Shock, 2003 Aug, 20(2), 123 - 9 Interaction between the innate and adaptive immune systems is required to survive sepsis and control inflammation after injury; Shelley O et al.; Substantial clinical and laboratory research has revealed that major injury causes abnormalities in both the innate and adaptive immune systems . However, the relative importance of each of these systems in the immune dysfunction after injury is poorly understood and difficult to establish by clinical studies alone . Rag1 (-/-) C57BL/6 mice (Rag1), which lack an adoptive immune system, and immune-sufficient wild-type (WT) C57BL/6 mice underwent 25% total body surface area burn injury or sham injury under anesthesia and were subjected to cecal ligation and puncture (CLP) at day 10 postinjury, a time of high CLP mortality in this model . To test the effect of adaptive immune deficiency on inflammatory cytokine production after injury, adaptive cell-depleted splenocytes from sham and burn WT and Rag1 mice were stimulated with LPS, and TNF-alpha and IL-6 production were assayed at days 1 and 7 postinjury . Intracellular expression of TNFalpha and IL-6 by F4/80 macrophages was also assessed on day 7 by intracellular cytokine staining . Finally, Rag1 animals were reconstituted with WT splenocytes, and the effect of such reconstitution on CLP survival and cytokine production was determined . Survival of sham WT animals after CLP was significantly higher (P < 0.01) than survival of burn WT and Rag1 sham and burn animals, all of which had equivalently low survival . Reconstitution of Rag1 animals with WT splenocytes restored CLP survival to WT sham levels . Splenocytes from Rag1 burn mice showed significantly augmented cytokine production when compared with WT burn mice on day 7 (P < 0.05) . Reconstitution of Rag1 mice with WT splenocytes at the time of injury returned cytokine production to WT levels . Intracellular cytokine expression in F4/80 macrophages was increased to a similar degree after burn, but not sham burn injury in Rag1, reconstituted Rag1 and WT animals . These studies demonstrate that the adaptive immune system is necessary for protection from polymicrobial sepsis and plays a significant role in regulating the inflammatory response to injury. Shock, 2003 Aug, 20(2), 101 - 9 Report of a case series of ultra low-frequency oscillations in cardiac output in critically ill adults with sepsis, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome; Seiver AJ et al.; Healthy physiological systems exhibit irregular variability whereas diseased systems display decreased signal variability or greater regularity . The objective of this article is to report a case series of critically ill adults who displayed ultra low-frequency periodic sinusoidal oscillations in cardiac output (ULF-CO) that were discovered during a clinical study testing software for continuous physiological monitoring . Data were collected from 13 critically ill surgical and trauma patients who required continuous cardiac output monitoring . Physiologic data were collected from clinical monitors . The computerized time series of cases displaying CO oscillations were manually reviewed . Ten patients with sepsis or the systemic inflammatory response syndrome exhibited 18 episodes of ultra low-frequency periodic oscillations (ULF-CO) with frequencies ranging from 0.0028 to 0.000053 Hz (periods, 6 to 316 min) . Intensive care unit mortality rate was 50% . The amplitude and coefficient of variation of cardiac output during ULF-CO ranged from 0.1-4.6 L and 3.9-14.3%, respectively . Duration of ULF-CO ranged from 4-108.1 h . ULF-CO could not be explained as a result of patterned artifact from measurement error or therapeutic intervention . ULF-CO may be a pathophysiologic marker that might serve the diagnosis, prognosis, and treatment of critical illness. Prof Nurse, 2003 Jul, 18(11), 618 - 20 Managing patients with sepsis in the general ward environment; Nassau J; The incidence of sepsis is rising, with many patients now being managed in general wards rather than in intensive care units, both with and without the support of critical care outreach teams . This paper looks at the organisms that can cause sepsis, its early recognition and the treatment and management of patients with this challenging condition. Eur J Pharmacol, 2003 Jul 4, 472(1-2), 111 - 8 Type II nitric oxide synthase activity is cardio-protective in experimental sepsis; Price S et al.; Overproduction of nitric oxide (NO) via the induction of NO synthase (NOS) II is implicated in the pathogenesis of the refractory hypotension that characterizes septic shock . However, clinical trials of nonselective NOS inhibitors have failed to afford a mortality benefit in patients with sepsis, and in those with depressed left ventricular function, death rates were increased . Such observations have led to the suggestion that a selective inhibitor of NOSII would be more effective in treating septic shock, although precisely how NO modulates cardiac function in these circumstances remains unclear . We therefore used an isolated ejecting rodent heart model to study the effects of NO and experimental sepsis (endotoxin 20 mg kg i.p.) on cardiac functions . Coronary flow and cardiac output and ventricular functions were reduced by LPS, effects that were partially obviated by supplementation of perfusate with the NO substrate, L-arginine . These improvements were partially blocked by the selective NOSII inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400W) and further reduced by the combined NOSI, II and III inhibitor L-nitro L-arginine methyl ester (L-NAME) . These findings suggest that NOSII is cardio-protective in the heart in sepsis and explain why its inhibition in man led to increased mortality in a subpopulation of patients. Clin Microbiol Rev, 2003 Jul, 16(3), 379 - 414 Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock; Van Amersfoort ES et al.; Bacterial sepsis and septic shock result from the overproduction of inflammatory mediators as a consequence of the interaction of the immune system with bacteria and bacterial wall constituents in the body . Bacterial cell wall constituents such as lipopolysaccharide, peptidoglycans, and lipoteichoic acid are particularly responsible for the deleterious effects of bacteria . These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds . Within the circulation bacterial constituents interact with proteins such as plasma lipoproteins and lipopolysaccharide binding protein . The interaction of the bacterial constituents with receptors on the surface of mononuclear cells is mainly responsible for the induction of proinflammatory mediators by the bacterial constituents . The role of individual receptors such as the toll-like receptors and CD14 in the induction of proinflammatory cytokines and adhesion molecules is discussed in detail . In addition, the roles of a number of other receptors that bind bacterial compounds such as scavenger receptors and their modulating role in inflammation are described . Finally, the therapies for the treatment of bacterial sepsis and septic shock are discussed in relation to the action of the aforementioned receptors and proteins. Clin Infect Dis, 2003 Jul 15, 37(2), 187 - 95 Epub 2003 Jul 08. Drotrecogin alfa (activated) treatment of older patients with severe sepsis; Ely EW et al.; The incidence of severe sepsis increases dramatically with advanced age, with a mortality rate that approaches 50% . The main purpose of this investigation was to determine both short- and long-term survival outcomes among 386 patients aged >or=75 years who were enrolled in the Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) trial . Subjects who were treated with drotrecogin alfa (activated; DAA) had absolute risk reductions in 28-day and in-hospital mortality of 15.5% and 15.6%, respectively (P=.002 for both), compared with placebo recipients . The relative risk (RR) for 28-day mortality was 0.68 (95% confidence interval {CI}, 0.54-0.87), and the in-hospital RR was 0.70 (95% CI, 0.56-0.88) . Resource use and patient disposition for DAA-treated patients compared favorably with those for placebo recipients . In addition, long-term follow-up data were available for 375 subjects (97.2%), and survival rates for DAA recipients were significantly higher over a 2-year period (P=.02) . The incidences of serious adverse bleeding during the 28-day study period in the DAA and placebo groups were 3.9% and 2.2%, respectively (P=.34) . There was no interaction between age and bleeding rates (P=.97) . In conclusion, older patients with severe sepsis have higher short- and long-term survival rates when treated with DAA than when treated with placebo but an increased risk of serious bleeding that is not aged related. Intensive Care Med, 2003 Sep, 29(9), 1464 - 71 Epub 2003 Jul 10. The costs of septic syndromes in the intensive care unit and influence of hospital-acquired sepsis; Brun-Buisson C et al.; OBJECTIVE: To document the costs and outcomes of the various forms of the septic syndromes {systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock), particularly those associated with infection acquired in an intensive care unit (ICU) . DESIGN: Prospective data collection for all septic patients admitted to a medical ICU during a 1-year period . Costs were computed from the viewpoint of the hospital . RESULTS: Mean total hospital costs were Euro 26,256, Euro 35,185, and Euro 27,083 for patients with sepsis, severe sepsis, and septic shock, respectively . Total costs varied slightly according to the site of infection and the severity of sepsis but were influenced mostly by its mode of acquisition: patients having sepsis associated with ICU-acquired infection incurred total costs about three times those of patients presenting with infection and sepsis on ICU admission (from Euro 39,908 in patients with ICU acquired sepsis to Euro 44,851 in patients with ICU-acquired septic shock) . Stratifying patients by the presence of ICU-acquired infection also showed that a first episode of infection complicated by ICU-acquired sepsis incurred at least 2.5 times more costs than a single episode of sepsis . CONCLUSIONS: In this series the medical costs of sepsis were not markedly influenced by its severity but by its mode of acquisition . Due to wide variations in ICU costs cost-effectiveness analyses of treatments for sepsis should document the case-mix of patients and the contribution to this of nosocomial infections. Ann Acad Med Singapore, 2003 May, 32(3), 418 - 20 The relationship between scoring systems and cytokine levels in neonatal sepsis; Caksen H et al.; In this study, 20 newborn infants with sepsis were evaluated and scored according to the criteria of Tollner and Rodwell and associates . Leukocyte count, serum C-reactive protein (CRP), tumour necrosis factor (TNF)-alpha and interluekin (IL)-6 levels were also studied in all infants . The aim of this study was to determine if a relationship exists between the scoring systems and the cytokine levels in neonatal sepsis . The infants were divided into two groups as blood culture positive and negative . Blood culture was positive in 12 (60%) infants . We did not find a significant difference for leukocyte count, cytokine levels and scoring systems between the blood culture positive and negative groups . However, we found a positive correlation between the scoring systems and serum CRP and TNF-alpha levels (P < 0.05), but no correlation with IL-6 . In conclusion, we suggest that only serum CRP level without performing scoring and studying serum TNF-alpha concentration may be used in early diagnosis of neonatal sepsis . However, further studies are necessary to define this because of the small sample size of our pilot study. Clin Diagn Lab Immunol, 2003 Jul, 10(4), 529 - 35 Administration of C1 inhibitor reduces neutrophil activation in patients with sepsis; Zeerleder S et al.; Forty patients with severe sepsis or septic shock recently received C1 inhibitor . In the present study we studied the effect of C1 inhibitor therapy on circulating elastase-alpha(1)-antitrypsin complex (EA) and lactoferrin (LF) levels in these patients to gain further insight about agonists involved in the activation of neutrophils in human sepsis . Elevated levels of EA and LF were found in 65 and 85% of the septic patients, respectively . Patients with elevated EA levels had higher organ dysfunction scores, higher levels of cytokines, and higher levels of complement activation products than patients with normal EA levels . C1 inhibitor therapy reduced EA as well as complement activation and IL-8 release in the patients with elevated EA on admission . We conclude that neutrophil activation in human sepsis correlates with the severity of organ dysfunction and involves complement and interleukin-8 as agonists . The effect of C1 inhibitor therapy on neutrophils may provide an explanation for the beneficial, although mild, effects of this treatment on organ dysfunction in sepsis. JAMA, 2003 Jul 9, 290(2), 238 - 47 Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial; Abraham E et al.; CONTEXT: The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis . Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation . OBJECTIVES: To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR . DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001, in 245 hospitals in 17 countries in North America, Europe, and Israel . PATIENTS: The primary efficacy population consisted of 1754 patients (> or =18 years) with severe sepsis and a high INR (> or =1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n = 880) or placebo (arginine citrate buffer, n = 874), and 201 patients with a low INR (<1.2) randomly assigned to receive the same dose of either tifacogin or placebo . MAIN OUTCOME MEASURE: All-cause 28-day mortality . RESULTS: Overall mortality at 28 days in the tifacogin-treated group (n = 880) vs the placebo group (n = 874) for high INR was 34.2% vs 33.9%, respectively (P =.88, Pearson chi2 test; P =.75, logistic regression model) . None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups . An analysis on the first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for tifacogin (P =.006, Pearson chi2 test) . Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels (P<.001, 2-sample t test) in patients with high and low INR . Overall mortality was lower in the tifacogin response in patients with low INR (12%; n = 83) vs placebo (22.9%; n = 118) (P =.051, Pearson chi2 test; P =.03, logistic regression model) . There was an increase in serious adverse events with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR) . CONCLUSIONS: Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR . Tifacogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR. J Surg Res, 2003 May 15, 111(2), 203 - 8 The combination of polymicrobial sepsis and endotoxin results in an inflammatory process that could not be predicted from the independent insults; Trentzsch H et al.; BACKGROUND: The variable clinical profile observed in critically ill patients is the result of multiple factors . Genetic determinants have recently been shown as confounding factors in the response to injury . However, other elements, such as the environment and the type of injury, could modify this response . The objective of this investigation was to study the effect of combining insults and different genetic backgrounds on the inflammatory response . MATERIALS: Male mice, C57BL/6J (B6) and A/J, were randomized to undergo cecal ligation and single puncture (CLP) or sham operation (SOP) . After 24 h of recovery, mice were randomized again into two groups, one group was injected with bacterial lipopolysaccharide (LPS; 15 mg/kg) and the other was injected with normal saline (NS) . An additional experimental group included mice that were not operated (NOP) and injected with LPS . Mice were evaluated by plasma cytokine content . RESULTS: The combination of insults resulted in an apparent additive effect for some cytokines, such as interleukin (IL) 6 . In contrast, tumor necrosis factor alpha (TNF-alpha) was considerably lower in the combined injury group with respect to injection of LPS alone . There was no relevant difference in IL-10 levels between any group, except that its decay was slower in the CLP + LPS group . Overall, cytokine levels were different between B6 and A/J mice indicating a genetic contribution . CONCLUSIONS: These results indicate that the response to stress is the combination of the type of injury and the genetic background of the subject . These observations also illustrate the difficulty in predicting the inflammatory response and underlying mechanism based on cytokine plasma levels. Br J Clin Pharmacol, 2003 Jul, 56(1), 25 - 31 Population pharmacokinetics of intramuscular gentamicin administered to young infants with suspected severe sepsis in Kenya; Thomson AH et al.; AIMS: To determine the population pharmacokinetics of intramuscular (i.m.) gentamicin in African infants with suspected severe sepsis . METHODS: Samples were withdrawn 1 h after a single i.m . injection of 8 mg x kg(-1) gentamicin and the next morning prior to any further dosing . Concentration-time data were analysed with the population pharmacokinetic package NONMEM . Data were fitted using a one-compartment model with a log-normal model for interindividual variability and an additive residual error model . The influence of a range of clinical characteristics was tested on the pharmacokinetics of intramuscular gentamicin and the effect of incorporating interindividual variability on bioavailability was examined . RESULTS: The data set comprised 107 patients and 203 concentrations . Peak concentrations ranged from 3.0 mg x L(-1) to 19.8 mg x L(-1) (median 10.6 mg x L(-1)) and 'next day' samples from 0.3 mg x L(-1) to 6.2 mg x L(-1).The best models were clearance/bioavailability (CL) (L x h(-1)) = 0.0913 x weight (kg) x (age (days) + 1)/11)0.130 and volume of distribution/bioavailability (V) = 2.02 x (1 + 0.277 x (weight -3)) . Therefore, an infant with the median weight of 3 kg and age 10 days would have a predicted CL of 0.274 L x h(-1) and V of 2.02 L . Interindividual variability in CL was 40% and in V was 42% . This model required a term for covariance between CL and V . When variability in bioavailability was introduced as an alternative model, interindividual variability in CL was 22%, in V 18% and in relative bioavailability 36% . CONCLUSIONS: Intramuscular administration of 8 mg x kg(-1) gentamicin daily to infants gives mean 1 h peak concentration of 10.6 mg x L(-1) and a trough concentration of less than 2 mg x L(-1) . Wide variability in the peak concentration may reflect variable absorption rate or bioavailability. Crit Care Clin, 2003 Jul, 19(3), 441 - 58 Coagulation dysfunction in sepsis and multiple organ system failure; Nimah M et al.; In patients diagnosed with sepsis, severe sepsis or septic shock, cytokine-mediated endothelial injury, and TF activation initiate a cascade of events that culminate in the development of coagulation dysfunction characterized as procoagulant and antifibrinolytic . This abnormal state predisposes the patient to develop microvascular thrombosis, tissue ischemia, and organ hypoperfusion . Multiple organ dysfunction syndrome may be a product of this pertubation in coagulation regulation . Treatments aimed at correcting this coagulation dysfunction have met with mixed success . Current data suggest that AT III replacement therapy has limited efficacy in adults with severe sepsis . In contrast, adult patients diagnosed with severe sepsis and organ failure and treated with aPC (drotrecogin alfa activate) have a significantly reduced risk of death when compared with placebo-treated patients . A phase III trial examining the efficacy of protein C replacement therapy in pediatric patients with severe sepsis and organ failure is underway. Crit Care Med, 2003 Jul, 31(7), 2068 - 71 Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis; Monneret G et al.; OBJECTIVE: Immunoparalysis has recently emerged as a possible cause explaining the failure of clinical trials in septic shock . Because human peripheral blood CD4+CD25+ T cells have been characterized as suppressor T cells, we hypothesized they might be increased in sepsis-induced immunoparalysis . DESIGN: Prospective, observational, clinical study . SETTING: Adult intensive care units in a university hospital . SUBJECTS: Patients with septic shock (n = 16) and healthy individuals (n = 36) . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: In patients with septic shock (mortality rate at 28 days, 56%; mean admission Simplified Acute Physiology Score II, 47), we first illustrated immunoparalysis by showing a severe diminished monocytic human leukocyte antigen (HLA)-DR expression . Afterward, compared with control values, we found in these patients a marked elevation of circulating CD4+CD25+ T cells that were also CD45RO+ and CD69- and overexpressed CTLA-4 . Importantly, nonsurvivors (n = 9) presented prolonged lower monocytic HLA-DR expression and higher percentage of CD4+CD25+ T-suppressor T cells . CONCLUSIONS: These data support the concept that the persistence of a pronounced immunoparalysis after septic shock is associated with a poor outcome . Whether CD4+CD25+ T cells directly participate in sepsis-induced immunoparalysis remains to be investigated. Crit Care Med, 2003 Jul, 31(7), 2015 - 21 Amelioration of endotoxin-induced sepsis in rats by membrane anchored lipid conjugates; Beck GCh et al.; OBJECTIVE: In the pathogenesis of septic shock, caused by either bacterial toxins or trauma, increased production of multiple proinflammatory mediators, such as phospholipase A(2) (PLA(2)), cytokines, and chemokines, is known to be of major importance . The present study was undertaken to investigate the influence of a newly designed extracellular PLA(2) inhibitor (ExPLI) on synthesis of proinflammatory mediators and mortality rate in a rat sepsis model . DESIGN: Prospective, randomized animal study . SETTING: Experimental laboratory . SUBJECTS: Male Wistar-rats weighing 200-300 g . INTERVENTIONS: Mortality was induced by intraperitoneal bolus administration of lipopolysaccharide 15 mg/kg in 22 rats that were pretreated with NaCl or ExPLI (150 mg/kg) . Furthermore, nine rats received a sublethal bolus of lipopolysaccharide (7.5 mg/kg) and nine rats received lipotechoic acid (8 mg/kg) simultaneously with or after ExPLI administration . Blood samples were collected from these rats, and cytokine concentrations were assessed by enzyme-linked immunosorbent assay . Lung and kidney were removed for RNA isolation and immunohistological analysis . MEASUREMENTS AND MAIN RESULTS: ExPLI treatment significantly reduced lipopolysaccharide-induced mortality of rats (90.9 and 36.4%, p <.05) . Up-regulation of tumor necrosis factor-alpha and interleukin-6 production in serum after endotoxin treatment was significantly inhibited when ExPLIs were administered at the time of or before sepsis induction by using lipopolysaccharide or lipotechoic acid (p <.01) . Similarly, messenger RNA expression of secreted PLA(2)-IIA, interleukin-1, or inducible nitric oxide synthase and the expression of intercellular adhesion molecule-1 were significantly down-regulated in lung and kidney of ExPLI-treated rats, as demonstrated by RNase protection assay, reverse transcription-polymerase chain reaction, or immunohistochemistry . CONCLUSIONS: ExPLIs may be considered as potentially effective compounds to prevent the production of inflammatory mediators and to improve mortality rate in septic patients. Crit Care Med, 2003 Jul, 31(7), 1947 - 51 Elevated nucleosome levels in systemic inflammation and sepsis; Zeerleder S et al.; OBJECTIVE: Multiple organ dysfunction syndrome is a frequent complication of severe sepsis and septic shock and has a high mortality . We hypothesized that extensive apoptosis of cells might constitute the cellular basis for this complication . DESIGN: Retrospective study . SETTING: Medical and surgical wards or intensive care units of two university hospitals . PATIENTS: Fourteen patients with fever, 15 with systemic inflammatory response syndrome, 32 with severe sepsis, and eight with septic shock . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: We assessed circulating levels of nucleosomes, specific markers released by cells during the later stages of apoptosis, with a previously described enzyme-linked immunosorbent assay in these 69 patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock . Severity of multiple organ dysfunction syndrome was assessed with sepsis scores, and clinical and laboratory variables . Elevated nucleosome levels were found in 64%, 60%, 94%, and 100% of patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock, respectively . These levels were significantly higher in patients with septic shock as compared with patients with severe sepsis, systemic inflammatory response syndrome, or fever, and in nonsurvivors as compared with survivors . In patients with advanced multiple organ dysfunction syndrome, nucleosome levels correlated with cytokine plasma levels as well as with variables predictive for outcome . CONCLUSIONS: Patients with severe sepsis and septic shock have elevated plasma levels of nucleosomes . We suggest that apoptosis, probably resulting from exposure of cells to excessive amounts of inflammatory mediators, might by involved in the pathogenesis of multiple organ dysfunction syndrome. J Immunol, 2003 Jul 15, 171(2), 909 - 14 Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells; Tinsley KW et al.; Dendritic cells are a phenotypically diverse group of APC that have unique capabilities to regulate the activity and survival of B and T cells . Although proper function of dendritic cells is essential to host control of invading pathogens, few studies have examined the impact of sepsis on dendritic cells . The purpose of this study was to determine the effect of sepsis on splenic interdigitating dendritic cells (IDCs) and follicular dendritic cells (FDCs) using a clinically relevant animal model . Immunohistochemical staining for FDCs showed that sepsis induced an initial marked expansion in FDCs that peaked at 36 h after onset . The FDCs expanded to fill the entire lymphoid zone otherwise occupied by B cells . Between 36 and 48 h after sepsis, there was a profound caspase 3 mediated apoptosis induced depletion of FDCs such that only a small contingent of cells remained . In contrast to the initial increase in FDCs, IDC numbers were decreased to approximately 50% of control by 12 h after onset of sepsis . IDC death occurred by caspase 3-mediated apoptosis . Such profound apoptosis induced loss of FDCs and IDCs may significantly compromise B and T cell function and impair the ability of the host to survive sepsis. Acta Paediatr Taiwan, 2003 Mar-Apr, 44(2), 104 - 5 Echovirus 11 sepsis in a neonate: report of one case; Hsiao CC et al.; Neonates infected with nonpolio enteroviruses are at high risk for developing significant illness, including sepsis-like illness, meningoencephalitis, myocarditis and/or hepatitis . Echoviruses and group B coxsackieviruses account for the majority of neonatal enterovirus infections . We reported a case of echovirus 11 infection in newborn associated with maternal infection . To our knowledge, this is the first reported fatal case of neonatal echovirus infection in Taiwan . Eventually, the baby expired because of severe sepsis-like illness, fulminant hepatitis, disseminated intravascular coagulation, and extensive hemorrhagic manifestations in spite of intensive care, intravenous immunoglobulin infusion and exchange transfusion. Acta Paediatr, 2003 May, 92(5), 582 - 7 Plasma nitrite/nitrate and endothelin-1 concentrations in neonatal sepsis; Figueras-Aloy J et al.; AIM: To determine the changes in plasma nitrite/nitrate (NOx) and endothelin-1 (ET-1) concentrations during neonatal sepsis . METHODS: In a prospective study, 60 consecutive newborns meeting the criteria for sepsis and without receiving exogenous nitric oxide (25 haemoculture-positive {HC+} and 35 haemoculture-negative {HC-}) were compared with 68 healthy newborns (46 full-term and 22 preterm) . NOx and ET-1 concentrations were measured in each newborn within 48 h of diagnosis of sepsis and then every third day up to three determinations . SNAP-II and SNAPPE-II severity scores were performed at the moment of highest clinical severity . RESULTS: At the beginning of the sepsis period, controls and septicaemic newborns had similar NOx and ET-1 levels, with the exception of infants with severe HC+ sepsis . Throughout the sepsis period, NOx increased in moderate HC+ sepsis and decreased in HC--sepsis, reaching a significant difference at the end of the study period (59.9 +/- 72.7 vs 33.9 15.3 micromol/L; p = 0.036) . Meanwhile, ET-1 in newborns with severe HC+ sepsis remained higher than that in the moderate HC+ sepsis group and HC--group, reaching significant differences in all the periods . The highest ET-1 value was positively correlated with SNAP-II and SNAPPE-II scores . CONCLUSION: NOx concentrations increased throughout the neonatal HC+ sepsis period, reaching significant differences after 7-9 d . The highest ET-1 levels in neonatal HC+ sepsis emerged before the NOx peak, at 3-5 d, and later decreased . Only newborns with severe HC+ sepsis presented a significant increase in ET-1 concentrations from the beginning of the septicaemic process. Mayo Clin Proc, 2003 Jul, 78(7), 869 - 81 The hematologic system as a marker of organ dysfunction in sepsis; Aird WC; Sepsis with acute organ dysfunction (severe sepsis) results from a systemic proinflammatory and procoagulant response to infection . Organ dysfunction in the patient with sepsis is associated with increased mortality . Although most organs have discrete anatomical boundaries and carry out unified functions, the hematologic system is poorly circumscribed and serves several unrelated functions . This review addresses the hematologic changes associated with sepsis and provides a framework for prompt diagnosis and rational drug therapy . Data sources used include published research and review articles in the English language related to hematologic alterations in animal models of sepsis and in critically ill patients . Hematologic changes are present in virtually every patient with severe sepsis . Leukocytosis, anemia, thrombocytopenia, and activation of the coagulation cascade are the most common abnormalities . Despite theoretical advantages of using granulocyte colony-stimulating factor to enhance leukocyte function and/or circulating numbers, large clinical trials with these growth factors are lacking . Recent studies support a reduction in the red blood cell transfusion threshold and the use of erythropoietin treatment to reduce transfusion requirements . Treatment of thrombocytopenia depends on the cause and clinical context but may include platelet transfusions and discontinuation of heparin or other inciting drugs . The use of activated protein C may provide a survival benefit in subsets of patients with severe sepsis . The hematologic system should not be overlooked when assessing a patient with severe sepsis . A thorough clinical evaluation and panel of laboratory tests that relate to this organ system should be as much a part of the work-up as taking the patient's blood pressure, monitoring renal function, or measuring liver enzymes. Mol Cell Proteomics, 2003 Jul, 2(7), 463 - 73 Epub 2003 Jun 26. A High-throughput Quantitative Multiplex Kinase Assay for Monitoring Information Flow in Signaling Networks: Application to Sepsis-Apoptosis; Janes KA et al.; To treat complex human diseases effectively, a systems-level approach is needed to understand the interplay of environmental cues, intracellular signals, and cellular behaviors that underlie disease states . This approach requires high-throughput, multiplex techniques that measure quantitative temporal variations of multiple protein activities in the intracellular signaling network . Here, we describe a single microtiter-based format that simultaneously quantifies protein kinase activities in the phosphatidylinositol 3-kinase pathway (Akt), nuclear factor-kappaB pathway (IKK), and three core mitogen-activated protein kinase pathways (ERK, JNK1, MK2) . These parallel high-throughput assays are stringently linear, redundantly specific, reproducible, and sensitive compared with classical low-throughput techniques . When applied to a model of sepsis-induced colon epithelial apoptosis, this approach identified a late phase of Akt activity as a critical mediator of cell survival that quantitatively contributed to the efficacy of insulin as an anti-apoptotic cue . Thus, sampling parallel nodes in the intracellular signaling network identified part of the molecular mechanism underlying the efficacy of insulin in the treatment of human sepsis. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue, 2003 Mar, 15(3), 135 - 8 {Clinical trial to verify the value of the CD14(+) monocyte human leukocyte antigen DR as a marker in evaluating immunosuppression in patients with severe sepsis}; Lin HY et al.; OBJECTIVE: To verify that CD14(+) monocyte human leukocyte antigen DR (HLA-DR) may serve as a reliable index for immunosupression, and for prediction of prognosis as well as to evaluate the efficacy of Thymopentin (TP-5) to enhance immunologic function in patients with severe sepsis, and to evaluate the validity of compensatory anti-inflammatory response syndrome (CARS) . METHODS: Patients in a SICU with symptoms and signs of severe sepsis conforming to the criteria set forth by ACCP/SCCM were enrolled in this clinical trial . CD14(+) monocyte HLA-DR was determined by flow cytometry . To those with HLA-DR<30%, TP-5, 1 mg, q.d . was administered till HLA-DR raised or death occurred . Before the treatment was begun and ended, CD14(+) monocyte HLA-DR(+) and cytokines{tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-10, IL-13} were respectively measured . RESULTS: Totally, 20 patients were enrolled in this study . Among them 15 survived and 5 died . After treatment with TP-5, CD14(+) monocyte HLA-DR was elevated in almost all the patients, including the nonsurvivors . However, only a statistically significant difference between the initial values and the final values was noted in the survivors . The levels of TNF-alpha and IL-6 dropped significantly concomitantly with the elevation of the CD14(+) monocyte HLA-DR in survivors . On the contrary, in the patients who died there was a tendency of an elevation of levels of these cytokines . No significant difference was found between the initial and final levels of both IL-10 and IL-13 with the treatment . CONCLUSION: 1 . It was reconfirmed that the CD14(+) monocyte HLA-DR could be a reliable and valuable index to judge immunosupression in septic patients and determine the effectiveness of immunostimulative therapy . 2 . It was reconfirmed that the level of CD14(+) monocyte HLA-DR can serve as an index to predict the outcome of septic patients . 3 . TP-5, as a new immunostimulative agent used in sepsis, might be effective to revert immunosupression . However, a further clinical trial with a larger number of patients and a better control should be done to finally verify it . 4 . It is found that immunosupression do not seem to be related with the balance between pro- and anti-inflammatory cytokines, suggesting that the hypothesis of CARS should be further appraised. J Biomed Sci, 2003 Jul-Aug, 10(4), 389 - 95 Sepsis correlated with increased erythrocyte Na+ content and Na+ - K+ pump activity; Hsieh CC et al.; The aims of the present study were twofold: (1) simultaneous determinations of Na(+) transport parameters of erythrocytes from 40 healthy donors and 28 septic patients as assessed by a score of severity of sepsis (SSS), and (2) examination of the correlation between the SSS and specific Na(+) transport abnormalities . Erythrocytes were obtained and loaded with different ionic compositions and cellular Na(+) contents before determination of the near-maximal Na(+) pump rate (Vmax), the physiological extrusion rate of Na(+) (v) and the number of ouabain-binding sites (Bmax) . In erythrocytes from septic patients, the cellular Na(+) content was 28% higher (p < 0.001), with no differences in water content compared to erythrocytes from healthy donors . This elevated Na(+) content was accompanied by significantly higher values for Vmax (43%), v (24%) and Bmax (48%) of the Na(+) pump in septic erythrocytes . Moreover, significant positive correlations existed between Vmax and SSS (p = 0.028) and between cellular Na(+) content and SSS (p = 0.005) . These data suggest that during sepsis, membrane alterations occur and result in an increased cellular Na(+) content . Active Na(+) transport (Vmax and v) was significantly stimulated, possibly as a consequence of a secondary response to the elevated Na(+) of cells . Both cellular Na(+) and Vmax correlated well with the severity of sepsis, suggesting that these altered transport parameters may reflect the progress of sepsis . J Vasc Interv Radiol, 2003 Jun, 14(6), 779 - 83 Fatal sepsis after uterine artery embolization with microspheres; de Blok S et al.; A case report of fatal sepsis after uterine artery embolization (UAE) with microspheres is presented . At autopsy, microspheres were found not only in arteries in the leiomyomata and myometrium but also in the parametria and the vagina, leading to a necrotic vaginal wall and uterine cervix . At present, polyvinyl alcohol particles are usually used in UAE . Recently, study results of the use of microspheres in embolization procedures have become available . The rationale for the choice of a specific embolization particle and the clinical implications of possible sepsis after UAE are discussed. Dtsch Med Wochenschr, 2003 Jun 20, 128(25-26), 1391 - 4 {Pylephlebitis with air in the portal vein system . An unusual focus in a patient with sepsis}; Kluge S et al.; HISTORY AND CLINICAL FINDINGS: A 30-year-old male was transferred to the intensive care unit with worsening sepsis of unknown origin and a known history of Crohn's disease . The patient presented with a five-day history of nausea, fever, and serous diarrhea . Clinical examination of the abdomen was unremarkable except for mild epigastric pain on palpation . INVESTIGATIONS: Computed tomography (CT) of the abdomen revealed gas within the intrahepatic branches of the portal venous system, thickening of the wall of the neoterminal ileum, and mild ascites . In addition, ultrasonography showed acute thrombosis of the portal vein and the superior mesenteric vein . No wall perfusion was seen in either the neoterminal ileum or the ascending colon on color Doppler sonography . DIAGNOSIS, TREATMENT AND COURSE: Based on the combination of portal vein thrombosis along with venous gas in the portal venous system and absence of intestinal perfusion, the diagnosis of pylephlebitis with septic shock was suspected and a laparotomy was performed . Intraoperative exploration revealed phlegmonous terminal