Chest, 2005 Jan, 127(1), 242 - 5 Inclusion criteria for clinical trials in sepsis: did the american college of chest physicians/society of critical care medicine consensus conference definitions of sepsis have an impact? Trzeciak S, Zanotti-Cavazzoni S, Parrillo JE, Dellinger RP. BACKGROUND: Over the last 25 years, a growing number of clinical trials have evaluated novel sepsis therapies . To promote uniformity in inclusion criteria for patient enrollment, the American College of Chest Physicians and Society of Critical Care Medicine first published consensus conference definitions for sepsis in 1992 . STUDY OBJECTIVES: To characterize (1) the utilization of specific criteria for patient enrollment in sepsis clinical trials and (2) the impact that the consensus conference definitions have had on these criteria . DESIGN: We used MEDLINE to identify clinical trials in sepsis from 1976 to 2001 . Clinical trials published after the consensus conference (ACC; from 1993 to 2001) were compared with trials published before the consensus conference (BCC; from 1976 to 1992) . RESULTS: We identified 176 clinical trials (ACC, 119 trials; BCC, 57 trials) . Clinical trials published ACC were more likely to utilize or reference a previously published standard for inclusion criteria (65% vs 11%, respectively; p < 0.001) . The consensus conference definitions were the standards used in 69% of these trials . The utilization of specified values for WBC count, temperature (T), heart rate (HR), and respiratory rate (RR) was significantly increased in the ACC group compared to the BCC group, as follows: WBC count, 62% vs 26%, respectively (p < 0.001); T, 89% vs 56%, respectively (p < 0.001); HR, 77% vs 26%, respectively (p < 0.001); and RR, respectively 76% vs 28% (p < 0.001) . ACC, clinical trials were less likely to require blood culture positivity (4 of 119 trials {3%} vs 9 of 57 trials {16%}, respectively; p < 0.006) and were more likely to incorporate markers of acute organ dysfunction (81 of 119 trials {68%} vs 28 of 57 trials {49%}, respectively; p < 0.03) in the inclusion criteria . CONCLUSIONS: (1) Since 1992 there has been a significant increase in the utilization of predefined sepsis criteria for patient enrollment in clinical trials, and this increase can be attributed to the existence of consensus conference definitions . (2) Compared to inclusion criteria BCC, inclusion criteria ACC were less reliant on blood culture positivity and were more likely to incorporate markers of organ dysfunction. Peptides, 2005 Mar, 26(3), 493 - 499 Octreotide ameliorates sepsis-induced pelvic inflammation in female rats by a neutrophil-dependent mechanism; Sener G et al.; Sepsis is a generalized inflammatory response, which involves organ systems remote from the locus of the initial infectious insult, accompanied by the release of cytokines and the subsequent formation of reactive oxygen and nitrogen species . The aim of this study was to investigate the possible protective effect of octreotide (OCT), a synthetic somatostatin analogue, against sepsis-induced oxidative damage in the uterine and ovarian tissues of rats . Sepsis was induced by caecal ligation and puncture method in female Wistar albino rats . Sepsis and sham operated (control) groups received either saline or OCT (50mug/kg, i.p.; Novartis) immediately after the operation and at 12h . Twenty-four hours after the surgery, rats were decapitated and serum TNF-alpha levels and tissue malondialdehyde (MDA) content, glutathione (GSH) levels and myeloperoxidase (MPO) activity were determined in the uterus and ovaries . Oxidant-induced tissue fibrosis was determined by tissue collagen contents, while the extent of tissue injuries was analyzed microscopically . Sepsis increased serum TNF-alpha levels and resulted in decreased GSH levels and increased MDA levels, MPO activity and collagen contents in both the uterus and the ovaries (p<0.05-0.001) indicating the presence of the oxidative damage, as also confirmed by histological analysis . On the other hand, OCT administration reversed these oxidant responses and reduced the severity of microscopic damage (p<0.001) . In conclusion, OCT protects against sepsis-induced oxidative injury of the uterine and ovarian tissues by diminishing neutrophil infiltration, an important source of oxygen free radicals . Our results suggest that OCT may be of therapeutic value in ameliorating sepsis-associated pelvic inflammation. Cytokine, 2005 Feb 21, 29(4), 169 - 75 Epub 2004 Dec 08. Sequential measurement of IL-6 blood levels in patients with systemic inflammatory response syndrome (SIRS)/sepsis; Oda S et al.; This study was undertaken to investigate whether sequential measurement of blood interleukin (IL)-6 levels using chemiluminescent enzyme immunoassay (CLEIA) would be useful for the management of patients with systemic inflammatory response syndrome (SIRS)/sepsis . Forty consecutive patients with SIRS/sepsis admitted to ICU were involved in the study . Blood IL-6 level was measured everyday throughout their ICU stay at the clinical laboratory by CLEIA method . The platelet count and the sequential organ failure assessment (SOFA) score were measured consecutively . The blood IL-6 levels were elevated in SIRS/sepsis patients and were extremely high in patients with septic shock . There was no significant difference in the blood IL-6 level on admission between survivors (n=27) and non-survivors (n=13) . However, the mean blood IL-6 level during ICU stay was significantly higher in the non-survivors (p<0.05) . There were significant correlation between the peak IL-6 blood level and the lowest platelet count, and between the peak IL-6 blood level and the maximum SOFA score, respectively . The platelet count became lowest 2.0+/-2.0 days later on average, and the SOFA score became maximal 2.5+/-1.4 days later on average following the day when IL-6 reached its peak value . Sequential measurement of blood IL-6 levels by CLEIA is useful in evaluating the severity and in predicting the outcome of the patients with SIRS/sepsis. Equine Vet J, 2005 Jan, 37(1), 53 - 9 Arterial lactate concentration, hospital survival, sepsis and SIRS in critically ill neonatal foals; Corley KT et al.; REASONS FOR PERFORMING STUDY: Blood lactate concentration has been shown to be a useful clinical indicator in human patients, but has not been formally investigated in critically ill foals . OBJECTIVE: To investigate the association of blood lactate with hospital survival, markers of cardiovascular status, metabolic acid base status, sepsis and systemic inflammatory response syndrome (SIRS) . METHODS: A database containing clinical, haematological, plasma biochemical and hospital outcome data on neonatal foals referred to an intensive care unit in 2000-2001 was analysed . Seventy-two foals for which arterial lactate was measured at admission were included in the study . RESULTS: Sixty-one foals had an admission lactate concentration > 2.5 mmol/l . Admission lactate was statistically associated with hospital survival, mean arterial pressure, blood creatinine concentration, bacteraemia, anion gap, lactate concentration at 18-36 h after admission and evidence of SIRS, but not with packed cell volume or heart rate . Lactate at 18-36 h was also associated with survival and evidence of SIRS . Anion gap, base excess, base excess due to unidentified anions (BEua), simplified strong ion gap or bicarbonate correctly classified foals for presence of hyperlactaemia (> 5 mmol/l) in < or = 80% of animals . CONCLUSIONS: Admission blood lactate gives important prognostic information . Lactate should be measured rather than assumed from the anion gap, base excess, BEua, simplified strong ion gap or bicarbonate . POTENTIAL RELEVANCE: Blood lactate concentrations at admission are clinically relevant in neonatal foals and warrant further investigation . This should include the clinical value of measuring changes in lactate in response to treatment. Anaesth Intensive Care, 2004 Dec, 32(6), 746 - 55 The use of real time rtPCR to quantify inflammatory mediator expression in leukocytes from patients with severe sepsis; Kalkoff M et al.; Real-time reverse transcriptase polymerase chain reaction (RT rtPCR) was used to quantify the pattern of inflammatory mediator mRNA expression in circulating leukocytes from adult patients diagnosed with severe sepsis . We analysed 29 blood samples from 26 severely septic patients with different septic sources and eight samples from eight healthy adult volunteers . RT rtPCR was used to quantify mRNA expression of 21 different inflammatory mediators in peripheral leukocytes . The median variability in gene expression in the sepsis patients was 10.5 times greater than the variability of the healthy comparison group . We found a significant change in the regulation for the following genes: C5aR (20-fold, P < 0.001), IL-8 (29-fold, P < 0.001), MMP9 (72-fold, P < 0.001), HSP70 (2.4-fold, P = 0.02), and RIP2 (1.8-fold, P < 0.04) were up-regulated . Conversely the median expression of IFNgamma, and IL-6 were zero (P < 0.001), and mtHSP (0.4-fold, P = 0.02) was significantly down-regulated . Using linear discriminant analysis, IFNgamma, IL-12, and TLR4 were correlated to a negative outcome . Different septic sources (peritonitis, burn, pneumonia and musculo-skeletal infections) resulted in significantly different mRNA patterns . The RT rtPCR is a useful tool to monitor the immune response in septic patients . We found a very high variability in inflammatory mediator expression among septic patients compared to healthy volunteers . This suggests that any future immune-modulatory therapy may need to be individualized to the patient's requirements as monitored by RT rtPCR . Different sources of sepsis may result in markedly different activation patterns. Int J Artif Organs, 2004 Dec, 27(12), 1077 - 82 High volume hemofiltration (HVHF) in sepsis: a comprehensive review of rationale, clinical applicability, potential indications and recommendations for future research; Honore PM et al.; HVHF can be still seen as a potent powerful immunomodulatory treatment in sepsis . Pleiotropical properties of HVHF give this treatment the possibility to affect not only SIRS but also cardiovascular compounds, clotting and post septic-insult immunoparalysis . By this multimodal approach, HVHF can alter the sepsis network through many targets . The crucial relationship between immunological changes, hemodynamics and survival must be found in future prospective randomised studies . Circulatory cytokines are no longer valuable players except for catecholamine-resistant septic shock . Definitions are of upmost value as ultrafiltrate volume has been correlated in terms of response and survival with the type of disease (sepsis or not) and severity (catecholamine-resistant shock or not) . This latter condition can be seen as the best indication for HVHF and probably even more for very high volume hemofiltration (VHVHF) . More studies are needed to clarify the role of HVHF in hyperdynamic septic shock (with or without acute renal failure), sepsis and SIRS . They can be seen as potential indications up to now . Possible interferences with activated protein C deserve more attention as both treatments can be given sequentially in the same septic patient or even concomitantly. Crit Care Med, 2005 Jan, 33(1), 221 - 3 Cognitive impairment in sepsis survivors from cecal ligation and perforation; Barichello T et al.; OBJECTIVE:: Critical illness survivors present long-term cognitive impairment, including problems with memory and learning . We evaluated cognitive performance in rats that survived from sepsis induced by cecal ligation and puncture (CLP) . DESIGN:: Prospective, controlled experiment . SETTING:: Animal basic science laboratory . SUBJECTS:: Male Wistar rats, weighing 300-350 g . INTERVENTIONS:: The rats underwent CLP (sepsis group) with "basic support" (saline at 50 mL/kg immediately and 12 hrs after CLP plus ceftriaxone at 30 mg/kg and clindamycin at 25 mg/kg 6, 12, and 18 hrs after CLP) or sham-operated (control group) . MEASUREMENTS AND MAIN RESULTS:: Ten days after surgery, the animals underwent three behavioral tasks: a) inhibitory avoidance task; b) habituation to an open field; and c) continuous multiple-trials step-down inhibitory avoidance task (CMSIA) . In the habituation to an open-field task, there were no differences in the number of crossings and rearings . The sepsis group showed significantly decreased performance in latency retention compared with the sham group in inhibitory avoidance . Furthermore, when tested by the habituation to an open-field task, the sepsis group did not show any difference between training and test, indicating memory impairment . In the CMSIA, the sepsis group showed a significant increase in the number of training trials required to reach the acquisition criterion . CONCLUSION:: Our data provide the first