Intensive Care Med, 2000 Aug, 26(8), 1076 - 81 Immediate IL-10 expression following major orthopaedic trauma: relationship to anti-inflammatory response and subsequent development of sepsis; Giannoudis PV et al.; OBJECTIVE: To assess the relationship between IL-10 release and anti-inflammatory response following blunt trauma . DESIGN: Prospective longitudinal clinical study . SETTING: Departments of trauma and anaesthetics in a university teaching hospital . PATIENTS: Forty-eight adult patients with a mean injury severity score of 14.5 (range 9-57) were prospectively studied following blunt trauma . MEASUREMENTS AND RESULTS: Venous blood samples were collected on arrival and at 16 and 24 h, and at 3, 5, and 7 days . Peripheral blood mononuclear cell (HLA-DR) expression on CD14 + monocytes was quantified by flow cytometry and serum IL-10 was assayed by ELISA . Anti-inflammatory response was defined as monocyte HLA-DR expression of less than 30% of that seen in healthy controls . Serum IL-10 levels in trauma patients on arrival was significantly elevated, 70.0 {48.0-92.1, 95% confidence interval, (CI)} compared to the control group, 3 (0-5) (P < 0.0001), and monocyte HLA-DR expression was significantly lower, 14.2 (12.1-16.3, 95% CI), in patients versus 25.2 (22.4-28.1) in controls (P < 0.001) . Patients with low HLA-DR expression (n = 14) had significantly higher serum IL-10 levels than those whose HLA-DR expression remained above 30% of the control value (n = 34), (P < 0.038) . In patients who developed sepsis (n = 11), serum IL-10 levels were greater on admission, {143.7 (80.2-207.2) pg/ml(-1)}, and remained elevated during the study period compared with non-complicated patients, {50.16 (33.5-66.8) pg/ml(-1)} . Immediate IL-10 (2 h following trauma) was negatively correlated with simultaneous HLA-DR expression, (r = -0.49, P = 0.0005) . CONCLUSION: These findings support the view that IL-10 release regulates monocyte HLA-DR expression and may be related to an anti-inflammatory response and development of sepsis following trauma. Shock, 2000 Sep, 14(3), 347 - 53 The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis; Schneider CP et al.; Studies have shown that immune responses are depressed in male mice, but not in proestrus females after trauma-hemorrhage (TH), resulting in increased mortality from subsequent sepsis in male mice compared with female mice . These gender-specific alterations in immune function are believed to be due to differences in sex steroid levels . Aromatase is a key enzyme in the sex steroid biosynthesis . Although earlier studies have shown that aromatase inhibitors prevent thymic atrophy in aged male rats, it remains unknown whether the use of 4-hydroxy-androstenedione (4-OHA) after TH in male mice has any salutary effects on the depressed immune responses . Male C3H/HeN mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (30+/-5 mmHg for 90 min) followed by adequate fluid resuscitation . 4-OHA (5 mg/kg) or vehicle was administrated s.c . just before resuscitation . At 2 h after resuscitation, the mice were killed, and spleens were harvested . Splenocyte proliferation, interleukin (IL-2), interferon (IFN-gamma), and IL-10 release and expression of androgen (AR) and estrogen receptors (ER)-alpha and -beta by immunoblot and reverse transcription-polymerase chain reaction (RT-PCR) were assessed . In another group, sepsis was induced by cecal ligation and puncture (CLP) 3 days after resuscitation, and survival was measured over a period of 10 days . A significant decrease in splenocyte proliferation, IL-2, and IFN-gamma release and increased release of IL-10 were observed in vehicle-treated mice . Animals treated with 4-OHA showed increased splenocyte proliferation, IL-2, and IFN-gamma release, and decreased IL-10 release . Immunoblot analysis showed decreased expression of the cytosolic AR, but no significant difference in the cytosolic and nuclear ER-alpha and -beta expression was observed in the vehicle-treated group after TH . In addition, AR and ER-beta mRNA expression was increased, whereas ER-alpha expression decreased in the vehicle-treated group after TH . ER-alpha expression decreased and ER-beta expression increased in the nucleus of 4-OHA treated mice as determined by immunoblot . There was no difference in the cytosolic AR expression in the 4-OHA-treated group after TH . AR and ER-beta mRNA expression was unaffected, whereas ER-alpha expression increased under such conditions . In additional groups, the increased mortality rate after TH and subsequent sepsis was significantly reduced by 4-OHA treatment . Thus, 4-OHA seems to be a novel and useful adjunct for restoring the depressed immune functions in males after TH and for decreasing mortality rates from subsequent sepsis. Shock, 2000 Sep, 14(3), 307 - 10; discussion 310-3 Gender differences in sepsis: genetically determined? Schroder J, Kahlke V, Book M, Stuber F. In the pathogenesis of sepsis, tumor necrosis factor (TNF) release and host reaction may be genetically determined as demonstrated for TNFbeta Ncol polymorphism . Gender differences are considered as another important prognostic variable in patients with sepsis with better survival for women . The effect of sexual dimorphism on the genetic background of sepsis, however, is unknown . In a prospective study at two university hospital surgical intensive care units, (Bonn and Kiel), the role of the genomic marker TNFbeta Ncol polymorphism was evaluated with respect to gender . Two-hundred and one patients (68 women and 133 men) with severe sepsis were evaluated . A fragment of genomic DNA including the polymorphic site of the restriction enzyme Ncol was amplified by means of polymerase chain reaction . The genotype of each patient was determined after Ncol digestion of the amplified product . The genotype distribution of patients homozygous for TNFB1, heterozygous or homozygous for TNFB2 was comparable between men and women with severe sepsis . In women, no difference in survival rate was found between the different genotypes, while mortality rate was significantly increased in men homozygous for TNFB2 compared with the other genotypes (P < 0.05; P < 0.01, chi2 test) . Overall, survival rate was higher for women (P < 0.05) but was not significantly different between men and women with respect to genotypes (P = 0.07 for TNFB2/B2) . Poor prognosis of surgical sepsis can be determined by male gender and the genomic marker TNFbeta Ncol polymorphism which should be considered for further therapeutic interventions in sepsis. J Surg Res, 2000 Oct, 93(2), 257 - 64 Effects of tumor necrosis factor-binding protein on hepatic protein synthesis during chronic sepsis; Cooney RN et al.; BACKGROUND: Cytokines are thought to play a role in the stimulation of protein synthesis in liver during inflammation and sepsis . We previously showed that administration of tumor necrosis factor-binding protein (TNFbp) prevents the sepsis-induced inhibition of protein synthesis in skeletal muscle . The purpose of the present set of experiments was to investigate the effect of TNFbp on hepatic protein synthesis and its ability to modulate the mechanisms responsible for increased hepatic protein synthesis during chronic (5-day) intraabdominal sepsis . MATERIALS AND METHODS: We examined the effects of TNFbp on hepatic protein synthesis during sepsis in four groups of rats: control, control + TNFbp, septic, and septic + TNFbp . Saline (1.0 ml) or TNFbp (1 mg/kg, 1.0 ml) was injected daily starting 4 h prior to the induction of sepsis . The effect of sepsis and TNFbp administration on hepatic protein synthesis in vivo was examined 5 days later . RESULTS: Sepsis increased the rate of protein synthesis by 35% relative to controls . Accelerated rates of protein synthesis were accompanied by increased total RNA content, eukaryotic initiation factor (eIF) 2alpha content, and phosphorylation of p70S6 kinase . Injection of TNFbp into septic rats for 5 days did not diminish the sepsis-induced stimulation of hepatic protein synthesis . Compared with controls, septic rats treated with TNFbp also showed elevated total RNA content, elF2alpha content, and phosphorylation of p70S6 kinase . No significant differences in any of the parameters measured were observed between untreated and TNFbp-treated septic rats . Treatment of control animals with TNFbp for 5 days was without effect on any of the parameters examined . CONCLUSIONS: TNFbp did not prevent the sepsis-induced stimulation of hepatic protein metabolism or modulate the septic-induced changes in factors regulating protein synthesis . Global rates of protein synthesis in livers from septic rats are accelerated by increases in the abundance or activity of components of translational apparatus . Wien Klin Wochenschr, 2000 Aug 25, 112(15-16), 735 - 7 Recurrent sepsis and seronegative arthritis in a patient with a selective IgG3 deficiency; Ambrozic J et al.; In a sixty-one-year-old patient with chronic polyarthritis, two life-threatening septic events were observed over a period of 6 months . The patient also had a selective IgG3 deficiency . The susceptibility to infection and chronic polyarthritis observed in this patient were very likely a consequence of the selective IgG3 deficiency. Kidney Int, 2000 Oct, 58(4), 1758 - 64 Mortality caused by sepsis in patients with end-stage renal disease compared with the general population; Sarnak MJ et al.; BACKGROUND: In the United States, infection is second to cardiovascular disease as the leading cause of death in patients with end-stage renal disease (ESRD), and septicemia accounts for more than 75% of this category . This increased susceptibility to infections is partly due to uremia, old age, and comorbid conditions . Although it is intuitive to believe that mortality caused by sepsis may be higher in patients with ESRD compared with the general population (GP), no such data are currently available . METHODS: We compared annual mortality rates caused by sepsis in patients with ESRD (U.S . Health Care Financing Administration 2746 death notification form) with those in the GP (death certificate) . Data were abstracted from the U.S . Renal Data System (1994 through 1996 Special Data request) and the National Center for Health Statistics . Data were stratified by age, gender, race, and diabetes mellitus (DM) . Sensitivity analyses were performed to account for potential limitations of the data sources . RESULTS: Overall, the annual percentage mortality secondary to sepsis was approximately 100- to 300-fold higher in dialysis patients and 20-fold higher in renal transplant recipients (RTRs) compared with the GP . Mortality caused by sepsis was higher among diabetic patients across all populations . After stratification for age, differences between groups decreased but retained their magnitude . These findings remained robust despite a wide range of sensitivity analyses . Indeed, mortality secondary to sepsis remained approximately 50-fold higher in dialysis patients compared with the GP, using multiple cause-of-death analyses; was approximately 50-fold higher in diabetic patients with ESRD compared with diabetic patients in the GP, when accounting for underreporting of DM on death certificates in the GP; and was approximately 30-fold higher in RTRs compared with the GP, when accounting for the incomplete ascertainment of cause of death among RTRs . Furthermore, despite assignment of primary cause-of-death to major organ infections in the GP, annual mortality secondary to sepsis remained 30- to 45-fold higher in the dialysis population . CONCLUSIONS: Patients with ESRD treated by dialysis have higher annual mortality rates caused by sepsis compared with the GP, even after stratification for age, race, and DM . Consequently, this patient population should be considered at high-risk for the development of lethal sepsis. Am J Physiol Heart Circ Physiol, 2000 Oct, 279(4), H1922 - 30 Diaspirin cross-linked Hb and norepinephrine prevent the sepsis-induced increase in critical O(2) delivery; Sielenkamper AW et al.; We hypothesized that support of arterial perfusion pressure with diaspirin cross-linked Hb (DCLHb) would prevent the sepsis-induced attenuation in the systemic O(2) delivery-O(2) uptake relationship . Awake septic rats were treated with a chronic infusion of DCLHb or a reference treatment {norepinephrine (NE)} to increase mean arterial pressure by 10-20% over 18 h . Septic and sham control groups received normal saline . Isovolemic hemodilution to create anemic hypoxia was then performed in a metabolic box during continuous measurement of systemic O(2) uptake . O(2) delivery was calculated from hemodynamic variables, and the critical point of O(2) delivery (DO(2 crit)) was determined using piecewise regression analysis of the O(2) delivery-O(2) uptake relationship . Sepsis increased DO(2 crit) from 4.99 +/- 0.17 to 6.69 +/- 0.42 ml x min(-1) x 100 g(-1) (P < 0.01), while O(2) extraction capacity was decreased (P < 0.05) . DCLHb and NE infusion prevented the sepsis-induced increase in DO(2 crit) {4.56 +/- 0.42 ml x min(-1) x 100 g(-1) (P < 0.01) and 5.04 +/- 0.56 ml x min(-1) x 100 g(-1) (P < 0.05), respectively} . This was explained by a 59% increase in O(2) extraction capacity in the DCLHb group compared with septic controls (P < 0.05), whereas NE treatment decreased systemic O(2) uptake in anemic hypoxia (1.51 +/- 0.08 vs . 