ileitis, a significant amount of cloudy fluid, and thrombosis of the mesenteric vein . A right-sided hemicolectomy with ileotransversostomy was performed . Histologic examination confirmed Crohn's disease that was associated with vasculitis and, in particular, with thrombophlebitis and subsequent transmural bowel necrosis . Antibiotic and anticoagulation therapy was resumed without further complications . CONCLUSION: In the differential diagnosis of sepsis, especially in combination with abdominal pain or gas in the portal venous system, pylephlebitis should be taken into account . Because of the high mortality, immediate further diagnostic testing and appropriate therapy of this rare diagnosis are necessary. Shock, 2003 Jul, 20(1), 5 - 9 A meta-analysis of controlled trials of anticoagulant therapies in patients with sepsis; Freeman BD et al.; Although coagulation abnormalities may partly underlie the physiologic derangements of the sepsis syndrome, anticoagulant therapies have produced mixed results on survival in clinical studies . We hypothesized that a meta-analysis of clinical trials of anticoagulants in sepsis may provide insight as to the therapeutic utility of targeting the clotting cascade in this syndrome . We searched electronic databases and reviewed bibliographies of pertinent articles to identify controlled clinical studies in which anticoagulants had been administered as adjunctive therapy to patients with sepsis . After establishing statistical homogeneity, odds ratios (OR; with 95% confidence intervals {CI}) for effect of these agents on mortality and bleeding complications were determined using Mantel-Haenszel methodology . Potential for publication bias was assessed by the use of a statistical test of funnel plot asymmetry . Weighted linear regression was performed to examine the effect of control group mortality rate on treatment efficacy . We identified 11 studies that satisfied our inclusion criteria . Collectively, these studies enrolled 4690 patients (range of 29-2314) and examined three agents: antithrombin III (2659 patients), tissue factor pathway inhibitor (210 patients), and activated protein C (1821 patients) . After establishing statistical homogeneity (P > 0.10, chi-square), we found that the OR (with 95% CI) for effect on mortality for these agents, relative to control treatment, was 0.8692 (0.7519-1.006) . Weighted linear regression analysis was consistent with a control group mortality dependent effect for these agents (P = 0.02) . Only five of the studies reported bleeding complications . Pooling the results of these five studies (4376 patients) resulted in an OR (with 95% CI) of 1.70 (1.40-2.07) relative to control treatment for bleeding risk . Anticoagulants as adjuvant therapy do not appear to improve outcome in sepsis and are associated with a significant risk of bleeding complications . To the extent that their treatment effect is dependent upon disease severity, the safety and efficacy of these agents may be enhanced by refinement in techniques of clinical stratification. Shock, 2003 Jul, 20(1), 1 - 4 Predictive value of monocyte histocompatibility leukocyte antigen-DR expression and plasma interleukin-4 and -10 levels in critically ill patients with sepsis; Hynninen M et al.; It has been suggested that excessive activation of the anti-inflammatory pathways in sepsis may lead to poor outcome of patients with sepsis . The aim of this study was to test the value of histocompatibility leukocyte antigen (HLA)-DR-expression on blood monocytes and plasma levels of interleukin (IL)-4 and -10 in prediction of hospital mortality in patients with sepsis . Sixty-one critically ill patients with sepsis were prospectively enrolled to this study in two university hospital intensive care units . Survivors (n = 41) and nonsurvivors (n = 20) differed significantly in HLA-DR expression at admission: survivors' median 84% (interquartile range 64%-98%) versus nonsurvivors' median 62% (interquartile range 47%-83%, P = 0.025 by Mann-Whitney test) . Similarly, the analysis revealed statistically significant differences between survivors and nonsurvivors in admission plasma IL-10 levels and in admission Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores, but not in IL-4 levels . The areas under receiver operating curves (AUC) showed that both monocyte HLA-DR expression and plasma IL-4 level showed poor discriminative power in prediction of hospital mortality (AUC < 0.70) . Only IL-10 levels on days 1 and 2 showed reasonable predictive power (AUCs 0.706 and 0.725, respectively) . The highest AUC values were those of APACHE-II (0.786) and admission SOFA score (0.763) . In conclusion, APACHE II and SOFA scores on admission showed better discriminatory power than HLA-DR expression and IL-10 and IL-4 levels in prediction of hospital mortality in critically ill patients with sepsis. Zhonghua Shao Shang Za Zhi, 2003 Apr, 19(2), 67 - 70 {The influence of continuous renal replacement therapy on the plasma levels of endotoxin and cytokines in severely burned patients with sepsis}; Li HB et al.; OBJECTIVE: To investigate the influence of continuous renal replacement therapy (CRRT) on the plasma levels of endotoxin and cytokines in severely burned patients with sepsis . METHODS: Ten burn patients who received CRRT and another 10 without CRRT were investigated in terms of the changes in their plasma concentrations of endotoxin and some cytokines (TNFalpha, IL-1beta, IL-6, IL-8) . RESULTS: The plasma concentrations of endotoxin and all the cytokines (TNFalpha, IL-1beta, IL-6, IL-8) after CRRT treatment were significantly lower than those before the treatment (P < 0.01), and the plasma levels of the above factors at all the time points after CRRT treatment than those in patients were evidently lower by routine treatment (P < 0.05 - 0.01) . CONCLUSION: CRRT treatment could effectively lower the plasma levels of endotoxin and some cytokines (TNFalpha, IL-1beta, IL-6, IL-8). J Orthop Surg (Hong Kong), 2003 Jun, 11(1), 73 - 9 Use of antibiotic-loaded polymethyl methacrylate beads in the management of musculoskeletal sepsis--a retrospective study; Mohanty SP et al.; OBJECTIVE: To assess the use of antibiotic-loaded polymethyl methacrylate beads in the management of chronic osteomyelitis of different aetiologies: infected osteosynthesis, infected open fractures, and haematogenous osteomyelitis . METHODS: Records of 49 patients with chronic osteomyelitis who were treated at Department of Orthopaedics, Kasturba Medical College, from 1995 to 1999 were studied retrospectively . The diagnosis of chronic osteomyelitis was made on the basis of clinical and radiographic features . Of the 49 patients, 4 had haematogenous osteomyelitis, which later proved to be tuberculosis, and were thus excluded . Antibiotic-loaded acrylic beads were implanted in the remaining patients after thorough debridement . The implant was removed primarily in 16 patients with infected osteosynthesis, who then underwent decompression and sequestrectomy . All wounds were closed primarily . Peri-operative antibiotics were given for 7 days . Beads were removed at the end of 3 weeks followed by bone grafting in 26 patients . Patients were followed up for an average period of 3.7 years . RESULTS: The infective organisms were sensitive to gentamycin in 26 cases and resistant in 19 cases; 14 cases were sensitive to cefuroxime, 11 to cloxacillin, 8 to ampicillin, and 5 to cotrimoxazole . Seven cases were resistant to all antibiotics tested . Of the 19 patients with gentamycin-resistant infection, only one had a poor result . No adverse systemic side-effects such as ototoxicity or nephrotoxicity were seen . Infection did not recur in 39 patients, but 6 patients had low-grade persistent infection at the last follow-up visit . CONCLUSION: In chronic infections, especially those following osteosynthesis, antibiotic beads are a valuable adjuvant . The most valuable advantage is that the wound can be closed primarily, thereby reducing the incidence of nosocomial infections and requirement of nursing care. J Vasc Res, 2003 Mar-Apr, 40(2), 149 - 58 Conducted vasoconstriction is reduced in a mouse model of sepsis; Lidington D et al.; The ability of an arteriole to conduct vasomotor responses along its length contributes to the control of organ perfusion . Sepsis, a systemic inflammatory response to infection, may compromise this control . We aimed to determine whether sepsis, induced by cecal ligation and perforation (CLP), reduces conducted vasoconstriction 24 h post-CLP . We locally stimulated mouse cremaster arterioles with KCl, measured the resulting local and the conducted constriction (500 microm upstream) and, based on these measurements, determined the communication ratio (CR(500)) as an index of the conducted response . Sepsis significantly reduced the CR(500) from 0.75 to 0.20 . Based on a mathematical model, this reduction was predicted to have a significant impact on blood flow control . In septic mice, either a 1-hour washout of the cremaster muscle with physiological saline or a treatment of this muscle with the tyrosine kinase inhibitor PP-2 (100 nM) restored the CR(500) to the control level . Treatment of septic arterioles with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (100 microM) partially restored the CR(500) from 0.2 to 0.4 . In control mice, lipopolysaccharide (LPS; 10 microg/ml) superfused over the cremaster muscle for 1 h reduced the CR(500); the nitric oxide (NO) donor S-nitroso-N-acetyl-penicillamine (50 microM) also reduced the CR(500) . Thus, LPS and NO could be two factors mediating reduced conduction of vasoconstriction in sepsis . We conclude that sepsis reduces the KCl-induced conducted vasoconstriction in the mouse cremaster muscle by a tyrosine kinase- and nitric oxide- dependent mechanism . J Endotoxin Res, 2003, 9(2), 113 - 8 Impact of sepsis-induced changes in plasma on LPS interactions with monocytes and plasma lipoproteins: roles of soluble CD14, LBP, and acute phase lipoproteins; Kitchens RL et al.; Sepsis-induced changes in human plasma decrease LPS association with monocytes by regulating dynamic interactions among LPS, monocytes, and plasma lipoproteins . In the physiological environment of undiluted human serum, we have found that: (i) LPS binds transiently to monocytes and is released into plasma lipoproteins; (ii) the release of LPS from monocytes is dependent upon lipoprotein acceptors and is enhanced by soluble CD14 (sCD14); and (iii) both lipoproteins and sCD14 can attenuate cytokine responses in monocytes that have already bound LPS . Whereas LPS binding protein (LBP) also inhibited LPS responses after LPS had bound to monocytes, this did not require extensive release of cell-bound LPS as was observed with sCD14 . In the serum of septic patients, both free LPS and monocyte-bound LPS were usually transferred to lipoproteins at an accelerated rate . In spite of a sharp decline in HDL levels, HDL remained the dominant LPS acceptor in many severely septic patients, whereas in some cases LPS binding shifted largely to a non-HDL lipoprotein fraction that co-eluted according to size with very low-density lipoprotein (VLDL) . Preliminary data suggest that these lipoproteins have a very low density, and they contain apolipoprotein E and higher than normal proportions of the total lipoprotein cholesterol, phospholipid, apolipoprotein B, and serum amyloid A . The data suggest that the VLDL fraction contains acute phase lipoproteins of significantly altered composition that can replace HDL as the dominant LPS acceptor during sepsis when HDL levels are low. J Endotoxin Res, 2003, 9(2), 91 - 5 Continuous cardiac output and hemodynamic monitoring: high temporal correlation between plasma TNF-alpha and hemodynamic changes during a sepsis-like state in cancer immunotherapy; Caorsi C et al.; Through continuous cardiac output monitoring, we investigated the temporal relationship between hemodynamic changes and plasma cytokines in a cancer patient who developed collateral sepsis to immunotherapy . A 52-year-old male with metastatic renal cell carcinoma received interleukin-2 (IL-2) infusion completing 72 h of administration . The patient developed 3 sepsis-like states including systemic inflammatory response syndrome (SIRS), shock, and multiple organ dysfunction syndrome (MODS) . Hemodynamic parameters including systemic vascular resistance index (SVRI), left ventricular stroke work index (LVSWI) and cardiac index (CI) were measured over 60 h . Peripheral blood was drawn when SVRI dropped 20% in the patient and plasma cytokines including TNF-alpha, IL-6 and IL-1beta were measured using ELISA . After 60 h of immunotherapy, the patient showed a 63.4% decrease in SVRI, 54.5% decrease in LVSWI and 65.4% increase in CI . The evaluation of systemic cytokines revealed different kinetic patterns: (i) a sustained increase in TNF-alpha levels through all 3 sepsis-like states; (ii) IL-6 increased preferentially during SIRS and shock, while up/down-responses were found during MODS; (iii) IL-1beta was undetectable