experimental demonstration that survivors from CLP show learning and memory impairment after complete physical recovery from sepsis. Crit Care Med, 2005 Jan, 33(1), 161 - 7 Correction of perioperative hypothermia decreases experimental sepsis mortality by modulating the inflammatory response; Xiao H et al.; OBJECTIVE:: The objective of this study was to investigate if the correction of perioperative hypothermia improves sepsis survival . DESIGN:: Mice with anesthesia-induced perioperative hypothermia had sepsis induced by cecal ligation and puncture and were treated with fluid resuscitation and antibiotics . The mice were either warmed (35 degrees C) or kept at room temperature for 1 hr in the immediate postoperative period . SETTING:: This study was conducted at a university research laboratory . SUBJECTS:: This study included adult, female outbred mice . INTERVENTIONS:: Immediately after surgery, mice were randomized to 1 hr of warming or maintained at room temperature . Warming was accomplished by placing the mice in a cage preheated to 35 degrees C . MEASUREMENT AND MAIN RESULTS:: The anesthesia-induced hypothermia resolved within 10 hrs, and perioperative warming reestablished normothermia within 1 hr . Restoring normothermia improved sepsis survival from 42% to 60% (p < .02) . Warming also significantly corrected the changes in body weight, reflecting improved overall physiological status . To examine the mechanism of this beneficial response, plasma levels of interleukin-6 were assessed . Warming was associated with a decrease in interleukin-6 levels in both those mice that died as well as survivors, reflecting a blunting but not complete inhibition of the inflammatory response . Among surviving mice, warming also significantly increased the peripheral blood cell count, including the neutrophils, an indication that warming augmented innate immunity . CONCLUSIONS:: Correction of perioperative hypothermia improves survival after sepsis by appropriately modulating the early inflammatory response. Crit Care Med, 2005 Jan, 33(1), 71 - 80 Epidemiology of sepsis in Victoria, Australia; Sundararajan V et al.; OBJECTIVE:: To determine the clinical and epidemiologic characteristics of patients with sepsis admitted to hospitals in Victoria, Australia, including the incidence of sepsis and severe sepsis, utilization of intensive care unit (ICU) resources, and hospital mortality . DESIGN:: A population-based hospital morbidity database generated from hospital discharge coding . SETTING:: State of Victoria, Australia (population, 4.5 million), the 4-yr period from July 1, 1999, to June 30, 2003 . PATIENTS:: A total of 3,122,515 overnight hospitalizations . INTERVENTIONS:: None . MEASUREMENTS AND MAIN RESULTS:: The overall hospital incidence of sepsis was 1.1%, with a mortality of 18.4% . Of septic patients, 23.8% received some care in an ICU . For these patients, hospital mortality was 28.9% . Severe sepsis, defined by sepsis and at least one organ dysfunction, occurred in 39% of sepsis patients and was accompanied by a hospital mortality of 31.1% . Fifty percent of patients with severe sepsis received at least some care in an ICU . CONCLUSIONS:: Australian state hospital administrative data reveal epidemiologic features of sepsis and severe sepsis that are strikingly similar to those recently reported from comparable populations in North American and Europe . This suggests that lessons learned in this area may be directly applicable internationally. Anaesthesia, 2005 Feb, 60(2), 155 - 62 Cost effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in the United Kingdom*; Davies A et al.; Summary Drotrecogin alfa (activated) is licensed in Europe for the treatment of severe sepsis in patients with multiple organ failure . We constructed a model to assess the cost effectiveness of drotrecogin alfa (activated) from the perspective of the UK National Health Service when used in adult intensive care units . Patient outcomes from a 28-day international clinical trial (PROWESS) and a subsequent follow-up study (EVBI) were supplemented with UK data . Cost effectiveness was assessed as incremental cost per life year and per quality adjusted life year saved compared to placebo alongside best usual care . Applying the 28-day mortality outcomes of the PROWESS study, the model produced a cost per life year saved of pound4608 and cost per quality adjusted life year saved of pound6679 . Equivalent results using actual hospital outcomes were pound7625 per life year and pound11 051 per quality adjusted life year . Drotrecogin alfa (activated) appears cost effective in treating severe sepsis in UK intensive care units. J Burn Care Rehabil, 2005 Jan-Feb, 26(1), 85 - 91 Role of the gastrointestinal tract in burn sepsis; Gosain A et al.; During the last 50 years, our understanding of the role of the gastrointestinal tract as a first-line defense against the development of postburn sepsis has increased dramatically . Starting with the concept of that gut-derived bacteria cause distant injury, investigators have delineated a complex series of physical changes in the barrier of the gastrointestinal tract . Along with an understanding of these physical changes has come an appreciation of the role of the immune system in modulating postburn organ failure . Importantly, recent investigations into the role of mesenteric lymph have fundamentally changed the paradigm of organ failure and have implicated the gut as a cytokine-secreting organ . This article traces the development of key concepts in the study of burn sepsis and their clinical implications. Crit Care Med, 2004 Nov, 32(11), 2234 - 2240 Epidemiology of sepsis in patients with traumatic injury; Osborn TM et al.; OBJECTIVE: To characterize the epidemiology of sepsis in trauma . DESIGN: Analysis of a prospectively collected administrative database (Pennsylvania trauma registry) . SETTING: All trauma centers in the state of Pennsylvania (n = 28) PATIENTS: All patients (n = 30,303) with blunt or penetrating injury admitted to Pennsylvania trauma centers over a 2-yr period (January 1996-December 1997) . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Incidence of sepsis in trauma, independent predictors of sepsis, and associated mortality were evaluated . Analyses controlled for age, gender, preexisting disease, injury type, Revised Trauma Score, Injury Severity Score, and admission vital signs . Sepsis occurred in 2% of all patients and was associated with a significant increase in mortality (23.1% vs . 7.6%, p < .001) compared with nonseptic patients . Respiratory tract infections were the most common cause of sepsis . Septic trauma patients had increased ICU length of stay (21.8 vs . 4.7 days, p < .001) and hospital length of stay (34.1 vs . 7.0 days, p < .001) . Logistic regression identified Injury Severity Score, Revised Trauma Score, lower admission Glasgow Coma Scale score, and preexisting diseases as significant independent predictors of sepsis, whereas female gender was associated with a decreased risk of sepsis . Increasing injury severity measured by Injury Severity Score was associated with increased incidence of sepsis . Moderate (Injury Severity Score 15-29) and severe injury (Injury Severity Score >/=30) had a six-fold and 16-fold, respectively, increased incidence of sepsis compared with mild injury . Multivariate analysis confirmed that the effect of sepsis on mortality was greater in trauma patients with mild injury than those with moderate or severe injury . CONCLUSIONS: This study reports the incidence of sepsis and its associated mortality and critical care resource utilization in a large, state-wide population-based trauma registry . Increasing injury severity, measured by Injury Severity Score, was a significant independent predictor of sepsis in trauma and was associated with increased intensive care unit resource utilization and mortality . These results suggest that future studies should attempt to delineate interventional strategies to prevent sepsis in trauma patients with moderate and severe injury, given their significantly increased risk. Crit Care Med, 2004 Nov, 32(11), 2207 - 2218 Hospital mortality and resource use in subgroups of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial; Laterre PF et al.; OBJECTIVE: To compare differences in hospital mortality and resource use in adult severe sepsis subjects randomized to receive drotrecogin alfa (activated) (DrotAA) or placebo in the PROWESS trial . DESIGN: Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled trial . SETTING: One hundred sixty-four tertiary care institutions in 11 countries . PARTICIPANTS: The 1,690 subjects with severe sepsis enrolled and treated with study drug in PROWESS, of whom 1,220 were alive at 28 days (the end of the original PROWESS follow-up) . INTERVENTIONS: DrotAA (n = 850), 24 microg/kg/hr for 96 hrs, or placebo (n = 840) . MEASUREMENTS AND MAIN RESULTS: New follow-up data through hospital discharge were merged with existing 28-day follow-up data . Hospital mortality was calculated for designated subgroups . Intensive care unit and hospital length of stay and Simplified Therapeutic Intervention Scoring System-28 (TISS-28) scores were calculated overall and in designated subgroups . Hospital discharge location was recorded . The 95% confidence interval of most subgroups contained the relative risk estimate for overall 28-day and hospital mortality . Median hospital length of stay and intensive care unit length of stay were similar in both treatment groups: 16 vs . 17 days (p = .22) and 9 vs . 9 days (p = .7) for placebo vs . DrotAA . No significant difference in TISS-28 scores was observed between treatment groups overall or in subgroups of disease severity . In subjects for whom discharge destination was reported, 42.8% of placebo subjects and 46.8% of DrotAA subjects (two thirds of survivors in each group) were discharged directly to home . CONCLUSIONS: Reduction in hospital mortality with DrotAA in most of the subgroups of PROWESS is consistent with the reduction in 28-day and hospital mortality observed in the overall PROWESS population . Additional survivors created with DrotAA treatment did not increase per-patient resource use or intensive care unit or hospital length of stay. Crit Care Med, 2004 Nov, 32(11), 2199 - 2206 The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis; Angus DC et al.; OBJECTIVE: To determine long-term survival for subjects with severe sepsis enrolled in the previous multiple-center trial (PROWESS) of drotrecogin alfa (activated) (DrotAA) vs . placebo . DESIGN: Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled trial . SETTING: One hundred sixty-four tertiary care institutions in 11 countries . PARTICIPANTS: The 1,690 subjects with severe sepsis enrolled and treated with study drug in PROWESS, of whom 1,220 were alive at 28 days (the end of the original PROWESS follow-up) . INTERVENTIONS: DrotAA (n = 850), 24 mug/kg/hr for 96 hrs, or placebo (n = 840) . MEASUREMENTS AND MAIN RESULTS: Long-term survival data were collected . We had follow-up information on 100% of subjects at 28 days, 98% at hospital discharge, 94% at 3 months, and 93% at 1 yr . The longest follow-up was 3.6 yrs . Hospital survival was higher with DrotAA vs . placebo (70.3% vs . 65.1%, p = .03) . There was no statistically significant difference in duration of survival time or in landmark survival rates in subjects who received DrotAA compared with those who received placebo (median duration of survival = 1113 days vs . 846 days for DrotAA vs . placebo, p = .10; landmark survival rates for DrotAA vs . placebo, 66.1% vs . 62.4% at 3 months {p = .11}, 62.2% vs . 60.3% at 6 months {p = .44}, 58.9% vs . 57.2% at 1 yr {p = .49}, and 52.6% vs . 49.3% at 2(1/2) yrs {p = .21}) . There was a significant interaction (p = .0008) between treatment assignment and baseline Acute Physiology and Chronic Health Evaluation (APACHE) II scores, suggesting qualitative differences in treatment effect with severity of illness . Subjects with APACHE II >/=25 had better survival time with DrotAA (median duration of survival: 450 vs . 71 days, p =.0005) . Survival rates were also higher at landmark time points (DrotAA vs . placebo, 58.9% vs . 48.4% at 3 months {p = .003}, 55.2% vs . 45.3% at 6 months {p = .005}, 52.1% vs . 41.3% at 1 yr {p = .002}, and 45.6% vs . 33.8% at 2(1/2) yrs {p = .001}) . In the APACHE II <25 group there was no significant difference in survival time or survival rates at landmark time points except at 1 yr (DrotAA vs . placebo, 65.5% vs . 