1.87 +/- 0.1 ml x min(-1) x 100 g(-1) in septic controls, P < 0.05) . We conclude that DCLHb ameliorated O(2) extraction capacity in the septic microcirculation, whereas NE decreased the metabolic demands of the tissues. Reg Anesth Pain Med, 2000 Sep-Oct, 25(5), 549 - 53 Maternal fever, neonatal sepsis evaluation, and epidural labor analgesia; Viscomi CM et al.; BACKGROUND AND OBJECTIVES: Numerous studies have found an association between epidural analgesia for labor and maternal fever (temperature > or =38 degrees C) . Maternal fever often results in treatment with maternal or neonatal antibiotics, neonatal sepsis evaluation, and increased costs . METHODS: Medline was used to identify literature regarding the association between epidural labor analgesia and maternal fever/neonatal sepsis . Studies examining thermoregulation during pregnancy and/or epidural analgesia were also reviewed . RESULTS: There appears to be a strong association between epidural labor analgesia and maternal fever . The link between epidural labor analgesia and neonatal sepsis evaluation is less clear . The incidence of confirmed neonatal sepsis does not increase with maternal epidural analgesia . Causes of the association between epidural labor analgesia and maternal fever include selection bias, altered thermoregulation, and increased shivering or decreased sweating with epidural analgesia . CONCLUSIONS: Maternal epidural labor analgesia is associated with maternal fever and possibly increased neonatal sepsis evaluation . There is no proof the relationship is causal. Crit Care Med, 2000 Sep, 28(9), 3137 - 45 Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis . Ibuprofen in Sepsis Study Group; Mangialardi RJ et al.; OBJECTIVE: Starling's equation indicates that reduced oncotic pressure gradients will favor edema formation, and the current consensus definition of acute respiratory distress syndrome (ARDS) excludes only the hydrostatic pressure contribution . We hypothesized that low serum total protein levels might correlate with the likelihood of ARDS in at-risk patients because serum total protein is the chief determinant of oncotic pressure in humans . DESIGN: Regression analysis to compare outcomes in patients with low serum total protein levels with outcomes in patients with normal serum total protein levels with respect to weight change, development of ARDS, and mortality . SETTING: Intensive care units (ICUs) of seven clinical centers in North America . PATIENTS: A total of 455 ICU patients who met consensus criteria for severe sepsis (178 of whom developed ARDS) from a recently completed prospective clinical trial . INTERVENTION: None . MEASUREMENTS AND MAIN RESULTS: We found that 92% of the patients developing ARDS had low or borderline serum total protein levels (<6 g/dL) . Logistic and multiple regression analyses confirmed that of 18 clinical variables, initial serum total protein level and protein change over time were the most statistically significant predictors of weight gain, prolonged mechanical ventilation, ARDS development, and mortality in the study population . This correlation remained significant after adjustment for the other major predictors of outcome present at baseline (ie, Acute Physiology and Chronic Health Evaluation II score) . CONCLUSIONS: Hypoproteinemia is significantly correlated with fluid retention and weight gain, development of ARDS and poor respiratory outcome, and mortality in patients with sepsis . Prospective, randomized trials of serum protein manipulation are needed to establish whether there is a cause-effect relationship to this association. Crit Care Med, 2000 Sep, 28(9 Suppl), S83 - 5 New therapeutic implications of anticoagulation mediator replacement in sepsis and acute respiratory distress syndrome; Vincent JL; OBJECTIVE: To examine the relationship between the coagulation and immune systems in sepsis and acute respiratory distress syndrome and to review published experimental and clinical studies that use anticoagulation mediator replacement strategies in these conditions . DATA SOURCES: MEDLINE database and bibliographies of relevant articles . STUDY SELECTION: Articles (both original and review) relating to coagulation abnormalities and anticoagulation mediator replacement therapy in sepsis and acute respiratory distress syndrome . DATA EXTRACTION: All applicable data were extracted . CONCLUSIONS: Coagulation abnormalities are common in the critically ill . Early studies using anticoagulation mediator replacement in patients with sepsis have suggested beneficial effects on organ function and outcome . The results from larger, randomized controlled trials are eagerly anticipated. Crit Care Med, 2000 Sep, 28(9 Suppl), S74 - 6 Coagulation inhibitor replacement during sepsis: useless? Hoffman JN, Faist E. OBJECTIVE: Because coagulatory activation in sepsis is triggered mainly by tissue factor release from endothelial cells and blood monocytes during their activation via proinflammatory cytokines, inhibition of coagulation by exogenous administration of coagulation inhibitors has been proposed . These strategies should allow us to prevent and treat excessive coagulatory activation, thereby potentially preventing sepsis-induced organ dysfunction . Potential therapies include the natural coagulation inhibitors antithrombin, activated protein C, and tissue factor pathway inhibitor, as well as direct thrombin inhibition by recombinant hirudin . DATA SOURCES: A limited review of the published literature using all sources was undertaken . STUDY SELECTION: Selected clinical and experimental studies with coagulatory inhibitors were analyzed . CONCLUSIONS: The biological properties of coagulatory activation during sepsis (coagulation as a protective mechanism to control the septic focus, e.g., fibrin deposition during peritonitis) are not completely understood . Therefore, one has to be careful when administering coagulatory inhibitors, especially because patients with multiple organ dysfunction syndrome often do not show the widespread fibrin deposition in nutritive blood vessels that have been seen experimentally . How might these patients benefit from thrombin inhibition? Coagulatory activation per se seems unlikely to directly cause deterioration of organ function, although it is involved in generalized endothelial activation with consecutive mediator release and increased leukocyte-endothelial cell interaction . Antagonism of inflammatory mediators and, consecutively, endothelial cell activation might be a better target in adjunctive sepsis therapy, with improvement in septic microcirculatory disturbances . Administration of natural pleiotropic coagulation inhibitors that are documented positive effects on the microcirculation, (such as activated protein C, antithrombin) seems to be promising. Crit Care Med, 2000 Sep, 28(9 Suppl), S68 - 73 Coagulation inhibitor replacement in sepsis is a potentially useful clinical approach; Thijs LG; In sepsis, levels of the endogenous coagulation inhibitors antithrombin III and protein C are lowered as a result of complex formation with multiple activated clotting factors . In addition, their activity can further be curtailed by proteolytic inactivation . Loss of antithrombin III and protein C activity blocks the endogenous control mechanism for thrombin generation resulting in a state of systemic activation of coagulation and inflammatory processes . Levels of tissue factor pathway inhibitor, a third endogenous coagulation inhibitor, are increased in sepsis rather than decreased, probably reflecting a depletion of the endothelial cell bound tissue factor pathway inhibitor pool with loss of its endothelial protective function . Administration of any of these three inhibitors in various animal species and sepsis models reduces morbidity and mortality . In addition to their anticoagulant effects, these inhibitors also have various anti-inflammatory activities that may contribute to their protective effects . Phase II studies in patients with severe sepsis using coagulation inhibitors have indicated that this therapeutic approach may be useful . Large-scale phase III trials will ultimately decide whether adjunctive coagulation inhibitor replacement will have a place in the treatment of patients with severe sepsis. Crit Care Med, 2000 Sep, 28(9 Suppl), S49 - 56 Protein C levels as a prognostic indicator of outcome in sepsis and related diseases; Fisher CJ Jr et al.; OBJECTIVE: To consider the appropriateness of protein C levels as a prognostic indicator for sepsis and related diseases . DATA SOURCES/STUDY SELECTION: Published research and review articles related to protein C deficiency in patients with sepsis and related diseases . DATA EXTRACTION AND SYNTHESIS: All applicable data were extracted, and relevant literature was cited to support factual statements in the text . The protein C pathway represents one of the major regulatory systems of hemostasis, exhibiting antithrombotic, profibrinolytic, and anti-inflammatory properties . Numerous studies have shown that acquired protein C deficiency is prevalent in the majority of septic patients (>85%) and is associated with increased morbidity and mortality in patients with severe sepsis and septic shock . This deficiency in protein C is not simply a transient marker for sepsis, but parallels the progress of the disease . In addition, protein C deficiency occurs in the presence of a wide range of pathogens and develops early in the disease process . CONCLUSIONS: A review of the relevant literature suggests that protein C levels may serve as a useful prognostic indicator of outcome in sepsis and related diseases. Crit Care Med, 2000 Sep, 28(9 Suppl), S38 - 43 Clinical trial results with antithrombin III in sepsis; Fourrier F et al.; OBJECTIVE: To present and discuss the rationale and results of clinical trials using antithrombin (AT) supplementation in patients with sepsis . DATA SOURCES/STUDY SELECTION: Review of all controlled (open or double-blind) studies of patients with severe sepsis or septic shock who were treated with AT concentrates to obtain better control of coagulation activation and inflammation . DATA EXTRACTION: AT is a major inhibitor of the coagulation cascade . Recent experimental studies have also shown that it can modulate the inflammatory reactions that occur during sepsis . An early and prolonged decrease in AT activity is well documented during sepsis-induced disseminated intravascular coagulation and during the systemic inflammatory response . Thus, supplementation with AT concentrates has been proposed as a potential therapy in sepsis patients . DATA SYNTHESIS: Numerous uncontrolled studies of AT supplementation in sepsis patients have been reported in the last 20 yrs . Since 1993, four placebo-controlled randomized studies have been performed in France, Germany, Northwestern Europe, and Italy . Three of these studies were subjected to a meta-analysis of 122 patients . Results showed a nonsignificant 22% reduction in the 30-day all-cause mortality and a reduction in the length of stay in the intensive care unit in the AT treated group . The Italian study of 120 patients demonstrated that the overall mortality was similar in the placebo and treated groups . However, post hoc analysis according to the Cox regression model showed that in patients with septic shock, AT supplementation significantly decreased the risk of death . CONCLUSIONS: Together, these studies are consistent with the positive effect seen with AT supplementation in patients with severe sepsis . A multicenter phase III trial is currently in progress to definitively document its effect on mortality. Crit Care Med, 2000 Sep, 28(9 Suppl), S34 - 7 Therapeutic rationale for antithrombin III in sepsis; Opal SM; OBJECTIVE: To review the preclinical evidence that provides the therapeutic rationale for antithrombin as a novel treatment for human sepsis . DATA SOURCES: A summary of published medical literature from MEDLINE search files and other reviews published about antithrombin use in sepsis . DATA SUMMARY: Antithrombin has a variety of antiinflammatory properties in addition to its functions as an endogenous anticoagulant that appear to have an important therapeutic role in the prevention of microvascular dysfunction and multiple organ injury in sepsis . Appropriate timing and dosing of antithrombin III is critical to realize its full therapeutic potential as an anti-sepsis therapy . CONCLUSIONS: Antithrombin is a potent inhibitor of thrombin-mediated vascular injury in the microcirculation in severe sepsis . This endogenous anticoagulant is rapidly depleted in the early phases of sepsis as a result of decreased synthesis, increased destruction, and enhanced clearance by thrombin-antithrombin complex formation . The therapeutic efficacy of antithrombin in experimental sepsis is readily demonstrable in numerous animal systems . Appropriately defined patient populations with early onset severe sepsis and/or septic shock may benefit from antithrombin therapy if it is administered in adequate doses at the optimal time interval. Crit Care Med, 2000 Sep, 28(9 Suppl), S31 - 3 Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis; Abraham E; Tissue factor mediated pathways leading to microvascular thromboses and endothelial activation appear to play an important role in the development of multiple organ failure associated with severe sepsis . Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of tissue factor associated coagulation cascades . In experimental models of severe sepsis, treatment with TFPI results in significant reduction in mortality . Similarly, a recently completed Phase II 210-patient study comparing placebo and infusions of TFPI showed trends toward a relative reduction in day 28 all-cause mortality in TFPI treated patients . These data suggest that coagulation cascades involving tissue factor contribute to organ dysfunction in critically ill septic patients . TFPI may be a useful therapy in improving outcome of severe sepsis. Crit Care Med, 2000 Sep, 28(9 Suppl), S25 - 30 Tissue factor pathway of coagulation in sepsis; Hack CE; OBJECTIVE: To review the role of the tissue factor pathway of coagulation in experimental sepsis . DATA SOURCES: Studies published in biomedical journals . STUDY SELECTION: Studies on the role of the tissue factor pathway in animal or human models for sepsis . DATA EXTRACTION AND SYNTHESIS: Variables reflecting tissue factor pathway activation in the various models are discussed; the effects of administration of tissue factor pathway inhibitors on these and inflammatory variables, as well as on the course and outcome, are analyzed . CONCLUSION: Activation of coagulation during experimental sepsis occurs mainly, if not exclusively, via the tissue factor pathway; inhibitors of this pathway improve mortality, presumably by a combined attenuating effect on coagulative and inflammatory responses. Crit Care Med, 2000 Sep, 28(9 Suppl), S12 - 9 Description of compensated and uncompensated disseminated intravascular coagulation (DIC) responses (non-overt and overt DIC) in baboon models of intravenous and intraperitoneal Escherichia coli sepsis and in the human model of endotoxemia: toward a better definition of DIC; Taylor FB Jr et al.; OBJECTIVE: Work toward a better definition of disseminated intravascular coagulation (DIC) by characterizing the difference between compensated and uncompensated responses of the hemostatic system to inflammatory stress in baboons and human subjects using global coagulation and molecular marker assays of hemostatic, inflammatory, and endothelial perturbation . DESIGN: We conducted prospective evaluation of the response of baboons to increasing concentrations of intravenous Escherichia coli, human subjects to intravenous endotoxin, and baboons to intraperitoneal E . coli . SETTING: Animal laboratory and medical intensive care facilities, University of Oklahoma Medical School laboratories . SUBJECTS: Cynocephalus baboons; normal healthy male human subjects (age, 24-37 yrs) . MEASUREMENTS AND MAIN RESULTS: Global coagulation assays, white blood cell counts, and molecular marker assays (ELISA) of components of the inflammatory and hemostatic systems, neutrophil release products, and endothelial injury . A fall in both fibrinogen concentration and platelet counts indicated a decompensated hemostatic response to inflammatory stress (ie, overt DIC) . These responses were observed 2-6 hrs after intravenous infusion of 10(9) and 10(10) colony-forming units (CFU)/g of E . coli and after implantation of 10(11) CFU/g of E . coli into the peritoneal cavity . However, 6 hrs after E . coli challenge, these tests were much less reliable as markers of overt DIC because the fibrinogen underwent an acute phase response and the platelet count fell and remained depressed for 48 hrs in the face of a coagulopathic response that was already beginning to resolve, as reflected by a rising fibrinogen concentration . This lack of reliability was particularly evident in the E . coli peritonitis studies, in which one third of the animals recovered, one third remained sick for up to 14 days, and one third died . In contrast, fibrin degradation products and the molecular markers thrombin/antithrombin, soluble fibrin monomer, protein C, and activated protein C/inhibitor complexes responded consistently in a dose-dependent manner regardless of the length of time after challenge . These variables exhibited this dose response to 106 and 108 CFU/g of E . coli in absence of a fall in fibrinogen concentration . This was defined as a compensated hemostatic response to inflammatory stress (ie, non-overt DIC) . The values of these variables correlated closely with rising concentrations of markers of neutrophil activation (elastase/alpha 1 antitrypsin) and endothelial injury (soluble thrombomodulin) . This was particularly evident in the human response to endotoxin, in which there was abundant evidence of hemostatic marker response in absence of a fall in platelet or fibrinogen concentration, both immediately after endotoxin infusion (first stage, 0-8 hrs after endotoxin) and later (second stage, 12-48 hrs after endotoxin) . CONCLUSION: Global coagulation tests are most useful in detecting overt consumptive coagulopathy (overt DIC) near the time of challenge or injury (1 to 6 hrs) . Molecular markers can detect and grade the degree of hemostatic stress of a non-overt consumptive coagulopathy (nonovert DIC) . These markers correlate with degree of endothelial cell injury and reveal a reperfusion injury stage (second stage) in the human endotoxin model of compensated hemostatic stress after all clinical symptoms have subsided and the subjects have returned to work. Cell Stress Chaperones, 2000 Jul, 5(3), 188 - 95 Attenuation of sepsis-induced apoptosis by heat shock pretreatment in rats; Chen HW et al.; Apoptosis is a process by which cells undergo a form of non-necrotic cellular suicide . Although it is a programmed process, apoptosis can be induced by various stressors . During sepsis, apoptosis has been regarded as an important cause of cell death in the immune system, leading to unresponsiveness to treatment . This study was designed to investigate how prior heat shock induction can influence the rate of apoptosis in animals that have experienced sepsis . Sprague-Dawley rats were used, and experimental sepsis was induced by cecal ligation and puncture (CLP) . Animals in the heated group were anesthetized and received heat shock by whole-body hyperthermia . They were sacrificed 9 h and 18 h after CLP as early and late sepsis, respectively . Apoptosis was evaluated by "DNA ladder" detection in agarose electrophoresis and Tdt-mediated dUTP nick end-labeling (TUNEL) assay . Hsp72 was detected by Western blot analysis . The results showed that the DNA ladder was detected most clearly in the thymus at the late phase of sepsis with time course dependence, while it showed less clearly in heat shock treated animals . Histopathological study by TUNEL assay obtained similar results in the thymus, where the cortex was more susceptible to apoptosis than the medulla . The Western blot analysis showed that the heat shock induced Hsp72 concomitant with an increase in Bcl-2:Bax ratio . In conclusion, heat shock pretreatment prevents rats from sepsis-induced apoptosis that may account for the better outcome of experimental sepsis . An increase in the Bcl-2:Bax ratio may in part explain the molecular mechanism of the effect of heat shock pretreatment. J Med, 2000, 31(1-2), 15 - 20 Interleukin 18 (IL-18) levels in patients with sepsis; Endo S et al.; IL-18 levels in the blood of 13 sepsis patients were assessed . The IL-18 values were significantly correlated with their Acute Physiology and Chronic Health Evaluation (APACHE) II scores, and they were a good reflection of the severity of the disease . There was also a strong correlation between the IL-18 values and the patients' inflammatory cytokine levels . The results suggested strong involvement of IL-18 in the pathogenesis of sepsis. Eur J Clin Invest, 2000 Sep, 30(9), 823 - 31 Disordered calcium homeostasis of sepsis: association with calcitonin precursors; Muller B et al.; BACKGROUND: Hypocalcemia and increased serum levels of calcitonin precursors are common in critically ill patients, especially in those with sepsis . We investigated calcium homeostasis in such patients . PATIENTS AND METHODS: Serum concentrations of total and ionized calcium and known factors influencing or reflecting calcium homeostasis were measured in 101 consecutive patients of a medical intensive care unit . Calcitonin precursor levels were determined using a highly sensitive radioimmunoassay . RESULTS: Critical illness per se was associated with decreased serum total and ionized calcium levels, which correlated with the severity of the underlying disease as measured by the APACHE II score . In addition, total and ionized hypocalcemia was more pronounced with increasing severity of infection (P < 0.02), and occurred in parallel with a marked increase of calcitonin precursors (P < 0.001) . Mature calcitonin levels, however, remained normal . Changes of serum ionized calcium concentrations from admission to discharge correlated significantly with changes in the serum calcitonin precursor concentration (r2 = - 0.14, P < 0.001) . Circulating vitamin D levels, parathyroid hormone levels and other markers reflecting calcium homeostasis did not correlate with the severity of infection . CONCLUSIONS: In critically ill patients with sepsis, markedly elevated circulating calcitonin precursors might play a role in the development of the pronounced hypocalcemia . The specific calcitonin precursor(s) responsible for this effect and the pathophysiological mechanism remain to be elucidated. Clin Sci (Lond), 2000 Oct, 99(4), 321 - 8 Insulin sensitivity of glucose and fat metabolism in severe sepsis; Chambrier C et al.; In order to quantify the changes in insulin sensitivity, particularly of endogenous glucose production and fat metabolism, in patients with severe sepsis, a prospective study was conducted in five normal subjects and in five patients with severe sepsis hospitalized in an intensive care unit . The responses of endogenous glucose production, glucose utilization, plasma fatty acids and ketone body concentrations to progressive increase in plasma insulin levels (exogenous insulin infusion rates of 0, 0.5, 1 and 2 m-units x min(-1) x kg(-1)) were measured using the isoglycaemic clamp technique . Total glucose turnover was determined with D-{6,6-(2)H(2)}glucose . In each group, plasma glucose was maintained at basal levels (control subjects, 4.32+/-0.22 mmol x l(-1); patients with sepsis, 7.10+/-2.29 mmol x l(-1); P<0.05) . Plasma insulin concentrations were comparable in the two groups at an insulin infusion rate of 0.4 m-unit x min(-1) x kg(-1) for controls and 0.5 m-unit x min(-1) x kg(-1) for patients with sepsis, but differed following infusion at 2 m-unit x min(-1) x kg(-1) (control subjects, 102+/-13.4 m-units x l(-1); patients with sepsis, 124.8+/-19.7 m-units x l(-1); P<0.05) . Endogenous glucose production was completely suppressed in control subjects by the first insulin infusion (0.4 m-unit x min(-1) x kg(-1)), but was only suppressed during infusion at 1 m-unit x min(-1) x kg(-1) insulin in patients with sepsis . The glucose utilization rate increased significantly with exogenous insulin infusion in control subjects, but did not increase in patients with sepsis . Plasma non-esterified (free) fatty acid and ketone body levels were significantly decreased in both groups by the infusion of exogenous insulin, but the sensitivity of lipolysis was impaired in patients with sepsis . In conclusion, sepsis impaired to a varying extent the action of insulin on endogenous glucose production, glucose utilization, lipolysis and ketogenesis . Whole-body glucose uptake was the most affected, with a total lack of response to the elevated insulin levels obtained in this study . Suppression of endogenous glucose production and lipolysis could only be achieved with higher doses of insulin than those required in normal subjects. Intensive Care Med, 2000 Jul, 26(7), 883 - 92 Leukocyte activation in sepsis; correlations with disease state and mortality; Muller Kobold AC et al.; OBJECTIVE: The immune response in sepsis shows a bimodal pattern consisting of an early, frequently exaggerated inflammatory response followed by a state of hyporesponsiveness often referred to as the compensatory anti-inflammatory response syndrome (CARS) . Insight into the disease state may be helpful in deciding whether to choose immune stimulatory or anti-inflammatory therapy in these patients and may determine clinical outcome . We hypothesized that poor outcome in patients with sepsis is related to the severity of CARS, as reflected in the degree of leukocyte activation . DESIGN: Prospective study . SETTING: Intensive and respiratory care unit at a university hospital . PATIENTS: Twenty consecutive patients with sepsis and 20 healthy age-matched volunteers . INTERVENTIONS: None . MEASUREMENTS AND RESULTS: Analysis of surface expression of HLA-DR, CD11b, ICAM-1, CD66b, CD63 and CD64 on neutrophils and monocytes by flow cytometry and determination of plasma concentrations of lactoferrin, interleukin 6 and neopterin by ELISA at the time of diagnosis . Patient data were related to those of controls; moreover patient data between survivors and non-survivors were compared . Increased expression of all markers, except HLA-DR, was