Sepsis

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 studied for 42 hours . MAIN OUTCOME MEASURES: Systemic and hepatic hemodynamics were measured and blood samples were drawn for determinations of arterial, mixed venous, and portal blood gases at baseline and at 14 consecutive time points, starting 1 hour after the burn . RESULTS: Burn caused a 4.6-fold increase in hepatic arterial vascular resistance and a 49% decrease in hepatic arterial blood flow . Postburn administration of angiotensin II receptor blocker DuP753 yielded a significant improvement in the hepatic arterial hemodynamics (only 12% increase in hepatic arterial vascular resistance and 8% decrease in hepatic arterial blood flow, P<.05 vs nontreated group, analysis of variance {ANOVA}) . Postlipopolysaccharide hepatic arterial blood flow was significantly reduced (12% of baseline, P<.05, ANOVA), in contrast to DuP753-treated animals (64% of baseline, P<.05 vs nontreated group, ANOVA) . Postburn blocking of angiotensin II receptors yielded a significant improvement in postlipopolysaccharide portal venous blood flow (85% of baseline vs 48% of baseline in nontreated animals, P<.05, ANOVA ) . Postburn endotoxemia resulted in a significant decrease of hepatic oxygen delivery (22% of baseline) and hepatic oxygen consumption (30% of baseline), while no marked changes were observed in the DuP753-treated group (P<.05 vs nontreated group, ANOVA) . CONCLUSIONS: Angiotensin II seems to play a pivotal role in burn- and sepsis-induced hepatic ischemia and reperfusion injury . Blocking angiotensin II receptors by DuP753 seems to abrogate this adverse effect of thermal injuries and sepsis on hepatic perfusion and oxygenation.

Inflamm Res, 2000 May, 49(5), 185 - 98
Endothelium function in sepsis; Volk T et al.; Endothelial cells can be the prime target for an infection and infected endothelial cells may serve as an initiating system for a systemic response as these cells are able to secrete many mediators known to be of paramount importance . Endothelial cell functions in turn are regulated by these circulating mediators . Cellular interactions with leukocytes revealed protective and destructive functions . Single cell and animal studies indicate that endothelial permeability is increased and apart from clinical obvious edema formation in septic patients, the endothelial component remains unknown . Endothelial coagulation activation has been shown in vitro, however human data supporting an endothelial procoagulatory state are lacking . Defects in endothelium dependent vasoregulation in animal models are well known and again human studies are largely missing . An imbalanced production of reactive oxygen species including nitric oxide has been found to be involved in all endothelial functions and may provide a common link which at present can be supported only in animal studies.

Microsc Res Tech, 2000 Aug 1, 50(3), 229 - 35
Anti-TNF therapies in rheumatoid arthritis, Crohn's disease, sepsis, and myelodysplastic syndromes; Raza A; An attempt has been made in this article to summarize the state-of-the-art clinical experience with the use of anti-TNF therapies in four diseased states with special emphasis on myelodysplastic syndromes . Given the central role of TNF-alpha in initiating and perpetuating the chronic damage produced in the diseased organs by controlling a cascade of pro-inflammatory cytokines, as well as its acute role in sepsis, theoretically speaking, neutralization of this peptide was a natural therapeutic choice . Results of the initial clinical trials appear encouraging and sometimes dramatic in their efficacy . The mechanism of response however, is interesting in that even when TNF-alpha is directly targeted by a monoclonal antibody, the resulting benefits can frequently not be attributed to TNF suppression alone . Rather, it appears that a more general effect on the T-lymphocytes is also contributing to the responses being seen . This raises the new possibility of combining anti-cytokine and anti-T-cell strategies to treat at least the more chronic diseases such as Crohn's disease and myelodysplastic syndromes . Continued clinical trials testing these strategies are clearly warranted .

Crit Care Med, 2000 Jun, 28(6), 2051 - 7
Linear and nonlinear analysis of hemodynamic signals during sepsis and septic shock; Toweill D et al.; OBJECTIVE: Neuroautonomic modulation of heart rate (HR) and blood pressure were assessed in sepsis or septic shock . We hypothesized that these metrics would be diminished in pediatric patients with sepsis and septic shock, indicating uncoupling of the autonomic and cardiovascular systems . DESIGN: Prospective case series . SETTING: Pediatric intensive care unit in a tertiary care children's hospital . PATIENTS: Thirty pediatric patients with sepsis or septic shock . INTERVENTIONS: None . MEASURES AND MAIN RESULTS: Metrics used included power spectral analysis, a linear frequency domain measure, and detrended fluctuation analysis, a nonlinear technique that assesses the degree of long-range correlation in HR or blood pressure . We found decreased low-frequency (2.68 +/- 0.24 vs . 3.37 +/- 0.17 {SEM} bpm2; p = .03) and high-frequency HR power (2.18 +/- 0.14 vs . 2.79 +/- 0.23 bpm2; p = .04) and increased detrended fluctuation analysis scaling exponent (1.22 +/- 0.06 vs . 1.00 +/- 0.07 bpm2; p = .02) in sepsis vs . shock patients, respectively . Compared with sepsis or shock, recovery was associated with increases in low-frequency (3.61 +/- 0.15 vs . 3.05 +/- 0.19 bpm2; p < .0001) and high-frequency HR power (3.11 +/- 0.15 vs . 2.50 +/- 0.22 bpm2; p < .0001) . CONCLUSIONS: We conclude that uncoupling of the autonomic and cardiovascular systems occurs over both short- and long-range time scales during sepsis, and the degree of uncoupling may help differentiate between sepsis, septic shock, and recovery states.

Crit Care Med, 2000 Jun, 28(6), 2026 - 33
Prediction of nosocomial sepsis in neonates by means of a computer-weighted bedside scoring system (NOSEP score)
Mahieu LM, De Muynck AO, De Dooy JJ, Laroche SM, Van Acker KJ.
OBJECTIVE: To develop an easy-to-use bedside scoring system, composed of clinical variables, hematologic variables, and risk factors of infection, to predict nosocomial sepsis in neonatal intensive care unit patients . SETTING: A neonatal intensive care unit in a university hospital, Antwerp, Belgium . PATIENTS: Over 2 yrs, we analyzed two groups of patients . First, we prospectively studied 104 episodes of presumed nosocomial sepsis in 80 neonates (derivation cohort), and then we retrospectively studied 50 episodes in 39 neonates (validation cohort) . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: We developed two versions of a scoring system to predict nosocomial sepsis in sick neonates . The first scoring system (NOSEP-1 score) was based on 15 clinical, 12 laboratory, and 17 historical variables potentially connected with infection; the second one (NOSEP-2 score) also included the culture results of central vascular catheters . Based on the odds ratios of all independent variables, an additive and weighted score was developed and validated in a cohort of 39 patients screened for nosocomial sepsis in the same center . The NOSEP-1 score consisted of three laboratory variables (C-reactive protein > or =14 mg/L, thrombocytopenia <150 x 10(9)/L, and neutrophil fraction >50%), one clinical factor (fever >38.2 degrees C {100.8 degrees F}), and one risk factor (parenteral nutrition for > or =14 days) . The NOSEP-2 score consisted of the same variables plus catheter-hub and catheter insertion site colonization data . Receiver operating characteristic curve analysis demonstrated good predictor performance of the NOSEP-1 score (area under the curve {Az} = 0.82 +/- 0.04 {SEM}) and NOSEP-2 score (Az = 0.84 +/- 0.04, p < .05) . We checked whether a complex computer-generated scoring system (CD-1 and CD-2 scores) based on the original numerical values of the items used in NOSEP-1 and NOSEP-2 would improve the prediction of nosocomial sepsis . The analysis showed the accuracy of bedside NOSEP-1 and NOSEP-2 scores to be comparable with the more cumbersome computer-generated CD-1 and CD-2 scores (receiver operating characteristic curve, Az: CD-1 score = 0.81 +/- 0.04, p = .69, and CD-2 score = 0.86 +/- 0.04, p = .96) . Finally, in the validation cohort, we showed that the developed scoring system has a good prediction potential for nosocomial sepsis (Hosmer-Lemeshow goodness-of-fit test, chi2 {19} = 16.34, p > .75) . CONCLUSIONS: The simple bedside scoring system NOSEP-1 composed of C-reactive protein, neutrophil fraction, thrombocytopenia, fever, and prolonged parenteral nutrition exposure provides a valuable tool for early identification of nosocomial sepsis . Its predictive power can be improved by adding central vascular catheter insertion site and hub colonization to the score.

Crit Care Med, 2000 Jun, 28(6), 1947 - 52
An improved clinically relevant sepsis model in the conscious rat; Mathiak G et al.; OBJECTIVE: To develop an improved small animal experimental paradigm that more closely mimics human sepsis . DESIGN: Prospective, randomized, controlled animal study . SETTING: Medical school research laboratory . SUBJECTS: Male Sprague-Dawley rats (280-320 g) . INTERVENTIONS: We monitored the hemodynamic, hematologic, and biochemical consequences of abdominal sepsis produced by intraperitoneal implantation of a fibrin clot containing Escherichia coli in conscious, antibiotic-treated, rats . MEASUREMENTS AND MAIN RESULTS: Similar to human sepsis, the implanted, infected clot (LD50 = 5-7 x 10(8) colony forming units/mL, n = 6) elevated cardiac index (>7% vs . sterile clot, p < .05, at 4 hrs), whereas mean arterial pressure and heart rate remained unaffected . The total peripheral resistance index and stroke volume index tended to decrease and increase, respectively . In contrast, an intravenous bolus injection of endotoxin (LD50 of E . coli lipopolysaccharide = 5.6 mg/kg, n = 7), the most commonly used sepsis model, induced profound hypodynamic responses manifested by a 27% decrease (vs . endotoxin vehicle, p < .01) in cardiac index, a 28% increase in the total peripheral resistance index (p < .01), and a 33% decrease in the stroke volume index (P < .01) . The infectious peritonitis model also displayed dose-dependent thrombocytopenia (<61%, p < .05), leukopenia (<60%, p < .05), and mortality rate (50% at 5-7 x 10(8) colony forming units/mL, p < .05) with a minimally elevated serum tumor necrosis factor-alpha level (145 vs . 12 +/- 6 pg/mL in controls, p < .05) . CONCLUSION: This rodent model of antibiotic-treated, intra-abdominal infection features key characteristics of clinical sepsis . Although the hyperdynamic response observed in septic patients undergoing resuscitation was not clearly elicited, this paradigm better mimics clinical sepsis compared with the commonly used endotoxin model . Thus, utilization of this paradigm may provide additional opportunities to explore mechanisms of sepsis and to examine novel therapeutics.

Crit Care Med, 2000 Jun, 28(6), 1931 - 9
Adenosine and nitric oxide regulate regional vascular resistance via interdependent and independent mechanisms during sepsis; Sam AD 2nd et al.; OBJECTIVE: Adenosine receptor blockade increases regional resting vascular resistance during sepsis . In healthy subjects, part of adenosine's actions are mediated via stimulation of nitric oxide synthase . Because nitric oxide synthase activity is thought to be a major contributor to altered vascular tone in sepsis, we tested the hypothesis that some of the nitric oxide-mediated resting regional resistance during sepsis is secondary to endogenous adenosine stimulation of nitric oxide synthase . DESIGN: Prospective, randomized, controlled experiment . SETTING: Shock-trauma and basic science laboratory . SUBJECTS: Male Sprague-Dawley rats . INTERVENTIONS: Twenty-four hours after sepsis or sham induction, rats were separated into two groups (n = 6 to 10 in each group) . Group 1 received a 10-min infusion of the adenosine antagonist 8-sulfophenyltheophylline (0.9 mg/kg x min) followed by a 10-min infusion of L-nitro-arginine-methyl ester (0.5 mg/kg x min) . Group 2 similarly received L-nitro-arginine-methyl ester followed by 8-sulfophenyltheophylline in the presence of L-nitro-arginine-methyl ester . MEASUREMENTS AND MAIN RESULTS: Hemodynamic and blood flow measurements (microspheres) were made before infusions, 10 mins after the administration of each single-agent infusion, and 10 mins after combined-agent infusions were administered . No significant resistance alterations were observed in nonseptic rats . In septic rats, adenosine receptor blockade alone increased hepatosplanchnic and skeletal muscle vascular resistance, but no further increases were seen when L-nitro-arginine-methyl ester was added . Nitric oxide synthase inhibition alone increased hepatosplanchnic and skeletal muscle vascular resistances . When 8-sulfophenyltheophylline was added to the infusion, skeletal muscle vascular resistance increased significantly more than with L-nitro-arginine-methyl ester alone, but there were no further increases in hepatosplanchnic resistance . Renal and adipose vascular resistances increased with L-nitro-arginine-methyl ester infusions, and 8-sulfophenyltheophylline produced no effect . CONCLUSIONS: During sepsis, nitric oxide caused resting vasodilation independent of adenosine in the renal and adipose vasculature . In the hepatosplanchnic circulation, there is reciprocal adenosine-nitric oxide interaction in maintaining resting regional resistance . Skeletal muscle displayed a dual adenosine-mediated (nitric oxide-independent) and nitric oxide-mediated (adenosine receptors required) interaction to regulate resting resistance during sepsis . These data indicate that in the hepatosplanchnic and skeletal muscle vasculature, all of the resting nitric oxide-mediated vasodilation is secondary to endogenous adenosine action, but in adipose and renal vasculature, resting nitric oxide mediated vasodilation is independent of adenosine . Endogenous adenosine also appears to play a significant role in determining resting skeletal muscle resistance that is independent of nitric oxide synthase during sepsis.

Crit Care Med, 2000 Jun, 28(6), 1701 - 8
Role of CuZn superoxide dismutase in regulating lymphocyte apoptosis during sepsis; Freeman BD et al.; OBJECTIVE: The lymphocyte is a principal mediator of the inflammatory response, and lymphocyte depletion via apoptosis may be an important mechanism of modulating inflammation . Increased oxygen consumption occurs during sepsis and results in the generation of reactive oxygen species . Although reactive oxygen species initiate apoptosis in many biological systems, their role in controlling lymphocyte apoptosis during sepsis is unclear . The objective of this study was to better characterize the role of oxidative stress in precipitating lymphocyte apoptosis during sepsis and to specifically define the role of the CuZn superoxide dismutase (SOD) enzyme complex, a major antioxidant defense, in modulating this process . DESIGN: Prospective, randomized, controlled study . SETTING: Research laboratory at an academic medical center . SUBJECTS: Mice that were either genetically normal or that were deficient in or overexpressed the enzyme CuZn SOD . INTERVENTIONS: Mice from each genetic group were randomized to no manipulation (control), sham surgery, or cecal ligation and puncture . Mice were killed 18-24 hrs after study entry, and the thymi and spleen were removed for analysis of apoptosis . MEASUREMENTS AND MAIN RESULTS: Lymphocyte apoptosis was assessed by three independent methods: light microscopy, fluorescent terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling, and DNA gel electrophoresis . Comparisons were performed using standard parametric statistical tests . Lymphocyte apoptosis was present in mice after CLP but not in control mice or in mice after sham surgery (p < .05) . Mice completely lacking CuZn SOD developed significantly more lymphocyte apoptosis than did either partially CuZn SOD-deficient or genetically normal mice (p < .05) . This apoptosis was more pronounced in the thymus than the spleen and, within the thymus, more prominent in the cortex than medulla (p < .05 for all) . In contrast, mice that overexpressed CuZn SOD did not differ in the amount of apoptosis after CLP compared with genetically normal mice (p = NS for all) . CONCLUSIONS: Oxidative stress occurs in sepsis and appears to be one stimulus for the development of lymphocyte apoptosis, a process that is partly regulated by CuZn SOD . However, we were unable to demonstrate that overexpression of this enzyme suppressed lymphocyte apoptosis, suggesting that either other antioxidant defenses or other pathways independent of oxidative stress may mediate lymphocyte elimination in this syndrome.

Anaesthesist, 2000 May, 49(5), 451 - 4
{The effect of hepatosplanchnic circulation in treatment of trauma and sepsis . Beyond O2-supply O2-uptake relationship?}; Trager K et al.; Sepsis and SIRS are characterised by increased hepatosplanchnic blood flow and oxygen transport due to sepsis-associated hypermetabolism with enhanced oxygen uptake . Regional hypermetabolism may be linked with a mismatch of oxygen availability and demand potentially resulting in a pathological splanchnic oxygen uptake/supply dependency . Splanchnic hypermetabolism has been hypothesised to be due to increased hepatic gluconeogenesis caused by accelerated glucose precursor uptake resulting from increased release from the peripheral tissues . This increased precursor efflux is triggered by cytokines . The response of splanchnic haemodynamics and oxygen kinetics, however, to therapeutic interventions does not necessarily parallel the different metabolic pathways . Therefore, understanding of both tissue perfusion and oxygenation as well as metabolism is pivotal for evaluating the effects of different therapeutic strategies in intensive care medicine.

J R Coll Surg Edinb, 2000 Jun, 45(3), 178 - 82
Sepsis and the systemic inflammatory response syndrome; Paterson RL et al.; Sepsis and the systemic inflammatory response syndrome are common and represent a major factor in morbidity and mortality in intensive care units and the critically ill . The pathogenesis of these syndromes is becoming increasingly understood and it is hoped that this will result in improved outcome . However, novel treatments have so far failed to live up to the expectations following extensive and promising in vitro and in vivo animal studies . The aim of this review is to detail the currently used definitions of systemic inflammatory response syndrome, sepsis and septic shock and to present an overview of our current understanding of the pathophysiology which underline these conditions.

Acta Clin Belg, 2000 Mar-Apr, 55(2), 79 - 87
Update on sepsis: pathophysiology and treatment; Vincent JL; Sepsis results from the activation of a complex cascade of mediators, an appropriate and necessary body response to infection or insult which can, however, become excessive and detrimental to the host . When the immunological host response is not well controlled, it may lead to multiple organ failure and death . This manuscript reviews the epidemiology and the major factors involved in the development of sepsis, and considers a number of therapeutic interventions that may help to better control the septic process and the related development of multiple organ failure.

J Crit Care, 2000 Jun, 15(2), 64 - 72
Impaired sarcoplasmic calcium release inhibits myocardial contraction in experimental sepsis; Patel D et al.; PURPOSE: In septic shock, myocardial dysfunction develops over the course of illness, but the mechanism of this depression is not clear . In this study, mechanisms of myocardial dysfunction were examined in a porcine model of Escherichia coli sepsis . MATERIALS AND METHODS: Animals were subjected to 4 hours of bacteria infusion (n = 5) (septic group) or saline infusion (n = 5) (nonseptic group), after which trabeculae were removed from the right ventricle and placed into a recirculating water bath . Measurements of steady-state contraction (SSC) were obtained at 0.5, 1, and 2 Hz . Indirect indices were used to assess abnormalities in myocardial calcium metabolism in sepsis . Extrasystoles (ES) were used to assess transsarcolemmal (TSL) calcium flux and were measured at 300 milliseconds, 400 milliseconds, and 500 milliseconds after the preceding stimulus . Postrest contraction (PRC) is an indicator of SR recirculation from the uptake to the release site and was obtained after interposing intervals of rest between steady-state beats at 0.5 Hz . Rapid-cooling contracture (RCC) is an indicator of sarcoplasmic reticulum (SR) content and was obtained at 0.5, 1, and 2 Hz and after interposing intervals of rest at 0.5 Hz . RESULTS: SSC was not different between groups at 0.5 Hz, but compared with the nonseptic group, SSC decreased at 1 and 2 Hz in the septic group (P < .05) . PRC and TSL were not different between groups . During rest intervals, calcium leaks out of SR through the ryanodine channel (ie, SR calcium release channel) . In the septic group, as assessed by RCC, SR calcium leak was less than that found in the nonseptic group . CONCLUSION: These results indicate that myocardial dysfunction in sepsis is frequency dependent, and that the mechanism is most likely caused by inhibition of SR calcium release owing to blockade of the ryanodine channel.

Metabolism, 2000 Jun, 49(6), 753 - 4
Concordant decreases of thyroxine and thyroxine binding protein concentrations during sepsis; Afandi B et al.; The principal thyroxine (T4) binding proteins were measured in 8 septic patients and 8 controls to determine the extent to which a decrease in their concentration contributes to the decrease in serum T4 in sepsis . T4 binding globulin (TBG) evaluated by radioimmunoassay (RIA) and radial immunodiffusion (RID) was 61% and 66%, respectively, of the normal mean value in sera from septic patients . Decreases of albumin and transthyretin (TTR) to 55% and 29%, respectively, of the normal mean concentration contributed to the loss of T4 binding power in these sera . Total serum binding of T4, calculated from the normal contribution of each protein to T4 binding and the reduction of its concentration in septic patients, was 55% of that in the normal controls . This decrease in the estimated protein binding of T4 was proportional to the decrease of serum T4 from a mean of 8.4 microg/dL in the normal controls to 4.7 microg/dL (56% of the control) in the septic patients . Because TBG binds most of the serum T4, the decrease in the TBG concentration was the major factor in the decrease of total T4 binding power . Since the concentration of the major T4 binding proteins decreased sufficiently to account for the decrease in serum T4, it is unnecessary to postulate the effects of additional factors such as binding inhibitors or modification of T4 binding protein affinity.

Pediatr Infect Dis J, 2000 Jun, 19(6), 531 - 5
Use of C-reactive protein to guide duration of empiric antibiotic therapy in suspected early neonatal sepsis; Bomela HN et al.; BACKGROUND: Serial C-reactive protein (CRP) measurements have been shown to be useful for guiding duration of antibiotic therapy in neonates . This study sought to determine whether this is a safe and practical approach in a developing country . METHODS: The study was conducted at the Johannesburg Hospital between September 15, 1998, and January 15, 1999 . Subjects included all neonates evaluated for suspected sepsis in the first 24 h of life who had negative initial and repeat CRP values (< or = 10 mg/l) {corrected} . Repeat CRP measurements were performed between 24 and 48 h after birth . Antibiotic therapy was stopped in these infants at 24 to 48 h, and they were observed until 72 h, when the final blood culture results were available . The number of positive blood cultures in this group was determined . RESULTS: The repeat CRP estimation correctly identified 99 of 100 infants in the study as not requiring further antibiotic therapy (negative predictive value, 99%; 95% confidence intervals, 95.6 to 99.97%) . The 1 infant with a positive blood culture was premature with a gestational age of 31 weeks . Eight babies required repeat evaluation for suspected sepsis, 4 presented on Day 3 to 4 and one of these babies died . All these neonates were of < or =33 weeks gestation . CONCLUSION: The use of serial CRP measurements to guide antibiotic therapy is a safe and practical approach in neonates with suspected sepsis in a developing country.

Am J Perinatol, 1999, 16(10), 525 - 30
Assessment of cord blood IL-6 levels as an indicator of neonatal sepsis; Perenyi A et al.; Based on the recognition that interleukin-6 (IL-6) is produced early in infection, IL-6 determinations have been used to identify infants with early onset bacterial sepsis . This study intended to assess the value of IL-6 in maternal, cord and infant peripheral blood as an index of sepsis, and examine the relationships of its values in mother and infants . The population consisted of 17 mother/infant pairs at high risk for neonatal infection . Eight of these infants had clinical signs of possible sepsis . Cord blood IL-6 levels in infants of mothers considered to be noninfected were lower than those born to women with chorioamnionitis . There was also a positive correlation between maternal and cord blood IL-6 values . There were no differences in maternal blood IL-6, whether they had infections or not . Also, peripheral infant blood obtained after birth did not differentiate between those born to women with or without chorioamnionitis, nor did it correlate with maternal blood IL-6 levels . Clinical symptoms of the infants did not correlate with either cord or peripheral blood IL-6 values . Although maternal prepartum treatment with antibiotics and/or steroids may influence their own and their infants' blood IL-6 levels, there is insufficient evidence to consider low infant blood IL-6 level a reliable predictor to rule out early newborn sepsis.

Burns, 2000 Sep, 26(6), 521 - 4
The relationship between tumor necrosis factor (TNF)-alpha and survival following granulocyte-colony stimulating factor (G-CSF) administration in burn sepsis; Arslan E et al.; Blood levels of tumor necrosis factor (TNF)-alpha were determined in 78 patients with burn sepsis . Of these patients, 51 were managed with additional administration of granulocyte colony-stimulating factor (G-CSF) in addition to routine treatment procedures (group A), while 27 received only routine treatment (group B) . G-CSF was administrated for at least nine and at most 14 days; doses were gradually decreased in each 3 day period . On the 1st, 4th, 7th, 10th and 15th days, blood levels of TNF-alpha were determined . We sought to determine whether TNF alpha levels had a prognostic value in the management of burn induced sepsis that was treated with G-CSF . In our study, patients with gradually decreasing TNF-alpha levels in the second 3 day period, were strong candidates for survival, because TNF-alpha levels decreased little in nonsurvivors but decreased greatly in survivors . The survival rate was 42/51 (82.3%) in group A and 9/27 (33.3%) in group B . In conclusion, G-CSF had positive effects on survival, and TNF-alpha was a predictor of prognosis in burn-induced sepsis.

Ann N Y Acad Sci, 2000 May, 904, 592 - 602
Similarity of changes in body composition in intensive care patients following severe sepsis or major blunt injury; Plank LD et al.; Critically ill patients admitted to the intensive care unit with severe sepsis or major blunt injury undergo massive changes in body composition . We compared these changes in 12 patients with generalized peritonitis, and in 18 patients with major blunt injury over a 21-day period soon after their admission . Body composition was measured as soon as the patients were hemodynamically stable, and again 5, 10, and 21 days later . In both groups, losses in total body protein (TBP) were greatest over the first 10 days . TBP lost over the study period averaged 13.1 +/- 1.3 (SEM)% for the sepsis group, and 14.6 +/- 1.3% for the trauma group . Total body water (TBW) lost postresuscitation averaged 11.1 +/- 1.3 L and 6.7 +/- 1.1 L for the two groups, respectively, these changes largely being accounted for by changes in extracellular water (ECW) . Our results demonstrate a striking similarity in the changes in total body protein for these two groups of critically ill patients . The sepsis patients retained approximately twice the volume of fluid of those with major trauma.

Ugeskr Laeger, 2000 May 15, 162(20), 2872 - 5
{Non-antibiotic treatment of sepsis}; Moller K et al.; Treatment of patients with sepsis with monoclonal antibodies against lipopolysaccharide, tumour necrosis factor or treatment with soluble TNF-receptors or interleukin-1 receptor antagonist have not had any effect on mortality . Treatment with intravenous polyclonal nonspecific immunoglobulin has been shown to have beneficial efficacy on mortality . However, the number of patients included in the latter treatment studies are limited, the patients studied are heterogeneous and do not allow to conclude that sepsis patients should be routinely treated with immunoglobulins.

Arch Phys Med Rehabil, 2000 Jun, 81(6), 830 - 3
Adrenal insufficiency masquerading as sepsis in a patient with tetraparesis: a case report; Lee LW et al.; Several endocrine changes have been reported in patients with tetraplegia after spinal cord injury (SCI) . These changes should be considered when prescribing medications that influence the endocrine pathways . Megestrol acetate has gained acceptance as a way to promote weight gain in cachectic patients without significant adverse effects . We present a case of a 51-year-old man with C5-C6 tetraparesis who was only 67% of his ideal body weight and was placed on megestrol acetate 5 months before admission for a urologic procedure . Postoperatively, the patient had severe hypotension and tachycardia that was interpreted as a septic or cardiac event . Further workup revealed subnormal levels of 8AM cortisol . An adrenocorticotrophic hormone stimulation test demonstrated results consistent with adrenal suppression . Hydrocortisone supplementation was started, and 6 months later cortisol levels were within normal limits . Cachexia, hypotension, and mild tachycardia are not uncommon in patients with SCI . When severe hypotension and tachycardia are seen in patients with tetraplegia, the diagnosis of adrenal insufficiency should be considered.

