Sepsis

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), CD40, and CD154 underwent cecal ligation and puncture (CLP) . Compared with WT mice, CD40 had improved survival in association with attenuated production of IL-12, TNF-alpha, and IL-6 . In contrast, CD154 mice behaved similar to WT mice with regard to mortality and cytokine production . The differential response of CD40 and CD154 mice to CLP was not due to a general attenuated response to inflammatory stimuli, as all three strains had similar survival after LPS administration, and CD40 macrophages had normal production of IL-12 in response to lipopolysaccharide . In contrast, CD40 macrophages had attenuated IL-12 production in response to Escherichia coli HSP70 (DnaK) . Furthermore, intraperitoneal administration of DnaK resulted in a 4-fold increase in IL-12 in WT mice, which was absent in CD40 mice . This data demonstrates CD154-independent CD40 activation in polymicrobial sepsis and suggests that bacterial HSP70 is capable of stimulating CD40 in vitro and in vivo.

Arch Surg, 2004 Nov, 139(11), 1199 - 203
Hypothyroidism and adrenal insufficiency in sepsis and hemorrhagic shock; Ho HC et al.; HYPOTHESIS: We hypothesized that hypothyroidism and adrenal insufficiency frequently occur together in critically ill patients . DESIGN: A prospective observational study . SETTING: Surgical intensive care unit of a university-affiliated tertiary referral center . PATIENTS: Sixty-six consecutive patients with severe sepsis, septic shock, and hemorrhagic shock who required pulmonary artery catheterization for resuscitation were studied . INTERVENTIONS: Thyrotropin and baseline cortisol levels were obtained at 3 am followed by intravenous injection of 250 mug of cosyntropin, a synthetic adrenocorticotropic hormone derivative . A second measurement of the cortisol level was performed 1 hour later . MAIN OUTCOME MEASURES: Incidence of hypothyroidism and adrenal insufficiency and mortality . RESULTS: Mean (SD) age was 62 (19) years . The mean (SD) Acute Physiology and Chronic Health Evaluation II score was 21 (5) . Twenty-seven patients (40.9%) had severe sepsis, 31 (46.9%) had septic shock, and 8 (12.1%) had hemorrhagic shock . Five patients (7.6%) had hypothyroidism alone and 35 (53.0%) had only adrenal insufficiency . Eight patients (12.1%) had both hypothyroidism and adrenal insufficiency . All patients with endocrine abnormalities were treated . Mortality for the total group was 15 (22.7%) of 66 patients . CONCLUSION: There is a 12% incidence of simultaneous hypothyroidism and adrenal insufficiency in our study and the routine testing for both may be indicated in this population of critically ill patients.

Crit Care Med, 2004 Nov, 32(11 Suppl), S571 - 7
Other supportive therapies in sepsis: an evidence-based review; Trzeciak S et al.; OBJECTIVE: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for other supportive therapies in sepsis that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis . DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee . METHODS: The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum . We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade . Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al . on p . S591 . CONCLUSION: Patients with severe sepsis should be treated with deep-vein thrombosis prophylaxis . Low-dose unfractionated heparin or low molecular weight heparin is preferred . Use of graduated compression devices is recommended in septic patients with contraindication to the use of heparin or combined with heparin in very high-risk patients . Stress ulcer prophylaxis should be given to all patients with severe sepsis . Histamine-2 receptor antagonists are more effective than sucralfate in decreasing bleeding risk and transfusion requirements . Proton pump inhibitors have not been assessed in a direct comparison with histamine-2 receptor antagonists but do demonstrate equivalency and ability to increase gastric pH.

Crit Care Med, 2004 Nov, 32(11 Suppl), S562 - 70
Adjunctive therapies in sepsis: an evidence-based review; Cariou A et al.; OBJECTIVE: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for adjunctive therapies in sepsis that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and to improve outcome in severe sepsis . DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee . METHODS: The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum . We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade . Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al . on p . S591 . CONCLUSION: Glycemic control (maintenance of glucose <150 mg/dL) is recommended . The beneficial effect of glycemic control appears to be related control of glucose and not the administration of insulin . Glycemic control should be combined with a nutritional protocol . The dialysis dose is important in sepsis-induced acute renal failure . Continuous hemofiltration offers easier management of fluid balance in hemodynamically unstable septic patients but in the absence of hemodynamic instability is equivalent to intermittent hemodialysis . It is uncertain whether high-volume hemofiltration improves prognosis in sepsis . Bicarbonate therapy is not recommended for the purpose of improving hemodynamics or reducing vasopressor requirements in the presence of lactic academia and pH >7.15.

Crit Care Med, 2004 Nov, 32(11 Suppl), S554 - 61
Sedation, analgesia, and neuromuscular blockade in sepsis: an evidence-based review; Vender JS et al.; OBJECTIVE: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for sedation, analgesia, and neuromuscular blockade in sepsis that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis . DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee . METHODS: The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum . We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade . Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al . on p . S591 . CONCLUSION: There is no preferred sedative or analgesic agent for use in the critically ill septic patient during mechanical ventilation . Protocols should be utilized for administration of sedation with predefined sedation scale targets . Either intermittent bolus sedation or continuous infusion sedation to predetermined end points with daily interruption/lightening of continuous infusion sedation with awakening and re-titration, if necessary, are recommended . Neuromuscular blockade should be avoided if possible and, if used continuously, requires twitch monitoring.

Crit Care Med, 2004 Nov, 32(11 Suppl), S548 - 53
Mechanical ventilation in sepsis-induced acute lung injury/acute respiratory distress syndrome: an evidence-based review; Sevransky JE et al.; OBJECTIVE: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for mechanical ventilation in sepsis-induced acute lung injury/acute respiratory distress syndrome (ARDS) that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis . DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee . METHODS: The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum . We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade . Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al . on p . S591 . CONCLUSION: A minimum amount of positive end-expiratory pressure should be set to prevent lung collapse at end expiration in ARDS . Setting the level of positive end-expiratory pressure may be guided by Fio2 requirement or measurement of thoracopulmonary compliance . Role of noninvasive positive-pressure ventilation in acute lung injury/ARDS is undefined . Small tidal volume ventilation and limitation of end-inspiratory plateau pressure is important in the management of ARDS and may be facilitated by permissive hypercapnia . Prone positioning should be considered in the severest of ARDS patients . The ideal fluid management strategy in ARDS is unknown . Weaning protocols should be in place that include spontaneous breathing trials and criteria for initiating such trials . The role of high-frequency oscillatory ventilation and airway pressure release ventilation in ARDS is uncertain.

Crit Care Med, 2004 Nov, 32(11 Suppl), S542 - 7
Use of blood products in sepsis: an evidence-based review; Zimmerman JL; OBJECTIVE: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for the use of blood products in sepsis that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and to improve outcome in severe sepsis . DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee . METHODS: The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum . We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade . Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al . on p . S591 . CONCLUSION: In the absence of extenuating circumstances and following resolution of tissue hypoperfusion, red blood cell transfusion should be targeted to maintain hemoglobin at 7.0 g/dL or greater . Erythropoietin is not recommended as a specific treatment for sepsis-associated anemia . Fresh-frozen plasma should be given for documented deficiency of coagulation factors and in the presence of active bleeding or before surgical or invasive procedures . Antithrombin administration is not recommended . Specific platelet transfusion thresholds are based on the presence or absence of bleeding, significant risk for bleeding, plans for surgery or invasive procedures, and platelet count </=5,000/mm.

Crit Care Med, 2004 Nov, 32(11 Suppl), S534 - 41
Recombinant human activated protein C in the treatment of severe sepsis: an evidence-based review; Fourrier F; OBJECTIVE: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for recombinant human activated protein C that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis . DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee . METHODS: The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum . We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade . Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al . on p . S591 . CONCLUSION: Recombinant human activated protein C is recommended in patients at high risk of death (septic shock, sepsis-induced acute respiratory distress syndrome, Acute Physiology and Chronic Health Evaluation II score of >/=25, and sepsis-induced multiorgan failure) and no absolute contraindication related to bleeding risk or relative contraindication that outweighs the potential benefit . The presence or absence of disseminated intravascular coagulation should not influence the decision to administer recombinant human activated protein C . Heparin should be withheld during administration of recombinant human activated protein C.

Crit Care Med, 2004 Nov, 32(11 Suppl), S527 - 33
Use of corticosteroid therapy in patients with sepsis and septic shock: an evidence-based review; Keh D et al.; OBJECTIVE: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for the use of corticosteroid therapy in patients with sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis . DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee . METHODS: The modified Delphi methodology used for grading recommendations built upon a 2001 publication sponsored by the International Sepsis Forum . We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade . Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al . on p . S591 . CONCLUSIONS: Low doses of corticosteroids are recommended in patients with septic shock . In the absence of vasopressor requirement, corticosteroids should not be used to treat sepsis . High-dose corticosteroids are not recommended in severe sepsis . The use of adrenal function tests to guide decisions on corticosteroid therapy, the weaning of steroids at the end of the treatment period, the decision to discontinue steroids earlier with resolution of shock, and the addition of oral fludrocortisone are considered optional approaches.

Biol Neonate . 2004 Nov 9;87(2):105-110 {Epub ahead of print}
Serum Amyloid A Protein Is a Useful Inflammatory Marker during Late-Onset Sepsis in Preterm Infants; Arnon S et al.; Background: Few studies demonstrated that serum amyloid A (SAA), a non-specific acute-phase reactant, could be used as a reliable early marker for the diagnosis of late-onset sepsis (LOS) . Objectives: To evaluate the diagnostic value and the dynamics of SAA levels during the course of LOS and to compare it to those of other inflammatory markers . Methods: Levels of SAA, C-reactive protein (CRP) and IL-6 together with clinical variables, biochemical parameters and cultures retrieved from all preterm infants suspected of LOS were checked at the first suspicion of sepsis and after 8, 24, 48 and 72 h . Results were compared to healthy, matched infants . Results: One hundred and sixteen infants were included in the study, 38 in the sepsis and 78 in the non-sepsis group . High levels of SAA were observed at sepsis onset, with a gradual decline thereafter, while CRP levels increased only at 24 h after sepsis onset . In the sepsis group, levels of SAA returned faster to baseline than CRP levels . Receiver-operating characteristic analysis values revealed that SAA at 10 mug/ml had the highest sensitivity at 0, 8 and 24 h after sepsis onset (95, 100 and 97%, respectively) and a negative predictive value (97, 100 and 98%, respectively) . Conclusions: SAA is an accurate acute-phase protein during LOS in preterm infants . Quick and reliable SAA kits can make this marker a useful tool in LOS in preterm infants . Copyright (c) 2005 S . Karger AG, Basel.

Vet Rec, 2004 Oct 16, 155(16), 485 - 9
Septic tenosynovitis of the tarsal sheath of an Arab gelding and suspected sepsis of the lateral digital flexor tendon subsequent to bacterial peritonitis; Archer DC et al.; A 21-year-old Arab gelding with clinical signs of acute peritonitis had a perforating ulcer on the mesenteric border of the jejunum which resulted in localised contamination of the abdomen with ingesta . The affected segment of jejunum was resected and the abdomen was lavaged extensively . Postoperatively, the gelding was treated with broad-spectrum antibiotics, non-steroidal anti-inflammatory drugs and intravenous fluids, but after four days it became acutely non-weight bearing on its right hindlimb, and a tendonitis of the lateral digital flexor tendon within the tarsal sheath was identified ultrasonographically . The septic tendonitis was treated with broad-spectrum antibiotics but progressed proximodistally within the tendon until it involved both the tarsal sheath and the associated tarsocrural joint, necessitating the euthanasia of the gelding.

Anaesth Intensive Care, 2004 Oct, 32(5), 619 - 29
The role of microvascular thrombosis in sepsis; Dixon B; The acute inflammatory response to sepsis gives rise to significant morbidity and mortality . The mechanisms underlying this form of tissue injury are poorly understood . This review examines the evidence that tissue ischaemia due, to generalized microvascular thrombosis may play an important role . Microvascular thrombosis is probably an adaptive response that prevents bacteria in the tissues reaching the systemic circulation via the capillaries . In time, a definitive response by leucocytes removes the bacteria and repairs the damaged tissues . There is however evidence that if microvascular thrombosis becomes generalized, then extensive tissue ischaemia may precipitate organ failure and death . Post-mortem studies of patients with sepsis demonstrate microvascular thrombi in many organs including the kidney, liver, lung, gut, adrenals and brain, and the degree of organ injury is related to the quantity of thrombi . Furthermore studies in human and animal models of sepsis demonstrate therapies that inhibit coagulation or promote fibrinolysis reduce organ failure and mortality . In view of the personal and economic burdens that tissue injury associated with the acute inflammatory response places on the community, further studies to establish the role of microvascular thrombosis are clearly required . Such studies may lead to new therapies to limit or prevent this form of injury.

J Cell Biochem, 2005 Feb 1, 94(2), 419 - 31
TNFalpha mediates sepsis-induced impairment of basal and leucine-stimulated signaling via S6K1 and eIF4E in cardiac muscle; Lang CH et al.; Decreased translation initiation adversely impacts protein synthesis and contributes to the myocardial dysfunction produced by sepsis . Therefore, the purpose of the present study was to identify sepsis-induced changes in signal transduction pathways known to regulate translation initiation in cardiac muscle and to determine whether the stimulatory effects of leucine can reverse the observed defects . To address this aim, sepsis was produced by cecal ligation and puncture (CLP) in anesthetized rats and the animals studied in the fasted condition 24 h later . Separate groups of septic and time-matched control rats also received an oral gavage of leucine . To identify potential mechanisms responsible for regulating cap-dependent mRNA translation in cardiac muscle, several eukaryotic initiation factors (eIFs) were examined . Under basal conditions, hearts from septic rats demonstrated a redistribution of the rate-limiting factor eIF4E due to increased binding of the translational repressor 4E-BP1 with eIF4E . However, this change was independent of an alteration in the phosphorylation state of 4E-BP1 . The phosphorylation of mTOR, S6K1, the ribosomal protein (rp) S6, and eIF4G was not altered in hearts from septic rats under basal conditions . In control rats, leucine failed to alter eIF4E distribution but increased the phosphorylation of S6K1 and S6 . In contrast, in hearts from septic rats leucine acutely reversed the alterations in eIF4E distribution . However, the ability of leucine to increase S6K1 and rpS6 phosphorylation in septic hearts was blunted . Sepsis increased the content of tumor necrosis factor (TNF)-alpha in heart and pre-treatment of rats with a TNF antagonist prevented the above-mentioned sepsis-induced changes . These data indicate that oral administration of leucine acutely reverses sepsis-induced alterations eIF4E distribution observed under basal conditions but the anabolic actions of this amino acid on S6K1 and rpS6 phosphorylation remain blunted, providing evidence for a leucine resistance . Finally, TNFalpha, either directly or indirectly, appears to mediate the sepsis-induced defects in myocardial translation initiation . (c) 2004 Wiley-Liss, Inc.

Rom J Intern Med, 2003, 41(1), 83 - 93
Investigation of TNF-alpha, IL-6, IL-8 and of procalcitonin in patients with neurologic complications in sepsis; Cojocaru IM et al.; Some mediators of inflammation are associated with sepsis, involving nervous system . Proinflammatory cytokines, TNF-alpha, IL-6, and IL-8, and procalcitonin (PCT), proinflammatory protein, were investigated in patients with neurologic complications in sepsis . TNF-alpha, IL-6, IL-8, and PCT were prospectively investigated in 62 patients with neurologic complications in sepsis . TNF-alpha and IL-6 were studied both in serum as in the CSF, IL-8 and PCT were studied only in serum . TNF-alpha, IL-6, and IL-8 were studied by ELISA (R & D Systems), and the PCT by immunoluminometric assay (BRAHMS) . Mean value of TNF-alpha in serum was 578+/-214 pg/ml, and in CSF was 458+/-167 pg/ml (p<0.01) . Mean value of IL-6 in serum was 749+/-213 pg/ml, and in CSF was 617.5+/-182 pg/ml (p<0.01) . Mean value of IL-8 in serum was 332+/-196 pg/ml (p<0.01) . Mean value of PCT in serum was 80+/-16 ng/ml (p<0.01) . The investigated parameters do not permit the identifying of cases with neurologic complications . The increased correlation coefficient between cytokines in serum and in CSF suggests the damage of the blood-brain barrier . The raise of PCT in serum, induced by TNF-alpha and IL-6, is an argument of the severity of sepsis.

Alcohol, 2004 Jun, 33(2), 139 - 45
Is maternal alcohol use a risk factor for early-onset sepsis in premature newborns?
Gauthier TW, Manar MH, Brown LA.
Because chronic alcohol abuse alters immune defenses and increases infection in adults, we tested the hypothesis that maternal alcohol use during pregnancy would increase the risk of sepsis in very low birth weight (VLBW) premature newborns . We performed a case-controlled analysis of VLBW newborns born at Grady Memorial Hospital (Atlanta, GA) . Alcohol exposure, as the predictive variable, was assessed by maternal self-report . The outcome variables were early-onset and multiple late-onset sepsis . Univariate analysis with Fisher exact test and multivariate analysis with the use of binary logistic regression were performed . Early-onset sepsis was 15-fold higher in the alcohol-exposed group (n=20) compared with findings for the matched control group (n=168) {alcohol-exposed group, 10%, vs . control group, 0.6%: odds ratio (OR) 6.8 (95% confidence interval {CI}, 2.7-17.1), P < or = .05} . Early-onset sepsis in the alcohol+cocaine-exposed group (n=64) did not differ from findings for the control group . The prevalence of multiple late-onset sepsis did not differ among the exposure groups . Logistic regression analysis, controlling for chorioamnionitis and premature prolonged rupture of membranes, demonstrated an independent, increased risk of early-onset sepsis with alcohol exposure {OR 16 (95% CI, 1.2-210), P < or = .05} . We conclude that alcohol exposure significantly increased the risk of early-onset sepsis in this group of VLBW newborns . The effects of maternal alcohol abuse during pregnancy on the risk of infection in the VLBW newborn require further analysis.

J Pediatr Endocrinol Metab, 2004 Oct, 17(10), 1435 - 42
Thyroid hormone levels and their relationship to survival in children with bacterial sepsis and septic shock; Yildizdas D et al.; OBJECTIVES: Reported studies have showed alternations of thyroid hormones in critical illness mostly in adults and some in children . In this study, we aimed to measure thyroid hormone levels in children with sepsis and septic shock and investigate the relationship of these hormones with clinical state and survival . PATIENTS AND METHODS: Thyroid hormone levels of children with sepsis and septic shock, and age- and sex-matched controls were measured . RESULTS: There were 51 children in sepsis (group S), 21 children in septic shock (group SS) and 30 in the control (group C) group . Total triiodothyronine (TT3) levels were (nmol/l): 0.91 +/- 0.22, 0.64 +/- 0.23, 2.11 +/- 0.59; free triiodothyronine (FT3) (pmol/l): 0.027 +/- 0.006, 0.018 +/- 0.007, 0.049 +/- 0.010; total thyroxine (TT4) (nmol/l): 100.62 +/- 21.93, 65.79 +/- 19.35, 109.65 +/- 19.35; free thyroxine (FT4) (pmol/l): 18.06 +/- 3.87, 10.32 +/- 1.29, 19.35 +/- 3.87; and thyroid stimulating hormone (TSH) (mIU/ml): 5.0 +/- 2.0, 4.8 +/- 2.4, 5.2 +/- 3.0, in children with sepsis, septic shock, and controls, respectively . The TT3, FT3, TT4, and FT4 levels of group SS were significantly lower than those of groups S and C . The TT3 and FT3 levels of group S were lower than in group C, but there was no significant difference between TT4, and FT4 levels of groups S and C . TSH levels were slightly decreased in both sepsis and septic shock, but the difference was not significant . Eleven (21.6%) children with sepsis and 15 (71.4%) children with septic shock died (p < 0.001) . The levels of TT3, FT3, TT4 and FT4 were markedly lower in non-survivors of groups S and SS compared to survivors (p < 0.001) . CONCLUSIONS: These changes in the hypothalamo-pituitary-thyroidal axis may suggest a possible prognostic value of thyroid hormone levels in children with sepsis and septic shock . To the best of our knowledge, this report is the first study to compare thyroid hormone levels in a large number of patients with sepsis and septic shock with those in healthy controls in childhood.

Genes Immun, 2004 Dec, 5(8), 631 - 40
TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study; Gordon AC et al.; Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis . Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results . This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock . A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia . Plasma levels of TNF (P = 0.02), sTNFRSF1A (P = 0.005) and sTNFRSF1B (P = 0.01) were significantly higher in those who died on ICU compared to those who survived . There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R = 0.51, P < 0.001; sTNFRSF1B R = 0.53, P < 0.001), and in particular with the degree of renal dysfunction . In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome . The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.

J Med Genet, 2004 Nov, 41(11), 808 - 13
TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury; Barber RC et al.; CONTEXT: Sepsis, organ failure, and shock remain common among patients with moderate to severe burn injuries . The inability of clinical factors to identify at-risk patients suggests that genetic variation may influence the risk for serious infection and the outcome from severe injury . OBJECTIVE: Resolution of genetic variants associated with severe sepsis following burn injury . PATIENTS: A total of 159 patients with burns > or =20% of their total body surface area or any smoke inhalation injury without significant non-burn related trauma (injury severity score (ISS)> or =16), traumatic or anoxic brain injury, or spinal cord injury and who survived more than 48 h post-admission . METHODS: Candidate single nucleotide polymorphisms (SNPs) within bacterial recognition (TLR4 +896, CD14 -159) and inflammatory response (TNF-alpha -308, IL-1beta -31, IL-6 -174) loci were evaluated for association with increased risk for severe sepsis (sepsis plus organ dysfunction or septic shock) and mortality . RESULTS: After adjustment for age, full-thickness burn size, ethnicity, and gender, carriage of the TLR4 +896 G-allele imparted at least a 1.8-fold increased risk of developing severe sepsis following a burn injury, relative to AA homozygotes (adjusted odds ratio (aOR) 6.4; 95% confidence interval (CI) 1.8 to 23.2) . Carriage of the TNF-alpha -308 A-allele imparted a similarly increased risk, relative to GG homozygotes (aOR = 4.5; 95% CI 1.7 to 12.0) . None of the SNPs examined were significantly associated with mortality . CONCLUSIONS: The TLR4 +896 and TNF-alpha -308 polymorphisms were significantly associated with an increased risk for severe sepsis following burn trauma.

Transplant Proc, 2004 Sep, 36(7), 2154 - 5
A case of fungal sepsis due to aspergillus spondylitis followed by cytomegalovirus infection in a renal transplant recipient; Park SB et al.; Although advances in immunosuppressive therapy have led to increased survival of renal transplant recipients, there are greater risks of developing infectious complications . Because of its rarity and the lack of medical awareness, aspergillus spondylitis is often misdiagnosed as tuberculous spondylitis, especially in its early stages . We report a case of aspergillus spondylitis in a renal transplant followed by cytomegalovirus (CMV) retinitis . CASE: A 59-year-old woman was admitted due to general weakness and abdominal discomfort . She had undergone renal transplantation 3 years previously . One month before admission, she was diagnosed with CMV retinitis and treated with IV ganciclovir . On admission, she suffered from lower abdominal pain . Colonoscopy revealed multiple circular or patchy ulcers with surrounding severe mucosal edema in the sigmoid colon findings consistent with intestinal tuberculosis . On hospital day 30, she complained of lower extremity paresthesia and weakness . An MRI of the spine revealed a well-demarcated paraspinal mass around the L2-4 body; tuberculous spondylitis was initially considered . But despite antituberculosis medication, the patient progressed to spastic paraparesis and sensory changes in both lower legs, requiring urgent surgical decompression . At hospital day 60, she suffered persistent fever and developed thrombocytopenia . Wound discharge continued and paraparesis became denser . A CT of the spine showed progression of the paraspinal abscess from the L2 body to the iliac crest . CT-guided psoas muscle drainage was performed . Fungal culture showed Aspergillus species . Despite antifungal therapy, the patient died after a prolonged hospital stay due to fungal sepsis and septic shock from aspergillosis.

Eur J Immunol, 2004 Dec, 34(12), 3664 - 73
CC chemokine receptor 2 regulates leukocyte recruitment and IL-10 production during acute polymicrobial sepsis; Feterowski C et al.; Chemokine receptors are important for recruiting leukocytes to sites of infection and may contribute to immune cell activation . The present study investigated the role of the chemokine receptor CCR2 in polymicrobial septic peritonitis . The results showed that peritoneal production of the CCR2 ligands CCL2 and CCL12 in septic mice was largely independent of the common Toll-like receptor signaling adaptor MyD88 . Antibody blockade of CCR2 reduced the recruitment of macrophages and neutrophils to the infected peritoneal cavities of both wild-type and MyD88-deficient mice, suggesting that CCR2 engagement contributes to the MyD88-independent cellular response against polymicrobial septic peritonitis . Notably, administration of blocking CCR2 antibodies markedly increased local and systemic IL-10 levels in septic wild-type mice, whereas IL-10 was not detected in MyD88-deficient mice irrespective of whether CCR2 was blocked or not . Inhibition of CCR2 directly augmented Toll-like receptor-induced IL-10, but not TNF and IL-6, production of macrophages in vitro . Concomitant with enhanced IL-10 production, CCR2 blockade caused impaired bacterial clearance and aggravated kidney injury in wild-type, but not MyD88-null mice . These results indicate that CCR2 engagement modulates the innate immune response to polymicrobial septic peritonitis by both MyD88-dependent and -independent processes and suggest that a major function of CCR2 in sepsis is to attenuate IL-10 production and IL-10-mediated suppression of host defense.

Minerva Anestesiol, 2004 Oct, 70(10), 739 - 43; 743-5
Use of IgM and IgA-enriched immunoglobulins in the treatment of severe sepsis and septic shock . Clinical experience; Berlot G et al.; AIM: The aim of this study was to evaluate if the currently available clinical data and the time elapsing from the diagnosis to the administration of IgM and IgA-enriched immunoglobulins can predict the outcome of patients with severe sepsis and septic shock not responding to the current treatments . METHODS: All patients with these diagnoses, who did not respond to the standard treatment from August 1999 to September 2002, were retrospectively enrolled in the study . The variables evaluated included: (a) SAPS II and age at admission; (b) body temperature, mean arterial pressure, PaO2/FIO2 ratio, creatinine, blood white cell count on the day before the administration of the IgM and IgA-enriched immuno-globulins; (c) sequential organ failure assessment (SOFA) score before and during the treatment; (d) time elapsing between the diagnosis and the treatment; (e) outcome . RESULTS: Overall, 22 patients have been enrolled (17 M, 5 F, age 54.3+/-14.5 years) . Eleven (50%) survived . None of the variables measured was different among survivors and nonsurvivors . Only the time elapsing from the diagnosis of severe sepsis and septic shock and the beginning of the treatment significantly differed among survivors and nonsurvivors (2.72 +/- 1.49 days vs 7.45 +/- 3.41 days respectively, p<0.005) . CONCLUSION: In patients with severe sepsis and septic shock the currently available clinical variables and severity score are not valuable in identifying those patients who could take the maximal advantage from the administration of the IgM and IgA-enriched immunoglobulins . Thus, their time of administration plays a major role in the treatment of septic patients unresponding to the conventional treatment.

Nutr Hosp, 2004 Sep-Oct, 19(5), 259 - 62
{Simultaneous haemocultures and diagnosis of catheter-related sepsis}; Gonzalez-Avila G et al.; OBJECTIVE: To determine the diagnosis value of simultaneous blood cultures . BACKGROUND: The clinical criteria is not enough to establish catheter-related sepsis diagnosis and remotion or replacement of catheter are not necessary . SUBJECTS: We evaluated 164 catheters used for total parenteral nutrition placement in 127 patients with cancer . Simultaneous blood samples--central and peripheral venous--were taken after seven at ten days of permanency or infection suspicion and compared with tip culture result . INTERVENTIONS: Sensitivity, specificity and predictive values were calculated . The tip culture was the gold standard . RESULTS: A positive central venous blood culture with negative peripheral blood culture result was sensitivity of 87.5% and specificity of 97.9%, an inverse result show a sensitivity of 62.5% . When both blood cultures were positive are correctly identified 83.3% of cases with a sensitivity of 93.9% and diagnostic correlation of 0.87 . CONCLUSIONS: The simultaneous blood cultures are high diagnostic value.

Artif Cells Blood Substit Immobil Biotechnol, 2004, 32(3), 401 - 11
Temporal effect of hemoglobin resuscitation on sepsis survival; Kim HW et al.; Hemoglobin (Hb)-based oxygen carriers are promising resuscitation fluids for hemorrhagic shock . However, infusion of large amounts of Hb-based material could interfere with reticuloendothelial function potentiating postresuscitation sepsis mortality . We investigated the temporal relationship between hemorrhage-resuscitation and sepsis survival . Male SD rats were subjected to hemorrhage and resuscitated with shed blood volumes of purified human hemoglobin solution (HS) . Sepsis was induced by cecal ligation and puncture (CLP) 24 h before, 0, 24, or 72 h after hemorrhage/resuscitation (H/R) and survival was monitored . In additional animals with or without Hb resuscitation, hepatic heme oxygenase-1 (HO-1) gene expression and HO activity were assessed . Seven-day survival for animals resuscitated with HS prior to sepsis induction was significantly higher than other groups . Animals resuscitated with HS showed hepatic HO-1 gene expression while non-HS resuscitated animals did not . In addition, hepatic HO activity levels were significantly higher in HS resuscitated animals than non-HS resuscitated animals . In conclusion, HS resuscitation does not appear to enhance postresuscitation sepsis mortality . Rather, when conducted concomitantly or prior to sepsis, HS resuscitation appears to improve survival from a subsequent sepsis challenge.

Med Sci Monit, 2004 Nov, 10(11), CR635 - 41 Epub 2004 Oct 26.
Severe sepsis in Poland--results of internet surveillance of 1043 cases; Kubler A et al.; BACKGROUND: Severe sepsis is a clinical syndrome frequently occurring in intensive care units (ICUs) when systemic infection results in multiorgan dysfunction . No Polish data concerning treatment and prognosis in this group of patients have been available to date . MATERIAL/METHODS: The Polish Working Group for Sepsis introduced in 2003 internet registration of severe sepsis cases treated in ICUs in Poland . Information about severe sepsis were entered including the type of infection, clinical course, methods and results of treatment . RESULTS: From 20.04.2003 to 10.01.2004, 1043 severe sepsis cases were reported by 104 ICUs . Mean age of patients was 59 years . Mean duration of treatment was 19 days, with mortality rate of 55% . In 60% dysfunction of 4 or more organs was diagnosed . In 55% the underlying disease was surgical and abdominal cavity was the primary infection site (47%) . Pathogens most likely to cause severe sepsis were G- (48%) and G+ (43%) bacteria, as well as fungi (21%) . Positive blood culture was obtained in 45% of patients . Treatment involved antibiotic and support of organ function . Activated protein C was used in 8.2%, causing a reduction of mortality . CONCLUSIONS: Severe sepsis in Polish ICUs develops most frequently in the course of intra-abdominal infections . Dysfunction of 4 or more organs caused observed high mortality (55%) Internet surveillance proved to be useful method of collecting information, widely accepted by personnel of ICUs.