observed on both neutrophils and monocytes from patients compared to healthy controls . HLA-DR expression on monocytes was significantly decreased in patients with sepsis (p < 0.01) . Expression of CD11b and HLE on neutrophils, and ICAM-1 on monocytes, were lower in patients who died compared to those who survived (p < 0.05) . CONCLUSION: In sepsis, both neutrophils and monocytes are activated compared to healthy controls . Poor prognosis is associated with a lower expression of activation markers on monocytes and neutrophils, suggesting that poor outcome in these patients may be due to the compensatory anti-inflammatory response. Biochem Soc Symp, 1999, 66, 149 - 66 Mitochondrial dysfunction in sepsis; Singer M et al.; The current mainstream view of organ failure induced by sepsis revolves around inflammation and loss of vascular control . However, there has been a resurgence in interest in bioenergetic failure due to mitochondrial dysfunction . This concept is not new--studies date back 30 years; however, the data have been highly conflicting with findings of either decreased, increased or unchanged mitochondrial activity and/or nucleotide levels . These studies are virtually all based on non-human cells, isolated perfused organs or in vivo animal models that have received a variety of insults ranging from mild to severe, and monitored for different durations ranging from minutes to weeks . As a generalization, there does appear to be depression of mitochondrial function with longer-duration models of greater severity . This is confirmed by the scanty human data currently available . This chapter provides an overview, and attempts to relate the biochemical changes to the clinical condition . The potential roles of nitric oxide, intracellular calcium and reactive oxygen species are highlighted. Pediatr Hematol Oncol, 2000 Sep, 17(6), 469 - 73 Granulocyte-macrophage colony-stimulating factor in the treatment of neonates with neutropenia and sepsis; Venkateswaran L et al.; To evaluate the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in improving neutrophil counts and survival of neutropenic septic neonates, the authors studied 8 neonates with gestational or postconceptional age at least 30 weeks; weight at least 1000 g; serious infection with concomitant neutropenia (absolute neutrophil count {ANC} < 3.0 x 10(9)/L) or leukopenia (white blood cell count < 5.0 x 10(9)/L) and anticipated survival at least 48 h . Patients received 5 micrograms/kg of GM-CSF intravenously for 5 consecutive days or until the ANC reached 20 x 10(9)/L . Clinical parameters and complete blood counts were monitored . Prestudy ANCs ranged from 0.05 to 2.7 x 10(9)/L . Four patients had positive blood cultures, 4 had necrotizing enterocolitis, and 1 was in septic shock . All patients had elevated C-reactive protein . All patients had resolution of neutropenia and survived the septic episodes . The use of GM-CSF in these patients merits further exploration. Vet Rec, 2000 Aug 12, 147(7), 184 - 8 Treatment of traumatically induced synovial sepsis in horses with gentamicin-impregnated collagen sponges; Summerhays GE; Eight horses with synovial sepsis induced by trauma were treated by arthroscopic/tenoscopic debridement and lavage followed by the implantation of a gentamicin-impregnated collagen sponge . Seven of them responded favourably and were sound six months after treatment . The other underwent a further surgical procedure and recovered . Gentamicin-impregnated collagen sponges appear to be a safe and useful adjunct in the treatment of septic joints and tendon sheaths, and have the advantage of being bioabsorbable. Int J Clin Lab Res, 2000, 30(1), 27 - 31 Combined leukocyte and erythrocyte aggregation in the peripheral venous blood during sepsis . An indication of commonly shared adhesive protein(s); Berliner AS et al.; We have used a simple slide test and image analysis to reveal the state of leukocyte and erythrocyte adhesiveness/aggregation in the peripheral blood of 28 patients with sepsis and 28 controls . A significant (P<0.00001) increment in both leukocyte and erythrocyte adhesiveness/aggregation was noted in patients compared with controls . Moreover, a significant (r=0.73, n=56, P<0.001) correlation was noted between the two adhesiveness/aggregation variables themselves, suggesting a common mechanism responsible for these adhesive phenomena . The significant correlation with fibrinogen suggests that this protein might be such a "non-specific glue." Our results indicate that a simple slide technique and image analysis can assess the aggregability of both white and red blood cells in septic patients . This might have clinical application when interventions to reduce cell aggregability are planned in order to improve blood flow in the microcirculation. Vox Sang, 2000, 79(1), 57 - 8 Transfusion-associated sepsis caused by Candida parapsilosis; Pinto V et al.; BACKGROUND AND OBJECTIVES: The contamination of blood components by bacteria is an adverse event, which, although very uncommon, has an exceptionally high mortality rate . CASE REPORT: A patient suffering from terminal adenocarcinoma of the ovary received a red blood cell unit . During the transfusion, the patient developed fever . Cultures of both the patient's blood and the blood unit were done, and she was treated with antibiotics . Forty-eight and seventy-two hours after the transfusion, Candida parapsilosis grew in the blood cultures of the red blood cell bag and of the patient . The infection was controlled with amphotericin . The patient died from cancer progression . CONCLUSIONS We describe the first case of transfusion-associated sepsis caused by C . parapsilosis. J Pediatr, 2000 Sep, 137(3), 345 - 50 Premature infants respond to early-onset and late-onset sepsis with leukocyte activation; Weinschenk NP et al.; OBJECTIVE: Leukocyte differentiation antigens are expressed on the cell membrane during activation . The purpose of this study was to evaluate leukocyte activation in premature neonates with sepsis . Paired blood samples from the same individual while sick and while convalescent were examined to quantify the expression of leukocyte antigens in these clinical states . METHODS: Mononuclear blood cells from 21 premature infants (24 to 30 weeks' gestation) were analyzed . The "sick" samples were drawn at the time of workup for sepsis; "convalescent" samples were drawn 20 days later . Samples were incubated with monoclonal antibodies to the lymphocyte antigens CD3, CD19, CD25, CD26, CD71, and CD69 and neutrophil antigens CD11b, CD11c, CD13, CD15, CD33, and CD66b . The cells were lysed, fixed, and analyzed by flow cytometry . RESULTS: Twenty-one infants enrolled in the study had multiple sepsis evaluations and had more than one sample available for a paired observation . CD33, CD66b, and CD19 levels were significantly elevated in both the presumed sepsis and culture-proven sepsis groups when compared with the samples drawn from those same patients when healthy . Expression of CD33 and expression of CD66b were correlated, and in a multivariate analysis the elevation of antigen expression was predictive of sepsis . CONCLUSIONS: Leukocytes from preterm newborn infants respond to infection with an increased expression of CD19, CD33, and CD66b on their cell surfaces. Pol Merkuriusz Lek, 2000 Jun, 8(48), 405 - 8 {Cellular immunity changes after total parenteral nutrition enriched with glutamine in patients with sepsis and malnutrition}; Slotwinski R et al.; The influence of glutamine on human immune system is multidirectional but the exact changes still remain unclear . In this study the effect of total parenteral nutrition (TPN) enriched with glutamine on some selected immunological and nutritional parameters was examined in twelve surgical patients with sepsis and malnutrition . The reason for glutamine supplementation was lack of clinical improvement after standard TPN . All patients received TPN enriched with glutamine for 10 days . Phenotypic analysis of peripheral blood mononuclear subsets (CD4, CD8, CD16, CD56, HLA-DR) were measured before, during (on days 2, 4, 6) glutamine administration and two days after (day 12) glutamine withdrawal . Simultaneously some nutritional parameters were assessed . The number and percentage of CD4, CD16, CD56 mononuclear subsets increased significantly on day 2 and stayed on the same level during observation (with exception in CD4 on day 6, 12 and CD56 on day 4) . No significant differences in CD8 and HLA-DR number and percentages were observed after TPN enriched with glutamine . BIA examination revealed on days 2 and 12 significant decrease of total body water and significant increase of body cell mass, intracellular water on day 12 . It was correlated with significant higher total lymphocytes count and significantly higher total protein, serum albumin, transferrin, cholesterol and CRP concentration . Results demonstrated that TPN supplemented with glutamine improved rapidly some immunological and nutritional parameters in surgical, malnutrition patients with sepsis. Crit Care Med, 2000 Aug, 28(8), 2793 - 8 Discrimination of sepsis and systemic inflammatory response syndrome by determination of circulating plasma concentrations of procalcitonin, protein complement 3a, and interleukin-6; Selberg O et al.; OBJECTIVE: To evaluate whether plasma concentrations of procalcitonin (PCT), interleukin-6 (IL-6), protein complement 3a (C3a), leukocyte elastase (elastase), and the C-reactive protein (CRP) determined directly after the clinical onset of sepsis or systemic inflammatory response syndrome (SIRS) discriminate between patients suffering from sepsis or SIRS and predict the outcome of these patients . DESIGN: Prospective study . SETTING: Medical intensive care unit at a university hospital . PATIENTS: Twenty-two patients with sepsis and 11 patients with SIRS . MEASUREMENTS AND MAIN RESULTS: The plasma concentrations of PCT, C3a, and IL-6 obtained < or =8 hrs after clinical onset of sepsis or SIRS but not those of elastase or CRP were significantly higher in septic patients (PCT: median, 16.8 ng/mL, range, 0.9-351.2 ng/mL, p = .003; C3a: median, 807 ng/mL, range, 422-4788 ng/mL, p < .001; IL-6: median, 382 pg/mL, range, 5-1004 pg/mL, p = .009, all Mann-Whitney rank sum test) compared with patients suffering from SIRS (PCT: median, 3.0 ng/mL, range, 0.7-29.5 ng/mL; C3a: median, 409 ng/mL, range, 279566 ng/mL; IL-6: median, 98 pg/mL, range, 23-586 pg/mL) . The power of PCT, C3a, and IL-6 to discriminate between septic and SIRS patients was determined in a receiver operating characteristic analysis . C3a was the best variable to differentiate between both populations with a maximal sensitivity of 86% and a specificity of 80% . An even better discrimination (i.e., a maximal sensitivity of 91% and a specificity of 80%) was achieved when PCT and C3a were combined in a "sepsis score." C3a concentrations also helped to predict the outcome of patients . Based on the sepsis score, a logistic regression model was developed that allows a convenient and reliable determination of the probability of an individual patient to suffer from sepsis or SIRS . CONCLUSIONS: Our data show that the determination of PCT, IL-6, and C3a is more reliable to differentiate between septic and SIRS patients than the variables CRP and elastase, routinely used at the intensive care unit . The determination of PCT and C3a plasma concentrations appears to be helpful for an early assessment of septic and SIRS patients in intensive care. Minerva Anestesiol, 2000 May, 66(5), 337 - 42 Cytopathic hypoxia . A concept to explain organ dysfunction in sepsis; Fink MP; The most common cause of death in patients with sepsis is the multiple organ dysfunction syndrome (MODS) . One important factor underlying the pathogenesis of MODS may be sepsis-induced alterations in cellular energy metabolism due to acquired intrinsic derangements in cellular respiration, a phenomenon that might be called "cytopathic hypoxia" . A number of different biochemical mechanisms have been postulated to account for cytopathic hypoxia in sepsis, including reversible inhibition of cytochrome oxidase by nitric oxide, irreversible inhibition of one or more mitochondrial respiratory complexes by peroxynitrite, and activation of the nuclear enzyme, poly-(ADP-ribosyl)-polymerase. Microvasc Res, 2000 Sep, 60(2), 131 - 40 Pulmonary microvascular changes during sepsis: evaluation using intravital videomicroscopy; McCormack DG et al.; A variety of pulmonary microvascular changes occur during sepsis . These include abnormal vascular reactivity, leukocyte sequestration, and leakage of protein into the alveoli . Based on intravital videomicroscopy we have developed a method to directly assess in vivo the changes that occur in the pulmonary microcirculation in a rat model of sepsis . Male Sprague-Dawley rats were assigned to control or sepsis groups . Sepsis was induced by cecal ligation and perforation . Twenty four hours later, rats were anesthetized, mechanically ventilated, and their lung prepared for intravital videomicroscopy . A specially designed transparent thoracic window was inserted into the chest wall . The dependent surface of the lung was superfused with saline solution and visualized with an inverted microscope . Vascular contractility, to