72.0% at 1 yr, p = .04) . CONCLUSIONS: The acute survival benefit observed in subjects with severe sepsis who received DrotAA persists to hospital discharge . The survival benefit loses statistical significance thereafter . Post hoc analysis suggests the effect of DrotAA varies by APACHE II score with improved long-term survival in subjects with APACHE II scores >/=25 but no benefit in those with lower scores. Crit Care Med, 2004 Nov, 32(11), 2173 - 2182 Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels; Panacek EA et al.; OBJECTIVE: To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6 . DESIGN: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial . SETTING: One hundred fifty-seven intensive care units in the United States and Canada . PATIENTS: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels . INTERVENTIONS: Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL . Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group . They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days . The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result . MEASUREMENTS AND MAIN RESULTS: In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group . Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9% . Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively . In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively . Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo . The safety profile of afelimomab was similar to that of placebo . CONCLUSIONS: Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels. J Immunol, 2005 Jan 15, 174(2), 1104 - 10 Changes in the Novel Orphan, C5a Receptor (C5L2), during Experimental Sepsis and Sepsis in Humans; Huber-Lang M et al.; Sepsis is associated with extensive complement activation, compromising innate immune defenses, especially in neutrophils (PMN) . Recently, a second C5a receptor (C5L2) was detected on PMN without evidence of intracellular signaling . The current study was designed to determine changes in C5L2 in blood PMN during sepsis . In vitro exposure of PMN to C5a, but not to fMLP, led to reduced content of C5L2 . Following cecal ligation and puncture-induced sepsis in rats, PMN demonstrated a time-dependent decrease in C5L2 . In vivo blockade of C5a during experimental sepsis resulted in preservation of C5L2 . Similarly, PMN from patients with progressive sepsis showed significantly reduced C5L2 expression (n = 26), which was virtually abolished in patients who developed multiorgan failure (n = 10) . In contrast, sepsis survivors exhibited retention of C5L2 (n = 12/13) . The data suggest that C5L2 on PMN diminishes during sepsis due to systemic generation of C5a, which is associated with a poor prognosis. Zhonghua Wai Ke Za Zhi, 2004 Nov 22, 42(22), 1377 - 80 {Effect of thymosin alpha(1) on immunological function and metabolism in peritoneal sepsis rats.}; Jiang J et al.; OBJECTIVE: To investigate the effect of thymosin alpha1 on immunological function and protein metabolism in peritoneal sepsis rats . METHODS: We observed the effect of thymosin alpha1 on T cell subclassification, TNFalpha, IL-6, IL-10, albumin, C-reactive protein (CRP) and mortality in cecal ligation and puncture (CLP) induced septic rats . RESULTS: Concentration of TNFalpha and IL-6 in CLP induced septic rats increased significantly, and concentration of IL-10 decreased significantly compared to control group . Thymosin alpha1 significantly decreased TNFalpha, IL-6, and significantly raised concentration of plasma IL-10, percent of CD(3), CD(4), and CD(4)/CD(8) in septic group . Thymosin alpha1 reduced degressive degree of albumin . Concentration of CRP increased in both septic groups, but was less prominently in thymosin alpha1 treated group . Thymosin alpha1 reduced cummulative 7-day mortality . CONCLUSION: Thymosin alpha1 can improve immunological function, inflammation condition and protein metabolism. Ann Pharmacother . 2005 Jan 4; {Epub ahead of print} Obesity Does Not Alter the Pharmacokinetics of Drotrecogin Alfa (Activated) in Severe Sepsis (February); Levy H et al.; BACKGROUND: Drotrecogin alfa (activated) {DrotAA} is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death . Patients whose actual body weight was >135 kg were excluded from the Phase III PROWESS trial . OBJECTIVE: To compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing </=135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2 ) of DrotAA in these patients . METHODS: PROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled . Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion . Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups . RESULTS: Patient weight range was 59-227 kg . There were 32 patients </=135 kg and 20 patients >135 kg enrolled . Median Clp was 0.45 L/h/kg (interquartile range {IQR} 0.37-0.54) for patients </=135 kg and 0.42 L/h/kg (IQR 0.33-0.54) for patients >135 kg (p = 0.692) . Median estimates of Css were 51.9 ng/mL (IQR 43.4-62.0) and 56.5 ng/mL (IQR 44.9-71.1; p = 0.570) . In patients </=135 kg, DrotAA had a median t1/2 of 16.7 minutes (IQR 13.9-20.0) compared with 16.0 minutes (IQR 12.9-19.8) in patients >135 kg (p = 0.767), for a composite median t1/2 of 16.3 minutes (IQR 14.2-18.8) . CONCLUSIONS: There is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing </=135 kg and >135 kg . DrotAA should be dosed by actual body weight. Indian J Gastroenterol, 2004 Nov-Dec, 23(6), 222 - 3 Peritonitis and fulminant sepsis due to spontaneous rupture of Iliopsoas abscess; Kumar S et al.; We report a 25-year-old woman who presented with fetures of peritonitis . At laparotomy, the cause of the pyoperitoneum was found to be a left-sided ilio-psoas abscess . This was drained, but the patient continued to deteriorate with sepsis, and died on the fourth post-operative day. Anaesthesist . 2004 Dec 30; {Epub ahead of print} {Vasopressin and terlipressin in sepsis and systemic inflammatory response syndrome Auswirkungen auf Mikrozirkulation, Sauerstofftransport, Metabolismus und Organfunktion.}; Ertmer C et al.; Vasopressin and terlipressin are increasingly used as alternative non-adrenergic vasopressors for hemodynamic support of septic patients with arterial hypotension . Despite excellent vasopressive effects, vasopressin analogues may potentially impair macrohemodynamics, oxygen transport and microvascular blood flow . Due to those unwanted side-effects, vasopressin and terlipressin may potentially compromise organ function and possibly foster the development of multiple organ failure . This review article discusses the results of clinical and experimental studies to judge the effects of vasopressin and terlipressin on microcirculation, oxygen supply, metabolism and organ function in patients with sepsis or systemic inflammatory response syndrome (SIRS) . Although vasopressin analogues are emerging as promising alternatives to treat catecholamine-refractory hypotension, there is no evidence that vasopressin receptor agonists improve outcome . To date, vasopressin and terlipressin can, therefore, not be recommended for routine clinical use. Surg Today, 2005 Jan, 35(1), 52 - 59 Melatonin Protects Against Oxidative Organ Injury in a Rat Model of Sepsis; Sener G et al.; PURPOSE: Based on the potent antioxidant effects of melatonin, we investigated the putative protective role of melatonin against sepsis-induced oxidative organ damage in rats . METHODS: Sepsis was induced by cecal ligation and puncture (CLP) in Wistar albino rats . Animals subjected to CLP and sham-operated control rats were given saline or melatonin 10 mg/kg intraperitoneally 30 min before and 6 h after the operation . The rats were killed 16 h after the operation and the biochemical changes were investigated in the liver, kidney, heart, lung, diaphragm, and brain tissues by examining malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity . We also examined the tissues microscopically . RESULTS: Sepsis resulted in a significant decrease in GSH levels and a significant increase in MDA levels and MPO activity (P < 0.05-P < 0.001) showing oxidative damage, which was confirmed by histological examination . Melatonin clearly reversed these oxidant responses and the microscopic damage, demonstrating its protective effects against sepsis-induced oxidative organ injury . CONCLUSION: The increase in MDA levels and MPO activity and the concomitant decrease in GSH levels demonstrate the role of oxidative mechanisms in sepsis-induced tissue damage . Melatonin, by its free radical scavenging and antioxidant properties, ameliorated oxidative organ injury . Thus, supplementing antiseptic shock treatment with melatonin may be beneficial in the clinical setting. Nursing, 2005 Jan, 35(1), 38 - 42 Sepsis: Taking a deeper look; Cheek DJ et al.; New discoveries about this complex disorder reveal how endothelial damage and protein C deficiency contribute to sepsis . Here's what it all means for you and your patients. J Perinatol . 2004 Dec 23; {Epub ahead of print} Practice Variation in Suspected Neonatal Sepsis: A Costly Problem in Neonatal Intensive Care; Spitzer AR et al.; OBJECTIVE:: The most common admission to intensive care nurseries is the infant with suspected neonatal sepsis . To determine the clinical practice of neonatologists with respect to this diagnosis, we examined a large neonatal database during a 2-year period of time . The goal of this study was to define whether there were optimal practice strategies that could identify a "benchmark" clinical approach for this diagnosis . DESIGN:: The PROACT((c)) database of ParadigmHealth was examined for all term infants with an admitting ICD - 9 code for suspected neonatal sepsis between January 1, 2001 and December 31, 2002 . Infants had to be asymptomatic by 24 hours of life with no significant respiratory signs and receiving oral feedings . All infants had negative blood cultures . Maternal risk factors were examined to determine if they influenced the duration of therapy . The impact of treatment upon subsequent length of stay was also evaluated . Several areas of the country were individually examined to see if possible regional variations existed with respect to treatment of suspected sepsis . RESULTS:: There were no significant differences noted in the management when maternal risk factors for suspected sepsis were assessed . In general, neonates were treated for 3.3+/-1.8 to 3.5+/-2.1 days, regardless of the number of maternal risk factors present at birth (p=NS) . Length of stay ranged from 4.2+/-2.1 to 4.4+/-1.9 days in these groups (p=NS) . The duration of treatment ranged from 1 to 10 days, even though all infants were clinically well and feeding by 24 hours of life . A total of 170 infants (17.0%) were treated for 4 to 6 days and 116 (11.6%) neonates received antibiotics for 7 to 10 days, even with negative blood cultures . One region of the country appeared to treat infants for a longer period of time than the other four regions examined, increasing the mean length of stay by 1.8 days (p<0.05) . CONCLUSIONS:: Treatment of neonates with suspected sepsis appears to be influenced by considerations other than maternal risk factors or the infant's clinical condition beyond the first day of life . There appears to be a great deal of practice variation among neonatologists confronted by patients with suspected sepsis . Awareness of this unnecessary variation may be of great value in reducing the duration of antibiotic therapy in the NICU and shortening the length of stay.Journal of Perinatology advance online publication 23 December 2004; doi:10.1038/sj.jp.7211252. Shock, 2005 Jan, 23(1), 88 - 96 EFFECTS OF A MEMBRANE-PERMEABLE RADICAL SCAVENGER, TEMPOL, ON INTRAPERITONEAL SEPSIS-INDUCED ORGAN INJURY IN RATS; Liaw WJ et al.; There is good evidence that endotoxemia, sepsis, and septic shock are associated with the generation and release of reactive oxygen species (ROS) such as superoxide anion (O2), indicating that oxygen-derived free radicals play an important role in the pathogenesis of sepsis/shock . Studies on the application of free oxygen radical scavengers to limit the damage to tissues and organs have been recently attempted . A stable piperidine nitroxide of low molecular weight (Tempol) can permeate biological membranes and scavenge O2 in vitro and in vivo . Thus, we investigated effects of Tempol on the circulatory failure and multiple organ injuries caused by a clinically relevant polymicrobial sepsis model in the rat-cecal ligation and puncture (CLP) . CLP not only successfully induced circulatory failure but also substantially increased plasma concentrations of glutamate-oxalate-transferase and glutamate-pyruvate-transferase (indicators of liver injury), creatinine and blood urea nitrogen (indicators of kidney injury), and decreased base excess in arterial blood in the late stage, indicating the development of multiple organ injury in this study . These were also confirmed by a histologic examination showing that the CLP-induced sepsis accompanied increase of polymorphonuclear neutrophil (PMN) infiltration in the lung and sequestration in the liver . Our results demonstrated that Tempol not only ameliorated the deterioration of hemodynamic changes and renal and liver injuries but also attenuated PMN infiltration in the lung and sequestration in the liver (histology) . In addition, Tempol improved the survival in CLP-induced septic rats . Moreover, Tempol reduced the plasma NO . and interleukin-1beta and organ O2 levels in CLP-treated rats . In conclusion, Tempol prevented circulatory failure and attenuated organ dysfunction/injury as well as decreased the mortality rate in CLP-treated animals . These beneficial effects of Tempol may be attributed to inhibition of ROS formation (e.g., NO . and O2), suggesting antioxidant (e.g., Tempol) is a potential therapeutic agent in the treatment of intraperitoneal septic shock. Shock, 2005 Jan, 23(1), 35 - 38 PLASMA VASCULAR ENDOTHELIAL GROWTH FACTOR IN SEVERE SEPSIS; van der Flier M et al.; Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor . The development of capillary leak is common in septic patients, and several sepsis-associated mediators may induce VEGF production . The potential role of VEGF during sepsis has not been studied to date . The aim of the study was first to assess whether circulating VEGF levels increase during sepsis, and second, to examine whether plasma VEGF levels are associated with disease severity . VEGF levels were measured in serial plasma samples of 18 patients with severe sepsis and in 40 healthy controls . VEGF levels were correlated to clinical signs and symptoms . VEGF levels were significantly elevated in sepsis patients compared with healthy controls (134 vs . 