Crit Care Med, 2004 May, 32(5 Suppl), S293 - 7 Tissue factor, coagulation proteases, and protease-activated receptors in endotoxemia and sepsis; Pawlinski R et al.; Inhibition of the tissue factor-factor VIIa complex reduces coagulation and inflammation in animal models of endotoxemia and sepsis and in patients with severe sepsis . However, the mechanism by which tissue factor-dependent activation of the coagulation cascade enhances inflammation is not known . We tested the hypothesis that coagulation proteases enhance inflammation during endotoxemia by activating protease-activated receptors (PARs) within the vasculature . We found that genetically modified mice expressing low levels of tissue factor exhibited reduced interleukin-6 expression and increased survival in a mouse model of endotoxemia compared with control mice . In contrast, hirudin inhibition of thrombin or a deficiency in either PAR-1 or PAR-2 did not affect interleukin-6 expression or mortality . However, combining hirudin treatment to inhibit thrombin signaling through PAR-1 and PAR-4 with PAR-2 deficiency reduced lipopolysaccharide-induced interleukin-6 expression and increased survival . Taken together, our results suggest that activation of multiple PARs by coagulation proteases enhances inflammation during endotoxemia. Crit Care Med, 2004 May, 32(5 Suppl), S280 - 6 Leukocyte and endothelial cell interactions in sepsis: relevance of the protein C pathway; Joyce DE et al.; OBJECTIVE: To give an overview of leukocyte and endothelial cell interactions in sepsis and to explore the role of the protein C pathway in modulating the innate immune response via its anti-inflammatory properties . DATA SOURCE: Novel in vitro data and a MEDLINE search for the terms "activated protein C," "recombinant human activated protein C," "inflammation," "leukocyte adhesion," and "sepsis" were used, along with clinical trial databases from the PROWESS trial and a phase I human endotoxin trial evaluating recombinant human activated protein C (drotrecogin alfa {activated}) . DATA EXTRACTION AND SYNTHESIS: The protein C pathway is positioned at the interface between the endothelium and the leukocyte response of the innate immune system . Activated protein C (APC) possesses profibrinolytic, anti-inflammatory, and anti-apoptotic properties, acting as an endothelial cell and microvascular modulator in opposition to thrombin and the proinflammatory cytokines . Distribution of the receptor for APC, endothelial protein C receptor, was detected on effector cells of the innate immune response . This suggests a further role for the protein C pathway in regulating inflammation . In neutrophils and eosinophils, an endothelial protein C receptor-mediated APC response leads to reduced migration in response to cytokine gradients . Endothelial protein C receptor may also suppress the apoptotic response in monocytes and enhance the expression of the adhesion integrin CD11b in granulocytes . The microvascular, anti-inflammatory influence of APC in sepsis is supported by suppression of endothelial cell adhesion molecules and the ability of APC to protect the endothelium from inflammatory insult . CONCLUSIONS: The coordinated effects of the protein C pathway on the endothelium and the leukocyte response of the innate immune system are supported by potential restriction of endothelial protein C receptor expression to cells of the innate immune system and by suppression of adhesion molecule expression on the endothelium by APC . Reduced neutrophil migration in response to cytokines is also mediated by endothelial protein C receptor . Further clinical studies will be needed to define the intrinsic role of the protein C pathway in coordinating the innate immune response in endothelium-based inflammation. Crit Care Med, 2004 May, 32(5 Suppl), S239 - 46 Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C; Yan SB et al.; OBJECTIVE: Coagulation activation is part of the acute innate host response to infection that, when uncontrolled, may contribute to organ dysfunction and death . Activated protein C limits excessive coagulation activation by inactivating factors Va and VIIIa . The factor V Leiden mutation (R506Q), a prothrombotic gene polymorphism, disrupts the activity of this natural anticoagulant by rendering factor Va partially resistant to inactivation by activated protein C . Previous findings in the mouse factor V Leiden endotoxemia model and in patients with severe sepsis suggest that factor V Leiden constitutes a rare example of a balanced gene polymorphism that may provide a survival advantage for heterozygous carriers with severe sepsis . We sought to confirm that carriers of this prothrombotic factor V Leiden mutation do not have an increased risk of developing severe sepsis and that carriers with severe sepsis derive similar treatment benefit from recombinant human activated protein C (drotrecogin alfa {activated}) as non-factor V Leiden carriers . DESIGN: Prospective collection of factor V Leiden status from two clinical studies of severe sepsis (PROWESS and ENHANCE) . SETTING:: A total of 447 clinical sites across 25 countries . PATIENTS: A total of 3894 adult patients with severe sepsis . INTERVENTION: Either 24 microg x kg x hr drotrecogin alfa (activated) (n = 3063) or placebo (n = 800) for 96 hrs or no exposure to the study drug (n = 31) . MAIN RESULTS: The effect of the factor V Leiden carrier status in severe sepsis in the PROWESS study has been previously reported . The combined data on factor V Leiden status from 3894 adult patients with severe sepsis from the PROWESS and ENHANCE (a single-arm, open-label study of drotrecogin alfa {activated}) studies are reported here . At study entry, 3.9% of patients (150/3894) presenting with severe sepsis were heterozygous carriers . No homozygous factor V Leiden carriers were identified . The proportion of factor V Leiden carriers in patients with severe sepsis differs slightly from that predicted (allelic frequency of 2.5%) by the Hardy-Weinberg equation for the general white population (p =.05) . There was no significant difference in baseline disease severity (Acute Physiology and Chronic Health Evaluation II score or number of organ dysfunctions) between heterozygous carriers and non-Leiden carriers . There was no significant difference in serious bleeding or thrombotic event rates with drotrecogin alfa (activated) treatment between heterozygous carriers and non-Leiden carriers . The 28-day mortality rates for heterozygous carriers and non-Leiden carriers with drotrecogin alfa (activated) treatment were 20.3% and 24.9%, respectively (risk ratio, 0.82; 95% confidence interval, 0.57-1.17) . CONCLUSIONS:: Compared with non-Leiden carriers, factor V Leiden heterozygous carriers may have a slightly decreased risk of developing severe sepsis from infection, do not seem to have increased mortality in severe sepsis, and derive similar benefit and risk profiles from drotrecogin alfa (activated) treatment . Therefore, factor V Leiden carriers should not be excluded from this new sepsis therapy. Crit Care Med, 2004 May, 32(5 Suppl), S233 - 8 Factor V Leiden polymorphism modifies sepsis outcome: evidence from animal studies; Weiler H et al.; OBJECTIVE: The high prevalence of the factor V Leiden mutation in certain populations has prompted speculation that the mutation may have been subject to positive selection during evolution, either by providing a survival benefit or by directly enhancing reproductive performance . We investigated the hypothesis that heterozygous factor V Leiden carrier status might protect against the lethal consequences of severe inflammatory disease . DATA SOURCE: Two mouse models (thrombomodulin-deficient TMPro mice and factor V Leiden mice), in which the endogenous protein C anticoagulant pathway is disrupted either at the level of protein C activation (TMPro mice) or at the level of factor V proteolysis by activated protein C (factor V Leiden mice), were employed . The mutant mouse strains were subjected to lethal doses of bacterial lipopolysaccharide . The effects of these two mutations on coagulation activation and inflammatory cytokine elaboration were observed and compared with those in wild-type mice . DATA SUMMARY: As has already been shown, heterozygous factor V Leiden carrier status improves the survival of mice subjected to endotoxemia induced by bacterial lipopolysaccharide . The survival of homozygous factor V Leiden mice did not differ from that of normal mice . The survival benefit derived from heterozygous factor V Leiden carrier status was only evident at doses of lipopolysaccharide producing death in approximately 50% of wild-type animals . At higher (LD90) or lower (LD10) doses of lipopolysaccharide, the survival of heterozygous factor V Leiden mice did not differ from that of wild-type mice . Concomitant administration of an LD90 dose of lipopolysaccharide and therapeutic heparin abolished the relative survival advantage of heterozygous factor V Leiden mice . Analysis of systemic coagulation and cytokine variables failed to provide conclusive evidence for altered coagulation activation or inflammatory cytokine production as the basis for the survival advantage associated with heterozygous factor V Leiden carrier status . CONCLUSIONS: The improved survival of mice heterozygous for the factor V Leiden mutation complements results from the analysis of the factor V Leiden subgroup of patients enrolled in the PROWESS trial . Such convergent findings in two different species strongly suggest that the factor V Leiden mutation is indeed a potent modifier of the response to severe inflammatory disease . The striking magnitude of the factor V Leiden survival benefit in the initial PROWESS population, and in mice, suggests that the as-yet unknown mechanism conferring this benefit is a rather potent endogenous modifier of the pathogenic pathways engaged in sepsis . Delineation of this pathway will be important for understanding the therapeutic mechanisms, or absence thereof, of agents designed to act at the interface of coagulation and inflammation. Crit Care Med, 2004 May, 32(5 Suppl), S223 - 8 Severe protein C deficiency predicts early death in severe sepsis; Macias WL et al.; OBJECTIVE: To explore the relationship between measures of baseline disease severity and survival time in patients with severe sepsis . DATA SOURCE: A retrospective evaluation of the placebo group from a large placebo-controlled phase III clinical trial (PROWESS) comprising a total of 840 patients with severe sepsis from 164 medical centers . DATA EXTRACTION AND SYNTHESIS: Data collected included baseline demographics and disease severity measurements, baseline protein C and interleukin-6 levels, 28-day and in-hospital survival rates, and cause of death to 28 days . The survival curve for the placebo patients can be divided into three segments during which the rate of death seemed to be different: the rapid alpha phase (day 0 to day 5), the beta phase (day 6 through day 15), and the gamma phase (day 16 to day 28) . The risk of death during each phase was statistically significantly different . More patients died of refractory shock during the alpha phase than in the beta and gamma phases, whereas more patients died of respiratory failure during the beta and gamma phases than during the alpha phase . Multiple organ failure was a frequent cause of death during all phases . Protein C levels at the start of each time interval were highly predictive of outcome within that phase, with continued protein C deficiency being associated with mortality . Patients who died during either the alpha or beta phases had higher interleukin-6 levels at baseline than those who died later or who eventually survived . CONCLUSIONS: The rate and cause of death for patients with severe sepsis differs during the 28-day postdiagnosis period . Severe protein C deficiency (<40% of the level of protein C in pooled normal human plasma) and high interleukin-6 levels were associated with early death that resulted predominantly from refractory shock and multiple organ dysfunction. Crit Care Med, 2004 May, 32(5 Suppl), S209 - 13 Endpoints in sepsis trials: more than just 28-day mortality? Vincent JL. To determine whether an intervention, either therapeutic or diagnostic, is effective, it needs to be assessed according to a predefined endpoint (or outcome measure), the choice of which will vary according to the aims of the study in question and the anticipated effects of the intervention being tested . Studies can have one of several functions (which are not always mutually exclusive), including providing evidence of biological efficacy, determining a clinically important benefit, and achieving regulatory approval . In trials of therapeutic efficacy in sepsis, mortality rates are a good endpoint because death is common and mortality rates are an unambiguous measure: patients either survive or they do not . However, the time at which mortality should be recorded is less clear cut, and this single endpoint provides no information regarding the biological activity or disease modification effects of the agent under investigation . In this article, we will briefly discuss some of the potential alternative endpoints that could be used in the assessment of antisepsis agents. Crit Care Med, 2004 May, 32(5 Suppl), S194 - 201 Protein C/activated protein C pathway: overview of clinical trial results in severe sepsis; Dhainaut JF et al.; OBJECTIVE: To review the results from clinical trials of treatments for severe sepsis involving the protein C/activated protein C pathway . DATA SOURCE: Published research and review articles (PubMed, from 1985 to 2003) relating to clinical trials of compounds involving the protein C pathway . DATA EXTRACTION AND SYNTHESIS: Protein C is converted to activated protein C when thrombin complexes with thrombomodulin . Sepsis is associated with rapid depletion of protein C and blunted endogenous protein C activation . Treatment with protein C concentrate is followed by increased activated protein C plasma levels and a dose-dependent decrease in d-dimer levels in children with purpura fulminans . This supplementation is safe . A phase III trial of recombinant human activated protein C (drotrecogin alfa {activated}) in severe sepsis demonstrated a 6.1% absolute reduction in 28-day mortality compared with placebo . The short- and long-term survival rates associated with drotrecogin alfa (activated) were better in patients at high risk of death associated with a better cost/effectiveness ratio . Treatment with drotrecogin alfa (activated) was associated with an increased risk of serious bleeding compared with placebo during the 28-day study period (3.5% vs . 