phenylephrine, (PE) and hypoxia of small (15-25 microm in diameter) and medium (40-50 microm) arterioles was examined . Leukocyte traffic in the pulmonary microcirculation was studied after in vivo labeling of leukocytes with Rhodamine and visualized with fluorescence microscopy . Leak of albumin into the alveolar space was measured with FITC-labeled albumin and fluorescence microscopy . Both small and medium sized pulmonary arterioles in septic animals exhibited attenuated vascular contractility to phenylephrine, but only medium-sized arterioles displayed hypocontractility to hypoxia . Further, in septic animals there was an increase in both the number of stationary leukocytes in the pulmonary microcirculation and an increase in alveolar capillary protein leak . We conclude: (1) direct visualization of the pulmonary microvascular pressor response to hypoxia and PE in the rat is possible using this technique, (2) similar to previous in vitro studies with larger vessels, pulmonary arterioles have an attenuated contractile response to PE and hypoxia in sepsis, and (3) there is an increase in both the number of stationary leukocytes and protein leak into the alveolus in the lungs of septic animals . J Nutr, 2000 Sep, 130(9), 2222 - 7 The relationship between plasma taurine and other amino acid levels in human sepsis; Chiarla C et al.; Although reports of decreased plasma taurine in trauma, sepsis and critical illness are available, very little is known about the relationships among changes in plasma taurine, other amino acid levels and metabolic variables . We analyzed a large series of plasma amino acid profiles obtained in trauma patients with sepsis who were undergoing total parenteral nutrition . The correlations between plasma taurine, other amino acid levels, parenteral substrate doses and metabolic and cardiorespiratory variables were assessed by regression analysis . Post-traumatic hypotaurinemia was followed by partial recovery toward less abnormal values when sepsis developed . Levels of taurine were directly and significantly related to levels of glutamate, aspartate, beta-alanine and phosphoethanolamine (and unrelated to other amino acids) . Levels of these amino acids increased simultaneously with increasing doses of leucine, isoleucine and valine in total parenteral nutrition . Decreasing taurine was associated with increasing lactate, arteriovenous O(2) concentration difference and respiratory index, and with decreasing cholesterol and cardiac index . These results characterize the relationships between plasma taurine and other amino acid levels in sepsis, provide evidence of amino acid interactions that may support taurine availability and show more severe decreases in plasma taurine with the worsening of metabolic and cardiorespiratory patterns. Baillieres Best Pract Res Clin Rheumatol, 1999 Mar, 13(1), 1 - 20 The host and the skeletal infection: classification and pathogenesis of acute bacterial bone and joint sepsis; Mader JT et al.; Bone and joints are normally sterile areas . Bacteria may reach these sites by either haematogenous spread or spread from an exogenous or endogenous contiguous focus of infection . Bone infection, or osteomyelitis, is characterized by a progressive infectious process resulting in inflammatory destruction of bone, bone necrosis and new bone formation . Joint infections, or infectious arthritis, arise either from the haematogenous spread of organisms through the highly vascularized synovial membrane or from direct extension of a contiguous bone or soft tissue infection . The most commonly involved joints are the knee and the hip, although any joint can become infected . Infectious arthritis is monoarticular in 90% of cases . Some of the questions to be answered in this chapter include: how bacteria reach and cause damage in the bones and joints; what the current classification systems of bone and joint infections are; what some risk factors and host factors associated with bone and joint infection are; what some current characteristics of musculoskeletal infections are and whether the damage to joints can be diminished by treatment . Arch Dis Child Fetal Neonatal Ed, 2000 Sep, 83(2), F139 - 42 Splanchnic haemodynamic disturbances in perinatal sepsis; Kempley ST et al.; AIM: To determine the effect of perinatal bacterial infection on the neonatal splanchnic circulation . SUBJECTS/SETTING: 76 premature infants with appropriate birth weight for gestation admitted for neonatal intensive care . METHODS: Doppler ultrasound was used to measure blood flow velocity and pulsatility index in the superior mesenteric artery and coeliac axis during the first 24 hours of life . Babies were classified according to the results of blood and surface cultures, as well as the presence or absence of maternal prolonged membrane rupture . RESULTS: Infection status had a significant effect on pulsatility index in both arteries, with that in the coeliac axis being reduced from 1.27 to 0.80 in babies with infection (p < 0.0001) . Coeliac axis blood flow velocity was significantly increased in those with infection (from 34.6 to 46.5 cm/s; p < 0.05) . CONCLUSION: As early as the first day of postnatal life, infected neonates show a pattern of splanchnic hyperaemia similar to that found in adult systemic inflammatory response syndrome. Dis Colon Rectum, 2000 Aug, 43(8), 1141 - 5 Risk factors for intra-abdominal sepsis after surgery in Crohn's disease; Yamamoto T et al.; PURPOSE: This study examined risk factors for intra-abdominal sepsis after surgery in Crohn's disease . METHODS: We reviewed 343 patients who underwent 1,008 intestinal anastomoses during 566 operations for primary or recurrent Crohn's disease between 1980 and 1997 . Possible factors for intra-abdominal sepsis were analyzed by both univariate (chi-squared test) and multivariate (multiple regression) analyses . RESULTS: Intra-abdominal septic complications, defined as anastomotic leak, intra-abdominal abscess, or enterocutaneous fistula, developed after 76 operations (13 percent) . Intra-abdominal septic complications were significantly associated with preoperative low albumin level (< 30 g/l; P = 0.04), preoperative steroids use (P = 0.03), abscess at the time of laparotomy (P = 0.03), and fistula at the time of laparotomy (P = 0.04) . The intra-abdominal septic complication rate was 50 percent (8/16 operations) in patients with all of these four risk factors, 29 percent (10/35 operations) in patients with three risk factors, 14 percent (14/98 operations) in patients with two risk factors, 16 percent (33/209 operations) in patients with only one risk factor, and 5 percent (11/208 operations) in patients with none of these risk factors (P<0.0001) . The following factors did not affect the incidence of septic complications; age, duration of symptoms, number of previous bowel resections, site of disease, type of operation (resection, strictureplasty, or bypass), covering stoma, and number, site, or method (sutured or stapled) of anastomoses . CONCLUSIONS: Preoperative low albumin level, steroid use, and the presence of abscess or fistula at the time of laparotomy significantly increased the risk of septic complications after surgery in Crohn's disease. Amino Acids, 2000, 18(4), 389 - 97 Taurine and pulmonary hemodynamics in sepsis; Chiarla C et al.; This study has been performed to characterize the relationship between changes in plasma taurine (TAU) and hemodynamic patterns in sepsis . Analysis of 249 plasma aminoacidograms (AA-grams) and associated measurements in a group of critically ill, mechanically ventilated septic patients, showed that decreases in TAU were significantly correlated with increases in pulmonary artery pressure and pulmonary vascular resistance, and with worsening of pulmonary dysfunction . All cases requiring positive end-expiratory pressure greater than 10cmH2O had TAU lower than 50 microM/L . Low TAU was paralleled by decreases in other sulfur-containing AA, phosphoethanolamine, beta-alanine, glutamate and aspartate, within a pattern of greater metabolic dysregulation . These data provide evidence of a link between severity of pulmonary dysfunction and reduced TAU availability in clinical sepsis . The implications relate also to the need for specific investigations of the clinical effect of exogenous TAU on proinflammatory mediator-induced pulmonary dysfunction. J Reprod Med, 2000 Jul, 45(7), 581 - 4 Mycobacterium chelonae sepsis associated with long-term use of an intravenous catheter for treatment of hyperemesis gravidarum . A case report; Katz VL et al.; BACKGROUND: Of the 1-2% of pregnant women who develop hyperemesis, the great majority are managed successfully with antiemetics and, when needed, short courses of parenteral medications . Only rarely will chronic parenteral therapy be necessary . Such therapy may be associated with significant complications . CASE: A 38-year-old woman, gravida 3, para 1, induced abortion 1, with a history of hyperemesis in her first pregnancy, developed recurrent hyperemesis at 9 weeks' gestation . After four admissions and a 5.45-kg weight loss at 12 weeks' gestation, a Groshong catheter was placed in the left subclavian vein . The patient was then managed with home droperidol infusions and intravenous hydration as needed . At 30 weeks' gestation she developed tender, erythematous nodules over her legs and right arm . Culture from a biopsy of the nodules grew Mycobacterium chelonae, as did the catheter tip . M chelonae is a ubiquitous, opportunistic, nontuberculous (atypical) mycobacterium . The patient responded slowly to clarithromycin . At 37 weeks she delivered a healthy, 4,080-g, male infant . Three months postpartum the nodules continued to resolve slowly on clarithromycin . CONCLUSION: When chronic parenteral therapy is required for hyperemesis gravidarum, attention must be given to potential complications . Indwelling catheters should be removed as soon as possible. Hypertension, 2000 Aug, 36(2), 250 - 8 Interactions between blood cells and retinal endothelium in endotoxic sepsis; Tsujikawa A et al.; Platelets and leukocytes are thought to play a leading role in the pathogenesis of many inflammatory conditions . To recruit flowing blood cells to the inflammatory region, it would be necessary for them to interact with vascular endothelial cells . Recently, many reports have indicated the resistance of spontaneous hypertensive rats (SHR) to endotoxic sepsis . Their resistance might be derived from suppressed interaction between these blood cells and endothelial cells . Therefore, SHR and age-matched Wistar-Kyoto rats (WKY) were induced with endotoxic sepsis by intravenous injection of lipopolysaccharide (LPS) . At 4, 12, 24, and 48 hours after induction, leukocyte-endothelial interactions in the retina were evaluated in vivo with acridine orange digital fluorography . Fluorescently labeled platelets were also injected to investigate platelet-endothelial interactions in the retina in endotoxic sepsis . Leukocyte rolling in SHR after LPS injection was significantly suppressed; the maximum number of rolling leukocytes was reduced by 80.1% at 12 hours after LPS injection in SHR compared with WKY . Subsequent leukocyte infiltration into the vitreous cavity was significantly inhibited in SHR . Furthermore, platelet-endothelial interactions in the retina were also suppressed in SHR treated with LPS . The maximum numbers of rolling and adherent platelets were reduced by 59.5% and 62.6%, respectively, in SHR compared with WKY . In both strains, leukocyte- and platelet-endothelial interactions were substantially inhibited by the blocking of P-selectin . These suppressed interactions could contribute to the reduction of leukocyte- and platelet-mediated tissue injury in endotoxic sepsis in SHR, resulting in their resistance to endotoxemia. J Surg Res, 2000 Sep, 93(1), 75 - 81 Lazaroid and pentoxifylline suppress sepsis-induced increases in renal vascular resistance via altered arachidonic acid metabolism; Krysztopik RJ et al.; Early sepsis leads to renal hypoperfusion, despite a hyperdynamic systemic circulation . It is thought that failure of local control of the renal microcirculation leads to hypoperfusion and organ dysfunction . Of the many mediators implicated in the pathogenesis of microvascular vasoconstriction, arachidonic acid metabolites are thought to be important . Vasoconstriction may be due to excess production of vasoconstrictors or loss of vasodilators . Using the isolated perfused kidney model, we describe a sepsis-induced rise in renal vascular resistance and increased production of key arachidonic acid metabolites, both vasoconstrictors and vasodilators, suggesting excessive production of vasoconstrictors as a cause for microcirculatory hypoperfusion . There is evidence of increased enzymatic production of arachidonic acid metabolites as well as nonenzymatic, free radical, catalyzed conversion of arachidonic acid . Pentoxifylline (a phosphodiesterase inhibitor) and U74389G (an antioxidant) both have a protective effect on the renal microcirculation during sepsis . Both drugs appear to alter the renal microvascular response to sepsis by altering renal arachidonic acid metabolism . This study demonstrates that sepsis leads to increased renal vascular resistance . This response is in part mediated by metabolites produced by metabolism of arachidonic acid within the kidney . The ability of drugs to modulate arachidonic acid metabolism and so alter the renal response to sepsis suggests a possible role for these agents in protecting the renal microcirculation during sepsis . J Pharmacol Exp Ther, 2000 Sep, 294(3), 1043 - 6 Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis; Ando H et al.; Development of severe sepsis is thought to result from the overproduction of cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and nitric oxide . Recently, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are antihypercholesterolemic agents, have been reported to inhibit lipopolysaccharide (LPS)-induced production of cytokines and nitric oxide in vitro . In this study, we tested these effects in vivo . After LPS administration (15 mg/kg i.p.) to CD-1 mice, serum levels of both TNF-alpha and IL-1beta transiently increased, and peaked at 2 h . After the peak responses of TNF-alpha and IL-1beta, serum levels of nitrite and nitrate increased until at least 8 h . Pretreatment of the mice with cerivastatin (20 mg/kg i.p . 