during the entire study period . A high temporal relationship between hemodynamic changes and plasma TNF-alpha, but not IL-6, was found . Although there are factors other than cytokines that can alter vascular resistance, this finding could represent an approach to evaluate the course of hemodynamia and probably the systemic cytokine expression after IL-2 administration in renal cancer. Eur J Anaesthesiol, 2003 Jun, 20(6), 429 - 42 Fluid therapy in sepsis with capillary leakage; Marx G; Sepsis is associated with a profound intravascular fluid deficit due to vasodilatation, venous pooling and capillary leakage . Fluid therapy is aimed at restoration of intravascular volume status, haemodynamic stability and organ perfusion . Circulatory stability following fluid resuscitation is usually achieved in the septic patient at the expense of tissue oedema formation that may significantly influence vital organ function . The type of fluid therapy, crystalloid or colloid, in sepsis with capillary leakage remains an area of intensive and controversial discussion . The current understanding of the physiology of increased microvascular permeability in health and sepsis is incomplete . Furthermore, there is a lack of appropriate clinical study end-points for fluid resuscitation . This review considers critically the clinical and experimental data analysing the assessment of capillary leakage in sepsis and investigating the effects of different fluid types on increased microvascular permeability in sepsis. Intensive Care Med, 2003 Jul, 29(7), 1052 - 61 Epub 2003 Jun 12. Red blood cell rheology in sepsis; Piagnerelli M et al.; Changes in red blood cell (RBC) function can contribute to alterations in microcirculatory blood flow and cellular dysoxia in sepsis . Decreases in RBC and neutrophil deformability impair the passage of these cells through the microcirculation . While the role of leukocytes has been the focus of many studies in sepsis, the role of erythrocyte rheological alterations in this syndrome has only recently been investigated . RBC rheology can be influenced by many factors, including alterations in intracellular calcium and adenosine triphosphate (ATP) concentrations, the effects of nitric oxide, a decrease in some RBC membrane components such as sialic acid, and an increase in others such as 2,3 diphosphoglycerate . Other factors include interactions with white blood cells and their products (reactive oxygen species), or the effects of temperature variations . Understanding the mechanisms of altered RBC rheology in sepsis, and the effects on blood flow and oxygen transport, may lead to improved patient management and reductions in morbidity and mortality. J Crit Care, 2003 Jun, 18(2), 115 - 20 Circulating endotoxin and antiendotoxin antibodies during severe sepsis and septic shock; Maury E et al.; The presence of circulating endotoxin is common during sepsis but its prognostic value is poor . We hypothesized that this lack of correlation with outcome could be related in part to the presence of circulating antiendotoxin antibodies . In a 14-bed medical intensive care unit, in an 821-bed tertiary teaching hospital, we prospectively assessed endotoxin and antiendotoxin antibodies in patients with severe sepsis or septic shock . Blood samples for the determination of circulating endotoxin and antiendotoxin antibodies were drawn when severe sepsis or septic shock were diagnosed (day 0) and then on day 1, day 2, and day 4 . Daily measurements of antiendotoxin antibodies did not discriminate survivors from nonsurvivors . No antibody depletion was observed . However, during follow-up, the antiendotoxin immunoglobulin (Ig)M antibody level increased among survivors but decreased among nonsurvivors (51.2 vs -44.8 MU/mL, P=007) . Circulating endotoxin was detectable among 9 of 17 patients on inclusion but neither the basal value nor sequential measurements correlated with outcome . These results suggest that during severe sepsis and septic shock, circulating endotoxin is a poor prognostic marker whereas the detection of an increase in IgM antiendotoxin antibody levels could identify survivors . This increase in IgM antibody levels could be attributed to a reactivation of the immune system . Copyright Elsevier Inc . All rights reserved. Eur Cytokine Netw, 2003 Jan-Mar, 14(1), 15 - 9 Anti-inflammatory response after infusion of p55 soluble tumor necrosis factor receptor fusion protein for severe sepsis; Butty VL et al.; OBJECTIVES: To investigate the effects of Lenercept , a recombinant soluble TNF receptor p55 fused to an immunoglobulin heavy chain IgG1, on the balance of pro- and anti-inflammatory mediators in sepsis . DESIGN: Post hoc analysis of a subgroup of patients enrolled in a multicenter phase III, prospective, double-blind, placebo-controlled, randomized study of Lenercept in severe sepsis . SETTING: Surgical and medical intensive care units, and postoperative recovery room of a tertiary care teaching hospital . PATIENTS: A total of 57 patients were enrolled in the multicenter study in our center . Intervention: Septic patients were randomly assigned to receive either Lenercept 0.125 mg/kg or placebo . The patients were followed for up to 28 days after randomization . MEASUREMENTS AND MAIN RESULTS: Circulating levels of TNF-alpha, IL-6, TNFsR75 and IL-1Ra were measured before and after treatment . The two groups were comparable with regard to age, gender and diagnosis distribution . The total level of TNF-alpha increased significantly in treated patients, compared to patients receiving placebo . The levels of the other inflammatory mediators did not differ between the two groups CONCLUSIONS: Lenercept -treated patients experienced a protracted TNF-alpha half-life, leading to higher total TNF-alpha levels throughout the study . However, the treatment had no effects on anti-inflammatory mediators . Therefore, peripheral inflammatory processes might not have been significantly modified by the treatment . This might account for the lack of efficacy this treatment in septic patients Clin Sci (Lond), 2003 Sep, 105(3), 383 - 91 Sepsis induces the transcription of the glucocorticoid receptor in skeletal muscle cells; Sun X et al.; Evidence from a recent study indicates that glucocorticoids (GCs) mediate skeletal muscle proteolysis during sepsis via the GC receptor (GR) pathway . Attempts to identify the mechanisms regulating GR gene expression in skeletal muscle during sepsis have been hampered by the lack of an appropriate in vitro model system that can mimic in vivo septic conditions . In the present study, we report that GR gene transcription in L6 myocytes in vitro is up-regulated by treatment with sera from septic rats in a manner similar to that measured in septic rats in vivo . Sera from septic rats were collected from animals in which sepsis was induced by caecal ligation and puncture and from control rats that were sham-operated . Finally, by treating L6 myotubes with the GR antagonist RU 38486, thereby preventing sepsis-induced GR transcription, we confirmed that the possible septic effect on the GR was due to increased GCs . L6 myocytes treated with sera from septic rats might therefore be useful as an experimental model for identifying the molecular mechanisms by which the GR regulates muscle cachexia during sepsis . Furthermore, RU 38486 inhibited the sepsis-induced increase in total and myofibrillar energy-dependent protein breakdown rates in incubated extensor digitorum longus muscles from septic and sham-operated rats, as measured by release of tyrosine and 3-methylhistidine respectively . Our results demonstrate for the first time that sepsis induces GR transcription in skeletal muscle, and supports the hypothesis that the GC-induced proteolysis under sepsis is partially a consequence of GR activation. Bone Marrow Transplant, 2003 Jun, 31(12), 1137 - 42 Procalcitonin, C-reactive protein, and endotoxin after bone marrow transplantation: identification of children at high risk of morbidity and mortality from sepsis; Sauer M et al.; We prospectively evaluated the capacity of serum procalcitonin (PCT), compared with serum levels of C-reactive protein (CRP) and endotoxin, to identify children at high risk for mortality from sepsis after BMT . Of 47 pediatric bone marrow transplantation patients studied, 22 had an uneventful course post-transplant (Group 1), 17 survived at least one septic event (Group 2), and eight died from multiorgan failure (MOF) following septic shock (Group 3) . Median concentrations of PCT over the course of the study were 1.3, 15.2, and 102.8 ng/ml, respectively, in each of the three groups (P<0.002 for each comparison) . Median concentrations of CRP were 91, 213, and 260 mg/l, respectively (P<0.001 for Group 1 vs Group 2 and Group 3; P=NS for Group 2 vs Group 3) . Median concentrations of endotoxin were 0.21, 0.30, and 0.93 U/l, respectively (P=NS for each comparison) . Median concentrations of PCT, in contrast to serum CRP and endotoxin, correlated with the severity of sepsis (8.2 ng/ml in 'sepsis' and 22.3 ng/ml in 'severe sepsis', P=0.028) and provided useful prognostic information during septic episodes. Arch Pediatr Adolesc Med, 2003 Jun, 157(6), 511 - 6 Beyond the complete blood cell count and C-reactive protein: a systematic review of modern diagnostic tests for neonatal sepsis; Malik A et al.; OBJECTIVE: To systematically review the accuracy of modern laboratory tests for the diagnosis of serious bacterial infection in newborns . METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched using the keywords newborn, infection, sepsis, and diagnosis . We included studies published from 1995 through 2001 that included infants younger than 90 days with proven bacterial growth in a sample from a sterile site . Whenever possible, relevant data were extracted to calculate likelihood ratios (LRs) for whether each test can diagnose a serious bacterial infection . Two independent reviewers selected and reviewed the articles (interobserver agreement, kappa = 0.80) . All disagreements were resolved by consensus . RESULTS: Of the 137 citations we retrieved, 37 articles met the inclusion criteria; 17 studies, evaluating 11 different tests, met the highest methodological criteria . The most commonly evaluated test was interleukin 6 (IL-6) level (n = 7 studies) . The remaining tests were each evaluated in no more than 3 studies . Positive LRs ranged from 1.5 to infinity . Six individual tests examined in 8 studies had LRs of more than 10 (range, 12.5- infinity ) . Combined tests also had a wide range of LRs (3.4-9.9) . All studies were performed in single medical centers and had small sample sizes, making recommendations according to gestational age criteria difficult . CONCLUSIONS: We found few methodologically rigorous studies of the accuracy of laboratory tests for the diagnosis of bacterial infection in newborns; in a significant proportion of studies, the accuracy of the tests could not be independently determined because of a lack of adequate data . There was marked heterogeneity in sample selection and cutoff levels for diagnosis of neonatal sepsis . A few tests showed promising accuracy, but there are insufficient data to support their confident use as clinical tools. Crit Care Med, 2003 Jun, 31(6), 1808 - 18 Modulation of tissue Toll-like receptor 2 and 4 during the early phases of polymicrobial sepsis correlates with mortality; Williams DL et al.; OBJECTIVE: To determine whether there was a correlation between induction of polymicrobial sepsis, modulation of tissue Toll-like receptor (TLR) gene, and protein expression and survival outcome . DESIGN: Prospective, randomized animal study . SETTING: University medical school research laboratory . SUBJECTS: Age- and weight-matched ICR/HSD mice . INTERVENTIONS: Sepsis was induced by cecal ligation and puncture (CLP) . No-surgery and sham (laparotomy)-operated mice were controls . We also examined tissue TLR2 and TLR4 messenger RNA and TLR4 protein levels in mice treated with an immunomodulator that increases survival in polymicrobial sepsis . In the immunomodulator study, mice were treated with glucan phosphate (50 mg/kg, intraperitoneally) 1 hr before CLP . No-surgery, sham surgery, glucan + no-surgery, sham surgery + glucan, and CLP groups were employed as controls . MEASUREMENTS AND MAIN RESULTS: Total RNA was isolated from liver, lung, and spleen at 0, 1, 3, 6, 8, and 24 hrs after CLP . TLR gene expression was assessed by reverse transcription-polymerase chain reaction . Tissue TLR4 protein levels were evaluated at 24 hrs by Western blot and immunohistochemistry . CLP sepsis increased (p <.05) liver and lung TLR2 and TLR4 gene expression compared with controls . TLR4 protein concentrations also were increased . Increased TLR2/4 gene and TLR4 protein expression correlated with mortality . Immunoprophylaxis with glucan phosphate increased (p <.001) long-term survival (20% vs . 