55 pg/mL; P < 0.001) . Serum albumin levels used as an indirect measure of vascular leak were decreased in septic patients . Increased plasma VEGF levels at study entry were correlated to severity of multiple organ dysfunction during the course of disease (Pearson correlation coefficient r = 0.75; P = 0.001) . Moreover, maximum VEGF levels in nonsurvivors were significantly higher than those in survivors (P = 0.018) . These data show that plasma VEGF levels are elevated during severe sepsis . Furthermore, our data indicate that plasma VEGF levels are associated with disease severity and mortality . Further study of the potential role of VEGF in the development of sepsis-associated capillary leak is indicated. Shock, 2005 Jan, 23(1), 25 - 9 Association between the severity of sepsis and the changes in hemostatic molecular markers and vascular endothelial damage markers; Iba T et al.; It is well known that disorders of coagulation and fibrinolysis play a major role in the development of organ dysfunction during sepsis . Furthermore, the importance of the early initiation of anticoagulation therapy for severe cases has been emphasized based on the success of recent clinical trials . The purpose of this study is to search for useful markers for predicting organ dysfunction . Plasma samples were prospectively collected from 78 patients within 48 h after the onset of sepsis . Hemostatic markers and endothelial damage markers were compared between the patients with and without organ dysfunction . The WBC and platelet counts were not different between the groups . In contrast, fibrin/fibrinogen degradation products, D-dimer, thrombin-antithrombin complex, plasmin alpha2-antiplasmin complex, soluble fibrin, and total plasminogen activator inhibitor-1 were significantly higher, and the antithrombin activity and protein C levels were lower in the patients with organ dysfunction . Thus, the changes in the hemostatic molecular markers were associated with organ dysfunction from an early stage of sepsis, and antithrombin and protein C activities were found to be the most reliable markers. Shock, 2005 Jan, 23(1), 11 - 7 Genetic determinants influencing the response to injury, inflammation, and sepsis; De Maio A et al.; The genetic background has recently been recognized as an important element in the response to injury, contributing to the variability in the clinical outcome of critically ill patients . The traditional approach to studying the genetic contribution requires the availability of families with multiple members who have experienced similar disease conditions, a situation that is nearly impossible to find in the case of trauma . Association studies looking at unrelated individuals across populations require large economic and labor-intensive efforts . Thus, a candidate gene approach has been the sole methodology used to correlate genetic variability with clinical outcome . However, this approach cannot provide a comprehensive description of a multigenic condition . Animal models are an alternative for studying the genetic contributions to variability in the response to injury . A murine model is ideal because a large set of inbred strains are available; congenic, consomic, transgenic, and recombinant strains can also be used . Employing this paradigm, we have demonstrated that the response to several stressors, such as injection of E . coli lipopolysaccharide (LPS) and polymicrobial sepsis induced by cecal ligation and puncture (CLP), is modified by the genetic background . The inflammatory response in mice has also been shown to be affected by sex, age, and other, nongenetic components such as diet . We have exploited the differences in response among various inbred mouse strains to map loci contributing to the inflammatory response . Fine mapping strategies allow the refinement of sets of candidate genes, which can be identified by positional cloning . Detection of genetic variation affecting the inflammatory response in murine models provides a basis for determining whether polymorphisms in orthologous human genes correlate with particular clinical outcomes from injury . Thus, discovery of these genes could impact patient care by acting as markers of a specific predisposition in humans. J Thromb Haemost, 2004 Dec, 2(12), 2096 - 102 Platelet function in sepsis; Yaguchi A et al.; BACKGROUND: Coagulation abnormalities and thrombocytopenia are common in severe sepsis, but sepsis-related alterations in platelet function are ill-defined . OBJECTIVES: The purpose of this study was to elucidate the effect of sepsis on platelet aggregation, adhesiveness, and growth factor release . PATIENTS and METHODS: Agonist-induced platelet aggregation was measured in platelet-rich plasma separated from blood samples collected from 47 critically ill patients with sepsis of recent onset . Expression of platelet adhesion molecules was measured by flow cytometry and the release of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) was measured by ELISA in the supernatant of platelet aggregation . RESULTS: Septic patients had consistently decreased platelet aggregation compared with controls, regardless of the platelet count, thrombin generation, or overt disseminated intravascular coagulation (DIC) status . The severity of sepsis correlated to the platelet aggregation defect . Adhesion molecules, receptor expression (CD42a, CD42b, CD36, CD29, PAR-1), and alpha-granule secretion detected by P-selectin expression remained unchanged but the release of growth factors was differentially regulated with increased VEGF and unchanged PDGF after agonist activation even in uncomplicated sepsis . CONCLUSIONS: Sepsis decreases circulating platelets' hemostatic function, maintains adhesion molecule expression and secretion capability, and modulates growth factor production . These results suggest that sepsis alters the hemostatic function of the platelets and increases VEGF release in a thrombin-independent manner. Eur J Health Econ, 2002 Jun, 3(2), 77 - 82 Burden of illness imposed by severe sepsis in Germany; Schmid A et al.; Sepsis is a systemic response to severe infection in critically ill patients and is among the most frequent causes of death in intensive care medicine . Every year between 44,000 and 95,000 persons suffer from this illness in Germany . With the help of a retrospective electronic chart analysis in three adult ICUs of three university hospitals we calculated by a bottom-up approach the direct costs of these patients yielding per patient costs of 23,297 euros on average . Linking the direct costs per patient with the incidence data, the total direct costs for severe sepsis in Germany per year were estimated to range from 1,025 to 2,214 million euros . Direct costs, however, were found to make up only about 28% of the burden of disease of severe sepsis . The indirect costs range between 2,622 and 5,660 million euros . Productivity loss due to premature death does account for the largest part of the indirect costs . In conclusion, severe sepsis imposes annual costs between 3,647 and 7,874 million euros to the German society. Br J Clin Pharmacol, 2005 Jan, 59(1), 54 - 61 The effect of sepsis upon gentamicin pharmacokinetics in neonates; Lingvall M et al.; AIM: To investigate the effect of sepsis upon the volume of distribution (Vd) of gentamicin in neonates . METHODS: A retrospective chart review was conducted of neonates admitted to Dunedin Hospital who had gentamicin concentrations performed between 1st January 2000 and 30th October 2003 . Data from 277 neonates, including a total of 576 gentamicin concentrations, were included in the pharmacokinetic analysis . Fifteen (5.4%) of the neonates had confirmed sepsis . Pharmacokinetic analyses were performed with NONMEM using a one compartment first order elimination model . Duration of infusion (D) was included as a parameter in the model . Covariates included sepsis (SEP), chronological age, gestational age (GA), birth weight, current weight, gender, Apgar score at 1 (AP1) and 5 (AP2) minutes, plasma C-reactive protein and serum creatinine . RESULTS: The initial model provided a mean estimates of clearance (CL) of 0.0460 l kg(-1) h(-1), volume of distribution (Vd) of 0.483 l kg(-1) and D of 0.748 h . The magnitudes of interpatient variability, expressed as CV%, were 29.2% for CL, 20.8% for Vd and 71.5% for D . The magnitude of residual variability in gentamicin concentrations was 88.0% . The final pharmacokinetic model was: CL = (0.0177 + 0.00147.(GA-20) + 0.000635.AP2) l kg(-1) h(-1), Vd = (0.483 +0.0656 . sepsis) l kg(-1), D = 0.672 h . The interpatient variability (CV%) was 22.8% for CL, 22.8% for Vd and 97.7% for D . The magnitude of residual variability in gentamicin concentrations was 83.3% . CONCLUSIONS: The 14% increase in Vd in septic neonates implies that larger doses may be required to achieve peak therapeutic concentrations in the presence of sepsis . D is an important parameter in neonatal pharmacokinetic models. Intensive Care Med, 2005 Jan, 31(1), 129 - 37 Epub 2004 Dec 17. Characterization of membrane N-glycan binding sites of lysozyme for cardiac depression in sepsis; Jacobs H et al.; PURPOSE: In sepsis, reversible myocardial depression has been ascribed to the release of mediators of inflammation . We previously found that lysozyme released from leukocytes from the spleen and other organs mediated myocardial depression in an Escherichia coli model of septic shock in dogs . We hypothesize that lysozyme binds to or cleaves a cardiac surface membrane N-glycoprotein to cause depression . The objectives of the present study were: 1) to determine whether the binding of lysozyme is reversible; 2) to assess the N-glycan structure to which lysozyme binds; 3) to examine whether nonenzymatic proteins, termed lectins, with a binding specificity similar to that of lysozyme could also cause depression; and 4) to assess whether the membrane to which lysozyme binds is affected by the enzymes protease type XIV and collagenase A, that are used to prepare single cell myocyte experiments.METHODS: We measured isometric contraction in a right ventricular trabecular preparation.RESULTS: We found that lysozyme binds in a reversible manner to the Man beta(1-4) GlcNAc beta(1-4)GlcNAc moiety in the tri-mannosyl core structure of high mannose/hybrid and tri-antennary carbohydrate classes where GlcNAc is N-acetylglucosamine and Man is mannose . Lectins with a specificity similar to that of lysozyme also caused depression, and lysozyme's depressant activity was eliminated by protease type XIV and collagenase A.CONCLUSIONS: These results indicate that lysozyme reversibly binds to a membrane glycoprotein to cause myocardial depression in sepsis . We further localize its binding site to a variant of the chitotriose structure in the tri-mannosyl core of the membrane glycoprotein. Ann N Y Acad Sci, 2004 Nov, 1026, 251 - 6 Effect of various acupuncture treatment protocols upon sepsis in Wistar rats; Scognamillo-Szabo MV et al.; Sepsis is a syndrome characterized by infection and generalized inflammatory response that can lead to organ failure and death . In this study we standardize a model to investigate acupuncture's effects upon sepsis . the objectives were to study the use of acupuncture in the infectious process and to formulate acupuncture's treatment protocol for sepsis . The CLP (cecal ligation and puncture) model in rats was used to induce sepsis through bacterial entrance into the peritoneal cavity . An acupuncture treatment protocol that enhanced survival and reversed the neutrophil impairment migration toward the peritoneal cavity in rats with sepsis was achieved . It seems that acupuncture can be used for the treatment of experimental infectious processes . The effects of acupuncture and related mechanisms are discussed. Blood . 