Postepy Hig Med Dosw, 2000, 54(2), 119 - 32
{Prognostic markers of sepsis and septic shock}; Kubler-Kielb J et al.; The first stage of systemic inflammatory response during sepsis and septic shock is the massive production of proinflammatory cytokines . Numerous clinical trials were done investigating various agents that were thought to stop this reaction . The results, however, were disappointing . Then it was realised that massive production of antiinflammatory cytokines could also be delirious . Persistent immunosuppression in the course of sepsis increased the risk of death . Therefore the proper balance between pro- and antiinflammatory mediators is extremely important and the methodologies available for monitoring immunological status in patients with sepsis and septic shock are currently of great interest.

Res Commun Mol Pathol Pharmacol, 1999, 105(1-2), 55 - 66
Differential induction of brain heme oxygenase-1 and heat shock protein 70 mRNA in sepsis; Fujiwara T et al.; We examined gene expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), which is the rate limiting enzyme in heme catabolism and is also known as heat shock protein 32 (HSP32), in the rat brain using a sepsis model induced by bacterial lipopolysaccharide (LPS) . Intraperitoneal injection of LPS (10 mg/kg) to rats caused the elevation of body temperature and white blood cell (WBC) counts as well as marked elevation of serum interleukin-6 (IL-6) level, showing the typical pathological characteristics of sepsis . In this model, HO-1 mRNA increased at 6 h after LPS administration and continued to rise until 30 h . In contrast, HSP70 mRNA increased only between 3 h and 6 h after LPS administration, returning completely to the control level by 12 h . HO-1 mRNA was expressed predominantly in the cortex and the medulla oblongata, while HSP70 mRNA was expressed mainly in the striatum . HO-1 and HSP70 mRNA levels thus showed distinctive time courses and tissue distribution in the brain, suggesting that gene expression of these heat shock proteins (HSPs) is separately regulated.

Wien Klin Wochenschr, 2000 Apr 21, 112(8), 341 - 52
{Cortisol in critically ill patients with sepsis: physiologic functions and therapeutic implications}; Briegel J; Modern immunology reveals that cortisol interacts with the immune response at virtually all levels exerting both suppressive and permissive effects . A pre-requisite for the defense against severe infections is the functional integrity of the hypothalamic-pituitary-adrenal axis (HPAA) resulting in adequate cortisol production . There is increasing evidence that cortisol physiology and regulation are substantially altered in the course of a septic shock . Patients with septic shock may suffer from relative adrenocortical insufficiency resulting in a relative deficiency of cortisol production . In addition, the number and the affinity of cellular glucocorticoid receptors are decreased by which cortisol action at cellular level is reduced . Since septic shock and adrenal insufficiency are sharing hemodynamic abnormalities such as hyperdynamic circulation and peripheral vasodilation, the administration of stress doses of hydrocortisone appears to be a rational therapeutic approach in patients with septic shock . Controlled studies have shown that stress doses of hydrocortisone attenuate the systemic inflammatory response . In two recent double-blind studies stress doses of hydrocortisone given in patients with septic shock have been demonstrated to reduce the time to shock reversal . The most important hemodynamic effect was an increase in systemic vascular resistance . Earlier weaning from vasopressor therapy was associated with a trend towards improvements in organ function and towards decreased mortality, respectively . Large-scale trials are on the way investigating the benefit of stress doses of hydrocortisone on the mortality of septic shock . The focus of this review are changes in glucocorticoid physiology and regulation during septic shock . Effects of stress doses of hydrocortisone on immune response and vascular tone in the course of a septic shock are being discussed.

Br J Haematol, 2000 May, 109(2), 342 - 8
Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis; Robbie LA et al.; Proteins influencing plasminogen activation to plasmin, namely plasminogen activators tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and their principal inhibitors, plasminogen activator inhibitor 1 (PAI-1) and PAI-2, were measured in the plasma, the polymorph and mononuclear cell fractions taken from patients with major sepsis who were entering a general intensive care unit . The purpose of this study was to elucidate the factors favouring the persistence of fibrin in the microvasculature and thus contributing to multiple organ failure . Levels of u-PA antigen in plasma rose in sepsis and u-PA activity, not detectable in normal plasma, appeared . Levels of u-PA antigen in the cell fractions fell concomitantly . t-PA antigen in plasma and in the mononuclear cell fraction rose in sepsis, but t-PA activity was not detectable . Plasma PAI-1 antigen levels were strikingly raised in sepsis, presumably accounting for the complete neutralization of t-PA activity . PAI-2 antigen, not normally detected in plasma, appeared in the plasma of some patients, whereas it disappeared from the cellular fractions . Appearance of PAI-2 in plasma was associated with non-survival of the patient . The observations indicate that all the agents involved in plasminogen activation are released into the plasma in major sepsis . The levels of PAI-1 reached were quantitatively sufficient to suppress all activity of the released t-PA, but the inhibitors did not prevent expression of u-PA activity in the circulation . Circulating active u-PA and PAI-2 in the plasma of patients with severe sepsis may represent material originating from leucocytes . Leucocyte release of these agents within fibrin deposits may influence the persistence of fibrin and thus the development of multiple organ failure.

Shock, 2000 Jun, 13(6), 485 - 91
High doses of intravenous immunoglobulin G enhance Kupffer cell phagocytic function during the late phase of sepsis and endotoxemia in rats; Ito Y et al.; The effect of intravenous immunoglobuln G (ivIG) on the hepatic microvascular inflammatory response during the late phase of sepsis and endotoxemia in rats was studied by using in vivo microscopy . One hour after administration of a clinically relevant dose of ivIG (0.5 g/kg body weight, Sandoglobulin), rats were subjected to polymicrobial sepsis induced by cecal ligation and puncture (CLP) or were injected intravenously with lipopolysaccharide (LPS, 0.1 mg/kg body weight) . Twenty-four hours after CLP or LPS, the number of leukocytes adhering to the sinusoidal wall was increased 11.0-fold in CLP-treated animals and 5.6-fold in LPS-treated animals, respectively, compared with the controls . Concomitantly, the numbers of swollen sinusoidal endothelial cells were increased 4.2-fold and 3.2-fold . The number of perfused sinusoids was decreased by 35% and by 24% . These responses were minimized by pretreatment with high doses of ivIG . Kupffer cell phagocytic activity in the periportal sinusoids in CLP-treated animals was decreased by 41%, whereas that in the centrilobular sinusoids in LPS-treated animals was increased by 72% . IvIG significantly elevated this activity in both CLP- and LPS-treated animals and the number of ED2-positive Kupffer cells in tissue sections . The results suggest that ivIG limits the hepatic microvascular inflammatory response during the late phase of sepsis and endotoxemia by affecting Kupffer cell function.

Methods Mol Biol, 2000, 138, 319 - 30
Rabbit models of pneumonia, peritoneal sepsis, and lung injury; Frevert CW et al.; To study the mechanisms that link sepsis with ARDS, many animal models have been developed . In this chapter, a rabbit model of sepsis secondary to an intrapulmonary or intraabdominal infection has been described . One advantage of the rabbit model of sepsis is that this species produces the C-X-C chemokine, IL-8 . In contrast, rodents, which are often used in studies of sepsis and ARDS, lack this important chemokine . A second advantage is the rabbit's size . This species is large enough so that the measurement of physiological parameters (e.g., mean arterial pressure, heart rate, etc.) is not difficult, but they are not so large that they require large quantities of precious reagents (e.g., recombinant proteins and MAbs) . A disadvantage of the rabbit model is that there are fewer reagents (e.g., recombinant cytokines and MAbs) available for the study of inflammation in rabbits when compared to mice.

J Surg Res, 2000 Jun 15, 91(2), 147 - 53
Neither Fas ligand nor endotoxin is responsible for inducible peritoneal phagocyte apoptosis during sepsis/peritonitis; Chung CS et al.; Regulation of the phagocyte apoptotic response appears to play a significant role in the pathophysiology of sepsis . In this regard, prior studies have shown that the onset of phagocyte apoptosis, as well as those agents that regulate it at the nidus of infection, differ significantly from those seen in circulation . The aim of this study therefore was to determine if the increase in inducible phagocyte apoptosis and caspase activities seen in the peritoneum during sepsis is due to endotoxin or Fas ligand . To study this, male C3H/HeN (endotoxin-sensitive), C3H/HeJ (endotoxin-tolerant), and C3H/HeJ-FasL(gld) (endotoxin-tolerant/FasL-deficient) mice were subjected to cecal ligation and puncture or sham operation . Twenty-four hours later, phagocytes were collected and cultured with lipopolysaccharide (LPS), then harvested for apoptosis (propidium iodide cell cycle or cell death ELISA analysis), cytokine release (ELISA), and caspase activity (fluorogenic assay) determination . The data indicate that there was a marked increase in apoptosis in LPS-stimulated phagocytes which was associated with a significant increase in caspase 3, 8, and 9 activities but a decrease in caspase 1 activity from C3H/HeN and C3H/HeJ-FasL(gld) septic mice and an increase in caspase 3 and 8 activities in phagocytes from C3H/HeJ septic mice . Furthermore, cells from septic mice, including all three strains, lost their ability to produce IL-1beta and IL-6 in response to LPS stimulation . The inability to completely suppress these changes suggests that neither endotoxin (via signaling through TLR-4 pathway) nor Fas ligand regulates the peritoneal phagocyte apoptotic responses seen during the late phase of polymicrobial sepsis/peritonitis .

J Surg Res, 2000 Jun 15, 91(2), 141 - 6
Immune suppression in polymicrobial sepsis: differential regulation of Th1 and Th2 responses by p38 MAPK; Song GY et al.; BACKGROUND: Studies have indicated that a shift from a Th1 to a Th2 response occurs that contributes to the late immunosuppression seen during sepsis . However, the mechanism by which this occurs is unknown . In this regard, mediators released in response to sepsis are thought to upregulate a family of stress-induced mitogen-activated protein kinases (MAPKs), such as JNK, ERK, and p38 MAPK, which may play a role in this process . MATERIALS AND METHODS: To determine the role of MAPK in immune suppression, we induced polymicrobial sepsis in C3H/HeN male mice using cecal ligation and puncture (CLP) . Splenic lymphocytes were harvested 24 h post-CLP and stimulated with the T-cell mitogen concanavalin A, and the expression and activation of these MAPKs were assessed by Western analysis . To determine the extent to which these MAPKs may have an impact on splenic immune function, cells were pretreated with a 10 microM concentration of the p38 MAPK inhibitor SB203580 or the MEK inhibitor PD98059 or with DMSO vehicle . The cells were then stimulated with 2.5 microg/ml of the T-cell mitogen concanavalin A, and cytokine release was then determined (by ELISA) . RESULTS: In the lymphocytes from CLP mice no JNK signal was detected, however, p38 expression and activation were markedly (P < 0.05, n = 6) increased . In contrast, the expression of activated ERK markedly decreased following septic challenge . The results indicate that p38 MAPK inhibition with SB203580 suppressed the sepsis-induced augmentation of interleukin-10 release while restoring the suppressed Th1 cytokine interleukin-2 release typically encountered following sepsis . Inhibition of ERK had no effect on cytokine release . Neither PD98059 nor SB203580 had an effect on interferon gamma release or on proliferative capacity . CONCLUSION: This would indicate that the induction of p38 MAPK activation in splenocytes contributes to the immunosuppression seen in late sepsis .

Blood Purif, 2000, 18(2), 149 - 55
Is there a future for adsorption techniques in sepsis?
Stegmayr BG.
During sepsis toxins released from, e.g., bacteria induce reactions of various cascade systems that may cause progression of the patient into septic shock, disseminated intravascular coagulation, multiorgan dysfunction syndrome and subsequent death . The use of conventional treatments using antibiotics, fluid substitution, inotropic drugs, respiration aid and dialysis is not enough to reverse the serious prognosis . The addition of various other drugs such as antibodies against various cytokines and cytokine receptors, pentoxiphylline, immunoglobulins or high doses of steroids is usually without benefit for the prognosis of the patient . Another possibility to reduce the extent of toxins and other harmful compounds in the circulation is the use of apheresis (removal by technical devices) . This can be done either in a nonselective way (plasma exchange, plasmapheresis) or more selectively using various adsorbers such as polymyxin B . The survival in studies varies between 50 and 80% . Besides the use of nonselective apheresis, the development of various selective adsorption techniques may be one approach to improve survival of these severely ill patients .

Biochim Biophys Acta, 2000 Jun 15, 1501(2-3), 211 - 8
The dissociation between upregulated endothelins and hemodynamic responses during polymicrobial sepsis; Ornan DA et al.; Polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase . Although studies have suggested that endothelins (ETs) contribute to the development of shock after a bolus injection of endotoxin, little is known about the role of ETs in the transition from the hyperdynamic phase to the hypodynamic phase of sepsis . To study this, male adult rats were subjected to sepsis by cecal ligation and puncture (CLP) followed by fluid resuscitation . Plasma levels of ET-1 and ET-2 were measured by radioimmunoassay at 2, 5, 10 h (i.e . the early stage of sepsis), and 20 h (late stage) following CLP or sham operation . Tissue levels of ET-1 and ET-2 were determined in the heart, lungs, small intestine, and spleen at 5 h after CLP or sham operation . In addition, preproendothelin-1 (precursor of ET-1) gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) at 5 h in the heart, lungs, small intestine, spleen, and liver . The results indicate that plasma levels of ET-1 and ET-2 were not different from values of sham groups at 2 and 20 h, but were significantly higher than the sham values at 5 and 10 h after CLP . While there were no significant increases in tissue levels of ET-1 and ET-2 at 5 h post-CLP, RT-PCR analysis indicates a significant upregulation of preproendothelin-1 gene expression in the heart, spleen, and liver (but not in the lungs or small intestine) at 5 h after the onset of sepsis . These results indicate that the heart, spleen, and liver appear to be important ET-producing organs during the early stage of sepsis . The lack of significant increases in tissue ET levels could be due to the possibility that the newly converted peptide is quickly transferred to the bloodstream . Since the hyperdynamic phase of sepsis occurs at 2-10 h and the hypodynamic phase occurs at 20 h after CLP, the increased plasma levels of ET at 5 and 10 h suggest that mediators other than ETs (such as adrenomedullin) are responsible for producing the biphasic hemodynamic responses during the progression of polymicrobial sepsis.

Am J Physiol Cell Physiol, 2000 Jun, 278(6), C1191 - 9
Bioactive products of arginine in sepsis: tissue and plasma composition after LPS and iNOS blockade; Lortie MJ et al.; Blockade or gene deletion of inducible nitric oxide synthase (iNOS) fails to fully abrogate all the sequelae leading to the high morbidity of septicemia . An increase in substrate uptake may be necessary for the increased production of nitric oxide (NO), but arginine is also a precursor for other bioactive products . Herein, we demonstrate an increase in alternate arginine products via arginine and ornithine decarboxylase in rats given lipopolysaccharide (LPS) . The expression of iNOS mRNA in renal tissue was evident 60 but not 30 min post-LPS, yet a rapid decrease in blood pressure was obtained within 30 min that was completely inhibited by selective iNOS blockade . Plasma levels of arginine and ornithine decreased by at least 30% within 60 min of LPS administration, an effect not inhibited by the iNOS blocker L-N(6)(1-iminoethyl)lysine (L-NIL) . Significant increases in plasma nitrates and citrulline occurred only 3-4 h post-LPS, an effect blocked by L-NIL pretreatment . The intracellular composition of organs harvested 6 h post-LPS reflected tissue-specific profiles of arginine and related metabolites . Tissue arginine concentration, normally an order of magnitude higher than in plasma, did not decrease after LPS . Pretreatment with L-NIL had a significant impact on the disposition of tissue arginine that was organ specific . These data demonstrate changes in arginine metabolism before and after de novo iNOS activity . Selective blockade of iNOS did not prevent uptake and can deregulate the production of other bioactive arginine metabolites.

Rev Med Chil, 1999 Nov, 127(11), 1339 - 44
{Systemic inflammatory response syndrome: is it comparable with severe sepsis?}; Hernandez G et al.; BACKGROUND: In 1992, a consensus conference defined the terms systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis and septic shock . Since then, numerous reports have validated the prognostic usefulness of these operative definitions . AIM: To evaluate if sepsis severity criteria, as defined by the Consensus Conference, can be applied to noninfectious SIRS . PATIENTS AND METHODS: Five hundred eighteen patients admitted to 5 intensive care units (ICU) from 4 hospitals were prospectively evaluated during a 3 months period . Patients that met at least one severity criteria were included . SIRS etiology, organ dysfunction and evolution were recorded in each patient . RESULTS: One hundred two patients were included: 79 with sepsis (group I) and 23 with noninfectious SIRS (group II) . ICU and hospital mortality were comparable (43 and 48% in sepsis compared to 43 and 51% in non infectious SIRS) . The most common sources of sepsis were pneumonia and peritonitis . Group II patients had a wide variety of diseases . ICU stay, APACHE score and number of organs with dysfunction were not different among groups . Only the incidence of renal dysfunction was higher in the septic group . CONCLUSIONS: The Consensus sepsis severity criteria can be applied to noninfectious SIRS, defining a population subset with similar high mortality and organ dysfunction incidence, although with greatly heterogeneous etiologies.

Crit Care Med, 2000 May, 28(5), 1534 - 9
Is prostacyclin responsible for producing the hyperdynamic response during early sepsis?
Wang P, Zhou M, Cioffi WG, Bland KI, Ba ZF, Chaudry IH.
OBJECTIVE: Although polymicrobial sepsis is characterized by an early hyperdynamic phase (2-10 hrs after cecal ligation and puncture {CLP}), followed by a late hypodynamic phase (20 hrs after CLP), it remains unknown whether prostacyclin or prostaglandin I2 (PGI2) plays a significant role in modulating the hyperdynamic state during early sepsis . The aim of this study was to determine whether inhibition of PGI2 synthesis prevents the occurrence of the hyperdynamic response during early sepsis . DESIGN: Prospective, controlled animal study . SETTING: A university research laboratory . SUBJECTS: Adult male Sprague-Dawley rats were subjected to sepsis by CLP . INTERVENTIONS AND MEASUREMENTS: Blood samples were collected at 2, 5, 10, or 20 hrs after CLP, and plasma concentrations of PGI2, in the form of its stable product 6-keto-PGF1alpha, were measured by radioimmunoassay . In additional studies, a PGI2 synthase inhibitor, tranylcypromine, was administered subcutaneously at the time of CLP and again at 3 hrs after CLP . At 5 hrs after the onset of sepsis, the maximal rates of the left ventricular pressure rise (+dP/dtmax) and fall (-dP/dtmax) were determined by an in vivo heart performance analyzer . Microvascular blood flow in the liver, small intestine, and spleen was assessed by laser Doppler flowmetry . MAIN RESULTS: Plasma concentrations of 6-keto-PGF1alpha increased significantly at 2-20 hrs after CLP . At 5 hrs after the onset of sepsis, +/-dP/dt(max) and microvascular blood flow in the tested tissues increased significantly . Inhibition of PGI2 synthase activity did not prevent the occurrence of hypercardiovascular responses under such conditions . Moreover, the administration of tranylcypromine significantly reduced circulating concentrations of 6-keto-PGF1alpha at 5 hrs after CLP . CONCLUSIONS: Because inhibition of PGI2 production did not prevent the occurrence of the hyperdynamic and hypercardiovascular response during the early stage of sepsis, mediators other than PGI2 appear to play a major role in producing the hyperdynamic response under such conditions.

Crit Care Med, 2000 May, 28(5), 1276 - 82
Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia; Grobmyer SR et al.; OBJECTIVES: To document changes in serum secretory leukocyte protease inhibitor (SLPI) in human sepsis and in experimental endotoxemia in vivo . To compare changes in serum SLPI in human sepsis with changes in interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha . To determine whether or not changes in SLPI correlate with the severity of multiple organ dysfunction syndrome as measured by the maximal multiple organ dysfunction score . Finally, because neutrophils have been implicated in tissue injury associated with organ dysfunction, to determine whether recombinant human SLPI blocks activation of isolated human neutrophils . DESIGN: Case-control study and ex-vivo cellular assay . SETTING: Surgical intensive care unit and clinical research center of university hospitals; laboratory of a medical school . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: There was a significant dose-dependent elevation (50.2+/-4.0 ng/mL, p = .01) in plasma SLPI 12 hrs after administration of lipopolysaccharide to seven healthy adults (36.4+/-2.3 ng/mL) . Further, serum concentrations of SLPI (132+/-15 ng/mL) were elevated in septic surgical patients compared with healthy controls (43+/-2 ng/mL, p < .01) and nonseptic surgical controls (69+/-10 ng/mL, p = .01) . Serum SLPI concentrations correlated (r2 = .71, p < .01) better with organ dysfunction as measured by maximal multiple organ dysfunction score than did serum IL-6 (r2 = .49, p < .01), IL-10 (r2 = .05, p = .22), or TNF-alpha (r2 = .02, p = .44) . We found that recombinant human SLPI in vitro inhibits TNF-alpha-induced hydrogen peroxide production by human neutrophils (ID50 = 1-2 microg/mL) . CONCLUSIONS: Serum SLPI is elevated in human sepsis and experimental endotoxemia . Maximal concentrations of serum SLPI correlate significantly with maximal multiple organ dysfunction scores in patients with sepsis . Secretory leukocyte protease inhibitor may function to limit ongoing neutrophil-mediated tissue injury associated with organ dysfunction.

Anesteziol Reanimatol, 2000 Mar-Apr, (2), 35 - 6
{An evaluation of the circulatory indices and of the blood oxygen-transport function in relation to the level of endogenous intoxication in patients with abdominal sepsis}; Plotkin LL et al.; Septic shock in the presence of abdominal sepsis is one of the main cases of death of surgical patients . Hemodynamics was studied by impedancometry in 46 patients with abdominal sepsis . Hemodynamic changes and oxygen transporting function of the blood correlated with the severity of endogenous intoxication . Erythrocyte adsorption capacity was regarded as endogenous intoxication marker.

Ann Trop Paediatr, 2000 Mar, 20(1), 27 - 33
Alterations in antioxidant status during neonatal sepsis; Batra S et al.; Septicaemia is a major threat to survival during the early stages of life . There are several reports that suggest that reactive oxygen species (ROs) play a role in a wide variety of diseases . We estimated the activity of xanthine oxidase (XO), malondialdehyde (MDA) content, creatine phosphokinase (CPK) activity, activities of key enzymatic antioxidants, such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and peroxidase (PO), and non-enzymatic antioxidants, viz . uric acid (UA) and albumin (ALB), in 30 neonates with sepsis and 20 age-matched controls . The babies were categorized as preterm/term, early onset/late onset, and shock/without shock, as per clinical and laboratory investigations . The study was carried out to evaluate the status of antioxidant enzymes and non-enzymatic antioxidants with a view to suggesting the introduction of antioxidant therapy in neonatal sepsis . The activities of serum XO, CPK, SOD and GPx, and the content of MDA were found to be significantly elevated in the neonates with sepsis when compared with controls . Conversely, the activity of PO and the levels of UA and ALB were decreased . The septic, full-term neonates registered significantly higher CPK activity (70%) than the preterm septic neonates . However, infants with late-onset and shock sepsis had a significant decrease in CPK activity (p < 0.05) compared with their corresponding sub-groups . Likewise, UA levels were found to be 28% depressed (p < 0.05) in the babies with late-onset sepsis and 51% increased (p < 0.001) in babies with shock compared with their respective sub-groups . Neonates with septic shock also registered a significant elevation in GPx activity (28%) compared with those without shock . This study suggests increased production of ROs in neonates with sepsis, as evidenced by the positive regulation of XO, SOD and GPx activity . The elevation of antioxidant enzymes, however, was not so effective as to protect from cellular damage and thereby result in higher MDA production . It is evident that antioxidant therapy might be useful in the management of neonates with sepsis but further detailed clinico-biochemical investigations are required to define effective antioxidant therapy.

J Trauma, 2000 May, 48(5), 832 - 9; discussion 839-40
Sex differences in posttraumatic cytokine release of endotoxin-stimulated whole blood: relationship to the development of severe sepsis; Majetschak M et al.; BACKGROUND: In experimental trauma-hemorrhage and sepsis, a sexual dimorphism of cell-mediated immune functions has been described, which has been related to higher susceptibility to and mortality from sepsis in males . Therefore, in the present study, sex differences with regard to cytokine release of endotoxin stimulated whole blood and its relation to the development of severe posttraumatic sepsis were investigated in blunt trauma patients with multiple injuries . METHODS: Eighty-four patients (25 female; 59 male) sustaining blunt injuries with an Injury Severity Score > 16 were enrolled in the study . Whole blood and serum were obtained during a 14-day period of hospitalization . The capacity of peripheral blood mononuclear cells to produce cytokines (tumor necrosis factor-alpha, interleukin {IL}-6, IL-8) was tested by using a whole blood assay . Serum samples were assayed for anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor beta1) and sex hormones (testosterone, estradiol, progesterone) . Patients were monitored daily for sepsis criteria according to the ACCP/ SCCM consensus conference 1992 . RESULTS: Within the entire patient population, sex differences in posttraumatic cytokine release were not detectable . Male trauma patients developing severe sepsis (n = 16) presented with a significantly increased cytokine producing capacity in the early posttraumatic period (< or = 24 hours after admission to the emergency room) when compared with males with an uncomplicated recovery . In females, differences between the subgroups of patients with (n = 7) and without development of severe sepsis were not detectable . There were no differences in systemic levels of anti-inflammatory cytokines within the early posttraumatic period between the subgroups of male and female patients with and without development of severe sepsis . In females, differences in sex hormone levels were not detectable, whereas in males, development of severe sepsis later was found to coincide with significantly decreased testosterone and increased estradiol serum levels . CONCLUSION: The present study demonstrates a sex-specific regulation of leukocyte function in patients with multiple injuries within the early posttraumatic period . In male patients with multiple injuries, increased cytokine-producing capacities may correspond to enhanced inflammatory responses, which increase susceptibility to sepsis, whereas in female patients, other regulatory mechanisms may be involved.

J Trauma, 2000 May, 48(5), 826 - 30; discussion 830-1
Prostaglandin E2 receptor antagonist (SC-19220) treatment restores the balance to bone marrow myelopoiesis after burn sepsis; Santangelo S et al.; BACKGROUND: Although prostaglandin E2 (PGE2) has been shown to be immunosuppressive, its role in the development of specific bone marrow myeloid lineages after thermal injury and sepsis has yet to be elucidated . The purpose of this study was to demonstrate that alterations in bone marrow progenitor proliferation favoring monocytopoiesis in burn sepsis can be restored by blocking the cellular interactions of PGE2 . METHODS: A murine model of burn sepsis with and without treatment with SC-19220, a PGE2 receptor antagonist, was used to determine peripheral monocyte and neutrophil counts as well as the colony forming potential of colony-stimulating factor responsive bone marrow progenitors . RESULTS: Burn sepsis augmented the growth of the early colony-forming unit granulocyte-macrophage and monocyte progenitors and the number of circulating monocytes, whereas granulocyte progenitors and circulating neutrophils demonstrated an opposite response . Treatment with SC-19220 nearly reversed these alterations . CONCLUSION: These data indicate that abrogating PGE2's actions during burn sepsis can restore the balance in bone marrow granulocyte and monocyte production, further consolidating the pivotal role PGE2 plays in the pathogenesis of burn sepsis.