12 and 1 h before LPS injection) reduced serum levels of TNF-alpha and IL-1beta at 2 h, and nitrite and nitrate at 8 h, by 93, 60, and 44%, respectively . In this model of sepsis, cerivastatin significantly (P =.016) improved the rate of 7-day survival from 26.7 to 73.3% . These results cast new light on the usefulness of cerivastatin in preventing severe sepsis. J Clin Immunol, 2000 May, 20(3), 212 - 5 Elevation of IL-18 in human sepsis; Grobmyer SR et al.; Interleukin-18 (IL-18) is a recently identified immunoregulatory cytokine that shares biochemical features with IL-1beta and acts in part by inducing interferon-gamma (IFN-gamma) . Endotoxic bacterial lipopolysaccharide (LPS) (1 or 2 ng/kg) was insufficient to increase plasma IL-18 in five healthy adults measured 3, 12, and 24 hr following challenge . In contrast, in the first 96 hr of admission to the surgical intensive care unit, mean maximal serum IL-18 was elevated (1,122 +/- 259 pg/ml) in nine septic patients compared to six healthy adults (191 +/- 42 pg/ml), P < 0.01) . Serum IL-18 concentrations in septic patients did not correlate with other measured inflammatory mediators: tumor necrosis factor, IL-6, IL-10, or secretory leukocyte protease inhibitor . Therefore, IL-18 circulates in healthy adults and is a component of the human systemic inflammatory response . Further, stimuli other than LPS may induce IL-18 production in vivo in human sepsis. Bone Marrow Transplant, 2000 May, 25 Suppl 2, S32 - 4 'Sepsis' and multi-organ failure: predictors of poor outcome after hematopoietic stem cell transplantation in children; Bonig H et al.; Prognostic scores, such as the PRISM and APACHE II, have been established, predicting with reasonable accuracy the outcome of patients admitted to intensive care units (ICU) . In keeping with previous reports, we found, however, that these scores failed to perform in a series of 28 recipients of hematopoietic auto- or allografts (BMT) who required ICU admission for reasons including respiratory (82%) and multi-organ (36%) failure . We therefore retrospectively analyzed the charts of these patients, evaluating predisposing factors and prognostic variables which might confound the validity of these ICU tools which in other clinical scenarios have proven so valuable . Of all the parameters tested, logistic analysis established the following as predictors for poor outcome: increased C-reactive protein (CRP) to > 10 mg/dl (P = 0.04), macroscopic hemorrhage (P = 0.04), hypotension (mean arterial pressure < normal) (P = 0.04) and GVHD > or = III (P = 0.002) . Most of these factors are not accounted for by the standard prognostic questionnaires . The development of an 'oncological' or 'post-BMT' risk of mortality score, taking into account these patients' specific clinical problems, might improve the risk assessment for this patient group, and might thus facilitate the timely recognition of those patients most in need of more intensive therapeutic measures. Br J Surg, 2000 Aug, 87(8), 1076 - 81 Analysis of risk factors for nosocomial sepsis in surgical patients; Farinas-Alvarez C et al.; BACKGROUND: This study aimed to identify patients at high risk for developing sepsis following surgery according to criteria determined by the American College of Chest Physicians and the Society of Critical Care Medicine Consensus Conference on sepsis . METHODS: A prospective case-control study was performed in surgical patients in a tertiary care centre over 1 year . Patients were identified by a daily prospective surveillance . Controls were selected randomly from the daily list of surgical inpatients . Data were collected prospectively . Crude and adjusted odds ratios (ORs) and their 95 per cent confidence intervals were computed using logistic regression analysis . RESULTS: During follow-up, 99 cases and 99 controls were identified . The main risk factors for sepsis found in the multivariate analysis were coma within 48 h before sepsis (OR 13.5, 95 per cent confidence interval 3.6-50.8), low serum albumin level at admission (OR 15.8, 5.4-46.4), two or more intrinsic co-morbidities (OR 11.8, 2.8-49.4) and parenteral nutrition (OR 5.1, 1.5-17.1) . Emergency surgery (OR 3.0, 1.4-6.4), abdominal surgery (OR 2.6, 1.0-6.8) and number of surgical interventions (OR 2.5, 1 . 1-6.1) were the variables related to surgery that significantly increased the risk of sepsis . Both the study on the Efficacy of Nosocomial Infection Control (SENIC) and the National Nosocomial Infections Surveillance indices showed a statistically significant trend with sepsis . CONCLUSION: Patient-related factors appear to represent the greatest risk for developing postoperative nosocomial sepsis, rather than factors associated with the surgery. Z Kardiol, 2000 Jun, 89(6), 477 - 84 {Inhalative strategies for improvement of pulmonary hemodynamics and gas exchange in sepsis and severe pulmonary hypertension}; Grimminger F et al.; Chronic pulmonary hypertension and septic lung failure display different clinical features resulting in severe disturbances in the pulmonary circulation . In these diseases, the pulmonary bloodflow is impaired by a pathologic constriction of blood vessels that may lead to right ventricular overloading as well as serious worsening of gas exchange mainly caused by ventilation/perfusion mismatch . Various mechanisms deteriorating the vascular function may induce both an irreversible and a reversible contraction of pulmonary vessels, respectively . Two pharmacological approaches exist to reduce the vascular resistance: Reduction of the increased vascular tone by relaxation of vascular smooth muscle cells (effect of vasodilators) . Inhibition of thrombus-mediated obliteration of the lung perfusion by use of anticoagulant and fibrinolytic drugs . Prevention of the structural reorganization of pulmonary vessels (vascular remodeling) by use of vasodilators with anti-inflammatory and anti-proliferative potency such as prostanoids . The systemic (intravenous or oral) application of vasodilative agents in sepsis and chronic pulmonary hypertension has, however, important side effects: Antagonism of the hypoxic pulmonary vasoconstriction aggravates the ventilation/perfusion mismatch (decrease in arterial oxygenation) . Side effects of these vasodilators (systemic hypotension) . The inhalative route of application is superior because of the pulmonary enrichment of the applied agent (pulmonary selectivity) . Furthermore, a preferential deposition in the well-ventilated areas of the lung is achieved (intrapulmonary selectivity) . Thus, the decrease in pulmonary-vascular resistance is paralleled by both optimized ventilation-perfusion matching and subsequently improved gas exchange . First clinical studies with inhaled nitric oxide and aerosolized prostacyclin have been performed in intubated and mechanically ventilated patients with septic lung failure . At present, the use of the long-acting prostacyclin analogue ilomedin for ambulant treatment of patients with chronic pulmonary hypertension is under investigation. Ann Pharmacother, 2000 Mar, 34(3), 393 - 7 Relationship between clinical and biologic variables and chloramphenicol pharmacokinetic parameters in pediatric patients with sepsis; Lugo Goytia G et al.; OBJECTIVE: To evaluate the influence of several clinical and biologic factors on the disposition kinetics of oral chloramphenicol in pediatric patients and to determine the usefulness of this information to predict chloramphenicol serum concentrations . STUDY DESIGN: The clinical, biologic, and pharmacokinetic data of 30 consecutive pediatric patients diagnosed with sepsis and admitted to a tertiary care center were analyzed retrospectively . The patients were randomly assigned to a study group and a validation group . The model was developed by a three-step approach involving Bayesian estimation of pharmacokinetic parameters, selection of covariates by principal component analysis, and final selection by stepwise multiple linear regression . The model was tested in the study group and compared with a general population model using a prediction error analysis . RESULTS: Regression analysis revealed that weight, albumin, and white blood cell (WBC) count were the most important determinants for chloramphenicol distribution volume, whereas age, WBC count, and serum creatinine were the most important determinants for chloramphenicol clearance . The performance of the constructed population model improved significantly in terms of both bias and precision compared with the general model when tested in the validation group . CONCLUSIONS: Clinical and biologic factors may significantly influence chloramphenicol's disposition in pediatric patients with sepsis and therefore should be considered in programming dosage regimens. Intensive Care Med, 2000 May, 26(5), 532 - 7 Plasmapheresis combined with continuous venovenous hemofiltration in surgical patients with sepsis; Schmidt J et al.; OBJECTIVE: To examine the effect of continuous venovenous hemofiltration (CVVHF) combined with plasmapheresis (TPE) in critically ill surgical patients after treatment of the septic focus . DESIGN: Observational pilot study . SETTING: University teaching hospital intensive care unit . INTERVENTIONS: TPE and CVVHF were administered 24 h after surgical and/or interventional treatment of septic focus . Arterial blood pressure, cardiac output, and systemic vascular resistance values were monitored . We examined the effect of the combined extracorporeal detoxification on outcome related to age, morbidity, organic failure rate, and initial APACHE II score . MEASUREMENTS AND RESULTS: Forty-three patients with sepsis were treated; 19 received TPE in combination with CVVHF, and 24 did not receive extracorporeal therapy . Overall mortality was 44.2% . In the therapy group mortality was lower (42.1 vs . 45.8%), but the primary organic failure rate was higher . The relationship between mortality and age was similar in the two groups . There was also no difference between the groups in the course of scores on APACHE II, multiple-organ failure, and sepsis severity . Only patients with an initial APACHE II score of 21-25 had a significant reduction in mortality after combined extracorporeal detoxification . Mortality of 17% in TPE/CVVHF patients with single- (pulmonary) and double-organ failure (renal/pulmonary) was significantly lower (P < 0.0001) than in untreated patients . CONCLUSIONS: Reduction in mortality in single- and double-organ failure was as high as 28% in septic patients with combined extracorporeal detoxification . A prospective randomized trial in sepsis and double-organ failure should be projected. Zhonghua Yi Xue Za Zhi, 1998 Jun, 78(6), 413 - 5 {Effect of recombinant human growth hormone on hypoalbuminemia in peritoneal sepsis: experimental and clinical research}; Li W et al.; OBJECTIVE: To investigate the effect of recombinant human growth hormone(rhGH) on hypoalbuminemia in peritoneal sepsis . METHODS: We observed rhGH on albumin mRNA expression and albumin sythesis in vitro and in vivo with the method of reverse-transcriptional polymerase chain reaction (RT-PCR) . RESULTS: rhGH significantly up-regulated albumin mRNA expression in vitro (143 +/- 6 vs 100.4 +/- 2.2, P < 0.01) and in vivo(152 +/- 8 Vs 100 +/- 3, P < 0.01), and obviously alleviated the inhibition of albumin mRNA expression induced by LPS (P < 0.05) . In cecal ligation and puncture-induced septic rats, rhGH significantly raised albumin synthesis(20.4 +/- 1.7 Vs 15.5 +/- 2.9 g/L, P < 0.01) and albumin mRNA expression . In patients with peritoneal sepsis, rhGH in combination with total parenteral nutrition markedly increased serum albumin, prealbumin, and transferrin concentration, but no apparent effect was observed in controls . CONCLUSION: rhGH significantly increases albumin mRNA expression and albumin synthesis in peritoneal sepsis. Surgery, 2000 Aug, 128(2), 133 - 8 IL-4-induced activation of the Stat6 pathway contributes to the suppression of cell-mediated immunity and death in sepsis; Song GY et al.; BACKGROUND: Although studies have shown that there is a marked depression in cell-mediated (T(H)(1)) immunity after the onset of sepsis, the