2.0%) . CONCLUSIONS: Treatment with protein C concentrate is followed by an improvement of the coagulopathy and is safe in children with purpura fulminans; however, a large trial involving a high dose is required to determine its effect on mortality and morbidity . Treatment with drotrecogin alfa (activated) leads to substantial reduction in mortality and has an acceptable risk/benefit ratio in septic patients at high risk of death. Eur J Echocardiogr, 2004 Jan, 5(1), 76 - 8 Candida sepsis with intramyocardial abscesses mimicking left ventricular noncompaction; Stollberger C et al.; Left ventricular (LV) noncompaction is a rare abnormality characterized by more than three trabeculations protruding from the LV wall, distal to the papillary muscles and visible in one echocardiographic image plane . The intertrabecular spaces are perfused from the LV cavity, as visualized on color Doppler imaging . Differential diagnoses of LV noncompaction are intraventricular thrombi, false tendons, aberrant bands, intramyocardial hematoma, cardiac metastases and the apical type of hypertrophic cardiomyopathy . Intramyocardial abscesses have not been reported as a differential diagnosis of LV noncompaction . In the patient presented, cardiac microabscesses due to candida sepsis mimicked LV noncompaction and should be considered in the differential diagnosis of LV noncompaction. South Med J, 2004 Apr, 97(4), 413 - 5 Acute splenic sequestration crisis resembling sepsis in an adult with hemoglobin SC disease; Wang-Gillam A et al.; Acute splenic sequestration crisis (ASSC) is a common complication of sickle cell anemia in children . ASSC is generally not seen in adults with the SS genotype but occasionally can be seen in adults with the SC genotype . We present a case of fulminant ASSC in an adult with hemoglobin SC who developed high fever, intense abdominal pain, leukocytosis, and jaundice. Acta Anaesthesiol Scand, 2004 May, 48(5), 637 - 41 Olprinone improves diaphragmatic contractility and fatigability during abdominal sepsis in a rat model; Miyakawa H et al.; BACKGROUND: Respiratory failure with diaphragmatic fatigability is common in patients suffering sepsis or septic shock . However, the development and progress of diaphragmatic fatigability remains poorly understood, and no method has been established to treat fatigability . In this study, we hypothesize that neutrophil activation contributes to the development of diaphragmatic fatigability . We also sought to investigate whether a phosphodiesterase inhibitor, olprinone, improves diaphragmatic fatigability associated with abdominal sepsis and inhibits an increase in myeloperoxidase activity in diaphragmatic muscle . METHODS: Male Wistar rats were randomly assigned to a sham group, coecal legation perforation group (CLP), and a phosphodiesterase inhibitor (PDE) pretreated group . At 16 h after surgical procedure, the left hemidiaphragm was removed for the measurement of diaphragmatic contractility and fatigability . In addition, for the measurement of serial changes in myeloperoxidase activity, the right hemidiaphragm was also removed at 4, 8 or 16 h after the surgical procedure in each group . RESULTS: In a septic model involving rats, we observed that diaphragmatic muscles were fatigable and myeloperoxidase activity increased . We also demonstrated that intraperitoneal administration of olprinone improves diaphragmatic fatigability and inhibits an increase in myeloperoxidase activity induced by abdominal sepsis . CONCLUSION: Olprinone represents a potential therapy for cases of respiratory failure with diaphragmatic fatigability resulting from inhibition of neutrophil activation. Immunology, 2004 May, 112(1), 153 - 60 Response of lung gammadelta T cells to experimental sepsis in mice; Hirsh M et al.; Gammadelta T cells link innate and adaptive immune systems and may regulate host defence . Their role in systemic inflammation induced by trauma or infection (sepsis) is still obscured . The present study was aimed to investigate functions of lung gammadelta T cells and their response to experimental sepsis . Mice were subjected to caecal ligation and puncture (CLP) to induce sepsis and acute lung injury (ALI), or to the sham operation . Animals were killed 1, 4, and 7 days postoperatively; lungs were examined by histology, and isolated cells were studied by flow cytometry . Absolute number of gammadelta T cells progressively increased in lungs during sepsis, and reached a seven-fold increase at day 7 after CLP (3.84 +/- 0.41 x 10(5)/lung; P = 0.0002 versus sham) . A cellular dysfunction was revealed one day after CLP, as manifested by low cytolytic activity (22.3 +/- 7.1%; P < 0.05 versus sham), low interferon-gamma (IFN-gamma; 8.5 +/- 2.5%; P < 0.05 versus control) and interleukin-10 (IL-10) expression, and high tumour necrosis factor-alpha expression (19.5 +/- 1.7%; P < 0.05 versus control) . The restoration of cytotoxicity, and increase in IFN-gamma and IL-10 expression was observed at day 7 of CLP-induced sepsis . In summary, our results demonstrate significant progressive accumulation of gammadelta T cells in lungs during CLP-induced ALI . The temporary functional suppression of lung gammadelta T cells found early after CLP may influence the outcome of sepsis, possibly being associated with uncontrolled inflammatory lung damage. Crit Care Med, 2004 Mar, 32(3), 660 - 5 Brain natriuretic peptide: A marker of myocardial dysfunction and prognosis during severe sepsis; Charpentier J et al.; OBJECTIVE: To investigate the value of brain natriuretic peptide plasma levels as a marker of systolic myocardial dysfunction during severe sepsis and septic shock . DESIGN: Prospective observational study . SETTING: Intensive care unit . PATIENTS: A total of 34 consecutive patients with severe sepsis (nine patients) or septic shock (25 patients) without previous cardiac, respiratory, or chronic renal failure . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Myocardial systolic performance was assessed by fractional area contraction (FAC) using echocardiography performed on days 2 (FACD2) and 8 . Plasma levels of brain natriuretic peptide were measured at days 1-4 and 8 after the beginning of severe sepsis . Among 34 patients (Simplified Acute Physiology Score II, 43 +/- 2.5), 15 (44%) presented with initial myocardial dysfunction (FACD2 < 50%) . Lungs were the origin of sepsis in 65% of patients . The 28-day mortality was 29% . Comparisons were performed between patients with (FACD2 < 50%) and without (FACD2 > or = 50%) myocardial dysfunction . Plasma levels of brain natriuretic peptide were significantly higher in patients with FACD2 < 50% than in those with FACD2 > or = 50% (p <.05) from day 2 to day 4 . Brain natriuretic peptide levels were also significantly higher on days 2 and 3 in patients who died during their intensive care unit stay (p <.05) . CONCLUSIONS: Systolic myocardial dysfunction is present in 44% of patient with severe sepsis or septic shock . In this setting, brain natriuretic peptide seems useful to detect myocardial dysfunction, and high plasma levels appear to be associated with poor outcome of sepsis, but further studies are needed. Hepatogastroenterology, 2004 Mar-Apr, 51(56), 439 - 42 The effects of the immunomodulators on the colonic anastomosis in an experimental model of intraperitoneal sepsis; Ergin E et al.; BACKGROUND/AIMS: The present study examined the effects of G-CSF and Levamisole used as immunomodulators on the colonic anastomosis healing in the presence of an intraabdominal infection . METHODOLOGY: 40 male Spraque-Dawley rats were randomly allocated to 4 groups each consisting of 10 animals . Standard colonic anastomosis, peritonitis and colonic anastomosis, peritonitis and colonic anastomosis and G-CSF, peritonitis and colonic anastomosis and Levamisole were applied to groups I, II, III and IV, respectively . The cecum of the rats in groups II, III and IV was ligated and perforated to create an intraabdominal sepsis model . G-CSF 50 microg/kg/day were given subcutaneously to group III and Levamisole 5 mg/kg/day were given perorally to group IV in the postoperative period until sacrifice . The rats were sacrificed on the fourth postoperative day . Bursting pressure and hydroxyproline level measurements of the anastomosis were evaluated . RESULTS: Bursting pressures of all groups were lower than the control group (p<0.001) . The mean bursting pressure of group III was significantly higher than group II (p<0.05) . The mean level of hydroxyproline in group III was significantly higher than group II (p<0.05) however; overall, it was lower in all groups than the control (p<0.05) . CONCLUSIONS: This study demonstrated that intraabdominal sepsis adversely affects healing of colonic anastomosis, and healing of the anastomosis becomes better and the mortality rate decreases by the use of G-CSF. J Perinat Med, 2004, 32(2), 176 - 80 The prognostic virtue of inflammatory markers during late-onset sepsis in preterm infants; Arnon S et al.; AIM: Late-onset sepsis (occurring after the first three days of life) is a serious complication in preterm infants . In order to assess the possible prognostic virtues of the acute phase inflammatory response in the disease, we compared the inflammatory response of preterm infants who died within 72 hours (h) (fulminant sepsis) to infants who recovered from the disease (non-fulminant sepsis) . METHODS: Of 42 preterm infants that were evaluated: 10 had fulminant sepsis and 32 non-fulminant sepsis . Acute phase inflammatory response markers-C-reactive protein (CRP), serum amyloid A (SAA), interleukin (IL)-6 levels and white blood cell (WBC) counts were measured at the first suspicion of LOS and after 8, 24 and 48 h . RESULTS: Small for gestational age (SGA) infants who were treated with fewer days of antibiotics characterized the fulminant sepsis group . The initial high levels of inflammatory markers were similar in both groups, but as early as 8 h after onset significantly lower levels of SAA, CRP and WBC counts were documented in the fulminant sepsis group . The inflammatory response remained low at 24 and 48 h in the fulminant sepsis group, while in the survivors, significantly increased inflammatory markers were measured . Decreases in the levels of the inflammatory markers preceded episodes of metabolic acidosis and arterial hypotension that were more common in the fulminant sepsis group . Infant mortality correlated inversely with SAA levels at 8 h and with CRP and WBC counts at 24 h after onset . CONCLUSION: SAA, CRP and WBC counts can be used as prognostic markers in LOS in preterm infants, with SAA being the earliest prognostic marker. Ann Fr Anesth Reanim, 2004 Mar, 23(2), 132 - 7 {A new role for neutrophils during sepsis: target and source of interleukin-12}; Ethuin F et al.; The immune response against a bacterial aggression involves the monocytes-macrophages and polymorphonuclear neutrophils (PMN) in the first line of defense . This natural or innate immunity controls the proliferation of micro-organisms while waiting for the development of aspecific immunity related to lymphocytes . Establishing a link between innate and specific immunity, interleukin-12 (IL-12) is an essential cytokine of the inflammatory response . In a first in vitro study, we showed that IL-12 potentiates the effect of LPS on the production of IL-8 by stimulated PMN, the main chemotactic and activating cytokine of neutrophils . IL-12 would thus support the local recruitment of PMN via an autocrine loop of amplification . In a second in vivo study in septic patients, we noted a defect in the pulmonary and systemic production of IL-12, suggesting a dysregulation of innate immunity during the course of sepsis. Curr Opin Crit Care, 2004 Apr, 10(2), 152 - 5 Splanchnic metabolism in acute liver failure and sepsis; Clemmesen O et al.; PURPOSE OF REVIEW: A number of papers have suggested that the splanchnic circulation and oxidative metabolism are compromised in critical illness . This review discusses this hypothesis and outlines the recent advances in the understanding of splanchnic metabolism with special focus on acute liver failure and hyperdynamic sepsis . RECENT FINDINGS: Splanchnic blood flow, oxygen delivery, and consumption are increased in both acute liver failure and sepsis . The capability of the liver to extract oxygen, even under extreme conditions, renders the liver less prone to hypoxia . A common feature of acute liver failure and sepsis is a hypermetabolic state with enhanced glycolysis and production of lactate and pyruvate . Human studies on other features of intermediary metabolism are sparse, but there are indications that several intermediary processes are severely compromised in patients with acute liver failure, whereas these processes are maintained in sepsis . SUMMARY: There is increasing evidence that both acute liver failure and sepsis are accompanied by a hypermetabolic state in the hepatosplanchnic area, characterized by enhanced glycolysis and hyperlactatemia . This should not be rigorously interpreted as an indication of hypoxia . In fact, clinically important splanchnic hypoxia may be a relatively uncommon phenomenon in such patients. Chin J Physiol, 2003 Dec 31, 46(4), 151 - 7 Body temperature control in sepsis-induced acute lung injury; Wang GC et al.; Body temperature is precisely regulated to maintain homeostasis in homeothermic animals . Although it remains unproved whether change of body temperature constitutes a beneficial or a detrimental component of the septic response, temperature control should be an important entity in septic experiments . We investigated the effect of body temperature control on the lipopolysaccharide (LPS)-induced lung injury . Acute lung injury in rats was induced by intratracheal spray of LPS and body temperature was either clamped at 37 degrees C for 5 hours or not controlled . The severity of lung injury was evaluated at the end of the experiment . Intratracheal administration of aerosolized LPS caused a persistent decline in body temperature and a significant lung injury as indicated by an elevation of protein-concentration and LDH activity in the bronchoalveolar lavage (BAL) fluid and wet/dry weight (W/D) ratio of lungs . Administration of LPS also caused neutrophil sequestration and lipid peroxidation in the lung tissue as indicated by increase in myeloperoxidase (MPO) activity and malondialdehyde (MDA) production, respectively . Control of body temperature at 37 degrees C after LPS (LPS/BT37, n = 11) significantly reduced acute lung injury as evidenced by decreases in BAL fluid protein concentration (983 +/- 189 vs . 1403 +/- 155 mg/L) and LDH activity (56 +/- 10 vs . 123 +/- 17 deltamAbs/min) compared with the LPS group (n = 11) . Although the W/D ratio of lung and MDA level were lower in the rats received temperature control compared with those received LPS only, the differences were not statistically significant . Our results demonstrated that intratracheal administration of aerosolized LPS induced a hypothermic response and acute lung injury in rats and controlling body temperature at a normal range may alleviate the LPS-induced lung injury. Crit Care Med, 2004 Apr, 32(4), 1004 - 10 Sepsis severity is the major determinant of circulating thrombopoietin levels in septic patients; Zakynthinos SG et al.; OBJECTIVE: To measure serum thrombopoietin levels and to investigate their relationship with platelet counts and other potential determinants in septic patients . DESIGN: Prospective study comparing septic patients and healthy volunteers . SETTING: General intensive care units in two tertiary university hospitals . PATIENTS: A total of 152 consecutive septic patients (69 with sepsis, 24 with severe sepsis, and 59 with septic shock) . Twenty-two healthy volunteers served as control subjects . Sepsis severity was determined by grading septic patients in those having sepsis, severe sepsis, and septic shock . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: After blood sampling, platelet counts, and serum thrombopoietin, interleukin-6 and C-reactive protein levels were measured . Platelets did not decrease in patients with sepsis, but they significantly decreased in patients with severe sepsis and septic shock (p <.01 vs . controls and sepsis) . In contrast, thrombopoietin levels (median {range}) increased in patients with sepsis (159 {34-1272} pg/mL) compared with controls (57 {33-333} pg/mL, p <.001), exhibiting further significant increase in patients with severe sepsis and septic shock (461 {73-1550} and 522 {45-2313} pg/mL, respectively, p <.001 vs . sepsis) . In multiple regression analysis, thrombopoietin levels were independently related only to sepsis severity (higher in patients with increased sepsis severity, p <.001) and platelet counts (higher in patients with lower platelet counts, p =.004) . Sepsis severity accounted for most of the variance explained by the model . Thrombopoietin was significantly related to interleukin-6 (r =.26) and C-reactive protein (r =.37, p <.001 for both) . In serial measurements, interleukin-6 peak values constantly preceded those of thrombopoietin, whereas peaks in thrombopoietin levels coincided with clinical episodes of septic shock . CONCLUSIONS: Sepsis severity is the major determinant of elevated thrombopoietin levels in septic patients, whereas platelet count is a secondary determinant . Thrombopoietin represents a potential marker of sepsis severity. Crit Care Med, 2004 Apr, 32(4), 981 - 5 Detailed cost analysis of care for survivors of severe sepsis; Lee H et al.; OBJECTIVES: The objectives of our study were to accurately describe the costs and resources required to treat survivors of severe sepsis subsequent to hospital discharge and to determine what factors influenced these costs . DESIGN: Observational cohort study . SETTING: Three regional intensive care units . PATIENTS: Patients with severe sepsis admitted to one of three regional intensive care units in southern Alberta between April 1, 1996, and March 31, 1999 . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Patients were identified using an intensive care unit research database; all survivors were followed prospectively for 3 yrs . Information on baseline patient characteristics, including acuity of illness (Acute Physiology and Chronic Health Evaluation II scores) and Charlson comorbidity scores, was collected . Costs considered included all episodes of inpatient and outpatient care and all physician claims . Of 787 patients who were admitted with severe sepsis, 502 survived to hospital discharge and were followed . Subsequent mean cost of care for years 1, 2, and 3 was CAN$20,855, $7,139 and $7,091, respectively . Using various regression models, the Acute Physiology and Chronic Health Evaluation II score and the Charlson comorbidity score were the only factors that consistently predicted higher healthcare costs in the first year after hospital discharge . Diabetes was the comorbid condition that best predicted subsequent cost . CONCLUSIONS: Cost of care for survivors of severe sepsis was highest in the first year after hospital discharge . Acuity of illness and patient comorbidity were the main determinants of cost . In assessing whether new therapeutic innovations for intensive care unit patients with severe sepsis are cost-effective, an accurate estimate of the cost of subsequent health care for survivors treated with and without the new intervention will be important. Pediatr Infect Dis J, 2004 Apr, 23(4), 346 - 9 Use of ciprofloxacin in neonatal sepsis: lack of adverse effects up to one year; Drossou-Agakidou V et al.; AIM: To investigate the adverse effects of ciprofloxacin administered to neonates with sepsis on the hematologic indices, the hepatic and renal function and the joints and growth at 1 year follow-up . METHODS: In this observational prospective study, 2 groups of septic neonates were studied, 116 neonates who received ciprofloxacin and 100 neonates matched for gestational age and birth weight who did not receive ciprofloxacin . In all neonates the leukocyte and platelet counts as well as the serum concentrations of transaminases, bilirubin, albumin, urea and creatinine were measured before initiation of treatment and on the 10th and 15th to 20th days after treatment initiation . In 77 and 83 infants of the ciprofloxacin and control groups, respectively, the growth at the end of the first year of life was evaluated . RESULTS: No significant differences between the two groups were found in the hematologic and biochemical indices as well as growth at the end of the first year of life . Also no clinical evidence of arthropathy was observed . CONCLUSIONS: Treatment of neonatal sepsis with ciprofloxacin resulted in no short term hematologic, renal or hepatic adverse effects and did not appear to be associated with clinical arthropathy or growth impairment at 1 year follow-up evaluation. Intensive Care Med, 2004 May, 30(5), 867 - 74 Epub 2004 Apr 06. Increased diffusion of soluble adhesion molecules in meningitis, severe sepsis and systemic inflammatory response without neurological infection is associated with intrathecal shedding in cases of meningitis; Megarbane B et al.; OBJECTIVE: Sepsis and systemic inflammatory response syndrome (SIRS) result in the release in plasma of inflammatory cytokines and soluble forms of adhesion molecules in relation to endothelial activation . This study was designed to compare cerebrospinal fluid (CSF) concentrations of adhesion molecules in meningitis and SIRS without neurological infection and to evaluate in meningitis whether they originate from passive diffusion through damaged blood-CSF barrier or from local production . DESIGN: Prospective observational study . SETTING: University hospital medical intensive care unit . PATIENTS: Nineteen patients with meningitis and 41 patients with sepsis or SIRS without cerebrospinal infection consecutively admitted to the critical care unit over an 18-month period . INTERVENTIONS: Soluble forms of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and cytokines (interleukin (IL)-1beta and TNF-alpha) were measured in paired CSF and blood samples . RESULTS: Serum concentrations of soluble adhesion molecules and cytokines were increased in the two groups, without significant differences . The CSF concentrations were elevated in both cases, whereas patients with meningitis demonstrated significantly higher CSF concentrations of soluble ICAM-1, VCAM-1, E-selectin, and TNF-alpha ( p<0.001), with higher corresponding CSF/serum ratios . Correlations between CSF and serum concentrations were found only in meningitis . These correlations were strong for soluble ICAM-1 (r(2)=0.7, p<0.001) and E-selectin (r(2)=0.9, p<0.001), but weaker for VCAM-1 . VCAM-1 CSF/serum ratios were increased, in comparison with ICAM-1 and E-selectin CSF/serum ratios, despite similar molecular weights . Serum and CSF levels of cytokines and adhesion molecules were not predictive of death for the whole population, except concentrations of ICAM-1 significantly increased in non-surviving patients ( p<0.05) . CONCLUSIONS: The CSF soluble adhesion molecules are increased in sepsis, SIRS and meningitis . In meningitis, the correlation between CSF and serum concentrations of adhesion molecules and the presence of a discrepancy of CSF/serum ratios for molecules of the same molecular weight may suggest intrathecal shedding in addition to diffusion through blood-CSF barrier. Vet Clin North Am Equine Pract, 2004 Apr, 20(1), 41 - 61 Sepsis in adults and foals; Roy MF; Sepsis develops in horses when the host response to the invading pathogens is not properly balanced according to the severity of the insult . Several clinical conditions frequently encountered in equine practice may be associated with the development of sepsis and have the potential to progress to more severe forms, such as severe sepsis, MODS, and septic shock . Consequently, it is important for equine practitioners to be aware of the manifestations,pathophysiology, and treatment of sepsis . Although enormous progress has been made in recent years in our understanding of the pathophysiology of sepsis . more work remains to be done in improving basic critical care guidelines and basic monitoring in equine intensive care units and in critically evaluating potential equine sepsis therapy . Fortunately, we can learn from the important advances made recently in the treatment of human sepsis patients;hence, rapid progress may be expected in a near future, especially as more and more veterinarians show interest in the discipline of equine critical care . With the completion of