2004 Dec 16; {Epub ahead of print} Reversal of long-term sepsis-induced immunosuppression by dendritic cell; Benjamim CF et al.; Severe sepsis leads to long-term systemic and local immunosuppression, which is the cause of a number of complications, including pulmonary infection . A therapeutic strategy that reverses this immunosuppression is required, given the ongoing high mortality rate of patients that have survived a severe sepsis . The present study demonstrates that experimental severe sepsis renders the lung susceptible to a normally innocuous A . fumigatus fungus challenge, due to a dominant lung type-2 cytokine profile . Dendritic cells (DCs) obtained from lung of mice subjected to cecal ligation and puncture (CLP) model were skewed towards type 2 cytokine profile, which occurred with exaggerated expression of Toll-like receptor 2 (TLR2) . The intrapulmonary transfer of bone-marrow derived DCs (BMDCs) in post-septic mice prevented fatal Aspergillus infection . This therapy reduced the overall inflammatory response, fungal growth in the lung and promote the balance of pro-inflamatory and supressive-cytokines in the lung . Thus, intrapulmonary DC supplementation appears to restore the pulmonary host response in the post-septic lung in our animal model . This data strongly suggests lung DCs are profoundly affected as a consequence of the systemic impact of severe sepsis and the identification of mechanisms that restore their function may serve as a key strategy to reverse sepsis-induced immunosuppression. Crit Care Med, 2004 Dec, 32(12), 2385 - 91 Sources of variability on the estimate of treatment effect in the PROWESS trial: implications for the design and conduct of future studies in severe sepsis; Macias WL et al.; OBJECTIVE: To elucidate sources of variability in the estimate of treatment effects in a successful phase 3 trial in severe sepsis and to assess their implications on the design of future clinical trials . DESIGN: Retrospective evaluation of prospectively defined subgroups from a large phase 3, placebo-controlled clinical trial (PROWESS) . SETTING: The study involved 164 medical centers . PATIENTS: Patients were 1,690 patients with severe sepsis . INTERVENTIONS: Drotrecogin alfa (activated) (Xigris) 24 microg/kg/hr for 96 hrs, or placebo . MEASUREMENTS AND MAIN RESULTS: All prospectively defined subgroups were examined to identify treatment effects that potentially differed across subgroup strata (assessed by Breslow-Day p < .10) . Potential interactions were identified for subgroups defined by a) presence vs . absence of a significant protocol violation (p = .07); b) original vs . amended protocol (p = .08); and c) Acute Physiology and Chronic Health Evaluation (APACHE) II quartile at baseline (p = .09) . No treatment benefit was observed in patients having a protocol violation, regardless of type . There appeared to be less treatment effect in patients enrolled under the original vs . amended protocol . The risk ratio exceeded 1.0 for patients in the lowest APACHE II score quartile . A highly significant correlation was observed between the sequence of enrollment at a site, the frequency of protocol violations, and the observed treatment effect . As enrollment increased, frequency of protocol violations decreased (p < .0001) and the treatment effect improved . The correlation between the sequence of enrollment and improvement in treatment effect remained even after removal of patients with protocol violations . Removal of the first block of patients at each site from the analysis reduced the extent of interaction by protocol version and APACHE II score . CONCLUSIONS: A learning curve appeared to be present within the PROWESS trial such that the ability to demonstrate efficacy improved with increasing site experience . This potential learning curve may have implications for design of future trials . Investigational sites may need to require a minimum level of protocol-specific experience to appropriately implement a given trial . This experience should be an important consideration in designing trials and analysis plans . Diligence by coordinating centers, site investigators, study coordinators, and sponsors is necessary to ensure that the protocol is executed as designed such that a treatment benefit, if present, will be evident. Tsitologiia, 2004, 46(8), 690 - 4 {Morphological and ultrastructural changes in the rat kidney after experimental sepsis} {Therapeutic effect of anti-HMGB1 antibody and anti-RAGE antibody on SIRS/sepsis} Unoshima M. Anesthesiology, Department of Brain and Nerve Science, Oita University, Faculty of MedicineHigh mobility group box-1 (HMGB1) is intranuclear architectural protein . Once HMGB1 released to extracellular, it has been implicated to act as a novel proinflammatory cytokine, called "Late mediator", in SIRS/sepsis . This danger signal transmits through receptor for advanced glycation end-products (RAGE) . In this study, we hypothesized whether treatment of anti-HMGB1 or anti-RAGE antibody would block LPS-lethality in septic mice . We measured survival rate of septic mice with or without antibodies, resulting in significant improvement with antibodies-treated mice . LPS-induced acute lung injury was almost disappeared by antibody treatment, because these antibodies were inhibited HMGB1 and RAGE expression in lung . Treatment of anti-HMGB1 or anti-RAGE antibody seems to be valid therapy against SIRS/sepsis. Nippon Rinsho, 2004 Dec, 62(12), 2291 - 5 {Evaluation of severity for systemic inflammatory response syndrome and sepsis}; Kurihara T et al.; Systemic inflammatory response syndrome (SIRS) is defined by four simple clinical and laboratory indices and now widely accepted for diagnosing sepsis . However, since the SIRS criteria include patients with a wide range of severity, other parameters are necessary to evaluate the severity and outcome of the patients . In this review, we discussed several methods to estimate the severity of SIRS, such as number of positive SIRS indices among four, duration of SIRS, plasma IL-6 and procalcitonin, etc. Nippon Rinsho, 2004 Dec, 62(12), 2285 - 90 {Analysis of heart rate variability is a useful tool to predict the occurrence of septic shock in the patients with severe sepsis}; Moriguchi T et al.; The normal heart rate is regulated by a number of interacting physiological control systems that operate on widely different time scales . Thus, instantaneous heart rate is not steady, but rather demonstrates continuous fluctuations . It has been recognized that power spectral analysis of heart rate variability (HRV) is a noninvasive method to assess cardiac autonomic modulation . We hypothesized that the loss of interconnectivity or coupling between heart and other organs results in the occurrence of septic shock in patients with severe sepsis . We found that the reduction of HRV precedes the occurrence of septic shock . Therefore, we conclude that analysis of HRV is a novel and useful tool to predict the occurrence of septic shock among the patients with severe sepsis. Nippon Rinsho, 2004 Dec, 62(12), 2281 - 4 {Monocyte HLA-DR expression as predictors of clinical outcome for patients with sepsis}; Yoshida S; It has been generally accepted that the frequency of the HLA-DR-antigen expression on monocytes reflects the individual's immune state; therefore it has been regarded as a key indicator of the immune status in SIRS (systemic inflammatory response syndrome)-sepsis . One of the diagnostic indices for the level of immunoparalysis, it characterizes CARS (compensatory anti-inflammatory response syndrome) . Lately, it has been frequently reported that the frequency of HLA-DR-antigen expression on monocytes is abnormally reduced in those patients with SIRS-sepsis . Reports suggest that the prognosis is very poor in cases with long-term sharp declines in HLA-DR-antigen expression on monocytes. Nippon Rinsho, 2004 Dec, 62(12), 2262 - 6 {Animal models for sepsis}; Koike K; Despite promising preclinical evidence, dozens of new anti-sepsis agents have failed to demonstrate clinical efficacy . One of the reasons may be that the preclinical trials were conducted using animal models that did not adequately reflect clinical realities . Various kinds of experiments utilized for the development of new agents were carried where bolus or short term continuous infusions of large doses of bacteria or endotoxin were administered intravenously . For the preclinical testing of agents, (1) i.v . bacteria and endotoxin models in which the total challenge dose of adequate bacteria or endotoxin is reduced and/ or the length of administration time is increased, and (2) peritonitis models, e.g., cecal ligation and puncture and peritoneal implantation of bacteria or endotoxin, will become reasonable choices. Nippon Rinsho, 2004 Dec, 62(12), 2177 - 83 {Basic concept and definition of SIRS and sepsis--present consideration and future perspectives}; Hirasawa H et al.; SIRS (systemic inflammatory response syndrome) is thought to be caused by hypercytokinemia . On the other hand, interleukin-6 (IL-6) is reported to be one of most easily measurable cytokines and we found that IL-6 blood levels on SIRS patients are above 1,500 pg/ml which is compatible to the previously reported values . Since only 6% of SIRS patients developed MOF according to our own data, we need not overestimate SIRS as a grave clinical signs . On the other hand, it is reported that cytokine-related genetic polymorphism may affect the cytokine production following insult, or may affect the development of SIRS following insult . Therefore, we must also consider genetic aspect of cytokine biology in future study. Nippon Rinsho, 2004 Dec, 62(12), 2173 - 6 {Understanding the pathogenetic mechanisms of SIRS and sepsis and development of innovative therapies of sepsis}; Aikawa N et al.; The concept of systemic inflammatory response syndrome (SIRS) was introduced in 1992 to define and objectively diagnose sepsis . Over the last decade, the definition of sepsis has been used for inclusion criteria of multicenter trials to develop innovative therapies of sepsis . With the recent understanding of the pathogenetic mechanisms of sepsis, many drugs have been tested, but only two drugs (activated protein C and neutrophil-elastase inhibitor) have been approved for clinical use in sepsis or SIRS . Further understanding of basic pathophysiology of SIRS and sepsis holds promise to develop a new therapeutic strategy to improve survival of patients with SIRS and sepsis. Inflamm Res, 2004 Oct, 53(10), 528 - 33 Drotrecogin alfa (activated) inhibits NF-kappa B activation and MIP-1-alpha release from isolated mononuclear cells of patients with severe sepsis; Brueckmann M et al.; OBJECTIVE AND DESIGN: Non-anticoagulant biological activities, such as anti-inflammatory and anti-apoptotic mechanisms of action, have been suggested for recombinant human activated protein C (rhAPC; drotrecogin alfa (activated)) . However, these mechanisms are much less characterized and understood than rhAPC's anticoagulant activity . Aim of the study was to determine the effect of rhAPC on the activity of the pro-inflammatory transcription factor nuclear factor kappa B (NF-kappaB) in mononuclear cells isolated from septic patients and to characterize an effect downstream from NF-kappaB activation, such as the release of the NF-kappaB-controlled chemokine Macrophage Inflammatory Protein-1-alpha (MIP-1-alpha) . SUBJECTS: Peripheral blood was obtained from 13 septic patients and from 8 healthy controls . METHODS: Mononuclear cells were isolated by Ficoll-Paque density gradient centrifugation and were incubated with or without rhAPC (10 microg/ml) for 2 h for the measurement of NF-kappaB activity in cell lysates or alternatively for 6 h for the determination of MIP-1-alpha levels in supernatants . NF-kappaB activity was measured by an ELISA-based assay directed against the p50 and the p65 subunit of NF-kappaB . RESULTS: RhAPC, at supra-pharmacological concentration (10 microg/ml), significantly inhibited NF-kappaB activity and the release of MIP-1-alpha ex vivo in isolated mononuclear cells from patients with severe sepsis . In mononuclear cells of healthy subjects, however, rhAPC did not change NF-kappaB activity . Basal NF-kappaB activity early in severe sepsis was not predictive for survival . CONCLUSIONS: RhAPC at supra-pharmacological concentration (10 microg/ml) inhibits the activity of NF-kappaB in ex vivo isolated mononuclear cells of septic patients as well as the release of MIP-1-alpha, a proinflammatory chemokine regulated by NF-kappaB . These findings may represent immunomodulatory pathways