mechanism by which this occurs remains unknown . In this regard, the T(H2) cytokine IL-4 is known to regulate T(H1) and T(H2) cell responsiveness primarily through the activation of the signal transducer and activation of transcription factor-6 (Stat6) pathway . METHODS: We hypothesized that IL-4 may contribute to the suppression of cell-mediated immunity and to death seen in sepsis and that IL-4 may be acting through the Stat6 pathway . To determine this, we induced cecal ligation and puncture (CLP) or sham-CLP in male BALB/c mice . Mice received 2 mg of monoclonal antibody against IL-4 or IgG control at 12 hours after CLP (ie, at the onset of immune suppression) . Splenic T cells were then isolated 24 hours after CLP and stimulated with monoclonal antibody to CD3 . Cytokine release and Stat6 phosphorylation (activation) were determined . In a separate group of animals, survival was assessed over 10 days . RESULTS: The results indicate that after CLP, T cells are suppressed in their ability to release the T(H1) cytokines, IL-2 and IFN-gamma . Alternatively, the release of T(H2) cytokines IL-10 and IL-4 is markedly increased after CLP . This was associated with an increase in phosphorylated Stat6 protein . In vivo treatment of mice with monoclonal antibody to IL-4 at 12 hours after CLP restores T(H1) responsiveness while preventing the increase in T(H2) cytokine release and Stat6 phosphorylation . Furthermore, neutralization of IL-4 markedly increased the survival rates in septic animals . CONCLUSIONS: Taken together, these data indicate that the T(H2) cytokine IL-4 contributes to the suppression of cell-mediated immunity and death associated with polymicrobial sepsis and suggest that IL-4 may be acting through the Stat6 pathway in septic animals. Crit Care Med, 2000 Jul, 28(7), 2600 - 7 Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 are increased in the plasma of children with sepsis-induced multiple organ failure; Whalen MJ et al.; OBJECTIVES: To determine concentrations of circulating adhesion molecules endothelial (E)-selectin, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 in children with sepsis-induced multiple organ failure (MOF), and to determine associations among increased concentrations of these circulating adhesion molecules and important outcome measures . DESIGN: Prospective study . SETTING: University pediatric intensive care unit . PATIENTS: A total of 77 consecutive children with sepsis and 14 acutely ill children without sepsis . INTERVENTIONS: Plasma E-selectin, ICAM-1, and VCAM-1 concentrations and organ failure index (indicating number of failed organ systems) were determined in 77 children on days 1 and 3 of sepsis, and in 14 control children on pediatric intensive care unit day 1 . Multivariate logistic regression analysis was used to determine associations between adhesion molecule concentrations and clinically relevant outcome measures . MEASUREMENTS AND RESULTS: Plasma concentrations of E-selectin, ICAM-1, and VCAM-1 were increased in children with sepsis vs . control on day 1 (p < .05) . Plasma VCAM-1 (but not ICAM-1 or E-selectin) was increased in children with more than three organ failures vs . children with less than three organ failures (p < .05) . Plasma ICAM-1 and VCAM-1 (but not E-selectin) concentrations independently predicted number of organs failed and development of more than three organ failures . Plasma ICAM-1 and VCAM-1 also predicted mortality and development of sequential (pulmonary/hepatic/renal) MOF (p < .05) . CONCLUSIONS: The pronounced and persistent increase in plasma VCAM-1 and ICAM-1 that occurs in children with sepsis and persistent MOF may indicate a phenotypic change in endothelium toward a more proinflammatory state . Alternatively, the source for these adhesion molecules may be activated leukocytes and other cell types . Future studies are required to determine the role of ICAM-1 and VCAM-1 in the pathogenesis of sepsis-induced MOF. Crit Care Med, 2000 Jul, 28(7), 2475 - 9 Lidocaine attenuates sepsis-induced diaphragmatic dysfunction in hamsters; Kodama S et al.; OBJECTIVES: Sepsis or endotoxemia causes diaphragmatic dysfunction, which may contribute to respiratory distress . Toxic free radicals are partly responsible for the pathogenesis . Lidocaine scavenges the reactive molecules . The purpose of the current study was to examine whether lidocaine prevents the diaphragmatic dysfunction of sepsis . DESIGN: Prospective, randomized animal study . SETTING: University research laboratory . SUBJECTS: A total of 40 male Golden-Syrian hamsters . INTERVENTIONS: The animals were randomly allocated to one of five groups (n = 8 each): hamsters undergoing sham laparotomy alone and receiving saline infusion (Sham group), those undergoing cecal ligation with puncture (CLP) and receiving an infusion of saline (Sepsis group), those undergoing sham laparotomy and receiving infusion of lidocaine, 2 mg/kg/hr (Sham-LID group), those undergoing CLP and receiving infusion of lidocaine, 1 mg/kg/hr (Sepsis-LID 1 group), and those undergoing CLP and receiving infusion of lidocaine, 2 mg/kg/hr (Sepsis-LID 2 group) . Subcutaneous infusion of saline or lidocaine was started 6 hrs before surgery and continued until 24 hrs after the operation when all hamsters were killed . MEASUREMENTS AND MAIN RESULTS: Diaphragmatic contractility and fatigability were assessed in vitro by using muscle strips excised from the costal diaphragms . Diaphragmatic levels of malondialdehyde (MDA), an index of free radicals-mediated lipid peroxidation, were also measured . Twitch and tetanic tensions in the Sepsis group were reduced compared with the Sham group . Tensions generated during fatigue trials were decreased, and MDA levels were elevated in diaphragms from the Sepsis group . An infusion of 2 mg/kg/hr lidocaine attenuated contractile dysfunction, aggravation of fatigability, and the increase in MDA formation . In contrast, 1 mg/kg/hr lidocaine failed to do so . Electrophysiologic diaphragmatic characteristics in the Sham-LID group were similar to those in the Sham group . CONCLUSIONS: Pretreatment with 2 mg/kg/hr but not 1 mg/kg/hr lidocaine attenuated sepsis-induced diaphragmatic dysfunction in hamsters assessed by contractile profiles and endurance capacity . This beneficial effect of lidocaine may be attributable, in part, to inhibition of lipid peroxidation in the diaphragm. Crit Care Med, 2000 Jul, 28(7), 2445 - 9 Stimulation of pulmonary big endothelin-1 and endothelin-1 by antithrombin III: a rationale for combined application of antithrombin III and endothelin antagonists in sepsis-related acute respiratory distress syndrome? Dschietzig T, Alexiou K, Laule M, Becker R, Schror K, Baumann G, Brunner F, Stangl K. OBJECTIVES: Antithrombin (AT) III reduces lung damage in animal models of septic acute respiratory distress syndrome (ARDS), which is generally attributed to stimulation of endothelial prostacyclin synthesis . However, clinical studies have failed so far to demonstrate mortality reduction by application of AT III . We investigated whether AT III stimulates pulmonary prostacyclin release . In addition, we hypothesized that it may promote pulmonary endothelins, thereby mitigating its own protective effect in the course of ARDS . DESIGN: Controlled experiment using isolated organs . SETTING: Experimental laboratory . SUBJECTS: Male Wistar rats . INTERVENTIONS: Isolated lungs were perfused over 120 mins in recirculatory mode in the presence of 50 microg/mL endotoxin (n = 11), 2U/mL AT III (n = 10), 5 U/mL AT III (n = 13), endotoxin plus 2 U/mL AT III (n = 5), or vehicle alone (controls, n = 13), respectively . MEASUREMENTS AND MAIN RESULTS: We determined the effects of AT III on vascular release of thromboxane B2, 6-keto-prostaglandin-F1alpha, big endothelin-1, and endothelin-1 . Control lungs released 59+/-23 pg/mL thromboxane B2, 1,480+/-364 pg/mL 6-keto-prostaglandin-F1alpha, 15.2+/-4.5 pg/mL big endothelin-1, and 0.46+/-0.13 pg/mL endothelin-1 . Exposure to endotoxin increased thromboxane B2 release 2.9-fold, 6-keto-prostaglandin-F1alpha release 1.6-fold, and endothelin-1 1.6-fold (p < .05 each); levels of big endothelin-1 were unchanged . AT III at 2 U/mL elevated production of big endothelin-1 (1.7-fold) and endothelin-1 (1.2-fold) (p < .05 for both) . AT III at 5 U/mL enhanced levels of big endothelin-1 (1.6-fold) and endothelin-1 (1.3-fold) (p < .05 for both) . Neither dose of AT III affected thromboxane B2 or 6-keto-prostaglandin-F1alpha concentrations . Application of 2 U/mL AT III plus endotoxin stimulated big endothelin-1 production (2.6-fold) compared with endotoxin or AT III alone (p < .05 for both), but did not further elevate endothelin-1 release . CONCLUSIONS: AT III does not stimulate pulmonary prostacyclin, but promotes pulmonary release of big endothelin-1 and endothelin-1 under basal and, particularly, under septic conditions, which may blunt the AT III-induced lung protection during ARDS . Therefore, we suggest combined application of AT III and endothelin antagonists in animal models of septic ARDS. Crit Care Med, 2000 Jul, 28(7), 2355 - 9 Neutrophil deformability in patients with sepsis, septic shock, and adult respiratory distress syndrome; Skoutelis AT et al.; OBJECTIVE: To investigate the deformability of morphologically active and passive neutrophils in patients with sepsis (SP), septic shock (SS), and adult respiratory distress syndrome (ARDS) . DESIGN: Prospective, observational study . SETTING: A university hospital intensive care unit and research laboratory . PATIENTS: Six patients with sepsis, six patients with septic shock, and six patients with ARDS . Eight healthy volunteers and eight ventilated but noninfected patients served as controls . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Morphologically passive and active neutrophil deformability as defined by the micropipette method was significantly decreased in patients with SP, SS, and ARDS associated with sepsis as compared with both control groups . Neutrophils from SS and ARDS patients were significantly more rigid as compared with neutrophils from SP patients but they did not differ from each other . The percentage of activated neutrophils was significantly higher in SP, SS, and ARDS patients . Increased passive neutrophil rigidity was significantly attenuated after coincubation with cytochalasin D . Tumor necrosis factor-alpha and interleukin-1beta serum levels were significantly higher in SP, SS, and ARDS patients . CONCLUSIONS: The entire neutrophil population is less deformable in SP, SS, and ARDS patients . The decreased deformability of passive neutrophils suggests that a direct mechanism involving actin polymerization, distinct from cell activation, is involved . These observations may be important in the mechanism of impaired vascular flow in patients with sepsis. Crit Care Med, 2000 Jul, 28(7), 2344 - 54 Plasma granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in critical illness including sepsis and septic shock: relation to disease severity, multiple organ dysfunction, and mortality; Presneill JJ et al.; OBJECTIVE: To define the circulating levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during critical illness and to determine their relationship to the severity of illness as measured by the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the development of multiple organ dysfunction, or mortality . DESIGN: Prospective cohort study . SETTING: University hospital intensive care unit . PATIENTS: A total of 82 critically ill adult patients in four clinically defined groups, namely septic shock (n = 29), sepsis without shock (n = 17), shock without sepsis (n = 22), and nonseptic, nonshock controls (n = 14) . INTERVENTIONS: None . MEASUREMENT AND MAIN RESULTS: During day 1 of septic shock, peak plasma levels of G-CSF, interleukin (IL)-6, and leukemia inhibitory factor (LIF), but not GM-CSF, were greater than in sepsis or shock alone (p < .001), and were correlated among themselves (rs = 0.44-0.77; p < .02) and with the APACHE II score (rs = 0.25-0.40; p = .03 to .18) . G-CSF, IL-6, and UF, and sepsis, shock, septic shock, and APACHE II scores were strongly associated with organ dysfunction or 5-day mortality by univariate analysis . However, multiple logistic regression analysis showed that only septic shock remained significantly associated with organ dysfunction and only APACHE II scores and shock with 5-day mortality . Similarly, peak G-CSF, IL-6, and LIF were poorly predictive of 30-day mortality . CONCLUSIONS: Plasma levels of G-CSF, IL-6, and LIF are greatly elevated in critical illness, including septic shock, and are correlated with one another and with the severity of illness . However, they are not independently predictive of mortality, or the development of multiple organ dysfunction . GM-CSF was rarely elevated, suggesting different roles for G-CSF and GM-CSF in human septic shock. Crit Care Med, 2000 Jul, 28(7), 2254 - 8 Volume expansion using pentastarch does not change gastric-arterial CO2 gradient or gastric intramucosal pH in patients who have sepsis syndrome; Forrest DM et al.; OBJECTIVE: In hypovolemic patients with sepsis syndrome, to determine the effects of colloid volume infusion using 10% pentastarch on abnormal gastric tonometer measurements (gastric intramucosal