several genome projects and the availability of high-throughput genetic techniques, one hopes that we will further refine our understanding of the events underlying the development of severe sepsis and septic shock, which could lead to more appropriate therapeutic intervention targeted to each individual according to the state of the immune response in that horse. Clin Liver Dis, 2004 Feb, 8(1), 83 - 94 Sepsis and cholestasis; Moseley RH; Sepsis-associated cholestasis should always be considered as part of the differential diagnosis of jaundice in the hospitalized or critically ill patient . The development of a disproportionate elevation of serum bilirubin in comparison with serum alkaline phosphatase and serum aminotransferases should be considered an early warning sign of an underlying infection, even in the absence of fever,leukocytosis, or other signs or symptoms . Prompt recognition and appropriate medical and surgical intervention may reduce morbidity and mortality. Inflamm Res, 2004 Apr, 53(4), 158 - 63 Epub 2004 Mar 18. Are IL-6, IL-10 and PCT plasma concentrations reliable for outcome prediction in severe sepsis? A comparison with APACHE III and SAPS II; Wunder C et al.; OBJECTIVE: Prospective examination whether changes in interleukin (IL)-6, IL-10 or procalcitonin (PCT) concentrations correlate with poor outcome in patients with severe sepsis in comparison with APACHE III or SAPS II . METHODS: 33 patients who fulfilled the criteria for severe sepsis have been included in the study . Blood samples were collected for cytokine and PCT determinations . The Acute Physiology, Age and Chronic Health Evaluation (APACHE) III score and the Simplified Acute Physiology Score (SAPS) II were calculated for 3 consecutive days . RESULTS: 14 out of 33 patients died of multiple organ failure . The areas under the ROC-curves for APACHE III and SAPS II indicated a poor discrimination between survivors and non-survivors . Plasma PCT and IL-10 concentrations were higher in non-survivors than in survivors . IL-6 levels showed no differences between groups . The multivariate analysis of the APACHE III, SAPS II, IL-10 and PCT data showed a significant relationship between APACHE III, PCT plasma levels and outcome . CONCLUSIONS: The data suggest that non-surviving patients have higher PCT and IL-10 values . Only APACHE III score and PCT plasma levels correlated with a poor outcome . Therefore, routine measurements of plasma PCT concentrations might be helpful to improve the mortality risk prediction in patients with severe sepsis. Am J Respir Crit Care Med, 2004 Aug 1, 170(3), 227 - 33 Epub 2004 Apr 01. Pulmonary neutrophil infiltration in murine sepsis: role of inducible nitric oxide synthase; Razavi HM et al.; Nitric oxide (NO) derived from inducible NO synthase (iNOS) contributes to the pathophysiology of acute lung injury (ALI) . The effect of iNOS on pulmonary neutrophil infiltration in ALI is not known . Thus, we assessed pulmonary microvascular neutrophil sequestration through intravital videomicroscopy and pulmonary neutrophil infiltration, reflected by myeloperoxidase activity and lavage neutrophil counts, after induction of sepsis by cecal ligation/perforation in wild-type (iNOS+/+) versus iNOS-/- mice . Pulmonary microvascular neutrophil sequestration was attenuated in septic iNOS-/- versus iNOS+/+ mice (15 +/- 1 vs . 20 +/- 1 leukocytes per field, p < 0.05), but lavage neutrophil counts were greater in iNOS-/- mice (5.7 +/- 1.5% vs . 0.7 +/- 0.1%, p < 0.05) between 6 and 18 hours after cecal ligation and perforation . When iNOS+/+ bone marrow was transplanted into bone marrow-depleted iNOS-/- mice (+ to - chimeras; iNOS limited to marrow-derived inflammatory cells), septic pulmonary microvascular neutrophil sequestration and lavage neutrophil counts were restored to levels seen in septic iNOS+/+ mice . In contrast, in - to + chimeras, pulmonary neutrophil trafficking was similar to iNOS-/- mice . In vitro cytokine-stimulated neutrophil transendothelial migration was significantly greater for iNOS-/- versus iNOS+/+ neutrophils (7.9 +/- 0.7% vs . 3.8 +/- 0.6%, p < 0.05) but was independent of endothelial iNOS . Thus, neutrophil iNOS-derived NO is an important autocrine modulator of pulmonary neutrophil infiltration in murine sepsis. Clin Orthop, 2004 Mar, (420), 26 - 31 Periprosthetic sepsis; Della Valle CJ et al.; The diagnosis of septic implant failure can be difficult to make, yet is imperative for optimal patient outcomes in revision total hip arthroplasty . In most cases, a thorough history and physical examination combined with preoperative laboratory tests and an intraoperative frozen section are sufficient to differentiate septic from aseptic failure . If preoperative laboratory test values are elevated, preoperative aspiration of the hip can be used in selected patients to confirm or exclude the diagnosis of infection . Nuclear medicine studies comprise a second-line investigation to evaluate patients with a painful total hip arthroplasty in whom revision surgery otherwise is not indicated . Intraoperative tissue appearance in combination with intraoperative Gram stains are unreliable for detecting periprosthetic sepsis, and neither is adequate when considered alone for ruling out infection at the time of revision total hip arthroplasty . It is imperative that the surgeon doing revision total hip arthroplasty thoroughly understands the relative utility of preoperative and intraoperative tests used to diagnose periprosthetic sepsis. Int J Clin Pract, 2004 Feb, 58(2), 125 - 9 Investigation of the course of proinflammatory and anti-inflammatory cytokines after burn sepsis; Ozbalkan Z et al.; Cytokines have been considered as important participants in the post-burn pathophysiological process . The aim of this study was to investigate the course of a proinflammatory cytokine interleukin-8 (IL-8) and an anti-inflammatory cytokine IL-10 in burned patients and whether there was a correlation between mortality and serum levels of these cytokines . Thirty-six acutely burned patients, admitted to Ankara Numune hospital burn unit, entered into the study . A series of serum samples were collected, and serum levels of IL-8 and IL-10 were determined using enzyme-linked immunosorbent assay kit . According to definition utilised, 21 patients developed septic shock and nine of them died . There was no mortality among the 17 non-septic patients . In all 36 patients, there was an increase in serum IL-8 levels, and a peak level was detected shortly after burn injury . The peak IL-8 value of the non-survivors was greater when compared with that of the others . On admission, a significant difference in serum IL-8 values was found between survivors and those who died . In all patients, a peak level of IL-10 was detected between 5 and 9 days of injury . In non-septic survivors, this peak level was less when compared with that of the others . After this peak level, in all patients, serum IL-10 levels showed a decrease, but in non-survivors, a second peak level was detected . A greater understanding of the pathology of the burn sepsis allows rationale use and assessment of current therapies . The results obtained in this study provide useful information on the formulation approaches to this task . Also, IL-8 and IL-10 are prognostic factors in burn sepsis. Intensive Care Med, 2004 May, 30(5), 911 - 7 Epub 2004 Mar 30. Hidden evidence to the West: multicentre, randomised, controlled trials in sepsis and systemic inflammatory response syndrome in Japanese journals; Bellomo R et al.; OBJECTIVE: To assess multicentre, randomised, controlled trials (MC-RCTs) of systemic inflammatory response syndrome (SIRS) and sepsis conducted in Japan, published in Japanese and not available to English-language medical databases . DESIGN: Methodological review . SUBJECTS: All Japanese RCTs relevant to SIRS and sepsis . INTERVENTION: Identification of manuscripts using a Japanese electronic library . Critical analysis of methodology and reporting quality using a modified Methodological Quality Assessment Score and the CONSORT group check list . MEASUREMENTS AND RESULTS: Three MC-RCTs were identified . In the first, 147 patients with septic shock were randomised to methylprednisolone (1000 mg i.v.) or placebo . In the second, 221 patients were randomised to 0.20 mg/kg per h or 0.004 mg/kg per h of sivelestat for acute lung injury with SIRS . In the third, 504 patients were randomised to immunoglobulin (5 g for 3 days) or to a control group . The average methodological quality score was higher than that of equivalent Western trials . The reporting quality (CONSORT checklist) was comparable to Western studies published during the same period . CONCLUSIONS: Despite sound methodology and quality, the information obtained from relatively large Japanese critical care trials is not widely available to English-speaking investigators and therefore might be ignored in meta-analyses. Saudi Med J, 2004 Mar, 25(3), 277 - 84 Can we reduce mortality in sepsis? Chehab MS. Considerable progress has been made over the last 2 decades in diagnosing and treating sepsis . Although the mortality rate is beginning to decline with the development of new therapeutic interventions, it still remains unacceptably high . Five such interventions are discussed in this review article to provide guidance for intensivists on the integration and implementation of new interventions into the intensive care unit . They were shown in randomized, controlled trials to reduce mortality by limiting the tidal volume in acute lung injury or acute respiratory distress syndrome, the early goal directed therapy, the use of recombinant human activated protein C, the use of moderate doses of steroids and the tight control of blood sugar . Each new intervention has a role in the management of sepsis, however they are not mutually exclusive . This article provides guidelines on optimal patient selection and timing for each intervention and provides advice on how to integrate new therapies in intensive care practice so that mortality rates can be reduced. Intensive Care Med, 2004 Oct, 30(10), 1974 - 8 Epub 2004 Mar 26. Effects of polyenylphosphatidylcholine on cytokines, nitrite/nitrate levels, antioxidant activity and lipid peroxidation in rats with sepsis; Demirbilek S et al.; OBJECTIVES: To determine the effect of pretreatment with polyenylphosphatidylcholine (lecithin, PPC) on plasma levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10, total nitrite/nitrate (NOx), and tissue levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in septic rats . DESIGN: Prospective, randomized, controlled animal study . SETTING: University laboratory . SUBJECTS: Forty-five Spraque-Dawley rats were divided into three groups: group C, sham-operated; group S, sepsis; and group P, sepsis pretreated with PPC . INTERVENTIONS: Rats were made septic by cecal ligation and puncture (CLP) . Group P rats were treated with PPC (100 mg/day orally) for 10 days before sepsis . Twenty-four hours later CLP, plasma concentrations of TNF-alpha, IL-6 and IL-10 and plasma levels of NOx were measured . SOD and MDA were determined in liver, lung and heart homogenates . MEASUREMENTS AND MAIN RESULTS: All rats in group P survived during the 24-h observation time after CLP, whereas survival rate in group S was 66.7% (10/15; P<0.05) . PPC significantly reduced plasma levels of TNF-alpha (P=0.006), IL-6 (P=0.007), IL-10 (P=0.016), NOx (P<0.001), and tissue levels of MDA (P<0.001) in group P with respect to in group S . Tissue levels of SOD significantly increased in group P when compared with group S (P<0.001) . CONCLUSIONS: These results show that PPC pretreatment exerts cumulative effects in decreasing the levels of cytokines, NOx, and tissue MDA concentrations, with a concomitant increase in survival in septic rats . Lecithin therapy may be a useful adjuvant therapy in controlling of the excessive production of the inflammatory cytokines in patients with severe sepsis . DESCRIPTOR: SIRS/sepsis, experimental studies. Nat Rev Immunol, 2004 Feb, 4(2), 133 - 42 The dark side of C5a in sepsis; Ward PA; Sepsis is a major clinical problem for which therapeutic interventions have been largely unsuccessful, in spite of promising strategies that were successful in animals, especially rodents . There is new evidence that sepsis causes excessive activation of the complement system and that this induces paralysis of innate immune functions in phagocytic cells due to effects of the powerful complement-activation product, C5a . This review describes our present understanding of how and why sepsis is a life-threatening condition and how it might be more effectively treated. Tidsskr Nor Laegeforen, 2004 Mar 18, 124(6), 782 - 4 {Should patients with severe sepsis be treated with activated protein C?