Microbes Infect, 2000 Apr, 2(4), 409 - 15
Sepsis: the critical role of iron; Bullen J et al.; Sepsis is a global problem which is exacerbated by increasing bacterial resistance to antibiotics . However, mechanisms of natural resistance can be extremely effective, and need to be exploited, but the availability of iron is critical for controlling bacterial growth . The diagnosis of sepsis and possible strategies for limiting iron availability are discussed.

J Surg Res, 2000 Jun 1, 91(1), 70 - 6
Mechanism of the beneficial effects of pentoxifylline during sepsis: maintenance of adrenomedullin responsiveness and downregulation of proinflammatory cytokines; Koo DJ et al.; BACKGROUND: Although it is known that pentoxifylline (PTX) produces various beneficial effects during sepsis, it remains unknown whether this agent has any salutary effects on the depressed vascular responsiveness to adrenomedullin (ADM), a novel potent vasodilatory peptide, under such conditions . MATERIALS AND METHODS: Adult male Sprague-Dawley rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) . One hour after CLP, PTX (50 mg/kg body wt) or vehicle (normal saline) was infused intravenously over 90 min . Twenty hours after CLP (i.e., the late, hypodynamic stage of sepsis), the thoracic aorta and small intestine were isolated and preconstricted by norepinephrine . Rat ADM (10(-7) M) was applied, and the percentage of ADM-induced relaxation in the aortic rings and resistance vessels in the small intestine was determined . In addition, plasma ADM was determined by radioimmunoassay and tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 levels were measured by enzyme-linked immunosorbent assay . RESULTS: The percentage of ADM-induced vascular relaxation in the aortic rings and resistance vessels of the isolated gut was significantly reduced 20 h after CLP . Administration of PTX early after the onset of sepsis, however, prevented the decrease in vascular ADM responsiveness at the macro- and microcirculatory levels . Plasma ADM levels increased after CLP, irrespective of PTX infusion, indicating that the effect of PTX was not mediated by altering ADM release . The upregulated TNF-alpha, IL-1beta, and IL-6 during late sepsis were, however, attenuated by PTX administration, suggesting that maintenance of ADM responsiveness by this agent appears to be due to downregulation of these cytokines . CONCLUSIONS: Since early administration of PTX maintains vascular ADM responsiveness even during the late stage of sepsis, this agent appears to be a useful adjunct in preventing the deterioration in hemodynamics and cardiovascular function during the progression of polymicrobial sepsis .

Wound Repair Regen, 2000 Mar-Apr, 8(2), 103 - 9
Growth hormone does not attenuate the inhibitory effects of sepsis on wound healing; Stamm J et al.; Chronic abdominal sepsis is associated with impaired tissue repair . Treatment of burn patients with growth hormone results in improved healing of skin graft donor sites . The goal of this study was to determine whether administration of growth hormone could attenuate the inhibitory effects of sepsis on cutaneous wound healing . Four groups of male Sprague Dawley rats were studied: control, control + growth hormone, sepsis, and sepsis + growth hormone . Sepsis was caused by implantation of a bacterial focus in the peritoneal cavity . Control animals underwent sham laparotomy, and polyvinyl alcohol sponge implants were placed in subdermal pockets in all animals . Saline or growth hormone (400 microg) was injected subcutaneously every 12 hours . On day 5, the incisional wounds and polyvinyl alcohol sponge implants were harvested . The breaking strength of abdominal incisions was measured . Granulation tissue penetration and quality were determined by scoring polyvinyl alcohol sponge implant histology from 1 to 4 in a blinded fashion . Collagen deposition in polyvinyl alcohol sponge implants was quantitated by hydroxyproline assay . Septic mortality was not altered by growth hormone administration . Septic animals showed a reduction in food consumption for 2 days after surgery (p < 0.05 vs . controls), which was not affected by growth hormone administration . The breaking strength of incisional wounds and hydroxyproline content of polyvinyl alcohol sponge implants was reduced in septic rats (p < 0.001 vs . controls) but administration of growth hormone for 5 days did not improve breaking strength or collagen deposition in either group . We conclude that the administration of growth hormone for 5 days did not improve collagen deposition or breaking strength in cutaneous wounds from control or septic animals . The results suggest that growth hormone treatment is unlikely to improve tissue repair in sepsis-induced catabolic illness.

J Am Geriatr Soc, 2000 May, 48(5 Suppl), S140 - 5
Dying with acute respiratory failure or multiple organ system failure with sepsis; Somogyi-Zalud E et al.; BACKGROUND: The dying experience of patients with acute respiratory failure (ARF) or multiple organ system failure with sepsis (MOSF) has not been described . OBJECTIVES: To describe patients dying from ARF or MOSF, including demographic characteristics, baseline function and quality of life, symptoms, preferences, use of life-sustaining treatments, satisfaction with care, and family burden . DESIGN: A multicenter prospective study . SETTING: Five US teaching hospitals, in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) . PARTICIPANTS: A total of 1295 adults who died during hospitalization for ARF or MOSF . MEASUREMENTS: Chart reviews and interviews with patients and surrogates . RESULTS: SUPPORT enrolled 2956 patients with ARF or MOSF, and 44% died during enrollment hospitalization . Quality of life before hospitalization was reported as fair by 87% of patients . The mean number of impairments in their baseline activities of daily living was 1.6 . At the time of death, 79% had a DNR order and 31% had an order to withhold ventilator support . The average time from the DNR order to death was 2 days . Dying patients spent an average of 9 days on a ventilator . Surrogates indicated that one out of four patients died with severe pain and one out of three with severe confusion . Families of 42% of the patients who died reported one or more substantial burden . CONCLUSIONS: Patients in this study reported substantial functional impairments and reduced quality of life . Limitations to aggressive treatments were usually implemented only when death was imminent . Family impact and physical and emotional suffering were substantial.

Crit Care Med, 2000 Apr, 28(4), 977 - 83
Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit; Muller B et al.; OBJECTIVE: The diagnosis of infection in critically ill patients is challenging because traditional markers of infection are often misleading . For example, serum concentrations of calcitonin precursors are increased in patients with infections . However, their predictive accuracy for the diagnosis of sepsis in unselected patients in a medical intensive care unit (ICU) is unknown . Therefore, we compared the usefulness of serum concentrations of calcitonin precursors, C-reactive protein, interleukin-6, and lactate for the diagnosis of sepsis in consecutive patients suffering from a broad range of diseases with an anticipated stay of > or =24 hrs in a medical ICU . DESIGN: Prospective cohort study . SETTING: Medical intensive care unit in a university medical center . PATIENTS: 101 consecutive critically ill patients . INTERVENTION: None . MEASUREMENTS AND MAIN RESULTS: Blood samples were collected at various time points during the course of the disease . Systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock were diagnosed according to standardized criteria, and patients were reclassified daily without prior knowledge of the serum concentrations of calcitonin precursors or interleukin-6 . At admission, 99% of the patients had systemic inflammatory response syndrome, 53% had sepsis, and 5% developed sepsis during their stay in the ICU . Calcitonin precursors, C-reactive protein, interleukin-6, and lactate levels increased with the severity of infection (p < .01, one-way analysis of variance) . In a receiver operating characteristic curve analysis, calcitonin precursors were found to be the most reliable laboratory variable for the diagnosis of sepsis as compared with C-reactive protein, interleukin-6, and lactate (p < .01, for each comparison) . Calcitonin precursor concentrations of >1 ng/mL had sensitivity of 89% and specificity of 94% for the diagnosis of sepsis . High serum concentrations of calcitonin precursors were associated with poor prognosis (p = .01) . CONCLUSIONS: In a medical ICU, serum calcitonin precursor concentrations are more sensitive and are specific markers of sepsis as compared with serum C-reactive protein, interleukin-6, and lactate levels.

Crit Care Med, 2000 Apr, 28(4), 950 - 7
Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients; Wanner GA et al.; OBJECTIVE: To compare procalcitonin (PCT) plasma levels of injured patients with the incidence and severity of systemic inflammatory response syndrome (SIRS), infection, and multiple organ dysfunction syndrome (MODS) and to assess the predictive value of PCT for these posttraumatic complications . DESIGN: Retrospective study comparing patients with mechanical trauma in terms of severity of injury, development of infectious complications, and organ dysfunctions . SETTING: Level I trauma center with emergency room, intensive care unit, and research laboratory . PATIENTS: Four hundred five injured patients with an Injury Severity Score of > or =9 points were enrolled in this study from January 1994 to February 1996 . INTERVENTIONS: Blood samples were collected on the day of admission and on days 1, 3, 5, 7, 10, 14, and 21 thereafter . MEASUREMENTS AND MAIN RESULTS: We determined PCT serum levels using a specific immunoluminometric assay . We retrospectively evaluated the occurrence of SIRS, sepsis, and MODS using patients' charts . Mechanical trauma led to increased PCT plasma levels dependent on the severity of injury, with peak values on days 1 and 3 (p < .05) and a continuous decrease within 21 days after trauma . Patients who developed SIRS demonstrated a significant (p < .05) increase of peak PCT plasma levels compared with patients without SIRS . The highest PCT plasma concentrations early after injury were observed in patients with sepsis (6.9+/-2.5 ng/mL; day 1) or severe MODS (5.7+/-2.2 ng/mL; day 1) with a sustained increase (p < .05) for 14 days compared with patients with an uneventful posttraumatic course (1.1+/-0.2 ng/mL) . Moreover, these increased PCT plasma levels during the first 3 days after trauma predicted (p < .0001; logistic regression analysis) severe SIRS, sepsis, and MODS . CONCLUSIONS: These data indicate that PCT represents a sensitive and predictive indicator of sepsis and severe MODS in injured patients . Routine analysis of PCT levels seems to aid early recognition of these posttraumatic complications . Thus, PCT may represent a useful marker to monitor the inflammatory status of injured patients at risk.

Zhonghua Wai Ke Za Zhi, 1997 Jul, 35(7), 398 - 401
{Prospective study of central venous catheter-related sepsis in critically ill patients}; Du B et al.; To evaluate the incidence of central venous catheter-related sepsis (CRS) in critically ill patients, we performed a prospective study of the central venous catheters (CVCs) in ICU of the Peking Union Medical College Hospital from Jan . 1995 to March 1996 . Of 151 CVCs, 13 (8.6%) had CRS, with an incidence of 16.7 episodes per 1000 catheter-days . Presence of infectious focus at catheterization, catheter insertion site, duration of catheterization, and the decrease of body temperature after catheter removal correlated with definite CRS, while difficulty of insertion, body temperature at catheter removal, as well as the decrease of body temperature after catheter removal correlated well with no CRS . The study showed that CRS is a serious problem in critically ill patients . Careful manipulation of CVCs is a major determinant in reducing the incidence of CRS.

Crit Care Med, 2000 Apr, 28(4 Suppl), N105 - 13
Apoptosis in sepsis; Mahidhara R et al.; Sepsis demonstrates a marked dysregulation of the immune system in its ability to fight infection . Previous models have focused on the mechanisms which upregulate and sustain the heightened immune response without addressing the role of down-regulation effectors . Attention has been drawn to these down-regulating mechanisms and their precise role in the pathophysiology of sepsis . Apoptosis is an evolutionarily conserved, energy-dependent mode of cell death requiring the initiation and regulation of complex genetic programs . It is the body's main method of getting rid of cells which are in excess, damaged, or no longer needed in a controlled manner . The role of this cellular phenomenon in physiology and pathophysiology has been the subject of intense scrutiny over the last decade . Much work has demonstrated that dysregulation of apoptosis does occur in immune and nonimmune cells in in vitro and in vivo models of sepsis . The difficulty has been in tying the phenomenology of apoptosis into the pathophysiology of sepsis . Further work is needed to make these connections to elucidate rational approaches for clinical applications of immunomodulation in sepsis.

Shock, 2000 May, 13(5), 404 - 9
Proinflammatory cytokines increase in sepsis after anti-adhesion molecule therapy; Welty-Wolf KE et al.; Cytokine mediators and leukocyte-endothelial cell adhesion molecules are critical and interdependent components of the acute inflammatory response in sepsis . We hypothesized that the administration of monoclonal antibodies to intercellular adhesion molecule-1 (CD54) or E- and L-selectin (CD62E/L) would decrease serum levels of the proinflammatory cytokines interleukin-1beta (IL-1), IL-6, and IL-8 and tumor necrosis factor receptor (TNFR-1) in baboons during sepsis . Adult male baboons received infusions of 1 x 10(9) colony forming units (CFU)/kg heat-killed Escherichia coli (E . coli) followed 12 h later by live E . coli (1 x 10(10) CFU/kg) . At the time of live bacterial infusion, six septic animals were treated with a monoclonal antibody to CD54 and six with an antibody to CD62E and L (1 mg/kg) . Eight untreated septic animals served as controls . Sequentially drawn serum samples were assayed for IL-1, IL-6, IL-8, and TNFR-1 using enzyme-linked immunoassay (ELISA) . Data were compared using Mann-Whitney U tests and Chi-square analyses . Median survival was decreased in both treatment groups compared to controls (P < 0.05) . Peak IL-1 level was higher than controls in septic animals treated with anti-CD54 but not anti-CD62E/L (P < 0.05, P = NS, respectively) . Elevations in IL-6, IL-8, and TNFR-1 were increased and prolonged in both antibody treated groups compared to controls (P < 0.05) . These results provide the first in vivo evidence that leukocyte-endothelial adhesion molecules CD54 and CD62E/L regulate cytokine production in sepsis.

Shock, 2000 May, 13(5), 379 - 85
Alterations in tissue glucose uptake during the hyperglycemic and hypoglycemic phases of sepsis; Maitra SR et al.; The purpose of the present study was to characterize the alterations in tissue glucose uptake during the hyperglycemic, euglycemic, and hypoglycemic phases of peritonitis . Rats had vascular catheters implanted, and sepsis was induced by cecal ligation and puncture . Rates of whole-body glucose appearance (Ra), disappearance (Rd), and metabolic clearance (MCR) were determined by the constant infusion of 3H-glucose, and in vivo glucose uptake (Rg) by individual tissues was assessed by using 14C-deoxyglucose . During the hyperglycemic phase of sepsis (2 h), glucose Ra and Rd were increased, but glucose MCR was unaltered . In contrast, during the euglycemic phase (6 h), the sepsis-induced increase in glucose Ra and Rd was associated with an elevation in the MCR . Finally, during the hypoglycemic phase (24 h), sepsis decreased glucose Ra and Rd and the glucose MCR . The sepsis-induced changes in Rg for skeletal muscle and adipose tissue mimic those seen for the whole body at each time point . Rg for skin and intestine was elevated at 2 h and 6 h but was not different from control values at 24 h . In contrast, the Rg for liver, lung, and spleen was increased at all 3 time points . In a second study, there was no difference in Rg for any tissue between 2-h septic rats and control animals in which blood glucose and insulin levels were artificially elevated to the same degree . In a third study, the prevailing glucose and insulin levels in control animals were decreased, by injection of the gluconeogenic inhibitor 3-mercaptopicolinic acid, to levels seen in 24-h septic rats . There was no difference in the Rg for muscle and adipose tissue between 24-h septic rats and hypoglycemic insulinopenic control animals . However, the Rg for liver, lung, and spleen remained elevated in 24-h septic rats, compared with hypoglycemic insulinopenic control values . These data indicate that the increased tissue glucose uptake observed during the early phase of sepsis is a consequence of concomitant changes in plasma glucose and insulin . In contrast, during the euglycemic and hypoglycemic stages of sepsis, glucose uptake in macrophage-rich tissues remains elevated and is independent of changes in glucose and insulin.

Am J Respir Crit Care Med, 2000 May, 161(5), 1602 - 7
Influence of rheologic changes and platelet-neutrophil interactions on cell filtration in sepsis; Kirschenbaum LA et al.; We examined the role of erythrocyte (red blood cell; RBC) aggregation and deformability, neutrophil (polymorphonuclear neutrophil; PMN) deformability, whole-blood viscosity, and platelet-neutrophil interactions on cell filtration in subjects who were critically ill with sepsis (CIS), critically ill noninfected subjects (CINS), and healthy controls (C) . We assessed cell deformability by filtration through filters of 5-microm pore size . Whole blood, RBC, PMN, and combinations of PMN and RBC were studied . Viscometry was done on isolated RBC . Platelet-PMN interactions were assessed with monoclonal antibodies to CD41 and activated CD63 platelet receptors, and to CD66b PMN receptors . Filtration pressure (Pi) for CIS was significantly greater than for C and CINS at both high and low PMN and RBC concentrations . Viscometry confirmed decreases in RBC deformability and demonstrated significant increases in RBC aggregation in CIS . Increments in Pi were significantly greater with PMN and PMN-RBC combinations suspended in platelet rich plasma (PRP) than in platelet poor plasma (PPP) for CIS as compared with CINS or C . Flow cytometry confirmed significantly greater platelet activation in CIS than in CINS or C (mean fluorescence: 39 +/- 9 lfu versus 18.7 +/- 4.0 lfu and 17.1 +/- 2.3 lfu, respectively) and greater platelet-PMN aggregation (mean fluorescence: 44.7 +/- 3.6 lfu versus 23 +/- 4.1 lfu, respectively) in CIS than in C . We conclude that decreased filtration of whole blood in CIS is related to decreases in RBC and PMN deformability, increases in RBC aggregation, and increased platelet-PMN interactions . Of these, the formation of platelet-PMN aggregates appeares to have the greatest effect in impairing cell filtration . These rheologic abnormalities may contribute to impaired microvascular blood flow in patients with sepsis.

Ren Fail, 2000 Mar, 22(2), 225 - 34
Polymyxin b-immobilized fiber reduces increased plasma endothelin-1 concentrations in hemodialysis patients with sepsis; Nakamura T et al.; We studied whether plasma endothelin (ET)-1 concentrations are altered in patients with septic shock who are undergoing hemodialysis and whether polymyxin B-immobilized fiber (PMX-F) treatment affects on these concentrations . Fifteen hemodialysis patients with septic shock treated with PMX-F (group A), 10 such patients who received conventional treatments (group B), 20 hemodialysis patients without septic shock (group C) and 20 healthy controls (group D) were included in this study . Plasma ET1 levels were measured by radioimmunoassay and endotoxin levels were determined by endospecy test . The survival rate in group A (67%) was higher than that in group B (30%) . Blood endotoxin levels decreased significantly from 36.4+/-8.2 pg/mL to 10.6+/-3.8 pg/mL (p < 0.01) after PMX-F treatment in group A . The pretreatment plasma ET-1 levels in patients in group A (58.6+/-9.8 pg/mL) and group B (56.8+/-7.8 pg/mL) were significantly higher than those in group C (p < 0.01) and group D (p < 0.001) . Plasma ET-1 levels in group C (11.2+/-3.2 pg/mL) were higher than those in group D (2.6+/-0.6 pg/mL) (p < 0.01) . Plasma ET-1 levels following hemodialysis (10.9+/-3.0 pg/mL) were not altered significantly compared with those before hemodialysis . Plasma ET-1 levels decreased significantly in group A after PMX-F treatment (11.4+/-3.6 pg/mL) (p < 0.01); the levels in group B were not altered after conventional treatment . Our data suggest that ET-1 may be associated with septic shock in patients undergoing hemodialysis and that PMX-F is effective in reducing plasma ET-1 levels in these patients.

Microcirculation, 2000 Apr, 7(2), 83 - 101
Microvascular dysfunction in sepsis; Lush CW et al.; The microvascular dysfunction which occurs in sepsis involves all three elements of the microcirculation: arterioles, capillaries, and venules . In sepsis, the arterioles are hyporesponsive to vasoconstrictors and vasodilators . Sepsis also reduces the number of perfused capillaries, thereby impacting on oxygen diffusion to mitochondria . In the venules of some tissues (e.g., mesentery) there is an inflammatory response characterized by neutrophil infiltration and protein leakage . In addition, PMN-endothelial adhesive interactions occur in precapillary microvessels and capillaries in organs, such as, the lung and heart . Thus, all these elements of the microcirculation are involved in the sepsis-induced inflammation . In this review we address emerging views on the mechanisms involved in the microvascular dysfunction induced by sepsis within the framework of these three basic elements of the microcirculatory unit.

J Nutr, 2000 May, 130(5), 1239 - 46
Glutathione turnover is increased during the acute phase of sepsis in rats; Malmezat T et al.; Glutathione metabolism during infection has been poorly documented . Glutathione concentrations and synthesis rates were studied in infected rats (2 d after infection) and in pair-fed controls . Glutathione synthesis rates were determined in liver, spleen, lung, small and large intestine, skeletal muscle, heart and blood by a 4-h or 6-h (15)N cysteine infusion . The activities of four hepatic enzymes involved in glutathione metabolism were also determined . Glutathione synthesis rates were significantly greater in liver (+465%), spleen (+388%), large intestine (+109%), lung (+100%), muscle (+91%) and heart (+80%) of infected rats compared with pair-fed controls . Glutathione concentrations were also greater in these tissues but were unaffected in small intestine and lower in blood . In keeping with the stimulation of liver glutathione synthesis, the activities of liver gamma-glutamyl-cysteine synthetase and glutathione reductase were significantly greater in liver of infected rats than of pair-fed rats . From the present study, we estimate that glutathione synthesis accounts for at least 40% of the enhanced cysteine utilization during infection . This increased utilization may be the primary cause of an enhanced cysteine requirement in infection.

Khirurgiia (Mosk), 2000, (4), 36 - 40
{Sepsis . Evaluation of views, necessity of terminology unification and diagnostic criteria}; Runov VA; Critical analysis of modern overview devoted to general infectious-inflammatory process and materials of original research (690 patients) provides a basis for discussion of diagnostic criteria of and new terminology . Wide introduction of researches on classification, criteria of diagnosis and terminology offered by North American conference (R . Bone et al., 1992) into practice is recommended . The given definitions better reflect the essence of homeostatic disorders in septic patients, allow to carry out early change of the program of treatment, to standardize approaches to diagnosis, monitoring and therapy and enable search in epidemiology of sepsis, choice of the best ways of scientific investigation.

J Pak Med Assoc, 2000 Mar, 50(3), 94 - 8
Rapid identification of neonatal sepsis; Anwer SK et al.; OBJECTIVE: To achieve rapid identification of neonatal sepsis . SETTING: Neonatal Intensive care unit (NICU) of a teaching hospital . METHOD: We evaluated fifty neonates who were admitted with clinical features suggesting sepsis or who had principal risk factors, e.g . Prematurity (< 36 weeks), Low birth weight (< 2.5 kg), H/o maternal pyrexia or prolonged rupture of membranes, birth asphyxia, unbooked cases or instrumentation . Five tests, i.e., Total Leukocyte Count (T.L.C.), Absolute Neutrophil Count, Immature/Total Neutrophil ratio (I.T . ratio), Platelet count and C-Reactive protein were used for rapid diagnosis of neonatal sepsis . RESULTS: C-reactive protein (C.R.P.) and absolute Neutrophil count had a sensitivity of over 60% with a specificity of 50% . White blood cell count had a specificity of 93% but a sensitivity of 14% . CONCLUSION: None of the tests used alone were reliable, but when in combination these five tests may help to diagnose sepsis within a few hours . Also, if the tests show a high negative predictive value, the neonate can be discharged early from the hospital, stopping the antibiotics, thereby reducing the cost of treatment and anxiety of the family.

Intensive Care Med, 2000, 26 Suppl 1, S124 - 8
Immunomodulatory therapies in sepsis; Kox WJ et al.; Despite advances in critical care medicine, mortality from sepsis in ICU patients remains high . In response to several infectious and non-infectious stimuli, monocytes/ macrophages release a number of mediators, including cytokines, involved in the proinflammatory response that underlies sepsis . The excessive release of these mediators results in the development of whole body inflammation, and plays an important role in the pathogenesis of sepsis and septic shock . In addition, patients with sepsis also undergo an anti-inflammatory phase (the compensatory anti-inflammatory response syndrome) and at times, a mixed response with both pro-and anti-inflammatory components (the mixed antagonistic response syndrome) . The initial systemic hyperinflammation is caused by production of inflammatory cytokines, especially tumour necrosis factor-a (TNF-alpha), and also interleukin-1 (IL-1), IL-6, and interferon gamma, which act synergistically with TNF-alpha in inducing shock in animal models . However, clinical trials aimed at downregulating these mediators using antibodies against endotoxin, TNF-alpha, antagonists of IL-1 or platelet activating factor have proved to be uniformly disappointing . Not only have these agents been found to have no effect, but they may also increase mortality . One of the reasons for such failure may be the lack of precise immunological monitoring during the course of sepsis . We have recently demonstrated that sepsis shows a biphasic immunological pattern during the initial and later phase: the early hyperinflammatory phase is counterbalanced by an anti-inflammatory response which may lead to a hypoinflammatory state . The latter is associated with immunodeficiency that is characterised by monocytic deactivation, so-called immunoparalysis . Interferon gamma-1 b has an immunoregulatory effect in patients with immunoparalysis during the compensatory anti-inflammatory response syndrome, not only restoring levels of HLA-DR expression but also reestablishing the ability of monocytes to secrete cytokines such as TNF-alpha . By monitoring immune status in septic patients, targeted intervention may lead to more success in immunomodulation of sepsis.

Intensive Care Med, 2000, 26 Suppl 1, S75 - 83
Clinical trials of mediator-directed therapy in sepsis: what have we learned?
Marshall JC.
Almost 60 randomized controlled clinical trials have been undertaken, testing the hypothesis that modulation of the endogenous host inflammatory response can improve survival for patients with a clinical diagnosis of sepsis . The results have been tantalizing, but frustrating, and no new agent has been introduced into clinical practice . Analysis of pooled data from studies of the use of an neutralizing antibody to tumor necrosis factor, or recombinant interleukin 1 receptor antagonist, show that these two approaches yield a statistically significant, but small improvement in 28 day all-cause mortality . However variability in results from one study to the next, the small absolute mortality reduction, the emerging evidence of a substantial potential for harm, and the predicted costs of recombinant biologic agents has engendered a climate of caution and pessimism . The challenge is to find methods of refining investigative approaches to maximize benefit and minimize harm . This paper reviews the recent history of sepsis clinical trials, focussing on emerging insights into the limitations of study entry criteria and measures of biologic activity and clinical benefit that may inform and direct future investigations . The biologic complexity of systemic inflammation, and the multiple interactions between clinical biology and the process of care suggest that future success in clinical research in sepsis will occur through the conduct of highly focussed investigations in a small number of dedicated centres of excellence.

Intensive Care Med, 2000 Feb, 26(2), 167 - 72
Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome; Wichmann MW et al.; OBJECTIVE: Laboratory studies demonstrated significant detrimental effects of male sex-steroids (testosterone) on immune functions following hemorrhagic shock and soft-tissue trauma . Moreover, better survival of female mice subjected to severe sepsis was observed when compared to male animals . The aims of the present study were to evaluate whether or not gender differences regarding incidence and mortality of severe sepsis do exist in surgical intensive care patients and to elucidate the influence of patient age on incidence and mortality of severe sepsis/septic shock . DESIGN: Data base review of prospectively collected data from surgical intensive care patients . SETTING: Surgical intensive care unit of the department of surgery of a university hospital . PATIENTS: Prospectively collected data of 4,218 intensive care patients (2,709 male, 1,509 female) . RESULTS: Significantly fewer female patients were referred to the intensive care unit (6.6 % vs 10.8 % of all patients; P < 0.05) leading to a significantly smaller proportion of female intensive care patients (35.8% vs 64.2%) . No gender differences regarding number of failing organs or surgical procedure (exception vascular surgery) were observed in patients with and without severe sepsis/septic shock, indicating that the patients studied are comparable regarding general health prior to admission to SICU . Among all female patients referred to SICU only 7.6 % developed severe sepsis/septic shock, while 10.4% of all male patients suffered from severe sepsis or septic shock (P < 0.05) . This gender difference results from a significantly lower incidence of severe sepsis/ septic shock in female patients between 60 and 79 years . No gender difference regarding mortality rates of severe sepsis/septic shock was observed (men 64.9 %, women 65.5%) . CONCLUSIONS: Our results indicate a significantly smaller number of female patients requiring intensive care as well as a significantly lower incidence of severe sepsis/septic shock in female intensive care patients . Mortality from severe sepsis/ septic shock, however, is not affected by gender.