CO2 tension, gastric intramucosal-arterial PCO2 gradient, and gastric intramucosal pH {pHi}) and on cardiac index, global oxygen delivery, and hemoglobin . DESIGN: Prospective prepost intervention study . SETTING: Tertiary care, university-affiliated 15-bed general systems intensive care unit . PATIENTS: Patients were studied who had sepsis syndrome, who had pulmonary arterial catheters in place, who were hypovolemic (pulmonary arterial occlusion pressure {PAOP} <15 mm Hg), and who had a gastric arterial PCO2 gradient >10 mm Hg . INTERVENTIONS: Baseline measurements of gastric intramucosal CO2 tension, gastric intramucosal-arterial PCO2 gradient, and pHi, as well as arterial lactate, pulmonary arterial occlusion, central venous and systemic arterial pressures, thermodilution cardiac output, and temperature . Boluses of 500 mL pentastarch were administered to a total of 1,000 mL or until PAOP was >18 mm Hg . Measurements were repeated at 30 mins and 120 mins postinfusion of pentastarch . MAIN RESULTS: Volume infusion using pentastarch did not change gastric PCO2, gastric-arterial PCO2 gradient, or pHi . Volume expansion with pentastarch significantly increased cardiac index, global oxygen delivery, and PAOP . Administration of pentastarch decreased hemoglobin and arterial lactate at 30 mins but not at 120 mins . CONCLUSIONS: Volume expansion using a colloidal solution of 10% pentastarch does not change abnormal intramucosal CO2 tension, gastric-arterial PCO2 gradient, or pHi in critically ill hypovolemic patients who have sepsis syndrome despite increasing cardiac index, oxygen delivery, and pulmonary artery occlusion pressure. Am J Physiol Endocrinol Metab, 2000 Aug, 279(2), E244 - 51 Synthesis rate of plasma albumin is a good indicator of liver albumin synthesis in sepsis; Ruot B et al.; Plasma albumin is well known to decrease in response to inflammation . The rate of albumin synthesis from both liver and plasma was measured in vivo by use of a large dose of L-{(2)H(3)-(14)C}valine in rats injected intravenously with live Escherichia coli and in pair-fed control rats during the acute-phase period (2 days postinfection) . The plasma albumin concentration was reduced by 50% in infected rats compared with pair-fed animals . Infection induced a fall in both liver albumin mRNA levels and albumin synthesis relative to total liver protein synthesis . However, absolute liver albumin synthesis rate (ASR) was not affected by infection . In plasma, albumin fractional synthesis rate was increased by 50% in infected animals compared with pair-fed animals . The albumin ASR estimated in the plasma was similar in the two groups . These results suggest that hypoalbuminemia is not due to reduced albumin synthesis during sepsis . Moreover, liver and plasma albumin ASR were similar . Therefore, albumin synthesis measured in the plasma is a good indicator of liver albumin synthesis. J Trauma, 2000 Jul, 49(1), 101 - 8 Hepatic blood flow and oxygen consumption after burn and sepsis; Tadros T et al.; BACKGROUND: Alteration in the hepatic circulation after burn and in sepsis seems to be an essential component in the development of multiple organ failure . METHODS: Female pigs (n = 12, 20-25 kg) were instrumented with ultrasonic flow probes on the portal vein and the common hepatic artery . Catheters were inserted in the superior mesenteric and left hepatic veins . After 5 days, all animals were anesthetized and six of them received 40% total body surface area third-degree burn . A total of 100 microg/kg Escherichia coli LPS was intravenously administered at 18 hours after burn . All animals were studied for 42 hours . RESULTS: Thermal injury resulted in a 48% decrease in hepatic arterial blood flow despite maintenance of normal cardiac output, resulting in a fall in hepatic oxygen delivery rate . Portal venous blood flow showed a 32% increase at 4 hours after burn . Post-LPS portal blood flow was significantly reduced for a period of 8 hours (51% of baseline (bl), p < 0.05 analysis of variance {ANOVA}) . The hepatic arterial blood supply was also significantly reduced (12-67% of bl, p < 0.05 ANOVA) during the first 4 hours after LPS, indicating loss of the hepatic arterial response . The following 12 hours, a hepatic reperfusion phase was observed with an elevation of the hepatic arterial blood flow to 152% of bl (p < 0.05 ANOVA) . Postburn endotoxemia resulted in a significant decrease of hepatic oxygen delivery (88%) and hepatic oxygen consumption (79%) . Although the burn injury did not affect the portal venous pressure, postburn endotoxemia caused a significant portal hypertension during a period of 8 hours (225% of bl, p < 0.05 ANOVA) . CONCLUSION: Postburn sepsis amplifies the selective vasconstrictive impact of thermal injury on hepatic arterial blood flow, yielding a pronounced ischemia/ reperfusion injury, associated with a critical reduction of hepatic oxygen delivery and consumption . A postburn septic challenge induces portal hypertension, which may account for previously documented gut barrier dysfunction. J Trauma, 2000 Jul, 49(1), 38 - 42 Alterations in glucose-6-phosphatase gene expression in sepsis; Maitra SR et al.; BACKGROUND: The influence of sepsis on the expression and activity of hepatic glucose-6-phosphatase (Glu-6-Pase) was examined during the early hyperglycemic phase and the later hypoglycemic phase . METHODS: Sepsis was induced in anesthetized, fasted rats by cecal ligation and puncture, and liver samples were taken at 0, 0.5, 1, 1.5, and 20 hours after cecal ligation and puncture . RESULTS: The mRNA abundance of hepatic Glu-6-Pase increased fourfold at 0.5 hours over healthy control values, two-fold after 1 hour, and returned to normal after 1.5 hours . This finding was followed by a corresponding increase in Glu-6-Pase activity and was coincident with increased plasma glucose levels and decreased liver glucose-6-phosphate (Glu-6-P) at 0.5 and 1 hours . Plasma insulin and glucagon levels remained unchanged during this period, whereas corticosterone levels increased 2.5-fold over control values . At 20 hours cecal ligation and puncture, plasma glucose levels returned to normal, coincident with a 90% reduction in Glu-6-Pase mRNA abundance . Glu-6-Pase activity and Glu-6-P concentration returned to normal levels, while insulin, glucagon, and corticosterone levels increased significantly, i.e., 40-fold, 6.5-fold, and 6-fold, respectively . CONCLUSION: The initial rise and subsequent decline in blood glucose correlate very well with a corticosterone-dependent induction of hepatic Glu-6-Pase, mRNA, and protein, followed by an insulin-dependent suppression of its expression. Shock, 2000 Jul, 14(1), 73 - 8 Procalcitonin and proinflammatory cytokine interactions in sepsis; Whang KT et al.; Immunoneutralization of procalcitonin (ProCT), a putative mediator of sepsis, has been shown to increase survival in an animal model of sepsis . To better understand the role that ProCT plays in the sepsis cascade, we studied the relationship of this hormone to the proximal proinflammatory mediators, IL-1beta and TNFalpha . Hamsters were made septic by i.p . implantation of Escherichia coli-impregnated agar pellets . A time line study of serum IL-beta, TNFalpha, and ProCT levels showed that the increase in the cytokines was transient and less than 2-fold over baseline, whereas ProCT increased >100-fold by 12 h and remains elevated through 24 h . TNFalpha (400 microg/kg) was injected into healthy animals, inducing an elevation in ProCT that was 25-fold greater than controls . ProCT (30 microg/kg) was given to healthy and septic animals . In healthy animals, there was no significant elevation in serum IL-1beta or TNFalpha levels . In septic animals, IL-1beta was modestly blunted at 3 h but not at 12 h, and there was no change in TNFalpha levels . ProCT did not initiate or enhance IL-1beta or TNFalpha expression; however, the massive and sustained elevation of this hormone seen in sepsis can be induced by the proximal cytokine, TNFalpha . This study suggests that ProCT is a secondary mediator that might augment and amplify but does not initiate the septic response . Immunoneutralization of ProCT may prove to be an important clinical strategy, in view of its sustained elevation and the difficulty in initiating therapy for sepsis during the early phases of illness. Thorac Cardiovasc Surg, 2000 Jun, 48(3), 145 - 50 Sepsis and catecholamine support are the major risk factors for critical illness polyneuropathy after open heart surgery'; Thiele RI et al.; BACKGROUND: Critical illness polyneuropathy (CIP) remains a problem after open heart surgery . Recently, we reported about a retrospectively performed study pointing out that sepsis, the application of higher amounts of catecholamines and intervention such as chronic venovenous hemodiafiltration may be involved in the onset of CIP . A prospectively performed study is presented in order to evaluate the significance of risk factors initially after open heart surgery . METHODS: From June 1997 until September 1998, patients undergoing open heart surgery and being ventilated beyond 3 days were prospectively enrolled in the study and underwent a standard protocol of electromyographic investigation in order to determine CIP . Several items were recorded: amount of catecholamines, serum levels of urea, creatinine, albumin, and glucose . The duration of sepsis and chronic venovenous hemodiafiltration were reevaluated . Additionally the age, the left ventricular end-diastolic pressure prior to the operation, the time of ICU stay and the time of ventilatory support were compared . RESULTS: Within the observation period, 37 adult patients could be enrolled in the study, whereas 12 patients did develop CIP and 7 patients did not . Patients developing CIP required significantly different amounts of epinephrine (0.17 +/- 0.02 vs . 0.09 +/- 0.01 mg/kg/day, p < 0.05, t-test) higher amounts of norepinephrine (0.06 +/- 0.02 vs . 0.02 +/- 0.01 mg/kg/day, p<0.05, t-test), and lesser dosages of dobutamine (2.2 +/- 0.5 vs . 4.9 +/- 0.7, p<0.05, t-test) . After cardiac surgery, the plasma levels of urea was initially significantly elevated in patients developing CIP (127.4 +/- 10.5 vs 97.3 +/- 18.5, p<0.05, t-test) Patients suffering from CIP stayed significantly longer in the ICU (40.3 +/- 11.7 vs . 19.6 +/- 11.3 days, p < 0.05 t-test) with an extended time of ventilator support . (769.6 +/- 05.0 vs 295.0 +/- 134.0 hours, p<0.05, t-test) . Patients of the CIP group were suffering significant longer from sepsis than patients without CIP . CONCLUSIONS: Sepsis and catecholamine support and an increased level of urea were associated with the development of CIP . The prevention of sepsis and a modulation of the catecholamine support in order to improve microcirculatory flow may reduce the onset of CIP in patients undergoing open heart surgery. Anesteziol Reanimatol, 2000 May-Jun, (3), 38 - 41 {Disorders of purine metabolism in patients with peritonitis complicated by sepsis}; Tolkach AB et al.; Progressive hypoxia and cell destruction leading to increased production of active oxygen forms by xanthinoxidase and manifesting by an increased level of uric acid in the blood in parallel with inhibited pentose cycle reaction due to low activity of glucose-6-phosphate dehydrogenase determine the severity of peritonitis. Anesteziol Reanimatol, 2000 May-Jun, (3), 29 - 33 {Abdominal sepsis: the integral assessment of the severity of patient condition and of multiple organ dysfunction}; Gel'fand EB et al.; Results of examinations of 247 patients with diffuse peritonitis and symptoms of abdominal sepsis are analyzed . Systemic inflammatory reaction in peritonitis patients can manifest by sepsis, severe sepsis, and infectious toxic (septic) shock . The severity of systemic inflammatory reaction syndromes can be evaluated by objective scores for evaluation of clinical states (APACHE II, SAPS) and the degree of multiple organ dysfunction/failure (MODS, SOFA) . Application of objective scores for evaluation of clinical states provides clinical stratification of abdominal sepsis, helps predict the disease course and outcome, and improve treatment strategy. Arch Surg, 2000 Jul, 135(7), 766 - 72 Trauma- and sepsis-induced hepatic ischemia and reperfusion injury: role of angiotensin II; Tadros T et al.; HYPOTHESIS: We hypothesized that angiotensin II, a potent vasoconstrictor, is involved in the occurrence of hepatic ischemia after burn and sepsis, and that administration of angiotensin II antagonist DuP753 would ameliorate this process . DESIGN: Randomized animal study . SETTING: University laboratory, investigational intensive care unit, University of Texas Medical Branch, Galveston . MATERIALS: Female pigs (n = 18, weighing 20-25 kg) . INTERVENTIONS: All animals were prepared with ultrasonic flow probes on the portal vein and the common hepatic artery . Catheters were inserted in the superior mesenteric and left hepatic veins . After 5 days all animals were anesthetized and 12 of them received 40% total body surface area third-degree burn . Escherichia coli lipopolysaccharide (100 microg/kg) was intravenously administered at 18 hours postburn DuP753 was administered intravenously in a dose of 1 microg/kg to 6 pigs immediately after the burn . All animals were st