide production increases in children with sepsis-induced multiple organ failure, we hypothesized impaired CYP 450 mediated drug metabolism in this population., Methods: Fifty-one consecutive children with sepsis and six critically ill children without sepsis were enrolled and given 18 mg/kg antipyrine per NG. Plasma antipyrine elimination rate, elimination half-life, and apparent oral clearance were measured and calculated. Plasma interleukin-6 and nitrite plus nitrate levels were measured and organs failing scored on days 1-3 of sepsis., Results: Children with sepsis had a twofold reduction in antipyrine clearance. Children with persistent failure of three or more organs had a fourfold reduction in antipyrine clearance. Antipyrine clearance was inversely correlated to circulating interleukin-6 and nitrite plus nitrate levels and to number of organ failures., Conclusions: Interpretation CYP 450 mediated drug metabolism is decreased in children with sepsis, related in part to the degree of inflammation and organ failure. For drugs metabolized by CYP 450 enzymes there is an urgent need to reevaluate the use of standard drug dosage schedules in the sepsis population

Objective: Based on the results of the PROWESS trial the European Agency for the Evaluation of Medicinal Products has recently approved drotrecogin alfa (activated) for treatment of adult patients with severe sepsis and multiple-organ failure. We report study's data on efficacy and safety in patients with multiple-organ dysfunction., Design and Setting: Randomized, double-blind, placebo-controlled, multicenter trial in 164 medical centers., Patients: 1271 patients (75.2% of the intention-to-treat population, n=1690) with multiple-organ dysfunction at study entry., Interventions: Drotrecogin alfa (activated) n=634, 24 micro g/kg per hour for 96 h or placebo ( n=637)., Results: Observed 28-day mortality was significantly lower with drug treatment than with placebo (26.5%vs. 33.9%), cardiovascular and respiratory organ dysfunction resolved more rapidly over the first 7 days, and serious bleeding events were more frequent (2.4% vs. 1.3%)., Conclusions: Treatment with drotrecogin alfa (activated) significantly reduced 28-day mortality and more quickly resolved cardiovascular and respiratory organ dysfunction. The difference in serious bleeding event rates may be clinically significant; however, the overall benefit-risk profile appears favorable.

Objective: To identify predictors of 30-day mortality and to assess the impact of neutropenia recovery (NR) on 30-day mortality in critically ill cancer patients (CICPs)., Design and Setting: Retrospective review of the medical records of the 102 neutropenic CICPs admitted to a medical intensive care unit (ICU) over a 10-year period., Intervention: None., Measurements and Results: Malignancies consisted of acute leukemia (n=42), lymphoma (n=23), myeloma (n=28), and solid tumors (n=9). Reasons for ICU admission were acute respiratory failure (n=81), shock (n=58), acute renal failure (n=33), and coma (n=13). Seventy patients needed conventional mechanical ventilation (MV) and 21 noninvasive MV, 67 vasopressor agents, and 28 dialysis. Sixty-two patients experienced NR during their ICU stay. In a multivariate logistic regression model, 30-day mortality was higher in patients with acute respiratory or renal failure and lower in patients with NR (OR, 0.09 [0.01-0.86]). This model assumed that patients who experienced NR in the ICU were merely these who did not die early in the ICU. To take into account the effect of time to occurrence of NR on time to death we secondarily used a Cox model including neutropenia duration and NR as time-dependent variables. In this second model, the only significant predictors of 30-day mortality were age, respiratory failure, renal failure, and coma., Conclusion: Organ failure but not disease progression or neutropenia duration affect 30-day mortality in neutropenic CICPs. ICU-acquired events might be modeled as time-dependent variables in a Cox model, rather than standard covariates in logistic regression models.

Objective: To compare outcome prediction using the Multiple Organ Dysfunction Score (MODS) and the Sequential Organ Failure Assessment (SOFA), two of the systems most commonly used to evaluate organ dysfunction in the intensive care unit (ICU)., Design: Prospective, observational study., Setting: Thirty-one-bed, university hospital ICU., Patients and Participants: Nine hundred forty-nine ICU patients., Measurements and Results: The MODS and the SOFA score were calculated on admission and every 48 h until ICU discharge. The Acute Physiology and Chronic Health Evaluation (APACHE) II score was calculated on admission. Areas under receiver operating characteristic (AUROC) curves were used to compare initial, 48 h, 96 h, maximum and final scores. Of the 949 patients, 277 died (mortality rate 29.1%). Shock was observed in 329 patients (mortality rate 55.3%). There were no significant differences between the two scores in terms of mortality prediction. Outcome prediction of the APACHE II score was similar to the initial MODS and SOFA score in all patients, and slightly worse in patients with shock. Using the scores' cardiovascular components (CV), outcome prediction was better for the SOFA score at all time intervals (initial AUROC SOFA CV 0.750 vs MODS CV 0.694, p<0.01; 48 h AUROC SOFA CV 0.732 vs MODS CV 0.675, p<0.01; and final AUROC SOFA CV 0.781 vs MODS CV 0.674, p<0.01). The same tendency was observed in patients with shock. There were no significant differences in outcome prediction for the other five organ systems., Conclusions: MODS and SOFA are reliable outcome predictors. Cardiovascular dysfunction is better related to outcome with the SOFA score than with the MODS.