J Pediatr (Rio J), 2004 Sep-Oct, 80(5), 407 - 10
The role of sample collection timing on interleukin-6 levels in early-onset neonatal sepsis; Procianoy RS et al.; OBJECTIVE: To assess different perinatal findings and sample collection timing in newborns with early-onset sepsis comparing those with low IL-6 levels to the ones with high levels . METHODS: Eighty-five newborn infants, with clinical signs of sepsis and/or positive blood cultures, had plasma IL-6 collected in the initial evaluation for early-onset sepsis in the first 96 hours of life . They were classified in two groups according to their plasma IL-6 levels: higher, and equal to or lower than IL-6 median value for the whole septic group . RESULTS: Median IL-6 for the whole group was 89 pg/ml . High and low level groups were formed by 42 and 43 newborns respectively . There were no differences between the two groups regarding gestational ages, birth weights, cesarean-section proportion, Apgar scores, number of neonates with maternal risk factors for infection, number of maternal intrapartum antibiotic therapy, and number of positive blood cultures . Median plasma IL-6 in the high level group was 287 pg/ml, and in the low level group 46 pg/ml (p < 0.001) . Median sample timing was 17.5 hours of life for the high level group and 36 hours of life for the low level group (p < 0.001) . There was a significant negative correlation coefficient between IL-6 levels and sample collection timing . CONCLUSION: Sample collection timing is an important factor for detection of high plasma IL-6 level in newborn infants with early-onset sepsis.

Wien Klin Wochenschr, 2002, 114 Suppl 1, 9 - 19
{Cortisol in critically ill patients with sepsis--physiological functions and therapeutic implications}; Briegel J; Modern immunology reveals that cortisol interacts with the immune response at virtually all levels exerting suppressive and permissive effects . A prerequisite for the defense of severe infections is the functional integrity of the hypothalamic-pituitary-adrenal axis (HPAA) resulting in adequate cortisol production . There is increasing evidence that cortisol physiology and regulation substantially change in the course of septic shock . Patients with septic shock may suffer from relative adrenocortical insufficiency resulting in a relative deficiency of cortisol . In addition, the number and the affinity of cellular glucocorticoid receptors are decreased which may reduce the cortisol action at the cellular level . Since septic shock and adrenal insufficiency are sharing hemodynamic abnormalities such as hyperdynamic shock and peripheral vasodilation, the administration of stress doses of hydrocortisone appears to be a rational therapeutic approach in patients with septic shock . Controlled studies reveal that stress doses of hydrocortisone attenuate the systemic inflammatory response . Recently, two double-blind studies demonstrated that stress doses of hydrocortisone given in patients with septic shock reduce the time to shock reversal . The most important hemodynamic effect was an increase in the systemic vascular resistance . The earlier weaning from vasopressor therapy was associated with a trend towards improvements in organ dysfunction and mortality, respectively . Large-scale trials are on the way to investigate the benefit of stress doses of hydrocortisone on mortality of septic shock . This paper will focus on changes in glucocorticoid physiology and regulation during septic shock and will discuss the effects of stress doses of hydrocortisone on immune response and vascular tone in the course of septic shock.

Wien Klin Wochenschr, 2002, 114 Suppl 1, 1 - 8
{Acute phase reaction and immunocompetence in sepsis and SIRS}; Burdon D et al.; The incidence of sepsis and SIRS, respectively is still rising . Mortality is 40 to 70% and, thus, remains very high in spite of major advances in intensive care medicine . Numerous experimental data have helped to explain isolated aspects of the pathophysiology of these disease states but the complex patho-mechanism remains to be elucidated . The discovery of the toll-like receptors and of the endotoxin-binding proteins LBP and BPI have substantially contributed to the understanding of the bacterial toxin-host interactions and may stimulate the development of new therapeutic strategies in the future . Pro- and anti-inflammatory cytokines play a central role in disease evolution, however the concept of organ-derived and organ-specific damage is gaining importance . Both inflammation and counter-regulation can occur at the same time in the circulation thus, making the evaluation of the patients' immunological status difficult . Additionally, several gene polymorphisms have been detected for example within the toll-like receptor genes and TNF genes . These polymorphisms document the existence of pre-disposing factors, which influence acute phase reaction as well as immuno-competence in sepsis . Both genes and gender will play an important role in the future to identify patients at risk and potentially, to design a specific and individualized immuno-therapies.

Nat Med, 2004 Nov, 10(11), 1216 - 21 Epub 2004 Oct 24.
Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis; Wang H et al.; Physiological anti-inflammatory mechanisms can potentially be exploited for the treatment of inflammatory disorders . Here we report that the neurotransmitter acetylcholine inhibits HMGB1 release from human macrophages by signaling through a nicotinic acetylcholine receptor . Nicotine, a selective cholinergic agonist, is more efficient than acetylcholine and inhibits HMGB1 release induced by either endotoxin or tumor necrosis factor-alpha (TNF-alpha) . Nicotinic stimulation prevents activation of the NF-kappaB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) . In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease . These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the alpha7nAChR might have therapeutic potential for the treatment of sepsis.

Expert Opin Drug Saf, 2004 Nov, 3(6), 625 - 37
Safety of drotrecogin alfa (activated) in the treatment of patients with severe sepsis; McCoy C; While severe sepsis continues to plague hospitals worldwide, new treatment modalities, including activated recombinant protein C (drotrecogin alfa, Xigris, Lilly), have become a standard treatment alternative in many institutional algorithms . Drotrecogin alfa was shown to have a beneficial effect on mortality versus placebo in the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial (p = 0.005), but its use is not completely without risk . An increased risk of bleeding, including severe bleeding episodes, exists ranging 3.5 - 5.2% in the drotrecogin alfa treatment group versus 2.0 - 5.0% in the placebo group . Patients at risk include those on concomitant heparin therapy (> 15,000 units/day), those with platelet counts <or= 30,000/mm(3), and those undergoing an invasive procedure during the scheduled infusion period . After almost three years on the US market, the reported incidence of severe bleeding episodes has risen only slightly from the pre-marketing era, at that time notable for restrictive treatment protocols, devoid of at-risk patients . Drotrecogin alfa, while a promising agent for severe sepsis, requires prudent patient evaluation for bleeding risks.

Clin Exp Immunol, 2004 Nov, 138(2), 221 - 9
Are alterations of lymphocyte subpopulations in polymicrobial sepsis and DHEA treatment mediated by the tumour necrosis factor (TNF)-alpha receptor (TNF-RI)? A study in TNF-RI (TNF-RI(-/-)) knock-out rodents; Hildebrand F et al.; Sepsis is associated with depression of T cell-dependent immune reactivity with proinflammatory cytokines, such as tumour necrosis factor (TNF)-alpha, playing an important role . Recent investigations describe an association between these immunological alterations and disturbances of the endocrine system, related most frequently to sex steroid hormones . Dehydroepiandrosterone (DHEA), one of the most abundant adrenal sex steroid precursors, seems to have a protective immunological effect towards septic insults . In this study, both the role of TNF-receptor I (RI) and possible interactions in the protective role of DHEA were investigated in a murine model of polymicrobial sepsis . Polymicrobial sepsis was induced by caecal ligation and puncture (CLP) in a murine model . The effects of DHEA on survival, clinical parameters and cellular immunity (T lymphocytes and natural killer (NK) cells) were investigated . CLP was performed in genetically modified TNF-RI knock-out (TNF-RI(-/-)) and genetically unmodified (wild-type, WT) mice . DHEA application was associated with a decrease in the mortality rate in WT animals . A mortality rate of 91.7% was observed in TNF-RI(-/-) mice after CLP . This mortality rate was reduced to 37.5% by the application of DHEA . In sham-operated TNF-RI(-/-) animals, a significantly higher proportion of NK cells within the lymphocyte population was measured compared with the corresponding WT group . After CLP, a significant increase in the percentage cell count of NK cells was recorded in WT mice . Overall, following DHEA application in WT mice, an alteration in the cellular immune response was characterized by a reduction in the percentage counts of CD4(+), CD8(+) and NK cells . In the group of TNF-RI(-/-) mice treated with DHEA, no increase in the percentage cell count of NK cells was observed after CLP . No data for cell analysis were available from the CLP-TNF-RI(-/-) mice treated with saline, due to the high mortality rate in these animals . DHEA reduces the complications of sepsis in a TNF-RI-independent manner . Our study suggests that NK cells are involved in the protective mechanism of DHEA in WT mice . It would therefore seem that DHEA represents a feasible alternative therapy for the dysregulated immune system in sepsis.

J Perinat Med, 2004, 32(5), 446 - 52
Amniotic cavity cultures, blood cultures, and surface swabs in preterm infants--useful tools for the management of early-onset sepsis?
Berger A, Witt A, Haiden N, Kretzer V, Heinze G, Pollak A.
AIMS: To evaluate the potential benefit of amniotic fluid and amniotic/placental membrane cultures for the management of early-onset sepsis in preterm infants . METHODS: The results of amniotic cavity cultures obtained during cesarean section and of peripheral blood cultures and surface swabs obtained from the preterm infant at the time of admission were analyzed with respect to the diagnosis of clinical sepsis in 221 preterm infants <34 weeks of gestation . RESULTS: 136 (61.5%) patients had negative amniotic cavity culture results or growth of contaminants, 56 (25.3%) had growth of Ureaplasma urealyticum, and 29 (13.1%) of other pathogens . The corresponding numbers for surface swabs were 82.8%, 11.6%, and 5.6% . A positive blood culture was found in only two neonates . Fifty-four patients (24.4%) had clinical early-onset sepsis . Patients with amniotic cavity culture results that were positive for other pathogens were significantly more likely to experience clinical sepsis than patients with negative culture results (51.7% vs 15.1%, OR 6.1, p<0.0001) . Regarding surface swabs, this correlation did not reach statistical significance . CONCLUSION: The strong association between positive amniotic cavity culture results and clinical early-onset sepsis supports the existence of a causal relation and provides evidence for the potential value of amniotic and/or placental membrane sampling in the management of early-onset sepsis in preterm infants . Surface swabs add no additional information and hence should not be performed routinely.

Srp Arh Celok Lek, 2004 May-Jun, 132(5-6), 182 - 6
{Systemic inflammatory response syndrome in surgical patients with sepsis}; Milic DJ et al.; Systemic inflammatory response syndrome and sepsis are common in surgically treated patients . Systemic inflammatory response syndrome represents a major factor of morbidity and mortality in these patients . The pathogenesis of these syndromes has been increasingly clarified . The objective of this review is to present an overview of our current understanding of the physiology underlying these conditions.

Am J Clin Pathol, 2004 Nov, 122(5), 765 - 71
Spleen depletion in neonatal sepsis and chorioamnionitis; Toti P et al.; Neonatal sepsis and chorioamnionitis induce morphologic modifications and shrinkage of the thymus . We show fetal and neonatal morphologic modifications of the spleen in the same autopsy subjects as previously used to describe thymus shrinkage, including 10 preterm or full-term neonates who died of proven sepsis within 48 hours after birth and 20 fetuses spontaneously aborted because of extensive ascending chorioamnionitis . Control subjects included 10 fetuses from induced termination of pregnancy and 10 neonates who died suddenly during the perinatal period without evidence of chorioamnionitis . Spleen cell populations were studied by means of immunohistochemical analysis . Neonatal sepsis occurred with severe spleen depletion, involving both B and T lymphocytes (P < .001) . Fetuses with chorioamnionitis also showed spleen cell depletion . These observations, to our knowledge not described before, indicate that preterm and term neonates show an inflammatory reaction similar to that of adult patients and that severe chorioamnionitis is associated with a nonspecific inflammatory response comparable to that of sepsis.

Shock, 2004 Nov, 22(5), 478 - 81
Role of chemically modified tetracycline on TNF-alpha and mitogen-activated protein kinases in sepsis; Maitra SR et al.; Chemically modified tetracyclines are orally active inhibitors of multiple proteases and cytokines . In this study, we focused on the regulation of tumor necrosis factor (TNF)-alpha and mitogen-activated protein kinases (MAPKs) in sepsis and their reduction by treatment with nonantimicrobial chemically modified tetracycline-3 (CMT-3), which retains their antiinflammatory activity . Sepsis was induced in rats by cecal ligation and puncture (CLP) . At 24 h and 1 h before CLP, treated rats received CMT-3 (25 mg/kg), and untreated rats received saline by gavage . At 0 h, 0.5 h, 1.5 h, and 24 h after CLP, blood and liver samples were collected . TNF-alpha was determined by ELISA, and MAPKs were determined by Western blot analysis . A significant activation of p38 MAPK was observed after 0.5 h and 1.5 h of sepsis that appeared to coincide with the increased circulating TNF-alpha level . The activation of p42/44 was increased after 24 h of sepsis, whereas that of SAPK/JNK was unaltered throughout the course of sepsis . CMT-3 pretreatment inhibited the TNF-alpha level as well as p38 MAPK activation seen after 0.5 and 1.5 h of CLP and also suppressed the activation of p42/44 after 24 h post-CLP . These results indicate increased activity of TNF-alpha and MAPK following sepsis and demonstrate the beneficial effect of CMT-3 in preventing the increase in TNF-alpha, p38 MAPK, p42/44 MAPK, and the progression of septic shock.

Shock, 2004 Nov, 22(5), 403 - 9
Increased expression of toll-like receptor-2 and -4 on leukocytes from patients with sepsis; Harter L et al.; The reduced responsiveness of monocytes or granulocytes toward endotoxin (endotoxin tolerance) during sepsis may depend on Toll-like receptors (TLR) . The expression of TLR-2 and TLR-4 was measured on neutrophils (PMN) and monocytes from patients with sepsis (n = 21) or healthy controls (n = 12) . Leukocytes (1 x 10/mL) were incubated at 37 degrees C with or without a TLR-4 (LPS 1 microg/mL) or a TLR-2 ligand (MALP-2 2 nM) . Surface expression of TLR-2 and TLR-4 at 0, 4, and 16 h was determined in FACS after staining with specific antibodies . The release of IL-8 and TNF-alpha was measured by ELISA . Freshly isolated PMN from patients with sepsis exhibited significantly (P < 0.05) higher mean fluorescence for TLR-2 (78.0 +/- 18.6) and TLR-4 (11.4 +/- 2.3) than controls (12.8 +/- 2.2 and 2.3 +/- 0.4) . Similarly, monocytes from patients exhibited higher TLR-2 and TLR-4 expression (300.8 +/- 40.6 and 92.7 +/- 12.1) than cells from controls (149.5 +/- 27.1 and 52.2 +/- 7.6) . In patients with sepsis, expression of TLR-2 and TLR-4 on PMN increased during 16 h of incubation (106.2 +/- 22.1 and 34.5 +/- 5.3), whereas it remained unchanged in controls (19.3 +/- 6.1 and 5.4 +/- 1.9) . Incubation with LPS or MALP-2 had no effect on TLR-4 or TLR-2 expression in cells from either controls or patients . Despite increased TLR expression in cells from patients with sepsis, the endotoxin-induced release of TNF-alpha and IL-8 was indistinguishable from that in controls . Therefore, the endotoxin tolerance seen in patients with sepsis does not depend solely on TLR-2 or TLR-4 expression, and other mechanisms must be involved.

J Pediatr Surg, 2004 Oct, 39(10), 1548 - 52
Persistent elevation of serum interleukin-6 in intraabdominal sepsis identifies those with prolonged length of stay; Latifi SQ et al.; BACKGROUND/PURPOSE: Elevated serum interleukin-6 (IL-6) levels in patients with intraabdominal sepsis have been associated with increased morbidity and mortality . The authors hypothesized that after surgical intervention a persistent elevation of IL-6 would more accurately reflect the inflammatory state and thus predict the subsequent time to recovery better than the preoperative value alone . METHODS: Nineteen consecutive children with peritonitis and manifestations of the systemic inflammatory response syndrome were enrolled prospectively . IL-6 levels were determined from pre- and postoperative serum samples (within 12 to 24 hours) by enzyme-linked immunosorbant assay (ELISA) . Patient postoperative length of stay (LOS) was recorded . RESULTS: Before surgery, patient serum IL-6 levels ranged from 48 to 132,546 pg/mL . LOS ranged from 4 to 60 days, with subjects falling into 2 groups of < or =11 (n = 14) and > or =25 (n = 5) days . Using an IL-6 level greater than 500 pg/mL to predict a prolonged LOS (>11 days), a persistent elevation of IL-6 postoperatively appears to increase the likelihood of a prolonged LOS . CONCLUSIONS: Persistent IL-6 levels greater than 500 pg/mL may be useful in identifying pediatric intraabdominal sepsis patients with prolonged LOS and presumably greater morbidity . Rapid identification of these patients may allow for novel therapeutic interventions.

Am J Med Sci, 2004 Oct, 328(4), 238 - 47
The endocrine system during sepsis; Brierre S et al.; Endocrinopathy during sepsis can manifest as hyperglycemia and insulin resistance or as insufficient production of either adrenal corticosteroids or vasopressin . The results of a recent large clinical trial have demonstrated that tight glycemic control with insulin can confer survival benefit to selected intensive care unit patients . Relative impairment of adrenocortical reserve has been suggested to be an important contributor to the pathogenesis of shock in sepsis . Replacement doses of glucocorticoids and mineralocorticoids have been associated with improved survival in the subset of patients with blunted results on adrenocorticotropin hormone stimulation tests . Posterior pituitary production of vasopressin is diminished in septic shock while sensitivity to its vasopressor effects is enhanced . Clinical trials are underway to determine whether administration of vasopressin can improve outcomes in patients with septic shock . Whether the euthyroid sick syndrome represents an adaptive or a maladaptive response to severe illness remains unclear.

Am J Med Sci, 2004 Oct, 328(4), 230 - 7
The lung in sepsis: fueling the fire; Happel KI et al.; Advances in our understanding of the molecular mechanisms underlying the pathophysiology of sepsis have generated considerable efforts in manipulating the host response during this frequently lethal condition . While existing trials of immune modulation have been largely unsuccessful, an appreciation for the roles of individual organ systems in sepsis is important to enable clinicians to discern how each functions as both a target for injury and a contributor to the derangement in homeostasis seen in sepsis . Such awareness will encourage treatment decisions aimed at optimizing conventional therapy while minimizing the adverse effects of supportive care, and it may also guide the incorporation of newer immunomodulatory therapeutics into our existing modalities . This article discusses the lung's response to sepsis, from the standpoint of organ dysfunction related to sepsis as well as its participation in the generation and maintenance of the systemic inflammatory state.

Am J Med Sci, 2004 Oct, 328(4), 220 - 9
Dysregulation of the immune response in severe sepsis; Pinsky MR; Sepsis is systemic expression of a generalized activation of the host's innate immunity as a result of varied types of insults . This expression involves a cellular inflammatory response that has both proinflammatory and antiinflammatory components, the primary trigger for which is an intracellular oxidative stress, induced by receptor-mediated transmembrane signal transduction or direct noxious injury . Sepsis reflects the interaction between pro- and anti-inflammatory intracellular mechanisms, the uncontrolled activation of which leads to cell exhaustion, organ dysfunction, and death . Successful clinical trials of novel treatments for the management of severe sepsis share a common ability to down-regulate this overall response, restoring normal proinflammatory responsiveness and mitochondrial energetic function.

Am J Med Sci, 2004 Oct, 328(4), 215 - 9
Recombinant human activated protein C in sepsis: assessing its clinical use; Haley M et al.; Based on the results of the phase III PROWESS trial, recombinant human activated protein C (rhAPC) was approved by the Food and Drug Administration (FDA) for use in severely septic patients . Concerns regarding rhAPC's inconsistent effects, incomplete understanding of its mechanism of action, and its safety in particular subgroups were raised during the FDA's evaluation . This study attempts to assess the cost-effectiveness rhAPC by comparing its effects during recent clinical use to its prior phase III trial testing and by considering other potentially less expensive treatments with effects that may overlap those of rhAPC . In patients with similar numbers of injured organs, mortality rates may be higher with rhAPC during clinical use compared with the phase III trial . There may also be an increased risk of hemorrhage and other adverse events that necessitate early discontinuation of treatment . Many of the patients receiving rhAPC during clinical use may have otherwise been excluded from its phase III trial testing . Data from several recent phase III trials as well as a recent meta-analysis suggest that heparin and physiologic dose steroids offer substantially less expensive alternatives to rhAPC . Further phase IV testing will be required to confirm such possibilities.

Am J Med Sci, 2004 Oct, 328(4), 205 - 14
Drotrecogin alfa (activated) for the treatment of severe sepsis and septic shock; Rice TW et al.; Coagulopathy and systemic inflammation are almost universal in patients with severe sepsis . Interaction between the two results in an intense inflammatory response and microthrombi formation in the vessels of multiple organs, resulting in organ dysfunction or severe sepsis . Recombinant human activated protein C, also known as drotrecogin alfa (activated), possesses anti-inflammatory, antithrombotic, and profibrinolytic properties . Treatment with drotrecogin alfa (activated) significantly reduces morbidity and mortality in patients with severe sepsis . An increased risk of bleeding during the infusion was the only side effect experienced . Recent data demonstrate that early administration of drotrecogin alfa (activated) is associated with lower mortality rates . Despite concern over its relatively high cost, analysis has demonstrated that recombinant human activated protein C is as cost-effective as other commonly used treatments in the intensive care unit.

Am J Med Sci, 2004 Oct, 328(4), 196 - 204
Coagulation in sepsis; Jagneaux T et al.; Activation of the coagulation cascade during invasive infection can result in purpura fulminans, with rapid progression of tissue ischemia, or may manifest as abnormal clotting indices alone . Although severe derangements in coagulation are associated with organ dysfunction and increased mortality, the contribution of coagulopathy to the pathophysiology of sepsis remains incompletely understood . Over the past decade, investigators have evaluated several therapeutic anticoagulant strategies in sepsis, and manipulation of the coagulation system has emerged as a key concept in the current management of this disease . Clinical observations during treatment of septic patients with the endogenous anticoagulant activated protein C have stimulated additional study of interactions between endothelial injury, coagulation, and inflammation . This review describes clotting abnormalities during sepsis and discusses the clinical experience with therapeutic strategies intended to oppose excessive coagulation.

J Crit Care, 2004 Sep, 19(3), 152 - 7
Should procalcitonin be introduced in the diagnostic criteria for the systemic inflammatory response syndrome and sepsis?
Giamarellos-Bourboulis EJ, Giannopoulou P, Grecka P, Voros D, Mandragos K, Giamarellou H.
PURPOSE: To define whether procalcitonin should be introduced in the diagnostic criteria of sepsis . METHODS: Procalcitonin was estimated in sera of 105 critically ill patients by an immunochemiluminometric assay . Diagnosis was settled by 3 types of criteria: A, the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) 1992 criteria; B, the ACCP/SCCM criteria and concentrations of procalcitonin above 1.0 ng/mL as indicative of SIRS/sepsis; and C, the ACCP/SCCM criteria and concentrations of procalcitonin 0.5 to 1.1 ng/mL for SIRS and above 1.1 ng/mL for sepsis . RESULTS: Criteria A identified 50.5% of patients with SIRS, 18.1% with sepsis, 0.9% with severe sepsis and 22.9% with septic shock; respective diagnosis by criteria B were 26.7%, 9.5%, 10.5% and 25.7%; and respective diagnosis by criteria C were 19.0%, 25.7%, 9.5%, and 25.7% . Sensitivity of concentrations between 0.5 ng/mL and 1.1 ng/mL was 25.6% for Systemic Inflammatory Response Syndrome (SIRS); and above 1.1 ng/mL 92.8% for sepsis . Sepsis-related death was associated with elevated procalcitonin upon presentation of a clinical syndrome . CONCLUSIONS: Despite the limited diagnostic value of procalcitonin for SIRS, concentrations of procalcitonin above 1.1 ng/mL are highly indicative for sepsis without, however, excluding the presence of SIRS.

Crit Care Med, 2004 Oct, 32(10), 2135 - 45
Sepsis: an arginine deficiency state?
Luiking YC, Poeze M, Dejong CH, Ramsay G, Deutz NE.
OBJECTIVE: Sepsis is a major health problem considering its significant morbidity and mortality rate . The amino acid L-arginine has recently received substantial attention in relation to human sepsis . However, knowledge of arginine metabolism during sepsis is limited . Therefore, we reviewed the current knowledge about arginine metabolism in sepsis . DATA SOURCE: This review summarizes the literature on arginine metabolism both in general and in relation to sepsis . Moreover, arginine-related therapies are reviewed and discussed, which includes therapies of both nitric oxide (NO) and arginine administration and therapies directed toward inhibition of NO . DATA: In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery, because both endogenous de novo production from citrulline and food intake are reduced . Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine in the arginase and NO pathways . As a result, lowered plasma arginine levels are usually found . Clinical symptoms of sepsis that are related to changes in arginine metabolism are mainly related to hemodynamic alterations and diminished microcirculation . NO administration and arginine supplementation as a monotherapy demonstrated beneficial effects, whereas nonselective NO synthase inhibition seemed not to be beneficial, and selective NO synthase 2 inhibition was not beneficial overall . CONCLUSIONS: Because sepsis has all the characteristics of an arginine-deficiency state, we hypothesise that arginine supplementation is a logical option in the treatment of sepsis . This is supported by substantial experimental and clinical data on NO donors and NO inhibitors . However, further evidence is required to prove our hypothesis.

Clin Nephrol, 2004 Sep, 62(3), 185 - 92
Sepsis and SOFA score: related outcome for critically ill renal patients; Carbonell N et al.; AIMS: To evaluate the influence of sepsis in critically ill patients with acute renal failure (ARF), and to analyze the value of the sequential organ failure assessment (SOFA) score for assessing the morbidity and related mortality of these patients . MATERIAL AND METHODS: A prospective observational study developed in a medical intensive care unit (ICU) of a tertiary care university hospital . Data were collected from January 1, 2001 - July 31, 2002 . The inclusion criterion was either a creatinine plasma level > or = 2 mg/dl on ICU admission or increases > or = 30% from its initial value . Sepsis was evaluated at the time of study inclusion, and patients were distributed into 2 groups (septic and nonseptic patients) . RESULTS: Two hundred patients with ARF were prospectively enrolled in the study (91 (45.5%) septic and 109 (54.5%) nonseptic patients) . Median age was 68 years in septic patients and 72 in nonseptic ones while the percentage of males in both groups was 66% vs 69%, respectively . Septic patients showed more organ failures and more respiratory, cardiovascular and coagulation failures at the time of study admission as well as a worse mean SOFA score during the first 4 days after inclusion (p < 0.01) . Mortality rate at the ICU was significantly higher in the septic group when compared to the nonseptic one (55% vs 19.3%, OR = 2.21 (1.65 - 2.97)) . Using stepwise logistic regression, acute tubular necrosis and oliguria in septic patients as well as cardiovascular failure (evaluated by SOFA score) in nonseptic patients were identified as independent risk factors for mortality . CONCLUSIONS: Septic and nonseptic ICU patients with ARF have an increased risk of ICU mortality depending on the type of organ failure . Although SOFA score does not predict outcome, it is a useful tool to categorize these patients and to describe a sequence of complications in critically ill patients.

Immunobiology, 2004, 209(1-2), 31 - 8
Lysophospholipid acyltransferases in monocyte inflammatory responses and sepsis; Jackson SK et al.; Acyltransferases are important in the regulation of membrane phospholipid fatty acyl composition and together with phospholipase A2 enzymes control arachidonic acid incorporation and remodelling within phospholipids . In addition, monocyte and macrophage acyltransferase activity has been shown to respond to various inflammatory cytokines under conditions that can induce enhanced cellular responses . Work in our laboratory indicates that the enzyme lysophosphatidylcholine acyltransferase may mediate the priming reactions of monocytes to the cytokine interferon-gamma . Our recent studies suggest that this enzyme might also affect the responses of monocytes to the bacterial agent lipopolysaccharide that may be important in the development of sepsis . This article summarises the relationship between monocyte lysophosphatidylcholine acyltransferase, lipopolysaccharide and sepsis.

Crit Care, 2004 Oct, 8(5), R291 - 8 Epub 2004 Jul 05.
Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care; Williams MD et al.; INTRODUCTION: Infection is an important complication in cancer patients, which frequently leads to or prolongs hospitalization, and can also lead to acute organ dysfunction (severe sepsis) and eventually death . While cancer patients are known to be at higher risk for infection and subsequent complications, there is no national estimate of the magnitude of this problem . Our objective was to identify cancer patients with severe sepsis and to project these numbers to national levels . METHODS: Data for all 1999 hospitalizations from six states (Florida, Massachusetts, New Jersey, New York, Virginia, and Washington) were merged with US Census data, Centers for Disease Control vital statistics and National Cancer Institute, Surveillance, Epidemiology, and End Results initiative cancer prevalence data . Malignant neoplasms were identified by International Classification of Disease (ninth revision, clinical modification) (ICD-9-CM) codes (140-208), and infection and acute organ failure were identified from ICD-9-CM codes following Angus and colleagues . Cases were identified as a function of age and were projected to national levels . RESULTS: There were 606,176 cancer hospitalizations identified, with severe sepsis present in 29,795 (4.9%) . Projecting national estimates for the US population, cancer patients account for 126,209 severe sepsis cases annually, or 16.4 cases per 1000 people with cancer per year . The inhospital mortality for cancer patients with severe sepsis was 37.8% . Compared with the overall population, cancer patients are much more likely to be hospitalized (relative risk, 2.77; 95% confidence interval, 2.77-2.78) and to be hospitalized with severe sepsis (relative risk, 3.96; 95% confidence interval, 3.94-3.99) . Overall, severe sepsis is associated with 8.5% (46,729) of all cancer deaths at a cost of 3.4 billion dollars per year . CONCLUSION: Severe sepsis is a common, deadly, and costly complication in cancer patients.

Anesteziol Reanimatol, 2004 Jul-Aug, (4), 47 - 9
{Diastolic malfunction in sepsis and septic shock}
{Differential choice of intensive care in abdominal sepsis}
{No authors listed}

The purpose of the case study was substantiation of a differential intensive care in abdominal sepsis with respect to its clinical-and-pathogenetic variations . Retro- and prospective clinical-and-biochemical parameters were investigated in 60 patients with disseminated peritonitis and abdominal sepsis . The patients were shared between 3 groups with respect to their clinical-and-laboratory findings . Clinical-and-pathogenetic types were defined for the clinical course of abdominal sepsis (AS) . It was found as necessary to add enteral detoxication to the combined intensive care scheme in type 1 AS . A single-stage intravenous perftoran infusion plus enteral detoxication are required in type 2 AS . And in type 3 AS, the therapeutic scheme should be expanded through intravenous infusion of perftoran with subsequent enteral detoxication.

Am J Pathol, 2004 Oct, 165(4), 1433 - 46
A protein C deficiency exacerbates inflammatory and hypotensive responses in mice during polymicrobial sepsis in a cecal ligation and puncture model; Ganopolsky JG et al.; During the systemic inflammatory state induced by sepsis, the potential for coagulopathy exists because of up-regulation of natural procoagulants and anti-fibrinolytics, and down-regulation of natural anti-coagulants, with protein C (PC) being a critical example of the latter case . PC functions as an anti-coagulant, profibrinolytic, and anti-inflammatory agent, and, thus, its administration or deficiency may affect the course and outcome of sepsis in patients . In this study, a cecal ligation and puncture model of septic peritonitis was applied to wild-type mice and littermates with a targeted heterozygous deficiency of PC (PC(+/-)) to characterize the importance of a PC-deficiency on polymicrobial sepsis . An enhanced mortality rate was found to accompany a PC deficiency . Plasma cytokines, as well as organ-specific expression of cytokine transcripts, were elevated in PC(+/-) mice . No signs of severe disseminated intravascular coagulation (DIC) were observed in wild-type or PC(+/-) mice, as indicated by an increase in fibrinogen levels and the invariability of platelet counts after cecal ligation and puncture . Consumption of coagulation factors was similar in both genotypes and a decrease in the PC mRNA and protein levels was more prominent in PC(+/-) mice . Renal and organ muscle damage was enhanced in PC(+/-) mice, as shown by increases in plasma blood urea nitrogen, creatinine, and creatinine kinase . Hypotension and bradycardia were more enhanced in PC(+/-) mice than in wild-type mice, thus provoking a more severe septic shock response . Thus, the hemodynamic role of PC during sepsis is of critical importance to the outcome of the disease.