Rev Hosp Clin Fac Med Sao Paulo, 1999 Jul-Aug, 54(4), 135 - 8
Low blood glucose levels and other complications during growth hormone supplementation in sepsis; Faintuch J et al.; Blood glucose levels in the high normal range or even moderate hyperglycemia is the expected profile in septic postoperative patients receiving high-calorie enteral alimentation . The addition of growth hormone as an anabolic agent should additionally reinforce this tendency . In a cancer patient undergoing partial gastrectomy with lymphadenectomy and suffering from postoperative subphrenic abscess and prolonged sepsis, tube feeding (38.3 kcal/kg/day) and growth hormone (0.17 IU/kg/day) were simultaneously administered for 25 days . Blood glucose levels were in the lower limits of the normal range before growth hormone introduction, and continued with a similar tendency during most of the therapeutic period . Two additional complications, namely heart arrest and peripheral edema, were documented during the same period . It is concluded that sepsis was the most likely mechanism for low glucose values, and that high-calorie enteral diet and growth hormone supplementation did not prevent that result . It is uncertain whether heart arrest was due to the drug, but its association with peripheral edema is well documented in clinical series.

Biochem Biophys Res Commun, 2000 Apr 29, 271(1), 197 - 202
Decreased gene expression of adrenomedullin receptor in mouse lungs during sepsis; Ono Y et al.; Plasma concentrations of adrenomedullin (AM) are markedly increased during sepsis, but the role of AM has not been clarified . Coexpression of calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP) 2 or 3 have been reported to form the adrenomedullin (AM) specific receptor . We examined the expression of CRLR and RAMP1, 2, and 3 in several tissues from mice in a sepsis model induced by lipopolysaccharide (LPS) . High expression of CRLR and RAMP2 mRNA was observed in lungs of normal mice, but it was markedly decreased in endotoxemic mice . It is suggested that the abundant binding sites of AM in lungs are formed by CRLR and RAMP2 in healthy subjects and that their reduction should contribute to the increase of plasma AM concentrations during sepsis . In contrast, LPS treatment markedly increased RAMP3 gene expression in lungs, spleen, and thymus . It is revealed that the distributions of receptor or binding sites of AM are changed in sepsis, and it is suggested that AM plays distinct roles in the clinical course of this syndrome .

Shock, 2000, 13(4), 325 - 9
Upregulation of inducible nitric oxide synthase and nitric oxide occurs later than the onset of the hyperdynamic response during sepsis; Shieh P et al.; Polymicrobial sepsis is characterized by an early, hyperdynamic phase (i.e., 2-10 h after cecal ligation and puncture {CLP}) followed by a late, hypodynamic phase (16 h after CLP or later) . Although nitric oxide (NO) plays an important role in the pathophysiologic response during sepsis, it remains unknown how early NO is upregulated after the onset of sepsis and which organs are responsible for producing the increased amount of NO . To study this, male rats were subjected to sepsis by CLP followed by fluid resuscitation . Blood samples were then taken at 2, 5, 10, or 20 h after CLP or sham operation . In additional groups of animals, the kidneys, small intestine, heart, liver, and lungs were harvested at 5 or 10 h after CLP . Plasma and tissue levels of nitrate and nitrite (NO3-/NO2-, stable products of NO) were determined by using a colorimetric assay . Inducible NO synthase (iNOS) mRNA was examined in various tissues harvested at 10 h after CLP by reverse transcription-polymerase chain reaction (RT-PCR) technique . The results indicate that plasma levels of NO3-/NO2- (mainly reflecting iNOS activity) did not increase at 2-5 h but were significantly elevated at 10-20 h after CLP . Tissue levels of NO3-/NO2- increased significantly in the kidneys, small intestines, heart, and liver at 10 h but not at 5 h after CLP . Similarly, iNOS gene expression was upregulated in the kidneys, small intestines, and liver . Thus, the above organs appear to be important sites responsible for producing the increased NO during sepsis . Because we previously showed that the hyperdynamic response occurs as early as 2 h after CLP and because iNOS-derived NO production is not upregulated earlier than 10 h after the onset of Sepsis, it appears that factors other than NO are responsible for producing the hyperdynamic response during sepsis.

World J Surg, 2000 Jun, 24(6), 655 - 63
Overview of modern management of patients with critical injury and severe sepsis; Streat SJ et al.; Over the last 10 years there have been substantial changes in the issues confronting intensivists and surgeons caring for critically ill patients . A substantial increase in the number of elderly patients with surgical illness and complex co-morbidity has accompanied the increase in the proportion of elderly in populations in the developed world . This phenomenon has been seen particularly with sepsis . Incidence rates for blunt trauma have declined overall, but the problems of the elderly trauma patient have become more evident . Major elective surgery remains a common indication for short-term intensive care in many countries, but the need for cost-containment has led to increased use of high-dependency care for many such patients . Expectations of both society and clinicians have increased, and this has been reflected in the increased demand for complex procedures (e.g., liver transplantation, cerebral artery aneurysm clipping, aortic aneurysm repair) in patients previously considered at too high risk . Along with these expectations have come pressures on clinicians to reduce costs at the same time as improving clinical outcomes . Despite many advances in the care of critically ill patients with injury or sepsis, mortality, morbidity, and cost remain high; and nutritional support is frequently required . The duration and extent of the metabolic changes seen in response to critical surgical illness and intensive care treatments have become better characterized . Although some of the changes in body water and fat are modifiable, loss of large amounts of (functional) protein has been resistant to various strategies so far studied.

World J Surg, 2000 Jun, 24(6), 630 - 8
Sequential metabolic changes following induction of systemic inflammatory response in patients with severe sepsis or major blunt trauma; Plank LD et al.; We have recently completed studies in critically ill patients with severe sepsis or major trauma that investigated sequential changes in the metabolic response following admission to the intensive care unit . Protein, water, and energy metabolism were measured using in vivo neutron activation analysis, tracer dilution, dual-energy x-ray absorptiometry, and indirect calorimetry . Over the 3-week study period both groups of patients lost 13% of their total body protein . The severe sepsis patients retained twice the volume of fluid of those with major trauma, and the return to normal hydration in the sepsis group was correspondingly prolonged, especially for those in the elderly age group . In both groups of patients resting energy expenditure increased progressively over the first week to around 40% above normal and was still elevated 3 weeks from onset of illness . A twofold increase in total energy expenditure occurred in both groups of patients between the first and second weeks of critical care admission . The prolonged hypermetabolism throughout the study period was not reflected in the concentrations of circulating proinflammatory cytokines, which fell rapidly over the first week . The pattern of changes seen in plasma proinflammatory and antiinflammatory cytokine concentrations is similar for sepsis and trauma . The remarkably similar metabolic sequelae seen in critically ill patients following the onset of severe sepsis or major trauma may constitute a universal response to the induction of the systemic inflammatory response syndrome.

Indian J Pediatr, 1998 Jan-Feb, 65(1), 79 - 84
Endotracheal aspirate cultures in predicting sepsis in ventilated neonates; Srinivasan HB et al.; Nosocomial infections are the most common complications encountered in the neonatal intensive care unit (NICU) . They are associated with high mortality and prolonged duration of hospitalization in the survivors, contributing to an increased cost of health care . In this article, we review the literature on the value of routine endotracheal aspirate cultures for the prediction of neonatal sepsis and provide guidelines to prevent nosocomial infections . Upon reviewing the literature it appears that the practice of routine cultures of endotracheal aspirate and cultures obtained from multiple body sites is an expensive proposition with low yield . The sensitivity of this test is at best 50% and all studies report a very low positive predictive value . The specificity of this test is 80%, hence its role is mainly limited to identifying infants who are at low risk for sepsis . As we do not have any reliable test for early diagnosis of neonatal sepsis and also to identify infants at high risk for sepsis, our main emphasis should be towards preventing nosocomial infections . Guidelines for reducing nosocomial infections are described.

Indian J Pediatr, 1998 Jan-Feb, 65(1), 63 - 78
Early diagnosis and treatment of neonatal sepsis; Gerdes JS et al.; Perinatally acquired bacterial neonatal sepsis is a low incidence, high risk disease with a relatively benign treatment . Accurate diagnosis is difficult because there is no definitive diagnostic test; even blood cultures have an unacceptably low sensitivity . Therefore, the clinician must accept that a number of neonates who do not have the disease will have treatment initiated for sepsis . In order to treat rapidly all infants with sepsis and to minimize therapy for those without infection, historical, clinical, and laboratory data can be used together in a management approach to achieve optimal results . A systemized approach using history, examination, sepsis screen laboratory tests, and cultures is presented to guide clinical management.

J Pediatr Surg, 2000 Apr, 35(4), 627 - 9
Fungal sepsis in a patient with duodenal hematoma; Glick RD et al.; A 4-year-old boy presented with a duodenal hematoma and was admitted for conservative management including nasogastric tube drainage and parenteral nutrition . Within 2 days, the child became fungemic and went on to require urgent laparotomy . This previously undescribed life-threatening complication of duodenal hematoma is discussed in the context of standard treatment of this injury.

Crit Care Clin, 2000 Apr, 16(2), 337 - 52, vii
Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock; Balk RA; Organ system dysfunction is a common adverse sequelae of severe sepsis and septic shock and has been reported to be the most common cause of death in the noncoronary intensive care unit . The pathophysiology of the development of multiple organ system dysfunction is likely multifactoral and may take several different pathways . The frequency of specific organ system involvement is dependent on the definition used to describe the organ dysfunction . The presence of organ dysfunction has great clinical impact on the underlying disease process, can prolong the hospital stay, increase the cost of care, and has been associated with an increase in mortality rate . At present, there is no recognized specific treatment for established organ failure, this primary attention has been directed toward prevention.

Crit Care Clin, 2000 Apr, 16(2), 319 - 36, vii
Metabolic derangements in sepsis and septic shock; Mizock BA; This article examines the spectrum of metabolic alterations in sepsis and septic shock . The clinical manifestations, neuroendocrine control, and bioenergetics of the "ebb" and "flow" phases of sepsis are reviewed . Characteristic alterations in carbohydrate, fat, and protein metabolism induced by sepsis are outlined . Finally, the implications of these metabolic alterations for the nutritional support of patients with sepsis are discussed.

Crit Care Clin, 2000 Apr, 16(2), 289 - 317
Acute lung injury and acute respiratory distress syndrome in sepsis and septic shock; Fein AM et al.; Sepsis remains the leading cause of ARDS, and ARDS is still an often fatal condition . With our expanding knowledge of the pathobiologic mechanisms and the relationship between these two entities, early recognition, treatment, and prevention of sepsis may prevent or hasten recovery from ARDS . Understanding the biologic markers involved in the complex inflammatory response of sepsis and acute lung injury offers the possibility of future investigations to target treatment based on these mediators.

Int J Mol Med, 2000 May, 5(5), 457 - 65
Mechanism of hepatocellular dysfunction during sepsis: the role of gut-derived norepinephrine (review); Koo DJ et al.; Despite major advances in the management of trauma victims, the incidence of sepsis has increased significantly over the past two decades . The increasingly high morbidity and mortality associated with sepsis could be attributed to the fact that early alterations of cellular functions are not recognized, thereby leading to delayed or inadequate treatment of the septic patient . In this regard, studies have demonstrated that hepatocellular function is depressed early after the onset of sepsis . Due to its major role in metabolism and host defense mechanisms, it is becoming increasingly evident that the liver is an important organ in the development of multiple organ dysfunction during sepsis . Mediators which are released from the gut have been implicated in initiating hepatocellular dysfunction via the release of inflammatory cytokines such as TNF-alpha by Kupffer cells, the resident macrophages present in the hepatic sinusoids . Kupffer cells, by virtue of their location in the mainstream of splanchnic blood flow, are positioned to receive a constant exposure to gut-derived mediators known to activate macrophages . In this review article, we will first describe the animal model of cecal ligation and puncture which has led to our understanding of the consequences of sepsis . We will then discuss the occurrence of hepatocellular dysfunction during early sepsis . The mechanism responsible for such a deleterious alteration in organ function, focusing especially on the role of gut-derived norepinephrine and its effect on TNF-alpha release by Kupffer cells, will be specifically discussed . Moreover, we will discuss potential approaches for modulating Kupffer cell inflammatory cytokine release and improving hepatocellular function during sepsis.

Indian Pediatr, 1999 Nov, 36(11), 1113 - 8
Multicenter randomized placebo controlled trial of therapy with intravenous immunoglobulin in decreasing mortality due to neonatal sepsis; Shenoi A et al.; OBJECTIVE: To determine whether therapy with intravenous immunoglobulin G (IVIG) would decrease mortality in neonatal sepsis . SETTING: Three tertiary care neonatal intensive care units in the city of Bangalore . METHODS: All neonates admitted to the Neonatal Intensive Care Units with the clinical diagnosis of sepsis and having at least C-reactive protein and one other rapid diagnostic criteria positive were enrolled . Neonates with a birth weight of less than 1000 g and those with any major congenital malformation were excluded . The neonates were randomized to receive 1 g/kg of IVIG on three consecutive days or an equivalent amount of placebo . The rest of the treatment including antibiotics and supportive care was as per the treating physician's decision . The main outcome variable was survival . RESULTS: The trial was carried out over a period of 8 months and recruited 58 neonates . Seven neonates who qualified but did not receive either IVIG or placebo were taken into a separate control group, and one baby who received only one dose of IVIG was excluded from the analysis . Twenty-five neonates were enrolled into the IVIG arm and 25 in the placebo arm . The neonates in the therapy and placebo groups were comparable in terms of birth weight (2144+/-675 g vs . 2072+/-682 g), gestation (37.0+/-3.56 vs . 35.8+/-3.52 weeks), sex distribution, duration of stay, and number requiring ventilation . The placebo group had a significantly higher number of babies with positive blood culture . Seven babies in each group died (p>0.05) . There was no significant benefit in using IVIG (OR 1.0; 95% CI 0.25-4.07) (p = 0.74) . CONCLUSION: In the sample studied therapy with IVIG did not reduce mortality in neonatal sepsis

Clin Exp Pharmacol Physiol, 2000 Mar, 27(3), 197 - 201
Nitric oxide production and hepatic dysfunction in patients with postoperative sepsis; Satoi S et al.; 1 . Although hepatic function is well known to deteriorate following bacterial infection, the underlying mechanisms remain poorly understood . We have previously reported that nitric oxide (NO) radical leads to a decrease in the ketone body ratio (KBR) and in ATP content due to the inhibition of mitochondrial electron transport in primary cultured rat hepatocytes . 2 . To evaluate the effects of NO radical on the liver in patients with postoperative sepsis, we analysed both the stable end-product of nitric oxide radical (NOx) as well as the arterial KBR (AKBR), which reflects liver tissue NAD+/NADH . 3 . Twenty patients who had undergone general abdominal surgery and who developed postoperative sepsis were divided into two groups: (i) surviving; and (ii) non-surviving . Blood samples were collected before the development of postoperative sepsis and every 3 days until the patient either died or was discharged from hospital . 4 . Plasma NOx levels in seven patients who subsequently died became progressively higher than those in the 13 surviving patients over the clinical course of postoperative sepsis . 5 . In the non-surviving group, the AKBR was significantly lower than in surviving patients, indicating impaired hepatic function . In contrast, plasma NOx levels in non-surviving patients were significantly higher than in surviving patients . 6 . Decreases in AKBR to levels below 0.7 in non-surviving patients followed high NOx levels . Moreover, plasma NOx levels were closely correlated with the AKBR, indicating that NO radical is associated with mitochondrial dysfunction in the liver . 7 . It is likely that the overproduction of NO radical plays an important role in causing fatal metabolic disorders in patients with postoperative sepsis.

Chirurg, 2000 Feb, 71(2), 159 - 65
{Immune paralysis of T-lymphocytes and monocytes in postoperative abdominal sepsis . Correlation of immune function with survival}; Heidecke CD et al.; In vitro functions of stimulated peripheral T cells and monocytes were investigate in patients experiencing sepsis following major visceral surgery . Cell culture supernatants were analyzed by ELISA for IL-2, IFN-gamma, IL-4, IL-10, TNF-alpha, IL-1 beta, and IL-12p40 . In addition, monocyte HLA class II expression was determined by flow cytometry . T cell secretion of IL-2, TNF-alpha, and in part IFN-gamma (but not IL-4) was significantly diminished in non-survivors throughout the entire course of sepsis, compared to controls and sepsis survivors . Production of IL-1 beta and IL-12 p40 by monocytes was strongly reduced in both survivors and non-survivors at the onset of sepsis . Persistence of depressed monocyte cytokine secretion correlated with lethality . Thus, overall suppression of cytokine production by T cells and monocytes was already observed at the beginning of postoperative sepsis . HLA class II expression by monocytes exhibited a strong and sustained down-regulation with no significant differences between sepsis survivors and non-survivors . In summary, suppression of both T cell and monocyte functions develops early during postoperative sepsis . Recovery of immune functions and severity of immune defects are associated with outcome.

Biochem Biophys Res Commun, 2000 Apr 2, 270(1), 215 - 21
Sepsis-induced muscle proteolysis is prevented by a proteasome inhibitor in vivo; Fischer D et al.; Sepsis-induced muscle proteolysis mainly reflects ubiquitin-proteasome-dependent protein degradation . The effect of in vivo administration of a proteasome inhibitor on muscle protein breakdown during sepsis is not known . We treated rats with the proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu-(O-t-butyl)-Ala-leucinal (PSI) or corresponding volume of vehicle i.p . 2 h before sham-operation or induction of sepsis by cecal ligation and puncture . The sepsis-induced increase in total and myofibrillar muscle protein breakdown was inhibited in rats treated in vivo with PSI and a maximal effect was seen following 15 mg/kg of the proteasome inhibitor . Results from in vitro experiments in which incubated muscles were treated with 100 microM PSI suggest that the drug has a direct effect on muscle and that the effect is specific for the proteasome . The results are important because they suggest that it may be possible to prevent or improve the cachectic response in skeletal muscle during sepsis by treatment with a proteasome inhibitor .

Cardiovasc Res, 2000 Mar, 45(4), 925 - 33
Biphasic redistribution of muscarinic receptor and the altered receptor phosphorylation and gene transcription are underlying mechanisms in the rat heart during sepsis; Dong LW et al.; OBJECTIVE: The purpose of this study was to investigate intracellular redistribution of muscarinic cholinergic receptor (m2AChR) and the roles of receptor phosphorylation and gene transcription as underlying mechanisms in the rat heart during different phases of sepsis . METHODS: Sepsis was induced by cecal ligation and puncture (CLP) . The density of m2AChR in the sarcolemmal and light vesicle fractions was studied using {3H}-quinuclidinyl benzilate ({3H}-QNB) . Phosphorylation of m2AChR was studied by labeling of the myocardial ATP pool by perfusing isolated hearts with {32P}H3PO4 followed by identification of the phosphorylated m2AChR with SDS-PAGE . The steady-state level of m2AChR mRNA was determined by RT-PCR and Southern blot analysis . RESULTS: Septic rat hearts exhibit an initial hypercardiodynamic (9 h after CLP, early sepsis) and a subsequent hypocardiodynamic (18 h after CLP, late sepsis) state . During early sepsis, the Bmax for {3H}-QNB binding was increased in sarcolemma (+69%) but decreased in light vesicles (-22%), whereas during late sepsis, the Bmax was decreased in sarcolemma (-20%) but increased in light vesicles (+32%) . The sum of Bmax for sarcolemmal and light vesicle fractions was increased during early sepsis (+43%) but decreased during late sepsis (-14%) . The phosphorylation of m2AChR was decreased during early sepsis (-73%) but increased during late sepsis (+36% to +90%) . The m2AChR mRNA abundance was increased during early sepsis (+52%) but decreased during late sepsis (-28%) . CONCLUSIONS: The m2AChR in the rat heart was externalized from light vesicles to sarcolemma (overexpression) during early sepsis but internalized from surface membranes to intracellular sites (underexpression) during late sepsis . Furthermore, changes in the receptor phosphorylation and gene transcription are responsible for the biphasic redistribution and the altered expression of m2AChR in the rat heart during the progression of sepsis.

J Immunol, 2000 Apr 1, 164(7), 3675 - 80
p53-dependent and -independent pathways of apoptotic cell death in sepsis; Hotchkiss RS et al.; Sepsis induces extensive apoptosis of lymphocytes, which may be responsible for the profound immune suppression of the disorder . Two potential pathways of sepsis-induced lymphocyte apoptosis, Fas and p53, were investigated . Lymphocyte apoptosis was evaluated 20-22 h after sepsis by annexin V or DNA nick-end labeling . Fas receptor-deficient mice had no protection against sepsis-induced apoptosis in thymocytes or splenocytes . p53 knockout mice (p53-/-) had complete protection against thymocyte apoptosis but, surprisingly, had no protection in splenocytes . p53-/- mice had no improvement in sepsis survival compared with appropriately matched control mice with sepsis . We conclude that both p53-dependent and p53-independent pathways of cell death exist in sepsis . This differential apoptotic response of thymocytes vs splenocytes in p53-/- mice suggests that either the cellular response or the death-inducing signal is cell-type specific in sepsis . The fact that p53-/- lymphocytes of an identical subtype (CD8-CD4+) were protected in thymi but not in spleens indicates that cell susceptibility to apoptosis differs depending upon other unidentified factors.

Infect Immun, 2000 Apr, 68(4), 1942 - 5
Predictive value of nuclear factor kappaB activity and plasma cytokine levels in patients with sepsis; Arnalich F et al.; The relationship between fluctuating cytokine concentrations in plasma and the outcome of sepsis is complex . We postulated that early measurement of the activation of nuclear factor kappaB (NF-kappaB), a transcriptional regulatory protein involved in proinflammatory cytokine expression, may help to predict the outcome of sepsis . We determined NF-kappaB activation in peripheral blood mononuclear cells of 34 patients with severe sepsis (23 survivors and 11 nonsurvivors) and serial concentrations of inflammatory cytokines (interleukin-6, interleukin-1, and tumor necrosis factor) and various endogenous antagonists in plasma . NF-kappaB activity was significantly higher in nonsurvivors and correlated strongly with the severity of illness (APACHE II score), although neither was related to the cytokine levels . Apart from NF-kappaB activity, the interleukin-1 receptor antagonist was the only cytokine tested whose level in plasma was of value in predicting mortality by logistic regression analysis . These results underscore the prognostic value of early measurement of NF-kappaB activity in patients with severe sepsis.

J Surg Res, 2000 Mar, 89(1), 31 - 7
The important role of the gut in initiating the hyperdynamic response during early sepsis; Yang S et al.; BACKGROUND: Although the initial response to sepsis includes a hyperdynamic phase and although the increased hepatic perfusion in early sepsis is due solely to the increased portal blood flow, it remains unknown whether the gut plays an important role in producing such a response . MATERIALS AND METHODS: Adult male Sprague-Dawley rats underwent a complete enterectomy (ER) before being subjected to sepsis by cecal ligation and puncture (CLP; the cecum was excised from the removed gut and stitched to the posterior peritoneum in ER groups) or sham operation . At 2 h after CLP (i.e., the early, hyperdynamic phase of sepsis), cardiac output and heart performance (+/-dP/dt(max)), as well as hepatic and renal blood flow, were measured . Systemic and regional oxygen delivery (DO(2)) and oxygen consumption (VO(2)) were also determined . RESULTS: Cardiac output, heart performance, organ blood flow, as well as DO(2) and VO(2), increased significantly 2 h after CLP . ER prior to the onset of sepsis, however, prevented the elevation of those parameters . ER in sham animals did not alter the measured parameters with the exception that portal blood flow decreased by 85% and hepatic arterial blood flow increased by 368%, resulting in no significant reduction in hepatic DO(2) and VO(2) . There were no changes in circulating blood volume among groups, indicating that the effect of ER on hemodynamics after CLP was not due to alterations in blood volume . CONCLUSION: Since ER immediately before the onset of sepsis prevents the increase in cardiac output and regional hemodynamics, the gut appears to play an important role in producing the hyperdynamic response during the early stage of polymicrobial sepsis .

J Chemother, 1999 Dec, 11(6), 536 - 40
Sepsis and septic shock: pro-inflammatory or anti-inflammatory state?
Antonelli M.
A considerable body of evidence indicates that together with an important pro-inflammatory reaction, a anti-inflammatory response contributes to the onset of sepsis and organ failure . At a local site of injury or infection and during the initial appearance of pro- and anti-inflammatory mediators in the circulation, the beneficial effects of these compounds counterbalance their harmful effects . Only when the balance between these two forces is lost may these substances become harmful . The sequelae of an unbalanced systemic inflammatory reaction include derangement of microcirculation, shock, transudation into organs and defects of coagulation . An unbalanced systemic compensatory anti-inflammatory response often results in anergy and immunosuppression . The pro-inflammatory and anti-inflammatory conditions may ultimately reinforce each other, creating a state of destructive immunologic dissonance . In the present report, recent literature on cytokines was reviewed together with the 89 clinical papers published between 1993 and 1997 on the role of cytokines during sepsis and other inflammatory reactions . Cytokines were analyzed in more than 5,000 patients . Sepsis and septic shock were the two groups most represented (2834 individuals and 550 respectively) . Only 12% (11) of the studies showed a correlation with the presence of sepsis or septic complications . Overall 27 (39%) studies found a correlation between levels of cytokine and mortality . Fifty (62%) of the 80 studies that investigated this correlation found that the amount of cytokines did not predict death . The rest of the 30 (48%) investigations depicted an unhomogeneous picture: even though 27 studies evidenced higher levels of cytokines in non-survivors, 3 studies found the opposite.

J Chemother, 1999 Dec, 11(6), 524 - 9
Management of the critically ill patient with severe sepsis; Vincent JL et al.; Sepsis is a common cause of morbidity and mortality among the critically ill patient population . However, no anti-sepsis therapy has yet been found to be effective and treatment is thus largely supportive . Adequate fluid resuscitation must be accompanied by effective ventilation, and adrenergic agents may be needed to restore perfusion pressure and improve myocardial function . Enteral nutritional support with specialized nutrients has beneficial effects on morbidity, and should be started early . Further research will allow better definition of the septic patient according to immune status and enable more effective targeting of future anti-sepsis treatments.

Klin Padiatr, 2000 Jan-Feb, 212(1), 10 - 5
{Procalcitonin in comparison to C-reactive protein as markers of the course of sepsis in severely immunocompromised children after bone marrow transplantation}; Sauer M et al.; BACKGROUND: PCT has recently drawn attention as a quite specific marker for bacterial, fungal, and parasitic origin of severe sepsis-syndrome . These specific properties could make PCT to an important tool for sepsis monitoring in severely immunocompromised children . The clinical value of PCT in comparison to CrP was investigated in children after bone marrow transplantation (BMT) . METHODS: PCT was measured in the serum of 48 children (median age 12.4 years) after BMT in a prospective study . Results were correlated with the clinical findings and compared to the C-reactive protein (CrP) . RESULTS: PCT showed a sensitivity for diagnosing a sepsis-syndrome of 56%, a specificity of 87%, a positive predictive value of 69%, and a negative predictive value of 80% . Regarding CrP they were 100%, 41%, 46% and 100% respectively . The relative risk to die due to sepsis-syndrome was 26.4 for PCT levels over 10 ng/ml and 4.0 for CrP levels over 200 mg/l . It could be shown furthermore that there can be a significant liberation of PCT even during hematological aplasia . CONCLUSION: (1) Measuring PCT levels in the sera of children undergoing BMT improves the possibility of diagnosing severe infection and gives an important prognostic tool . (2) Measuring PCT can be recommended if severe sepsis-syndrome is suspected and there is an additional need for differential diagnosis and prognostic evaluation.