}; Laake JH et al.; BACKGROUND: Xigris (recombinant human activated protein C) has recently been introduced as a treatment for severe sepsis following a large multicentre trial (the PROWESS trial) . MATERIAL AND METHODS: Critical review of the original paper, follow-up studies and commentaries, and subgroup analyses from the US Food and Drug Administration . RESULTS: Changes in trial design after the start of the trial as well as inconsistent results in two phases of the trial make interpretation difficult . The overall trial results indicate a small benefit from treatment with activated protein C . However, subgroup analysis reveals that several groups of patients appeared to have little benefit . The drug may have severe and potentially lethal side effects in some patients . INTERPRETATION: Although activated protein C may have beneficial effects in some patients with severe sepsis, the effect on different subgroups of patients remains to be clarified . We conclude that there is at present insufficient documentation for a recommendation of activated protein C in patients with severe sepsis. Tidsskr Nor Laegeforen, 2004 Mar 18, 124(6), 779 - 81 {Severe sepsis treated with activated protein C}; Froyshov S et al.; BACKGROUND: Severe sepsis is a common cause of mortality in critically ill patients . Drotrecogin alfa (activated), synonymous with recombinant human activated protein C (rhAPC), is a new therapeutic tool with anticoagulant, anti-inflammatory and profibrinolytic properties with proven effect in reducing mortality in severe sepsis . MATERIAL AND METHODS: As part of a multi-centre study, the patients received an infusion of rhAPC, 24 microg/kg/h for 96 hours according to an open-labeled phase IIIb study protocol . RESULTS: Out of a total of 28 patients, 6 (21%) died before day 28 . One of the deaths was classified as possibly related to rhAPC . In three patients rhAPC was transiently stopped because of surgery or postoperative bleeding . Use of the compound rarely interfered with commonly used diagnostic and therapeutic procedures . INTERPRETATION: Treatment with rhAPC is easily carried out in an intensive care unit . Patients with severe sepsis and two or more failing vital organs should be considered for treatment with rhAPC. Am J Pathol, 2004 Apr, 164(4), 1435 - 45 Disturbed homeostasis of lung intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 during sepsis; Laudes IJ et al.; Cecal ligation and puncture (CLP)-induced sepsis in mice was associated with perturbations in vascular adhesion molecules . In CLP mice, lung vascular binding of (125)I-monoclonal antibodies to intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 revealed sharp increases in binding of anti-ICAM-1 and significantly reduced binding of anti-VCAM-1 . In whole lung homogenates, intense ICAM-1 up-regulation was found (both in mRNA and in protein levels) during sepsis, whereas very little increase in VCAM-1 could be measured although some increased mRNA was found . During CLP soluble VCAM-1 (sVCAM-1) and soluble ICAM-1 (sICAM-1) appeared in the serum . When mouse dermal microvascular endothelial cells (MDMECs) were incubated with serum from CLP mice, constitutive endothelial VCAM-1 fell in association with the appearance of sVCAM-1 in the supernatant fluids . Under the same conditions, ICAM-1 cell content increased in MDMECs . When MDMECs were evaluated for leukocyte adhesion, exposure to CLP serum caused increased adhesion of neutrophils and decreased adhesion of macrophages and T cells . The progressive build-up in lung myeloperoxidase after CLP was ICAM-1-dependent and independent of VLA-4 and VCAM-1 . These data suggest that sepsis disturbs endothelial homeostasis, greatly favoring neutrophil adhesion in the lung microvasculature, thereby putting the lung at increased risk of injury. Int Immunopharmacol, 2004 Mar, 4(3), 327 - 47 Immune cells: free radicals and antioxidants in sepsis; Victor VM et al.; The excessive production of reactive oxygen species (ROS), associated with inflammation, leads to a condition of oxidative stress . Oxidative stress is a major contributing factor to the high mortality rates associated with several diseases such as endotoxic shock . This condition can be controlled to a certain degree by antioxidant therapies . Immune cells use ROS in order to support their functions and therefore need adequate levels of antioxidant defenses in order to avoid the harmful effect of an excessive production of ROS . This review discusses the toxic effects of endotoxin, paying particular attention to immune function . It continues by analyzing the mechanism to which specific cells of the immune system recognize endotoxin, and the resulting pathways leading to nuclear factor-kappaB activation and proinflammatory gene transcription . We also focus on the involvement of reactive oxygen and nitric oxide (NO) and the protective role of antioxidants . The potential clinical use of antioxidants in the treatment of sepsis and the effects on the redox state of the immune cells are discussed. Ann N Y Acad Sci, 2003 Dec, 1010, 742 - 7 Transient leukocytosis, granulocyte colony-stimulating factor plasma concentrations, and apoptosis determined by binding of annexin V by peripheral leukocytes in patients with severe sepsis; Weiss M et al.; This study was undertaken to clarify the relation between transient increases in the numbers of leukocytes and granulocyte colony-stimulating factor (G-CSF) plasma concentrations as well as the degree of apoptosis, as determined by binding of annexin V by these cells in patients with severe sepsis and septic shock . Over a 6-month period, annexin V binding by leukocytes was determined daily using flow cytometry and FITC-labeled annexin V in 33 postoperative patients with severe sepsis or septic shock during their intensive care unit stay . The percentage of annexin V binding neutrophils, monocytes, and lymphocytes was significantly lower, and G-CSF plasma concentrations were higher in patients than in controls on most days . Nine, 19, and 18 peaks in neutrophil, monocyte, and lymphocyte counts (increase of >/=30% within 2 days, followed by a decrease of >/=30% within 2 days) occurred in 6, 11, and 16 patients . During leukocyte peaks, the absolute numbers of annexin V binding neutrophils, monocytes, and lymphocytes paralleled those of neutrophil, monocyte, and lymphocyte numbers . However, the percentage of annexin V binding neutrophils, monocytes, and lymphocytes did not differ significantly from one day to another . Increased G-CSF serum concentrations preceded neutrophil and monocyte peaks . In conclusion, apoptosis of leukocytes is lowered during severe sepsis and septic shock in critically ill patients . Moreover, the degree of apoptosis does not increase during transient leukocytosis . G-CSF might contribute to the low degree of apoptosis of neutrophils and monocytes in those patients. Curr Drug Targets Inflamm Allergy, 2004 Mar, 3(1), 11 - 7 Modulation of innate immune responses in the treatment of sepsis and pneumonia; Schultz MJ et al.; In the last decades several preclinical models for sepsis have been used to study the pathophysiologic processes during sepsis . Although these studies revealed promising immunomodulating agents for the treatment of sepsis, clinical trials evaluating the efficacy of these new agents in septic patients were disappointing . It should be realized that most of the preclinical models for sepsis lack a localized infectious source from which the infection disseminates . Studies on the effects of several immunomodulating strategies have demonstrated strikingly opposite results when using models for sepsis with a more natural route of infection, such as pneumonia, and when using models for sepsis lacking an infectious focus . In this review we will compare models for sepsis and models for pneumonia . We advise to use a combination of models, including models for sepsis and models for localized infections, to test new immunomodulating strategies before starting any clinical trial evaluating a new immunomodulating therapy. Crit Care, 2004 Apr, 8(2), R91 - 8 Epub 2004 Feb 20. Quality of life of survivors from severe sepsis and septic shock may be similar to that of others who survive critical illness; Granja C et al.; INTRODUCTION: The objective of the present study was to compare the health-related quality of life (HR-QoL) of survivors from severe sepsis and septic shock with HR-QoL in others who survived critical illness not involving sepsis . METHODS: From March 1997 to March 2001, adult patients in an eight-bed medical/surgical intensive care unit (ICU) of a tertiary care hospital admitted with severe sepsis or septic shock (sepsis group; n = 305) were enrolled and compared with patients admitted without sepsis (control group; n = 392) . Patients younger than 18 years (n = 48) and those whose ICU stay was 1 day or less (n = 453) were excluded . In addition, patients exhibiting nonsevere sepsis on admission were excluded (n = 87) . Finally, patients who developed nonsevere sepsis or severe sepsis/septic shock after admission were also excluded (n = 88) . RESULTS: In-hospital mortality rates were 34% in the sepsis group and 26% in the control group . There were no differences in sex, age, main activity (work status), and previous health state between groups . Survivors in the sepsis group had a significantly higher Acute Physiology and Chronic Health Evaluation II score on admission (17 versus 12) and stayed significantly longer in the ICU . A follow-up appointment was held 6 months after ICU discharge, and an EQ-5D (EuroQol five-dimension) questionnaire was administered . A total of 104 sepsis survivors and 133 survivors in the control group answered the EQ-5D questionnaire . Sepsis survivors reported significantly fewer problems only in the anxiety/depression dimension . Although there were no significant differences in the other dimensions of the EQ-5D, there was a trend towards fewer problems being reported by sepsis survivors . CONCLUSION: Evaluation using the EQ-5D at 6 months after ICU discharge indicated that survivors from severe sepsis and septic shock have a similar HR-QoL to that of survivors from critical illness admitted without sepsis. Crit Care, 2004 Apr, 8(2), R82 - 90 Epub 2004 Feb 10. Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism {ISRCTN74215569}; Kinasewitz GT et al.; INTRODUCTION: PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers . Here we report data collected at study entry for 1690 patients and over the following 7 days for the 840 patients who received placebo (in addition to usual standard of care) . METHODS: Nineteen biomarkers of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed to determine the relationships between baseline values and their change over time, with 28-day survival, and type of infecting causative micro-organism . RESULTS: Levels of 13 of the 19 biomarkers at baseline correlated with Acute Physiology and Chronic Health Evaluation II scores, and nearly all patients exhibited coagulopathy, endothelial injury, and inflammation at baseline . At study entry, elevated D-dimer, thrombin-antithrombin complexes, IL-6, and prolonged prothrombin time were present in 99.7%, 95.5%, 98.5%, and 93.4% of patients, respectively . Markers of endothelial injury (soluble thrombomodulin) and deficient protein C, protein S, and antithrombin were apparent in 72%, 87.6%, 77.8%, and 81.7%, respectively . Impaired fibrinolysis (elevated plasminogen activator inhibitor-1) was observed in 44% of patients . During the first 7 days, increased prothrombin time (which is readily measurable in most clinical settings) was highly evident among patients who were not alive at 28 days . CONCLUSION: Abnormalities in biomarkers of inflammation and coagulation were related to disease severity and mortality outcome in patients with severe sepsis . Coagulopathy and inflammation were universal host responses to infection in patients with severe sepsis, which were similar across causative micro-organism groups. Crit Care, 2004 Apr, 8(2), 122 - 9 Epub 2003 Sep 29. Clinical review: corticotherapy in sepsis; Prigent H et al.; The use of glucocorticoids (corticotherapy) in severe sepsis is one of the main controversial issues in critical care medicine . These agents were commonly used to treat sepsis until the end of the 1980s, when several randomized trials casted serious doubt on any benefit from high-dose glucocorticoids . Later, important progress in our understanding of the role played by the hypothalamic-pituitary-adrenal axis in the response to sepsis, and of the mechanisms of action of glucocorticoids led us to reconsider their use in septic shock . The present review summarizes the basics of the physiological response of the hypothalamic-pituitary-adrenal axis to stress, including regulation of glucocorticoid synthesis, the cellular mechanisms of action of glucocorticoids, and how they influence metabolism, cardiovascular homeostasis and the immune system . The concepts of adrenal insufficiency and peripheral glucocorticoid resistance are developed, and the main experimental and clinical data that support the use of low-dose glucocorticoids in septic shock are discussed . Finally, we propose a decision tree for diagnosis of adrenal insufficiency and institution of cortisol replacement therapy. Indian J Pathol Microbiol, 2003 Oct, 46(4), 610 - 2 Early diagnosis of neonatal septicemia by sepsis screen; Zawar MP et al.; A study of 100 neonates with clinical suspicion of septicemia, admitted in neonatal intensive care unit of SCSM General Hospital, Solapur was carried out to assess the utility of various indices of sepsis screen . Bacterial and hematological profile of these neonataes was studied . Parameters of sepsis screen such as leukocyte count, band form to neutrophil ratio, neutrophils with toxic granulations, micro ESR and test for C-reactive protein were analysed to know their sensitivity and specificity. Arch Pharm Res, 2004 Feb, 27(2), 232 - 8 The beneficial effect of Trolox on sepsis-induced hepatic drug metabolizing dysfunction; Park SW et al.; Trolox is a hydrophilic analogue of vitamin E . The aim of this study was to investigate its effects on hepatic injury, especially alteration in cytochrome P450 (CYP)-dependent drug metabolism during polymicrobial sepsis . Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) . The rats were treated intravenously with Trolox (2.5 mg/kg) or vehicle, immediately after CLP . Serum aminotransferases and lipid peroxidation levels were markedly increased 24 h after CLP . This increase was attenuated by Trolox . Total CYP content and NADPH-P450 reductase activity decreased significantly 24 h after CLP . This decrease in CYP content was attenuated by Trolox . At 24 h after CLP, there was a significant decrease in the activity of these CYP isozymes: CYP1A1, 1A2, 2B1, and 2E1 . However, Trolox differentially inhibited the decrease in CYP isozyme activity . Trolox had little effect on the decrease in CYP1A1 activity but Trolox significantly attenuated decreases in CYP1A2 and 2E1 activities . In fact, Trolox restored CYP2B1 activity to the level of activity found in control rats . Our findings suggest that Trolox reduces hepatocellular damage as indicated by abnormalities in hepatic drug-metabolizing function during sepsis . Our data also indicates that this protection is, in part, caused by decreased lipid peroxidation. Microvasc Res, 2004 Mar, 67(2), 182 - 91 C1-inhibitor reduces hepatic leukocyte-endothelial interaction and the expression of VCAM-1 in LPS-induced sepsis in the rat; Croner RS et al.; INTRODUCTION: Increased leukocyte-endothelial interaction (LEI) leading to hepatic microperfusion disorders is proposed as major contributor for hepatic failure during sepsis . Recently it has been demonstrated that complement inhibition by C1-inhibitor (C1-INH) is an effective treatment against microcirculatory disturbances in various diseases . The purpose of this study was to investigate the influence of C1-INH on microcirculation and LEI in the liver in a rat model of sepsis . MATERIALS AND METHODS: Rats received lipopolysaccharides (LPS) from Escherichia coli intravenously . Controls received Ringer solution only . Ninety minutes after LPS infusion some animals were treated with C1-INH intravenously (LPS + C1-INH) . Others (LPS + SC) and controls (Ringer + SC) received sodium chloride (SC) . Hepatic LEI and mean erythrocyte velocity (MEV) were quantified by intravital microscopy (IVM) 90 min after LPS or Ringer infusion (0) and 30, 60, 90 and 120 min following treatment . VCAM-1 m-RNA in hepatic tissue, C3a, TNF-alpha and hepatic enzyme liberation in blood was analysed . RESULTS: Leukocyte sticking to the endothelial wall in postsinusoidal venules was significantly reduced in the LPS + C1-INH vs . the LPS + SC group 30, 60, 90 and 120 min after treatment . VCAM-1 m-RNA expression in the hepatic tissue was markedly and C3a levels in plasma were significantly reduced in the LPS + C1-INH vs . the LPS + SC group . No differences in TNF-alpha levels were detected between these two groups . MEV was improved in the LPS + C1-INH vs . the LPS + SC group . CONCLUSIONS: Our results indicate that even upon delayed treatment hepatic adhesion molecule expression and LEI can be reduced by C1-INH . The multifunctional regulator may reduce hepatic microcirculatory disturbances during sepsis under clinical conditions. J Neuroimmunol, 2004 Apr, 149(1-2), 90 - 100 Chronic morphine accelerates the progression of lipopolysaccharide-induced sepsis to septic shock; Ocasio FM et al.; Opiate addicts have been shown to have a high susceptibility to bacterial infection . We investigated how treatment with morphine alters lipopolysaccharide (LPS)-induced inflammatory responses in the rat . Chronic morphine alone elevated serum endotoxin levels . Animals treated with morphine and LPS (250 microg/kg) developed hypothermia, decreased mean arterial pressure (MAP), increased plasma thrombin anti-thrombin III (TAT) complex, and approximately 67% of animals exhibited progressive intramicrovascular coagulation . Morphine also enhanced LPS-induced leukocyte-endothelial adhesion (LEA), suppressed leukocyte flux, and corticosterone production, and elevated interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 serum levels . Our study presents both the molecular and cellular mechanisms underlying the potentiated LPS-induced inflammation and accelerated progression to septic shock seen with chronic morphine exposure. Forensic Sci Int, 2004 Feb 10, 140(1), 21 - 3 Cocaine-associated abscesses with lethal sepsis after splenic infarction in an 17-year-old woman; Dettmeyer R et al.; Well known complications related to cocaine use are myocardial insufficiency, myocardial infarction, myocarditis, aortic dissection, neurologic damages, ischemic colitis, thrombotic phenomenons, renal infarction and acute liver failure . Cases of splenic infarctions related to cocaine use are extremely rare . A 17-year-old drug addict was found by her boy-friend liveless in her bed . She was well known using cocaine since years . Autopsy revealed multiple splenic infarctions with secondary mixed bacterial infection and abscesses . Petechial bleedings were found and microabscesses in the myocardium, the meninges and the kidneys . The absolutely rare bacterial infection of the cocaine-associated splenic infarction leads to sepsis with lethal course. Surg Infect (Larchmt), 2003 Winter, 4(4), 363 - 77 Myocardial inflammatory responses to sepsis complicated by previous burn injury; Horton JW et al.; BACKGROUND: It is generally accepted that an initial injury such as burn trauma alters immune function such that a second insult increases the morbidity and mortality over that observed with each individual insult . We have shown previously that either burn trauma or sepsis promotes cardiomyocyte secretion of TNF-alpha and IL-1beta, cytokines that have been shown to produce myocardial contractile dysfunction . This study determined whether a previous burn injury (given eight days prior to sepsis) (1) provides a preconditioning phenomenon, decreasing inflammatory responses to a second insult or (2) exacerbates inflammatory response observed with either injury alone . METHODS: Anesthetized Sprague-Dawley rats were given either burn injury over 40% total body surface area, sepsis alone (intratracheal S . pneumoniae, 4 x 10(6) colony forming units) or sepsis eight days after burn; all rats received lactated Ringer's solution . Hearts harvested 24 h after onset of sepsis alone or sepsis plus eight-day burn were used to (1) isolate cardiomyocytes (collagenase) or (2) assess contractile function (Langendorff) . Cardiomyocytes loaded with 2 microg/mL Fura-2AM or sodium-binding benzofuran isophthalate were used to measure intracellular calcium and sodium concentrations (Nikon inverted microscope, Grooney optics, InCyt Im2 Fluorescence Imaging System) . Additional cardiomyocytes were used to measure myocyte-secreted TNFalpha, IL-1, IL-6, IL-10 (pg/ml, ELISA) . RESULTS: Either burn trauma alone or sepsis alone promoted TNF-alpha, IL-1beta, nitric oxide, IL6 and IL-10 secretion by cardiomyocytes (p < 0.05) . Producing aspiration-related pneumonia eight days postburn produced myocardial pro- and anti-inflammatory responses and increased myocyte Ca2+/Na+ concentrations to a significantly greater degree than the responses observed after either insult alone . CONCLUSIONS: A previous burn injury alters myocardial inflammatory responses, predisposing the burn-injured subject to exaggerated inflammation, which correlates with greater myocardial dysfunction. Surg Infect (Larchmt), 2003 Winter, 4(4), 355 - 62 Risk factors for severe sepsis in secondary peritonitis; Anaya DA et al.; BACKGROUND: The incidence and risk factors for severe sepsis (SS, organ failure associated with infection) in the context of peritonitis are not well established; thus, it is not clear which patients require more aggressive operative or pharmacologic intervention . We set out to determine risk factors for severe sepsis in a large cohort of patients with intra-abdominal infection . METHODS: Patients admitted for peritonitis over a four-year interval were identified using a Washington State administrative hospital discharge database . This cohort was identified by ICD-9 CM diagnoses and diagnosis-related group (DRG) assignment . Patients with organ failure were identified by ICD-9 CM diagnoses codes using a previously validated classification scheme . Independent risk factors for SS were identified using stepwise Poisson regression . RESULTS: A total of 11,202 patients with peritonitis were identified, 11% of whom developed SS . The crude relative risk of death in patients with SS was 13 (95% CI, 11.1-15.2) times greater than those without . Severe sepsis was present in 424 (62%) of the 686 decedents . Multivariate analysis showed that source of infection, extent of peritonitis, increasing age, and pre-existing organ dysfunction were independently associated with SS . CONCLUSIONS: Severe sepsis complicates the course of 11% of all patients with peritonitis . Risk factor analysis identifies a subset of patients at greatest risk for severe sepsis . These are the patients who should be targeted for evaluation of novel pharmacologic interventions or more aggressive surgical intervention. J Paediatr Child Health, 2004 Apr, 40(4), 221 - 6 Growth hormone and insulin-like growth factor 1 levels and their relation to survival in children with bacterial sepsis and septic shock; Onenli-Mungan N et al.; OBJECTIVES: Despite improved supportive care, the mortality of sepsis and septic shock is still high . Multiple changes in the neuroendocrine systems, at least in part, are responsible for the high morbidity and mortality . A reduced circulating level of insulin-like growth factor and an elevated level of growth hormone are the reported characteristic findings early in the course of sepsis and septic shock in adults . The aim of this study was to evaluate the changes of growth hormone/insulin-like growth factor 1 axis in sepsis and septic shock and investigate the relationship between these hormones and survival . METHODS: Fifty-one children with sepsis (S), 21 children with septic shock (SS) and 30 healthy, age- and sex-matched children (C) were enrolled in this study . Growth hormone, insulin-like growth factor 1 and cortisol levels of the sepsis and septic shock groups were obtained before administration of any inotropic agent . RESULTS: Growth hormone levels were 32.3 +/- 1.5 microIU/mL (range 4-56), 15.9 +/- 0.6 microIU/mL (range 11-28) and 55.7 +/- 2.7 microIU/mL (range 20-70) in S, C and SS groups, respectively . The difference between the growth hormone levels of the S and C groups, S and SS groups, and C and SS groups were significant (P < 0.001) . Non-survivors (54.7 +/- 1.6 microIU/mL) had significantly higher growth hormone levels than survivors (29.4 +/- 1.5 microIU/mL) (P < 0.001) . Insulin-like growth factor 1 levels were 38.1 +/- 2.1 ng/mL (range 19-100), 122.9 +/- 9.6 ng/mL (range 48-250) and 22.2 +/- 1.9 ng/mL (range 10-46) in the S, C and SS groups, respectively, and the difference between the insulin-like growth factor 1 levels of the S and C, S and SS, and C and SS groups were significant (P < 0.001) . Non-survivors (8.8 +/- 1.1 micro g/dL) had significantly lower cortisol levels than survivors (40.9 +/- 2.1 microg/dL) (P < 0.001) . We detected a significant difference between the levels of cortisol in non-survivors (19.7 +/- 1.8 microg/dL) and survivors (33.9 +/- 0.9 microg/dL) (P < 0.01) . CONCLUSIONS: There were elevated levels of growth hormone with decreased levels of insulin-like growth factor 1 in children during sepsis and septic shock compared to healthy subjects . In addition, there were even higher levels of growth hormone and lower levels of insulin-like growth factor 1 in non-survivors than in survivors . We think that both growth hormone and insulin-like growth factor 1 may have potential prognostic value to serve as a marker in bacterial sepsis and septic shock in children . As there is insufficient data in the paediatric age group, more studies including large numbers of patients and additionally evaluating cytokines and insulin-like growth factor binding proteins are needed. Ann Biomed Eng, 2004 Feb, 32(2), 233 - 44 Increased nonstationarity of neonatal heart rate before the clinical diagnosis of sepsis; Cao H et al.; The clinical diagnosis of neonatal sepsis is