J Nutr, 2004 Oct, 134(10 Suppl), 2768S - 2774S; discussion 2796S-2797S
In vivo whole body and organ arginine metabolism during endotoxemia (sepsis) is dependent on mouse strain and gender; Luiking YC et al.; Arginine metabolism involves various organs such as the kidney, the intestines, and the liver, which act together in an interorgan axis . Major pathways for arginine production are protein breakdown and de novo arginine production from citrulline; disposal of arginine is mainly used for protein synthesis or used by the enzymes arginase and nitric oxide synthase (NOS) . To assess in vivo organ arginine metabolism under normal conditions and during endotoxemia we used a mouse model, and analyzed for gender and strain differences . Male and female inbred FVB and C57BL6/J mice were anesthetized and catheterized to study whole body, gut, liver, renal and muscle metabolism, using a stable isotope infusion protocol . Animals were treated with saline or lipopolysaccharide . Plasma arginine levels tended to be higher in female mice, although levels were not significantly different from male mice (P = 0.09) . Although not all significantly different, whole body arginine production and arginine clearance tended to be higher in C57BL6/J mice (P < 0.1), while citrulline (P = 0.05), NO (P = 0.08), and de novo arginine (P < 0.01) production were higher in FVB mice . During endotoxemia, NO production increased in general (P < 0.05), while whole body arginine clearance increased in FVB mice, but decreased in C57BL6/J mice (P < 0.01) . At the organ level, portal-drained viscera (PDV) arginine metabolism was higher in FVB than in C57BL6/J mice (P < 0.05) . During endotoxemia, liver arginine metabolism decreased in general (P < 0.05), while strain differences existed for PDV, muscle, and renal arginine metabolism . In conclusion, stable isotope techniques in multicatheterized mice allow measurements of arginine metabolism on whole body and organ level . Strain and gender differences are present in arginine metabolism under physiological conditions and during endotoxemia.

Curr Infect Dis Rep, 2004 Oct, 6(5), 367 - 373
Genetic Susceptibility to Sepsis: A Possible Role for Mannose-binding Lectin; Garred P et al.; Sepsis is an increasing problem in modern medicine and the leading cause of death in noncoronary intensive care unit patients . Over the past few years, several studies have provided data indicating that relatively common polymorphisms in genes encoding proteins of importance for innate immune recognition, the inflammatory response, and for coagulation and fibrinolysis, are associated with susceptibility for and outcome of sepsis . Recently, several studies have shed light on the importance of deficiency of mannose-binding lectin (MBL) as a susceptibility factor for sepsis . This review summarizes the evidence that critically ill patients carrying MBL-variant alleles may be at increased risk for severe sepsis . The prospect for the future is that genetic profiling may guide in identifying critically ill patients at increased risk for sepsis and poor outcome, and in tailoring a more individual and effective therapy.

Curr Infect Dis Rep, 2004 Oct, 6(5), 361 - 366
Toll-like Receptors and Sepsis; Ishii KJ et al.; Recent evidence suggests that Toll-like receptors (TLRs) play a major role in innate immunity to recognize specific molecular patterns derived from pathogens, including lipid, protein, DNA, and RNA, and to fight against pathogens . Each TLR displays a difference in the expression pattern, intracellular localization, and signaling pathway, resulting in the distinct immune responses . The resultant immune activation augments host resistance to a variety of infectious organisms . However, such responses may exceed the threshold to maintain host homeostasis in the case of sepsis . TLR-mediated innate immune activation also induces several molecules shown to negatively regulate TLR signaling . Thus, TLRs may play an important role in positive and negative regulation of immune responses during sepsis.

Curr Infect Dis Rep, 2004 Oct, 6(5), 354 - 360
Advances in Sepsis Treatment; Rice TW et al.; Investigations of novel sepsis treatments have proven ineffective in the past . Despite advances in overall care of critically ill patients, therapies specifically designated for sepsis were lacking . However, research unveiled a complex interaction between the coagulation and inflammation systems, which has served as an impetus for innovative pharmacologic therapies in the treatment of patients with sepsis . This article summarizes the results of trials involving drotrecogin alfa (activated), or recombinant human activated protein C, the only medicine currently approved by the US Food and Drug Administration for the treatment of severe sepsis . In addition, the beneficial effects of early, goal-directed resuscitation, guided by continuous central venous oxygen saturations, are discussed, with the issues involved in the use of corticosteroids in a subset of patients with septic shock . This article also reviews the beneficial effects of tight glycemic control in postoperative critically ill patients and considers whether the data can be extrapolated to medical patients.

J R Nav Med Serv, 2004, 90(1), 13 - 5
The first fatal case of capnocytophaga canimorsus sepsis caused by a cat scratch; McLean CR et al.; A case is presented of fatal capnocytophaga canimorsus sepsis caused by a neglected cat scratch . Although fatalities are known to occur as a result of sepsis caused by this organism, death following cat scratch transmission has not previously been reported . The case is important as it demonstrates how a seemingly innocuous injury can have devastating consequences that may have been prevented by simple first aid measures.

Free Radic Biol Med, 2004 Oct 15, 37(8), 1282 - 9
Ascorbate protects against impaired arteriolar constriction in sepsis by inhibiting inducible nitric oxide synthase expression; Wu F et al.; Compromised microvascular responsiveness is one of the key factors associated with mortality of septic patients . The present study addresses the mechanism of protection by ascorbate against impaired vasoconstriction in septic mice . Sepsis (i.e., cecal ligation and puncture (CLP) model) elevated both plasma protein carbonyl (i.e., an index of oxidative stress) and plasma nitrite/nitrate (NOx) levels, reduced baseline mean arterial blood pressure (MABP), and inhibited the MABP pressor response to angiotensin II (Ang II) at 6 h post-CLP . At the microvascular level, sepsis increased the inducible nitric oxide synthase (iNOS) mRNA level in cremaster muscle arterioles (18-25 microm diameter) at 3 h post-CLP, and impaired vasoconstriction to Ang II in these arterioles at 6 h post-CLP . At 24 h post-CLP, sepsis resulted in 9% survival . An intravenous bolus of ascorbate (200 mg/kg body wt) given 30 min prior to CLP prevented the protein carbonyl and NOx increases, partially restored the baseline arterial pressure, and completely protected against all arteriolar iNOS mRNA increases, arteriolar constriction hyporesponsiveness, and pressor response impairment . Survival increased to 65% . In septic mice, iNOS gene knockout resulted in protection of arteriolar constriction and pressor responses identical to that provided by ascorbate . Ascorbate bolus given 3 h post-CLP protected against the increase in plasma NOx concentration and against the pressor response impairment . We conclude that ascorbate may protect arteriolar vasoconstrictor responsiveness in sepsis by inhibiting excessive NO production.

Am J Surg, 2004 Sep, 188(3), 212 - 20
Benefit/risk profile of drotrecogin alfa (activated) in surgical patients with severe sepsis; Barie PS et al.; BACKGROUND: The Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial examined the safety and efficacy of drotrecogin alfa (activated) (Xigris) in adult patients with severe sepsis . A clinical evaluation committee examined clinical data for each patient enrolled in PROWESS . However, there were no surgeons on the committee, and thus questions remained regarding the safety and efficacy of drotrecogin alfa (activated) in surgical patients . METHODS: Masked to treatment, a Surgical Evaluation Committee adjudicated the presence and type of operation, timing of surgery, infection, and adequacy of source control of surgical patients included in PROWESS . RESULTS: Twenty-eight percent of PROWESS cases were confirmed as surgical . The absolute risk reduction for mortality in all surgical patients was 3.2% and 9.1% for patients undergoing intraabdominal procedures . Serious bleeding during the infusion and 28-day period was similar between surgical and nonsurgical patients . CONCLUSIONS: Consistent with the overall PROWESS results, drotrecogin alfa (activated) has a favorable benefit/risk profile in surgical patients .

SADJ, 2004 Jun, 59(5), 208 - 9
New concepts in treatment of sepsis; le Roux P; Critically ill patients still commonly die of the effects of sepsis, despite numerous interventions . Earlier trials investigated mostly anti-inflammatory strategies, based on the prevailing theory that sepsis represents an uncontrolled inflammatory response . We now know that sepsis represents a biphasic response to infection, and the initial pro-inflammatory response that we have targeted thus far is invariably followed by a prolonged period of immune suppression . Indeed, a patient may oscillate between a pro- and anti-inflammatory state repeatedly . The use of steroids remains controversial, and should probably be reserved for a select subset of patients . The coagulation cascade has a powerful effect on inflammation, and manipulation by means of Activated Protein C has been beneficial . It appears tremendously advantageous to resuscitate the critically ill patient early and aggressively to maintain normal oxidative metabolism . This, coupled with the rigorous maintenance of a physiologically neutral milieu (particularly blood glucose levels) seems to be the most powerful weapon we have to manage the critically ill patient with sepsis.

Crit Care Clin, 2004 Oct, 20(4), 651 - 60; viii
Sepsis and septic shock in pregnancy; Sheffield JS; Sepsis is the leading cause of death in critically ill patients in the United States . Improvements in the critical care management of septic shock have led to a decrease in the mortality rate in the past decade . Septic shock in obstetric patients is rare . Pregnant women as a group are younger and have fewer comorbid conditions . Though little is known regarding the treatment of sepsis and septic shock in pregnancy, the same principles and treatment modalities discussed in this article should govern the management of pregnant women.

Curr Opin Crit Care, 2004 Oct, 10(5), 354 - 63
Management of severe sepsis and septic shock; Sessler CN et al.; PURPOSE OF REVIEW: Severe sepsis and septic shock are common and deadly conditions for which the epidemiology, pathogenesis, and management continue to evolve . Recent publications (2003 and early 2004) have been systematically reviewed for important new original research and scholarly reviews, with an emphasis on clinical advances in adults . RECENT FINDINGS: Important new epidemiologic studies establish the increasing frequency (nearly 9% per year) and falling mortality rates associated with sepsis . Sepsis definitions were reviewed by a group of experts, and the principal features of the 1991 consensus conference definitions were supported, with a new framework for evaluation of sepsis proposed . New research and thoughtful reviews continue to elucidate the pathogenesis of sepsis, with emphasis on innate immunity and time-based changes in immune status, varying from hyperreactive immunity and inflammation to immune depression with enhanced risk for nosocomial infections . A comprehensive evidence-based approach to the management of severe sepsis is presented in an important document developed by representatives from many critical care and infectious disease societies . Management includes early targeted resuscitation, broad empiric antibiotic coverage and source control, effective shock evaluation and treatment, adjuvant therapy with recombinant human activated protein C and moderate-dose hydrocortisone in selected patients, and comprehensive supportive care . Recently published multicenter clinical trials for novel agents have been disappointing, particularly for a nitric oxide synthase inhibitor that effectively supported blood pressure but increased mortality . SUMMARY: The works reviewed reflect the advances in the care of patients with sepsis .

Int J Legal Med . 2004 Sep 4; {Epub ahead of print}
Serial monitoring of interleukin-1beta, soluble interleukin-2 receptor and lipopolysaccharide binding protein levels after deathA comparative evaluation of potential postmortem markers of sepsis; Reichelt U et al.; We prospectively monitored the postmortem course of interleukin-1beta (IL-1beta), soluble interleukin-2 receptor (sIL-2R) and lipopolysaccharide binding protein (LBP) in septic and non-septic fatalities to evaluate their potential as biochemical postmortem markers of sepsis . Serum concentrations were determined by chemiluminescent immunometric assays . In both the sepsis group and the control group a postmortem increase of IL-1beta levels with the progression of time after death was observed, in both groups mainly starting from the reference concentration of healthy individuals (5 pg/ml) and with no significant differences at later time points postmortem . SIL-2R (reference limit 1,000 U/ml) was highly elevated in all individuals included in the sepsis group at all time points postmortem with statistically significant differences between the sepsis and control groups ( p<0.01) . An excessive postmortem decrease of sIL-2R serum levels associated with progression of time after death was observed in all cases included in the sepsis group in contrast to just 1 out of 16 control cases . LBP (reference limit <10 g/ml) was elevated in all sepsis cases whereas in the control group LBP levels were below 10 micro g/ml in 88% . The postmortem time course of LBP serum concentrations showed a continuous increase in both the sepsis and control groups . We conclude that sIL-2R and LBP seem to represent appropriate diagnostic tools for the postmortem diagnosis of sepsis in forensic autopsy practice . sIL-2R serum levels above 1,000 U/ml and LBP serum levels above 10 micro g/ml in peripheral venous blood obtained in the early postmortem interval can be regarded as diagnostic hints for an underlying septic condition in a deceased person.

Shock, 2004 Oct, 22(4), 364 - 8
Age disproportionately increases sepsis-induced apoptosis in the spleen and gut epithelium; Turnbull IR et al.; Both aging and sepsis independently increase splenic and gut epithelial apoptosis . Sepsis-induced apoptosis in either cell type is also associated with increased mortality in young mice . We sought to determine whether age alters sepsis-induced splenic and gut epithelial cell death . Young (2 months) and aged (22 months) male ND4 mice were subjected to either single-puncture cecal ligation and puncture (CLP) with a 23-gauge needle or sham laparotomy . Apoptosis was assessed 24 hours later in the spleen and gut epithelium by active caspase 3 and hematoxylin and eosin staining . Aged septic mice had increased splenic apoptosis compared with either young septic animals or aged sham animals (15 vs . 7 vs . 5 apoptotic cells/high-powered field, P < 0.05) . Similarly, aged septic animals had an elevation in gut epithelial cell death compared with either young septic or aged sham mice (33 vs . 16 vs . 6 apoptotic cells/100 contiguous crypts, P < 0.05) . Elevated intestinal cell death was not associated with changes in either gut proliferation or cell division . To verify that the increase in splenic apoptosis seen in septic aged animals was not strain specific, double-puncture CLP with a 25-gauge needle or sham laparotomy was performed on young (4 months) or aged (24 months) C57BL/6 male mice . Similar to results seen in outbred animals, aged septic animals in this inbred strain had increased splenic apoptosis compared with either young septic animals or aged sham animals (23 vs . 7 vs . 4 apoptotic cells/ high powered field, P < 0.05) . These results indicate that although infection and aging each independently cause an increase in splenic and gut epithelial apoptosis, their combination leads to a disproportionate increase in cell death in these rapidly dividing cell populations,and potentially plays a role in the marked increase in mortality seen with aging in sepsis.

Shock, 2004 Oct, 22(4), 309 - 13
Macrophage migration inhibitory factor levels correlate with fatal outcome in sepsis; Bozza FA et al.; Macrophage migration inhibitory factor (MIF) is a cytokine playing a critical role in the pathophysiology of experimental sepsis . The purpose of this study was to determine the levels of MIF and to compare those to interleukin-6 (IL-6) levels in predicting mortality among critically ill patients with sepsis . The levels of MIF and IL-6 were measured in 25 patients with septic shock, 17 patients with sepsis, and 11 healthy volunteers . The median plasma concentrations of MIF and IL-6 were significantly higher in patients with septic shock and in patients with sepsis than in healthy controls . MIF levels were significantly different between survivors and nonsurvivors, as were IL-6 levels . Discriminatory power in predicting mortality, as assessed by the areas under receiver operating characteristic curves (AUROC), was 0.793 for MIF and 0.680 for IL-6 . Finally, high plasma levels of MIF (> 1100 pg/mL) had a sensitivity of 100% and a specificity of 64% to identify the patients who eventually would evolve to a fatal outcome . Thus, our data suggest that an elevated MIF level in recently diagnosed septic patients appears to be an early indicator of poor outcome and a potential entry criterion for future studies with therapeutic intervention aiming at MIF neutralization.

Intensive Care Med, 2004 Sep, 30(9), 1821 - 8 Epub 2004 Jun 15.
Modulation of hypoxic pulmonary vasoconstriction is time and nitric oxide dependent in a peritonitis model of sepsis; Fischer LG et al.; OBJECTIVE: This study assessed modulation of hypoxic pulmonary vasoconstriction (HPV) in isolated perfused rat lungs during sepsis induced by cecal ligation and perforation (CLP) at different times and its relationship to nitric oxide synthases (NOS) . DESIGN AND SETTING: Prospective controlled trial in a university research laboratory . SUBJECTS: 102 male Sprague-Dawley rats . INTERVENTIONS: Groups 1-3 received sham laparotomy 6 h before lung isolation: group 1, only laparotomy; group 2, concurrently L- N6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg); group 3, concurrently N(Omega)-nitro-L-arginine methylester (L-NAME, 5 mg/kg) . Groups 4-6 received CLP 6 h before lung isolation: group 4, only CLP; group 5, concurrently L-NIL; group 6, concurrently L-NAME . The same experiments were carried out with sham and CLP treatment for 24 h (groups 7-12) . Exhaled NO from rats' lungs was measured after anesthesia and tracheostomy . After the pulmonary circuit was isolated and perfused, angiotensin II (0.1 microg) was injected into the inflow tract . The lungs were ventilated with the hypoxic mixture (HPV, 3% O2) for 10 min and then again with the normoxic mixture (21% O2) for an equal period . Changes in perfusion pressure were measured . Endothelial (eNOS) and inducible NOS (iNOS) expression of the lungs was determined . MEASUREMENTS AND RESULTS: Treatment with L-NAME but not L-NIL increased HPV in sham lungs . HPV was unaltered after CLP 6 h and decreased after CLP 24 h compared to sham . In CLP animals eNOS protein expression was reduced whereas iNOS expression was increased compared to sham animals . Exhaled NO, reflecting NOS activity was twice as high in the CLP 24 h group than in the CLP 6 h group . CONCLUSIONS: In the CLP sepsis model modulation of HPV was time-dependent . In addition, vasoconstriction to hypoxic stimuli was dependent on NOS activity.

Proc Nutr Soc, 2004 Aug, 63(3), 437 - 41
Anti-cytokine and anti-inflammatory therapies for the treatment of severe sepsis: progress and pitfalls; Minnich DJ et al.; The medical care of patients with sepsis or severe inflammatory response syndromes has seen tremendous technological advancements in recent years; yet, several clinical studies with anti-cytokine therapies targetted to this population have met with disappointing results . Four primary factors have been identified that represent potential pitfalls involving the use of biological response modifiers in critically-ill patients . First, the physiological response in the stressed patient is complex . Redundancy within this system may not allow a single intervention to produce a clinical response . Second, the critically-ill patient population is heterogenous and important factors including the age of the patient, associated co-morbidities, the nature of the original injury and the presence or absence of an ongoing injury can modulate the effectiveness of a specific therapy . Third, the timing of the therapeutic intervention can be difficult to standardize among patients and can often produce differing results . A greater understanding of the physiological response to injury has shown that there are both proinflammatory and anti-inflammatory processes ongoing simultaneously . Determining the optimal time to intervene within this framework can be problematic . Fourth, the presence of genetic polymorphisms within the general population has identified subsets of individuals who may have different physiological responses to similar stresses . The relative proportions of patients with these polymorphisms within clinical trials may affect outcome and data analysis . Thus, a better understanding of these issues will result in improvement of the experimental design of clinical trials involving anti-cytokine therapies and critically-ill patients . Avoidance of these pitfalls will enhance the quality and utility of outcomes research in this subset of patients.

Exp Lung Res, 2004 Oct-Nov, 30(7), 615 - 33
Induction of inducible nitric oxide synthase by lipopolysaccharide/interferon gamma and sepsis down-regulates 5-lipoxygenase metabolism in murine alveolar macrophages; Coffey M et al.; Pretreatment with lipopolysaccharide (LPS) suppresses rat alveolar macrophage leukotriene synthesis in a nitric oxide (NO)-dependent mechanism . The authors examined the effect of NO on alveolar macrophage leukotriene synthesis following in vitro and in vivo models of sepsis . Treatment of alveolar macrophages from inducible NO synthase (iNOS) wild-type but not knock-out mice with LPS inhibited leukotriene synthesis . iNOS was induced early in alveolar macrophages from cecal ligation and puncture rats and mice compared to sham animals with associated reduced leukotriene synthesis . iNOS knock-out mice were protected from the decrease in alveolar macrophage 5-lipoxygenase metabolism . iNOS regulates alveolar macrophage 5-lipoxygenase metabolism following endotoxin exposure . Copyright Taylor & Francis Inc.

NMR Biomed, 2004 Aug, 17(5), 319 - 26
Tissue oxygenation in sepsis; new insights from in vivo EPR; James PE et al.; Nitric oxide (NO) is a key mediator in the maldistribution of oxygen by tissue and organ dysfunction observed in sepsis . Despite this, few techniques are capable of measuring these parameters directly in vivo . We describe here several techniques that have been developed by our group to address this directly by in vivo EPR in animal models of sepsis . Oxygen-sensitive materials can be implanted or administered and report on local tissue pO2 . Spin trapping of NO can simultaneously report on tissue NO content . Repeat measures of these parameters can be made directly from a defined tissue site, allowing development of new models and experiments to study the defects in tissue and organ function seen in sepsis .

Pharmacoeconomics, 2004, 22(14), 895 - 906
Pharmacoeconomic implications of new therapies in sepsis; Wood KA et al.; Severe sepsis is a major healthcare problem, characterised by a high incidence, mortality and cost . New breakthroughs in treatment are quite diverse, including: (i) more effective regimens for generic, inexpensive broad anti-inflammatory agents (corticosteroids); (ii) a recombinant protein (drotrecogin-alfa {activated}); and (iii) a protocol-based treatment approach (early goal-directed therapy) . Economic analyses of new sepsis agents should adopt the societal perspective, which requires prolonging the time horizon beyond that currently typically studied in sepsis trials, so that patient-centred outcomes can be more fully captured . Sepsis affects a very diverse group of patients, and if findings are to be generalisable, careful attention must be paid to study entry criteria and differences in effects and costs across different patient subgroups . Existing care patterns for sepsis are also quite diverse, with the consequence that the incremental effects on costs and outcomes could vary widely by practice pattern, again affecting generalisability . Furthermore, many sepsis patients receive multiple other therapies, which together with therapies under study may have varied and unintended, potentially costly or dangerous adverse effects, which could have a large influence on cost-effectiveness estimates . Finally, there are a number of large yet potentially hidden costs of sepsis, such as the long-term costs of managing patients who develop sepsis or the costs of introducing different interventions into clinical practice . Such costs must also be addressed in economic analyses.The search for new anti-sepsis strategies remains vigorous and exciting . We recommend wider incorporation of economic analyses into the study of potential new therapies, with appropriate attention to the caveats discussed above . Clinical demand to use new agents must be balanced against the economic consequences of their use.

J Gastrointest Surg, 2004 Sep-Oct, 8(6), 645 - 52
Mesenteric lymph collected during peritonitis or sepsis potently inhibits gastric motility in rats; Glatzle J et al.; Gastrointestinal motility is strongly inhibited during peritonitis or sepsis and proinflammatory cytokines released into mesenteric lymph during an acute gastrointestinal insult mediate systemic responses . We investigated whether mesenteric lymph collected during peritonitis or sepsis inhibits gastric motility and gastric emptying . Mesenteric lymph was collected for 12 hours from three experimental groups: vehicle (saline, 1 ml, intraperitoneally {ip}, control lymph), peritonitis (0.5% acetic acid, 1 ml, ip, peritonitis lymph), and sepsis (lipopolysaccharide {LPS}, 5 mg/kg, 1 ml, ip, sepsis lymph) . Gastric motility and gastric emptying were measured in recipient rats in response to lymph injections into the jugular vein . Quantitative polymerase chain reaction (PCR) for tumor necrosis factor alpha (TNFalpha) gene expression in the jejunum and in lymph cells were measured during sepsis . Mesenteric lymph flow significantly increased during peritonitis or sepsis (lymph flow {ml} per 60 minutes; control 2.45 +/- 0.04; peritonitis 2.67 +/- 0.07; sepsis 3.25 +/- 0.1, p < 0.01 vs . control) . Injection of peritonitis or sepsis lymph (1 ml) produced a significant and prolonged inhibition of gastric motility in recipient rats (decrease in intragastric pressure and duration: control lymph -0.14 +/- 0.05 cm H(2)O, 1.89 +/- 1.31 minutes; peritonitis lymph: -0.56 +/- 0.06 cm H(2)O, 9.9 +/- 0.9 minutes; sepsis lymph: -0.51 +/- 0.05 cm H(2)O, 6.9 +/- 0.6 minutes; p < 0.001 vs . control for all comparisons) . Gastric emptying was significantly inhibited by continuous infusion of sepsis lymph (3 ml per 60 minutes; gastric emptying: saline 81% +/- 4%; control lymph: 80% +/- 6%; sepsis lymph: 44% +/- 10%; p < 0.001 vs . control) . TNFalpha gene expression in the gut wall of the jejunum increased during sepsis over 90-fold within the first 2 hours and decreased continuously thereafter (relative TNFalpha mRNA transcription: basal 1.0 +/- 0.05; LPS 2 hours: 91.9 +/- 2.6, p < 0.001 vs . basal; 12 hours: 24.7 +/- 16.8, not significant {NS}; 24 hours: 7.0 +/- 3.4, NS) . In conclusion, mediators in mesenteric lymph, possibly cytokines, may be responsible for the inhibition of gastric motility during peritonitis or sepsis . Because the composition of mesenteric lymph probably reflects the interstitial fluid of the gut wall, monitoring visceral lymph might be an extremely beneficial tool to determine mediators released during impaired gut wall function.

Annu Rev Med . 2004 Aug 30; {Epub ahead of print}
Therapeutic Intervention and Targets for Sepsis; Rice TW et al.; Sepsis syndrome, a systemic response to infection, can beget devastating outcomes even in previously normal individuals . Recent research in septic patients has led to the discovery that early goal-directed resuscitation guided by continuous monitoring of mixed venous hemoglobin saturation, along with moderate doses of corticosteroids, can reduce mortality . An improved understanding of the complex interaction between the inflammatory and coagulant systems in sepsis pathophysiology has resulted in novel treatments, such as recombinant human activated protein C, which improves survival in patients with severe sepsis and a high risk of death . However, despite an increased understanding of the complex pathophysiology of this syndrome and the discovery of new, effective treatments, severe sepsis still results in significant morbidity and mortality . Consequently, investigations continue into additional therapeutic agents directed against novel targets . Following a review of recent advances in sepsis treatment, we briefly discuss a few of the new, promising therapeutic strategies currently being investigated . Expected online publication date for the Annual Review of Medicine Volume 56 is January 7, 2005 . Please see for revised estimates.

Peptides, 2004 Aug, 25(8), 1369 - 72
Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients; Struck J et al.; Adrenomedullin and PAMP are potent vasodilatory peptides derived from a common larger precursor peptide . Elevation of circulating levels of both peptides has been described for diseases involving dysfunction of the cardiovascular system . However, the reliable quantification has been hampered by their short half-life times and - as known for Adrenomedullin -- the existence of a binding protein . Here we report the identification of another peptide derived from the Adrenomedullin precursor, termed proADM 45-92, which is present in large concentrations in plasma of septic shock patients . This peptide is produced in stoichiometric amounts to Adrenomedullin and PAMP, but -- contrary to them -- is apparently non-functional and stable . Thus, proADM 45-92 represents a suitable diagnostic target which could be used to assess the concentrations of Adrenomedullin gene products released into the bloodstream.

Crit Care Med, 2004 Sep, 32(9), 1928 - 48
Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update; Hollenberg SM et al.; OBJECTIVE: To provide the American College of Critical Care Medicine with updated guidelines for hemodynamic support of adult patients with sepsis . DATA SOURCE: Publications relevant to hemodynamic support of septic patients were obtained from the medical literature, supplemented by the expertise and experience of members of an international task force convened from the membership of the Society of Critical Care Medicine . STUDY SELECTION: Both human studies and relevant animal studies were considered . DATA SYNTHESIS: The experts articles reviewed the literature and classified the strength of evidence of human studies according to study design and scientific value . Recommendations were drafted and graded levels based on an evidence-based rating system described in the text . The recommendations were debated, and the task force chairman modified the document until <10% of the experts disagreed with the recommendations . CONCLUSIONS: An organized approach to the hemodynamic support of sepsis was formulated . The fundamental principle is that clinicians using hemodynamic therapies should define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis by monitoring a combination of variables of global and regional perfusion . Using this approach, specific recommendations for fluid resuscitation, vasopressor therapy, and inotropic therapy of septic in adult patients were promulgated.

Crit Care Med, 2004 Sep, 32(9), 1916 - 21
Adrenergic agents modify cerebral edema and microvessel ultrastructure in porcine sepsis; Moss RF et al.; OBJECTIVE: To investigate the effects of adrenergic agents on the cerebral response to sepsis . DESIGN: Prospective, randomized, controlled, experimental animal study . SETTING: Medical school research laboratories . SUBJECTS: Twenty-eight middle white pigs (25-30 kg) . INTERVENTIONS: Pigs were anesthetized, mechanically ventilated, and randomly assigned to one of the following groups: cecal peritonitis (n = 5), cecal peritonitis with dopexamine (n = 5), cecal peritonitis with dopexamine and the beta2-adrenergic receptor antagonist ICI 118,551 (n = 4), cecal peritonitis with methoxamine (n = 5), cecal peritonitis with dopexamine and methoxamine (n = 4), and sham-operated (n = 5) . Sham-operated pigs were killed after laparotomy, and pigs with cecal peritonitis were killed 8 hrs after its induction . Samples of frontal cerebral cortex were taken immediately after death, processed for light and electron microscopy, and then subjected to morphometric analysis . MEASUREMENTS AND MAIN RESULTS: There was significantly more (p <.0005) cerebral perimicrovessel edema in pigs with cecal peritonitis (80.2 microm2 +/- 5.3 sem) than in sham-operated pigs (26.2 microm2 +/- 2.7 sem) and significantly less (p <.0005) perimicrovessel edema in dopexamine-treated pigs with cecal peritonitis (39.8 microm2 +/- 5.5 sem) than in pigs with cecal peritonitis alone (80.2 microm2 +/- 5.3 sem) . There was no significant difference between the amount of perimicrovessel edema in pigs with cecal peritonitis treated with dopexamine plus ICI118,551 and pigs with cecal peritonitis alone . The mean cerebral microvessel endothelial cell cross-sectional area in methoxamine-treated pigs with cecal peritonitis (26.3 microm2 +/- 2.6 sem) was significantly greater than that in pigs with cecal peritonitis alone (16.3 microm2 +/- 2.1 sem, p =.008) or in sham-operated pigs (12.3 microm2 +/- 1.3 sem, p =.0005) . CONCLUSIONS: Dopexamine protects against cerebral edema formation in sepsis by stimulation of beta2-adrenergic receptors, whereas the alpha1 adrenoceptor agonist methoxamine induces cerebral microvessel endothelial cell swelling.

Crit Care Med, 2004 Sep, 32(9), 1851 - 9
Effect of long-term and high-dose antithrombin supplementation on coagulation and fibrinolysis in patients with severe sepsis; Hoffmann JN et al.; OBJECTIVE: Sepsis is frequently associated with coagulatory activation, which may contribute to deteriorated organ function . Antithrombin is one important endogenous coagulation inhibitor that is therapeutically applied during sepsis . This study investigates the effect of 14-day antithrombin application on coagulatory variables . DESIGN: Prospective study . SETTING: Surgical intensive care unit of a university hospital . PATIENTS: Forty patients with severe sepsis . INTERVENTIONS: Patients with severe sepsis were randomly assigned to receive either conventional intensive care treatment (n = 20, controls) or antithrombin substitution that aimed at a plasma antithrombin activity > or =120% during a long-term (14-day) study period (n = 20, antithrombin) . To allow comparative analysis of laboratory variables over time, all patients who did not survive the 14-day-period (five controls and six antithrombin patients) were prospectively excluded from the final evaluation . Their data were included in an intent-to-treat analysis . MEASUREMENTS AND MAIN RESULTS: Antithrombin supplementation normalized global coagulation tests and increased prothrombin activity as well as fibrinogen concentration, reflecting less coagulation factor consumption (percent change from baseline in prothrombin activity, p <.01 vs . controls at days 9, 11-14 of antithrombin vs . controls {unpaired Student's t-test}; fibrinogen concentration, p <.01 vs . controls at days 10, 11, 13, and 14 of antithrombin) . Simultaneously, antithrombin reduced contact system activation as indicated by increasing prekallikrein activities over time (% change, p <.01 vs . controls at days 6, 9-14) and increased protein C activities when compared with controls (% change, p <.01 vs . controls at days 10-14) . Most changes occurred from day 7 to day 14 of antithrombin supplementation . Antithrombin did not influence C1 esterase inhibitor, plasminogen, alpha2 antiplasmin, or platelet counts (p >.01) . CONCLUSION: In this first study on long-term antithrombin therapy, antithrombin significantly reduced septic coagulatory response in patients with severe sepsis when given over 14 days.