Surgery, 2000 Mar, 127(3), 309 - 15
Sepsis after major visceral surgery is associated with sustained and interferon-gamma-resistant defects of monocyte cytokine production; Weighardt H et al.; BACKGROUND: Recent clinical trials failed to demonstrate beneficial effects of anti-inflammatory sepsis therapy . The present study therefore asked the following questions: Is there evidence for immunosuppression during postoperative sepsis? When, during the septic course, may immunosuppression develop? Can defective cellular functions be restored by in vitro treatment with interferon-gamma (IFN-gamma)? METHODS: The study included 35 patients with sepsis after major visceral surgery and 85 control patients . Monocyte secretion of interleukin (IL)-1 beta, IL-12 p40 and p70, IL-18, tumor necrosing factor, and IL-10 with or without IFN-gamma treatment and its correlation with the course and outcome of postoperative sepsis were determined . RESULTS: Postoperative sepsis was associated with an immediate defect of endotoxin-stimulated monocyte production of IL-12 p40, IL-1 beta, and IL-10 in both surviving and nonsurviving patients . During the final phase of postoperative sepsis, a significant recovery of IL-12 p40 and IL-1 beta secretion, but not of IL-10 production, correlated with survival . Despite the exposure of monocytes in vitro to IFN-gamma for 16 hours, the production of the biologically active IL-12 p70 heterodimer was severely suppressed both in survivors and nonsurvivors, although the secretion of the p40 subunit was restored . In contrast, IFN-gamma treatment resulted in a significant suppression of monocyte IL-1 beta production in all patient subgroups . Alterations of monocyte tumor necrosing factor secretion were not observed . The production of IL-18 was below the limits of detection in all samples . CONCLUSIONS: Postoperative sepsis was associated with immediate monocyte defects that affected both pro- and anti-inflammatory cytokine secretion, which suggests that immunosuppression is a primary rather than a compensatory response to a septic challenge . Sepsis survival correlated with the recovery of the proinflammatory, but not the anti-inflammatory, response . The treatment of monocytes with IFN-gamma did not reconstitute defective proinflammatory cytokine production.

Ann Surg, 2000 Mar, 231(3), 399 - 407
Inhibition of tyrosine kinase signaling after trauma-hemorrhage: a novel approach for improving organ function and decreasing susceptibility to subsequent sepsis; Jarrar D et al.; OBJECTIVE: To determine whether administration of a tyrosine kinase inhibitor after trauma-hemorrhage has any beneficial effects on cardiovascular parameters and hepatocellular function and on survival rate after subsequent sepsis . BACKGROUND: Increased inflammatory cytokine release and concomitant activation of intracellular signaling pathways contributes to multiple organ dysfunction and increased susceptibility to subsequent sepsis after severe hemorrhagic shock . METHODS: Male Sprague-Dawley rats underwent a midline laparotomy (i.e., soft-tissue trauma induced) and were then bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximal shed blood volume was returned in the form of Ringer's lactate . The rats were then resuscitated with four times the shed blood volume in the form of Ringer's lactate during a 60-minute period . A tyrosine kinase inhibitor, AG 556 (7.5 mg/kg), or vehicle was administered intraperitoneally at the middle of resuscitation . At 24 hours after resuscitation, various in vivo parameters such as heart performance, cardiac index, and hepatocellular function (i.e., the maximum velocity and the overall efficiency of indocyanine green clearance) were determined . Phosphorylation state of the mitogen-activated protein kinases p44/42 and p38 in the liver was assessed by Western blot analysis . In additional groups of rats, sepsis was induced by cecal ligation and puncture at 20 hours after hemorrhage . The necrotic cecum was excised 10 hours thereafter, and the survival rate was monitored for a period of 10 days . RESULTS: AG 556 treatment restored the depressed cardiovascular and hepatocellular functions after trauma-hemorrhage and resuscitation, which was associated with reduced phosphorylation of mitogen-activated protein kinases p44/42 and p38 . Moreover, treatment with AG 556 significantly increased the survival rate of rats after trauma-hemorrhage and induction of subsequent sepsis compared with vehicle-treated rats . CONCLUSION: Inhibition of tyrosine kinase signaling after trauma-hemorrhage may represent a novel therapeutic approach for improving organ functions and decreasing the death rate from subsequent sepsis under such conditions.

Crit Care Med, 2000 Feb, 28(2), 445 - 50
Changes of the hemostatic network in critically ill patients--is there a difference between sepsis, trauma, and neurosurgery patients?
Boldt J, Papsdorf M, Rothe A, Kumle B, Piper S.
OBJECTIVE: To study the time course of coagulation data in intensive care patients . DESIGN: Prospective, descriptive study . SETTING: Clinical investigation on a surgical and neurosurgical intensive care unit of a university hospital . PATIENTS: Fifteen patients with severe trauma (injury severity score, 15 to 25), 15 sepsis patients secondary to major surgery, and 15 neurosurgery patients (cancer surgery) were studied . INTERVENTIONS: Standardized intensive care therapy . MEASUREMENTS AND MAIN RESULTS: Standard coagulation data and molecular markers of coagulation activation and fibrinolytic activity (soluble thrombomodulin, protein C, free protein S, thrombin/antithrombin III complex, plasmin-alpha 2-antiplasmin complex, tissue plasminogen activator, platelet factor 4, beta-thromboglobulin were measured from arterial blood samples on the day of admission to the intensive care unit (trauma/neurosurgery patients) or on the day of diagnosis of sepsis (baseline value) and serially during the next 5 days . Antithrombin III, fibrinogen, and platelet counts were highest in neurosurgery patients but without significant differences between sepsis and trauma patients . Thrombin/antithrombin III complex increased in the sepsis patients (from 22.6+/-4.2 microg/L to 39.9+/-6.8 microg/L), but decreased in trauma (from 40.2+/-5.1 microg/L to 17.6+/-4.0 microg/L) and neurosurgery patients (from 28.2+/-4.2 microg/L to 16.2+/-3.8 microg/L) . Tissue plasminogen activator increased in the sepsis patients (from 14.4+/-3.9 microg/L to 20.7+/-3.8 microg/mL) and remained almost unchanged in the other two groups . Soluble thrombomodulin plasma concentration increased significantly in the sepsis group (max, 131.8+/-22.5 ng/mL), while it remained elevated in the trauma (max, 75.5+/-5.9 ng/mL) and was almost normal in the neurosurgery patients . Protein C and free protein S remained decreased only in the sepsis group . CONCLUSIONS: Alterations of the hemostatic network were seen in all three groups of critically ill patients . Hemostasis normalized in the neurosurgery patients and posttraumatic hypercoagulability recovered within the study period . By contrast, monitoring of molecular markers of the coagulation process demonstrated abnormal hemostasis in the sepsis patients during the entire study period indicating ongoing coagulation disorders and abnormalities in fibrinolysis in these patients.

Clin Nutr, 2000 Feb, 19(1), 35 - 41
Fever and sepsis during neutropenia are associated with expansion of extracellular and loss of intracellular water; Schwenk A et al.; BACKGROUND AND AIMS: Shifts from intracellular to extracellular water are features of a catabolic reaction to sepsis . Bedside assessment of fluid shifts was carried out in neutropenic patients at high risk of systemic infection . METHODS: Multifrequency bioelectrical impedance analysis was performed in 41 patients with leukemia or high-malignant lymphoma and chemotherapy-induced neutropenia . RESULTS: Hydration was stable during afebrile periods except for transient intra- and extracellular dehydration after chemotherapy . The risk of over-hydration and dehydration increased 3-fold during fever . Over-hydration was more severe when occurring during fever . Extracellular water was highly variable and tended to increase, and intracellular water was slowly depleted . During sepsis, these alterations were enhanced . Changes in hydration status did not predict subsequent progression to sepsis because it developed more slowly than other symptoms of infection . CONCLUSIONS: Extracellular over-hydration and intracellular dehydration are observed in febrile infection in neutropenia, similar to severe sepsis . If the technical limits of bioelectrical impedance are taken into account, this method may be useful for non-invasive monitoring of these features of metabolic stress .

J Lab Clin Med, 2000 Feb, 135(2), 188 - 98
Inflammation-induced systemic proteolysis of inter-alpha-inhibitor in plasma from patients with sepsis; Balduyck M et al.; Inter-alpha-inhibitor (IalphaI) is a human plasma serine proteinase inhibitor . It contains one light peptide chain called bikunin that exerts antiproteinase activity and other antiinflammatory functions . Bikunin is covalently linked to two heavy chains that, after tissular diffusion, stabilize the extracellular matrix . Owing to its negative acute-phase reactant character and its susceptibility to proteolysis, IalphaI has been implicated in the pathophysiology of sepsis . Moreover, IalphaI has been shown to exert a protective effect on a pig model of endotoxic shock . Twenty patients admitted to the intensive care unit (ICU) for a septic syndrome were included in the present study . IalphaI and antithrombin III (ATIII) levels were measured on admission . Sequential measurements of IalphaI could be done in 4 patients . We demonstrate that IalphaI levels are significantly decreased in plasma samples collected on admission from patients with sepsis (59 +/- 32 mg/L vs 241 +/- 70 mg/L; P < .0001) . This decrease was greater in severe sepsis and septic shock than in sepsis . Death was not predictable from initiol IalphaI levels . In 2 patients with a favorable course, IalphaI values regularly increased during the ICU stay . By sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by immunoblot analysis and microsequencing, we characterized IalphaI-related components in plasma from several patients; they obviously arise from IalphaI through proteolytic cleavage . Thus, systemic proteolysis and decreased biosynthesis both contribute to the fall in the plasma level of IalphaI . Because IalphaI is very sensitive to proteolysis by polymorphonuclear granulocytes (PMNs) that are stimulated during sepsis, we suggest that IalphaI plasma level would be a useful marker for neutrophil proteinase activity . ATIII, as well as IalphaI, is considered a negative acute phase protein . Because in vitro ATIII is less susceptible than IalphaI to proteolysis by PMNs and because their relative levels weakly correlated, we suggest that an unspecific systemic proteolysis is not significantly involved in the ATIII deficiency occurring in sepsis.

Br Med Bull, 1999, 55(1), 212 - 25
Adjunctive therapy in sepsis: a critical analysis of the clinical trial programme; Cohen J; Despite intensive efforts, the development of novel drugs for the treatment of sepsis has proved to be extremely difficult . A large number of clinical trials have ended in failure . A critical analysis of this record suggests that there is no single reason for these problems . Rather, the explanation lies in part with unexpected failures in the drugs themselves, and in part with the difficulties of trial design in this particular group of patients . In future, trials in this area are likely to be more highly focused, with even stricter protocol definitions to try and ensure a homogeneous patient population.

Br Med Bull, 1999, 55(1), 196 - 211
The gastrointestinal tract as a barrier in sepsis; Rowlands BJ et al.; The gastrointestinal tract is an organ of digestion and absorption which is metabolically active and has specific nutrient requirements . In health, it has an additional function as a major barrier, protecting the body from harmful intraluminal pathogens and large antigenic molecules . In disease states, such as sepsis when the mucosal barrier is compromised, micro-organisms and their toxic products gain access to the portal and systemic circulations producing deleterious effects . Under these circumstances, systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) develop leading to deterioration and death of the patient in the intensive care unit . Therapeutic strategies for such patients in the intensive care unit aim to support general immune function and maintain the structure and function of the gastrointestinal tract . For these therapies to be successful, the underlying septic or necrotic focus must be ablated using appropriate surgical or other invasive techniques.

Br Med Bull, 1999, 55(1), 30 - 48
The role of the endothelium in modulating vascular control in sepsis and related conditions; Wort SJ et al.; The majority of deaths amongst critically ill patients requiring intensive care are attributable to sepsis and its sequelae: septic shock, the systemic inflammatory response syndrome (SIRS) and the acute respiratory distress syndrome (ARDS) . Patients within the ICU who develop these conditions and fail to survive succumb to multiple organ dysfunction syndrome (MODS) . ARDS is considered to be the pulmonary component of MODS and is characterized by pulmonary hypertension, often in the setting of systemic hypotension . Endothelial cells, normally responsible for modulating vascular tone, becomes dysfunctional in sepsis . Pro-thrombotic, pro-inflammatory and vasoactive mediators are released including nitric oxide (NO), endothelins (ETs) and products of cyclo-oxygenase metabolism . It is probably the disordered production of these mediators in vascular beds that results in MODS . This review highlights recent research in this area with particular emphasis on possible therapeutic options.

Br Med Bull, 1999, 55(1), 12 - 29
Inflammatory cell activation in sepsis; Bellingan G; The body relies for protection on an effective inflammatory response . To sustain an armoury of inflammatory cells in a state of permanent activation would be impossible and a system whereby such cells can be rapidly activated is, therefore, employed . Upon transition from the resting to activated state inflammatory cells perform multiple defensive functions and are then removed, limiting the duration of inflammation . Neutrophils are the major circulating inflammatory cells but macrophages exert a more powerful regulatory effect . If the inflammatory response is inadequate there is a risk of overwhelming sepsis . By contrast, an unregulated response can lead to systemic inflammation and consequent multiple organ damage . This review focuses on the mechanisms whereby inflammatory cells are activated, how the regulatory system may misfunction and how it may in the future be manipulated to therapeutic advantage.

Eur J Pharmacol, 2000 Feb 18, 389(2-3), 209 - 15
Effects of nitric oxide-modulating amino acids on coronary vessels: relevance to sepsis; Mitchell JA et al.; Excessive nitric oxide (NO) production in septic shock is thought to contribute to the associated profound hypotension . Here we show that despite induction of NO synthase (NOS) in the hearts of endotoxin-treated rats, coronary vascular responses to the contractile peptide endothelin-1, were not modified . This was not due to any change in the expression of endothelin receptors . However, when the substrate for NOS, L-arginine, was added to the perfusate, increases in coronary perfusion pressure stimulated by endothelin were reduced in hearts from endotoxin-treated animals compared to those from controls . In addition, L-glutamine, which blocks the generation of L-arginine from intracellular stores, enhanced the increase in perfusion pressure stimulated by endothelin-1 . These data suggest that L-arginine becomes rate limiting for the production of NO in the coronary vessels during septic shock . Moreover, it suggests that vascular reactivity may be modulated positively or negatively by supplementation with the relevant amino acids.

Blood, 2000 Mar 1, 95(5), 1680 - 6
The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis; Taylor FB Jr et al.; The influence of the endothelial protein C receptor (EPCR) on the host response to Escherichia coli was studied . Animals were treated with 4 separate protocols for survival studies and analysis of physiologic and biochemical parameters: (1) monoclonal antibody (mAb) that blocks protein C/activated protein C binding to EPCR plus sublethal numbers of E coli (SLEC) (n = 4); (2) mAb to EPCR that does not block binding plus SLEC (n = 3); (3) SLEC alone (n = 4); and (4) blocking mAB alone (n = 1) . Those animals receiving blocking mAb to EPCR plus sublethal E coli died 7 to 54 hours after challenge, whereas all animals treated with the other protocols were permanent survivors . Histopathologic studies of tissues from animals receiving blocking mAb plus SLEC removed at postmortem were compared with those animals receiving SLEC alone killed at T+24 hours . The animals receiving the blocking mAb exhibited consumption of fibrinogen, microvascular thrombosis with hemorrhage of both the adrenal and renal cortex, and an intense influx of neutrophils into the adrenal, renal, and hepatic microvasculature, whereas the tissues from animals receiving only sublethal E coli exhibited none of these abnormal histopathologic changes . Compared with the control animals, the animals receiving the blocking mAb exhibited significantly elevated serum glutamic pyruvic transaminase, anion gap, thrombin-antithrombin complex, IL-6, IL-8, and soluble thrombomodulin . The levels of circulating activated protein C varied too widely to allow a clear determination of whether the extent of protein C activation was altered in vivo by blocking protein C binding to EPCR . We conclude that protein C/activated protein C binding to EPCR contributes to the negative regulation of the coagulopathic and inflammatory response to E coli and that EPCR provides an additional critical step in the host defense against E coli . (Blood . 2000;95:1680-1686)

Surgery, 2000 Feb, 127(2), 209 - 16
Neutrophils express tissue factor in a monkey model of sepsis; Todoroki H et al.; BACKGROUND: Although tissue factor (TF) is involved in hemostasis, thrombogenesis, inflammation, and cellular immune response, its source in sepsis remains controversial . Recently, we found that, in addition to monocytes and endothelial cells, neutrophils may express TF in a rabbit model . The purpose of this study was to determine whether neutrophils could be a source of TF in a monkey model of sepsis . METHODS: TF messenger RNA (mRNA) and protein in neutrophils were assayed by in situ hybridization and immunohistochemistry in tissues obtained from monkeys after injection of lipopolysaccharide (LPS) (n = 3) and after injection of saline as a control (n = 2) . Coagulation parameters were measured before and at 1.5 and 3 hours after injections . RESULTS: In LPS-treated monkeys, TF mRNA and protein were induced not only in monocytes and endothelial cells, but also in neutrophils accumulating in the liver 3 hours after LPS injection . Thrombin-antithrombin III complex and fibrin degradation products D-dimer levels were significantly increased at 3 and 1.5 hours after LPS injection compared with controls . CONCLUSIONS: Neutrophils are a source of TF and are implicated in direct activation of the coagulation cascade in the early phases of sepsis in the monkey . These results give important information for the treatment of sepsis.

J Perinatol, 1999 Jun, 19(4), 307 - 10
Ignác Semmelweis and the etiology of fetal and neonatal sepsis; Raju TN; It is well-known that Ignac Semmelweis discovered the etiology and prophylaxis of puerperal sepsis . However, few historians have focused on his understanding of the pathophysiology of fetal and neonatal sepsis . Based on several key observations, Semmelweis realized that puerperal fever (also known as "childbed fever") could be transmitted to the fetus, especially when the first stage of labor was prolonged and multiple examiners performed vaginal examinations while their fingers were contaminated . This insight was particularly valuable in that it helped him decipher the mystery of puerperal sepsis . This paper presents some of these concepts and supporting evidence.

J Pathol, 2000 Feb, 190(3), 373 - 86
Microcirculatory dysfunction in sepsis: a pathogenetic basis for therapy?
Lehr HA, Bittinger F, Kirkpatrick CJ.
Sepsis is a frequent complication of multiple organ dysfunction syndrome and remains a major problem of intensive care medicine . It is also a common factor in the final cause of death in hospital populations . Clinical observations, assisted by invasive monitoring techniques as well as pathological-anatomical studies, clearly indicate that microcirculatory dysfunction lies at the centre of sepsis pathogenesis . Numerous animal models, from rodents to primates, many of which employ bacteria or their toxins, especially endotoxins, have helped to shed light on the pathomechanisms leading to this dysregulation in the peripheral circulation . Among these are activation of humoral and cellular inflammatory mediator systems, with special emphasis on neutrophil-endothelial interactions, affecting endothelial barrier function and vasoregulation and ultimately leading to severely perturbed oxygen transport and utilization . In vitro studies have provided more insight into the molecular mechanisms involved in this microcirculatory dysfunction, although much more attention must be directed towards microvascular endothelial cells and the role of heterogeneity of response in various vascular beds . These experimental data must in turn be validated by comparing with the human in situ situation, both clinical and morphological . This review aims at a critical appraisal of the clinical and experimental evidence for sepsis-induced dysregulation of the microcirculation and how knowledge of the underlying cellular and molecular pathology could be used to make therapy more rational and effective . To date, therapeutic approaches, such as anti-cytokine and anti-oxidant regimens, which have been highly successful in experimental models, have failed to demonstrate clinical efficacy . Newer approaches, such as targeting the coagulation system, nitric oxide synthesis or intracellular signal transduction, are also discussed . The necessity to focus on the role of anti-inflammatory mediators, as well as the pathogenetic significance of important molecular groups, such as the heat shock proteins, which until now have been given scant attention, will be stressed .

Khirurgiia (Mosk), 2000, (1), 47 - 53
{Systemic inflammatory response syndrome and sepsis in maxillofacial surgery clinic}; Gritsuk SF et al.; A total of 106 patients with surgical infection in maxillofacial region were studied . Clinical and laboratory diagnostic data on surgical infection and sepsis in maxillofacial surgery are presented . Integral indices of blood circulation, respiration, brain and liver metabolism, regarding severity of surgical infection were determined . Pathogenetically substantiated therapy of sepsis is proposed.

Antimicrob Agents Chemother, 2000 Mar, 44(3), 693 - 6
A double-blind placebo-controlled study of an infusion of lexipafant (Platelet-activating factor receptor antagonist) in patients with severe sepsis; Suputtamongkol Y et al.; Platelet-activating factor (PAF) is a potent endogenous proinflammatory mediator implicated in the pathogenesis of septic shock . A double-blind randomized placebo-controlled trial of an intravenous PAF receptor antagonist (lexipafant) was conducted with 131 adult Thai patients with suspected severe sepsis (66 of whom had positive blood cultures) . Detailed serial clinical, biochemical, and cytokine measurements were performed . Lexipafant treatment was well tolerated . The 28-day mortality in the lexipafant group (61.4%) was similar to that in the placebo group (62.6%) . There was also no evidence that lexipafant affected clinical or biochemical measures of disease severity or the profile of sequentially measured plasma cytokine levels . PAF may not have an important role in the pathogenesis of severe sepsis.

Am J Respir Crit Care Med, 2000 Feb, 161(2 Pt 1), 517 - 26
Impaired hepatic extraction and increased splanchnic production contribute to lactic acidosis in canine sepsis; Chrusch C et al.; In septic shock, the extent to which lactic acidosis (LA) is a consequence of splanchnic lactate overproduction (SLP) or impaired hepatic lactate extraction (HLE) is not clear . We examined SLP and HLE in E . coli sepsis in dogs . We further determined the effects of vasopressor treatments, which included phenylephrine, dopamine, norepinephrine, and a combination of dobutamine and norepinephrine treatment, on SLP and HLE in respective groups . The animals were studied while anesthetized and ventilated . During sepsis, SLP increased as compared with presepsis (-0.017 versus 0.07 mmol/min, p < 0.05), but this increase could not be explained by reduced splanchnic oxygen delivery (SOD) . During sepsis, HLE increased as compared with baseline (0.8 versus 8%, p < 0.05), but was significantly lower than that found during lactic acid loading in nonseptic dogs . None of the vasopressor treatments had a detrimental effect on SLP . These results indicate that LA in sepsis occurs secondary to an increase in splanchnic lactate production that is not related to reduced splanchnic oxygen delivery, as well as to a decrease in hepatic lactate extraction . Effects of different vasoactive agents did not alter either splanchnic lactate production or hepatic lactate extraction in this sepsis model.

Am J Surg, 1999 Dec, 178(6), 556 - 9
Attenuating tumor necrosis factor alpha does not ameliorate other cytokine and peroxidase products during sepsis; Mazolewski PJ et al.; BACKGROUND: Recent trials utilizing single anticytokine agents have shown no consistent survival benefit in improving the outcome of sepsis . Since an entire cascade of mediators contributes to the underlying pathophysiology, it is not surprising that monotherapy has proven unsuccessful . The purpose of this study was to measure the effects of attenuating tumor necrosis factor (TNF)alpha early in sepsis . METHODS: Three groups of Sprague-Dawley rats were studied . All animals were infused with live Escherichia coli, with group I and group II rats additionally receiving a matrix metalloproteinase inhibitor . Serum levels of TNFalpha, interleukin (IL)-6, malondialdehyde (MDA), and lipid hydroperoxide (LOOH) were compared . RESULTS: TNFalpha showed a significant decrease, yet IL-6, MDA, and LOOH (markers of sepsis) levels remained abnormally elevated . CONCLUSION: Despite significantly attenuating TNFalpha, the septic response continued . This supports the concept that in sepsis, monotherapy directed at attenuating a single cytokine cannot overcome the tissue-damaging effects of an entire cascade of mediators.

Shock, 2000 Feb, 13(2), 110 - 6
Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs . cecal ligation and puncture; Remick DG et al.; Sepsis remains a serious clinical problem despite intense efforts to improve survival . Experimental animal models of sepsis have responded dramatically to immunotherapy blocking the activity of cytokines . Despite these preclinical successes, human clinical trials have not demonstrated any improvement in survival . We directly compared the mortality, morbidity, and immunopathology in two models of sepsis, one due to lipopolysaccharide (LPS) and the other to cecal ligation and puncture (CLP) . BALB/c mice were injected intraperitoneally with 250 microg of LPS or subjected to CLP with an 18-gauge needle . Both models yielded similar mortality (> 85%) and morbidity . Additionally, neutropenia and lymphopenia developed in both groups . Plasma and peritoneal levels of cytokines (TNF, IL-1, IL-6, and the chemokines KC and MIP-2) were measured at 1.5, 4, and 8 h after challenge . LPS induced substantially higher levels of cytokines in both compartments with peak levels between 1.5 and 4 h that began to decline at 8 h . In contrast, cytokine levels in the CLP model were continuing to increase at the 8 h-time point and often exceeded the LPS-induced values at this time . Our data demonstrate that the LPS and CLP models have similar mortality but significant differences in the kinetics and magnitude of cytokine production . Immunotherapy for sepsis based on cytokine production after LPS challenge is misdirected because the LPS model does not accurately reproduce the cytokine profile of sepsis.

Inflamm Res, 1999 Dec, 48(12), 651 - 6
Detection of an approximately 100 kD protein with strong immunoreactivity to antibodies specific for inducible nitric oxide synthase (iNOS) but without NOS activity in neutrophils of patients suffering from sepsis: results of a preliminary study; Richter N et al.; OBJECTIVE: The study was designed to evaluate the expression of inducible nitric oxide synthase (iNOS) in activated human neutrophils . SUBJECTS AND METHODS: By Western blotting and immunocytochemical staining, iNOS expression was analyzed in neutrophils from patients with sepsis who we classified by high plasma nitrate as subjects with activated NO metabolism . For comparison, rats treated with Zymosan documented to induce iNOS were analyzed . RESULTS: Strong immunoreactivity to antibodies for iNOS was detected in leukocytes of Zymosan treated rats and in neutrophils of septic patients . Such immunoreactivity was absent in untreated rats and healthy subjects . In rats, the immunoreactivity was associated to the 130 kD protein as expected for iNOS . In contrast, the intense iNOS staining in neutrophils of septic patients was associated to an approximately 100 kD protein . Despite the iNOS staining, no increased NOS activity could be demonstrated in the neutrophils of septic patients . CONCLUSIONS: The detection of an approximately 100 kD protein with immunoreactivity to antibodies recognizing human iNOS but without NOS activity in neutrophils of patients with sepsis should initiate studies to elucidate the origin and function of this protein.