70%) but inhibited (p <.05) CLP-induced increases in tissue TLR2 and TLR4 messenger RNA expression as well as TLR4 protein expression . CONCLUSIONS: Early increases in TLR2/4 gene and TLR4 protein expression correlated with mortality, whereas blunting TLR gene and protein expression correlated with improved long-term survival . This suggests that early up-regulation of tissue TLR2/4 may play a role in the proinflammatory response and pathophysiology of polymicrobial sepsis. Crit Care Med, 2003 Jun, 31(6), 1737 - 41 Comparison of procalcitonin and C-reactive protein as markers of sepsis; Luzzani A et al.; OBJECTIVE: To compare the clinical informative value of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations in the detection of infection and sepsis and in the assessment of severity of sepsis . DESIGN: Prospective study . SETTING: Medicosurgical intensive care unit . PATIENTS: Seventy consecutive adult patients who were admitted to the intensive care unit for an expected stay >24 hrs . INTERVENTIONS: None . MEASUREMENTS: PCT and CRP plasma concentrations were measured daily during the intensive care unit stay . Each patient was examined daily for signs and symptoms of infection and was classified daily in one of the following four categories according to the American College of Chest Physicians/Society of Critical Care Medicine criteria: negative, systemic inflammatory response syndrome, localized infection, and sepsis group (sepsis, severe sepsis, or septic shock) . The severity of sepsis-related organ failure was assessed by the sepsis-related organ failure assessment score . MAIN RESULTS: A total of 800 patient days were classified into the four categories . The median plasma PCT concentrations in noninfected (systemic inflammatory response syndrome) and localized-infection patient days were 0.4 and 1.4 ng/mL (p <.0001), respectively; the median CRP plasma concentrations were 79.9 and 85.3 mg/L (p =.08), respectively . The area under the receiver operating characteristic curve was 0.756 for PCT (95% confidence interval {CI}, 0.675-0.836), compared with 0.580 for CRP (95% CI, 0.488-0.672) (p <.01) . The median plasma PCT concentrations in nonseptic (systemic inflammatory response syndrome) and septic (sepsis, severe sepsis, or septic shock) patient days were 0.4 and 3.65 ng/mL (p <.0001), respectively, whereas those for CRP were 79.9 and 115.6 mg/L (p <.0001), respectively . The area under the receiver operating characteristic curve was 0.925 for PCT (95% CI, 0.899-0.952), compared with 0.677 for CRP (95% CI, 0.622-0.733) (p <.0001) . The linear correlation between PCT plasma concentrations and the four categories was much stronger than in the case of CRP (Spearman's rho, 0.73 vs . 0.41; p <.05) . A rise in sepsis-related organ failure assessment score was related to a higher median value of PCT but not CRP . CONCLUSION: PCT is a better marker of sepsis than CRP . The course of PCT shows a closer correlation than that of CRP with the severity of infection and organ dysfunction. Crit Care Med, 2003 Jun, 31(6), 1691 - 6 Methodologic quality and genotyping reproducibility in studies of tumor necrosis factor -308 G-->A single nucleotide polymorphism and bacterial sepsis: implications for studies of complex traits; Peters DL et al.; OBJECTIVE: Studies of genetic associations with common diseases, such as between cytokine gene polymorphisms and severe bacterial sepsis, have reached conflicting conclusions . Failure to follow methodologic standards may have contributed to discordant findings . The -308 G-->A transition in the tumor necrosis factor-alpha promoter has been genotyped by a variety of methods . Based on our observation of genotyping inaccuracies, we sought to determine whether published studies followed a series of acceptable methodologic standards and whether failure to follow the standard of genotyping reproducibility could lead to erroneous conclusions about gene-disease associations . DESIGN: Systematic review and reanalysis of banked genetic material . We applied a published series of seven methodologic standards to five reports of the association between this variant and bacterial sepsis . We then studied the accuracy of restriction fragment length polymorphism for the -308 site using DNA from a cohort of injury victims . SETTING: Surgery research laboratory . MEASUREMENTS AND MAIN RESULTS: We observed that methodologic quality was not uniform and that reproducibility of genotyping was infrequently met . In our subjects, we found that 4 of 46 heterozygotes analyzed by restriction fragment length polymorphism were actually GG-homozygotes (9% misclassified) according to alternative genotyping methods . CONCLUSIONS: Failure to confirm genotype may have led to conclusions that this polymorphism is not associated with sepsis or outcome . Our observations have implications for the conduct and evaluation of studies of complex genetic disease. Crit Care Med, 2003 Jun, 31(6), 1612 - 9 Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial; Schuster DP et al.; OBJECTIVE: Platelet-activating factor (PAF) is a potent proinflammatory mediator implicated in the pathogenesis of both severe sepsis and acute respiratory distress syndrome . One of the regulatory pathways for PAF involves degradation to the inactive metabolite lyso-PAF by the enzyme PAF acetylhydrolase (PAF-AH) . Because reduced concentrations of the natural form of PAF-AH have been reported in septic patients, the present study was conducted to determine whether treatment with recombinant human PAF-AH (rPAF-AH, Pafase) was safe when administered after the onset of severe sepsis and whether it decreases the prevalence of acute respiratory distress syndrome and 28-day all-cause mortality . DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter trial . SETTING: Thirty-three medical and surgical intensive care units located in the United States . PATIENTS: A total of 127 patients with severe sepsis, but without established acute respiratory distress syndrome, were enrolled in the study . Randomization occurred within 12 hrs of the onset of severe sepsis . Patients then received 1.0 mg/kg rPAF-AH (n = 45), 5.0 mg/kg rPAF-AH (n = 39), or placebo (n = 43) administered intravenously, once daily, for five consecutive days . MEASUREMENTS AND MAIN RESULTS: Demographic and baseline clinical characteristics of the three treatment groups were similar, except for a significantly higher prevalence of respiratory tract infections as the cause of severe sepsis in patients treated with 1.0 mg/kg rPAF-AH . There were no treatment-related deaths, and the overall prevalence of adverse events was similar among rPAF-AH-treated and placebo-treated patients . There were no significant differences in the prevalence of acute respiratory distress syndrome among the three treatment groups . However, 28-day all-cause mortality was 21% in the 1.0 mg/kg rPAF-AH group, 28% in the 5.0 mg/kg rPAF-AH group, and 44% in the placebo group (overall chi-square p =.07; 1.0 mg/kg rPAF-AH vs . placebo, p =.03) . A trend toward reduced multiple organ dysfunction also was observed in the 1.0 mg/kg rPAF-AH group compared with the placebo group (p =.11) . CONCLUSION: The results from this study indicate that rPAF-AH was well tolerated and should be pursued as a potential new treatment to decrease mortality in patients with severe sepsis. Crit Care, 2003 Jun, 7(3), R24 - 34 Epub 2003 Mar 17. Severe sepsis: variation in resource and therapeutic modality use among academic centers; Yu DT et al.; BACKGROUND: Treatment of severe sepsis is expensive, often encompassing a number of discretionary modalities . The objective of the present study was to assess intercenter variation in resource and therapeutic modality use in patients with severe sepsis . METHODS: We conducted a prospective cohort study of 1028 adult admissions with severe sepsis from a stratified random sample of patients admitted to eight academic tertiary care centers . The main outcome measures were length of stay (LOS; total LOS and LOS after onset of severe sepsis) and total hospital charges . RESULTS: The adjusted mean total hospital charges varied from 69 429 dollars to US237 898 dollars across centers, whereas the adjusted LOS after onset varied from 15.9 days to 24.2 days per admission . Treatments used frequently after the first onset of sepsis among patients with severe sepsis were pulmonary artery catheters (19.4%), ventilator support (21.8%), pressor support (45.8%) and albumin infusion (14.4%) . Pulmonary artery catheter use, ventilator support and albumin infusion had moderate variation profiles, varying 3.2-fold to 4.9-fold, whereas the rate of pressor support varied only 1.92-fold across centers . Even after adjusting for age, sex, Charlson comorbidity score, discharge diagnosis-relative group weight, organ dysfunction and service at onset, the odds for using these therapeutic modalities still varied significantly across centers . Failure to start antibiotics within 24 hours was strongly correlated with a higher probability of 28-day mortality (r2 = 0.72) . CONCLUSION: These data demonstrate moderate but significant variation in resource use and use of technologies in treatment of severe sepsis among academic centers . Delay in antibiotic therapy was associated with worse outcome at the center level. J Infect Dis, 2003 Jun 15, 187 Suppl 2, S364 - 9 Nuclear factor-kappaB and its role in sepsis-associated organ failure; Abraham E; Nuclear factor (NF)-kappaB is involved in regulating the transcription of many of the immunomodulatory mediators involved in the development of sepsis-induced organ failure . Kinase pathways involving p38 and Akt and initiated by engagement of Toll-like receptors modulate transcriptional activity of NF-kappaB, but apparently through different mechanisms . Increased activation of NF-kappaB occurs with sepsis, and greater levels of nuclear accumulation of NF-kappaB are associated with higher rates of mortality and worse clinical outcome . The percentage of apoptotic neutrophils is reduced in sepsis, and inhibition of nuclear translocation of NF-kappaB restores neutrophil apoptosis to baseline levels . In models of sepsis, suppression of NF-kappaB activation decreases acute inflammatory processes and organ dysfunction . Because NF-kappaB occupies a central role in signaling pathways important in sepsis, modulation of NF-kappaB activity may be an appropriate therapeutic target in patients with sepsis. J Infect Dis, 2003 Jun 15, 187 Suppl 2, S308 - 14 Use of transcriptome data to unravel the fine structure of genes involved in sepsis; Stevenson BJ et al.; The sequence of the human genome is providing researchers with the scaffold upon which genes are built . The definition of the boundaries of the genes themselves and of their complex architecture requires a mapping of the transcriptome to the genome . A methodology was developed for generating a detailed transcriptome map and for reconstituting transcripts by using the genome as a template . As a demonstration of the potential of this method, the structure of the human Toll-like receptor (TLR) genes was reevaluated . For all TLR genes for which a genomic sequence was available (i.e., all except TLR10), novel features of the gene structure were discovered . These features include multiple alternative polyadenylation sites, additional exons or splice variants, and overlaps with other genes . These findings have implications for the analysis of TLR gene expression and for the diversity of the proteins encoded by these genes. Colorectal Dis, 2001 Mar, 3(2), 115 - 21 A simple, inexpensive, life-saving way to perform iterative laparotomy in patients with severe intra-abdominal sepsis; Doyon A et al.; Between 1 June 1993 and 31 December 1998, 17 patients underwent temporary abdominal closure with 3L urological irrigation bags, because in most cases, there was massive sepsis leading to the conclusion that primary closure was not advisable . Indicative of the seriousness of these conditions, Apache score averaged 19 (range 10-30) . The technique consisted of suturing a double thickness of irrigation bags to each side of the wound, and joining the two bags in the midline with running sutures . Abdominal lavage with large quantities of fluid was performed every other day . This type of closure was used for a mean duration of 15 days . Mean length of hospitalization was 60 days . There were only three deaths (17.6%) . No incisional hernia occurred after the iterative laparotomies . Deleting patients with acute pancreatitis would have reduced the death rate to only 7% . A 3L urological irrigation bag costs pound 11.60 (24.40 dollars CAN) while a Marlex mesh costs pound 81.40 (171.00 dollars CAN) . We conclude that the usage of 3L urological plastic bags is a simple, safe and efficient method for temporary closure of the abdomen. Shock, 2003 Jun, 19(6), 533 - 7 G protein and adenylate cyclase complex-mediated signal transduction in the rat heart during sepsis; Wu LL et al.; Changes in the protein level of various subunits of GTP-binding protein and the activity of adenylate cyclase in the rat heart during different phases of sepsis were studied . Sepsis was induced by cecal ligation and puncture (CLP) . Experiments were divided into three groups: control, early sepsis, and late sepsis . Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after CLP . The protein levels of various subunits of GTP-binding protein were determined by Western blot analysis . The activity of adenylate cyclase was measured based on the rate of formation of cAMP from {alpha-32P}ATP . The results show that protein levels of G alphas and G beta remained stable during the early and the late phases of sepsis . The protein levels of G alpha i-2 and G alpha i-3 remained relatively unaltered during the early phase of sepsis, but they were increased by 46.5% (P < 0.05) and 61.3% (P < 0.01), respectively, during the late phase of sepsis . The basal adenylate cyclase activity remained unchanged during the early phase while it was decreased by 25.7% (P < 0.05) during the late phase of sepsis . The isoproterenol-stimulated adenylate cyclase activity was unchanged during early sepsis while it was decreased by 44.6% (P < 0.01) during late sepsis . These data demonstrate that during the late hypodynamic phase of sepsis, myocardial G alpha i-2 and G alpha i-3 protein levels were increased and the increases were coupled with a reduction in adenylate cyclase activity . Because GTP-binding proteins mediate sympathetic control of cardiac function, the present findings may have a pathophysiological significance in contributing to the understanding of the pathogenesis of cardiac dysfunction during the late stage of sepsis. Shock, 2003 Jun, 19(6), 513 - 8 Mast cells and resistance to peritoneal sepsis after burn injury; Shelley O et al.; A mouse model of burn injury demonstrates increasing mortality to an infectious challenge in the form of cecal ligation and puncture (CLP) reaching a peak at 10 days after injury . Because it is widely believed that peritoneal mast cells play an important role in the defense against peritoneal sepsis, we wished to explore the possibility that peritoneal mast cell dysfunction contributed to increased CLP mortality after burn injury . Kit(W-v) C57BL/6 mice, which were shown to lack peritoneal mast cells by cytospin and flow cytometry, and normal littermate control animals were subjected to 25% burn or sham burn injury and 10 days later underwent CLP . Burn injured Kit(W-v) and normal littermates had a high CLP mortality when compared with sham-injured Kit(W-v) and normal littermates (P < 0.003), but the sham- and burn-injured Kit(W-v) and normal littermate animals did not differ from one another with respect to CLP mortality . This result prompted a comparison of CLP mortality in untreated WBB6F1 Kit(W/W-v) mice, known to be mast cell deficient, and normal littermate controls, as well as untreated C57BL/6 Kit(W-v) and normal littermates . The WBB6F1 Kit(W/W-v) mice showed significantly increased mortality after CLP as compared with the littermate controls (P = 0.03), whereas both C57BL/6 Kit(W-v) and littermate controls had very low mortality after CLP . A study of peritoneal cell populations 24 h after CLP failed to reveal an obvious cause for the difference in CLP survival between the two mast cell-deficient strains . Tumor necrosis factor-alpha (TNF-alpha) measurements in peritoneal fluid showed appreciable amounts of TNF-alpha in the littermate controls of both strains and little in the fluid obtained from the mast cell-deficient animals of both strains . We conclude that peritoneal mast cell dysfunction is unlikely to be a major cause of decreased resistance to peritoneal sepsis in burn-injured animals and that the importance of peritoneal mast cells in combating peritoneal sepsis in the mouse appears to be strain dependent. Intensive Care Med, 2003 Oct, 29(10), 1782 - 9 Epub 2003 May 29. Oxidative parameters and mortality in sepsis induced by cecal ligation and perforation; Ritter C et al.; OBJECTIVE: This study assessed parameters of free radical damage to biomolecules, mitochondrial superoxide production, superoxide dismutase, and catalase activities and their relationship to sepsis mortality . DESIGN AND SETTING: Prospective animal study in a university laboratory for experimental . SUBJECTS: 140 male Wistar rats . INTERVENTIONS: The animals were randomly divided into three groups: sham-operated (n=20), cecal ligation and perforation resuscitated with normal saline (n=40), and cecal ligation and perforation with normal saline plus antibiotics (n=40) . MEASUREMENTS AND RESULTS: Blood samples were collected from all animals 3, 12, and 24 h after CLP through a jugular catheter inserted before CLP . Rats were evaluated during 5 days after the intervention . Nonsurvivor animals were grouped according to the duration between sepsis induction and death, and oxidative parameters were compared to survivors and sham-operated . Lipid peroxidation, protein carbonyls, and superoxide dismutase were significantly increased in nonsurvivor septic rats and were predictive of mortality . We demonstrated that there is a different modulation of superoxide dismutase and catalase in nonsurvivors during the course of septic response . There was a marked increase in superoxide dismutase activity without a proportional increase in catalase activity in nonsurvivors . CONCLUSIONS: This is the first report of plasma superoxide dismutase as an earlier marker of mortality . Ours results might help to clarify an important aspect of oxidative response to sepsis, i.e., an increase in superoxide dismutase activity without a proportional increase in catalase activity J Pediatr Surg, 2003 Jun, 38(6), 966 - 70 Mechanism of intestinal-derived fungal sepsis by gliotoxin, a fungal metabolite; Upperman JS et al.; BACKGROUND/PURPOSE: Gut barrier dysfunction resulting from fungal overgrowth may be caused by the interaction of gliotoxin (GT), a fungal metabolite, with enterocytes . The goal of this study was to determine the mechanisms by which gliotoxin (GT), a fungal metabolite, causes enterocyte apoptosis . METHODS: The authors measured enterocyte apoptosis, caspase-3 activity, pro-caspase-3, and poly (ADP-ribose) polymerase (PARP) cleavage in GT-exposed IEC-6 cells, a rat intestinal cell line . RESULTS: GT induced apoptosis in IEC-6 cells . The pan-caspase inhibitor ZVAD suppressed this GT-mediated apoptosis . GT induced a 15-fold increase in caspase-3 activity over media control . The authors detected PARP cleavage by after GT exposure . DTT pretreatment decreased apoptosis compared with GT alone . CONCLUSIONS: This study supports the concept that fungal overgrowth may lead to gut barrier dysfunction by the local release of gliotoxin and the induction enterocyte apoptosis. J Trauma, 2003 May, 54(5), 959 - 66 The risk factors and time course of sepsis and organ dysfunction after burn trauma; Fitzwater J et al.; BACKGROUND: Sepsis and organ dysfunction are common and likely contribute to death after burn trauma . We sought to define relationships between sepsis, severe multiple organ dysfunction (MOD), and death after burn trauma . METHODS: Adults with > or = 20% total body surface area burns were prospectively enrolled . Information regarding infection, severity of sepsis, and organ failure was collected daily . Risk factors (e.g., age, burn size, shock) were analyzed for their association with severe MOD, complicated sepsis, and death . We characterized the temporal relationship between organ failure and sepsis . RESULTS: Of 175 patients, 27% developed severe MOD, 17% developed complicated sepsis, and 22% died . Full-thickness burn size, age, and inhalation injury were associated with MOD, sepsis, and death . Infection preceded MOD in 83% of patients with both . A base deficit of > or = 6 mEq/L at 24 hours after injury was associated with death . CONCLUSION: When it occurs, severe MOD is usually preceded by infection . In addition, an elevated base deficit at 24 hours and septic shock are the most important factors associated with and possibly contributing to death after burn trauma. Can J Neurol Sci, 2003 May, 30(2), 98 - 105 Progress in clinical neurosciences: sepsis-associated encephalopathy: evolving concepts; Wilson JX et al.; Systemic sepsis commonly produces brain dysfunction, sepsis-associated encephalopathy, which can vary from a transient, reversible encephalopathy to irreversible brain damage . The encephalopathy in the acute phase clinically resembles many metabolic encephalopathies: a diffuse disturbance in cerebral function with sparing of the brain stem . The severity of the encephalopathy, as reflected in progressive EEG abnormalities, often precedes then parallels dysfunction in other organs . Recent research has revealed a number of potentially important, non-mutually exclusive, mechanisms that have therapeutic implications. J Obstet Gynecol Neonatal Nurs, 2003 May-Jun, 32(3), 348 - 56 The lived experience of nurses caring for newborns with sepsis; Rubarth LB; OBJECTIVE: To describe the lived experience of nurses who care for newborns with sepsis . DESIGN: Phenomenology, a qualitative study using open-ended, tape-recorded interviews, followed by a focus group discussion . The data were analyzed using Colaizzi's step-by-step procedure, resulting in an essential structure of the experience . SETTING: The nursery and neonatal intensive-care unit of a large community hospital in the southwestern United States . PARTICIPANTS: Eleven registered nurses who cared for newborns in both a transitional nursery and the neonatal intensive-care unit were interviewed individually or in a focus group . RESULTS: Three major themes were generated from the data: (a) "Dealing With Death and the Blessings of Life," (b) "Sepsis: The Cancer in the NICU," and (c) "Losing the Dream: Parents' Reactions." The nurses had feelings of helplessness and frustration while caring for these sick newborns . Nurses described the changes in newborns' condition as sepsis developed, the actions taken to reverse the downhill course, and the experiencing of the outcome . Nurses perceived that parents responded with overwhelming fear, guilt, and loss of control . CONCLUSIONS: The nurse caring for the infant with sepsis experiences many different emotions, reactions, and perceptions . These findings can assist nurses to have a better understanding of the role of the nurse and the emotional burden of working in the NICU. Int J Surg Investig, 2000, 2(1), 9 - 15 S-adenosylmethionine immunomodulator treatment in sepsis; Garcia-Alvarez F et al.; BACKGROUND: S-adenosylmethionine (SAMe) is a forerunner of glutathione . AIMS: The aim of the present study is to ascertain this drug effect on T-lymphocytes and cytokines in an experimental model of surgical sepsis . METHODS: Rats were allotted in two groups . In the control group, rats underwent anaesthesia and laparatomy with cecal ligation and puncture (CLP) . In the second group, rats underwent the same CLP and received SAMe (14 mg/kg) i.m., on the 1st (1PO) and 2nd (2PO) postoperative days . A week before surgery (PRE), on the 1PO and on the 3PO: IL-1, IL-2, IL-4, IL-6, IL-10 and TNF levels (ELISA & MoAb), and CD3, CD4, CD8 cell and IL-2R percentages (%) (flow cytometry & MoAb) were determined in peripheral blood . RESULTS: Rats receiving SAMe do not show changes of CD3%, CD4% and IL-1 levels but show a significant increase of CD8% on the 3PO, showing a significant difference with regard to controls (p < 0.01) . Both groups show a similar IL-2R variation pattern: increasing on 1PO (p < 0.05) and decreasing on 3PO (p < 0.05) . CONCLUSION: In sepsis: SAMe inhibits the decrease of circulating immune-active cells and the IL-1 increase . This drug seems to have effects useful in avoiding immunological alterations in sepsis, that need to be tested in humans. Intensive Care Med, 2003 Aug, 29(8), 1245 - 52 Epub 2003 May 28. Is low monocyte HLA-DR expression helpful to predict outcome in severe sepsis? Perry SE, Mostafa SM, Wenstone R, Shenkin A, McLaughlin PJ. OBJECTIVE: Low monocyte human leukocyte antigen-DR (HLA-DR) expression has been reported to be an indicator of poor survival in critically ill septic patients . We assessed its usefulness as a prognostic indicator in order to identify possible interventions to normalise HLA-DR expression in those patients with lowered monocyte HLA-DR . DESIGN: HLA-DR expression was measured on separated monocytes of septic patients, using flow cytometry, and HLA-DR upregulation was measured by the same techniques after ex vivo stimulation with granulocyte macrophage colony stimulating factor (GM-CSF) . APACHE II score, age, sex and outcome were determined for all patients . SETTING: A single-centre study at the Royal Liverpool University Hospital in a medico-surgical 13-bed intensive care unit . PATIENTS AND PARTICIPANTS: All septic patients ( n=70) fulfilling the criteria of the ACCP for the diagnosis of sepsis were recruited for the study with informed consent from day 1 of diagnosis of sepsis and monocyte HLA-DR expression measured on 3 consecutive days . Patients were excluded from the study if they were on immunosuppressive therapy . Normal healthy volunteers ( n=45) were included . RESULTS: Low monocyte surface expression and median fluorescence density HLA-DR expression was not associated with a high mortality . High APACHE II scores were not correlated with low HLA-DR expression . However, in those patients where HLA-DR expression was lowered, this could be restored ex vivo by GM-CSF . CONCLUSIONS: In the group of septic patients under study, HLA-DR was not a useful prognostic marker of outcome . We did not find a higher mortality in the group of patients who had low expression . These findings are contradictory to some previously reported findings, and the possible reasons are discussed. Crit Care Med, 2003 May, 31(5), 1560 - 7 Measures, markers, and mediators: toward a staging system for clinical sepsis . A report of the Fifth Toronto Sepsis Roundtable, Toronto, Ontario, Canada, October 25-26, 2000; Marshall JC et al.; BACKGROUND: Sepsis is not a single disease but a complex and heterogeneous process . Its expression is variable, and its severity is influenced by the nature of the infection, the genetic background of the patient, the time to clinical intervention, the supportive care provided by the clinician, and a number of factors as yet unknown . The evaluation of effective therapies has been hampered by limitations in our ability to characterize the process and to stratify patients into more homogeneous groups with respect to pathogenesis . OBJECTIVES: To develop a taxonomy of markers relevant to clinical research in sepsis and to propose a testable candidate system for stratifying patients into more therapeutically homogeneous groups . DATA SOURCE: An expert roundtable discussion and a MEDLINE review using search terms "marker" and "sepsis." RESULTS: Markers provide information in one or more of three domains: diagnosis, prognosis, and response to therapy . More than 80 putative markers of sepsis have been described . All correlate with the risk of mortality (prognosis), yet none has shown utility in stratifying patients with respect to therapy (diagnosis) or in titrating that therapy (response) . Their limitations arise from the challenges of establishing causality in a complex disease process such as sepsis and of stratifying patients into more homogeneous populations . The former limitation may be addressed through a modification of Koch's postulates to differentiate causality from simple association . The latter suggests the need for a staging system analogous to those used in other complex disease processes such as cancer . A candidate framework for such a system, based on the infection, the host response, and the extent of organ dysfunction (the IRO system) is described . CONCLUSIONS: Advances in the understanding and management of patients with sepsis will necessitate more rigorous approaches to disease description and stratification . Models should be developed, tested, and modified through clinical studies rather than through consensus. Crit Care Med, 2003 May, 31(5), 1495 - 501 Pathogenic role of interleukin-6 in the development of sepsis . Part II: Significance of anti-interleukin-6 and anti-soluble interleukin-6 receptor-alpha antibodies in a standardized murine contact burn model; Pallua N et al.; OBJECTIVE: The in vivo effects of anti-interleukin-6 (anti-IL-6) and anti-interleukin-6-alpha receptor (anti-IL-6R) monoclonal antibodies on immune response and survival rate of a burn with subsequent infection were assessed . SUBJECTS: Ten-week-old C 57 BL/6J mice received a standardized contact burn; 48 hrs later endotoxin (LPS) was injected intraperitoneally to induce systemic inflammation . Ten different groups were studied . Groups I-IV sustained a burn and/or a LPS-stimulus but did not receive any anti-cytokines and served as controls . Treatment groups V-X sustained the same injuries but also received anti-IL-6 and anti-IL-6R intravenously either before or after the LPS stimulus . In a further part of the study, a lethal dose of LPS was injected (LPS-LD(100) group) followed by an injection of anti-IL-6 antibody and/or anti-IL-6R antibody . MEASUREMENTS: Serum concentrations of IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and white blood cell and platelet counts were determined, and the survival rate over a 2-wk period was assessed . RESULTS: Treatment with anti-IL-6 slightly decreased the inflammatory response when it was given before or after LPS application . The inflammatory response was not decreased after treatment with anti-IL-6R . In the groups that received a combination of anti-IL-6 and anti-IL-6R, there was a significant reduction of the inflammatory response . This was more pronounced when the anti-cytokines were applied after LPS application . A significant reduction in mortality could be shown with both antibodies in the treatment groups and the groups that had received a lethal dose of LPS (LPS-LD(100) group) . CONCLUSIONS: IL-6 has a low inflammatory potential, and IL-6R has no inflammatory potential by itself . In contrast, the IL-6/IL-6R complexes have a higher inflammatory potential . Mortality could be reduced by each antibody alone as well as by the combination, supporting the hypothesis that the inflammatory and lethal potentials of IL-6 are not identical . The study suggests that the use of antibodies against IL-6 or IL-6R is effective in the prevention of systemic inflammation in a murine burn model. Crit Care Med, 2003 May, 31(5), 1490 - 4 Pathogenic role of interleukin-6 in the development of sepsis . Part I: Study in a standardized contact burn murine model; Pallua N et al.; OBJECTIVE: To establish a representative model for the evaluation of interleukin (IL)-6 and IL-6 receptor for pathogenicity and lethality in the postburn period . DESIGN: Ten-week-old C 57 BL/6J mice received a 20% body surface area contact burn and/or lipopolysaccharide (LPS) 48 hrs later . Standardized burns were created with a metal stamp of 150 degrees C of defined pressure and surface area (2.4525 Newton/0.00166 m2) over a period of 11 secs . The depth of dermal injury was verified histologically . The following groups were formed: I: no burn, no LPS (n = 35); II: burn, no LPS (n = 140); III, no burn, LPS (n = 56); and IV, burn, LPS (n = 80), to study the effect of burn alone, sepsis alone, or the combination . Lethal LPS dose (LD100) was determined by application of LPS in increasing doses (200, 300, 400, and 500 microg, n = 32) after burns . MEASUREMENTS: Concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), and leukocytes, platelets and organ pathology were evaluated . SETTING: Research laboratory . RESULTS: Burn and LPS showed an additive effect on the release of IL-6 but not of TNF-alpha and IFN-gamma . Leukocyte and platelet numbers decreased significantly (group IV) compared with the other groups (I-III) . The maximal levels of IL-6 in group IV were reached earlier than those of TNF-alpha . The contact burn model has a mortality rate of 30%, which is close to clinical outcome . We found the model of contact burn superior to scald or flame burn models . A dose of 400-microg LPS was found to be the lethal LPS dose (LD100) . CONCLUSIONS: Our data suggest that preexisting burn injury increases the response to endotoxin . TNF-alpha is not involved in priming . IL-6 on the other hand is a very representative parameter for priming . Because TNF-alpha was obviously not the causative factor, it was concluded that the application of anti-IL-6-mAb should be of great value . Therefore, a therapeutic application was designed, see part II. Crit Care Med, 2003 May, 31(5), 1382 - 8 Adrenocortical hormones in survivors and nonsurvivors of severe sepsis: diverse time course of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol; Marx C et al.; OBJECTIVE: Activation and suppression of immune responses are crucial events during sepsis . Based on substantial new data, a complex picture of differential immune-enhancing and immunosuppressive actions of adrenocortical steroids is emerging . The adrenal androgen dehydroepiandrosterone and its precursor, dehydroepiandrosterone-sulfate, show a considerable decrease with increasing age and serve as functional antagonists to endogenous glucocorticoids . Therefore, we examined time-dependent changes in dehydroepiandrosterone, dehydroepiandrosterone-sulfate, cortisol, adrenocorticotropin, and inflammatory variables in surviving and nonsurviving patients with severe sepsis . DESIGN: Prospective observational study in consecutive patients . SETTING: Medical and interdisciplinary intensive care units in two university hospitals and one city hospital . PATIENTS: Thirty nonsurgical patients (25 men and 5 women) with severe sepsis (American College of Chest Physicians/Society of Critical Care Medicine criteria); 15 survivors (mean age, 54 +/- 14 yrs; Acute Physiology and Chronic Health Evaluation III score, 59 +/- 35) and 15 nonsurvivors (mean age, 63 +/- 15 yrs; Acute Physiology and Chronic Health Evaluation III score, 67 +/- 24) were included . Hormones were compared individually and between survivors/nonsurvivors by sequential blood drawings from early sepsis till time of recovery/death . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: During early sepsis, cortisol (nmol/L) was not significantly higher in survivors than nonsurvivors (750 +/- 121 vs . 454 +/- 92, p <.08) and decreased in survivors (p <.01) during late sepsis . During early sepsis, dehydroepiandrosterone-sulfate (percentage of age-matched normal levels) was higher in survivors than nonsurvivors (85 +/- 19 vs . 22 +/- 7, p <.01) . Dehydroepiandrosterone-sulfate decreased in survivors (p =.0001) but remained low in nonsurvivors during late sepsis . Dehydroepiandrosterone (percentage of age-matched normal levels) was not significantly elevated in survivors compared to nonsurvivors during early sepsis (282 +/- 42 vs . 214 +/- 63, p <.08) . Dehydroepiandrosterone decreased in survivors (p <.01) but not in nonsurvivors during late sepsis . Linear regression for dehydroepiandrosterone levels showed a reconstitution of age dependence only in survivors during recovery . Adrenocorticotropin levels did not change . The dehydroepiandrosterone-sulfate/cortisol ratio decreased significantly in both survivors and nonsurvivors, whereas dehydroepiandrosterone/cortisol ratio only decreased in survivors during course of sepsis . CONCLUSIONS: During sepsis, adrenal androgens and glucocorticoids show a diverse time-dependent course in survivors and nonsurvivors. Crit Care Med, 2003 May, 31(5), 1359 - 66 Lipoprotein metabolism in patients with severe sepsis; van Leeuwen HJ et al.; OBJECTIVE: Lipoproteins have been implicated to play a role in innate immunity . Changes in lipoprotein levels have been reported in a variety of inflammatory disorders . Not much is known about lipoprotein metabolism in patients with severe sepsis . We conducted an ancillary study in a multiple-center phase III sepsis trial to investigate the dynamics of plasma lipoproteins in patients with severe sepsis . DESIGN: Prospective analysis in patients meeting criteria for severe sepsis as part of a multiple-center sepsis study (KyberSept) with antithrombin III (Kybernin P) . SETTING: University hospital intensive care unit . PATIENTS: Seventeen patients were included in the study . INTERVENTIONS: Randomized patients received a loading dose of 6000 IU of antithrombin III (Kybernin P) or placebo followed by a 96-hr continuous infusion of 250 IU/hr antithrombin III (Kybernin P) or placebo . In each patient, serial blood samples for total cholesterol, lipoprotein cholesterol, triglycerides, apolipoprotein A-1, apolipoprotein B, and C-reactive protein determination as well as clinical data were collected over 28 days . MEASUREMENTS AND MAIN RESULTS: Plasma cholesterol levels rapidly decreased from 2.67 +/- 2.02 mmol/L on day 0 to a nadir of 1.41 +/- 0.70 mmol/L on day 3, followed by a slow increase to 4.18 +/- 1.94 mmol/L on day 28 . High-density lipoprotein (HDL) cholesterol concentrations decreased rapidly from 0.84 +/- 0.92 mmol/L to a nadir of 0.42 +/- 0.35 mmol/L on day 3, to show a slow increase during the following 4 wks to 0.84 +/- 0.42 mmol/L . The low-density lipoprotein (LDL) cholesterol concentrations were already low (0.94 +/- 0.81 mmol/L) at study entry, to show a progressive increase to subnormal values (2.01 +/- 0.94 mmol/L) at 4 wks . Nadir and recovery lipoprotein concentrations were significantly different (paired Student's t-test, p <.05) . A significant correlation was found between HDL cholesterol and apolipoprotein A-1 (r =.714, p <.05) and between LDL cholesterol and apolipoprotein B (r =.733, p <.05) . There was no statistical difference in lipoprotein concentrations either between survivors and nonsurvivors or between patients receiving antithrombin III or placebo.Serum amyloid A was a major apoprotein (45%) in HDL at the start of the sepsis and was slowly replaced by apolipoprotein A-1 during recovery . A positive correlation was found between plasma C-reactive protein concentrations and serum amyloid A concentrations in HDL (r =.68