Biochim Biophys Acta, 2004 Sep 6, 1690(1), 42 - 53
Left ventricular mitogen activated protein kinase signaling following polymicrobial sepsis during streptozotocin-induced hyperglycemia; Gupta A et al.; We hypothesized that sepsis during hyperglycemia would activate left ventricular (LV) mitogen activated protein kinase (MAPK) signaling mechanisms and modulate generation of endothelin-1 (ET-1) and nitric oxide (NO) that can contribute to the progression of LV dysfunction . A single injection of streptozotocin (STZ, 60 mg/kg, via tail vein) was used to produce type 2 diabetes in male SD rats . Polymicrobial sepsis and sham-sepsis were induced using single i.p . injection of cecal inoculum and sterile 5% dextrose water, respectively, on the 13th and 27th day following STZ injection . Both 2-week (2-wk) and 4-wk diabetes groups were associated with hyperglycemia and weight loss . LV end diastolic pressure (LVEDP) was significantly increased in 4-wk diabetes but not in 2-wk diabetes group . Plasma concentration of tumor necrosis factor-alpha (TNF-alpha) was significantly increased in 4-wk diabetes+sepsis group as compared to sham, 2-wk diabetes+sepsis and sepsis groups . Elevated plasma and LV ET-1 and NO byproducts (NOx) along with LV preproET-1 and inducible nitric oxide synthase (iNOS) protein expression were observed in 4-wk but not in 2-wk diabetes group . Sepsis further elevated LV iNOS and preproET-1 in 4-wk diabetes group . Up-regulated phosphorylation of LV p38-MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2) and heat shock protein-27 (Hsp27) was observed in 4-wk diabetes group . Sepsis caused a factorial increase in LV p38-MAPK and Hsp27 phosphorylation and iNOS up-regulation but not ERK1/2 following progression from 2-wk to 4-wk diabetes . The study provides evidence that sepsis up-regulated LV iNOS, p38-MAPK phosphorylation and elevated LVEDP during 4-wk diabetes . We concluded that sepsis contributes in the development of LVEDP dysfunction and alteration in signaling mechanisms depending upon the progression from 2-wk to 4-wk diabetes in the rat.

Anesth Analg, 2004 Sep, 99(3), 864 - 71, table of contents
Bradykinin-induced pulmonary vasoconstriction is time and inducible nitric oxide synthase dependent in a peritonitis sepsis model; Fischer LG et al.; In an isolated perfused lung model, bradykinin induced pulmonary vasoconstriction in rats made septic by the injection of lipopolysaccharide (LPS) . To mimic the pathophysiology of sepsis in humans more closely, we investigated pulmonary endothelial injury in a peritonitis model (cecal ligation and perforation; CLP) . Male Sprague-Dawley rats were randomly divided into nine groups (n = 6-8) . LPS and CLP rats were compared after 6 h with and without treatment with a selective inhibitor of inducible nitric oxide synthase (iNOS), L-N(6)-(1-iminoethyl)-lysine . Time dependency was investigated in CLP-treated rats at 24 h . The pulmonary circulation was isolated and perfused with a constant flow after the rats' tracheas were intubated and ventilated . Bradykinin (1, 3, and 6 microg) was injected, and changes in perfusion pressure were measured . Lungs were harvested for Western blot analysis to determine the role of iNOS in pulmonary endothelial dysfunction . In contrast to CLP 24 h rats, dose-dependent bradykinin-induced pulmonary vasoconstriction was observed in LPS and CLP 6 h rats . Concomitant administration of L-N(6)-(1-iminoethyl)-lysine significantly attenuated this vasoconstriction in both groups . The iNOS protein was expressed in lung homogenates from LPS 6 h and CLP 6 h but not from CLP 24 h rats . Both sepsis models caused bradykinin-induced pulmonary vasoconstriction, with the CLP groups demonstrating a time dependency of this effect . In conjunction with the time-dependent decrease in iNOS protein, the attenuated bradykinin-induced vasoconstriction due to selective iNOS inhibition suggests an important role for iNOS in pulmonary endothelial injury for both sepsis models.

J Immunol, 2004 Sep 1, 173(5), 3035 - 43
Characterization of the systemic loss of dendritic cells in murine lymph nodes during polymicrobial sepsis; Efron PA et al.; Dendritic cells (DCs) play a key role in critical illness and are depleted in spleens from septic patients and mice . To date, few studies have characterized the systemic effect of sepsis on DC populations in lymphoid tissues . We analyzed the phenotype of DCs and Th cells present in the local (mesenteric) and distant (inguinal and popliteal) lymph nodes of mice with induced polymicrobial sepsis (cecal ligation and puncture) . Flow cytometry and immunohistochemical staining demonstrated that there was a significant local (mesenteric nodes) and partial systemic (inguinal, but not popliteal nodes) loss of DCs from lymph nodes in septic mice, and that this process was associated with increased apoptosis . This sepsis-induced loss of DCs occurred after CD3(+)CD4(+) T cell activation and loss in the lymph nodes, and the loss of DCs was not preceded by any sustained increase in their maturation status . In addition, there was no preferential loss of either mature/activated (MHCII(high)/CD86(high)) or immature (MHCII(low)/CD86(low)) DCs during sepsis . However, there was a preferential loss of CD8(+) DCs in the local and distant lymph nodes . The loss of DCs in lymphoid tissue, particularly CD8(+) lymphoid-derived DCs, may contribute to the alterations in acquired immune status that frequently accompany sepsis.

Clin Exp Immunol, 2004 Sep, 137(3), 469 - 77
CD40-CD154 interactions between macrophages and natural killer cells during sepsis are critical for macrophage activation and are not interferon gamma dependent; Scott MJ et al.; Natural killer (NK) cell interactions with macrophages have been shown to be important during bacterial sepsis in activating macrophages to improve bacterial clearance . The mechanism for this increased activation, however, is unclear . This study determines the relative roles of interferon (IFN)-gamma and CD40/CD154 direct cell interactions on macrophage and NK cell activation in an experimental model of sepsis . Splenic NK cells and peritoneal macrophages were isolated and cultured alone or in coculture, with and without LPS . CD69 expression on NK cells, phagocytosis ability of macrophages, and cell cytokine production was assessed at 24 and 48 h . Coculture of NK cells and macrophages significantly increased activation levels of both cell types, and through experiments culturing NK cells with supernatants from stimulated macrophages and macrophages with supernatants from stimulated NK cells, this activation was determined to be cell-contact-dependent . Similar experiments were conducted using NK cells from IFN-gamma deficient (-/-) mice, as well as anti-IFN-gamma neutralizing antibody . These experiments determined that IFN-gamma is not required for NK or macrophage activation, although it did augment activation levels . Experiments were again repeated using peritoneal macrophages from CD40-/- mice or splenic NK cells from CD154-/- mice . CD40/CD154 interactions were important in the ingestion of bacteria by macrophages, but did not affect NK cell activation at 24 h . There was, however, a protective effect of CD40/CD154 interactions on NK cell activation-induced cell death that occurred at 48 h . CD40/CD154 interactions between macrophages and NK cells are therefore important in macrophage phagocytosis, and are not dependent on IFN-gamma.

Blood, 2004 Dec 15, 104(13), 3958 - 64 Epub 2004 Dec 15.
Patients with severe sepsis vary markedly in their ability to generate activated protein C; Liaw PC et al.; Activated protein C (APC) supplementation significantly reduces mortality in patients with severe sepsis, presumably by down-regulating coagulation, inflammation, and apoptosis . In vivo, endogenous APC is generated from protein C (PC) "on demand" in response to elevated thrombin levels . Thrombomodulin and endothelial cell protein C receptor are endothelial receptors required to generate APC endogenously . Since these receptors may be down-regulated in sepsis, we measured plasma markers of APC generation in 32 patients with severe sepsis to determine whether APC generation is impaired and whether markers of APC generation correlate with 28-day mortality . Relative to normals, all patients had elevated F1 + 2 and thrombin-antithrombin complex (TAT) levels (markers of thrombin generation and inhibition, respectively), and 28 of 32 patients had reduced PC levels . In 20 patients, APC levels paralleled elevated F1 + 2 levels, whereas 12 patients had low APC levels despite elevated F1 + 2 levels, suggesting that APC generation is impaired in the latter . No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels, F1 + 2 levels, and APACHE II (acute physiology and chronic health evaluation) scores . Baseline APC levels were higher in survivors (P = .024), and baseline F1 + 2/APC ratios were lower in survivors (P = .047) . Larger studies are warranted to establish whether APC generation profiles aid in managing sepsis.

Am J Physiol Heart Circ Physiol, 2004 Dec, 287(6), H2535 - 44 Epub 2004 Dec.
Effect of sepsis on skeletal muscle oxygen consumption and tissue oxygenation: interpreting capillary oxygen transport data using a mathematical model; Goldman D et al.; Inherent in the inflammatory response to sepsis is abnormal microvascular perfusion . Maldistribution of capillary red blood cell (RBC) flow in rat skeletal muscle has been characterized by increased 1) stopped-flow capillaries, 2) capillary oxygen extraction, and 3) ratio of fast-flow to normal-flow capillaries . On the basis of experimental data for functional capillary density (FCD), RBC velocity, and hemoglobin O2 saturation during sepsis, a mathematical model was used to calculate tissue O2 consumption (Vo2), tissue Po2 (Pt) profiles, and O2 delivery by fast-flow capillaries, which could not be measured experimentally . The model describes coupled capillary and tissue O2 transport using realistic blood and tissue biophysics and three-dimensional arrays of heterogeneously spaced capillaries and was solved numerically using a previously validated scheme . While total blood flow was maintained, capillary flow distribution was varied from 60/30/10% (normal/fast/stopped) in control to 33/33/33% (normal/fast/stopped) in average sepsis (AS) and 25/25/50% (normal/fast/stopped) in extreme sepsis (ES) . Simulations found approximately two- and fourfold increases in tissue Vo2 in AS and ES, respectively . Average (minimum) Pt decreased from 43 (40) mmHg in control to 34 (27) and 26 (15) mmHg in AS and ES, respectively, and clustering fast-flow capillaries (increased flow heterogeneity) reduced minimum Pt to 14.5 mmHg . Thus, although fast capillaries prevented tissue dysoxia, they did not prevent increased hypoxia as the degree of microvascular injury increased . The model predicts that decreased FCD, increased fast flow, and increased Vo2 in sepsis expose skeletal muscle to significant regions of hypoxia, which could affect local cellular and organ function.

Acta Anaesthesiol Scand, 2004 Sep, 48(8), 960 - 7
Primary sepsis in a university hospital in northern Sweden: a retrospective study; Jacobson S et al.; BACKGROUND: Severe sepsis and septic shock are associated with high mortality rates . Data on sepsis outcome from Scandinavian countries are sparse . The aim of this study was to examine the length of stay (LOS) in the ICU, ICU mortality and costs of care for adult patients with primary sepsis in a university hospital in northern Sweden . METHODS: We performed a retrospective data analysis of records of 92 patients admitted over a 3-year period, under the diagnosis of sepsis or urosepsis . Demographic data, admission category, APACHE II score, aetiology and severity of sepsis, ICU LOS, mortality and TISS were analyzed . RESULTS: Eighty-one adult patients were identified by standard definitions as suffering from sepsis . The median ICU length of stay was 4.2 days, 6 days for survivors and 2.1 days for non-survivors . Thirteen out of 20 deaths occurred within the first 3 days after admission . Overall ICU mortality rate was 24.7% while the ICU mortality for patients with septic shock was 57.7% . The mean costs of care for patients with sepsis were 3139 Euros day(-1) and the cost of care per patient surviving sepsis was 38,494 Euros . CONCLUSION: The incidence of primary sepsis in our ICU was low . Previous reports on high mortality in association with severe sepsis and septic shock are valid also at our hospital . The ICU-LOS was shorter than previously reported, while our costs of care were in the same range as stated by others . This retrospective analysis is valid for interpretation of the applicability of currently available sepsis therapies.

Crit Care, 2004 Aug, 8(4), R234 - 42 Epub 2004 Jun 10.
Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction; Castelli GP et al.; INTRODUCTION: Both C-reactive protein (CRP) and procalcitonin (PCT) are accepted sepsis markers . However, there is still some debate concerning the correlation between their serum concentrations and sepsis severity . We hypothesised that PCT and CRP concentrations are different in patients with infection or with no infection at a similar severity of organ dysfunction or of systemic inflammatory response . PATIENTS AND METHODS: One hundred and fifty adult intensive care unit patients were observed consecutively over a period of 10 days . PCT, CRP and infection parameters were compared among the following groups: no systemic inflammatory response syndrome (SIRS) (n = 15), SIRS (n = 15), sepsis/SS (n = 71) (including sepsis, severe sepsis and septic shock {n = 34, n = 22 and n = 15}), and trauma patients (n = 49, no infection) . RESULTS: PCT and CRP concentrations were higher in patients in whom infection was diagnosed at comparable levels of organ dysfunction (infected patients, regression of median {ng/ml} PCT = -0.848 + 1.526 sequential organ failure assessment {SOFA} score, median {mg/l} CRP = 105.58 + 0.72 SOFA score; non-infected patients, PCT = 0.27 + 0.02 SOFA score, P < 0.0001; CRP = 84.53 - 0.19 SOFA score, P < 0.005), although correlation with the SOFA score was weak (R = 0.254, P < 0.001 for PCT, and R = 0.292, P < 0.001 for CRP) . CRP levels were near their maximum already during lower SOFA scores, whereas maximum PCT concentrations were found at higher score levels (SOFA score > 12).PCT and CRP concentrations were 1.58 ng/ml and 150 mg/l in patients with sepsis, 0.38 ng/ml and 51 mg/l in the SIRS patients (P < 0.05, Mann-Whitney U-test), and 0.14 ng/ml and 72 mg/l in the patients with no SIRS (P < 0.05) . The kinetics of both parameters were also different, and PCT concentrations reacted more quickly than CRP . CONCLUSIONS: PCT and CRP levels are related to the severity of organ dysfunction, but concentrations are still higher during infection . Different sensitivities and kinetics indicate a different clinical use for both parameters.

Crit Care, 2004 Aug, 8(4), R221 - 8 Epub 2004 May 27.
Effects of volume resuscitation on splanchnic perfusion in canine model of severe sepsis induced by live Escherichia coli infusion; Lagoa CE et al.; INTRODUCTION: We conducted the present study to investigate whether early large-volume crystalloid infusion can restore gut mucosal blood flow and mesenteric oxygen metabolism in severe sepsis . METHODS: Anesthetized and mechanically ventilated male mongrel dogs were challenged with intravenous injection of live Escherichia coli (6 x 10(9) colony-forming units/ml per kg over 15 min) . After 90 min they were randomly assigned to one of two groups - control (no fluids; n = 13) or lactated Ringer's solution (32 ml/kg per hour; n = 14) - and followed for 60 min . Cardiac index, mesenteric blood flow, mean arterial pressure, systemic and mesenteric oxygen-derived variables, blood lactate and gastric carbon dioxide tension (PCO2; by gas tonometry) were assessed throughout the study . RESULTS: E . coli infusion significantly decreased arterial pressure, cardiac index, mesenteric blood flow, and systemic and mesenteric oxygen delivery, and increased arterial and portal lactate, intramucosal PCO2, PCO2 gap (the difference between gastric mucosal and arterial PCO2), and systemic and mesenteric oxygen extraction ratio in both groups . The Ringer's solution group had significantly higher cardiac index and systemic oxygen delivery, and lower oxygen extraction ratio and PCO2 gap at 165 min as compared with control animals . However, infusion of lactated Ringer's solution was unable to restore the PCO2 gap . There were no significant differences between groups in mesenteric oxygen delivery, oxygen extraction ratio, or portal lactate at the end of study . CONCLUSION: Significant disturbances occur in the systemic and mesenteric beds during bacteremic severe sepsis . Although large-volume infusion of lactated Ringer's solution restored systemic hemodynamic parameters, it was unable to correct gut mucosal PCO2 gap.

Crit Care, 2004 Aug, 8(4), R180 - 4 Epub 2004 May 14.
Epidemiology of sepsis in Norway in 1999; Flaatten H; INTRODUCTION: Sepsis and severe sepsis are associated with high hospital mortality . Little is known about the occurrence of sepsis in general hospital populations . The goal of the present study was to reveal the epidemiology of sepsis in Norwegian hospitals over 1 year . METHODS: Patients admitted to all Norwegian hospitals during 1999 (n = 700,107) were analyzed by searching the database of the Norwegian Patient Registry for markers of sepsis, using International Classification of Diseases (ICD)-10 codes for sepsis and severe infections . In patients with such diagnoses, demographic data, hospital outcome data and ICD-10 codes for organ dysfunction were also retrieved . Sepsis was further classified as primary or secondary, and severe (sepsis with vital organ dysfunction) or nonsevere . The age-adjusted mortality rate, and the sepsis rates for all hospital admissions and in the Norwegian population were calculated . RESULTS: A total of 6665 patients were classified as having sepsis, and of these 2121 (31.8%) had severe sepsis . The most frequent failing organ system was the circulatory system, and 1562 had septic shock . Mortality increased from 7.1% (in those with no documented organ dysfunction) to 71.8% (in those with three or more organ dysfunctions) . The mean mortality was 13.5%, and the mortality of severe sepsis was 27% . The incidence of sepsis was 9.5/1000 hospital admissions and 1.49/1000 inhabitants in 1999 . CONCLUSION: Sepsis is not uncommon in Norwegian hospitals and is associated with high hospital mortality, which is similar to recent findings from the USA . Awareness of sepsis and its appropriate treatment is mandatory in Norway if we are to reduce mortality from sepsis by 25% in the next 5 years.

Crit Care, 2004 Aug, 8(4), R172 - 9 Epub 2004 May 14.
The influence of N-acetyl-L-cystein infusion on cytokine levels and gastric intramucosal pH during severe sepsis; Emet S et al.; INTRODUCTION: The purpose of the present study was to evaluate the effects of continuously infused N-acetyl-L-cystein (NAC) on serum cytokine levels and gastric intramucosal pH in humans suffering from severe sepsis . METHODS: Fifty-three patients were included in the study . In the NAC group (n = 27), after an initial intravenous bolus of NAC (150 mg/kg over 5 min), a continuous intravenous infusion of 12.5 mg/kg per hour was given for 6 hours . Patients in the control group (n = 26) were administered dextrose (5% solution) at the same dosage . We recorded the following: haemodynamic parameters, nasopharyngeal temperature, arterial blood gas changes, plasma cytokine levels, biochemical parameters, intramucosal pH, length of stay in the intensive care unit, duration of of mechanical ventilation and mortality . All measurements were taken at baseline (15 min before the start of the study) and were repeated immediately after the bolus infusion, and at 24 and 48 hours after initiation of the continuous NAC infusion . RESULTS: No differences were found between groups in levels of the major cytokines, duration of ventilation and intensive care unit stay, gastric intramucosal pH and arterial oxygen tension/inspired fractional oxygen ratio (P > 0.05) . CONCLUSION: We found that NAC infusion at the doses given did not affect cytokine levels, outcomes, or gastric intramucosal pH in patients with severe sepsis . Because of the limited number of patients included in the study and the short period of observation, our findings need confirmation in larger clinical trials of NAC infused in a dose-titrated manner . However, our results do not support the use of NAC in patients with severe sepsis.

Crit Care, 2004 Aug, 8(4), R153 - 62 Epub 2004 May 14.
Prevalence and incidence of severe sepsis in Dutch intensive care units; van Gestel A et al.; INTRODUCTION: Severe sepsis is a dreaded consequence of infection and necessitates intensive care treatment . Severe sepsis has a profound impact on mortality and on hospital costs, but recent incidence data from The Netherlands are not available . The purpose of the present study was to determine the prevalence and incidence of severe sepsis occurring during the first 24 hours of admission in Dutch intensive care units (ICUs) . METHODS: Forty-seven ICUs in The Netherlands participated in a point prevalence survey and included patients with infection at the time of ICU admission . Clinical symptoms of severe sepsis during the first 24 hours of each patient's ICU stay were recorded and the prevalence of severe sepsis was calculated . Then, the annual incidence of severe sepsis in The Netherlands was estimated, based on the prevalence, the estimated length of stay, and the capacity of the participating ICUs relative to the national intensive care capacity . RESULTS: The participating ICUs had 442 beds available for admissions, which was estimated to be 42% of the national ICU capacity . At the time of the survey, 455 patients were currently admitted and 151 were included in the analysis; 134 (29.5%) patients met criteria for severe sepsis . The most common failing organ system was the respiratory system (90%), and most patients were admitted following surgery (37%) and were admitted because of acute infection (62%) . The most prevalent source of infection was the lung (47%) . The estimated duration of ICU stay for severe sepsis patients was 13.3 +/- 1.1 days . CONCLUSION: The annual number of admissions for severe sepsis in Dutch ICUs was calculated at 8643 +/- 929 cases/year, which is 0.054% of the population, 0.61% of hospital admissions and 11% of ICU admissions.

Crit Care, 2004 Aug, 8(4), 243 - 52 Epub 2004 May 25.
Science review: mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids; Prigent H et al.; This review describes current knowledge on the mechanisms that underlie glucocorticoid insufficiency in sepsis and the molecular action of glucocorticoids . In patients with severe sepsis, numerous factors predispose to glucocorticoid insufficiency, including drugs, coagulation disorders and inflammatory mediators . These factors may compromise the hypothalamic-pituitary axis (i.e . secondary adrenal insufficiency) or the adrenal glands (i.e . primary adrenal failure), or may impair glucocorticoid access to target cells (i.e . peripheral tissue resistance) . Irreversible anatomical damages to the hypothalamus, pituitary, or adrenal glands rarely occur . Conversely, transient functional impairment in hormone synthesis may be a common complication of severe sepsis . Glucocorticoids interact with a specific cytosolic glucocorticoid receptor, which undergoes conformational changes, sheds heat shock proteins and translocates to the nucleus . Glucocorticoids may also interact with membrane binding sites at the surface of the cells . The molecular action of glucocorticoids results in genomic and nongenomic effects . Direct and indirect transcriptional and post-transcriptional effects related to the cytosolic glucocorticoid receptor account for the genomic effects . Nongenomic effects are probably subsequent to cytosolic interaction between the glucocorticoid receptor and proteins, or to interaction between glucocorticoids and specific membrane binding sites.

Crit Care, 2004 Aug, 8(4), 229 - 30 Epub 2004 Jun 09.
N-acetylcysteine in clinical sepsis: a difficult marriage; Spapen H; The high morbidity and mortality of severe sepsis and septic shock fosters a continuous search for novel therapies that go beyond pure correction of oxygenation and hemodynamics . Within this scope, N-acetylcysteine shows great promise . Beside proven anti-oxidant, anti-inflammatory and cytoprotective effects, N-acetylcysteine does also ensure endothelial protection and enhances microvascular blood flow . Studies that put these highly favourable properties to the clinical test remain scarce but are definitely needed to determine whether N-acetylcysteine has a place in our therapeutic armamentarium against sepsis.

Crit Care, 2004 Aug, 8(4), 227 - 8 Epub 2004 May 25.
Insulin and metabolic substrates during human sepsis; Finney SJ; Rusavy and colleagues recently endeavoured to dissect out the metabolic effects of insulin in patients with severe sepsis, in the setting of normoglycaemia . Twenty stable patients were studied 3-7 days after admission using a euglycaemic clamp at two supraphysiological insulin levels . Increased doses of exogenous insulin caused preferential use of glucose as a metabolic substrate, while total energy expenditure remained constant . Consequently, hyperinsulinaemia reduced tissue oxygen demand and catabolism of protein in patients with sepsis; the benefits of these effects are not proven . The effects of insulin at different time points in sepsis were not examined.

Crit Care, 2004 Aug, 8(4), 222 - 6 Epub 2004 Jul 09.
Severe sepsis epidemiology: sampling, selection, and society; Linde-Zwirble WT et al.; Three new articles in Critical Care add to an expanding body of information on the epidemiology of severe sepsis . Although there have been a range of approaches to estimate the incidence of severe sepsis, most studies report severe sepsis in about 10 +/- 4% of ICU patients with a population incidence of 1 +/- 0.5 cases per 1000 . Importantly, the availability of ICU services may well determine the number of treated cases of severe sepsis, and it seems clear that these studies are reporting the treated incidence, not the incidence, of severe sepsis . In the future, we must focus on whether all severe sepsis should be treated, and, consequently, what level of ICU services is optimal.

Am J Perinatol, 2004 Aug, 21(6), 365 - 8
Late-onset Mycobacterium abscessus sepsis in a very low birthweight premature infant: diagnostic and therapeutic challenges; Di Pentima MC et al.; Late-onset sepsis (after 3 days of life) is a frequent a complication found in very low birth weight (VLBW, 1000 to 1500 g) premature infants . We report the second case of late-onset sepsis caused by an uncommon pathogen, Mycobacterium abscessus.

Dig Dis Sci, 2004 Jun, 49(6), 1054 - 61
The effect of hyaluronan-based agents on adhesion formation in an intraabdominal sepsis model; Tuzuner A et al.; Because of the technical difficulty during subsequent surgical intervention, adhesion remains the most important predictor of outcome in the staged procedures following emergent colorectal surgery . The aim of this study was to assess the long-term effects of hyaluronan (HA)-based adhesion barriers 3 months following the infectious insult to the peritoneal cavity . Wistar albino rats were divided into three sham and four infectious groups, each consisting of 20 rats . Sham groups consisted of a control group (I), which had undergone manipulation of the cecum in the first operation and saline irrigation following the cecal resection in the second operation; an HA-based bioresorbable membrane (BM) group (II), in which 20 x 20- and 35 x 25-mm pieces of HA-based bioresorbable membrane were placed over the cecectomy area and under the midline incision, respectively, with other conditions the same as for the control (I) group; and an HA-based solution (S) group (II), where HA solution was used as an irrigation solution, with other conditions the same as for the control group (I) . Infectious groups consisted of a septic group (IV), which had undergone cecal ligation and puncture in the first operation and saline irrigation following the cecal resection in the second operation; a sepsis + HA-BM group (V), in which two sheets of membrane were applied, with other conditions the same as for the septic group (IV); a sepsis + HA-S group (VI), in which HA solution was used as an irrigation solution, with conditions otherwise the same as for the septic group (IV); and a sepsis + HA-BM + HA-S group (VII), where HA solution was used as an irrigation solution and two sheets of membrane were applied, with other conditions the same as for the septic group (IV) . At the end of the 3-month period, mortality, septic complications, and intraabdominal adhesions (adhesion scores and adhesion tensile strength measurements) were recorded . Significantly denser adhesions were found in the septic group (IV) when compared to the others (P < 0.001) . HA-S significantly reduced not only the incidence of adhesion but also the adhesion tensile strength in infectious groups (P < 0.001 compared to the sepsis group) . However, HA-BM significantly reduced adhesion tensile strength only . Irrigation of the peritoneal cavity with HA-S may prove to be useful to shorten the reversal time period and decrease morbidity following staged procedures for intraabdominal sepsis.

Amino Acids, 2004 Aug, 27(1), 97 - 100 Epub 2004 Mar 16.
The relationship between plasma cholesterol, amino acids and acute phase proteins in sepsis; Chiarla C et al.; The purpose of the study was to correlate degree of hypocholesterolemia to changes in plasma levels of amino acids and other metabolic variables in severely injured septic patients . Measurements included plasma cholesterol, full amino-acidograms, acute phase proteins, complementary variables and blood cell counts . The Fischer plasma molar amino acid ratio (leucine+isoleucine+valine)/(phenylalanine+tyrosine) was calculated . Plasma cholesterol for all measurements (n=145) was 3.1+/-1.1 mmol/L and, upon entry in the study, it was correlated inversely with sepsis severity score (p<0.05) . Along the clinical course, changes in cholesterol were clearly paralleled by opposite changes in C-reactive protein, which was the best correlate of cholesterol (r2=0.70, p<0.0001) . Furthermore cholesterol was inversely related to phenylalanine, fibrinogen, lactate and white blood cell count, and directly to the Fischer molar amino acid ratio, cystathionine, methionine, glycine and transferrin (r2 between 0.36 and 0.15, p<0.0001 for all) . Within this pattern of correlations, cholesterol was also directly related to alkaline phosphatase, which accounted for the effect of cholestasis, when present . For any given value of the other variables, cholesterol increased significantly with increase in alkaline phosphatase (p<0.0001) . C-reactive protein (CRP, mg/dl) and alkaline phosphatase (ALKPH, U/L) together in the same regression explained 79% of the variability of cholesterol (CHOL, mmol/L): CHOL=5.90-0.74{Log(e)CRP}+0.004{ALKPH}; multiple r2=0.79, p<0.0001 . Inclusion in this regression of other variables did not increase the r2 . By using only amino acid variables, the best fit was provided by a regression including the Fischer ratio and cystathionine, which explained 55% of the variability of cholesterol (multiple r2=0.55 p<0.0001), and this result was not improved by the inclusion of other amino acids . These data show that severity of hypocholesterolemia in sepsis is quantifiably related to changes in plasma amino acids, and to severity of acute phase response and metabolic decompensation . More study is needed to understand whether hypocholesterolemia in sepsis has only diagnostic or prognostic implications, or that it may also contribute actively to worsening of the disease.

Am J Physiol Regul Integr Comp Physiol, 2004 Dec, 287(6), R1434 - 40 Epub 2004 Aug 12.
Production of arginine by the kidney is impaired in a model of sepsis: early events following LPS; Lortie MJ et al.; Lipopolysaccharide (LPS) is used experimentally to elicit the innate physiological responses observed in human sepsis . We have previously shown that LPS causes depletion of plasma arginine before inducible nitric oxide synthase (iNOS) activity, indicating that changes in arginine uptake and/or production rather than enhanced consumption are responsible . Because the kidney is the primary source of circulating arginine and renal failure is a hallmark of septicemia, we determined the time course of changes in arginine metabolism and kidney function relative to iNOS expression . LPS given intravenously to anesthetized rats caused a decrease in mean arterial blood pressure after 120 min that coincided with increased plasma nitric oxide end products (NOx) and iNOS expression in lung and liver . Interestingly, impairment of renal function preceded iNOS activity by 30-60 min and occurred in tandem with decreased renal arginine production . The baseline rate of renal arginine production was approximately 60 micromol.h(-1).kg(-1), corresponding to an apparent plasma half-life of approximately 20 min, and decreased by one-half within 60 min of LPS . Calculations based on the systemic production and clearance show that normally only 5% of kidney arginine output is destined to become nitric oxide and that <25% of LPS-impaired renal production was converted to NOx in the first 4 h . In addition, we provide novel observations indicating that the kidney appears refractory to iNOS induction by LPS because no discernible enhancement of renal NOx production occurred within 4 h, and iNOS expression in the kidney was muted compared with that in liver or lung . These studies demonstrate that the major factor responsible for the rapid decrease in extracellular arginine content following LPS is impaired production by the kidney, a phenomenon that appears linked to reduced renal perfusion.