Arch Surg, 2000 Feb, 135(2), 198 - 203
Plasma alpha-glutathione S-transferase: a sensitive indicator of hepatocellular damage during polymicrobial sepsis; Koo DJ et al.; HYPOTHESIS: Since studies have found the liver enzyme alpha-glutathione S-transferase (alphaGST) to be a marker of hepatic injury after hemorrhagic shock, alphaGST also may serve as a sensitive indicator of hepatocellular damage during the early stage of polymicrobial sepsis . DESIGN, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Male adult rats were subjected to the cecal ligation and puncture (CLP) model of polymicrobial sepsis or sham operation, followed by fluid resuscitation with isotonic sodium chloride solution . Systemic blood samples were taken at 2, 5, 10, or 20 hours after CLP or sham operation . Plasma levels of alphaGST and lactate were determined using an enzyme immunoassay and enzymatic assay, respectively . Additional animals were examined for morphologic alterations in liver ultrastructure of septic animals using electron microscopy . RESULTS: A similar level of alphaGST (mean +/- SEM, 30.5 +/- 3.5 microg/L) was found in the sham group at all measured time points . Although plasma levels of alphaGST did not change at 2 hours after CLP, they were elevated by 249% at 5 hours after the onset of sepsis and continued to increase throughout the septic course . Plasma lactate levels were significantly increased only at 20 hours after CLP (P<.001) . Previous studies have shown that liver transaminase levels did not increase at 5 hours, but at 10 and 20 hours after CLP . In addition, electron microscopy revealed structural changes in hepatocyte morphology at 5 and 20 hours after CLP that were indicative of hepatocellular injury . CONCLUSION: Since plasma alphaGST levels increased earlier than plasma lactate and liver transaminase levels, alphaGST may be a more sensitive indicator of early liver injury and should be used in monitoring hepatocellular damage during the progression of sepsis.

Crit Care Med, 2000 Jan, 28(1), 232 - 5
Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation; Abraham E et al.; Definitions for sepsis, septic shock, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) were developed by consensus conferences with the goal of achieving standardization of terminology and improved homogeneity of patient populations in clinical studies . Although such definitions have been useful in epidemiologic investigations, the criteria specified by the consensus conferences are broad and insufficiently specific to address the problem of heterogeneous mechanisms leading to clinical syndromes . An important challenge is to progress from clinical syndromes, as presently defined, to more specific entities that are delineated by alterations in specific immunologic or biochemical pathways . Such mechanistic definitions will provide more homogeneous groups of patients who can be identified at early stages of their clinical course . This approach encourages focused investigation of pathways leading to organ system dysfunction and death and, also, provides an efficient framework for the development of new therapies useful in critically ill patients.

Anasthesiol Intensivmed Notfallmed Schmerzther, 1999 Dec, 34(12), 789 - 92
{Splenic rupture as a complication of ventilation in the prone position and pneumococcal sepsis as a late complication}; Brettner F et al.; We are reporting the case of a female patient who had to undergo splenectomy after she suffered splenic rupture as a result from "kinetic therapy" during the treatment for pulmonary failure secondary to sepsis . Four years later the patient was again admitted with a clinical picture consistent with sepsis . Two blood cultures were positive for pneumococci confirming the diagnosis of pneumococcal sepsis . This paper discusses the potential risks of kinetic therapy in patients with ARDS . After splenectomy there is increased risk of infection with certain bacteria, funghi, viruses and protozoa . The most common bacterial pathogen is pneumococcus . A polyvalent vaccine is available for prophylaxis . Although penicillin G is still commonly used as an antibiotic therapy for pneumococcal infection, increased resistance of pathogens to penicillin must be anticipated . Alternative antibiotic regimens are demonstrated.

Eur J Pediatr, 2000 Mar, 159(3), 168 - 9
Procalcitonin may help differentiate disseminated herpes simplex viral infection from bacterial sepsis in neonates; Hatherill M et al.; Disseminated herpes simplex virus infection is a potentially fatal condition which may be difficult to differentiate from bacterial sepsis . We report the case of a neonate with overwhelming herpes simplex (type 2) viraemia who presented with 'septic shock' . CONCLUSION: A low procalcitonin level (1.6 ng/ml), inconsistent with bacteraemia, suggests an alternative aetiology and may strengthen the case for antiviral therapy.

J Appl Physiol, 2000 Feb, 88(2), 401 - 8
Effects of ventilation on the surfactant system in sepsis-induced lung injury; Malloy JL et al.; The present study examined the effects of mechanical ventilation, with or without positive end-expiratory pressure (PEEP), on the alveolar surfactant system in an animal model of sepsis-induced lung injury . Septic animals ventilated without PEEP had a significant deterioration in oxygenation compared with preventilated values (arterial PO(2)/inspired O(2) fraction 316 +/- 16 vs . 151 +/- 14 Torr; P < 0.05) . This was associated with a significantly lower percentage of the functional large aggregates (59 +/- 3 vs . 72 +/- 4%) along with a significantly reduced function (minimum surface tension 17.7 +/- 1.8 vs . 11.8 +/- 3.8 mN/m) compared with nonventilated septic animals (P < 0.05) . Sham animals similarly ventilated without PEEP maintained oxygenation, percent large aggregates and surfactant function . With the addition of PEEP, the deterioration in oxygenation was not observed in the septic animals and was associated with no alterations in the surfactant system . We conclude that animals with sepsis-induced lung injury are more susceptible to the harmful effects of mechanical ventilation, specifically lung collapse and reopening, and that alterations in alveolar surfactant may contribute to the development of lung dysfunction.

Plast Reconstr Surg, 1999 Aug, 104(2), 426 - 34
Transarticular bony defects after trauma and sepsis: arthrodesis using vascularized fibular transfer; Ring D et al.; Ten male patients with previously infected bony defects involving both sides of an articulation underwent arthrodesis using a vascularized fibular transfer . The average age of these patients was 38 years (range, 20 to 60 years) . The size of the bony defect averaged 9 cm (range, 3 to 21 cm) . The ankle was involved in five patients, the knee in two patients, the wrist in two patients, and the elbow in one patient . Nine cases represented septic pseudarthroses (eight after trauma and one after attempted ankle arthrodesis) . One patient had a defect across the wrist after debridement of a chronic infection . The patients were followed for an average of 71 months (range, 26 to 144 months) . Nine patients healed after the index vascularized fibular transfer, and one patient (ankle arthrodesis) required a second cancellous bone-grafting procedure for delayed union at the junction of the fibula with the talus . Four of seven patients with lower limb involvement had residual leg length discrepancies averaging 5 cm (range, 3 to 8 cm), and one had a persistent 20-degree internal rotation deformity . Two of the patients with upper limb involvement had stiff digits . Five of the nine previously employed patients returned to their former occupation (including heavy labor in four cases) . Complications included two wound separations, one case of instability of the donor ankle after removal of a large fibular graft (related in part to a prior injury), and one fracture at the junction of the fibular graft with the local bone 10 months after the index procedure, which united after plate fixation and application of autogenous cancellous bone graft . Arthrodesis using a transfer of vascularized fibular bone represents a viable option for limb salvage in the face of an infected transarticular bony defect.

Shock, 2000 Jan, 13(1), 24 - 8
Magnolol attenuates peroxidative damage and improves survival of rats with sepsis; Kong CW et al.; Reactive oxygen species and peroxidative damage are implicated in the pathophysiology of sepsis . Magnolol is a compound extracted from the Chinese medicinal herb Magnolia officinalis and has multiple pharmacological effects, notably antioxidant functions . To determine whether magnolol can modulate the course of sepsis, survival rate and biochemical parameters were analyzed in rats with sepsis with various treatment protocols . Magnolol at doses ranging from 10(-9) g/kg to 10(-5) g/kg was administered either before or after induction of sepsis by cecal ligation and puncture . Magnolol did not modulate the course of sepsis induced by two cecal punctures . When one cecal puncture was performed, a moderately evolving type of sepsis was induced, and the survival rate of affected rats was significantly improved by pretreatment with 10(-7) g/kg magnolol . The beneficial effect was partially retained if magnolol was administered 6 hours after onset of sepsis when a higher dose (10(-5) g/kg) was used . The intensity of lipid peroxidation in plasma, liver, and lung of septic rats was also attenuated in a treatment-dependent manner . Magnolol at this dose range exerted these beneficial effects probably through its antioxidant efficacy . These significant results may suggest magnolol as a candidate agent for the treatment of sepsis.

Shock, 2000 Jan, 13(1), 1 - 7
Caspases -2, -3, -6, and -9, but not caspase-1, are activated in sepsis-induced thymocyte apoptosis; Tinsley KW et al.; Sepsis induces extensive lymphocyte cell death that may contribute to immune depression and morbidity/mortality in the disorder . bcl-2 is a member of a new class of oncogenes that prevents cell death from an array of noxious stimuli . Transgenic mice that overexpress BCL-2 in T lymphocytes are resistant to sepsis-induced T cell apoptosis, and mortality was decreased in sepsis . The purpose of this study was to identify key initiator and executioner "caspases" involved in sepsis-induced lymphocyte apoptosis and to determine if BCL-2 acts prior to caspase activation . Thymi were removed 5-22 h post-cecal ligation and puncture (CLP) or sham surgery . Apoptosis was evaluated in thymocytes by annexin-V FITC labeling and flow cytometry . Caspase-1 activity was determined by western blot analysis of the procaspase protein and p20 subunit of the activated caspase; activities of caspases -2, -6, and -9 were determined by colorimetric assays using specific substrates conjugated to a color reporter molecule . Caspase-3 activity was determined both by western blot and by a fluorogenic assay in which a fluorescent compound was generated . Thymocytes from CLP mice had markedly increased apoptosis and activation of caspases -2, -3, -6, and -9 in comparison with thymocytes of sham-operated mice . Caspase-1 was not activated . BCL-2 prevented sepsis-induced thymocyte apoptosis and inhibited activation of all caspases . We conclude that sepsis causes activation of multiple caspases and that BCL-2 acts upstream as an inhibitor of caspase activation . The pattern of caspase activation suggests a mitochondrial mediated pathway.

Eur J Surg, 1999 Dec, 165(12), 1129 - 33
Reduced B cell HLA-DR expression and natural killer cell counts in patients prone to sepsis after injury; Ditschkowski M et al.; OBJECTIVE: To examine the influence of natural killer (NK) cells and HLA-DR molecules on B cells in the development of severe sepsis after injury . DESIGN: Prospective study . SETTING: Medical school, Germany . SUBJECTS: 46 severely injured (Injury Severity Score >16) patients . INTERVENTIONS: Blood samples were taken immediately after admission and subsequently for 14 days . MAIN OUTCOME MEASURES: HLA-DR expression on B cells and counts of B and NK cells measured by flow cytometry, and morphological estimation of large granular lymphocytes by microscopy . RESULTS: HLA-DR expression on circulating B cells was significantly reduced from days 6-14 after admission in 13 patients with subsequent severe sepsis compared with 33 patients who did not develop sepsis . In septic patients NK cell counts were significantly decreased from day 4 onwards (p < 0.05) . CD16+/CD56+ cells correlated with the morphology of large granular lymphocytes . CONCLUSION: In severely injured patients reduced counts of NK cells and HLA-DR molecules on B lymphocytes seem to be part of an immune deviation that is associated with the development of severe sepsis.

Minerva Anestesiol, 1999 Nov, 65(11), 759 - 67; discussion 768
{Correlations between molecular biology of sepsis and of other primordial stressors}; Novelli GP et al.; The molecular response to endotoxins includes the molecular responses to light, oxygen and heat which may be regarded as parts of a single ancestral stress . Laboratory data suggest that a) light stress provokes molecular responses that are also caused by oxidative stress and endotoxins; b) heat stress activates heat shock proteins, as do oxidative stress and endotoxins; the former protect against oxidative stress, heat stress and endotoxins; c) oxidative stress activates antioxidant enzymes like endotoxin; these protect against endotoxins; d) endotoxin-related stress activates the molecular responses to all the aforesaid primordial stresses . Many laboratory findings prompt us to conclude that the molecular response to endotoxemia and sepsis is an archetypal response common to all forms of primordial stress.

Proc Soc Exp Biol Med, 2000 Jan, 223(1), 82 - 7
Dexamethasone blocks sepsis-induced protection of the heart from ischemia reperfusion injury; Spanier AJ et al.; Previous investigations have shown that sepsis, while causing cardiac dysfunction, can protect the heart from ischemia-reperfusion injury . Sepsis-induced protection may be due to nitric oxide produced by an inducible form of nitric oxide synthase generated in response to cytokines released during sepsis . The glucocorticoid dexamethasone has been shown to inhibit the synthesis of the inducible form of nitric oxide synthase (iNOS) . The goals of this study were to determine if dexamethasone would prevent sepsis-induced cardiac dysfunction and sepsis-induced protection of the heart from ischemia-reperfusion injury . In this experiment, rats were made septic by injecting Escherichia coli into the dorsal subcutaneous space . Control rats were injected with sterile saline . At the time of surgery, some of the control and septic animals were injected intraperitoneally with dexamethasone (3 mg/kg) . The next day, 24-26 hr after injection of the first dose of E . coli, animals were anesthetized, and hearts were removed and studied in the isovolumic beating-heart preparation . Left ventricular end diastolic pressure was set to 5 mmHg, and left ventricular pressure was measured continuously throughout the protocol . Left ventricular developed pressure (LVDP) was used as an index of LV function . After stabilization, hearts were made globally ischemic for 35 min and then reperfused for 25 min . As has been shown previously, sepsis depressed LVDP but also protected the heart from further depression of LVDP by ischemia and reperfusion . Dexamethasone prevented both sepsis-induced cardiac dysfunction and sepsis-induced protection of the heart from ischemia-reperfusion injury . In addition plasma nitrite/nitrate levels were not different from control levels in the dexamethasone-treated septic rats whereas levels were elevated in the septic animals . The dexamethasone mediated abrogation of sepsis-induced cardiac dysfunction and protection during ischemia-reperfusion injury may be due to suppression of nitric oxide production.

J Gastrointest Surg, 2000 Jan-Feb, 4(1), 70 - 6
Interleukin-10 protects against lethality of intra-abdominal infection and sepsis; Rongione AJ et al.; The aim of this study was to determine whether interleukin-10 would alter locally derived and systemic proinflammatory cytokine expression and protect from the lethality of cecal ligation and puncture . Three groups of Sprague-Dawley rats were used . Group 1 underwent cecal manipulation . Groups 2 and 3 underwent cecal ligation and puncture . Group 2 received intraperitoneal saline injections beginning 1 hour after cecal ligation and puncture and every 3 hours thereafter for 24 hours . Group 3 received intraperitoneal interleukin-10 one hour after cecal ligation and puncture and every 3 hours thereafter . Animals were killed at 6 and 24 hours after cecal ligation and puncture or sham operation . Serum tumor necrosis factor-alpha (TNF-alpha) levels were determined by enzyme-linked immunosorbent assay . TNF-alpha messenger RNA expression was determined by reverse transcriptase-polymerase chain reaction using Beta-actin as the internal standard . There was a twofold increase (P <0.001) in TNF-alpha mRNA in the liver at 6 and 24 hours after cecal ligation and puncture when compared to rats treated with interleukin-10 . There was a twofold increase (P <0.05) in TNF-alpha mRNA in the lung observed only at 24 hours after cecal ligation and puncture when compared to rats treated with interleukin-10 . Serum levels of TNF-alpha were elevated at 6 hours in control animals, and this effect was abolished by the administration of interleukin-10 . There was no difference in mortality rates at 6 hours (0% for all groups); however, at 24 hours 57% (4/7) mortality was observed in group 2 vs . 0% (0/20) in groups 1 and 3 . Interleukin-10 given after the onset of cecal ligation and puncture protects against the lethality of intra-abdominal sepsis.

Biochem Biophys Res Commun, 2000 Jan 19, 267(2), 504 - 8
The gene expression of ubiquitin ligase E3alpha is upregulated in skeletal muscle during sepsis in rats-potential role of glucocorticoids; Fischer D et al.; Muscle protein breakdown during sepsis is associated with upregulated expression and activity of the ubiquitin-proteasome proteolytic pathway . Previous studies suggest that ubiquitination of proteins in skeletal muscle is regulated by the ubiquitin ligase E3alpha together with the 14 kDa ubiquitin-conjugating enzyme E2(14k) . The E3alpha gene was cloned only recently . The influence of sepsis on the gene expression of E3alpha in skeletal muscle has not been reported . In the present study, induction of sepsis in rats by cecal ligation and puncture resulted in increased mRNA levels for E3alpha in white, fast-twitch but not in red slow-twitch muscle . Treatment with the glucocorticoid receptor antagonist RU38486 (10 mg/kg) prevented the sepsis-induced increase in E3alpha and E2(14k) mRNA levels . The present study is the first report of increased E3alpha expression in skeletal muscle during sepsis . The results lend further support to the concept that glucocorticoid-mediated upregulation of the ubiquitin-proteasome proteolytic pathway is involved in sepsis-induced muscle cachexia . Increased expression of both E3alpha and E2(14k) suggests that muscle proteins are degraded in the N-end rule pathway during sepsis .

Semin Thromb Hemost, 1999, 25(6), 531 - 5
Neonatal sepsis: a challenge in hemostaseology; Kreuz W et al.; Several therapeutic approaches to sepsis and disseminated intravascular coagulation (DIC) have shown promising results in animal models . Large controlled trials in humans, however, have failed to show a clearly beneficial effect of a single drug or substance on outcome and survival so that treatment remains uncertain . As one researcher stated: " . . . sepsis is a classical example of a disease greater than the sum of its parts; it is a complex process in which intervention in one area might have only a modest effect on the final outcome." We believe that the complex pathophysiological setting of septic shock will undoubtedly require a multifaceted approach . Consequently, we attempt to arrest DIC and restore adequate tissue perfusion by intervention with heparin, AT and if possible protein C (PC) in the earliest stage of the disease, with the aim of blocking ongoing microthrombus formation and to support fibrinolysis . Growing understanding of the basic underlying mechanisms teaches us how to successfully stabilise the individual decompensated sub-systems like coagulation in septic patients . We should learn to accept these steps to reach the goal of a better outcome in terms of survival in this devastating illness.

J Crit Care, 1999 Dec, 14(4), 186 - 90
Nitric oxide metabolism in canine sepsis: relation to regional blood flow; Tanigawa K et al.; PURPOSE: To investigate the role of nitric oxide (NO) in early endotoxemia on the systemic and regional blood flow by measuring the plasma nitrite/nitrate (NOx) and blood nitrosyl-hemoglobin (NO-Hb) levels . MATERIALS AND METHODS: This was a prospective, controlled, experimental study conducted in an animal research laboratory on 15 male mongrel dogs . Escherichia coli endotoxin (1 mg/kg) was injected intravenously . RESULTS: Hepatic, renal, and iliac blood flow and cardiac output (CO) were measured before and 15, 30, 45, 90 and 180 minutes after injection of Escherichia coli endotoxin (1 mg/kg) (n = 6) . NOx efflux from the organs was calculated by measuring plasma NOx levels . The arterial blood levels of NO-Hb were also measured (n = 4) . As control studies, blood samples from dogs (n = 5) without exposure to endotoxin were assayed at 180 minutes for NOx and NO-Hb . Following endotoxin injection, mean arterial pressure decreased and reached its lowest value at 90 minutes (baseline vs . 90 minutes: 119.1+/-5.8 vs . 82.5+/-16.7 mm Hg, P<.0001) . Hepatic artery blood flow increased significantly (baseline vs . 180 minutes: 23.6+/-12.0 vs . 170.0+/-68.4 mL/ min, P<.0001) . There were no significant changes in plasma levels of NOx, uptake or release of NOx across the measured vascular beds, NO-Hb levels at any time point . In the portal system, the portal vein flow correlated with NOx release (R = 0.69, P<.0001) . CONCLUSION: In the early phase of endotoxemia in the dog, the significant reduction in systemic vascular resistance and hepatic arterial resistance are not associated with any measurable NOx release in the systemic circulation or the liver.

Eur J Emerg Med, 1999 Sep, 6(3), 259 - 61
'Popping': a cause of soft tissue sepsis in chronic drug abusers; Graham CA et al.; Septic complications arising from drug misuse are well documented . It is likely that most complications occur as a result of attempted intravenous (i.v.) injection . We report four cases of soft tissue infections where the patients were unable to obtain i.v . access and gave injections of drugs using a technique known as 'popping' . 'Popping' is the deliberate injection of drugs subcutaneously or intramuscularly when i.v . access is not possible . This practice is further discussed and the literature associated with soft tissue infections from drug misuse is reviewed.

Lancet, 1999 Dec 4, 354(9194), 1955 - 61
Effect of home-based neonatal care and management of sepsis on neonatal mortality: field trial in rural India; Bang AT et al.; BACKGROUND: Neonatal care is not available to most neonates in developing countries because hospitals are inaccessible and costly . We developed a package of home-based neonatal care, including management of sepsis (septicaemia, meningitis, pneumonia), and tested it in the field, with the hypothesis that it would reduce the neonatal mortality rate by at least 25% in 3 years . METHODS: We chose 39 intervention and 47 control villages in the Gadchiroli district in India, collected baseline data for 2 years (1993-95), and then introduced neonatal care in the intervention villages (1995-98) . Village health workers trained in neonatal care made home visits and managed birth asphyxia, premature birth or low birthweight, hypothermia, and breast-feeding problems . They diagnosed and treated neonatal sepsis . Assistance by trained traditional birth attendants, health education, and fortnightly supervisory visits were also provided . Other workers recorded all births and deaths in the intervention and the control area (1993-98) to estimate mortality rates . FINDINGS: Population characteristics in the intervention and control areas, and the baseline mortality rates (1993-95) were similar . Baseline (1993-95) neonatal mortality rate in the intervention and the control areas was 62 and 58 per 1000 live births, respectively . In the third year of intervention 93% of neonates received home-based care . Neonatal, infant, and perinatal mortality rates in the intervention area (net percentage reduction) compared with the control area, were 25.5 (62.2%), 38.8 (45.7%), and 47.8 (71.0%), respectively (p<0.001) . Case fatality in neonatal sepsis declined from 16.6% (163 cases) before treatment, to 2.8% (71 cases) after treatment by village health workers (p<0.01) . Home-based neonatal care cost US$5.3 per neonate, and in 1997-98 such care averted one death (fetal or neonatal) per 18 neonates cared for . INTERPRETATION: Home-based neonatal care, including management of sepsis, is acceptable, feasible, and reduced neonatal and infant mortality by nearly 50% among our malnourished, illiterate, rural study population . Our approach could reduce neonatal mortality substantially in developing countriesPIP: The article presents the effect of home-based neonatal care and management of sepsis on neonatal mortality in the Gadchiroli district of India . The study responds to the growing need for the reduction of neonatal mortality rate in developing countries . Sample population involved 39 intervention and 47 control villages in the Gadchiroli district . Baseline data for 2 years (1993-95) were collected from these districts . Neonatal care was introduced in the intervention villages in 1995-98, wherein village health workers trained in neonatal care made home visits and managed sepsis and other neonatal problems . Other workers recorded all births and deaths in the intervention and the control area (1993-98) to estimate mortality rates . Findings showed that the net percentage reduction in the third year of intervention for the neonatal mortality rate was 25.5 (62.2%); for the infant mortality rate, 38.8 (45.7%); and for the perinatal mortality rate, 47.8 (71.0%) . Case fatality in neonatal sepsis declined from 16.6% before treatment to 2.8% after treatment by village workers (p 0.01) . The article concludes that home-based neonatal care, including management of sepsis could reduce neonatal mortality substantially in developing countries .

Sud Med Ekspert, 1999 Sep-Oct, 44(5), 3 - 6
{Combined trauma and sepsis in forensic medical practice}; Kolontarev BA et al.; The relationship between combined injury and sepsis is an important problem of forensic medicine . A total of 227 cases with combined injuries have been investigated postmortem at Bureau of Forensic Medical Expert Evaluations of Moscow in 1997 . Sepsis developed in 9.7% cases . The studies revealed a direct cause-and-effect relationship between mechanical injuries and development of sepsis in the overwhelming majority of cases . Sepsis may develop at any period of the traumatic disease, except the first one, and the infection is prone to generalization in the remote postoperative period.

Am J Perinatol, 1999, 16(7), 365 - 72
Preeclampsia does not increase the risk for culture proven sepsis in very low birth weight infants; Paul DA et al.; The risk of sepsis associated with neutropenia in infants born to mothers with preeclampsia remains controversial . The objective of this study is to investigate the incidence of culture-proven sepsis along with changes in the complete blood count in very-low-birth-weight infants born to mothers with preeclampsia . We conducted a retrospective cohort study of infants cared for at a single tertiary care neonatal intensive care unit during a 4-year period . Infants born to mothers with preeclampsia (n = 88) were compared to infants born to mothers without preeclampsia (n = 416) by univariate and multivariate analysis . Although infants born to mothers with preeclampsia had lower absolute neutrophil and platelet counts throughout the first week of life, they were no more likely to have a platelet count <100,000 /mm3, and only more likely to be neutropenic at 24 and 72 hr of life compared to infants born to mothers without preeclampsia . After controlling for potential confounding variables, there was no increase in the odds of culture proven sepsis in infants born to mothers with preeclampsia (odds ratio 1.6, 95% confidence intervals 0.7-3.6, p = 0.3) compared to those infants born to mothers without preeclampsia . We conclude that very-low-birth-weight infants born to mothers with preeclampsia are not at increased risk of culture proven sepsis despite a reduction in absolute neutrophils.

Tidsskr Nor Laegeforen, 1999 Nov 10, 119(27), 4061 - 5
{Nitric oxide--an important mediator in sepsis?}; Kirkeboen KA et al.; Animal experiments suggest that hyperproduction of nitric oxide (NO) by the inducible isoform of the enzyme NO synthase (iNOS) may contribute to hypotension, cardiodepression and vascular hyporeactivity in septic shock . Lipopolysaccarides and cytokines, like tumor necrosis factor, interleukin-1 and interferon-gamma, have been shown to induce iNOS in the endothelium, vascular smooth muscle cells, macrophages and different parenchymal cells . In several animal models of septic shock, treatment with inhibitors of NO synthesis has been shown to improve haemodynamic variables and survival . In human septic shock, inhibition of NO synthesis has been shown to alter haemodynamic variables in short term studies . However, a large multicentre study was recently stopped due to increased mortality in patients in septic shock treated with the NO synthase inhibitor NG-monomethyl-L-arginine . The aim of this review is to discuss the role of NO in sepsis and the potential therapeutic implications of NO as a target in treatment of human septic shock . We emphasize that many septic patients have preexisting endothelial dysfunction or lung diseases, which may predispose to severe adverse effects during systemic inhibition of NO synthesis . We also focus on the lack of direct evidence for iNOS expression in human septic shock and on the discrepancy between animal and human data.

Indian J Med Res, 1999 Sep, 110, 98 - 101
Role of intrapartum antibiotics in prevention of vertical transmission of neonatal sepsis; Bagga R et al.; The present study evaluates the role of prophylactic intrapartum antibiotics in the prevention of neonatal sepsis . Labour and delivery characteristics of 1478 women delivering at the Nehru Hospital, PGIMER, Chandigarh were recorded . Intrapartum antibiotics (ampicillin, with or without gentamycin) were given to 69 per cent women . The neonatal sepsis rate was 1.56 per cent . This was not significantly lower in the women who received intrapartum antibiotics (1.47 vs 1.75%) . Though there was a lowering of neonatal sepsis rate with intrapartum antibiotic administration when the duration of labour was more than 12 h (1.67 vs 3.09%), duration of ruptured membranes was more than 6 h (1.93 vs 3.81%) and number of pelvic examination was 3 or more (1.63 vs 4.54%), it was not statistically significant . It was concluded that intrapartum antibiotics as per the existing protocol did not prevent neonatal sepsis.