preceded by abnormal heart rate (HR) characteristics of transient decelerations and reduced variability, which intuitively appear to be more nonstationary than normal HR variability . Our goals were to investigate stationarity of HR, and to devise measures useful for early diagnosis of neonatal sepsis . In this context, we define non-stationarity to be present when the observed data differ from surrogate data generated by stationary Gaussian noise with arbitrary linear correlations . We devised statistical methods for determining stationarity of HR data based on the two-sample Kolmogorov-Smirnov (KS) test . We compared distributions of KS distances between small sample epochs from clinical data with those of isospectral surrogates and of surrogates generated using the amplitude-adjusted Fourier transform technique, reasoning that they should differ significantly for nonstationary data . We found significant evidence of non-stationarity for records longer than 1 min . We developed new HR measures based on the empirical cumulative distribution function (ECDF) that are highly significantly associated with sepsis, but are not correlated with HR measures such as moments or sample entropy . We conclude that neonatal HR data cannot be assumed to be stationary, and become even less stationary prior to sepsis. Eur Surg Res, 2004 Mar-Apr, 36(2), 116 - 22 Metoclopramide and cellular immune functions during polymicrobial sepsis; Oberbeck R et al.; Metoclopramide (MCP) has been demonstrated to restore the depressed cellular immune function after hemorrhage by increasing the release of the immunomodulatory pituitary hormone prolactin . We investigated the effect of MCP on serum prolactin concentrations, on cellular immune functions (immune cell distribution, splenocyte proliferation, apoptosis and cytokine release) and on the survival 48 h after induction of a polymicrobial sepsis in mice . Administration of MCP increased circulating serum prolactin concentrations and splenocyte apoptosis rate and improved cellular cytokine release, but did not affect mortality of septic mice . We therefore conclude that administration of MCP modulated splenocyte apoptosis and cytokine release in a murine model of sepsis without an impact on the survival . Furthermore, this effect may be mediated by an increased endogenous prolactin release . Ann R Coll Surg Engl, 2004 Mar, 86(2), 75 - 81 Hunterian Lecture: Insulin resistance in human sepsis: implications for the nutritional and metabolic care of the critically ill surgical patient; Carlson GL; Loss of the anabolic effect of insulin (insulin resistance) is a key component of the adverse metabolic consequences of sepsis and may contribute to the apparent lack of efficacy of feeding regimens in critically ill patients . The mechanisms which underlie the development of insulin resistance in stress remain unclear . In this series of studies, the locus of insulin resistance in the septic patient was shown to lie within the metabolic pathways of glucose storage (glycogen synthesis) within skeletal muscle, was noted to be unrelated to the actions of hormone mediators such as leptin and was shown not to be associated with altered nutrient-induced thermogenesis during total parenteral nutrition (TPN) . Clinically applicable maximal rates of glucose-based TPN for septic patients were calculated . A technique was also developed in which insulin resistance could be induced and studied in healthy volunteers . These studies demonstrated that insulin resistance develops within 7 h of an inflammatory stimulus and, as in clinical sepsis, is characterised by selective impairment of glucose storage . Finally, a series of related studies indicated that the magnitude and nature of the inflammatory response in vivo could be enhanced by exogenous insulin infusion, indicating links between the hormone systems involved in intermediary metabolism and the inflammatory response . These findings have significant implications for the optimal design of feeding regimens for critically ill patients. Br J Nutr, 2004 Mar, 91(3), 423 - 9 Effects of glutamine supplementation on innate immune response in rats with gut-derived sepsis; Yeh SL et al.; The present study examined the effect of glutamine (Gln)-enriched diets before sepsis or Gln-containing total parenteral nutrition (TPN) after sepsis, or both, on the phagocytic activity and blood lymphocyte subpopulation in rats with gut-derived sepsis . Rats were assigned to a control group or one of four experimental groups . The control group and groups 1 and 2 were fed a semipurified diet; groups 3 and 4 had part of casein replaced by Gln . After feeding the diets for 10 d, sepsis was induced by caecal ligation and puncture (CLP); TPN was maintained for 3 d after CLP . The control group and groups 1 and 3 were infused with conventional TPN and groups 2 and 4 were supplemented with Gln in the TPN solution . All rats were killed 3 d after CLP or sham operation to examine their immune responses . The results showed that compared with the control group, the phagocytic activities of peritoneal macrophages were enhanced in groups 3 and 4, but not in groups 1 and 2 . The proportion of CD3+ cells in group 1 was significantly lower (P<0.05) than that of the control group, whereas no differences were observed among the control and Gln-supplemented groups . The CD4+ cell proportion was significantly lower (P<0.05) in group 1 compared with the control group and groups 3 and 4 . These findings suggest that Gln-enriched diets before CLP significantly enhanced peritoneal macrophage phagocytic activity, preserved CD4+ cells and maintained blood total T lymphocytes in gut-derived sepsis . However, parenteral Gln administration after caecal ligation and puncture had no favourable effects on modulating immune response in septic rats. Clin Hemorheol Microcirc, 2004, 30(2), 107 - 15 Platelet aggregation and blood rheology in severe sepsis/septic shock: relation to the Sepsis-related Organ Failure Assessment (SOFA) score; Alt E et al.; Abnormalities in blood rheology and platelet dysfunction might play a role in the pathogenesis of multiple organ failure in septic patients by reducing microvascular blood flow . To determine whether alterations in blood rheology and in platelet function are related to the severity of organ dysfunction, we prospectively studied plasma fibrinogen, red cell aggregation, plasma viscosity, hematocrit, whole blood viscosity and platelet aggregation in relation to the Sepsis-related Organ Failure Assessment (SOFA) score in 34 consecutive patients with severe sepsis/septic shock . We found that patients had higher plasma fibrinogen, red cell aggregation and plasma viscosity (p < 0.01), but lower hematocrit, whole blood viscosity and ADP-induced platelet aggregation than controls (p < 0.01) . Platelet aggregation (p < 0.01), but not other rheological variables, were inversely related to the SOFA score . Only platelet count was linked to poor clinical outcome (p < 0.05) . We conclude that blood rheology and platelet function are severely altered in patients with severe sepsis/septic shock . Our findings suggest progressive platelet dysfunction with advancing severity of the disease . Platelet dysfunction might play a more important role in the pathogenesis of the multi organ dysfunction syndrome than abnormalities in blood rheology. Clin Hemorheol Microcirc, 2004, 30(2), 77 - 82 Lipid peroxidation and deformability of red blood cells in experimental sepsis in rats: The protective effects of melatonin; Yerer MB et al.; Sepsis has been associated with a lipopolysaccharide (LPS) induced bacterial infection and causes biochemical, hemodynamic and physiological alterations in a system . Erythrocyte deformability is very critical for a microcirculatory system to function effectively . Hence, we were interested in examining the effects of a potent antioxidant, melatonin (Mel), on lipid peroxidation and deformability of eythrocytes in LPS-induced experimental sepsis . Male Swiss Albino rats were used in 6 groups, each group comprising of 10 animals . The first group was the control, and the other groups were administered LPS (10 mg/kg, i.p.), Mel (10 mg/kg, i.p.), LPS + L-NAME (5 mM, i.p.), Mel + LPS and Mel + LPS + L-NAME, respectively . Deformability of the RBCs decreased significantly (p < 0.05) in the LPS group in comparison to all other groups . This reduction was prevented with both L-NAME and Mel, but was not as significant as when administering L-NAME or Mel alone . This result was adversely seen in nitric oxide levels, i.e . RBCD was reduced when the NO levels were higher . Therefore in the Mel group the NO levels were reduced while the RBCD enhanced . In addition to these, as an index of lipid peroxidation, the Malondialdehyde levels were elevated in LPS groups whereas the deformability was reduced . This lipid peroxidation was suppressed by Mel and/or L-NAME significantly, where the RBCD was enhanced . These results show that, Melatonin can elevate the RBCD in experimental sepsis due to its nitric oxide scavenging activity and antioxidant effect as revealed by lipid peroxidation. Liver Int, 2003 Dec, 23(6), 440 - 8 Coagulation disorders in patients with cirrhosis and severe sepsis; Plessier A et al.; BACKGROUND: In patients with cirrhosis, severe sepsis may stimulate the extrinsic coagulation pathway resulting in thrombin generation and fibrin formation . AIMS: To compare 23 patients with severe sepsis to 13 infected patients without severe sepsis and 18 patients without infection . METHODS: Zymogen forms of clotting factors involved in the extrinsic pathway (i.e., factors VII + X, V, prothrombin), and the presence of soluble fibrin were assessed . RESULTS: Zymogen forms of clotting factors were significantly lower, while Child-Pugh score and the proportion of patients with soluble fibrin were higher in the severe-sepsis group than in the other groups . Decreased zymogen levels were independently correlated with an elevated Child-Pugh score and the presence of severe sepsis . In the severe-sepsis group, after adjustment for the severity of cirrhosis, decreased zymogen levels were associated with significant increases in the relative risk ratios of in-hospital death . CONCLUSIONS: Cirrhotic patients with severe sepsis have decreased blood levels of zymogen forms of factors VII+X, V, and prothrombin, which may be due not only to the severity of cirrhosis but also, at least in part, to the consumption of these zymogens by the extrinsic coagulation pathway. Mycoses, 2004 Feb, 47(1-2), 72 - 5 Histological detection of intramyocardial abscesses in Candida sepsis mimicking left ventricular non-compaction/hypertrabeculation on echocardiography; Stollberger C et al.; Left ventricular non-compaction/hypertrabeculation (LVHT) is a rare cardiac abnormality characterized by more than three trabeculations protruding from the left ventricular wall, apically to the papillary muscles, visible in one echocardiographic image plane and intertrabecular spaces, perfused from the ventricular cavity . LVHT is frequently associated with neuromuscular disorders . Differential diagnoses of LVHT are intraventricular thrombi, false tendons, aberrant bands, intramyocardial hematoma, cardiac metastases and the apical type of hypertrophic cardiomyopathy . Intramyocardial abscesses have not been reported as a differential diagnosis of left ventricular non-compaction . In the presented case, cardiac microabscesses as a result of Candida sepsis mimicked left ventricular non-compaction in a 55-year-old man with hypopharyngeal carcinoma who died 20 days after chemotherapy . These microabscesses were not visible on echocardiography but were detected only at histologic examination of the myocardium . This case shows that intramyocardial abscesses as a result of Candida sepsis are a rare differential diagnosis of LVHT. Intensive Care Med, 2004 Apr, 30(4), 536 - 55 Epub 2004 Mar 03. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock; Dellinger RP et al.; OBJECTIVE: To develop management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis . DESIGN: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee . The modified Delphi methodology used for grading recommendations built upon a 2001 publication sponsored by the International Sepsis Forum . We undertook a systematic review of the literature graded along 5 levels to create recommendation grades from A-E, with A being the highest grade . Pediatric considerations were provided to contrast adult and pediatric management . PARTICIPANTS . Participants included 44 critical care and infectious disease experts representing 11 international organizations . RESULTS . A total of 46 recommendations plus pediatric management considerations . CONCLUSIONS . Evidence-based recommendations can be made regarding many aspects of the acute management of sepsis and septic shock that will hopefully translate into improved outcomes for the critically ill patient . The impact of these guidelines will be formally tested and guidelines updated annually, and even more rapidly when some important new knowledge becomes available. Mol Interv, 2002 Jul, 2(4), 212 - 5 IRAK-4: A New Drug Target in Inflammation, Sepsis, and Autoimmunity; Wietek C et al.; Two very recent publications, by Suzuki et al . and Li et al., describe the cloning, characterization, and the effects of knockout mice deficient in interleukin-1-associated receptor kinase-4 (IRAK-4), the newest member of the IRAK family . IRAK-4 requires its kinase activity to activate NF-kappaB, and IRAK-4 also activates MAP kinases . Wietek and O'Neill discuss the data indicating that IRAK-4 lies upstream of and activates IRAK-1, and that IRAK-4 is essential for innate immunity. Anesteziol Reanimatol, 2003 Nov-Dec, (6), 27 - 9 {Basic characteristics of lipid metabolism in patients with sepsis during kidney replacement therapy}; Shcherbakova LN et al.; The changing indices of lipid metabolism were studied in patients with sepsis who were undergoing the substitution renal therapy . A sharp reduction of high-density lipoproteins (HDLP) and a higher concentration of triglyceride (TG) and of an extremely low-density lipoproteins (ELDLP) were shown in the blood plasma of such patients irrespective of a clinical outcome . The positive dynamics of TG and ELDLP concentrations as observed in the process of treatment was considered to be a good prognostication sign in sepsis and septic shock. Intensive Care Med, 2004 May, 30(5), 748 - 56 Epub 2004 Feb 26. Stress-hyperglycemia, insulin and immunomodulation in sepsis; Marik PE et al.; Stress-hyperglycemia and insulin resistance are exceedingly common in critically ill patients, particularly those with sepsis . Multiple pathogenetic mechanisms are responsible for this metabolic syndrome; however, increased release of pro-inflammatory mediators and counter-regulatory hormones may play a pivotal role . Recent data suggests that hyperglycemia may potentiate the pro-inflammatory response while insulin has the opposite effect . Furthermore, emerging evidence suggests that tight glycemic control will improve the outcome of critically ill patients . This paper reviews the pathophysiology of stress hyperglycemia in the critically ill septic patient and outlines a treatment strategy for the management of this disorder. Intensive Care Med, 2004 Jul, 30(7), 1468 - 73 Epub 2004 Feb 28. Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma; Brunner M et al.; OBJECTIVE: T1/ST2, a member of the interleukin (IL)-1 receptor superfamily, is predominantly expressed on type-2 T helper (Th2) cells but not Th1 cells, and plays a role in cell proliferation and Th2 immune response . The relation of soluble ST2, Th1-Th2 cytokine profile, and immunoglobulin (Ig) production in sepsis and trauma patients is not well known . DESIGN AND SETTING: Case-control study at a university hospital intensive care unit . PATIENTS: Fifteen patients recruited within 24-48 h of diagnosis of sepsis, 13 trauma patients recruited within 24 h after admission to the ICU, 11 patients who underwent abdominal surgery, and 15 healthy volunteers served as control . MEASUREMENTS AND RESULTS: ELISA was utilized to detect serum soluble ST2, IL-2, IFN-gamma, IL-10, and Ig production . Serum levels of soluble ST2 were significantly increased in septic patients (8420+/-2169 pg/ml) as compared with trauma (2936+/-826 pg/ml), abdominal surgery (1423+/-373 pg/ml), and healthy controls (316+/-72 pg/ml; p<0.001, respectively) . These results were accompanied by an increase of IgG1 and IgG2 production, and decrease of IL-2 and IFN-gamma synthesis in septic patients . IL-10 was significantly increased in both septic and trauma patients . CONCLUSIONS: Our results demonstrate that soluble ST2, a marker for Th2 cytokine producing cells, is increased in sepsis and trauma patients, and they provide further evidence for a shift from Th1- to Th2-biased cells. Nutrition, 2004 Mar, 20(3), 286 - 91 Glutamine supplementation enhances mucosal immunity in rats with Gut-Derived sepsis; Lai YN et al.; OBJECTIVE: Supplemental glutamine (Gln) has been demonstrated to improve the immunologic response and reduce mortality in rodents with sepsis . However, the effects of Gln on gut-associated lymphoid tissue function after infection and sepsis are not clear . We investigated the effects of Gln-supplemented diets before sepsis, Gln-enriched total parenteral nutrition (TPN) after sepsis, or both on the intestinal immunity in rats with gut-derived sepsis . METHODS: Male Wistar rats were assigned to control and four experimental groups . The control and experimental groups 1 and 2 were fed a semi-purified diet; in experimental groups 3 and 4, part of the casein in the diets was replaced with Gln . After feeding rats the respective diets for 10 d, sepsis was induced by cecal ligation and puncture (CLP) in the experimental groups, whereas the control group underwent a sham operation; at the same time, the internal jugular vein of all rats was cannulated . All rats were maintained on TPN for 3 d . The control group and groups 1 and 3 were infused with conventional TPN, and groups 2 and 4 were given a TPN solution supplemented with Gln, which provided 25% of total amino acid nitrogen . All rats were killed 3 d after the sham operation or CLP . Intestinal immunoglobin A levels, total lymphocyte yields, and lymphocyte subpopulations in Peyer's patches were analyzed . RESULTS: Total Peyer's patch lymphocyte numbers were significantly higher in the Gln-supplemented groups than in the control group . Distributions of CD3+ and CD4+ in group 1 were significantly lower than those in the control group, whereas no differences were observed among the control and Gln-supplemented groups . Plasma immunoglobulin A levels were higher in the Gln-supplemented groups than the control group and group 1 . Intestinal immunoglobulin A levels were significantly higher in groups 2 and 4 than in the control group and group 1 . CONCLUSIONS: Preventive use of a Gln-supplemented enteral diet before CLP or intravenous Gln supplementation after CLP have similar effects in promoting proliferation of total lymphocyte in gut-associated lymphoid tissue, enhancing IgA secretion, and maintaining T-lymphocyte populations in Peyer's patches . Gln administered before and after CLP did not seem to have a synergistic effect on enhancing mucosal immunity in rats with gut-derived sepsis. Gac Sanit, 2004 Jan-Feb, 18(1), 50 - 7 {Cost-effectiveness of drotrecogin alpha {activated} in the treatment of severe sepsis in Spain}; Sacristan JA et al.; INTRODUCTION: The PROWESS clinical trial has shown that treatment with drotrecogin alpha (activated) in patients with severe sepsis is associated with a reduction in the absolute risk of death compared with standard treatment . The aim of the present study was to assess the cost-effectiveness of drotrecogin alpha (activated) versus that of standard care in the treatment of severe sepsis in Spain . PATIENTS AND METHODS: A decision analysis model was drawn up to compare costs to hospital discharge and the long-term efficacy of drotrecogin alpha (activated) versus those of standard care in the treatment of severe sepsis in Spain from the perspective of the health care payer . Most of the information for creating the model was obtained from the PROWESS clinical trial . A two-fold baseline analysis was performed: a) for all patients included in the PROWESS clinical trial and b) for the patients with two or more organ failures . The major variables for clinical assessment were the reduction in mortality and years of life gained (YLG) . Cost-effectiveness was expressed as cost per YLG . A sensitivity analysis was applied using 3% and 5% discount rates for YLG and by modifying the patterns of health care, intensive care unit costs, and life expectancy by initial co-morbidity and therapeutic efficacy of drotrecogin alpha (activated) . RESULTS: Treatment with drotrecogin alfa (activated) was associated with a 6.0% drop in the absolute risk of death (p = 0.005) when all of the patients from the PROWESS trial were included and with a 7.3% reduction (p = 0.005) when the analysis was restricted to patients with two or more organ failures . The cost-effectiveness of drotrecogin alfa (activated) was 13,550 euros per YLG with respect to standard care after analysing all of the patients and 9,800 euros per YLG in the group of patients with two or more organ failures . In the sensitivity analysis, the results ranged from 7,322 to 16,493 euros per YLG . The factors with the greatest impact on the results were the change in the efficacy of drotrecogin alfa (activated), adjustment of survival by initial co-morbidity and the application of discount rates to YLG . CONCLUSIONS: Treatment with drotrecogin alfa (activated) presents a favorable cost-effectiveness ratio compared with other health care interventions commonly used in Spain. Obes Surg, 2004 Jan, 14(1), 107 - 15 Use of drotrecogin alfa (activated) in bariatric surgery patients with severe sepsis syndrome: experience in an urban community teaching hospital; Savel RH et al.; BACKGROUND: Severe sepsis syndrome (SSS) and septic shock have an associated mortality ranging from 31 to 60% . Drotrecogin alfa (activated), activated protein C (APC), has been shown in a recent trial to decrease mortality from 44 to 31% in patients with SSS and a high risk of death . We present 3 patients who developed SSS after bariatric surgery and were treated with APC as part of comprehensive therapy for sepsis . METHODS: At our institution, patients must have SSS plus an APACHE II score >or= 25 in order to receive APC . JL is a 43-year-old man who developed SSS (APACHE II score 26) after Roux-en-Y gastric bypass . ML is a 33-year-old man who developed SSS (APACHE II=28) because of a distal obstruction 2.5 years after gastric bypass surgery . TQ was a 35-year-old man who developed SSS (APACHE II=35) in the setting of laparoscopic banding . RESULTS: After receiving 90% of the 96-hour infusion, JL developed ecchymoses and a decrease in his platelet count; thus, the drug was stopped . ML received a full 96-hour infusion . Both patients made a full recovery from their SSS and were successfully discharged from the hospital . TQ developed septic shock and expired despite all efforts . CONCLUSION: Weight alone should not be considered a contraindication to the use of APC . Close coordination between the intensivist and surgeon is recommended for bariatric surgery patients with SSS, so that a rapid determination can be made as to the patient's risk of death and eligibility to receive APC. Front Biosci, 2004 May 01, 9, 1637 - 41 Sepsis associated encephalopathy (SAE): a review; Green R et al.; Sepsis associated encephalopathy (SAE) is a poorly understood condition that is associated with severe sepsis and appears to have a negative influence on survival . The incidence of encephalopathy secondary to sepsis is unknown . Amino acid derangements, blood-brain barrier disruption, abnormal neurotransmitters, and direct CNS effect are possible causes of septic encephalopathy . Research has not defined the pathogenesis of SAE. Front Biosci, 2004 May 01, 9, 1201 - 17 NF-kappaB action in sepsis: the innate immune system and the heart; Brown MA et al.; Sepsis is the clinical syndrome that results from a host's inflammatory response to infection via activation of the innate immune system . This response involves a complex network of inflammatory mediators that is self-reinforcing . When this immune response progresses uncontrollably, it can ultimately result in cardiovascular collapse and death . This complex inflammatory response is comprised of multiple mediators including cytokines such as TNF-alpha and IL-1beta, that are synthesized and secreted in response to signaling by receptors of the Toll-like receptor (TLR) family of pattern recognition receptors (PRR) that bind to pathogen associated molecules . A central downstream element of TLR-dependent signaling is the pleiotropic transcription factor NF-kappaB . NF-kappaB has been implicated in the regulation of multiple biological phenomena and disease states, including apoptosis, cell growth, stress response, innate immunity and septic shock . NF-kappaB-dependent genes are numerous and several have been implicated in the pathogenesis of sepsis and associated with cardiac dysfunction in sepsis . NF-kappaB activation occurs in multiple organs and cell types, and may be primarily protective in one tissue but injurious in another . Thus, a detailed understanding of the molecular basis of the pathophysiology of sepsis is needed in order to specifically block pro-inflammatory and pro-apoptotic signaling in the heart, while avoiding adverse effects in other organs. Eur J Anaesthesiol, 2004 Feb, 21(2), 132 - 8 Assessing fluid responsiveness by stroke volume variation in mechanically ventilated patients with severe sepsis; Marx G et al.; BACKGROUND AND OBJECTIVE: Our hypothesis was that stroke volume variation during mechanical ventilation of the lungs would allow accurate prediction and monitoring of changes in cardiac index in response to fluid loading in patients with severe sepsis . METHODS: This was a prospective clinical study in a university hospita