Scand J Infect Dis, 2004, 36(6-7), 507 - 9
Disseminated Penicillium marneffei sepsis in a HIV-positive Thai woman in Denmark; Mens H et al.; We report the first case of disseminated Penicillium marneffei infection, in a 32-y-old HIV positive Thai woman, in Denmark . Untreated it is a life-threatening infection . Therefore it is extremely important to consider P . marneffei in patients who are immunocompromized and who have been travelling to Southeast Asia or China.

Life Sci, 2004 Sep 3, 75(16), 2015 - 26
Effect of ascorbic acid on hepatic vasoregulatory gene expression during polymicrobial sepsis; Kim JY et al.; The aim of this study was to investigate the effects of ascorbic acid on hepatic vasoregulatory gene expression during polymicrobial sepsis . Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) . Rats received either vehicle (n = 10) or ascorbic acid (AA, 100 mg/kg, n = 10) intravenously immediately after the CLP procedure . Serum aminotransferase levels and hepatic lipid peroxides markedly increased 24 h after CLP and this increase was attenuated by AA treatment . The hepatic concentrations of reduced glutathione decreased in CLP animals . This decrease was inhibited by AA . CLP significantly increased the mRNA level of ET-1 (p < 0.01) and ETB receptor (p < 0.01) in livers; an increase that was prevented by AA treatment . There were no significant changes in ETA mRNA expression among any of the experimental groups . There were significant increases in the mRNA expression of nitric oxide synthases (p < 0.01) and heme oxygenase-1 (p < 0.01) in livers from CLP animals . This increase was prevented by AA treatment . The expression of tumor necrosis factor-alpha and cyclooxygenase-2 mRNAs significantly increased 4.9-fold (p < 0.01) and 4.4-fold (p < 0.01) in livers from CLP animals, respectively . This increase was attenuated by AA treatment . Our data suggest that AA reduces oxidative stress and lipid peroxidation, regulates the hepatic vasoregulatory gene expression in polymicrobial sepsis and thus it could reduce hepatic microvascular dysfunction during sepsis.

Vojnosanit Pregl, 2004 Mar-Apr, 61(2), 137 - 43
{Importance of determination of proinflammatory cytokines in the blood of polytraumatized patients with sepsis}; Surbatovic M et al.; Severe sepsis and trauma complicated with multiple organ dysfunction syndrome (MODS) are among the leading causes of death in intensive therapy units, with mortality rate exceeding 50% . The outcome is not determined only by infection or trauma, but also by the intensity of immuno-inflammatory response, which is essential for host defence, but if uncontrolled leads to MODS . Pro-inflammatory cytokines (tumor necrosis factor-alpha--TNF-alpha, IL-1, IL-8, IL-12, IFN-gamma, etc.) represent a part of this immuno-inflammatory response to an insult . The results of the clinical investigation of correlation between pro-inflammatory cytokines (IL-8, IL-12, TNF-alpha, IFN-gamma), the outcome (survivors, non-survivors), and the severity (systemic inflammatory response syndrome--SIRS--less severe, and MODS--more severe) in polytraumatised patients with sepsis are presented in this paper . Mean values of IL-8 were 1.3-fold higher in non-survivors (p<0.05), and 60-fold higher in MODS group (p<0.01) . Mean values of IL-12 were 1.6-fold higher in survivors (p<0.01), while the values between SIRS and MODS group did not differ significantly; mean values of TNF-alpha were 3-fold higher in survivors (p<0.05), and 46-fold higher in MODS group (p<0.01) . Mean values of IFN-gamma did not differ significantly between the two groups regarding the outcome and severity . The obtained results indicated that IL-8 was a reliable predictor of lethal outcome and MODS (p<0.01), IL-12 a reliable predictor of survival (p<0.05), and TNF-alpha a reliable predictor of survival (p<0.05) and MODS (p<0.01).

Pharmacoeconomics, 2004, 22(12), 793 - 813
Economic aspects of severe sepsis: a review of intensive care unit costs, cost of illness and cost effectiveness of therapy; Burchardi H et al.; Severe sepsis remains both an important clinical challenge and an economic burden in intensive care . An estimated 750,000 cases occur each year in the US alone (300 cases per 100,000 population) . Lower numbers are estimated for most European countries (e.g . Germany and Austria: 54-116 cases per year per 100,000) . Sepsis patients are generally treated in intensive care units (ICUs) where close supervision and intensive care treatment by a competent team with adequate equipment can be provided . Staffing costs represent from 40% to >60% of the total ICU budget . Because of the high proportion of fixed costs in ICU treatment, the total cost of ICU care is mainly dependent on the length of ICU stay (ICU-LOS) . The average total cost per ICU day is estimated at approximately 1200 Euro for countries with a highly developed healthcare system (based on various studies conducted between 1989 and 2001 and converted at 2003 currency rates) . Patients with infections and severe sepsis require a prolonged ICU-LOS, resulting in higher costs of treatment compared with other ICU patients . US cost-of-illness studies focusing on direct costs per sepsis patient have yielded estimates of 34,000 Euro, whereas European studies have given lower cost estimates, ranging from 23,000 Euro to 29,000 Euro . Direct costs, however, make up only about 20-30% of the cost of illness of severe sepsis . Indirect costs associated with severe sepsis account for 70-80% of costs and arise mainly from productivity losses due to mortality . Because of increasing healthcare cost pressures worldwide, economic issues have become important for the introduction of new innovations . This is evident when introducing new biotechnology products, such as drotrecogin-alpha (activated protein C), into specific therapy for severe sepsis . Data so far suggest that when drotrecogin-alpha treatment is targeted to those patients most likely to achieve the greatest benefit, the drug is cost effective by the standards of other well accepted life-saving interventions.

Rev Med Suisse Romande, 2004 Jun, 124(6), 329 - 32
{New therapeutic strategies in severe sepsis and septic shock}; Oddo M et al.; Severe sepsis and septic shock are an important cause of mortality . Until recently, in spite of major progresses in our understanding of the pathogenic mechanisms of this syndrome, clinicians had only a limited therapeutic arsenal . Considerable efforts have been made in the past few years to develop novel therapeutic interventions to reduce mortality in sepsis . So far, five specific therapies have proven their efficacy to achieve such goal in large randomised controlled trials: early goal-directed therapy, recombinant activated protein C, moderate doses of steroids, low tidal volume ventilation in acute respiratory distress syndrome and intensive insulin therapy to control hyperglycemia . This review will focus on these recently acquired therapeutic modalities, that are presently available to clinicians for the treatment of severe sepsis and septic shock.

Circulation, 2004 Aug 17, 110(7), 880 - 5 Epub 2004 Aug 02.
Prior statin therapy is associated with a decreased rate of severe sepsis; Almog Y et al.; BACKGROUND: Statins have anti-inflammatory properties that are independent of their lipid-lowering abilities . We hypothesized that statin therapy before the onset of an acute bacterial infection may have a protective effect against severe sepsis . The aim of this study was to determine whether patients treated with statins develop severe sepsis less frequently . METHODS AND RESULTS: In this prospective observational cohort study, consecutive patients admitted with presumed or documented acute bacterial infection were enrolled . The primary outcomes were the rate of severe sepsis and intensive care unit (ICU) admission . Of the 361 patients enrolled, 82 (22.7%) were treated with statins before their admission . Both groups had a similar severity of illness on admission . Severe sepsis developed in 19% of patients in the no-statin group and in only 2.4% of the statin group (P<0.001) . Statin treatment was associated with a relative risk of developing severe sepsis of 0.13 (95% CI, 0.03 to 0.52) and an absolute risk reduction of 16.6% . The overall ICU admission rate was 10.2% (37/361): 12.2% of the no-statin group required ICU admission, whereas in the statin group only 3.7% were admitted to the ICU (P=0.025), reflecting a relative risk of ICU admission of 0.30 (95% CI, 0.1 to 0.95) . CONCLUSIONS: Prior therapy with statins may be associated with a reduced rate of severe sepsis and ICU admission . If supported by prospective controlled trials, statins may have a role in the primary prevention of sepsis.

BMJ . 2004 Aug 28;329(7464):480 . Epub 2004 Aug 02.
Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis; Annane D et al.; OBJECTIVE: To assess the effects of corticosteroids on mortality in patients with severe sepsis and septic shock . DATA SOURCES: Randomised and quasi-randomised trials of corticosteroids versus placebo (or supportive treatment alone) retrieved from the Cochrane infectious diseases group's trials register, the Cochrane central register of controlled trials, Medline, Embase, and LILACS . REVIEW METHOD: Two pairs of reviewers agreed on eligibility of trials . One reviewer entered data on to the computer and four reviewers checked them . We obtained some missing data from authors of trials and assessed methodological quality of trials . RESULTS: 16/23 trials (n = 2063) were selected . Corticosteroids did not change 28 day mortality (15 trials, n = 2022; relative risk 0.92, 95% confidence interval 0.75 to 1.14) or hospital mortality (13 trials, n = 1418; 0.89, 0.71 to 1.11) . There was significant heterogeneity . Subgroup analysis on long courses (> or = 5 days) with low dose (< or = 300 mg hydrocortisone or equivalent) corticosteroids showed no more heterogeneity . The relative risk for mortality was 0.80 at 28 days (five trials, n = 465; 0.67 to 0.95) and 0.83 at hospital discharge (five trials, n = 465, 0.71 to 0.97) . Use of corticosteroids reduced mortality in intensive care units (four trials, n = 425, 0.83, 0.70 to 0.97), increased shock reversal at 7 days (four trials, n = 425; 1.60, 1.27 to 2.03) and 28 days (four trials, n = 425, 1.26, 1.04 to 1.52) without inducing side effects . CONCLUSIONS: For all trials, regardless of duration of treatment and dose, use of corticosteroids did not significantly affect mortality . With long courses of low doses of corticosteroids, however, mortality at 28 days and hospital morality was reduced.

Crit Care Med, 2004 Aug, 32(8), 1764 - 70
Time-dependent mitochondrial-mediated programmed neuronal cell death prolongs survival in sepsis; Messaris E et al.; OBJECTIVE: To investigate whether apoptosis is a possible mechanism of brain dysfunction occurring in septic syndrome . DESIGN: Experimental prospective study . SETTING: Laboratory of Surgical Research at the University of Athens . SUBJECTS: Male pathogen-free Wistar rats . INTERVENTIONS: Rats (n = 112) were subjected to sepsis by cecal ligation and puncture . Sham-operated animals (n = 40) underwent the same procedure but without ligation or puncture . Septic animals were either randomly divided (n = 62) in six groups and studied at 6, 12, 24, 36, 48, and 60 hrs after the operation or monitored (n = 50) for 48 hrs as a survival study group . Sham-operated animals were killed at 6, 12, 24, 36, 48, and 60 hrs after the procedure . Brain and cecum were then removed and postfixed in paraffin sections . Apoptosis was evaluated by light microscopy in hematoxylin and eosin-stained specimens and by transmission electron microscopy . In paraffin-embedded sections, immunostaining for bax, bcl-2, cytochrome c, and caspase-8 was done . MEASUREMENTS AND MAIN RESULTS: In septic rats, increased apoptosis was detected in neurons of the CA1 region of the hippocampus, in choroid plexus, and in Purkinje cells of the cerebellum . Bax immunopositivity was found decreased after the septic insult (p =.03) . Bax immunoreactivity was altered as the septic syndrome evolved; it was up-regulated in the early stages (6-12 hrs) and progressively decreased in the late phases (p =.001) . Cytochrome c presented a similar regional pattern of expression and was found to be the sole gene marker carrying an independent prognostic role (p =.03) . Both bcl-2 and caspase-8 expression remained at constant levels at all times evaluated . CONCLUSIONS: There is evidence that more neurons undergo apoptosis during sepsis than in normal brain tissue in certain sites where the blood-brain barrier is compromised . In this phenomenon, mitochondrial gene regulators such as bax and products such as cytochrome c seem to play important regulating and prognostic roles, respectively.

Crit Care Med, 2004 Aug, 32(8), 1747 - 52
Delayed administration of human inter-alpha inhibitor proteins reduces mortality in sepsis; Wu R et al.; OBJECTIVE: We have recently shown that administration of human inter-alpha inhibitor proteins (IalphaIp) very early after the onset of sepsis maintains cardiovascular stability and reduced mortality . However, it remains unknown whether injection of IalphaIp at later time points of sepsis has any beneficial effects . We therefore hypothesized that IalphaIp and its active component bikunin are reduced in sepsis and that the delayed administration of IalphaIp also improves survival rate . DESIGN:: Prospective, controlled, and randomized animal study . SETTING: A research institute laboratory . SUBJECTS:: Male adult Sprague-Dawley rats . INTERVENTIONS: Rats were subjected either to polymicrobial sepsis by cecal ligation and puncture (CLP) or to sham operation followed by the administration of normal saline solution (i.e., fluid resuscitation) . MEASUREMENTS AND MAIN RESULTS:: Bikunin gene expression in the liver was measured by reverse transcription polymerase chain reaction . Plasma concentrations of IalphaIp were determined by Western blot at 5 and 20 hrs after CLP . IalphaIp clearance was assessed by injecting radioactive IalphaIp at 12 hrs post-CLP, and the half-life was determined . In addition, IalphaIp (30 mg/kg of body weight) or vehicle was administered at 1, 5, or 10 hrs (single treatment) or at both 10 and 20 hrs (double treatment) post-CLP . The necrotic cecum was excised at 20 hrs post-CLP, and 10-day survival was recorded . The results indicate that bikunin gene expression decreased significantly at 20 hrs post-CLP . Moreover, IalphaIp concentrations decreased significantly at 5 and 20 hrs post-CLP, and its half-life increased from 5.6 +/- 0.3 hrs to 11.8 +/- 2.7 hrs (p <.05), suggesting down-regulation of IalphaIp in sepsis despite the decreased clearance . Administration of IalphaIp at 1 hr post-CLP improved the survival rate from 50% to 92% (p <.05), whereas there was no significant improvement when IalphaIp was administrated at 5 or 10 hrs post-CLP . However, double injection of IalphaIp at 10 and 20 hrs post-CLP (i.e., severe sepsis) increased the survival rate from 44% to 81% (p <.05) . CONCLUSION: Since delayed but repeated administration of human IalphaIp improves survival after CLP, this compound appears to be a useful agent for the treatment of severe sepsis.

Crit Care Med, 2004 Aug, 32(8), 1637 - 42
Early lactate clearance is associated with improved outcome in severe sepsis and septic shock; Nguyen HB et al.; OBJECTIVE: Serial lactate concentrations can be used to examine disease severity in the intensive care unit . This study examines the clinical utility of the lactate clearance before intensive care unit admission (during the most proximal period of disease presentation) as an indicator of outcome in severe sepsis and septic shock . We hypothesize that a high lactate clearance in 6 hrs is associated with decreased mortality rate . DESIGN: Prospective observational study . SETTING: An urban emergency department and intensive care unit over a 1-yr period . PATIENTS: A convenience cohort of patients with severe sepsis or septic shock . INTERVENTIONS: Therapy was initiated in the emergency department and continued in the intensive care unit, including central venous and arterial catheterization, antibiotics, fluid resuscitation, mechanical ventilation, vasopressors, and inotropes when appropriate . MEASUREMENTS AND MAIN RESULTS: Vital signs, laboratory values, and Acute Physiology and Chronic Health Evaluation (APACHE) II score were obtained at hour 0 (emergency department presentation), hour 6, and over the first 72 hrs of hospitalization . Therapy given in the emergency department and intensive care unit was recorded . Lactate clearance was defined as the percent decrease in lactate from emergency department presentation to hour 6 . Logistic regression analysis was performed to determine independent variables associated with mortality . One hundred and eleven patients were enrolled with mean age 64.9 +/- 16.7 yrs, emergency department length of stay 6.3 +/- 3.2 hrs, and overall in-hospital mortality rate 42.3% . Baseline APACHE II score was 20.2 +/- 6.8 and lactate 6.9 +/- 4.6 mmol/L . Survivors compared with nonsurvivors had a lactate clearance of 38.1 +/- 34.6 vs . 12.0 +/- 51.6%, respectively (p =.005) . Multivariate logistic regression analysis of statistically significant univariate variables showed lactate clearance to have a significant inverse relationship with mortality (p =.04) . There was an approximately 11% decrease likelihood of mortality for each 10% increase in lactate clearance . Patients with a lactate clearance> or =10%, relative to patients with a lactate clearance <10%, had a greater decrease in APACHE II score over the 72-hr study period and a lower 60-day mortality rate (p =.007) . CONCLUSIONS: Lactate clearance early in the hospital course may indicate a resolution of global tissue hypoxia and is associated with decreased mortality rate . Patients with higher lactate clearance after 6 hrs of emergency department intervention have improved outcome compared with those with lower lactate clearance.

Emerg Med Australas, 2004 Aug, 16(4), 324 - 35
Drotrecogin alfa: a role in emergency department treatment of severe sepsis?
McLeay AM.
Human protein C is a serine protease that circulates in the blood as an inactive zymogen . It is converted to its active form by interaction with thrombomodulin on the endothelial wall . Activated protein C has a significant role in maintaining haemostasis, and is a major mechanism of controlling microvascular thrombosis . Recent reports describe the use of drotrecogin alfa (recombinant activated protein C) in severe sepsis, a condition relevant to emergency medicine . This review describes the physiology of the protein C pathway and its importance in sepsis . It will also focus on the use of drotrecogin alfa in sepsis, and its use in the ED.

SADJ . 2004 May;59(4):163, 165.
An update on the pathophysiology of sepsis; le Roux P; Mortality among critically ill patients has been attributed to the development of sepsis . About 28% of patients with sepsis still die, despite numerous interventions . Trials on sepsis investigated mostly anti-inflammatory strategies, based on the prevailing theory that sepsis represents an uncontrolled inflammatory response . None of these showed convincing benefit in humans, despite promising results in animal studies . The reason for this is becoming clear: sepsis represents a biphasic response to infection, and the initial pro-inflammatory response that we have targeted thus far is invariably followed by a prolonged period of immune suppression . In addition, a patient may oscillate between a pro- and anti-inflammatory state repeatedly . A single magic bullet therapy is thus unlikely to work . The mediators of this process are the cytokines, and a lot of research is focussed on modulating these to achieve a better outcome . In addition, the central role of the coagulation cascade in mediating inflammation and sepsis is becoming clear, and therapies addressing this mechanism are promising.

J Leukoc Biol, 2004 Sep, 76(3), 571 - 6 Epub 2004 Jul 26.
Polymorphonuclear leukocytes from patients with severe sepsis have lost the ability to degrade fibrin via u-PA; Moir E et al.; Fibrin persistence in the vasculature is an important complication of sepsis that can often lead to mortality . We have previously established that polymorphonuclear leukocytes (PMN) from healthy individuals have the capacity to degrade fibrin via urokinase-type plasminogen activator (u-PA) . We have also demonstrated an increase in u-PA antigen in the plasma of patients suffering from septic shock . In this study, we investigate the hypothesis that PMN from patients with sepsis have lost their fibrinolytic ability and that this might contribute to the persistence of fibrin deposits . We show here that PMN from these patients do not express any u-PA activity, despite retaining some u-PA antigen . Additionally, thrombi prepared from the whole blood of the patients exhibit reduced endogenous lysis compared with those from healthy individuals . These data indicate that loss of fibrinolytic activity from PMN may be a contributing factor in fibrin persistence in the microvasculature in sepsis.

Biochim Biophys Acta, 2004 Aug 4, 1689(3), 212 - 8
Increased gut-derived norepinephrine release in sepsis: up-regulation of intestinal tyrosine hydroxylase; Zhou M et al.; Studies have shown that increased gut-derived norepinephrine (NE) release plays an important role in producing hepatocellular dysfunction at the early stage of sepsis . Although the gut has been demonstrated to be the major source of NE in sepsis, it remains unknown whether the increased NE is associated with up-regulation of intestinal NE biosynthesis enzymes such as tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) . To determine this, adult male rats were subjected to sepsis by cecal ligation and puncture (CLP) followed by fluid resuscitation . Small intestinal samples were harvested at 2 h (i.e., early sepsis) or 20 h (late sepsis) after CLP or sham-operation . Protein levels of TH and DBH were determined by Western blot analysis and immunohistochemistry . Their gene expression was assessed by RT-PCR technique . The results indicate that intestinal TH protein levels increased significantly at 2 and 20 h after CLP, while DBH was not altered under such conditions . Immunohistochemical examination shows that both TH and DBH were located in intestinal sympathetic nerve fibers and TH staining was markedly increased in septic animals . TH gene expression increased significantly at 2 h but not at 20 h after CLP, while DBH gene expression was not altered in sepsis . Thus, the increased TH gene and protein expression appears to be responsible for the increased gut-derived NE in sepsis.

Adv Neonatal Care, 2004 Jun, 4(3), 141 - 53; quiz 154-7
Guide to a systematic physical assessment in the infant with suspected infection and/or sepsis; Short MA; This article provides the resources for the bedside caregiver to conduct a focused physical assessment of the infant with suspected sepsis . The importance of obtaining a complete history to identify associated obstetric and neonatal risk factors is emphasized . Further evaluation of the infant's clinical presentation for signs and symptoms suggestive of a systemic inflammatory response to infection is discussed, along with a step-by-step guide to a systematic physical assessment . Strategies to evaluate physical findings in context with the available diagnostic data to develop a differential diagnosis are provided . The international consensus definitions for the sepsis continuum are presented and are compared and contrasted to the definitions more commonly used in the neonatal population . The article provides tables that can serve as checklists to structure a thorough obstetric and neonatal history and to further evaluate the infant's systemic inflammatory response to infection.

Ann Surg, 2004 Aug, 240(2), 321 - 30
Adrenomedullin and adrenomedullin binding protein-1 attenuate vascular endothelial cell apoptosis in sepsis; Zhou M et al.; OBJECTIVE: To determine whether vascular endothelial cell apoptosis occurs in the late stage of sepsis and, if so, whether administration of a potent vasodilatory peptide adrenomedullin and its newly reported specific binding protein (AM/AMBP-1) prevents sepsis-induced endothelial cell apoptosis . SUMMARY BACKGROUND DATA: Polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase . Our recent studies have shown that administration of AM/AMBP-1 delays or even prevents the transition from the hyperdynamic phase to the hypodynamic phase of sepsis, attenuates tissue injury, and decreases sepsis-induced mortality . However, the mechanisms responsible for the beneficial effects of AM/AMBP-1 in sepsis remain unknown . METHODS: Polymicrobial sepsis was induced by cecal ligation and puncture in adult male rats . Human AMBP-1 (40 microg/kg body weight) was infused intravenously at the beginning of sepsis for 20 minutes and synthetic AM (12 microg/kg body weight) was continuously administered for the entire study period using an Alzert micro-osmotic pump, beginning 3 hours prior to the induction of sepsis . The thoracic aorta and pulmonary tissues were harvested at 20 hours after cecal ligation and puncture (ie, the late stage of sepsis) . Apoptosis was determined using TUNEL assay, M30 Cytodeath immunostaining, and electromicroscopy . In addition, anti-apoptotic Bcl-2 and pro-apoptotic Bax gene expression and protein levels were assessed by RT-PCR and Western blot analysis, respectively . RESULTS: Vascular endothelial cells underwent apoptosis formation at 20 hours after cecal ligation and puncture as determined by three different methods . Moreover, partial detached endothelial cell in the aorta was observed . Bcl-2 mRNA and protein levels decreased significantly at 20 hours after the onset of sepsis while Bax was not altered . Administration of AM/AMBP-1 early after sepsis, however, significantly reduced the number of apoptotic endothelial cells . This was associated with significantly increased Bcl-2 protein levels and decreased Bax gene expression in the aortic and pulmonary tissues . CONCLUSION: The above results suggest that vascular endothelial cell apoptosis occurs in late sepsis and the anti-apoptotic effects of AM/AMBP-1 appear to be in part responsible for their beneficial effects observed under such conditions.

Artif Organs, 2004 Aug, 28(8), 747 - 50
Molecular adsorbents recirculating system dialysis for liver insufficiency and sepsis following right ventricular assist device after cardiac surgery; Hein OV et al.; We report a case of right heart failure (RHF) and sepsis with liver insufficiency in a 70-year-old patient after coronary artery bypass graft surgery . Three hours after surgery the patient suddenly developed therapy refractory cardiac arrest caused by RHF . He had to have emergency surgery, under which the graft to the right coronary artery was revised and a right ventricular assist device was implanted . Heart function recovered and the assist device was explanted on day 1 after surgery . Thoracic closure was performed on day 5 after surgery . The patient went into septic shock on day 11 . Liver dysfunction developed postoperatively and worsened the course of sepsis . Therefore, MARS (molecular adsorbents recirculating system) dialysis was performed once on day 20 after surgery . Liver function improved after MARS therapy and the patient recovered from sepsis . On day 46 the patient was transferred from the ICU of another hospital to one of the peripheral wards, to be finally discharged on day 67.

Clin Exp Immunol, 2004 Aug, 137(2), 402 - 7
Rapid simultaneous measurement of multiple cytokines using 100 microl sample volumes--association with neonatal sepsis; Hodge G et al.; Early diagnosis of neonatal infection has proved problematic due to the inadequacy of currently available laboratory tests . Neonatal sepsis is associated with an increase in plasma-derived cytokine levels, but an increase of a single cytokine cannot identify neonatal sepsis specifically and multiple cytokine levels are required . The time constraints and relatively large volume of plasma required to measure multiple cytokines from newborn infants by conventional enzyme-linked immunosorbent assay (ELISA) techniques is prohibitive . We therefore applied cytometric bead array (CBA) technology for simultaneous measurement of multiple cytokines from a group of 18 term neonates with infection confirmed by culture and a control group . 'Normal' ranges were established for each cytokine from 1-7-, 8-14- and 15-21-day-old newborns . There was no significant change in the levels of cytokines from infants in different control age groups, suggesting that basal cytokine levels are unchanged in the first 3 weeks of life . In the patient groups, however, there was a significant difference in several cytokines between the different age groups . Interleukin (IL)-6, IL-10 and IL-12 were increased significantly in the 1-7-day-old patient group compared to either the 8-14 and 15-21 age group, suggesting that infection in utero is associated with increased levels of these cytokines compared to infection acquired following birth . When individual patient cytokine levels were compared to normal control reference ranges, two patients failed to show significant elevation of any cytokine tested . All other patients showed elevated levels of between one and nine cytokines tested (mean of 4.6) . There was no correlation between elevated cytokine levels and types of infective organism or patient age . In conclusion, neonatal sepsis is associated with the elevation of multiple plasma cytokines . The use of CBA kits is a rapid, easy, low sample volume and sensitive method to measure multiple plasma cytokines.

Shock, 2004 Aug, 22(2), 137 - 44
Polymicrobial sepsis induces divergent effects on splenic and peritoneal dendritic cell function in mice; Ding Y et al.; Dendritic cells (DCs) are professional antigen-presenting cells that act as sentinels in the cell-mediated response against invading pathogens associated with septic challenge . The purpose of the present study was to determine whether there is a loss of dendritic cells and/or changes in function of these cells in septic mice . Here we report that the number of DCs, in both spleen and peritoneum, decreased over 24 h postsepsis {cecal ligation and puncture (CLP)} when compared with sham . The most dramatic change was seen in the peritoneal cavity . This decrease appeared to be caused mainly by the depletion of immature DCs rather than mature DCs . This change was LPS independent and minimally affected by FasL; however, overexpression of human Bcl-2 gene provides protection of the septic peritoneal DCs . Moreover, although the level of IL-12 release decreased significantly in splenic DCs obtained from CLP mice, IL-12 secretion was markedly elevated by peritoneal DCs as well as in both plasma and peritoneal fluid at 24 h post-CLP . In peritoneal cells, the expression of CD40, CD80, and CD86 was unchanged, but their respective ligands CD40L, CD28, and CD152 all increased in mice 24 h after CLP, although no such change was observed in splenocytes . Regardless of the presence or absence of antigen, peritoneal DCs from CLP mice showed higher capacity to stimulate T-cell proliferation than those cells from the sham control . However, splenic DCs from CLP mice only showed augmented capacity to induce antigen-dependent stimulation of T-cell proliferation . Together, these data indicate that sepsis produces divergent functional changes in splenic and peritoneal DC populations.

Int J Exp Pathol, 2004 Jun, 85(3), 147 - 57
Activity of lung neutrophils and matrix metalloproteinases in cyclophosphamide-treated mice with experimental sepsis; Hirsh M et al.; Sepsis in patients receiving chemotherapy may result in acute respiratory distress syndrome, despite decreased number of blood neutrophils {polymorphonuclear neutrophils (PMNs)} . In the present study, we investigated the correlation of cyclophosphamide (CY)-induced neutropenia with the destructive potential of lung PMN in respect to formation of septic acute lung injury (ALI) . Mice were treated with 250 mg/kg of CY or saline (control) and subjected to cecal ligation and puncture (CLP) or sham operation . ALI was verified by histological examination . Lung PMNs and matrix metalloproteinases (MMPs) were assessed by flow cytometry and gelatin zymography . CLP in CY-treated mice induced a typical lung injury . Despite profound neutropenia, CY treatment did not attenuate CLP-induced ALI . This might relate to only a partial suppression of PMN: CY has significantly reduced PMN influx into the lungs (P = 0.008) and suppressed their oxidative metabolism, but had no suppressive effect on degranulation (P = 0.227) and even induced MMP-9 activity (P = 0.0003) . In CY-untreated animals, peak of CLP-induced ALI coincided with massive PMN influx (P = 0.013), their maximal degranulation (P = 0.014) and activation of lung MMP-9 (P = 0.002) . These findings may indicate an important role of the residual lung PMN and activation of MMP-9 in septic lung injury during CY chemotherapy.

Neuroimmunomodulation, 2004, 11(4), 214 - 23
Adrenergic modulation of survival and cellular immune functions during polymicrobial sepsis; Oberbeck R et al.; OBJECTIVE: An immunomodulatory effect of epinephrine has been reported that is supposed to be mediated via beta-adrenergic receptors . The effect of epinephrine and/or beta-adrenergic blockade on cellular immune functions during systemic inflammation has not yet been investigated . METHODS: Male NMRI mice were treated with either an infusion of epinephrine (0.05 mg/kg/h i.p.), administration of the nonselective beta-adrenoceptor antagonist propranolol (0.5 mg/kg s.c.), or a combination of epinephrine and propranolol after induction of a polymicrobial sepsis by cecal ligation and puncture . Forty-eight hours thereafter survival and cellular immune functions (splenocyte proliferation, splenocyte apoptosis and cytokine release, distribution of leukocyte subsets) were determined . RESULTS: Infusion of epinephrine did not affect lethality of septic mice but induced alterations of splenocyte apoptosis, splenocyte proliferation and IL-2 release and was associated with profound changes of circulating immune cell subpopulations . Treatment with propranolol augmented the epinephrine-induced increase of splenocyte apoptosis, did not affect the decrease of splenocyte proliferation and IL-2 release, augmented the release of IL-6 and antagonized the mobilization of natural killer cells observed in epinephrine-treated animals . Furthermore, these immunologic alterations were accompanied by a significant increase of sepsis-induced mortality . Coadministration of propranolol and epinephrine augmented the propranolol-induced changes of splenocyte apoptosis and IL-6 release and was associated with the highest mortality of septic mice . CONCLUSION: Epinephrine infusion modulated cellular immune functions during systemic inflammation without an impact on survival . A pharmacologic beta-adrenergic blockade partly augmented the epinephrine-induced immune alterations and was associated with a pronounced increase of mortality . This effect was further augmented by a combination of epinephrine infusion and beta-adrenergic blockade . These data indicate that adrenergic mechanisms modulate cellular immune functions and survival during sepsis, with these effects being mediated via alpha- and beta-adrenergic pathways .