Yale J Biol Med, 1998 Nov-Dec, 71(6), 485 - 91
Sepsis: clinical dilemmas; Murray MJ; Sepsis, manifested by systemic inflammatory response syndrome (SIRS), septic shock and multiple organ dysfunction syndrome (MODS), remains the leading cause of morbidity and mortality in critically ill patients . Despite advances and our knowledge of sepsis, there remain clinical dilemmas that impact how we treat patients . These clinical dilemmas include hypotension, cardiac dysfunction and altered oxygen consumption . There is increasing recognition that treatment of these problems does not necessarily improve outcome . As we improve our understanding of sepsis, there is increased recognition that improvement in morbidity and survival will come not only from treating the manifestations of sepsis but also the endogenous mediators responsible for the development of these clinically important conditions . This manuscript discusses the clinical dilemmas associated with sepsis, current therapy and future directions for managing sepsis.

Pediatr Nephrol, 1999 Nov, 13(9), 927 - 9
46,XY gonadal dysgenesis associated with congenital nephrotic syndrome and sepsis; Sheu JN et al.; The occurrence of nephrosis in the first 3 months of life is rare and is termed 'congenital nephrotic syndrome.' The congenital nephrotic syndrome is a group of heterogeneous diseases with a clinical course that differs markedly from the childhood nephrotic syndrome . The coexistence of a congenital nephrotic syndrome and gonadal dysgenesis in a 46,XY karyotype with normal female external genitalia is extremely rare . Frequent severe infections are often seen in the Finnish type, but sepsis leading to death is rare in the neonatal onset of gonadal dysgenesis . This report describes an unusual case of complete XY gonadal dysgenesis in a 46,XY female neonate with the congenital nephrotic syndrome and overwhelming sepsis.

Ann Hematol, 1999 Nov, 78(11), 524 - 8
Frequency of very late fatal sepsis after splenectomy for hereditary spherocytosis: impact of insufficient antibody response to pneumococcal infection; Eber SW et al.; Very late sepsis in splenectomized patients with hereditary spherocytosis has been seen rarely up to now; the frequency and the immunodeficiency causing it are largely unknown . Within the past 7 years we have learned of four cases of sepsis or meningitis (three fatal) in adult patients with hereditary spherocytosis who had been splenectomized years earlier . The estimated frequency of very late postsplenectomy infections is 0.69 cases of sepsis or meningitis in 1000 patient-years (0.46 deaths in 1000 patient-years) . Pneumococci were proven in two patients . The surviving patient showed low antibody titers against pneumococcal serotypes even after pneumococcal meningitis and subsequent vaccination . There have been several reports of an insufficient response to pneumococcal vaccination in patients with severe infections . We recommend determination of pneumococcal antibody titers after immunization in every splenectomized patient: Nonresponders to vaccination may be at high risk for overwhelming postsplenectomy infection . Our data demonstrate that there is a lifelong risk for severe postsplenectomy infections and therefore the lasting need for immediate antibiotic therapy in any case with sudden onset of high fever.

Wien Klin Wochenschr, 1999 Nov 12, 111(21), 868 - 75
{Infection, sepsis and cardiac arrhythmia}; Heinz G; In clinical practice, the occurrence of arrhythmias in a critical ill patient is often assumed to be due to underlying infection or sepsis . This relationship has been suggested by both case reports and textbooks of Internal Medicine . Two scenarios are deemed possible: The occurrence of "preexisting" arrhythmias in susceptible patients (those with an arrhythmogenic substrate, e.g . a myocardial infarction scar) and the occurrence of arrhythmias mediated in some way through the infection/sepsis in otherwise unsusceptible patients . The present overview portrays the scarcity of data and shows that neither scenario is supported by firm data . While sinus tachycardia is among the spectrum of expected abnormalities during infection or sepsis, bradycardia may be observed in selected cases . This seems to occur relatively frequently in patients with fungemia.

Clin Nucl Med, 1999 Dec, 24(12), 927 - 30
Biliary sepsis as a cause of appearance of endoluminal Tc-99m HMPAO-labeled leukocytes: a case report; Robins PD et al.; A case is presented that shows the abnormal early appearance of Tc-99m HMPAO-labeled leukocytes within the small bowel lumen as a result of septic cholangitis . It is essential to perform early images with Tc-99m HMPAO-labeled leukocytes to differentiate between the appearance of abnormal uptake in the bowel and normal physiologic excretion, which occurs later in the renal and biliary tracts . Endoluminal radiolabeled leukocytes have been described in several clinical settings unrelated to bowel disease, such as swallowed activity from sinus or pulmonary infection, and it is important to differentiate this from primary gastrointestinal disease . To our knowledge, acute pyogenic cholangitis has not been shown previously as a cause of these appearances and should be included in the differential diagnosis for the early appearance of mobile radiolabeled leukocytes in the lumen of the gastrointestinal tract.

Arch Surg, 1999 Dec, 134(12), 1342 - 7
Gender-based differences in outcome in patients with sepsis; Eachempati SR et al.; HYPOTHESIS: Among factors postulated to affect outcome in sepsis is the gender of the patient, with a suggestion that females may have lower mortality . This study tested the hypothesis that female patients admitted to the surgical intensive care unit with a documented infection have a lower mortality rate . DESIGN: Retrospective analysis of a prospectively collected data set . SETTING: Surgical intensive care unit of a university hospital medical center . METHODS: Analysis of a consecutive series of 1348 patients who had signs of systemic inflammatory response syndrome on admission to a surgical intensive care unit . A cohort of 443 patients (32.9%) admitted with documented infection--and who therefore had sepsis, severe sepsis, or septic shock--constituted the study population . For each patient, APACHE (Acute Physiology and Chronic Health Evaluation) II and III scores, systemic inflammatory response syndrome score, gender, age, and hospital mortality were recorded . Chi2 With Fisher exact test was performed to compare mortality rates between males and females . Univariate analysis of variance was used to compare continuous variables in discrete populations . Multivariate analysis of variance was used to determine which factors independently predicted mortality . PRIMARY OUTCOME MEASURES: Mortality, intensive care unit length of stay, hospital length of stay, and maximal multiple organ dysfunction score . Outcomes stratified by gender . RESULTS: Patients had mean +/- SEM age of 67+/-1 years; mean +/- SEM APACHE II and III scores of 20.1+/-0.4 and 67.7+/-1.0 points, respectively . There were no demographic differences between genders . Overall, 104 (23.5%) of 443 patients with sepsis died . The difference in mortality rates between female and male patients was not significant, except in octogenarians (P = .05) . Multivariate analysis of variance, APACHE III (P<.001), maximal multiple organ dysfunction score (P<.001), and female gender (P =.02) predicted mortality . In females, APACHE III (P = .03) and maximal multiple organ dysfunction score (P<.001) predicted mortality, but age did not . CONCLUSION: Female gender is an independent predictor of increased mortality in critically ill surgical patients with documented infection.

Proc Natl Acad Sci U S A, 1999 Dec 7, 96(25), 14541 - 6
Prevention of lymphocyte cell death in sepsis improves survival in mice; Hotchkiss RS et al.; Sepsis induces extensive lymphocyte apoptosis, a process which may be beneficial to host survival by down-regulating the inflammatory response or, alternatively, harmful by impairing host defenses . To determine the beneficial vs . adverse effects of lymphocyte apoptosis in sepsis, we blocked lymphocyte apoptosis either by N-benzyloxycarbonyl-Val-Ala-Asp(O-methyl) fluoromethyl ketone (z-VAD), a broad-spectrum caspase inhibitor, or by use of Bcl-2 Ig transgenic mice that selectively overexpress the antiapoptotic protein Bcl-2 in a lymphoid pattern . Both z-VAD and Bcl-2 prevented lymphocyte apoptosis and resulted in a marked improvement in survival . z-VAD did not decrease lymphocyte tumor necrosis factor-alpha production . Considered together, these two studies employing different methods of blocking lymphocyte apoptosis provide compelling evidence that immunodepression resulting from the loss of lymphocytes is a central pathogenic event in sepsis, and they challenge the current paradigm that regards sepsis as a disorder resulting from an uncontrolled inflammatory response . Caspase inhibitors may represent a treatment strategy in this highly lethal disorder.

Shock, 1999 Dec, 12(6), 421 - 7
Attenuation of catecholamine-induced immunosuppression in whole blood from patients with sepsis; Bergmann M et al.; Studies performed on healthy volunteers have revealed that catecholamines down-regulate the lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)alpha, interleukin (IL)-6, and IL-1beta . We extended this observation and show that this effect is based on changes in the mRNA concentration of these cytokines . Catecholamines are increased in severe sepsis due to endogenous production and have to be administered exogenously when the disease has proceeded to the state of prolonged hypotension . We here investigated whether the immunomodulating effect of catecholamines could also be demonstrated in the blood of patients with prolonged severe sepsis and of those in prolonged septic shock . Blood was stimulated ex vivo with LPS in the presence and absence of epinephrine and the cytokine protein concentration was determined . In blood of healthy volunteers, epinephrine reduced the LPS-stimulated synthesis of TNFalpha by 62.5% (P< 0.0001), of IL-6 by 39% (P< 0.0001), and of IL-1beta by 40% (P= 0.015), and increased the LPS-stimulated IL-10 production by 77.8% (P < 0.0001) . Correspondingly, in blood of patients with prolonged severe sepsis, TNFalpha was reduced by 67.2% (P < 0.0001) and IL-6 was reduced by 32.9% (P < 0.0001); IL-1beta and IL-10 were not modulated by catecholamines in these patients . In blood samples of patients in prolonged septic shock, epinephrine did not modulate cytokine levels of IL-6 and IL-10, and decreased TNFalpha only by 36.4% (P < 0.0001) . Interestingly, epinephrine suppressed the IL-1beta production by 73% (P < 0.0001) in blood of patients in prolonged septic shock, which was twice as much as in blood samples of healthy volunteers . The altered response of septic blood to catecholamines might be due to an altered reactivity of leukocytes in the prolonged disease although an additional role of preexisting catecholamines cannot be completely excluded.

Rheumatology (Oxford), 1999 Dec, 38(12), 1272 - 4
Frequency of sepsis after local corticosteroid injection (an inquiry on 1160000 injections in rheumatological private practice in France); Seror P et al.; OBJECTIVES: The principal aims of this study were to determine the frequency of sepsis after local corticosteroid injection (SALCSI), to compare the results with those of the literature and to determine the main factors leading to a decrease in the frequency of SALCSI . METHODS: A retrospective study was conducted among 69 rheumatologists in private practice . Sixteen items were studied and are reported . RESULTS: The mean number of years of private practice in rheumatology was 20.9 . The total number of CS injections (CSI) was 1160000 for an average of 809 CSI per year and per therapist . The mean number of CSI performed by one rheumatologist was 16 800 . Fifteen SALCSI had occurred, which corresponds to a frequency of 1/77300 CSI . The rate of SALCSI for the older rheumatologists was lower than that of their younger colleagues . The frequency of use of corticosteroid packaged in a sterile syringe (CSPSS) was approximately 85% . Nine out of the 15 cases of sepsis had occurred after the use of CS not packaged in a sterile syringe and six after the use of CSPSS . Thus, the frequency of SALCSI was 1/162000 after the use of CSPSS and 1/21000 after the use of CS not packaged in a sterile syringe . CONCLUSIONS: The mean frequency of SALCSI in Paris and the surrounding area was 1/77300 during the last 21 yr, a decrease since the 1960s and 1970s . This decreased incidence is in part due to the greater experience of the rheumatologist, but even more to the use of CSPSS.

Klin Khir, 1999, (10), 12 - 3
{The use of efferent approach of detoxication and immunologic correction in the combined treatment of acute sepsis}; Lagoda AE et al.; In 90 patients with an acute sepsis application of cryopreserved hepatocytes and splenic sections had promoted detoxication and immunocorrection, improved the rehabilitational indexes significantly.

Crit Care Med, 1999 Nov, 27(11), 2361 - 6
A prospective study of the use of a dobutamine stress test to identify outcome in patients with sepsis, severe sepsis, or septic shock; Rhodes A et al.; OBJECTIVE: To more clearly define the relationship between an oxygen flux test, oxygen supply dependency, and outcome in patients with sepsis, severe sepsis, or septic shock . DESIGN: Prospective, interventional clinical trial . SETTING: A teaching hospital general intensive care unit in London, UK . PATIENTS: A total of 36 patients with sepsis, severe sepsis, or septic shock were studied during a 10-month period . INTERVENTIONS: After resuscitation, patients were given an intravenous infusion of dobutamine at 10 microg/kg/min for 1 hr . Cardiac and respiratory variables were measured before the infusion and then while the infusion was in progress . Any patient who was able to increase his or her oxygen consumption by >15% was designated a responder to the test . MEASUREMENTS AND MAIN RESULTS: Hemodynamic, oxygen transport, and lactate measurements were made at baseline and after 1 hr of the dobutamine infusion . All patients were then followed up until hospital discharge . Responders to this test had a hospital mortality of 14%, whereas nonresponders had a mortality of 91% (p<.01) . The responders were characterized by being younger (p<.05), having higher Acute Physiology and Chronic Health Evaluation III scores (p<.05), and having a greater requirement for inotropic support (p<.05) . After the test, the responders had significantly higher oxygen delivery (p<.01) and oxygen consumption (p<.05) than the nonresponders, as well as a significantly greater temperature increase as a result of the infusion (p<.05) . The nonresponders were unable to increase either oxygen delivery or oxygen consumption to the dobutamine . This test was highly predictive of outcome (p<.0001) . The identification of an increase in both oxygen delivery and oxygen consumption (oxygen supply dependency) was not associated with a poor outcome . CONCLUSION: A dobutamine oxygen flux test provides evidence of the intrinsic function of cells . The inability of these cells to increase oxidative metabolism during sepsis, as indicated by the dobutamine test, is associated with a high mortality.

Khirurgiia (Mosk), 1999, (10), 35 - 8
{Modern aspects of wound sepsis in war surgical trauma}; Briusov PG et al.; The results of the treatment of 1020 wounded with symptoms of wound infection have been studied . The wounded were admitted with developed complications from the hospitals in Afghanistan . The syndrome of systemic inflammatory reaction detected in 239 (23.4%) wounded was the indication for application of the whole complex of antiseptic treatment . Sepsis in patients with complicated gunshot wounds was revealed only in 54 wounded, i.e . in 5.4% . Early diagnosis and multicomponent therapy resulted in a decrease of mortality rate in wound sepsis up to 9.3%.

Khirurgiia (Mosk), 1999, (10), 24 - 8
{Biliary sepsis: some peculiarities of pathogenesis}; Gal'perin EI et al.; Results of clinical study of 87 biliary sepsis patients and experimental study on 54 rats with obstructive jaundice and cholangitis are presented . Own and literary data are compared . Specific immune and portal haemodynamic changes, provoced by obstructive jaundice are main pathogenic factors defining specific course of biliary sepsis . These changes are: 1) gut bacterial and endotoxin translocation, portal endotoxaemia; 2) reduction of RES and Kupfer cell function and endotoxin break into the systemic circulation; 3) liver parenchyma ischemia and milliary abscess formation; 4) portal blood flow shunting into the general circulation additionally increasing systemic endotoxaemia . These factors determine rapid, even fulminate development of milliary abscesses of the liver and multiorganic failure . The authors suggest that etiologic and pathogenic factors, causing peculiarities of the clinical course should be indicated in the diagnosis of septic patient.

Khirurgiia (Mosk), 1999, (10), 9 - 12
{On the problems of sepsis classification}; Petrov VP; The article is devoted to classification of sepsis . Two classifications are compared: the Russian one, developed in A.V . Vishnevsky Institute of Surgery (phase I--the initial one or toxemia, phase 2--septicemia; 3--septicopyemia), and the American one, accepted in 1991 in Chicago which singles out three forms of sepsis (sepsis, severe sepsis or sepsis-syndrome, and septic shock) . Both classifications are thoroughly analysed and it is stated that there is no principal disagreement in the definition of phases of the course and description of clinical stages of sepsis . The necessity for universal classification of sepsis is emphasized.

Khirurgiia (Mosk), 1999, (10), 4 - 8
{Surgical sepsis-definition of the notion . Problems of terminology}; Svetukhin AM et al.; The problems of terminology are discussed, as well as classification and definition of sepsis . Comparative analysis of traditional for our country and up-to-date foreign classifications is carried out . The criteria for diagnosis of sepsis are discussed . On the basis of 20-year experience in examination and treatment of patients with sepsis, the authors set forth their own stand, suggesting two varieties of sepsis for consideration: common complication of surgical infection, a rare disease.

J Paediatr Child Health, 1999 Oct, 35(5), 488 - 92
Sepsis, severe sepsis and septic shock in paediatric multiple organ dysfunction syndrome; Goh A et al.; OBJECTIVES: To determine the association between severity of sepsis with outcome and severity of illness in children with multiple organ dysfunction syndrome (MODS) . MATERIALS: Four hundred and ninety-five consecutive paediatric intensive care unit (PICU) admissions were analysed . multiple organ dysfunction syndrome was defined as simultaneous dysfunction of >/= 2 organ system and sepsis by the American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference definition . RESULTS: Eighty-four patients developed MODS . The incidence of sepsis, severe sepsis and septic shock in these patients was 10.7%, 23.8% and 17.9%, respectively . Worsening categories of sepsis were associated with: (1) a higher mean admission Paediatric Risk of Mortality (PRISM II): 36.6 +/- 25.9, 56.8 +/- 32.1 and 73.6 +/- 28.5%, respectively (P = 0 . 005), (2) a larger number of organ dysfunctions: mean MODS index of 37%, 46% and 58%, respectively (P = 0.007), and (3) a higher mortality: 22.2%, 65% and 80%, respectively (P = 0.03) . CONCLUSION: Presence of sepsis, severe sepsis and septic shock was associated with an increasing severity of illness, increased number of organ dysfunctions and a distinct risk of mortality among critically ill children.

Nippon Geka Gakkai Zasshi, 1999 Oct, 100(10), 674 - 8
{Recent clinical trials for sepsis: analysis of the results and future perspectives}; Wakabayashi G et al.; Recent clinical trials with experimental immunotherapeutic agents for sepsis have not proven their overall benefit yet although some studies suggested significant effect of these antisepsis therapies . This review article summarizes the results of these trials, their analysis, lessons learned from past failure, and future perspectives for immunotherapies as anti-sepsis treatments.

Infect Immun, 1999 Dec, 67(12), 6603 - 10
Immunopathologic alterations in murine models of sepsis of increasing severity; Ebong S et al.; We investigated inflammatory and physiologic parameters in sepsis models of increasing lethality induced by cecal ligation and puncture (CLP) . Mice received imipenem for antibiotic therapy, and groups were sacrificed at 2, 4, 8, 12, 16, 20, and 24 h after CLP . The severity of sepsis increased with needle puncture size (lethality with 18-gauge puncture {18G}, 100%; 21G, 50%; 25G, 5%; sham treatment, 0%) . While the temperature (at 12 h) and the activity and diurnal rhythm (at day 4) of the 25G-treated CLP group recovered to normal, the 21G and 18G treatment groups exhibited severe hypothermia along with decreased activities . A direct correlation was also observed between the severity of sepsis and cytokine (interleukin 1beta {IL-1beta}, tumor necrosis factor {TNF}, IL-6, and IL-10) concentrations in both the peritoneum and the plasma . There were substantially higher cytokine levels in the more severe CLP models than in the sham-treated one . Peritoneal and plasma TNF levels were always less than 40 pg/ml in all models . None of the cytokines in the septic mice peaked within the first hour, which is in contrast to the results of most endotoxin models . Chemokine (KC and macrophage inflammatory protein 2) profiles also correlated with the severity of sepsis . Except for the chemokines, levels of inflammatory mediators were always higher at the site of inflammation (peritoneum) than in the circulation . Our study demonstrated that sepsis of increasing severity induced increased cytokine levels both within the local environment (peritoneum) and systemically (plasma), which in turn correlated with morbidity and mortality.

Int J Mol Med, 1999 Dec, 4(6), 575 - 83
Organ dysfunction following hemorrhage and sepsis: mechanisms and therapeutic approaches (Review); Jarrar D et al.; Despite significant advances in the management of trauma victims, sepsis and the ensuing multiple organ failure remain the leading causes of death in the surgical intensive care unit . Although much effort has been focused on the mediators released in large quantities following shock and sepsis, blockade of mediators such as proinflammatory cytokines has not yet resulted in a successful therapy . However, as more studies are forthcoming, the mechanisms responsible for cell and organ dysfunctions following trauma-hemorrhage and sepsis are becoming better understood, and promising new therapeutic approaches are currently being evaluated . In order to understand the precise mechanisms responsible for cellular dysfunction and consequently irreversible organ damage and multiple organ failure, it is important to correlate various pathophysiological changes with mediators and signal transduction pathways at the cellular and subcellular level . In this review we focus first on factors and mediators responsible for producing cell and organ dysfunctions, especially hepatocellular dysfunction, following trauma, hemorrhagic shock, and sepsis . The changes in signaling transduction pathways will also be discussed, specifically the role of mitogen-activated protein kinases, transcription factors, nitric oxide, heat shock proteins, and inflammatory cytokines in the development of cell and organ dysfunctions following trauma-hemorrhage and sepsis . Moreover, potential therapeutic approaches for improving cell and organ functions under adverse circulatory conditions are included.

Curr Opin Clin Nutr Metab Care, 1998 Mar, 1(2), 217 - 24
Regulation of skeletal muscle protein turnover during sepsis; Vary TC; Wasting of skeletal muscle protein is a prominent feature of the metabolic response to sepsis . Persistent protein wasting leads to muscle dysfunction and prolongs recovery from the septic insult . Unfortunately, conventional nutritional support alone does not prevent the sepsis-induced weight loss and catabolism of muscle . Hence, mechanisms other than substrate deficiency appear to be involved in the derangements in protein metabolism during sepsis . The catabolism of muscle during sepsis results from a stimulation of proteolysis and an inhibition of protein synthesis . Despite the importance of these pathways in maintaining muscle mass, the regulation of protein synthesis and proteolysis during sepsis remains poorly understood . This review summarizes the mechanisms responsible for alterations in protein synthesis and degradation in muscle during sepsis at the biochemical level . The ability of hormones (insulin, insulin-like growth factor I, glucocorticoids) or cytokines (tumor necrosis factor, interleukin-1) to act as mediators or modulators of protein catabolism is also examined . A picture is emerging suggesting that cytokines may influence skeletal muscle protein metabolism during sepsis both indirectly, through inhibition of the regulatory actions of anabolic hormones on protein turnover, and directly, through modulation of the protein synthesis and degradation enzymatic machinery.

Kidney Int Suppl, 1999 Nov, 72, S99 - 103
Hemofiltration treatment for sepsis: is it time for controlled trials?
Rogiers P.
While the use of hemofiltration to treat septic shock has potential benefits, the existing studies are difficult to compare because of their variety of inclusion criteria . The concept is to remove the various mediators of severe sepsis and septic shock, such as cytokines and eicosanoids, so that acute renal failure and the resultant multi-organ failure and possible death can be delayed or prevented . The dilemmas include: (a) hemofiltration cannot distinguish between these pro-inflammatory mediators as they are of similar molecular weights, and thus it is difficult to determine which one or combination should be eliminated for the best hemodynamics; (b) timing of the hemofiltration to remove a particular cytokine may make a difference in patient outcome; (c) the most efficacious convection rate of ultrafiltration has not been determined yet; (d) since these mediators quickly saturate the membrane, it should be frequently changed, and thus biocompatibility, availability and costs are added issues; (e) the choice of buffer is different according to the diagnosis of these critically ill patients . Before designing clinical trials, further experimentation is necessary to explore these problems.

Kidney Int Suppl, 1999 Nov, 72, S84 - 7
Tumor necrosis factor-alpha during continuous high-flux hemodialysis in sepsis with acute renal failure; Lonnemann G et al.; Suppressed ex vivo endotoxin (ET)-induced production of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), in isolated mononuclear cells (PBMCs) is associated with fatal outcome in severe sepsis . PBMCs from surviving patients, but not those from nonsurviving patients, recover their capacity to produce normal amounts of TNF-alpha . We tested the influence of two modalities of continuous renal replacement therapy (CRRT) on ex vivo-induced whole-blood production of TNF-alpha and inhibitory TNF-soluble receptor type I (TNFsRI) in 12 patients with acute renal failure and sepsis (APACHE II score 22 to 30) . METHODS: Standard continuous venovenous hemofiltration (CVVH; 36 liters of bicarbonate substitution fluid per day) was performed in 7 patients using polyamid hemofilters (FH66; Gambro) . In an additional five patients, we performed daily 18 hours of high-flux hemodialysis (CHFD) using polysulfon F60S dialyzers (Fresenius) and 75 liters of bicarbonate dialysate using the GENIUS single-pass batch dialysis system . Samples were separated from the blood circuit as well as from the ultrafiltrate/spent dialysate lines at the start, during, and end of treatment . Whole-blood samples were incubated with 1 ng/ml of ET for three hours at 37 degrees C . Ultrafiltrate or dialysate samples were incubated with donor whole blood in the presence of ET to measure suppressing activity in ultrafiltrate and spent dialysate . RESULTS: At the start of CRRT, ET-induced whole-blood TNF-alpha production was suppressed to approximately 10% of that in normal controls . During CVVH, median ET-induced TNF-alpha production increased from 0.35 ng/ml at the start to 1.2 ng/ml at three hours, but decreased to pre-CVVH levels at the end of a 24-hour period . In contrast, in patients on CHFD, the median ET-induced TNF-alpha production was 0.5 ng/ml at the start, 1.1 ng/ml at 3 hours, 1.6 ng/ml at six hours, and 1.5 ng/ml at the end of 18 hours of treatment . The ultrafiltrate obtained after three hours of CVVH did not contain suppressing activity . In CHFD, the spent dialysate as compared with fresh dialysate suppressed ET-induced TNF-alpha production in donor blood by 33% throughout the 18 hours of treatment . Whole-blood production of TNFsRI did not change significantly at any time point during CVVH or CHFD . CONCLUSION: These data suggest that high-volume CHFD is superior to standard CVVH in removing a suppressing factor of proinflammatory cytokine production . As CVVH only transiently improves TNF-alpha production, it is most likely that the putative suppressing factor is removed because of saturable membrane adsorption in CVVH . In CHFD, there is a combination of adsorption and detectable diffusion into the dialysate . It remains to be shown whether a further increase in the volume of dialysate per day is able to not only improve but normalize the cytokine response and improve outcome in septic patients with acute renal failure.

Med Klin (Munich), 1999 Oct 15, 94 Suppl 3, 54 - 7
{Significance of selenium in intensive care medicine . Clinical studies of patients with SIRS/sepsis syndrome}; Gartner R et al.; Selenium is an essential component of the intracellular antioxidant system as a structural component of the active center of the glutathione peroxidase enzymes . These selenoenzymes play a major role in protecting cells against peroxidation, especially lipid peroxidation and selenium seems to play a direct role in the regulation of inflammatory processes . In conditions of systemic inflammatory response or sepsis, patients are exposed to severe oxidative stress . These patients already have both, a decreased plasma selenium and glutathione peroxidase activity at admission to the ICU as has been shown in several studies . The degree of selenium deficiency is correlated with the severity of disease and the incidence of mortality . The reason for the low plasma selenium levels is unknown . Especially it would be of interest a) if the low plasma selenium is the consequence of the systemic inflammatory response with distribution of selenium in other compartments of the body, b) most important, whether the substitution of selenium might improve the outcome and decrease the mortality rate of these patients . In 2 independently performed intention-to-treat studies including patients with systemic inflammatory response syndrome or sepsis a beneficial effect of selenium supplementation on multiple organ function and outcome could already be demonstrated as well as a tendency of an improved mortality rate . A prospective analytical study clearly could demonstrate the inverse relationship between low plasma selenium and morbidity and mortality of patients with SIRS/sepsis . The results of these studies are so convincing, that we propose a randomized, prospective, double blind multicenter phase-III study including patients with systemic inflammatory response syndrome or sepsis to investigate, whether a high-dose selenium substitution in addition to the recommended treatment strategies for patients with sepsis improves outcome and mortality rate of these patients.