by which rhAPC exerts specific anti-inflammatory activity in vitro in addition to its known anticoagulant and profibrinolytic activity and should be further investigated in an in vivo setting. Arch Pharm Res, 2004 Nov, 27(11), 1123 - 6 Protective constituents against sepsis in mice from the root cortex of Paeonia suffruticosa; Li G et al.; The bioassay-guided fractionation of protective agents against sepsis-induced lethality from the root cortex of Paeonia suffruticosa ANDREWS (Ranunculaceae) led to the isolation of eight known compounds: paeonol (1), 2,5-dihydroxy-4-methoxyacetophenone (2), acetovanillone (3), paeonoside (4), paeoniflorin (5), oxypaeoniflorin (6), apiopaeonoside (7), and methyl 3-hydroxy-4-methoxybenzoate (8) . Among them, 3 showed the highest survival rate (100% with a dose of 30 mg/kg versus 17% for the control experiment) and reduced alanine aminotransferase level to be a half of the control value on the sepsis model induced by lipopolysaccharide/D-galactosamine. J Neuroimmunol, 2005 Jan, 158(1-2), 50 - 7 Adrenergic modulation of cytokine release in bone marrow progenitor-derived macrophage following polymicrobial sepsis; Muthu K et al.; Catecholamines may impact on the pathophysiology of sepsis by attenuating proinflammatory cytokine and augmenting antiinflammatory cytokine production by macrophages . We tested this premise in bone marrow monocyte progenitor-derived macrophages . Polymicrobial sepsis was induced in mice through cecal ligation and puncture . ER-MP 12 monocyte progenitors were isolated and differentiated into macrophages in vitro 72 hr later . Lipopolysaccharide (LPS)-stimulated cytokine production was measured with and without epinephrine, IL-10 and anti-IL-10 antibody . Epinephrine significantly increased IL-10 production, but attenuated TNF-alpha release exclusively through beta2 adrenergic receptors, and is independent of IL-10 production . Together, these results suggest that epinephrine can promote a potent antiinflammatory response in sepsis. Med Sci (Paris), 2004 Dec, 20(12), 1115 - 8 {Myocardial depression in sepsis}; Gibot S et al.; Myocardial dysfunction frequently accompanies severe sepsis and septic shock . It is now clear that such a myocardial depression, as evidenced by biventricular alteration, is present during the early phase of sepsis in most patients . Myocardial depression exists despite a fluid loading-dependent hyperdynamic state and usually recovers within 7 to 10 days in survivors . Myocardial dysfunction does not appear to be due to irreversible structural abnormalities nor to myocardial hypoperfusion, but rather linked to many circulating mediators including cytokines . At a cellular level, reduced myocardial contractility could be related in part to apoptosis and induced by both nitric oxide-dependent and nitric oxide-independent mechanisms . However, whatever the mechanism involved, it leads to calcium homeostasis abnormality . The present review describes both the diagnosis procedure and the molecular and cellular pathways of sepsis-induced myocardial depression. Am J Physiol Lung Cell Mol Physiol . 2004 Dec 3; {Epub ahead of print} The anti-inflammatory response is associated with mortality and severity of infection in sepsis; Ashare A et al.; Using a murine model of sepsis, we found that the balance of tissue pro- to anti-inflammatory cytokines directly correlated with severity of infection and mortality . Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP) . Liver tissue was analyzed for levels of interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), tumor necrosis factor alpha (TNFalpha), and soluble TNF receptor 1 (sTNFR1) by ELISA . Bacterial DNA was measured using quantitative real-time PCR . After CLP, early predominance of pro-inflammatory cytokines (6 hours) transitioned to anti-inflammatory predominance at 24 hours . The elevated anti-inflammatory cytokines were mirrored by increased tissue bacterial levels . The degree of anti-inflammatory response compared to pro-inflammatory response correlated with the bacterial concentration . To modulate the timing of the anti-inflammatory response, mice were treated with IL-1ra prior to CLP . This resulted in decreased pro-inflammatory cytokines, earlier bacterial load and increased mortality . These studies show that the initial tissue pro-inflammatory response to sepsis is followed by an anti-inflammatory response . The anti-inflammatory phase is associated with increased bacterial load and mortality . These data suggest that it is the timing and magnitude of the anti-inflammatory response that predicts severity of infection in a murine model of sepsis. Am J Pathol, 2004 Dec, 165(6), 2187 - 96 Novel chemokine responsiveness and mobilization of neutrophils during sepsis; Speyer CL et al.; Blood neutrophils (PMN) are usually unresponsive to CC chemokines such as monacyte chemotactic protein-1 and macrophage inflammatory protein-1 alpha . In rodents, the lung buildup of PMN as determined by myeloperoxidase (MPO) activity after airway instillation of bacterial lipopolysaccharide (LPS) was independent of MCP-1 and MIP-1 alpha . In striking contrast, during sepsis following cecal ligation and puncture (CLP), blood PMN demonstrated mRNA for CC chemokine receptors . Furthermore, PMN from CLP, but not from sham rodents, bound MCP-1 and MIP-1 alpha and responded chemotactically in vitro to both MCP-1 and MIP-1 alpha . In CCR2(-/-) mice or WT mice treated in vivo with antibodies to either MCP-1 or MIP-1 alpha, MPO activity was greatly attenuated in CLP animals . In CLP mice, increased serum IL-6 levels were found to be dependent on CCR2, MCP-1, and MIP-1 alpha . When PMN from CLP rodents were incubated in vitro with either MCP-1 or MIP-1 alpha, release of IL-6 was also shown . These findings suggest that sepsis fundamentally alters the trafficking of PMN into the lung in a manner that now engages functional responses to CC chemokines. Croat Med J, 2004 Dec, 45(6), 715 - 20 Sequential organ failure assessment score as the determinant of outcome for patients with severe sepsis; Vosylius S et al.; AIM: To evaluate the impact of organ dysfunction in severe sepsis and determine the effectiveness of organ dysfunction scores to discriminate outcome after admission to the intensive care unit (ICU) . METHODS: Patients with a diagnosis of severe sepsis and at least one organ dysfunction on the first day in the ICU (n=117) were included in the prospective observational study . The presence of organ dysfunction was assessed using a Sequential Organ Failure Assessment (SOFA) . The severity of illness was assessed using a Simplified Acute Physiology Score (SAPS) II during the first 24 hours after the admission to the ICU . The main outcome was survival status on day 28 after admission to the ICU . RESULTS: Most common sites of infection were intra-abdominal and respiratory system (77 and 38 cases, respectively) . Median SAPS II score on admission was 47 points (25th-75th quartiles range, 37-57 points) . Twenty eight days survival rate was 41% . The best discrimination results were shown for cumulative scores with the highest for the SOFA score on day 3 in the ICU . The ability to discriminate outcome on day 1 was weak for the presence of dysfunction in all organ systems except neurological . The discriminative power of organ dysfunction scores increased during the stay in the ICU . Neurological and cardiovascular dysfunctions were the independent risk factors for mortality . CONCLUSION: The SOFA scores showed high accuracy in describing the course of organ dysfunction for the patients with severe sepsis . Evolving organ dysfunction following admission to the ICU strongly affected the outcome . Cumulative SOFA scores were better in discriminating outcome compared to single organ dysfunction scores. Biol Pharm Bull, 2004 Dec, 27(12), 2024 - 7 Protective effect of protocatechuic acid isopropyl ester against murine models of sepsis: inhibition of TNF-alpha and nitric oxide production and augmentation of IL-10; Yan JJ et al.; Antioxidants have been shown to be effective in murine models of sepsis . Protocatechuic acid has antioxidant activity . In the present study, the protective effects of protocatechuic acid and its derivatives were investigated in a mouse model of septic shock induced by lipopolysaccharide (LPS)/D-galactosamine (GalN) . Pretreatment of animals with protocatechuic acid effectively suppressed LPS/GalN-induced lethality; protocatechuic acid isopropyl ester was the most effective among the various derivatives of protocatechuic acid . Protocatechuic acid isopropyl ester was also effective in protection against the high-dose LPS-induced shock . Pretreatment with protocatechuic acid isopropyl ester effectively suppressed the LPS/GalN-induced increase in plasma tumor necrosis factor (TNF)-alpha alanine aminotransferase (ALT), nitrite/nitrate levels, and hepatic malondialdehyde levels . In contrast, it markedly enhanced the LPS/GalN-induced increase in plasma interleukin (IL)-10 levels, without any changes in IL-6 plasma levels . These results suggest that protocatechuic acid isopropyl ester could be useful for the prevention of sepsis. Mol Pharmacol . 2004 Dec 2; {Epub ahead of print} Nuclear Factor-{kappa}B Decoy Oligodeoxynucleotides Prevent Acute Lung Injury in Mice with Cecal Ligation and Puncture-Induced Sepsis; Matsuda N et al.; The transcription factor nuclear factor-kappaB (NF-kappaB) plays a key role in expression of many inflammatory genes responsible for the pathophysiology of sepsis-induced acute lung injury . We investigated whether the introduction of synthetic double-stranded oligodeoxynucleotides (ODNs) with consensus NF-kappaB sequence as transcription factor decoy can prevent acute lung injury with suppression of pulmonary expression of multiple genes involved in its pathological process in a cecal ligation and puncture septic mouse model . NF-kappaB decoy ODNs were introduced with the aid of the haemagglutinating virus of Japan-envelope vector method . Northern blot analysis indicated that transfection of NF-kappaB decoy ODN, but not of its scrambled form, resulted in a significant inhibition of sepsis-induced gene overexpression of inducible nitric-oxide synthase (iNOS), cyclooxygenase-2, histamine H1-receptor, platelet activating factor receptor, and bradykinin B1 and B2 receptors in lung tissues . Histological damage in lungs (wall thickening, inflammatory infiltrate, and hemorrhage), increased pulmonary vascular permeability, and blood gas exchange impairment were clearly documented in mice after cecal ligation and puncture . These changes were strongly eliminated by the introduction of NF-kappaB decoy, but not of the scrambled ODN . The effects of the iNOS inhibitor FR260330 on these histological and functional derangements compared unfavorably with those of NF-kappaB decoy ODN transfection . Our results suggest that ODN decoy, acting as in vivo competitor for the transcription factor's ability to bind to cognate recognition sequence, may represent an effective strategy in the treatment of septic acute lung injury. Nurs Crit Care, 2004 Nov-Dec, 9(6), 257 - 63 Sepsis strategies: an ICU package? Ruffell AJ. --Mortality of patients with severe sepsis remains at unacceptable levels and recent new strategies are not being widely embraced . --Five strategies are discussed within this article {low tidal volumes in acute lung injury/acute respiratory distress syndrome, early goal-directed therapy, drotrecogin alfa (activated), moderate dose corticosteroids and tight control of blood glucose} . --The critical care nurse plays a leading role in the detection, monitoring and treatment of patients with severe sepsis . --The role of the critical care nurse within the multidisciplinary team is explored . --Education, combination of strategies and the use of protocols are discussed. Magy Seb, 2004 Aug, 57(4), 229 - 35 {Significance of Toll-like receptors in the pathophysiology of surgical sepsis}; Romics L Jr et al.; The discovery of Toll-like receptors has substantially changed our knowledge of pathogen recognition . 