Crit Care Med, 2004 Jul, 32(7), 1460 - 9
Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity; Taneja R et al.; OBJECTIVE: The resolution of neutrophil (PMN)-mediated inflammation occurs through the apoptosis, or programmed cell death, of the neutrophil . PMN apoptosis is inhibited by a variety of inflammatory stimuli; moreover, PMN from critically ill septic patients show profoundly delayed rates of apoptosis in vitro . Since apoptosis is effected through the activity of intracellular cysteine proteases (caspases), we evaluated caspase expression and activity in neutrophils from septic patients and compared them with caspase expression and activity of resting or lipopolysaccharide-activated neutrophils from healthy volunteers . DESIGN: Prospective observational cohort study . SETTING: Tertiary level intensive care unit and associated research laboratory . SUBJECTS: Thirty-six intensive care unit patients with sepsis; ten healthy laboratory controls . INTERVENTIONS: Collection of up to 10 mL of whole blood for in vitro study of rates of apoptosis, expression and activity of caspases-1, -3, and -9, activation of nuclear factor-kappaB, and change in mitochondrial transmembrane potential . MEASUREMENTS AND MAIN RESULTS: Following 24 hrs of in vitro culture, 52 +/- 7.8% of control neutrophils, but only 29 +/- 5.4% of lipopolysaccharide-stimulated (1 microg/mL) PMN, showed nuclear changes of apoptosis . Only 6.2 +/- 1.1% of neutrophils from septic patients were apoptotic after 24 hrs . Significant nuclear translocation of nuclear factor-kappaB was evident in septic PMN, and inhibition of apoptosis was partially abrogated by prevention of nuclear factor-kappaB dissociation with pyrrolidine dithiocarbamate . Caspase-3 transcription and catalytic activity were significantly reduced in both patients' and lipopolysaccharide-treated PMN; caspase-1 transcription and activity were increased by lipopolysaccharide but reduced in septic patients . In contrast, caspase-9 transcription and activity were reduced in septic patients but not in lipopolysaccharide-treated PMN . Decreased caspase-9 activity was associated with sustained maintenance of mitochondrial transmembrane potential and reduced translocation of cytochrome c from the mitochondria to the cytosol . CONCLUSIONS: Apoptosis of circulating neutrophils from patients with clinical sepsis is profoundly suppressed, through a mechanism that involves activation of nuclear factor-kappaB that is associated with reduced activity of caspases-9 and -3 and maintenance of mitochondrial transmembrane potential and that differs in important respects from the inhibitory effects seen following the exposure of healthy neutrophils to inflammatory stimuli.

Ann Intern Med, 2004 Jul 6, 141(1), 47 - 56
Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose; Minneci PC et al.; BACKGROUND: Previous meta-analyses demonstrated that high-dose glucocorticoids were not beneficial in sepsis . Recently, lower-dose glucocorticoids have been studied . PURPOSE: To compare recent trials of glucocorticoids for sepsis with previous glucocorticoid trials . DATA SOURCES: Systematic MEDLINE search for studies published between 1988 and 2003 . STUDY SELECTION: Randomized, controlled trials of sepsis that examined the effects of glucocorticoids on survival or vasopressor requirements . DATA EXTRACTION: Two investigators independently collected data on patient and study characteristics, treatment interventions, and outcomes . DATA SYNTHESIS: The 5 included trials revealed a consistent and beneficial effect of glucocorticoids on survival (I2 = 0%; relative benefit, 1.23, {95% CI, 1.01 to 1.50}; P = 0.036) and shock reversal (I2 = 0%; relative benefit, 1.71 {CI, 1.29 to 2.26}; P < 0.001) . These effects were the same regardless of adrenal function . In contrast, 8 trials published before 1989 demonstrated a survival disadvantage with steroid treatment (I2 = 14%; relative benefit, 0.89 {CI, 0.82 to 0.97}; P = 0.008) . In comparison with the earlier trials, the more recent trials administered steroids later after patients met enrollment criteria (median, 23 hours vs . <2 hours; P = 0.02), for longer courses (6 days vs . 1 day; P = 0.01), and in lower total dosages (hydrocortisone equivalents, 1209 mg vs . 23 975 mg; P = 0.01) to patients with higher control group mortality rates (mean, 57% vs . 34%; P = 0.06) who were more likely to be vasopressor-dependent (100% vs . 65%; P = 0.03) . The relationship between steroid dose and survival was linear, characterized by benefit at low doses and increasing harm at higher doses (P = 0.02) . LIMITATIONS: We could not analyze time-related improvements in medical care and potential bias secondary to nonreporting of negative study results . CONCLUSIONS: Although short courses of high-dose glucocorticoids decreased survival during sepsis, a 5- to 7-day course of physiologic hydrocortisone doses with subsequent tapering increases survival rate and shock reversal in patients with vasopressor-dependent septic shock.

Biol Neonate, 2004, 86(3), 170 - 5 Epub 2004 Jun 29.
Use of once-daily netilmicin to treat infants with suspected sepsis in a neonatal intensive care unit; Brooks JR et al.; Once-daily administration of aminoglycoside antibiotics has become the most acceptable dosing schedule for the majority of patients . There are few published data on the impact of post-natal age on aminoglycoside concentrations in preterm infants receiving once-daily dosage regimens . Netilmicin was administered as a once-daily dose of 4 mg/kg . In 141 episodes of suspected sepsis in 123 babies, trough netilmicin concentrations ranged from undetectable to 4.0 mg/l . Netilmicin concentrations were above a level of 2 mg/l in 10.6% of episodes . Netilmicin concentrations decreased with increasing post-natal age and weight . Levels were higher in males compared to females . Increased creatinine concentrations were associated with higher netilmicin concentrations . This study emphasises the importance of post-natal age as a determinant of aminoglycoside concentrations with a once-daily dosing regimen in a neonatal intensive care population . Trough levels should be carefully monitored and consideration given to extending dosage intervals particularly when netilmicin is administered once daily to preterm infants in the first week of life.

Ann Fr Anesth Reanim, 2004 Jun, 23(6), 575 - 80
{Short term effects of hypertonic saline during severe sepsis and septic shock}; Muller L et al.; OBJECTIVE: Assessment of haemodynamic effects of 250 ml hypertonic saline 7.5% (HS) perfusion in critically ill patients with severe sepsis or septic shock . STUDY DESIGN: Observational study . PATIENTS: Twelve mechanically ventilated patients with severe sepsis or septic shock requiring a pulmonary artery catheter and volume loading . INTERVENTION: Two hundred and fifty millilitres HS were given over 15 min . Were measured: heart rate (HR), mean arterial pressure (MAP) and pulmonary artery pressure (MPAP), pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), cardiac index (CI), indexed systemic vascular resistance (ISVR), indexed pulmonary vascular resistance (IPVR), plasma sodium, chloride, protein and haemoglobin concentrations and arterial blood lactate . Studied parameters were assessed at baseline (T(0)) and 5 (T(0)) and 105 min (T(120)) after the end of HS infusion . RESULTS: MAP, HR and RAP were not altered . HS increased PAPM (25 +/- 5-30 +/- 6 mmHg), PCWP (13 +/- 3-18 +/- 4 mmHg) and CI (3.5 +/- 1.2-4.6 +/- 1.1 l/min per m(2)) at T(20) (P < 0.05) . ISVR and IPVR were decreased at T(20) . Protein and haemoglobin were decreased at T(20) . Sodium and chloride were increased at T(20) (from 136 +/- 4 to 147 +/- 4 and from 110 +/- 6 to 123 +/- 6 mmol/l, respectively, P < 0.01) and T(120) . CONCLUSION: In patients with severe sepsis or septic shock, 250 ml HS transiently (<120 min) increases CI and PCWP and induces an increase in sodium and chloride concentrations.

Med Sci Monit, 2004 Jul, 10(7), BR233 - 7 Epub 2004 Jun 29.
Pentoxyphilline as a cyclooxygenase (cox-2) inhibitor in experimental sepsis; Modzelewski B et al.; BACKGROUND: The aim of this study is to assess the impact of pentoxyphilline (PTX) on the pattern of serum concentrations of certain pro-inflammatory cytokines and their soluble receptors in relation to the animal's survival period . MATERIAL/METHODS: Diffuse peritonitis was elicited by means of cecal ligation and puncture (CLP) in 45 adult Wistar rats . The pattern of soluble TNF receptor p55 type 1 and p75 type 2 in reference to TNF-alpha and IL-1beta concentration in animals with experimental diffuse peritonitis (EDP) was estimated . All animals were divided into 3 groups . RESULTS: In both groups where animals received medication, the percentage of survival was higher than in the controls . An increase in CRP concentration was observed in all study animals . An increase in TNFalpha concentration was noted during the first 12 hours of the experiment . There was an increase in soluble TNFR p55 concentrations in all study groups until the 24th hour of the experiment, then a decrease until the end of the observation period . The concentration of soluble TNF p75 receptor gradually increased over time in all groups . In group I a constant rise of IL-1beta serum concentration was observed . CONCLUSIONS: Pentoxyphilline administration in animals in the early stage of diffuse peritonitis causes the TNFalpha serum concentration to decrease, but it does not improve the overall survival period . Late pentoxyphilline administration does not alter the course of diffuse peritonitis in rat.

Am J Hematol, 2004 Jul, 76(3), 225 - 9
Hemostatic markers and the sepsis-related organ failure assessment score in patients with disseminated intravascular coagulation in an intensive care unit; Okabayashi K et al.; We investigated the correlation between disseminated intravascular coagulation (DIC) score and hemostatic parameters and sepsis-related organ failure assessment (SOFA) score with clinical outcome of patients with DIC in an intensive care unit (ICU) . The SOFA score was markedly elevated in patients with DIC relative to patients without DIC and significantly higher in non-survivors than in survivors . Abnormalities in almost all hemostatic parameters were significant in patients with DIC, but there was no significant difference in almost all hemostatic parameters between survivors and non-survivors . However, plasma antithrombin (AT) levels were significantly lower in non-survivors than in survivors . Soluble fibrin (SF) and tissue type plasminogen activator (tPA)-plasminogen activator inhibitor-I (PAI-I) complex correlated significantly with the SOFA score, whereas AT levels correlated significantly and negatively with the SOFA score . We conclude that the SOFA score is useful for predicting outcome in DIC patients in the ICU, and that hemostatic parameters, especially plasma AT levels, are also useful markers for organ failure and clinical outcome .

J Med Assoc Thai, 2004 May, 87(5), 573 - 7
Congenital tuberculosis presenting as sepsis syndrome; Chanta C et al.; A 20 day old male infant presented with fever, respiratory distress and poor feeding for 7 days . He was referred from a community hospital and diagnosed as sepsis . Physical examination revealed hepatosplenomegaly . A chest radiograph showed miliary infiltration of both lungs . Smear of gastric washing for AFB was positive . Congenital tuberculosis was diagnosed, the infant was successfully treated with antituberculous drugs and followed up monthly for 1 year . He had good health and normal development after the illness.

Cytometry, 2004 Jul, 60B(1), 14 - 22
Cytometric bead assay of cytokines in sepsis: a clinical evaluation; Vedrine C et al.; BACKGROUND: The clinical relevancy of an attractive new multiparametric method, cytometric beads assay (CBA), was evaluated for the monitoring of cytokines in sepsis . METHODS: A total of 52 samples (26 patients) were simultaneously tested by CBA and chemiluminescence (IL-6, IL-8, IL-1beta, and TNFalpha) or ELISA (IL-10, IL-12 p40, IL-12 p70, and soluble TNFalpha-RI) . RESULTS: CBA standard curves were linear from 20-5,000 ng/L except for IL-1beta (40-5,000 ng/L) . IL-6 and IL-8 were detected in 41 and 48 samples (44-5,000 ng/L and 22-5,000 ng/L), respectively, and out of range in six samples . IL-10 and IL-1beta were detected in 14 and 15 samples (21-1,548 ng/L and 29-582 ng/L), respectively . TNFalpha was rarely detected, and IL-12 p70 was never detected . Accuracy and repeatability were good (CV for IL-6 was 2.1-8.7%; for IL-8 3.7-5.3%; for IL-10 2.5-9.1%; for IL-12 5.2-6.5%; for IL-1 beta 4-12%; and for TNFalpha 3-19.3%) . Reproducibility of four standard curves and 20 samples (-1.1 to +1.03%) was excellent between tests done at two- to six-week intervals . CBA values were correlated (r2 > 0.89; P < 0.001) with our reference methods, but were lower on CBA (TNFalpha 45% +/- 8; IL-6 49% +/- 7), probably due to interactions with patients' serum, as confirmed by spiking diluted standards in one patient's serum with end stage renal failure and high levels of TNF soluble receptor (i.e., TNFalpha levels 34 and 21%) . CONCLUSIONS: Finally, these results suggest that IL-6, IL-8, IL-1beta, and Il-10 are clinically promising for sepsis evaluation . However, sensitivity of TNFalpha has to be improved and IL-12 p70 should be replaced with more relevant parameters such as TNF-R, procalcitonin, or neopterin .

J Reprod Med, 2004 May, 49(5), 387 - 8
Sepsis and multisystem organ failure in a woman attempting interval delivery in a triplet pregnancy: a case report; Hoffman MK et al.; BACKGROUND: Interval delivery of the fetuses in multiple gestations has been shown to increase perinatal survival . CASE: A woman attempting interval delivery of triplets at 21 weeks developed chorioamnionitis, acute respiratory distress syndrome and tubular necrosis 7 days after delivery of the first fetus . CONCLUSION: When counseling women about the typically favorable outcomes of delayed interval deliveries, physicians should also warn of the potential risk of complications.

J Am Soc Nephrol, 2004 Jul, 15(7), 1936 - 42
Late creation of vascular access for hemodialysis and increased risk of sepsis; Oliver MJ et al.; The creation of fistulas or grafts before starting dialysis is recommended, but whether it reduces major adverse events is largely unknown . The objective of this study was to determine if early access creation was associated with a reduced risk of hospitalization from sepsis and mortality . Fistulas or grafts created at least 4 mo before starting hemodialysis were defined as Early creations (n = 1240), and accesses created between 4 mo and 1 mo before starting hemodialysis were defined as Just Prior creations (n = 997) . Accesses created within 1 mo of starting dialysis or after were defined as Late creations (reference group, n = 3687) . Hemodialysis catheter use was defined as insertion, removal, or manipulation of a catheter before the occurrence of sepsis . Eighty percent of accesses were fistulas . Early access creation was associated with a relative risk (RR) of sepsis of 0.57 (95% CI, 0.41 to 0.79) compared with Late access creation . Catheter use increased the risk of sepsis by 1.41 (95% CI, 1.14 to 1.81) . The risk of sepsis with Early creation decreased to 0.48 (95% CI, 0.35 to 0.65) if catheter use was not adjusted . Early access creation was associated with lower mortality (RR 0.76; 95% CI 0.58 to 1.00), but this association became nonsignificant if catheter use and sepsis were adjusted . Catheter use and sepsis independently increased mortality . This study demonstrates that fistula creation at least 4 mo before starting chronic hemodialysis is associated the lowest risk of sepsis and death, primarily by reducing the use of hemodialysis catheters.

Khirurgiia (Mosk), 2004, (6), 39 - 41
{Problems of diagnosis of surgical sepsis in children}; Mironov PI; Results of treatment of 263 children with surgical sepsis aged from 3 to 14 years were analyzed . Diagnosis of sepsis was based on recommendations of ACCP/SCCM (1991) . For diagnosis of sepsis in children it is recommended to use criteria of syndrome of systemic inflammatory response (SSIR) in M.Parker's modification, scale of assessment of severity state - PRISM, classification of organ insufficiency by L.Doughty et al . Diagnosis of sepsis may be regarded as timely when 3 and more symptoms of SSIR persist in a child with pyoinflammatory disease during 24 hours of intensive care and in PRISM scale severity corresponding to experted lethality > or = 1,0% . When syndromes of multiorgan insufficiency are revealed, diagnosis of sepsis must be regarded as delayed.

Arch Dis Child Fetal Neonatal Ed, 2004 Jul, 89(4), F289 - 92
Early enteral feeding and nosocomial sepsis in very low birthweight infants; Flidel-Rimon O et al.; BACKGROUND: The interrelations between early enteral feeding, necrotising enterocolitis (NEC), and nosocomial sepsis (NS) remain unclear . OBJECTIVE: To evaluate the effect of age at the introduction of enteral feeding on the incidence of NS and NEC in very low birthweight (VLBW< 1500 g) infants . METHODS: Data were collected on the pattern of enteral feeding and perinatal and neonatal morbidity on all VLBW infants born in one centre during 1995-2001 . Enteral feeding was compared between infants with and without NS and/or NEC . RESULTS: The study sample included 385 infants . Of these, 163 (42%) developed NS and 35 (9%) developed NEC . Enteral feeding was started at a significantly earlier mean (SD) age in infants who did not develop nosocomial sepsis (2.8 (2.6) v 4.8 (3.7) days, p = 0.0001) . Enteral feeding was introduced at the same age in babies who did or did not develop NEC (3.1 (2) v 3.7 (3) days, p = 0.28) . Over the study period, the mean annual age at the start of enteral feeding fell consistently, and this correlated with the mean annual incidence of NS (r(2) = 0.891, p = 0.007) . Multiple logistic regression analysis showed age at start of enteral feeding, respiratory distress syndrome, and birth weight to be the most significant predictors of risk of NS (p = 0.0005, p = 0.024, p = 0.011) . CONCLUSIONS: Early enteral feeding was associated with a reduced risk of NS but no change in the risk of NEC in VLBW infants . These findings support the use of early enteral feeding in this high risk population, but this needs to be confirmed in a large randomised controlled trial.

Clin Infect Dis, 2004 Jul 1, 39(1), 38 - 46 Epub 2004 Jun 01.
Polyclonal immunoglobulin for treatment of bacterial sepsis: a systematic review; Pildal J et al.; Randomized trials of adjunctive treatment of bacterial sepsis with polyclonal immunoglobulin show conflicting results . We performed a systematic review and a meta-analysis of the results of randomized trials that compared reductions in mortality rates in patient groups treated with polyclonal immunoglobulin versus either placebo or no treatment in addition to conventional treatment . High-quality trials had adequate concealment of allocation, were double-blinded and placebo-controlled, and made data available for intention-to-treat analyses . Twenty trials were included . Meta-analysis of all trials showed a relative risk of death with immunoglobulin treatment of 0.77 (95% confidence interval {CI}, 0.68-0.88) . High-quality trials (involving a total of 763 patients, 255 of whom died) showed a relative risk of 1.02 (95% CI, 0.84-1.24), whereas other trials (involving a total of 948 patients, 292 of whom died) showed a relative risk of 0.61 (95% CI, 0.50-0.73) . Because high-quality trials failed to demonstrate a reduction in mortality, polyclonal immunoglobulin should not be used for treatment of sepsis except in randomized clinical trials.

Int J Artif Organs, 2004 May, 27(5), 352 - 9
Incidence and definition of sepsis and associated organ dysfunction; Dremsizov TT et al.; AIMS: To discuss the incidence, outcome and predisposing factors to systemic inflammatory response syndrome (SIRS), sepsis, and multiple organ failure . METHODS: A qualitative review of the literature . RESULTS: Case definitions of sepsis and severe sepsis, though clarified recently, are still arbitrary . It seems, however, that SIRS is not useful in identifying severe sepsis while organ failure has become a cornerstone for this definition . Incidence of severe sepsis appears to be approximately 10% of all ICU admissions, totaling nearly one million cases annually in the U.S . alone, and rising . Mortality associated with these events is still high, especially among ICU patients . Recent studies have been demonstrating an association between a variety of genetic polymorphisms and progression to and dying from sepsis . CONCLUSION: Recently there has been an increasing amount of information enabling characterization of the epidemiology of sepsis, which may help to direct appropriate care in the coming years.

Shock, 2004 Jul, 22(1), 46 - 50
Transcriptional regulation of cardiac sarcoplasmic reticulum calcium-ATPase gene during the progression of sepsis; Wu G et al.; Changes in sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) gene expression in the rat heart during different phases of sepsis were studied . Sepsis was induced by cecal ligation and puncture (CLP) . Septic rats were divided into two groups: the early hyperdynamic (9 h after CLP, early sepsis) and the late hypodynamic (18 h after CLP; late sepsis) groups . Western blot analyses reveal that SERCA2a protein level remained unaltered during early sepsis but was decreased by 59% during late sepsis . Northern blot analyses show that the steady-state level of SERCA2a mRNA stayed unchanged during the early phase but was decreased by 43% during the late phase of sepsis . Nuclear runoff assays show that the transcription rate of SERCA2a gene transcript remained unaffected during early sepsis but was decreased by 34% during late sepsis . The actinomycin D pulse-chase studies indicate that the half-life of SERCA2a mRNA was unaffected during the early and the late phases of sepsis . These findings demonstrate that during the early phase of sepsis, the protein level, the mRNA abundance, and the transcription rate of SERCA2a remained unaltered, whereas during the late phase of sepsis, the rate of transcription of SERCA2a was decreased, and the decreased transcription rate was associated with decreases in SERCA2a mRNA abundance and SERCA2a protein level in the rat heart . Based on these data, it is concluded that SERCA2a gene expression decreased during the late phase of sepsis in the rat heart and that the decreased expression was regulated at the transcriptional level.

Shock, 2004 Jul, 22(1), 40 - 5
Response of lung NK1.1-positive natural killer cells to experimental sepsis in mice; Hirsh M et al.; Natural killer cells (NKC) participate in the initiation of the immune response and coordination between innate and adaptive immune mechanisms . Their role in systemic inflammation induced by trauma or infection (sepsis) is still controversial . In the present study, lung NKC and their response to experimental sepsis were investigated . Mice were subjected to cecal ligation and puncture (CLP) to induce sepsis and acute lung injury (ALI) . Animals were sacrificed 1, 4, and 7 days postoperatively, and lung histopathology, pulmonary vascular permeability, and inflammatory cells accumulation were assessed . On day 4, parameters of ALI were most prominent, and lung NK1.1+CD3- cells were isolated and studied by flow cytometry . Although CLP did not change the absolute number of lung NKC (2.47 +/- 0.52 x 10(5)/lung compared with 2.97 +/- 0.27 x 10(5)/lung in the sham group), the peak of the CLP-induced ALI was associated with severe dysfunction of lung NKC . Cell cytotoxicity decreased to 25.1 +/- 2.4% (P = 0.002), and percentage of perforin-positive NKC to 2.7 +/- 0.5% (P = 0.03) . Cytokine profile of lung NK1.1+CD3- cells was prominently changed . The percentage of IFN-gamma-positive cells decreased to 19.7 +/- 5.7% (P = 0.047), but TNF-alpha-positive cells grew to 26.7 +/- 3.3% (P = 0.02) . In summary, severe CLP-induced dysfunction of lung NK1.1+CD-3 cells was demonstrated . This may influence the outcome of the animals during sepsis and acute lung damage.

Shock, 2004 Jul, 22(1), 34 - 9
Superoxide anion overproduction in sepsis: effects of vitamin e and simvastatin; Durant R et al.; Oxidative stress during sepsis induces tissue damage, leading to organ dysfunction and high mortality . The antioxidant effects of vitamin E have been reported in several diseases, but not in sepsis . Statins have cholesterol-independent anti-inflammatory effects that are related to a decrease of isoprenoid proteins and oxidative stress . Therefore, we evaluated superoxide anion (O2- degree) production and ex vivo effects of vitamin E and simvastatin in sepsis . Fourteen healthy volunteers, 14 intensive care unit (ICU) nonseptic, and 14 ICU patients with sepsis were included in this prospective study . Plasma cholesterol, triglyceride, and vitamin E levels were determined by routine laboratory tests . Superoxide anion production was measured in the venous blood by chemiluminescence technique after phorbol myristate acetate stimulation . Effects of vitamin E and simvastatin on O2- degree production was investigated ex vivo . Luminescence was indexed to the leukocyte count . We also investigated the in vitro effect of simvastatin on translocation of NADPH oxidase p21 Rac2 subunit in THP-1 monocytic cell line . The ratio of vitamin E/cholesterol + triglycerides was significantly decreased in septic as compared with nonseptic patients and volunteers . The O2- degree production was significantly higher in the group of septic patients than in the others, regardless of the polymorphonuclear leukocyte count . Vitamin E and simvastatin induced ex vivo an inhibition of O2- degree production of 20% and 40% respectively . In vitro, simvastatin inhibited phorbol myristate acetate-induced- O2- degree production by monocytes through NADPH oxidase inactivation . We conclude that sepsis is associated with a significant decrease in vitamin E and an overproduction of O2- degree . Vitamin E and simvastatin lessen this phenomenon through NADPH oxidase inactivation.

Shock, 2004 Jul, 22(1), 29 - 33
Expression profiling: toward an application in sepsis diagnostics; Prucha M et al.; Sepsis is a common and serious health problem whereby improvements in diagnosis are crucial in increasing survival rates . To test whether profiling transcription is applicable to sepsis diagnosis, we analyzed whole blood using a microarray containing probes for 340 genes relevant to inflammation . The patient's gene expression pattern was highly homogenous, resulting in 69% of differentially expressed genes . With a positive predictive value of 98%, a list of 50 differentially expressed genes was compiled, and randomly chosen transcripts were confirmed by PCR . Here, we present the first evidence that microarrays can identify typical gene expression profiles in the blood of patients with severe sepsis . Regardless of the heterogeneity of the patients, we observed a striking correlation between the conventional diagnostic classification and our approach . The unity of responses suggests that the principle of this multiparameter approach can be adapted to early stage sepsis diagnosis.

Am J Med Sci, 2004 Jun, 327(6), 369 - 72
Capnocytophaga canimorsus sepsis with purpura fulminans and symmetrical gangrene following a dog bite in a shelter employee; Deshmukh PM et al.; The authors describe a fatal case of purpura fulminans with symmetrical peripheral gangrene and sepsis caused by Capnocytophaga canimorsus in a 45-year-old, previously healthy woman who was bitten by a dog at an animal shelter where she was employed . Absent in this patient were the usual risk factors, including immunosuppression, alcohol abuse, corticosteroid therapy, and splenectomy . The patient's presentation to the emergency room late in the course of the infection probably effected her death . C canimorsus should be strongly suspected in any case of septicemia following a dog bite . Prompt therapy may influence the potentially fatal course of systemic infection . Employees and/or volunteers who work in animal shelters should be cognizant of the potential risks of a dog or cat bite and follow recommended procedures when such an incident occurs.

Eur J Surg Suppl, 2003 Jul, (588), 23 - 7
Quality of life, morbidity, and mortality after surgical intensive care: a follow-up study of patients treated for abdominal sepsis in the surgical intensive care unit; Haraldsen P et al.; OBJECTIVE: To evaluate the long-term outcome of patients treated in the surgical intensive care unit (SICU) for abdominal sepsis . DESIGN: Retrospective study . SETTING: University hospital, Sweden . SUBJECTS: 210 consecutive patients treated for abdominal sepsis in the SICU at Lund University Hospital during the period January 1983 to December 1995 . MAIN OUTCOME MEASURES: Background information, morbidity, and mortality . Follow-up of surviving patients with interview and completion of a quality of life (QoL) assessment . Information collected postmortem from the registers of the Swedish National Board of Health and Welfare . RESULTS: At follow-up, 45 patients of the 151 who survived the initial hospital stay had died, 41 were lost to follow up and 16 chose not to participate in the study; 49 patients completed the study . Median QoL scores were significantly impaired (p < 0.01) although subjective QoL did not change significantly . In-hospital mortality was 28% (59/210) and total mortality over the time period 50% (104/210) . CONCLUSION: Most patients who survived after treatment of abdominal sepsis in the SICU regained good health and their functional status was restored . Subjective QoL remained unchanged.

Therapie, 2004 Jan-Feb, 59(1), 31 - 40
{Role of endothelial dysfunction in sepsis mortality}; Metais C et al.; During the past decade, a unifying hypothesis has been developed to explain the vascular changes that occur in septic shock on the basis of the effect of inflammatory mediators on the vascular endothelium . The vascular endothelium plays a central role in the control of microvascular flow, and it has been proposed that widespread vascular endothelial activation, dysfunction and eventually injury occur in septic shock, ultimately resulting in multiorgan failure . This has been characterised in various models of experimental septic shock . Now, direct and indirect evidence for endothelial cell alteration in humans during septic shock is emerging . The present review details recently published literature on this rapidly evolving topic.

J Lab Clin Med, 2004 Jun, 143(6), 352 - 7
Effects of dichloroacetate and ubiquinone infusions on glycolysis activity and thermal sensitivity during sepsis; L'Her E et al.; Energy-metabolism disturbances during sepsis are characterized by enhanced glycolytic fluxes and reduced mitochondrial respiration . However, it is not known whether these abnormalities are the result of a specific mitochondrial alteration, decreased pyruvate dehydrogenase (PDH) complex activity, depletion of ubiquinone (CoQ(10); electron donor for the mitochondrial complex III), or all 3 . In this study we sought to specify metabolism disturbances in a murine model of sepsis, using either a PDH-activator infusion (dichloroacetate, DCA) or CoQ(10) supplementation . After anesthesia, Sprague-Dawley rats received intravenous saline solution (control; n = 5), DCA (n = 5; 20 mg/100 g), or CoQ(10) (n = 5; 1 mg/100 g), before the induction of sepsis . Increased plasma lactate levels and increased muscle glucose content were observed after 4 hours in the control group . In the DCA group, a decrease in the muscle content of lactate (P <.05) and an increase in muscle glucose content (P <.05) were observed at 4 hours, but no lactatemia variation was noted . In the CoQ(10) group, only increased plasma lactate levels were observed . Increased muscle glycolysis fluxes were observed after 4 hours in the control group, but to a slighter degree in both the DCA and CoQ(10) groups . Only DCA restored a normal temperature sensitivity in the hyperthermia range, but we noted no differences in survival time . In conclusion, only DCA infusion restores normal glycolysis function.

Crit Care Med, 2004 May, 32(5), 1100 - 8
CD14 receptor occupancy in severe sepsis: results of a phase I clinical trial with a recombinant chimeric CD14 monoclonal antibody (IC14); Reinhart K et al.; OBJECTIVE: Binding of bacterial cell wall components to CD14 and co-receptors on myeloid cells results in cellular activation and production of proinflammatory mediators . A recombinant anti-CD14 monoclonal antibody (IC14) has been shown to decrease lipopolysaccharide-induced responses in animal and human models of endotoxemia . This study was performed to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical pharmacology of IC14 in patients with severe sepsis . DESIGN: Randomized, double-blind, placebo-controlled, dose-ranging, multiple-center trial . SETTING: Six medical and surgical intensive care units located in Germany and The Netherlands . PATIENTS: Forty patients with severe sepsis . INTERVENTIONS: IC14 was administered intravenously to eight patients/cohort as single (1 mg/kg or 4 mg/kg) or multiple doses (4 mg/kg daily for 4 days, or 4 mg/kg on day 1 followed by 2 mg/kg daily for 3 days) . A placebo group (two patients/cohort) was also included . MEASUREMENTS AND MAIN RESULTS: The overall incidence and types of adverse events were similar among treatment groups . One patient in the group receiving multiple-dose IC14 4 mg/kg daily for 4 days experienced an anaphylactic reaction after receiving the first dose of study drug . IC14 did not induce antibody formation or increase the incidence of secondary bacterial infection . A mean IC14 serum concentration of approximately 1 microg/mL was required to achieve 50% of maximum membrane-bound CD14 receptor occupancy on peripheral blood monocytes . The pattern of proinflammatory and anti-inflammatory cytokines, chemokine, soluble receptor, soluble E-selectin, and acute phase proteins in response to treatment was highly variable by patient and IC14 treatment group . CONCLUSIONS: Single and multiple doses of IC14 were generally well tolerated and did not induce antibody formation or increase the incidence of secondary bacterial infection . The results suggest that CD14 blockade with IC14 warrants further clinical investigation to determine its ability to attenuate the proinflammatory response due to infection.

Chest, 2004 Jun, 125(6), 2238 - 46
Serum levels of the apoptosis-associated molecules, tumor necrosis factor-alpha/tumor necrosis factor type-I receptor and Fas/FasL, in sepsis; De Freitas I et al.; STUDY OBJECTIVE:s: Numerous reports suggest that apoptosis may play an important role in the sepsis syndrome . The objective of the present study was to examine the levels of molecules associated with apoptosis belonging to the tumor necrosis factor (TNF)-alpha/TNF type-I receptor (TNFRI) and Fas ligand (FasL)/Fas receptor (Fas) pathways in patients with sepsis . PATIENTS AND METHODS: Twenty-two patients with sepsis (14 patients with severe sepsis and 8 patients with sepsis), and 6 healthy volunteers were evaluated . Sequential analysis of the serum levels of TNF-alpha, TNFRI, FasL, and Fas were performed in these patients using enzyme-linked immunosorbent assays . RESULTS: Detectable levels of TNF-alpha were found in only 8 of 14 patients with severe sepsis . Patients with severe sepsis and sepsis had similarly increased levels of FasL, compared with healthy individuals (p < 0.05) . Higher levels of TNFRI and Fas were found in patients with severe sepsis than in patients with sepsis and healthy volunteers (p < 0.001 and p < 0.01, respectively) . Fas levels were also higher in patients who died than in those who survived (p < 0.01) . A direct relationship was found between serum levels of TNFRI and Fas, and multiorgan dysfunction (sequential organ failure assessment score) {p < 0.0001} . CONCLUSIONS: These results suggest that the TNF-alpha/TNFRI and FasL/Fas systems may be involved in the pathogenesis of sepsis . Serum levels of the death-receptors, TNFRI and Fas, could serve as potential markers of the severity of human sepsis.

Chest, 2004 Jun, 125(6), 2206 - 16
Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis; Bernard GR et al.; STUDY OBJECTIVE: To gather additional 28-day all-cause mortality and safety data among adult patients with severe sepsis who were treated with drotrecogin alfa (activated) . DESIGN: Prospective, single-arm, multicenter clinical trial . SETTING: Eighty-five study sites in the United States and two in Puerto Rico . PARTICIPANTS: Adult patients (273 patients) with a diagnosis of severe sepsis, which was defined as a systemic inflammatory response due to acute infection and one or more sepsis-induced organ dysfunctions present for </= 48 h, as in the recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial . INTERVENTIONS: Drotrecogin alfa (activated) {Xigris; Eli Lilly and Company; Indianapolis, IN}, 24 micro g/kg/h, as a continuous IV infusion for a duration of 96 +/- 1 h . MEASUREMENTS AND RESULTS: The primary end point was all-cause mortality, which was assessed 28 days after the start of the infusion of drotrecogin alfa (activated) . Serious bleeding was monitored to day 28 . Comparisons of mortality were made to treatment groups from two double-blind, placebo-controlled clinical trials (PROWESS United States and the Secretory Phospholipase A2 Inhibitor {sPLA2I} in Severe Sepsis trial) that used similarly defined patient populations from the United States . For the 273 adult patients enrolled in this study, the 28-day all-cause mortality rate was 26.4% . This mortality rate was 6% lower than that observed in the placebo groups in the PROWESS US trial (32.9%) and the sPLA2I trial (33.2%), and was similar to that of the group treated with drotrecogin alfa (activated) in the PROWESS US trial (24.4%) . One nonfatal intracranial hemorrhage was reported in the Extended Evaluation of Recombinant Human Activated Protein C United States trial (ENHANCE US) {0.35%} . Serious bleeding events during the infusion period occurred in 11 patients (4.0%) compared to 10 patients (2.8%) in the PROWESS US drotrecogin alfa (activated) treatment group . CONCLUSIONS: Despite the limitations associated with comparisons across trials, this study provides confirmatory evidence of the efficacy and safety of drotrecogin alfa (activated) documented in the PROWESS trial.

J Immunol, 2004 Jun 15, 172(12), 7583 - 91
Akt decreases lymphocyte apoptosis and improves survival in sepsis; Bommhardt U et al.; Sepsis induces extensive death of lymphocytes that may contribute to the immunosuppression and mortality of the disorder . The serine/threonine kinase Akt is a key regulator of cell proliferation and death . The purpose of this study was to determine whether overexpression of Akt would prevent lymphocyte apoptosis and improve survival in sepsis . In addition, given the important role of Akt in cell signaling, T cell Th1 and Th2 cytokine production was determined . Mice that overexpress a constitutively active Akt in lymphocytes were made septic, and survival was recorded . Lymphocyte apoptosis and cytokine production were determined at 24 h after surgery . Mice with overexpression of Akt had a marked improvement in survival compared with wild-type littermates, i.e., 94 and 47% survival, respectively, p < 0.01 . In wild-type littermates, sepsis caused a marked decrease in IFN-gamma production, while increasing IL-4 production >2-fold . In contrast, T cells from Akt transgenic mice had an elevated production of IFN-gamma at baseline that was maintained during sepsis, while IL-4 had little change . Akt overexpression also decreased sepsis-induced lymphocyte apoptosis via a non-Bcl-2 mechanism . In conclusion, Akt overexpression in lymphocytes prevents sepsis-induced apoptosis, causes a Th1 cytokine propensity, and improves survival . Findings from this study strengthen the concept that a major defect in sepsis is impairment of the adaptive immune system, and suggest that strategies to prevent lymphocyte apoptosis represent a potential important new therapy.

Am J Physiol Endocrinol Metab, 2004 Oct, 287(4), E721 - 30 Epub 2004 Jun 08.
Differential effect of sepsis on ability of leucine and IGF-I to stimulate muscle translation initiation; Lang CH et al.; Polymicrobial sepsis impairs skeletal muscle protein synthesis, which results from impairment in translation initiation under basal conditions . The purpose of the present study was to test the hypothesis that sepsis also impairs the anabolic response to amino acids, specifically leucine (Leu) . Sepsis was induced by cecal ligation and puncture, and 24 h later, Leu or saline (Sal) was orally administered to septic and time-matched nonseptic rats . The gastrocnemius was removed 20 min later for assessment of protein synthesis and signaling components important in peptide-chain initiation . Oral Leu increased muscle protein synthesis in nonseptic rats . Leu was unable to increase protein synthesis in muscle from septic rats, and synthetic rates remained below those observed in nonseptic + Sal rats . In nonseptic + Leu rats, phosphorylation of eukaryotic initiation factor (eIF)4E-binding protein 1 (4E-BP1) in muscle was markedly increased compared with values from time-matched Sal-treated nonseptic rats . This change was associated with redistribution of eIF4E from the inactive eIF4E.4E-BP1 to the active eIF4E.eIF4G complex . In septic rats, Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E distribution were completely abrogated . Sepsis also antagonized the Leu-induced increase in phosphorylation of S6 kinase 1 and ribosomal protein S6 . Sepsis attenuated Leu-induced phosphorylation of mammalian target of rapamycin and eIF4G . The ability of sepsis to inhibit anabolic effects of Leu could not be attributed to differences in plasma concentrations of insulin, insulin-like growth factor I, or Leu between groups . In contrast, the ability of exogenous insulin-like growth factor I to stimulate the same signaling components pertaining to translation initiation was not impaired by sepsis . Hence, sepsis produces a relatively specific Leu resistance in skeletal muscle that impairs the ability of this amino acid to stimulate translation initiation and protein synthesis.

Clin Perinatol, 2004 Mar, 31(1), 53 - 67
The role of molecular genetics in the pathogenesis and diagnosis of neonatal sepsis; Del Vecchio A et al.; Polymorphisms within genes encoding endogenous mediators of inflammation are good candidates for the individual differences in systemic inflammatory responses of neonates to infection . Ina similar manner, polymorphisms in the genes encoding drug metabolizing enzymes, drug transporters, and drug receptors can influence a neonate's risk of an adverse drug reaction or can alter the efficacy of drug treatment . Additionally, molecular tools are proving valuable in the diagnosis of neonatal infection . This article gives an overview of the genetic susceptibility to sepsis, discusses the use of molecular genetics in diagnostic tests for infection, and reviews the potential for more effective and specific therapies for sepsis based on genetic variability.

Zhongguo Wei Zhong Bing Ji Jiu Yi Xue, 2004 Jun, 16(6), 355 - 7
{Alterations in myocardial function in early stage of sepsis in rabbits}; Pan XJ et al.; OBJECTIVE: To study the alterations in myocardial function in early stage of sepsis . METHODS: Twenty rabbits were randomly divided into two groups . In the control group (n=10) only laparotomy was done, and in the sepsis group the animals received cecal ligation and puncture (CLP) . In both groups left ventricular catheter was placed via right internal carotid artery . Left ventricular systolic peak pressure (LVSP), maximal positive change in filling pressure versus time (+dp/dt max), maximal negative change in filling pressure versus time (-dp/dt max) were monitored, and serum troponin I (TnI) was measured per hour for five times (0, 1, 2, 3, 4 hours after operation) . RESULTS: Compared to the basic levels, LVSP, +dp/dt max and -dp/dt max decreased significantly an hour after CLP in sepsis group (all P<0.05), with the tendency of decrease with elapse of time . Serum TnI increased significantly an hour after CLP in sepsis group, and continued to increase with the passage of time . In contrast, no significant change was observed in control group . CONCLUSION: Cardiac muscle is injured, and myocardial systolic and diastolic functions are depressed in early stage of sepsis in rabbit model.

Zhongguo Wei Zhong Bing Ji Jiu Yi Xue, 2004 Jun, 16(6), 352 - 4
{Change in intestinal function in sepsis in rat}; Li JY et al.; OBJECTIVE: To study the barrier function, absorption, permeability and peristalsis of intestine in sepsis in rats . METHODS: A Wistar rat model of sepsis was reproduced by ischemia/reperfusion (I/R) of the intestine combined with endotoxin challenge . Animal were randomly divided into normal, I/R 1 hours (I/R 1), I/R 2 hours (I/R 2), I/R 4 hours (I/R 4) and I/RL groups . The following parameters were measured in the experiments: (1) diamin oxidase activity (DAO), D-lactate and D-xylose levels in blood using spectrophotometry; (2) transit function of small intestine; (3) pathological examination of small intestine by light microscope . RESULTS: The results showed that plasma DAO activity was increased in I/R 1, I/R 4 and I/RL (all P<0.05), and small intestinal tissue DAO was decreased in I/R 2 and I/RL (both P<0.05) . Negative correlations were found between plasma and intestinal DAO (r=-0.909, P<0.001) . Plasma D-lactate was elevated significantly in I/R 1, I/R 2, and I/RL (all P<0.05) . D-xylose content was increased at I/R1 and I/RL groups (both P<0.05), and it was significantly higher than controls at 3 hours . Similarly, a positive correlation was found between plasma DAO activity and plasma D-lactate level (r=0.559, P<0.05) . CONCLUSION: The intestinal barrier function, absorption function, permeability, and transit are impaired after gut ischemia/reperfusion combined with endotoxin challenge.

Ann Med, 2004, 36(3), 194 - 203
Comparison of mechanisms after post-hoc analyses of the drotrecogin alfa (activated) and antithrombin III trials in severe sepsis; Wiedermann CJ et al.; Severe sepsis is a heterogeneous syndrome in a heterogeneous population . The current scheme of classification does not enable distinction between systemic inflammatory response syndrome, sepsis and severe sepsis on the basis of the underlying biochemical, immunological and abnormal coagulation features . Planning, implementation and assessment of results of intervention studies on severe sepsis thus present enormous challenges . Two such studies were published in the year 2001 . The study investigating the drug drotrecogin alfa (activated) was positive in the day-28 mortality endpoint; however, post-hoc analyses have raised controversies regarding the manner in which the study was carried out, the consistency of results presented, and the suggested mechanism of action . On the other hand, the KyberSept study that investigated antithrombin III reported negative results for the day-28 mortality endpoint, despite correct performance of the study . This, however, was not interpreted to mean proof of therapeutic inefficacy of administering antithrombin III and post-hoc analyses raise the suspicion of an undesirable drug interaction between antithrombin III and heparin . Apparently, neither of the sepsis studies meets the criteria which lie at the basis of critical assessment of the success or failure of clinical trials that could more significantly affect clinical treatment decisions.

Ned Tijdschr Geneeskd, 2004 May 15, 148(20), 975 - 8
{Sepsis, a complicated syndrome with major medical and social consequences}; Bakker J et al.; Severe sepsis is a life-threatening complication of infection . Due to associated organ-failure treatment in an Intensive Care Unit is usually indicated . Since sepsis is defined by the combination and progression of clinical events, correct definitions are essential to enable good comparison between study results and determination of suitable treatment . Severe sepsis is associated with a mortality of 20-60% and decreases the health-related quality of life in survivors . It is estimated that annually in the Netherlands 9000 patients are admitted to an Intensive Care Unit with severe sepsis . Direct medical costs of severe sepsis are estimated at {symbol: see text} 19,500 per patient . Costs correlate strongly with the length of stay . Annually Euro dollar 168,6 million is spent on severe sepsis, which represents 0.5% of all health-care costs and 1.7% of the annual hospital budget in the Netherlands.

Minerva Anestesiol, 2004 May, 70(5), 417 - 23
{Identification of the patient with sepsis}; Rossi B et al.; Sepsis may be defined as a clinical syndrome caused by an organism's response to infection . The complex alterations triggered by the infection include inflammation and systemic coagulopathy in the absence of effective fibrinolysis . Possible manifestations vary in entity and severity, ranging from systemic inflammatory response syndrome (SIRS) to septic shock and multiorgan dysfunction syndrome (MODS) . The nurse can play a fundamental role in the timely recognition of SIRS and in the early identification of the onset of signs of organ damage . In this way, an additional aid to establishing diagnosis can be provided and targeted treatment instituted . Following a brief presentation of the pathophysiology and epidemiology of sepsis, the manifestations and attendant risks are described, the most appropriate monitoring methods and the main nursing tasks in treating sepsis are discussed . We present the results of our experience in identifying patients with sepsis through the application of selection criteria adopted from clinical studies on the use of activated protein C.

Minerva Anestesiol, 2004 May, 70(5), 365 - 71
Ethyl pyruvate: a novel treatment for sepsis and shock; Fink MP; Pyruvic acid is a simple 3 carbon a-keto-monocarboxylic acid . Recognition that pyruvate is an effective scavenger of reactive oxygen species (ROS) prompted investigators to use it as therapeutic agent for various pathological conditions that are thought to be mediated by redox dependent phenomena, like myocardial, intestinal or hepatic ischemia/reperfusion-induced injury . Ethyl Pyruvate showed to be more effective and safer than equimolar doses of sodium pyruvate . Ethyl Pyruvate showed to have anti-inflammatory effects . In animal models Ethyl Pyruvate improved hyperpermeability and bacterial translocation due to endotoxemia and improved the development of renal disfunction as well as some of the morphological findings of kidney injury . The pharmacological basis for the anti-inflammatory effects of EP remains to be explained . It is plausible that EP mediates suppression of NF-KB activation and secretion of NO and of pro-inflammatory cytokines.

Minerva Anestesiol, 2004 May, 70(5), 339 - 50
{Protein C and coagulation in sepsis}; D'Angelo A et al.; The last few years have clarified the tight link between inflammation and coagulation . In addition to the identification of new regulatory mechanisms of the coagulation system and of an explosive number of mediators of inflammation, it is now clear that the existence of a positive feed-back between inflammation and coagulation leads to reciprocal activation of both pathways . Plasma levels of acute phase proteins involved in coagulation and fibrinolysis are elevated during inflammation, while natural anticoagulant mechanisms are depressed . Pro-inflammatory cytokines "activate" cell membranes exposed to flowing blood (endothelium, platelets, monocytes, neutrophils) which from physiologically inert or anticoagulant become procoagulant . Increased tissue factor expression results in increased thrombin formation within the microcirculation . Thrombin is central to fibrin deposition but it also plays a key role in cell-mediated mechanisms involving inflammation, cell proliferation and activation of the natural anticoagulant protein C . Depression of natural anticoagulant mechanisms, occurring in severe sepsis, results in uncontrolled thrombin formation, with pro-inflammatory activity prevailing, and the feed-back loop of inflammation and coagulation ultimately leading to multi-organ failure . However, both in the clinical setting and in animal experiments, heparin or direct anticoagulants have shown no effect on survival even if blocking fibrin deposition . Organ failure is only partially due to the thrombotic occlusion of the microcirculation, while other mechanisms of endothelial damage are probably more relevant in the development of ischemia . The endothelium is central to the maintenance of the natural anticoagulant mechanisms (TFPI, antithrombin, protein C) . The protein C system, in addition to dumping thrombin formation, specifically modulates inflammation by cell signaling . This system is markedly depressed in severe sepsis . The infusion of activated protein C, or restoring normal levels of protein C within the circulation - depending on the individual bleeding risk are powerful tools to treat the endothelitis responsible for the clinical sequelae of severe sepsis.

J Clin Invest, 2004 Jun, 113(11), 1641 - 50
Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response; Liliensiek B et al.; While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation . The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation . Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response . However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture . Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells . These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation.

J Appl Physiol, 2004 Oct, 97(4), 1349 - 57 Epub 2004 May 28.
Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model; Cui X et al.; Previous analysis showed that selective inhibitors of five different host inflammatory mediators administered for sepsis, although beneficial with severe sepsis and high-control mortality rates, were ineffective or harmful with less severe sepsis . We hypothesized that severity of sepsis would also influence inhibition of superoxide anion, another inflammatory mediator . To test this, 6-h infusions of M40401, a selective SOD mimetic, or placebo were given to antibiotic-treated rats (n=547) starting 3 h after challenge with differing doses of intravenous Escherichia coli designed to produce low- or high-control mortality rates . There was a positive and significant (P=0.0008) relationship between the efficacy of M40401 on survival rate and control mortality rates . M40401 increased or decreased the log (odds ratio of survival) (means +/- SE), dependent on whether control mortality rates were greater or less than the median (66%) (+0.19 +/- 0.12 vs . -0.25 +/- 0.10, P=0.01) . In a subset of animals examined (n=152) at 9 h after E . coli challenge, M40401 increased (mean effect +/- SE compared with control) mean arterial blood pressure (8 +/- 5 mmHg) and decreased platelets (-37 +/- 22 cells x 10(3)/ml) with high-control mortality rates but had opposing effects on each parameter (-3 +/- 3 mmHg and 28 +/- 19 cells x 10(3)/ml, respectively) with low rates (P < or = 0.05 for the differing effects of M40401 on each parameter with high- vs . low-control mortality rates) . A metaregression analysis of published preclinical sepsis studies testing SOD preparations and SOD mimetics showed that most (16 of 18) had control mortality rates >66% . However, across experiments from published studies, these agents were less beneficial as control mortality rate decreased (P=0.03) in a relationship not altered (P=not significant) by other variables associated with septic challenge or regimen of treatment and which was similar, compared with experiments with M40401 (P=not significant) . Thus, in these preclinical sepsis models, possibly related to divergent effects on vascular function, inhibition of superoxide anion improved survival with more severe sepsis and high-control mortality rates but was less effective or harmful with less severe sepsis . Extrapolated clinically, inhibition of superoxide anion may be most efficacious in septic patients with severe sepsis and a high risk of death.

J Perinatol, 2004 Jun, 24(6), 389 - 91
Actinomyces species and cerclage placement in neonatal sepsis: a case report; Knee DS et al.; A 26-year-old female with a history of preterm labor and cerclage placement presented at 29 weeks gestation . Twin girls were delivered at 2917 weeks . Twin A presented with clinical sepsis at birth . Twin A's blood cultures became positive for Actinomyces species on day of life 15 . Despite aggressive medical management twin A died at 35 days of life.

Shock, 2004 Jun, 21(6), 549 - 55
Isolation of bona fide differentially expressed genes in the 18-hour sepsis liver by suppression subtractive hybridization; Hsieh YC et al.; In late sepsis, it has been established that the liver plays a major role in the initiation of multiorgan failure, which is the most lethal complication in hospitals . The molecular mechanism underlying liver failure that results from sepsis remains elusive . This study was undertaken to identify the bona fide differentially expressed genes in the 18-h septic liver by suppression subtractive hybridization, and the data were corroborated by Northern blot analysis . The differential gene expression profile renders a clue as to the genes involved in septic liver failure . The cecal ligation and puncture (CLP) model of a polymicrobial septic rat was used, with the late sepsis referring to animals sacrificed at 18 h after CLP . We have identified three upregulated genes (TII-kininogen, serine protease inhibitor 2.2 {Spi2.2}, and alpha 2 macroglobulin {alpha M}) and six down-regulated genes (hydroxysteroid dehydrogenase {3 alpha HSD}, EST189895/mouse RNase4, bile acid-CoA-amino acid N-acyltransferase {kan-1/rBAT}, IF1, albumin, and alpha 2u-globulins {alpha 2u-G PGCL1}) . Among these genes, the 3 alpha HSD and kan-1/rBAT are involved in bile acid metabolism . The IF1 plays a crucial role in any disease that involves ATP hydrolysis by F1F0-ATPase . The alpha 2M, TII-kininogen, and Spi2.2 are protease inhibitors . The functions of the alpha 2u-G PGCL1 and EST189895/mouse RNase4 genes are unknown . The present results suggest that the roles of disturbance of bile acid metabolism/synthesis and the abolishment of ATP production may contribute to liver failure during late sepsis.

Shock, 2004 Jun, 21(6), 505 - 11
Cecal ligation and puncture versus colon ascendens stent peritonitis: two distinct animal models for polymicrobial sepsis; Maier S et al.; Colon ascendens stent peritonitis (CASP) and cecal ligation and puncture (CLP), two animal models designed to closely mimic the clinical course of intra-abdominal sepsis, were compared . In the past, immunomodulatory therapies developed in animal studies failed to be successful in humans . As a consequence, the established animal sepsis models were criticized . It has been proposed that present models had to be reevaluated, and new, clinically more relevant models should be evolved . CLP procedure was performed puncturing once (CLP{1}) or twice (CLP{2}) the ligated cecum of C57BL/6 mice . In the CASP model, a stent with defined diameter was surgically inserted into the ascending colon . Survival, bacterial load, immunohistochemistry, and serum cytokine levels were analyzed in the groups . Survival after CASP procedure correlated strongly with the stent diameter, whereas the number of punctures in CLP did not significantly change survival rate . Bacterial loads of peritoneal lavage, liver, and lung, as well as serum cytokine levels (tumor necrosis factor, interleukin 1 beta, interleukin 10) steadily increased from 6 to 24 h after the CASP procedure . In contrast, continuously low amounts of bacteria and cytokines were found in CLP mice at any point of time . Twenty-four hours after CLP surgery, the ligated cecum was covered by adhesive small bowel loops, whereas in CASP mice, the intestinal leakage was then still present . The CASP model mimics closely the clinical course of diffuse peritonitis with early and steadily increasing systemic infection and inflammation (systemic inflammatory response syndrome) . In contrast, CLP reveals a model of intra-abdominal abscess formation with sustained and minor signs of systemic inflammation.

Blood Coagul Fibrinolysis, 2004 Jan, 15(1), 39 - 43
The effect of fibrinogen concentrate administration on coagulation abnormalities in a rat sepsis model; Kaspereit F et al.; Disseminated intravascular coagulation is a disorder that affects the function of the clotting system and is frequently associated with sepsis or septic shock . One of its leading symptoms is the decrease in circulating fibrinogen . We investigated the effect of fibrinogen concentrate (Haemocomplettan P) on fibrinogen plasma levels, coagulation parameters and mortality in a rat model of sepsis-induced disseminated intravascular coagulation . The disseminated intravascular coagulation was characterized by elevated thrombin-antithrombin complex and a sharp drop in circulating fibrinogen . Coagulation abnormalities were evaluated by thrombelastography . Plasma fibrinogen levels decreased from 2.06 +/- 0.2 to 0.16 +/- 0.1 g/l following administration of bacterial lipopolysaccharide . Thrombelastographic measurements revealed a concurrent decrease in maximum amplitude and an increase in reaction time . Treatment with fibrinogen concentrate (Haemocomplettan P, 25-200 mg/kg body weight intravenously) resulted in a statistically significant dose-dependent increase in fibrinogen plasma levels and amelioration of the measured coagulation abnormalities . Fibrinogen plasma concentrations were restored to normal levels when 200 mg/kg body weight fibrinogen concentrate was administered . A significant decrease in sepsis-induced mortality was observed in animals treated with Haemocomplettan P .

Curr Opin Crit Care, 2004 Jun, 10(3), 208 - 12
Postresuscitation disease after cardiac arrest: a sepsis-like syndrome?
Adrie C, Laurent I, Monchi M, Cariou A, Dhainaou JF, Spaulding C.
PURPOSE OF REVIEW: Despite advances in cardiac arrest resuscitation, neurologic impairments and other organ dysfunctions cause considerable mortality and morbidity after restoration of spontaneous cardiac activity . The mechanisms underlying this postresuscitation disease probably involve a whole-body ischemia and reperfusion syndrome that triggers a systemic inflammatory response . RECENT FINDINGS: Postresuscitation disease is characterized by high levels of circulating cytokines and adhesion molecules, the presence of plasma endotoxin, and dysregulated leukocyte production of cytokines: a profile similar to that seen in severe sepsis . Transient myocardial dysfunction can occur after resuscitation, mainly as a result of myocardial stunning . However, early successful angioplasty is independently associated with better outcomes after cardiac arrest associated with myocardial infarction . Coagulation abnormalities occur consistently after successful resuscitation, and their severity is associated with mortality . For example, plasma protein C and S activities after successful resuscitation are lower in nonsurvivors than in survivors . Low baseline cortisol levels may be associated with an increased risk of fatal early refractory shock after cardiac arrest, suggesting adrenal dysfunction in these patients . SUMMARY: Postresuscitation abnormalities after cardiac arrest mimic the immunologic and coagulation disorders observed in severe sepsis . This suggests that therapeutic approaches used recently with success in severe sepsis should be investigated in patients successfully resuscitated after cardiac arrest.

Curr Opin Infect Dis, 2004 Jun, 17(3), 205 - 11
Activated protein C in sepsis: emerging insights regarding its mechanism of action and clinical effectiveness; Haley M et al.; PURPOSE OF REVIEW: Dysregulation of endogenous coagulant and anticoagulant systems is now believed to play an important role in the pathogenesis of sepsis and septic shock . Reductions in host activated protein C levels and resultant microvascular thrombosis provided a basis for the use of recombinant human activated protein C in sepsis . Although controversial, the findings from an initial phase III trial testing this agent resulted in its approval for use in patients with severe sepsis and high risk of death . This review highlights emerging insights into the biology of protein C and activated protein C in sepsis, summarizes additional analysis growing out of the phase III trial testing recombinant human activated protein C, and assesses the cost-effectiveness that the clinical use of the agent has had thus far . RECENT FINDINGS: Binding of activated protein C to the endothelial cell protein C receptor is recognized to result in a growing number of actions including increased activity of activated protein C itself and inhibition of both nuclear factor-kappaB, a central regulator in the host inflammatory response, and apoptosis . Additional analysis of the original phase III trial testing recombinant human activated protein C appears to emphasize one of the US Food and Drug Administration's original concerns regarding an association between severity of sepsis and this agent's effects . Postmarketing analysis and growing experience with other anticoagulant agents and corticosteroids in sepsis raise questions regarding the ultimate cost-effectiveness of activated protein C . SUMMARY: The protein C pathway is important both to coagulant and inflammatory pathways during sepsis . Based on emerging investigations, its actions appear to be increasingly complex ones . Despite potentially promising results in an initial phase III trial, the role of recombinant human activated protein C in the treatment of septic patients must continue to be evaluated.

Clin Chem, 2004 Aug, 50(8), 1301 - 14 Epub 2004 May 27.
Toward resolving the challenges of sepsis diagnosis; Carrigan SD et al.; Sepsis in the United States has an estimated annual healthcare cost of 16.7 billion dollars and leads to 120,000 deaths . Insufficient development in both medical diagnosis and treatment of sepsis has led to continued growth in reported cases of sepsis over the past two decades with little improvement in mortality statistics . Efforts over the last decade to improve diagnosis have unsuccessfully sought to identify a "magic bullet" proteic biomarker that provides high sensitivity and specificity for infectious inflammation . More recently, genetic methods have made tracking regulation of the genes responsible for these biomarkers possible, giving current research new direction in the search to understand how host immune response combats infection . Despite the breadth of research, inadequate treatment as a result of delayed diagnosis continues to affect approximately one fourth of septic patients . In this report we review past and present diagnostic methods for sepsis and their respective limitations, and discuss the requirements for more timely diagnosis as the next step in curtailing sepsis-related mortality . We also present a proposal toward revision of the current diagnostic paradigm to include real-time immune monitoring.

Br J Surg, 2004 Jun, 91(6), 762 - 8
Interleukin 13 and inflammatory markers in human sepsis; Collighan N et al.; BACKGROUND: Interleukin (IL) 13 is an anti-inflammatory cytokine that reduces inflammatory cytokine production, and enhances monocyte survival and MHC class II and CD23 expression . The only report of IL-13 in human sepsis noted no increase in IL-13 concentration, in contrast to animal data . This study further examined the expression of IL-13 in relation to human sepsis . METHODS: In a prospective observational study of 31 patients (24 men) with sepsis or septic shock, high-sensitivity enzyme-linked immunoabsorbent assay (ELISA) was used to quantify levels of tumour necrosis factor (TNF) alpha on admission, and on days 1, 3, 5 and 7 thereafter . IL-13 and IL-2 were assayed by standard ELISA, and HLA-DR on CD14-positive monocytes was measured by flow cytometry . RESULTS: Twenty-three patients developed septic shock . Monocyte HLA-DR levels showed greater depression and a slower recovery in shocked than non-shocked patients . The serum IL-13 concentration was significantly higher in the shocked group from admission to day 3, but subsequently decreased to levels similar to those in the non-shocked group . IL-13 concentrations were higher in non-survivors . The TNF-alpha concentration was higher in those with septic shock than in those without . The TNF-alpha level correlated with IL-13 concentration (r(S) = 0.61, P = 0.002) . The IL-13/TNF-alpha ratio was greater in patients with shock than those with sepsis only (P = 0.017) . IL-2 was undetectable . CONCLUSION: In human sepsis and septic shock, IL-13 correlated with TNF-alpha expression, but its effect on HLA-DR class II molecules remains unclear .

J Infect Chemother, 2004 Apr, 10(2), 110 - 4
Plasma hepatocyte growth factor is increased in early-phase sepsis; Sekine K et al.; To elucidate the involvement of hepatocyte growth factor (HGF) in systemic inflammatory response syndrome (SIRS) and sepsis, we investigated the plasma levels of HGF, as well as those of various proinflammatory and anti-inflammatory cytokines, in 50 patients who visited our emergency department (ED) . The patients were divided into four groups, depending on the existence of SIRS and infection: group 1 (G1), no infection and no SIRS; group 2 (G2), infection and no SIRS; group 3 (G3), no infection and SIRS; and group 4 (G4), infection and SIRS (e.g., sepsis) . We found that plasma HGF levels in G4 were significantly higher than those in the groups without infection (G1 and G3) . However, the correlations between HGF and other cytokines were comparatively low compared with those between any other pairs of cytokines, suggesting independent regulation of HGF production in vivo . High plasma HGF was significantly correlated with the presence of infection and with serum total bilirubin (TB) level on multivariate logistic regression analysis . Considering HGF's known functions, we speculated that high plasma HGF levels may indicate the occurrence or necessity for tissue protection and regeneration after acute systemic insults in sepsis.