11 Toll-like receptors have so far been described in humans . These recognize distinct pathogen associated molecular patterns, as well as endogenous ligands and small molecular synthetic compounds . TLRs have a multifunctional role in pathogen-triggered immune responses and represent an important connection between the "innate" and "adaptive" immunity . The role of the TLRs in the recognition of pathogens renders them a key figure in the activation of the immune response during surgical sepsis . However, emerging evidence points to a fundamental role in tumorigenesis, transplantation, wound healing, atherogenesis and inflammatory bowel disease . The aim hence was to review experimental data pertaining to the activation of TLR signalling pathways in conditions associated with surgical sepsis . A systematic review of the literature was undertaken by searching the MEDLINE database for the period 1966-2004 without language restriction . The paper also analyses the possible therapeutic utilization of the TLR signalling pathways in surgical sepsis. Surgeon, 2003 Aug, 1(4), 187 - 206 Surgical sepsis: dysregulation of immune function and therapeutic implications; Boontham P et al.; Sepsis is defined clinically as the systemic inflammatory response of the host to the documented systemic infection . The pathophysiological disturbance involves both the innate and adaptive immune systems encompassing cellular immunity, humoral components and the complement system . Dendritic cells (antigen-presenting cells) are key cells involved in the regulation of the immune response in sepsis, in particular in activating T cells and especially inducing the production and secretion of specific cytokines . These are the main mediators in establishing prominent disturbances of inflammation in patients with sepsis . The clinical features of the sepsis syndrome may vary from minor clinical disturbances to severe multiple organ failure and death of the host . Appropriate therapeutic strategies for patients with sepsis utilise conventional therapy and new novel forms of treatment, which are showing promise for the future. Crit Care, 2004 Dec, 8(6), 462 - 8 Epub 2004 Dec. Bench-to-bedside review: sepsis is a disease of the microcirculation; Spronk PE et al.; Microcirculatory perfusion is disturbed in sepsis . Recent research has shown that maintaining systemic blood pressure is associated with inadequate perfusion of the microcirculation in sepsis . Microcirculatory perfusion is regulated by an intricate interplay of many neuroendocrine and paracrine pathways, which makes blood flow though this microvascular network a heterogeneous process . Owing to an increased microcirculatory resistance, a maldistribution of blood flow occurs with a decreased systemic vascular resistance due to shunting phenomena . Therapy in shock is aimed at the optimization of cardiac function, arterial hemoglobin saturation and tissue perfusion . This will mean the correction of hypovolemia and the restoration of an evenly distributed microcirculatory flow and adequate oxygen transport . A practical clinical score for the definition of shock is proposed and a novel technique for bedside visualization of the capillary network is discussed, including its possible implications for the treatment of septic shock patients with vasodilators to open the microcirculation. Crit Care, 2004 Dec, 8(6), R474 - 82 Epub 2004 Dec. Effects of lornoxicam on the physiology of severe sepsis; Memis D et al.; INTRODUCTION: The purpose of the present study was to evaluate the effects of intravenous lornoxicam on haemodynamic and biochemical parameters, serum cytokine levels and patient outcomes in severe sepsis . METHODS: A total of 40 patients with severe sepsis were included, and were randomly assigned (20 per group) to receive either lornoxicam (8 mg administered intravenously every 12 hours for six doses) or placebo . For both groups the following were recorded: haemodynamic parameters (heart rate, mean arterial pressure), nasopharyngeal body temperature, arterial blood gas changes (pH, partial oxygen tension, partial carbon dioxide tension), plasma cytokine levels (IL-1beta, IL-2 receptor, IL-6, IL-8, tumour necrosis factor-alpha), biochemical parameters (lactate, leucocytes, trombocytes, creatinine, total bilirubin, serum glutamate oxalate transaminase), length of stay in the intensive care unit, duration of mechanical ventilation and mortality . All measurements were obtained at baseline (before the start of the study) and at 24, 48 and 72 hours from the start of lornoxicam/placebo administration . RESULTS: No significant differences were found between the intravenous lornoxicam and placebo groups in major cytokines, duration of ventilation and length of intensive care unit stay, and inspired fractional oxygen/arterial oxygen tension ratio (P > 0.05) . CONCLUSION: In these patients with severe sepsis, we found intravenous lornoxicam to exert no effect on haemodynamic and biochemical parameters, cytokine levels, or patient outcomes . Because of the small number of patients included in the study and the short period of observation, these findings require confirmation by larger clinical trials of intravenous lornoxicam, administered in a dose titrated manner. Crit Care, 2004 Dec, 8(6), R409 - 13 Epub 2004 Dec. An international sepsis survey: a study of doctors' knowledge and perception about sepsis; Poeze M et al.; BACKGROUND: To be able to diagnose and treat sepsis better it is important not only to improve the knowledge about definitions and pathophysiology, but also to gain more insight into specialists' perception of, and attitude towards, the current diagnosis and treatment of sepsis . METHODS: The study was conducted as a prospective, international survey by structured telephone interview . The subjects were intensive care physicians and other specialist physicians caring for intensive care unit (ICU) patients . RESULTS: The 1058 physicians who were interviewed (including 529 intensivists) agreed that sepsis is a leading cause of death on the ICU and that the incidence of sepsis is increasing, but that the symptoms of sepsis can easily be misattributed to other conditions . Physicians were concerned that this could lead to under-reporting of sepsis . Two-thirds (67%) were concerned that a common definition is lacking and 83% said it is likely that sepsis is frequently missed . Not more than 17% agreed on any one definition . CONCLUSION: There is a general awareness about the inadequacy of the current definitions of sepsis . Physicians caring for patients with sepsis recognise the difficulty of defining and diagnosing sepsis and are aware that they miss the diagnosis frequently. Circ J, 2004 Dec, 68(12), 1215 - 8 A case of heparin-induced thrombocytopenia with sepsis and congestive heart failure--first autopsy report on Japan--; Sawaki D et al.; An 84-year-old man was referred to the emergency department with severe dyspnea . Based on his physical findings, electrocardiogram, X-ray and echocardiographic findings, congestive heart failure was suspected and drip infusion of prophylactic heparin against intracardiac thrombosis was commenced together with dopamine, nitroglycerin and furosemide . Diuresis occurred and the pulmonary congestion ameliorated remarkably . Starting on the 20th hospital day, the platelet count was gradually reduced (from 256,000 to 55,000 /microl) and the fibrin degradation product concentration rose (27.6 microg/ml) . However, prothrombin time was not prolonged (89%), the concentration of antithrombin III was low -normal (69%) and the fibrinogen concentration was high (650 mg/dl) . Thus, heparin-induced thrombocytopenia (HIT), rather than disseminated intravascular coagulation (DIC), was suspected . Heparin was withdrawn on the 24th hospital day and replaced by nafamostat mesilate after which the platelet count was restored to 100,000 /microl . Enzyme-linked immunosorbent assay for HIT antibodies was positive . Unfortunately, the patient died from uncontrolled sepsis on the 29th hospital day . At autopsy, platelet-rich thrombi were found in the small pulmonary arteries and intestinal arteries . No evidence of DIC, such as fibrin-rich thrombosis, was observed . This is the first autopsy report of HIT in Japan. Am J Physiol Regul Integr Comp Physiol . 2004 Nov 24; {Epub ahead of print} SEPSIS STIMULATES CALPAIN ACTIVITY IN SKELETAL MUSCLE BY DECREASING CALPASTATIN ACTIVITY BUT DOES NOT ACTIVATE CASEPASE-3; Wei W et al.; We examined the influence of sepsis on the expression and activity of the calpain and caspase systems in skeletal muscle . Sepsis was induced in rats by cecal ligation and puncture (CLP) . Control rats were sham-operated . Calpain activity was determined by measuring the calcium-dependent hydrolysis of casein and by casein zymography . The activity of the endogenous calpain inhibitor calpastatin was measured by determining the inhibitory effect on calpain activity in muscle extracts . Protein levels of micro- and m-calpain and calpastatin were determined by Western blotting and calpastatin mRNA was measured by real-time PCR . Caspase-3 activity was determined by measuring the hydrolysis of the fluorogenic caspase-3 substrate Ac-DEVD-AMC and by determining protein and mRNA expression for caspase-3 by Western blotting and real-time PCR, respectively . In addition, the role of calpains and caspase-3 in sepsis-induced muscle protein breakdown was determined by measuring protein breakdown rates in the presence of specific inhibitors . Sepsis resulted in increased muscle calpain activity caused by reduced calpastatin activity . In contrast, caspase-3 activity, mRNA levels, and activated caspase-3 29kDa fragment were not altered in muscle from septic rats . Sepsis-induced muscle proteolysis was blocked by the calpain inhibitor calpeptin but was not influenced by the caspase-3 inhibitor Ac-DEVD-CHO . The results suggest that sepsis-induced muscle wasting is associated with increased calpain activity, secondary to reduced calpastatin activity, and that caspase-3 activity is not involved in the catabolic response to sepsis. Dtsch Med Wochenschr, 2004 Nov 26, 129(48), 2586 - 9 {"The intensive care simulator": a new teaching-concept to train severe sepsis management}; Breuer G et al.; BACKGROUND AND OBJECTIVE: In addition to basic research and development of new therapeutic strategies, the education of health care professionals who manage sepsis patients is an important step to decrease the high mortality of severe sepsis . Patient simulators are increasingly used for teaching in anaesthesia . A training program in sepsis management was developed, using a full-scale anaesthesia simulator including the setting of a modern intensive care unit, and its results were evaluated by means of a questionnaire . METHODS: The simulator is controlled from a separate room using a controlling computer provided with physiological models and pharmacokinetic as well as pharmacodynamic patterns of substances commonly used in anaesthesia and intensive care . An important element of the training program is the subsequent debriefing with different modules, according to the individual deficits and needs of the participants detected during simulation . RESULTS: From September 2002 to July 2004 82 physicians participated in the training program . 4 weeks after the training 52 % of the participants stated that they had changed their treatment behaviour due to the training content . They assessed the interactive simulator workshop semiquantitatively on a scale from 1 ("absolutely correct") to 7 ("not correct at all") as follows: Sepsis simulation training (SST) improves identification (mean+/-SD) (2.3 +/- 1.3) and treatment (2.5 +/- 1.2) of patients with severe sepsis, and SST including true-life scenarios is more appropriate than traditional lectures (1.5 +/- 0.7) . CONCLUSION: The presented SST could be an effective way to train intensive care specialists in severe sepsis management. J Surg Res, 2004 Dec, 122(2), 180 - 3 Correlation of plasma and tissue oxidative stresses in intra-abdominal sepsis; Koksal GM et al.; BACKGROUND: The aim of this study was to investigate the correlation between plasma and tissue oxidative stress and the antioxidative response, by measuring malon dialdehyde (MDA) and glutathione (GSH) in late sepsis induced by cecal ligation and perforation . MATERIALS AND METHODS: A prospective, randomized, controlled experimental study in rats was done . Forty rats, weighing 200-250 g, were randomly divided into two groups (n = 20) . In group 1, laparotomy was performed under aseptic conditions, and the cecum ligated and perforated . The abdomen was closed . In group 2, sham control, there was only laparotomy . Twenty-four hours later, blood samples were taken by cardiac puncture for plasma MDA and GSH, followed by harvesting of samples from lung, liver, kidney, and heart in both groups . RESULTS: In the liver, lung, plasma, heart, and kidney, MDA concentrations were increased in the sepsis group after 24 h (P < 0.001 for all organ samples) . In the same organs, GSH concentrations were decreased by sepsis (P < 0.001 for all organ samples) . In both groups, plasma MDA was positively correlated to MDA in heart (r = 0.82, P < 0.001), liver (r = 0.76, P < 0.001), lung (r = 0.78, P < 0.001), and kidney (r = 0.73, P < 0.001) . Similarly, plasma GSH was positively correlated to GSH in liver (r = 0.93, P < 0.001), heart (r = 0.86, P < 0.001), lung (r = 0.91, P < 0.001), and kidney (r = 0.79, P < 0.001) . CONCLUSIONS: Plasma MDA and GSH were positively correlated with tissue MDA and GSH in intra-abdominal sepsis in a rat model. Med Mycol, 2004 Oct, 42(5), 479 - 81 Candida glabrata sepsis secondary to oral colonization in bone marrow transplantation; Redding SW et al.; Candida glabrata has emerged as a common cause of fungal sepsis in bone marrow transplant patients, particularly those receiving fluconazole prophylaxis . Colonization of the lower GI tract and indwelling catheters have been thought to be the primary sources of systemic infection with Candida . We report on a bone marrow transplant patient who developed Candida glabrata sepsis from pre-existing oral colonization. J Thromb Haemost, 2004 Nov, 2(11), 1924 - 33 Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation; Dhainaut JF et al.; Disseminated intravascular coagulation (DIC) is a serious condition associated with sepsis . Clinical management of DIC is hampered by lack of clear diagnostic criteria . The International Society on Thrombosis and Haemostasis (ISTH) has proposed a diagnostic scoring algorithm for overt DIC based on routine laboratory tests . The objective was to assess a modified version of the ISTH scoring system and determine the effect of drotrecogin alfa (activated) (DrotAA, recombinant human activated protein C) on patients with DIC . The large database from the PROWESS clinical trial in severe sepsis was retrospectively used to assess a modified ISTH scoring system . Baseline characteristics and treatment effects of DrotAA were evaluated . At baseline, 29% (454/1568) of patients had overt DIC . Overt DIC was a strong predictor of mortality, independent of APACHE II score and age . Placebo-treated patients with overt DIC had higher mortality than patients without (43 vs . 27%) . DrotAA-treated patients with overt DIC had a trend towards greater relative risk reduction in mortality than patients without (29 vs . 18%, P = 0.261) but both groups had greater relative risk reduction than placebo-treated patients . Serious bleeding rates during DrotAA infusion in patients with and without overt DIC were slightly increased (P = 0.498), compared with placebo, while clinically overt thrombotic events during the 28-day period were slightly reduced (P = 0.144) . Modified ISTH overt DIC scoring may be useful as an independent assessment for identifying severe sepsis patients at high risk of death with a favorable risk/benefit profile for DrotAA treatment . Patients without overt DIC also received significant treatment benefit. J Perinatol . 2004 Nov 18; {Epub ahead of print} Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Does Not Alter Sepsis Outcome in Ventilated Very Low Birth Weight infants; John Baier R et al.; OBJECTIVE:: This study compared the effect of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms on the incidence and outcome of sepsis in ventilated very low birth weight infants . STUDY DESIGN:: Infectious complications were retrospectively determined in 295 (234 African-American, 58 Caucasian and three Hispanic) mechanically ventilated very low birth weight (VLBW) infants (<1500 g at birth) and compared ACE I/D genotype . RESULTS:: The incidence of the D allele in the study population was 0.60 . A total of 113 (38.3%) infants were homozygous DD, 128 (43.4%) were heterozygous ID and 54 (18.3%) were homozygous II . One or more episodes of late BSI developed in 28 (52%) of 54 infants with the II genotype, 66 (52%) of 128 infants with the ID genotype and 52 (46%) of 113 infants with the DD genotype (p=0.618) . Neither the rates of non-CONS BSI (II: 24%, ID: 23%, DD: 22%; p=0.937) nor multiple bacteremic/fungemic episodes (II: 13%, ID: 16%, DD: 12%; p=0.641) were different between genotype groups . The ACE I/D polymorphism had no effect on sepsis-related mortality (II: 7%, ID: 5%, DD: 4%; p=0.692) . Sepsis mortality for infants with late BSI was 14% in infants with the II genotype, 9% with the ID genotype and 10% with the DD genotype (p=0.764) . CONCLUSIONS:: The ACE I/D polymorphism does not have a significant effect on the incidence or outcome of sepsis in ventilated VLBW infants.Journal of Perinatology advance online publication, 18 November 2004; doi:10.1038/sj.jp.7211231. Fundam Clin Pharmacol, 2004 Dec, 18(6), 679 - 83 Decreased aortic smooth muscle contraction in a rat model of multibacterial sepsis; Wang C et al.; We investigated whether blockade of the smooth muscle cell (SMC) inducible nitric oxide synthase (iNOS)-soluble guanylyl cyclase (sGC) vasodilator pathway would restore the fall in vasoreactivity produced by sepsis following cecal ligation and perforation (CLP) in rats . Contraction of adjacent aortic rings paired for the presence or absence of endothelial cells (EC) was recorded following high {K(+)}(e) (40 mm) or norepinephrine (NE, 10(-8) to 10(-5) m) in the presence of the nitric oxide synthase inhibitor (NOS), N(G)-nitro-l-arginine methyl ester (l-NAME, 0.3 mm) or the sGC inhibitor, 1H-{1,2,4}oxadiazolo{4,3-alpha}quinoxalin-1-one (ODQ, 5 mum) . In EC-denuded rings, sepsis halved SMC contraction induced by high {K(+)}(e) or NE; neither l-NAME nor ODQ produced an increase in NE E(max) or high {K(+)}(e)-evoked contraction . In conclusion, SMC contractility is globally reduced in CLP; this reduction does not appear to be explained by induction of SMC NOS in this CLP model. J Manag Care Pharm, 2004 Nov-Dec, 10(6), 521 - 30 Severe sepsis in managed care: analysis of incidence, one-year mortality, and associated costs of care; Braun L et al.; OBJECTIVE: To determine severe sepsis (SS) incidence, hospital mortality, 1-year mortality, and costs associated with care in a sample of enrollees in a nationally representative individual practice association (IPA)-network managed care organization (MCO) . METHODS: This was a retrospective analysis of administrative claims data for commercial (not managed Medicare) members . We identified MCO members hospitalized for SS between July 1995 and December 1998 . SS cases were identified by a combination of ICD-9-CM codes for infection and organ dysfunction . Enrollment information, physician, facility, and pharmacy claims were analyzed . Subjects with continuous enrollment were followed for 1 full year of observation . Costs were health plan payments to providers, after subtraction of member cost-share amounts . RESULTS: The incidence rate was 0.91 cases of SS per 1,000 enrollees, increasing with age . The mean age of SS patients was 50 years, and 53% were male . Approximately 63% received surgical intervention . Mortality was 21% during the first hospitalization and 36.1% at 1 year . During follow-up, 47.1% of survivors were rehospitalized . Mean index hospitalization length of stay and costs were 16 days and 26,820 dollars, with 1-year inpatient and outpatient costs totaling 48,996 dollars . Mean outpatient costs per survivor were 8,363 dollars, and mean per-patient-per-month (PPPM) outpatient costs were 906 dollars . Total follow-up costs including rehospitalization were similar for nonsurvivors compared with survivors (7,710 dollars versus 8,522 dollars, P=0.274), but PPPM costs were higher for nonsurvivors (1,760 dollars versus 699 dollars, P<0.001) . CONCLUSIONS: Incidence, hospital, and 1-year mortality rates were lower in this population compared with literature reports and were associated with a lower average age in this managed care population . Mean SS hospitalization costs were high, and nearly one half of survivors required rehospitalization within 1 year . Study results suggest the need to evaluate SS interventions for improvement in health outcomes and cost outcomes, particularly in postsurgical patients. Shock, 2004 Dec, 22(6), 582 - 5 Effects of sesame oil on oxidative stress after the onset of sepsis in rats; Hsu DZ et al.; The aim of this study was to investigate effects of sesame oil on oxidative stress after the onset of sepsis in rats . Effects of sesame oil on lipid peroxidation, superoxide anion, superoxide dismutase, catalase, glutathione, and nitrite after the onset of endotoxin intoxication were determined . To further examine the protective effect of sesame oil on sepsis, a mortality study was also conduced in cecal ligation and puncture-induced sepsis in rats . Sesame oil was given orally 6 h after endotoxin administration and cecal ligation and puncture, and parameters were then measured in another 6 h . Data demonstrated that a single dose of sesame oil reduced lipid peroxidation 6 h after endotoxin intoxication . Superoxide anion counts were decreased, glutathione levels were increased, and activities of superoxide dismutase and catalase, as well as nitrite levels, were not altered in lipopolysaccharide plus sesame oil-treated groups compared with lipopolysaccharide-treated groups . Furthermore, sesame oil given 6 h after cecal ligation and puncture significantly increased survival rate . Thus, we suggested that sesame oil could be used as a potent antioxidant to reduce oxidative stress after the onset of sepsis in rats. Shock, 2004 Dec, 22(6), 562 - 8 Impact of the indigenous flora in animal models of shock and sepsis; Wells CL et al.; Septicemia is currently the 10th leading cause of death in the United States, and shock and trauma patients are the source of much of the morbidity and mortality associated with septicemia . There is substantial evidence that the composition of the indigenous flora plays an important role in modulating outcome variables in animal models of shock and sepsis . Germ-free animals that lack an indigenous flora are not as susceptible to shock as their conventionally reared counterparts . And, in conventionally reared animals, the composition of the intestinal flora can also modulate outcome in shock and sepsis . For example, certain bacterial species/strains disseminate from the intestinal tract more easily than others, antibiotic-induced alterations of the flora can modulate the incidence of systemic spread, and a certain threshold number of intestinal bacteria facilitates extraintestinal dissemination . The composition of the intestinal flora can also affect intestinal permeability, the production of inflammatory mediators, and the responses of immune cells in extraintestinal sites . And, there is evidence that prior exposure to endotoxin, via either the oral or systemic route, can influence outcome in animals challenged with parenteral endotoxin, a widely used model of endotoxin shock . The general composition of intestinal flora of experimental animals can be characterized with relative ease . This knowledge can aid data interpretation, either to help explain irreproducible or expected results or to verify that observed differences are likely related to the dependent variable studied rather than the composition of the indigenous flora. Shock, 2004 Dec, 22(6), 548 - 54 Diminished ERK 1/2 and p38 MAPK phosphorylation in skeletal muscle during sepsis; Vary TC et al.; Sepsis induces weight loss and the loss of skeletal muscle proteins, in part through an inhibition of protein synthesis secondary to an inhibition of the key steps controlling mRNA translation in skeletal muscle . We have previously shown that sepsis decreases the phosphorylation of eIF4E . The present study examines the phosphorylation of Erk 1/2 MAPK and p38 MAPK in skeletal muscle of rats with a chronic (5-day) intra-abdominal septic abscess . Mnk1 catalyzes the phosphorylation of eIF4E, and Mnk1 is activated by phosphorylation via Erk1/2 MAPK and p38 MAPK . Sepsis resulted in a significant decrease in the steady-state phosphorylation of Erk 1/2 and p38 MAPKs compared with sterile inflammation . To examine the mediators responsible for decreased phosphorylation of Erk 1/2 and p38 MAPKs, rats were treated with TNF binding protein (TNFbp) or infused for 24 h with TNF . Treatment of septic rats with TNFbp resulted in an increase in the phosphorylation of both Erk 1/2 and p38 MAPKs in skeletal muscle . This was associated with enhanced phosphorylation of eIF4E . In contrast, constant intravenous infusion of TNF-alpha for 24 h resulted in a complete inhibition of p38 MAPK phosphorylation while Erk 1/2 MAPK phosphorylation was increased . The net effect was a modest increase in eIF4E phosphorylation . The results suggest altered regulation of Erk 1/2 and p38 MAPK signal translation pathways by endogenously produced TNF, or some compound dependent on TNF may modulate, in part, the phosphorylation state of eIF4E in skeletal muscle during sepsis. Shock, 2004 Dec, 22(6), 538 - 42 Cd40 but not CD154 knockout mice have reduced inflammatory response in polymicrobial sepsis: a potential role for Escherichia coli heat shock protein 70 in CD40-mediated inflammation in vivo; Nolan A et al.; The CD40-CD154 system controls various aspects of the host inflammatory response in models of cellular and humoral immunity . Recently, we described a role for CD40 in the innate immune response in polymicrobial sepsis . However, recent data suggests that CD40 maybe activated by CD154 or directly via bacterial heat shock protein (HSP) 70 . Therefore, we decided to test the mechanism of CD40 activation in murine polymicrobial sepsis . Wild-type (WT),