Am J Physiol Heart Circ Physiol, 2004 Sep, 287(3), H1296 - 302 Epub 2004 May 20.
Upregulation of cardiovascular ghrelin receptor occurs in the hyperdynamic phase of sepsis; Wu R et al.; Ghrelin, a newly identified endogenous ligand for growth hormone secretagogue receptor 1a (GHSR-1a, i.e., ghrelin receptor), was recently demonstrated to be a potent vasoactive peptide . Although sepsis is characterized by an early, hyperdynamic phase, it remains unknown whether ghrelin or GHSR-1a plays a role in the cardiovascular response to sepsis . To determine this, polymicrobial sepsis was induced by cecal ligation and puncture in male adult rats . At 5 h (i.e., early sepsis) or 20 h (i.e., late sepsis) after cecal ligation and puncture, blood and tissue samples were collected . Ghrelin levels and ghrelin and GHSR-1a mRNA expression were assessed by RIA and RT-PCR, respectively . In addition, GHSR-1a protein levels in aorta, heart, and small intestine were determined by Western blotting . The vascular response to ghrelin was determined by using an isolated gut preparation . A primary rat aortic smooth muscle cell culture was used to determine the effects of LPS on GHSR-1a expression . The results indicate that although ghrelin levels decreased at early and late sepsis, its receptor was markedly elevated in early sepsis . Moreover, ghrelin-induced relaxation in resistance blood vessels of the isolated small intestine increased significantly during early sepsis but was not altered in late sepsis . Furthermore, GHSR-1a expression in smooth muscle cells was significantly increased at mRNA and protein levels with stimulation by LPS at 10 ng/ml . These results demonstrate that GHSR-1a expression is upregulated and vascular sensitivity to ghrelin stimulation is increased in the hyperdynamic phase of sepsis.

Ther Apher Dial, 2004 Jun, 8(3), 185 - 9
Treatment of multiple organ failure through sepsis by surgery and blood purification; Asanuma Y et al.; For the treatment of multiple organ failure (MOF) through sepsis, we have commonly applied various blood purification modalities during the perioperative period . From January 1996 to December 2000, 33 patients with MOF through sepsis were admitted and operated on in the First Department of Surgery, Akita University School of Medicine, and 21 of these 33 patients were treated using various blood purification modalities during the perioperative period: endotoxin-adsorbing therapy using polymyxin B (PMX) in 17 patients, continuous hemofiltration (CHF)/continuous hemodiafiltration (CHDF) in 15 patients, and plasma exchange (PE) and CHDF in 3 patients . Of the outcome of these 33 patients with MOF through sepsis, 17 survived and 16 died (48% mortality) . Of the 21 patients with MOF through sepsis treated by surgery and blood purification, 12 survived and 9 died (43% mortality) . We evaluated APACHE II and the number of failed organs before operation . Amongst the group with 12 survivors and 9 deaths, Acute Physiology and Chronic Health Evaluation II (APACHE II) was 15 +/- 5, 23 +/- 2 and the number of failed organs was 2.7 +/- 0.7, 3.9 +/- 0.8, respectively . An increased APACHE II score and number of failed organs were significantly associated with mortality . As to the treatment of MOF through sepsis due to acute peritonitis, patients with APACHE II scores ranging from 15 to 20, and those with 2-3 failed organs seem to be the candidates for the application of blood purification during the perioperative period.

Crit Care, 2004 Jun, 8(3), 180 - 9 Epub 2004 Apr 29.
Bench-to-bedside review: understanding genetic predisposition to sepsis; Villar J et al.; Sepsis is a complex syndrome that develops when the initial, appropriate host response to an infection becomes amplified, and is then dysregulated . Among other factors, the innate immune system is of central importance to the early containment of infection . Death from infection is strongly heritable in human populations . Hence, genetic variations that disrupt innate immune sensing of infectious organisms could explain the ability of the immune system to respond to infection, the diversity of the clinical presentation of sepsis, the response to current medical treatment, and the genetic predisposition to infection in each individual patient . Such genetic variations may identify patients at high risk for the development of sepsis and organ dysfunction during severe infections . Single base variations, known as single nucleotide polymorphisms (SNPs), are the most commonly used variants . There has been great interest in exploring SNP in those genes involved in the inflammatory cascade resulting from the systemic inflammatory response to micro organisms . The rationale for studying gene SNPs in critical illnesses seeks to identify potential markers of susceptibility, severity, and clinical outcome; seeks to identify potential markers for responders and non-responders in clinical trials, and seeks to identify targets for therapeutic intervention . In this review, we focus on the current state of association studies of those genes governing the powerful bacterial infection-induced inflammation and provide guidelines for future studies describing disease associations with genetic variations based on current recommendations . We envision a time in the near future when genotyping will be include in the standard evaluation of critically ill patients and will help to prioritize a therapeutic option.

Am J Physiol Cell Physiol, 2004 Sep, 287(3), C730 - 6 Epub 2004 May 19.
Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis; Deng J et al.; Enhanced adrenergic stimulation and catecholamine release are important components of the pathophysiology of sepsis . Under physiological conditions, adrenergic stimulation has been shown to be a negative regulator of proinflammatory cytokine production through increasing IL-10 production . Here we have investigated if adrenergic stimulation similarly inhibits TNF-alpha and IL-6 production by splenic macrophages isolated from a polymicrobial sepsis model . Male B(6)D(2)F(1) mice were subjected to sham (S), laparotomy (Lap), and cecal ligation and puncture (CLP) under anesthesia . Splenic macrophages were isolated 72 h after the initial injury and were stimulated with endotoxin (LPS) in the presence and absence of epinephrine . Compared with S and Lap, splenic macrophages from the CLP group produced significantly less TNF-alpha and IL-6 and more IL-10 when stimulated with LPS . Macrophage cultures from CLP animals incubated with either epinephrine or IL-10 for 2 h had significantly reduced TNF-alpha and IL-6 release in response to LPS . However, similar cultures pretreated with IL-10 antibody before the addition of exogenous epinephrine failed to reverse the attenuation of LPS-stimulated cytokines . Pretreatment of macrophage cultures with beta(2)- (ICI-118551) but not beta(1)-adrenergic (atenolol) receptor antagonists reversed the epinephrine-mediated cytokine attenuation following LPS treatment . Data are also presented that demonstrate the involvement of protein kinase A activation with adrenergic agonist but not with IL-10 stimulation . Taken together, these findings suggest that adrenergic mechanisms may influence peripheral tissue macrophage inflammatory cytokine response following trauma and sepsis, independent of the effects of IL-10.

Blood, 2004 Sep 1, 104(5), 1375 - 82 Epub 2004 May 18.
Transduction of NO-bioactivity by the red blood cell in sepsis: novel mechanisms of vasodilation during acute inflammatory disease; Crawford JH et al.; Sepsis is an acute inflammatory disease characterized by dysfunctional blood flow and hypotension . Nitric oxide (NO) is elevated during sepsis and plays an integral role in the associated vascular pathology . However, precise mechanisms and functions of NO in sepsis remain unclear . In this study, we show that red blood cells (RBCs) are foci for nitrosative reactions during acute inflammation, resulting in the formation of cells that can promote systemic vascular relaxation in an uncontrolled manner . Specifically, using experimental models of endotoxemia and surgical sepsis, NO adducts were found in the RBCs, including S-nitrosohemoglobin (SNOHb) . These RBCs, referred to as septic RBCs, spontaneously stimulated vasodilation in a manner consistent with elevated SNOHb concentrations . Moreover, relaxation was cyclic guanosine monophosphate (cGMP) dependent and was inhibited by RBC lysis and glutathione but not by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline 1-oxyl 3-oxide (C-PTIO) . The potential mechanism of septic RBC-mediated vasorelaxation is discussed and may involve the intermediate, nitroxyl (HNO) . Coupled with data showing that NO adducts in septic RBCs were dependent on the inducible nitric oxide synthase and correlated with plasma nitrite, these findings provide a novel framework to understand mechanisms underlying dysfunctional blood flow responses during sepsis . Specifically, the concept that RBCs directly mediate systemic hypotension through NO-dependent mechanisms is discussed.

J Evol Biol, 2004 May, 17(3), 629 - 41
Sexual selection on morphological and physiological traits and fluctuating asymmetry in the black scavenger fly Sepsis cynipsea; Blanckenhorn WU et al.; Previous univariate studies of the fly Sepsis cynipsea (Diptera: Sepsidae) have demonstrated spatiotemporally variable and consequently overall weak sexual selection favouring large male size, which is nevertheless stronger on average than fecundity selection favouring larger females . To identify specific target(s) of selection on body size and additional traits possibly affecting mating success, two multivariate field studies of sexual selection were conducted . In one study using seasonal replicates from three populations, we assessed 15 morphological traits . No clear targets of sexual selection on male size could be detected, perhaps because spatiotemporal variation in selection was again strong . In particular, there was no (current) selection on male abdomen length or fore coxa length, the only traits for which S . cynipsea males are not smaller than females . Interestingly, copulating males had a consistently shorter fore femur base, a secondary sexual trait, and a wider clasper (hypopygium) gap, an external genital trait . In a second study using daily and seasonal replicates from one population, we included physiological measures of energy reserves (lipids, glucose, glycogen), in addition to hind tibia length and fluctuating asymmetry (FA) of all pairs of legs . This study again confirmed the mating advantage of large males, and additionally suggests independent positive influences of lipids (the long-term energy stores), with effects of glucose and glycogen (the short-term energy stores) tending to be negative . FA of paired traits was not associated with male mating success . Our study suggests that inclusion of physiological measures and genital traits in phenomenological studies of selection, which is rare, would be fruitful in other species.

Intensive Care Med, 2004 Jun, 30(6), 1032 - 40 Epub 2004 May 18.
Coagulation in sepsis; Amaral A et al.; Coagulation abnormalities, ranging from a simple fall in platelet count to full-blown disseminated intravascular coagulation, are a common occurrence in critically ill patients and have been associated with increased mortality . In sepsis, activation of the extrinsic coagulation pathway by tissue factor induces increased coagulation, and simultaneous depression of the inhibitory mechanisms of coagulation, and suppression of the fibrinolytic system results in a procoagulant state that may lead to the formation of microvascular thrombi disturbing organ microcirculation and promoting the development of organ dysfunction . Many inflammatory mediators are involved in the activation of coagulation, but many coagulation proteins are themselves actively involved in the inflammatory process . In this article, we explore the complex relationship between inflammation and coagulation and how improved understanding of this interaction has led to the development of new therapeutic agents for patients with severe sepsis.

Gynecol Obstet Invest, 2004, 58(2), 84 - 90 Epub 2004 May 12.
Amniotic fluid tumor necrosis factor-alpha is a marker for the prediction of early-onset neonatal sepsis in preterm labor; Park KH et al.; BACKGROUND: Our purpose was to determine whether amniotic fluid concentrations of tumor necrosis factor-alpha are of value in the prediction of early-onset neonatal sepsis (proven or suspected) in patients with preterm labor and intact membranes . METHODS: The relationship between amniotic fluid tumor necrosis factor-alpha concentrations and early-onset neonatal sepsis was examined in 59 consecutive patients with preterm labor and intact membranes who delivered preterm neonates within 72 h after transabdominal amniocentesis . Early-onset neonatal sepsis was defined either as the presence of a positive blood culture or as suspected sepsis within 72 h of delivery . Tumor necrosis factor-alpha was determined by enzyme-linked immunosorbent assays . RESULTS: Patients delivering neonates with early-onset neonatal sepsis had significantly higher median amniotic fluid TNF-alpha concentrations than patients delivering neonates without early-onset neonatal sepsis (p < 0.0005) . An amniotic fluid tumor necrosis factor-alpha concentration > or =41 pg/ml had a sensitivity of 82% (23/29) and specificity of 79% (38/48) in the prediction of early-onset neonatal sepsis . Multiple logistic regression indicated that elevated amniotic fluid tumor necrosis factor-alpha (> or =41 pg/ml) was the only independent predictor of early-onset neonatal sepsis (odds ratio 12.9, 95% confidence interval 1.3-125.3, p=0.01) after correction for known confounding variables . CONCLUSIONS: (1) Amniotic fluid tumor necrosis factor-alpha is a marker for the prediction of early-onset neonatal sepsis in patients with preterm labor and intact membranes . (2) Amniotic fluid tumor necrosis factor-alpha is a better independent predictor of early-onset neonatal sepsis than placental histologic finding or amniotic fluid culture .

Surg Infect (Larchmt), 2004 Spring, 5(1), 29 - 37
Inhibition of cyclooxygenase-2 by NS-398 following hemorrhage and subsequent sepsis: no beneficial effects in either gender; Kahlke V et al.; BACKGROUND: Inhibition of cyclooxygenase-2 with a reduction of prostaglandin E(2)production by the specific antagonist NS-398 has been shown to have beneficial effects on immune function and survival in a trauma model . Immune function after experimental hemorrhagic shock and subsequent sepsis may be gender-related, with enhanced immunity and better survival in females . However, it remains unclear if the observed effect of NS-398 treatment is gender-related following hemorrhagic shock and subsequent sepsis . METHODS: Male and female CBA/J mice (age: 2-3 months) were subjected to hemorrhagic shock (35 +/- 5 mm Hg for 90 min and fluid resuscitation) or sham operation . At resuscitation and after 20 and 40 h each received either NS-398 10 mg/kg or placebo i.p . At 48 h after resuscitation, either splenocytes and peritoneal macrophages (pM phi) were harvested (n = 8 per group), or polymicrobial sepsis was induced by cecal ligation and puncture (CLP) . Following CLP, either 10-day survival (n = 15 per group) was determined or pM phi and splenocytes were harvested 4 h after CLP (n = 8 per group) . Cytokine release of pM phi, and splenocyte proliferation and responsiveness in vitro were assessed . RESULTS: Treatment with NS-398 led to lower PGE(2) levels as compared to placebo-treated animals, reaching significance (p < 0.05) in males . Placebo-treated males had significantly depressed proinflammatory immune response (IL-1, IL-6, IL-2, IFN-gamma) after hemorrhagic shock and experienced further suppression by CLP (all, p < 0.05) . In contrast, young females displayed unchanged cytokine release after hemorrhagic shock, but a comparable suppression following CLP . Treatment with NS-398 did not influence cytokine release nor survival . CONCLUSIONS: Despite a significant reduction of PGE(2) concentration, NS-398 treatment has no beneficial effects on cytokine release and survival in this model of hemorrhage and subsequent sepsis.

Pharmacoeconomics, 2004, 22(7), 445 - 76
Drotrecogin alfa (activated): a pharmacoeconomic review of its use in severe sepsis; Frampton JE et al.; Drotrecogin alfa (activated) {Xigris} (DAA), the recombinant form of human activated protein C, is approved as an adjunctive therapy for patients with severe sepsis (sepsis associated with > or = 1 organ system failure {OSF}) . In the international, randomised, double-blind, placebo-controlled PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) study, the absolute reduction in 28-day all-cause mortality with intravenous DAA 24 micro g/kg/h for 96 hours plus conventional care versus conventional care alone was 6.1%.Although lacking statistical power, a prospectively planned subgroup analysis of this study suggested that the absolute reduction in mortality increased in patients with a baseline APACHE (Acute Physiology and Chronic Health Evaluation) II score of > or = 25 or > or = 2 OSFs, with no clear treatment effect in patients with an APACHE II score of < or = 24 or 1 OSF.Three fully published cost-effectiveness/cost-utility models of DAA plus conventional care relative to conventional care alone adopted a national healthcare payer's and/or societal perspective in North America . The base-case (baseline) discounted incremental cost per life-year gained (LYG) with DAA for all patients with severe sepsis was $US15,801-33,300 (year of costing 2000-2002) . The results were more favourable for patients with an APACHE II score of > or = 25 ($US10,833-19,723 per LYG), but considerably worse for patients with an APACHE II score of < or = 24 based on a post hoc reanalysis by the US FDA.Among several fully or partly published cost-effectiveness/cost-utility models that adopted a national healthcare payer's perspective in continental Western European countries, the base-case (baseline) undiscounted incremental cost per LYG was broadly similar and more favourable for patients with > or = 2 OSFs (9660-11,300 euros; year of costing/publication 1998/1999, 2000, 2002 or 2003) than for all patients with severe sepsis (13,436-15,071 euros) in those studies that reported both analyses . The DAA acquisition cost accounts for up to 95% of the additional cost of using the drug.In conclusion, DAA is a major advance in the treatment of severe sepsis, based on the significant mortality reduction observed in the PROWESS study . From a hospital/hospital pharmacy perspective, the drug is associated with a high acquisition cost and a small increase in other short-term costs . From a societal or national healthcare payer's perspective, however, its administration to patients who meet the PROWESS study inclusion criteria, especially individuals with more severe disease (e.g APACHE II score of > or =25 and/or > or = 2 OSFs), has a lifetime cost-effectiveness profile that compares well to that of many widely accepted therapies .

Pediatr Surg Int, 2004 May, 20(5), 369 - 71 Epub 2004 May 05.
Surgical risk factors for Hickman catheter sepsis: a prospective study; Babu R et al.; Catheter-related sepsis (CRS) is a major cause of morbidity in patients receiving chemotherapy and prolonged parenteral nutrition . To determine whether avoiding emergency insertions by using a planned elective list and adopting a 'no-touch' technique has a role in reducing CRS, all cuffed central venous catheters inserted by the open method between 1999 and 2000 were prospectively followed for a total duration of 12 months . The incidence of early sepsis (within 30 catheter days) that could be attributed to surgical factors was studied . CRS was defined as the presence of any two of the following: (1) signs of clinical sepsis without an obvious focus; (2) positive cultures in blood obtained from the catheter; and (3) clinical improvement following removal . A total of 146 catheters were inserted in 130 patients; 15 had a second and 1 had a third catheter inserted . Early CRS was encountered in 13 cases (9%); 95 catheters were inserted on an elective list and 51 on an emergency basis . The distributions of age, sex, number of lumens, neutrophil count, and underlying diagnosis were similar between the groups . There was no significant difference (P = 1) between elective (9/95) and emergency (4/51) insertions . A total of 47 catheters were inserted by the 'no-touch' technique and 48 by the manual technique . There was no significant difference in early sepsis (P = 0.7) between the two techniques (6/47 vs 3/48) . Thus avoiding emergency insertion or adopting a 'no-touch' technique does not reduce early CRS . Larger prospective studies are warranted to identify surgical risk factors.

Dis Mon, 2004 Apr, 50(4), 168 - 213
Optimum treatment of severe sepsis and septic shock: evidence in support of the recommendations; Balk RA; Severe sepsis and septic shock are among the most common causes of death in noncoronary intensive care units . The incidence of sepsis has been increasing over the past two decades, and is predicted to continue to rise over the next 20 years . While our understanding of the complex pathophysiologic alterations that occur in severe sepsis and septic shock has increased greatly asa result of recent clinical and preclinical studies, mortality associated with the disorder remains unacceptably high . Despite these new insights, the cornerstone of therapy continues to be early recognition, prompt initiation of effective antibiotic therapy, and source control, and goal-directed hemodynamic, ventilatory,and metabolic support as necessary . To date, attempts to reduce mortality with innovative, predominantly anti-inflammatory therapeutic strategies have been extremely disappointing . Observations of improved outcomes with physiologic doses of corticosteroid replacement therapy and activated protein C (drotrecogin alfa{activated}) have provided new adjuvant therapies for severe sepsis and septic shock in selected patients . This article reviews the components of sepsis management and discusses the available evidence in support of these recommendations . In addition, there is a discussion of some promising new strategies.

Zhongguo Wei Zhong Bing Ji Jiu Yi Xue, 2004 May, 16(5), 271 - 3
{Association between a genomic polymorphism within the CD14 locus and severe sepsis susceptibility as well as prognosis in patients after extensive burns}; Lin J et al.; OBJECTIVE: To investigate the relation of a lipopolysaccharide receptor CD14C-159T gene polymorphism to severe sepsis susceptibility and prognosis in patients with extensive burns . METHODS: The study group consisted of 118 normal controls and 16 patients with burns covering more than 60 percent total body surface area . Typing of each patient for the CD14C-159T gene polymorphism was performed by analyzing restriction fragments of a Hae III-digested DNA fragment obtained using polymerase chain reaction (PCR-RFLP) . Genotypes were then related to the susceptibility and mortality rate of severe sepsis . RESULTS: The overall allele frequency (C 43.7 percent, T 56.3 percent) and genotype distribution (C homozygous 12.5 percent, C/T 62.5 percent, T homozygous 25.0 percent) were in agreement with the distribution in healthy volunteers . Genotype distribution in patients with severe sepsis was different from that in patients with an uncomplicated clinical course . Development of severe sepsis was increased in patients homozygous for the allele T (71.4 percent) than that of the non- sepsis patients (44.4 percent) . CONCLUSION: The single base pair polymorphism at position-159 in the CD14 gene promoter might influence the development of severe sepsis in patients with extensive burns.

J Perinatol, 2004 Jul, 24(7), 446 - 53
Prevention and treatment of nosocomial sepsis in the NICU; Clark R et al.; Nosocomial sepsis is a serious problem for neonates who are admitted for intensive care . It is associated with an increase in mortality, morbidity, and prolonged length of hospital stay . Thus, both the human and fiscal costs of these infections are high . Although the rate of nosocomial sepsis increases with the degree of both prematurity and low birth weight, no specific lab test has been shown to be very useful in improving our ability to predict who has a "real" blood-stream infection and, therefore, who needs to be treated with a full course of antibiotics . As a result, antibiotic use is double the rate of "proven" sepsis and we are facilitating the growth of resistant organisms in the neonatal intensive care unit . The purpose of this article is to describe simple changes in process, which when implemented, can reduce nosocomial infection rates in neonates and improve outcomes.

Am J Health Syst Pharm, 2004 Apr 15, 61(8), 765 - 74; quiz 775-6
Appraisal of four novel approaches to the prevention and treatment of sepsis; Kumar A et al.; PURPOSE: Four novel approaches to the management of sepsis are discussed . SUMMARY: Drotrecogin alfa (activated) has FDA-approved labeling for use in the treatment of severe sepsis . Risk of bleeding and identification of the most suitable patients have been the major issues related to use of this drug . Tight glycemic control and early goal-directed therapy (EGDT) are promising supportive strategies . Both have challenged existing views regarding safe glucose levels and the usefulness of increased oxygen delivery in sepsis . The routine maintenance of euglycemia is resource intensive, however, and benefits during treatment of sepsis are unclear . Very early initiation of measures to optimize hemodynamic variables and the ability to identify patients with cryptic shock appear to be key reasons for successful EGDT . The use of corticosteroids for septic shock has been extensively researched and has provoked controversy . Selection of patients likely to benefit on the basis of relative adrenal insufficiency and prolonged treatment may account for recently observed positive results . A model for combining the four strategies is proposed . CONCLUSION: Novel strategies for treating sepsis include drotrecogin alfa (activated), tight glycemic control, EGDT, and low-dose corticosteroids.

J Clin Invest, 2004 May, 113(9), 1318 - 27
Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis; Jia SH et al.; Pre-B cell colony-enhancing factor (PBEF) is a highly conserved 52-kDa protein, originally identified as a growth factor for early stage B cells . We show here that PBEF is also upregulated in neutrophils by IL-1beta and functions as a novel inhibitor of apoptosis in response to a variety of inflammatory stimuli . Induction of PBEF occurs 5-10 hours after LPS exposure . Prevention of PBEF translation with an antisense oligonucleotide completely abrogates the inhibitory effects of LPS, IL-1, GM-CSF, IL-8, and TNF-alpha on neutrophil apoptosis . Immunoreactive PBEF is detectable in culture supernatants from LPS-stimulated neutrophils, and a recombinant PBEF fusion protein inhibits neutrophil apoptosis . PBEF is also expressed in neutrophils from critically ill patients with sepsis in whom rates of apoptosis are profoundly delayed . Expression occurs at higher levels than those seen in experimental inflammation, and a PBEF antisense oligonucleotide significantly restores the normal kinetics of apoptosis in septic polymorphonuclear neutrophils . Inhibition of apoptosis by PBEF is associated with reduced activity of caspases-8 and -3, but not caspase-9 . These data identify PBEF as a novel inflammatory cytokine that plays a requisite role in the delayed neutrophil apoptosis of clinical and experimental sepsis.

Circulation, 2004 Jun 1, 109(21), 2560 - 5 Epub 2004 May 03.
HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis; Merx MW et al.; BACKGROUND: HMG-CoA reductase inhibitors, such as simvastatin, have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering but to date have not been used to treat severe inflammatory disease such as sepsis . We thus approached the question of whether treatment with simvastatin might improve cardiovascular function and survival in sepsis . METHODS AND RESULTS: Mice treated with simvastatin and rendered septic by cecal ligation and perforation (CLP) show a mean survival time close to 4 times the value found in untreated mice . This dramatic improvement is based on a complete preservation of cardiac function and hemodynamic status, which are severely impaired in untreated CLP mice {eg, 20 hours after CLP, cardiac output declined from 1.24+/-0.09 to 0.87+/-0.11 mL x min(-1) x g(-1) in untreated mice (P<0.005; n=12), while remaining unaltered (1.21+/-0.08 mL x min(-1) x g(-1) at baseline and 1.15+/-0.1 mL x min(-1) x g(-1) 20 hours after CLP, P=NS, n=12) in CLP mice treated with simvastatin} . Untreated CLP mice remained refractory to beta-stimulation, whereas the responsiveness to dobutamine was restored by treatment with simvastatin . Susceptibility of coronary flow to endothelial nitric oxide synthase (eNOS) stimulation by bradykinin was close to 3 times as pronounced in untreated CLP mice as in untreated sham-operated mice, indicating a high level of eNOS activation secondary to sepsis . In addition, treatment with simvastatin reversed inflammatory alterations in CLP mice, namely, increased monocyte adhesion to endothelium . CONCLUSIONS: Simvastatin, which is well established in the treatment of lipid disorders and coronary artery disease, might have the additional potential of being an effective agent in sepsis treatment.

J Infect Dis, 2004 May 15, 189(10), 1897 - 904 Epub 2004 Apr 28.
A2A adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis; Sullivan GW et al.; BACKGROUND: Sepsis is currently treated with antibiotics and various adjunctive therapies that are not very effective . METHODS: Mouse survival (4-5 days) and peritoneal and blood bacteria counts were determined after challenge with intraperitoneal lipopolysaccharide (LPS) or live Escherichia coli . RESULTS: The A(2A) adenosine receptor (AR) agonist 4-{3-{6-amino-9-(5-ethylcarbamoyl-3, 4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl}-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL146e; 0.05-50 mu g/kg) protected mice from challenge with LPS, and protection occurred when treatment was delayed up to 24 h after challenge . Deletion of the A (2A) AR gene, Adora2a, inhibited protection by ATL146e . A putative A (3)AR agonist, N(6)-3-iodobenzyladenosine-5'-N-methyluronamide (IB-MECA; 500 mu g/kg but not 5 or 50 mu g/kg) protected mice from challenge with LPS . The protective effects of both ATL146e and IB-MECA were counteracted by the A(2A) AR selective antagonist 4-(2-{7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-yl-amino}ethyl)-phenol . In the live E . coli model, treatment with ATL146e (50 mu g/kg initiated 8 h after infection) increased survival in mice treated with ceftriaxone (5 days) from 40% to 100% . Treatment with ATL146e did not affect peritoneal numbers of live E . coli at the time of death or 120 h after infection but did increase numbers of peritoneal neutrophils and decreased the number of live E . coli in blood . CONCLUSIONS: AR agonists increase mouse survival in endotoxemia and sepsis via A(2A) AR-mediated mechanisms and reduce the number of live bacteria in blood.

Pediatrics, 2004 May, 113(5), 1209 - 15
Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants; Poindexter BB et al.; BACKGROUND: Glutamine is one of the most abundant amino acids in both plasma and human milk, yet it is not included in standard intravenous amino acid solutions . Previous studies have suggested that parenteral nutrition (PN) supplemented with glutamine may reduce sepsis and mortality in critically ill adults . Whether glutamine supplementation would provide a similar benefit to extremely low birth weight (ELBW) infants is not known . METHODS: We performed a multicenter, randomized, double-masked, clinical trial to assess the safety and efficacy of early PN supplemented with glutamine in decreasing the risk of death or late-onset sepsis in ELBW infants . Infants 401 to 1000 g were randomized within 72 hours of birth to receive either TrophAmine (control) or an isonitrogenous study amino acid solution with 20% glutamine whenever they received PN up to 120 days of age, death, or discharge from the hospital . The primary outcome was death or late-onset sepsis . RESULTS: Of the 721 infants who were assigned to glutamine supplementation, 370 (51%) died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control (relative risk: 1.07; 95% confidence interval: 0.97-1.17) . Glutamine had no effect on tolerance of enteral feeds, necrotizing enterocolitis, or growth . No significant adverse events were observed with glutamine supplementation . CONCLUSIONS: Parenteral glutamine supplementation as studied did not decrease mortality or the incidence of late-onset sepsis in ELBW infants . Consequently, although no harm was demonstrated, routine use of parenteral glutamine supplementation cannot be recommended in this population.

Pediatrics, 2004 May, 113(5), 1181 - 6
To tap or not to tap: high likelihood of meningitis without sepsis among very low birth weight infants; Stoll BJ et al.; CONTEXT: Neonatal meningitis is associated with significant morbidity and mortality . We speculated that meningitis may be underdiagnosed among very low birth weight (VLBW) infants because of the failure to perform lumbar punctures (LPs) in infants with suspected sepsis . OBJECTIVE: This study was undertaken to review the epidemiology of late-onset meningitis in VLBW (401-1500 g) infants and to evaluate the concordance of cerebrospinal fluid (CSF) and blood culture (BC) results . METHODS: VLBW infants (excluding those with intraventricular shunts) born at centers of the National Institute of Child Health and Human Development Neonatal Research Network from September 1, 1998, through December 31, 2001, were studied . Late-onset meningitis was defined by culture-based criteria and classified as meningitis with or without associated sepsis . Unadjusted comparisons were made using chi2 tests and adjusted comparisons using regression models . RESULTS: Of 9641 VLBW infants who survived >3 days, 2877 (30%) had > or = 1 LPs, and 6056 (63%) had > or = 1 BC performed after day 3 . One hundred thirty-four infants had late-onset meningitis (1.4% of all patients; 5% of those with an LP) . Pathogens associated with meningitis were similar to those associated with sepsis . One third (45 of 134) of the infants with meningitis had negative BCs . Lower gestational age and prior sepsis increased risk for meningitis . Compared with uninfected infants, those with meningitis had a longer time on mechanical ventilation (28 vs 18 days), had longer hospitalizations (91 vs 79 days), were more likely to have seizures (25% vs 2%), and were more likely to die (23% vs 2%) . CONCLUSIONS: Meningitis is a serious complication among VLBW infants, associated with increased severity of illness and risk of death . Of note, one third of the infants with meningitis had meningitis in the absence of sepsis . Because CSF cultures were performed only half as often as BCs, this discordance in blood and CSF culture results suggests that meningitis may be underdiagnosed among VLBW infants.

Crit Care Med, 2004 May, 32(5 Suppl), S309 - 12
Beyond sepsis: activated protein C and ischemia-reperfusion injury; Levi M et al.; OBJECTIVE: To review potential clinical situations beyond sepsis in which activated protein C might be an effective treatment . DATA SOURCE: Published articles between 1970 and 2003 on experimental and clinical studies of activation of both coagulation and inflammation in various disease states . DATA SYNTHESIS AND CONCLUSION: The efficacy of activated protein C in sepsis might rely on the fact that it can modulate both coagulation and inflammation . Therefore, administration of activated protein C could be beneficial in disease states that are also characterized by the simultaneous activation of these systems . Ischemia-reperfusion injury of various organs may represent such a state . Indeed, the involvement of the protein C system has been demonstrated in various experimental studies of ischemia-reperfusion, including studies in renal ischemia-reperfusion syndromes, coronary atherosclerosis and acute coronary syndromes, and intestinal ischemia and reperfusion . In some of these models, activated protein C administration, or other interventions in the protein C system, was shown to be beneficial.

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