Intensive Care Med, 1999 Oct, 25(10), 1165 - 8
Cardiac troponin: a new serum marker of myocardial injury in sepsis; Fernandes CJ Jr et al.; OBJECTIVE: Echocardiogram-derived left ventricular ejection fraction (LVEF) is usually utilized to evaluate left ventricular function, including that of septic patients . However, LVEF is greatly influenced by afterload . The aim of this study was to test the hypothesis that troponin I, a serum marker of myocardial injury, may be able to detect left ventricular involvement by the septic process, being at least as sensitive an indicator of left ventricular dysfunction as LVEF in these patients . DESIGN: Comparison of echocardiogram-derived LVEF with serum levels of troponin I in ten critically ill septic patients . SETTING: General intensive care unit in a tertiary care private hospital . PATIENTS: Ten critically ill septic patients with no previous documented heart disease . MEASUREMENTS AND RESULTS: Patients were simultaneously submitted to a two-dimensional echocardiogram and troponin I determinations . LVEFs and troponin I levels were analyzed in a two-by-two table in order to validate troponin I as a new biochemical marker of myocardial injury in sepsis . All the patients whose LVEF was < 0.5 had elevated troponin I levels (kappa = 0.61, p = 0.035) . CONCLUSIONS: Identification of myocardial dysfunction in septic patients has been a challenging task . Troponin I, a serum marker of myocardial injury, may be of great help in the recognition of myocardial involvement by sepsis in a noninvasive and readily available way.

J Am Coll Surg, 1999 Nov, 189(5), 450 - 8
Interventions to improve cardiopulmonary hemodynamics during laparoscopy in a porcine sepsis model; Grief WM et al.; BACKGROUND: Laparoscopy is increasingly used in severely ill and acutely septic patients . In animals undergoing laparoscopy, the hemodynamic response to sepsis is blunted . Specific interventions to augment the hemodynamic potential may make laparoscopic intervention a safer alternative in septic patients . We compared different interventions to improve hemodynamic performance during exploratory laparoscopy in a porcine endotoxic shock model . STUDY DESIGN: Domestic pigs (n = 12) received intravenous lipopolysaccharide injection and underwent surgical abdominal exploration using either laparoscopy or conventional laparotomy . For comparison, pigs exposed to endotoxin underwent laparoscopy with these interventions: intravenous infusions of prostacyclin (n = 5) or indomethacin (n = 4), intravenous crystalloid resuscitation (n = 5), pulmonary hyperventilation (n = 4), or abdominal insufflation with air (n = 5) . Hemodynamic measurements and blood gas analyses were obtained using Swan-Ganz and arterial catheters . RESULTS: Septic animals treated with prostacyclin undergoing laparoscopy had a higher cardiac index (CI, p < 0.01), stroke volume (SV; p < 0.001) and oxygen delivery (p < 0.05) than the untreated group . Likewise, treatment with indomethacin was associated with a higher CI (p < 0.001), SV (p < 0.005), and oxygen delivery (p < 0.005) compared with the untreated group . These effects may be secondary to a decreased pulmonary vascular resistance, demonstrated in the animals that received either prostacyclin (p < 0.05) or indomethacin (p < 0.05) . In addition, animals given aggressive fluid resuscitation had a significantly higher CI (p < 0.05) and SV (p < 0.001) than those with normal fluid resuscitation during laparoscopy . Manipulation of arterial pH by insufflation of the abdomen with air to create the pneumoperitoneum, or by aggressively hyperventilating the animals, did not improve CI . CONCLUSIONS: Adverse effects of laparoscopy on cardiovascular hemodynamics in the septic state may be mediated by increased pulmonary vascular resistance, diminished venous return, or both . Specific interventions to reverse these variables may ameliorate hemodynamic changes seen.

Acta Clin Belg, 1999 Aug, 54(4), 201 - 6
Liver perfusion and hepatocellular inflammatory response in sepsis; Smets D et al.; Sepsis is characterized by disturbances in liver perfusion and alterations in intrahepatic cellular functions and interactions . This provokes structural and functional liver damage as well as hepatocellular activation that is believed to perpetuate the immuno-inflammatory response . Changes in hepatic perfusion during sepsis are still poorly understood due to the heterogeneity of septic animal models and the difficult accessibility of the hepatic circulation in humans . Sinusoidal blood flow is severely compromised during sepsis due to a decline in perfused sinusoidal area in association with a decrease in sinusoidal flow velocity . Imbalances in the production of nitric oxide may account for these (micro) circulatory disorders . Interactions between liver macrophages, activated endothelial cells and hepatocytes determine the intensity of inflammation and contribute to initial liver damage . Hepatocellular injury is then enhanced by attracted and invading neutrophils . The management of hepatic dysfunction during sepsis is largely supportive and based on prevention and vigorous resuscitation including early nutritional support and adequate oxygenation . Interestingly, experimental studies suggest that pharmacological interventions with significant hemodynamic effects, such as dobutamine and nitric oxide synthase inhibitors, may adversely affect the liver during the septic process.

J Card Surg, 1998 Nov-Dec, 13(6), 440 - 4
Stentless xenograft repair of excavating aortic root sepsis; Katsumata T et al.; BACKGROUND: A variety of surgical techniques are used to manage a disintegrated aortic annulus in patients with endocarditis and excavating aortic root sepsis . Homograft root replacement is preferable in this setting but suitable homografts are restricted in availability and excision of the aortic root carries the risk of postoperative bleeding . As an alternative we used a stentless porcine xenograft root (Medtronic Freestyle valve) to manage this problem . METHODS: Three male patients with active endocarditis presented with aortic root abscess and partial or complete aorto-left ventricular discontinuity . One had prosthetic valve endocarditis, and the abscess cavity entered the right atrium in another . The porcine aortic root was successfully implanted using the modified subcoronary technique providing a repair within the aortic root with proximal and distal suture lines that excluded the disintegrating tissues from the blood stream . All patients were treated with intravenous antibiotics for 6 weeks postoperatively and none suffered recurrent infection (follow-up > 6 months) . CONCLUSION: The stentless porcine aortic root implanted within the human aorta provides an additional surgical option for excavating aortic root sepsis.

Schweiz Med Wochenschr, 1999 Oct 2, 129(39), 1410 - 7
{Activation of plasma cascade systems in sepsis: role of C1 inhibitors}; Zeerleder S et al.; During sepsis the complement system, the contact activation system and the coagulation cascade are activated . Activation of these plasmatic cascades contributes to the development of multiple organ failure and the high mortality rate of severe sepsis and septic shock . C1-inhibitor is the main inhibitor of the classical pathway of the complement system (C1s and C1r), of the contact activation system (factor XIIa and kallikrein) and of the intrinsic pathway of coagulation (factor XIa) . During sepsis, C1-inhibitor is proteolytically inactivated . The increase of inactivated C1-inhibitor in plasma correlates positively with mortality in septic patients . C1-inhibitor substitution has been shown to reduce the mortality in experimental animals with severe sepsis or septic shock . Only a few cases of C1-inhibitor substitution in patients with severe sepsis or septic shock have been reported . C1-inhibitor has been shown to attenuate the activation of the complement system and the contact activation system and to improve hypotension . Based on this convincing pathophysiological concept and the results of the animal studies, we initiated the "Bernese C1-inhibitor study", a randomised double-blind and placebo-controlled pilot study involving administration of C1-inhibitor to patients with severe sepsis or septic shock . If the results of this pilot study confirm the results of the reports mentioned above, they will serve as a base for larger multicentre studies.

Fetal Diagn Ther, 1999 Sep-Oct, 14(5), 262 - 3
Extrasystoles in the fetal CTG during labour might be a first sign of fetal-neonatal sepsis; van Kordelaar LS et al.; A case of extrasystoles in the fetal electrocardiogram during labour is presented as a possible early sign of fetal-neonatal sepsis . Colleagues are invited to respond similar experience.

J Trauma, 1999 Oct, 47(4), 719 - 23
Systemic activation of tissue-factor dependent coagulation pathway in evolving acute respiratory distress syndrome in patients with trauma and sepsis; Gando S et al.; BACKGROUND: Extravascular coagulation and fibrin deposition coupled with perturbations of intravascular coagulation occurs in association with acute respiratory distress syndrome (ARDS) . To evaluate the pathogenetic role of an extrinsic coagulation pathway in the intravascular coagulation of ARDS patients and to explore the time course of the changes of tissue factor levels, platelet counts, and disseminated intravascular coagulation (DIC), we performed a prospective cohort study . METHODS: The study subjects consisted of 113 patients: 27 patients with ARDS, 31 patients at risk for but not developing the syndrome, and 55 patients without ARDS . According to the underlying disease, the patients were further subdivided into two groups: patients with trauma (n = 76) and patients with sepsis (n = 37) . Ten normal healthy volunteers served as control subjects . Plasma tissue factor antigen (tissue factor) levels and platelet counts were measured on the day of admission and on days 1 through 4 after admission . Simultaneously, the DIC scores were determined . RESULTS: The values of tissue factor in the patients with ARDS were significantly more elevated than those measured in the other two groups (p < 0.001) and control subjects (p < 0.001) on the day of admission . The values continued to be markedly high up to day 4 of admission . On the day of admission, the platelet counts in the ARDS patients showed significantly lower values (p < 0.05) than those in the other two groups . The incidence of DIC and the DIC scores in ARDS patients were significantly higher than those in the other two groups . The tissue factor levels (r(s) = 0.428, p < 0.0001) and DIC scores (r(s) = 0.357, p < 0.0002) correlated significantly with Lung Injury Score . When the patients were subdivided into two subgroups, i.e., trauma and sepsis, some differences of the tissue factor levels were noted between the two groups . CONCLUSION: We demonstrated that tissue-factor dependent coagulation pathway of plasma is extensively activated in patients with ARDS, followed by intravascular coagulation and platelet consumption . We further provide precise information on the time course of tissue factor levels and DIC in patients with ARDS and those at risk for developing this syndrome.

J Trauma, 1999 Oct, 47(4), 706 - 12
Differential alterations in systemic and regional oxygen delivery and consumption during the early and late stages of sepsis; Yang S et al.; BACKGROUND: Studies have indicated that regional changes in oxygen utilization during sepsis cannot be predicted from the changes in the whole body oxygen delivery (DO2) and consumption (VO2) . The aim of this study, therefore, was to determine whether differential alterations in systemic and regional DO2 and VO2 occur during the early and late stages of sepsis . METHODS: Adult male Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP) . At 5 hours (i.e., the early, hyperdynamic phase of sepsis) or 20 hours (i.e., the late, hypodynamic phase) after CLP, cardiac output, and organ blood flow were measured by radioactive microspheres . Systemic and regional DO2 and VO2 were determined and plasma levels of lactate were measured . RESULTS: Cardiac output and blood flow to the liver, small intestine, and kidneys increased at 5 hours and decreased at 20 hours after CLP . Although both systemic DO2 and VO2 increased at 5 hours after CLP, systemic DO2 but not VO2 decreased at 20 hours . At 5 hours after CLP, intestinal and renal DO2 increased . However, DO2 in all the tested organs decreased at 20 hours after CLP . VO2 increased in the liver, small intestine, and kidneys at 5 hours after CLP but decreased only in the liver and small intestine at 20 hours after the onset of sepsis . Moreover, plasma lactate levels increased at the late stage of sepsis . CONCLUSION: Because hepatic and intestinal VO2 but not systemic and renal VO2 decreased at 20 hours after CLP, the liver and small intestine seem to be more vulnerable to the hypoxic insult during the hypodynamic stage of polymicrobial sepsis.

J Appl Physiol, 1999 Oct, 87(4), 1279 - 86
Sepsis increases contraction-related generation of reactive oxygen species in the diaphragm; Nethery D et al.; Recent work indicates that free radicals mediate sepsis-induced diaphragmatic dysfunction . These previous experiments have not, however, established the source of the responsible free radical species . In theory, this phenomenon could be explained if one postulates that sepsis elicits an upregulation of contraction-related free radical formation in muscle . The purpose of the present study was to test this hypothesis by examination of the effect of sepsis on contraction-related free radical generation {i.e . , formation of reactive oxygen species (ROS)} by the diaphragm . Rats were killed 18 h after injection with either saline or endotoxin . In vitro hemidiaphragms were then prepared, and ROS generation during electrically induced contractions (20-Hz trains delivered for 10 min) was assessed by measurement of the conversion of hydroethidine to ethidium . ROS generation was negligible in noncontracting diaphragms from both saline- and endotoxin-treated groups (2.0 +/- 0 . 6 and 2.8 +/- 1.0 ng ethidium/mg tissue, respectively), but it was marked in contracting diaphragms from saline-treated animals (19.0 +/- 2.8 ng/mg tissue) and even more pronounced (30.0 +/- 2.8 ng/mg tissue) in diaphragms from septic animals (P < 0.01) . This enhanced free radical generation occurred despite the fact that the force-time integral (i.e., the area under the curve of force vs . time) for control diaphragms was higher than that for the septic group . In additional studies, in which we altered the stimulation paradigm in control muscles to achieve a force-time integral similar to that achieved in septic muscles, an even greater difference between control and septic muscle ROS formation was observed . These data indicate that ROS formation during contraction is markedly enhanced in diaphragms from endotoxin-treated septic animals . We speculate that ROS generated in this fashion plays a central role in producing sepsis-related skeletal muscle dysfunction.

J Infect Dis, 1999 Nov, 180(5), 1584 - 9
Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock; Opal SM et al.; Plasma endotoxin and lipopolysaccharide-binding protein (LBP) levels were measured in a group of 253 patients at the onset of severe sepsis and/or septic shock . Endotoxin levels were significantly greater than control levels (n=33; mean +/- SD, 5.1+/-7.3 pg/mL) in 78.3% of patients . Median endotoxin levels in patients with sepsis were 300 pg/mL (25%-75% interquartile range, 110-726 pg/mL) . LBP levels were elevated in 97% of patients compared with normal control values of 4.1+/-1.65 microgram/mL . Median LBP levels in patients with sepsis were 31.2 microgram/mL (interquartile range, 22.5-47.7 microgram/mL) . Median endotoxin levels at study entry were more highly elevated (515 vs . 230 pg/mL; P<.01), and LBP levels were less highly elevated (28.0 vs . 33.2 microgram/mL; P<.05) in nonsurvivors than survivors over the 28-day study period . No correlation was found between endotoxin and LBP levels . The quantitative level of both endotoxin and LBP may have prognostic significance in patients with severe sepsis.

Rev Med Chil, 1999 Jun, 127(6), 719 - 27
{Effect of catecholamines on splanchnic perfusion in sepsis}; Hernandez G et al.; Splanchnic ischemia is frequent in sepsis and septic shock and is related to impairment in intestinal permeability, derangement in mucosal barrier functions and translocation of proinflammatory mediators . These changes can contribute to the pathogenesis of multiple organ failure . Vasoactive drugs such as dobutamine and dopexamine can improve splanchnic perfusion and gastric intramucosal pH during sepsis . However, contradictory results have been obtained with dopamine and norepinephrine . On the other hand, epinephrine further impairs splanchnic perfusion . In view of the contradictory effects of different vasoactive drugs, gastric tonometry must be measured during their use, to find the optimal drug combination that optimizes splanchnic blood flow.

Shock, 1999 Oct, 12(4), 274 - 9
Liver protein kinase A activity is decreased during the late hypoglycemic phase of sepsis; Hsu C et al.; Changes in protein kinase A (PKA, or cAMP-dependent protein kinase) activity in the rat liver during different metabolic phases of sepsis were investigated . Sepsis was induced by cecal ligation and puncture (CLP) . Experiments were divided into 3 groups: control, early sepsis, and late sepsis . Early and late sepsis refer to those animals killed at 9 and 18 h, respectively, after CLP . Hepatic PKA was extracted and partially purified by acid precipitation, ammonium sulfate fractionation, and diethylaminoethyl (DEAE)-cellulose chromatography . PKA was eluted from DEAE-cellulose column with a linear NaCl gradient . Two peaks of PKA, type I (eluted at low ionic strength) and type II (eluted at high ionic strength), were collected and their activities were determined on the basis of the rate of incorporation of {gamma-32-P}ATP into histone . The results show that during early sepsis, both type I and type II PKA activities remained unchanged . During late sepsis, type I PKA activity was decreased by 40.7-53.6%, whereas type II PKA activity was unaffected . Kinetic analysis of the data on type I PKA during the late phase of sepsis reveals that the Vmax (maximal velocity) values for ATP, cAMP, and histone were decreased by 40.7, 53.6, and 47.3%, respectively whereas the Km (substrate concentration required for half-maximal enzymatic activity) values for ATP, cAMP, and histone were unaltered . These data indicate that type I PKA was inactivated during the late hypoglycemic phase of sepsis in the rat liver . Because PKA-mediated phosphorylation plays an important role in the regulation of hepatic glucose metabolism, an inactivation of PKA may contribute to the development of hypoglycemia during the late phase of sepsis.

Shock, 1999 Oct, 12(4), 268 - 73
Procalcitonin and proinflammatory cytokine in 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.

Neth J Med, 1999 Sep, 55(3), 132 - 41
The central role of monocytes in the pathogenesis of sepsis: consequences for immunomonitoring and treatment; Haveman JW et al.; Despite important advances in critical care medicine during the last two decades, the mortality rate of sepsis has remained high, probably because the pathogenesis of sepsis is still incompletely understood . Recent studies have shown that sepsis is a bimodal entity . The first phase is characterized by the systemic release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and IL-8, and by activation of the complement and coagulation cascades . In the second phase, anti-inflammatory mediators such as transforming growth factor-beta (TGF-beta), IL-10 and prostaglandin E2 (PGE2) may be released in an effort to counteract ongoing inflammation . Depending whether the pro- or anti-inflammatory response predominates, sepsis results in a systemic inflammatory response syndrome (SIRS), or a compensatory anti-inflammatory response syndrome (CARS) . So far, most efforts to intervene in the immunopathogenesis of sepsis have been directed at the pro-inflammatory response . None of these interventions has been shown to improve the prognosis of sepsis, possibly because many patients were already in a state in which anti-inflammatory responses dominated . Recently, it has been shown that decreased expression of HLA-DR on monocytes in patients with sepsis constitutes a marker for CARS . We suggest that HLA-DR expression on monocytes might constitute a useful indicator of the immunological status of the individual patient with sepsis and a guide for treatment . Patients with CARS, as manifested by low HLA-DR expression, might benefit from immunostimulants, while patients with SIRS and normal or high monocyte HLA-DR expression should receive treatment directed to interfere with pro-inflammatory pathways.

Crit Care Med, 1999 Sep, 27(9), 1814 - 8
Sensitivity and specificity of various markers of inflammation for the prediction of tumor necrosis factor-alpha and interleukin-6 in patients with sepsis; Oberhoffer M et al.; OBJECTIVES: To determine correlations and predictive strength of surrogate markers (body temperature, leukocyte count, C-reactive protein {CRP}, and procalcitonin {PCT}) with elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in septic patients . DESIGN: Prospective consecutive case series . SETTING: Surgical intensive care unit (ICU) of a university hospital . PATIENTS: A total of 175 patients experiencing intensive care unit stays >48 hrs categorized for sepsis according to ACCP/ SCCM Consensus Conference criteria . MEASUREMENTS AND MAIN RESULTS: CRP and PCT were both significantly correlated with TNF-alpha and IL-6 . Based on the area-under-the-curve of the receiver operating characteristics curves, predicting capability was highest for PCT (0.814 for TNF-alpha >40 pg/mL and 0.794 for IL-6 >500 pg/mL), moderate with CRP (0.732 and 0.716, respectively), and lowest for leukocyte count (0.493 and 0.483, respectively) and body temperature (0.587 and 0.589, respectively) . Sensitivity, specificity, positive, and negative predictive values and test effectiveness all followed this same pattern of being highest for PCT followed by CRP, with leukocyte count and body temperature being lowest . CONCLUSION: PCT may be an early and better marker of elevated cytokines than the more classic criteria of inflammation.

Crit Care Med, 1999 Sep, 27(9), 1760 - 7
The patient-related costs of care for sepsis patients in a United Kingdom adult general intensive care unit; Edbrooke DL et al.; OBJECTIVE: To determine the patient-related costs of care for critically ill patients with severe sepsis or early septic shock . DESIGN: Retrospective, longitudinal, observational study during a 10-month period . SETTING: Adult general intensive care unit (ICU) in a university hospital located in the United Kingdom . PATIENTS: The study population consisted of 213 patients admitted consecutively to the ICU during a 10-month period . Thirty-six patients were identified using standard definitions as having developed sepsis and analyzed by group (according to the day on which sepsis was diagnosed): Group 1 patients were septic at admission to ICU (n = 16); group 2 patients were septic on their second day in the ICU (n = 10); and group 3 patients developed sepsis after their second day in the ICU (n = 10) . One hundred and seventy-seven ICU patients without sepsis were used as the comparative group (group 4) . INTERVENTIONS: None . MAIN RESULTS: Patient-related costs of care, length of ICU stay, and ICU and hospital mortality rates were compiled.The median daily costs of care for patients in groups 1, 2, and 3 were $930.74 (interquartile range $851.59-$1,263.96); $814.47 ($650.89-$1,123.06), and $1,079.39 ($705.02-$1,295.96), respectively; these were significantly more than the group 4 patient's daily cost of $750.38 ($644.10-$908.55) (p < .01) . The median total cost of treating the group 4 patients was $1,666.87 ($979.71-$2,772.03), significantly less than for the patients with sepsis (p < .01) . The difference in total costs of care between the sepsis groups was also significant (p < .05), with a group 1 patient costing $3,801.55 ($1,865.28-$11,676.08), a group 2 patient costing $13,089.17 ($5,792.94-$22,235.18), and a group 3 patient costing $17,962.78 ($13,030.83-$28,546.73) . Patients in groups 1, 2, and 3 stayed in the ICU for 3.3 days (1.3-11.3), 16.5 days (8.9-22), and 16.1 days (10.9-9), respectively . Significant differences were found among the three groups (p < 0.05), as well as between the patients with sepsis and those without (p < 0.001), whose median length of stay was 1.9 days (0.9-3.6) . The ICU mortality rates were 50% each for groups 1 and 2, 60% for group 3, and 20% for group 4 . Only one patient with sepsis and 16 patients without sepsis died in the hospital ward, producing overall mortality rates of 56% for group 1 and 29% for group 4 . CONCLUSIONS: Patients with severe sepsis or early septic shock had a high mortality rate, spent prolonged periods of time in the ICU, and were significantly more expensive to treat than nonsepsis ICU patients.

Acta Paediatr, 1999 Aug, 88(8), 880 - 4
Contribution of interleukin-6 in distinguishing between mild respiratory disease and neonatal sepsis in the newborn infant; Kallman J et al.; The purpose of this study was to investigate if early samples of interleukin-6 (IL-6) could distinguish early bacterial sepsis from respiratory diseases in the newborn . IL-6 and C-reactive protein (CRP) were measured at onset of symptoms in newborns evaluated for sepsis during the first week of life . Five groups of children were investigated: proven sepsis, clinical sepsis, respiratory distress syndrome (RDS), transient tachypnoea of the newborn (TTN) and controls . IL-6 was also analysed at the time when CRP was at its maximum level . The results showed that initial IL-6 distinguished proven and clinical sepsis from TTN, but not from RDS . Initial CRP was of no value for diagnosis . Our conclusion is that early IL-6 makes it possible to avoid antibiotics in children with TTN and contributes to the diagnosis of sepsis faster than CRP.

Eur J Anaesthesiol, 1999 Aug, 16(8), 539 - 42
Minimal leptin elimination into ultrafiltrate during continuous venovenous haemofiltration in patients with sepsis; Bohrer H et al.; Intensive care patients with organ failure often suffer an acute catabolic state . Leptin is a 16-kDa hormone which is produced by mature adipocytes and correlates with human energy expenditure . We investigated whether continuous venovenous haemofiltration, which may eliminate molecules up to 20-30 kDa, is capable of removing human leptin . Leptin measurements were made in the plasma of 15 patients with sepsis before continuous venovenous haemofiltration (T0) and during the procedure at 24 h (T1), 48 h (T2), and 72 h (T3), using samples taken before and after haemofiltration . In addition, measurements were made in the ultrafiltrate at T1-T3 . The plasma leptin level at T0 was 17.6 ng mL-1 . The concentration at T1 was 17.5 ng mL-1 pre-filter and 26.5 ng mL-1 post-filter (T2: 14.2/23.2 ng mL-1; T3: 12.4/16.3 ng mL-1) . This concentration effect after haemofiltration was also seen with albumin . The values measured at T3 tended to be lower than those recorded at T1 . The mean leptin levels in the ultrafiltrate were 0.15-0.18 ng mL-1 . The range of leptin levels in the ultrafiltrate was thus only 0.5-3% of that measured in plasma . We conclude that human leptin is only minimally elimininated into the ultrafiltrate by continuous venovenous haemofiltration and that plasma leptin levels may decrease during sepsis.

Respirology, 1999 Sep, 4(3), 207 - 12
Recent advances in the management of pleural sepsis: what is the evidence?
Lim TK.
The management of pleural sepsis involves early diagnosis, administration of appropriate antibiotics, recognition of poor prognostic features and timely intervention to drain the infected pleural space . Important recent advances in the management of pleural sepsis include better imaging techniques, the use of flexible image-guided drainage catheters, adjunctive intrapleural thrombolytic therapy and the introduction of interventional thoracoscopy . These advances have been augmented, in the past year, by results from prospective controlled studies comparing different therapeutic options . This review describes an evidence-based approach to the management of pleural sepsis which incorporates recent therapeutic advances.

Shock, 1999 Sep, 12(3), 174 - 80
Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds; Hoffmann JN et al.; Myocardial dysfunction due to sepsis is common in patients with multiple organ dysfunction syndrome and is believed to be produced by inflammatory mediators . Some of these mediators may be eliminated by continuous hemofiltration, which is a standard procedure in an ICU for renal replacement therapy . This study was designed to directly compare the effects of ultrafiltrates from patients with sepsis (UFs) with ultrafiltrates from healthy volunteers (UFh) in well-characterized cardiomyocyte culture systems . Isovolemic hemofiltration (filtration rate: 2 L/h, polyamide membrane) was performed during 12 hours in 5 patients with severe sepsis (Elebute Score >20) and simultaneously reduced left ventricular contractility (left ventricular stroke work index {LVSWI} <30 g m/m2) and in 5 healthy volunteers . Inflammatory mediator concentrations (interleukin {IL}-1beta, IL-6, IL-8, tumor necrosis factor {TNF} alpha, C3a, and C5a) were measured in plasma and ultrafiltrate samples taken shortly after the beginning of the hemofiltration procedure . Cell culture experiments were done comparing UFs with UFh by using spontaneously beating or electrically driven neonatal rat cardiomyocyte cultures . UFs contained significantly higher amounts of IL-1, IL-8, and C3a when compared to UFh . Simultaneously, UFs induced a decrease in the contraction frequency of electrically-stimulated cardiomyocytes, whereas UFh had no effect . The cardiotoxic effect could be reversed by the addition of a high concentration (2.4 mM) of Ca++ . Hemofiltration did not alter parameters of cardiac performance during 12 hours in patients with sepsis . UFs induced significant cardiotoxic effects in rat cardiomyocytes, whereas UFh showed no cardiotoxicity . Contact of blood with the hemofiltration membrane did not induce activation of cardiotoxic mediators . Significantly higher filtration rates may be required to improve left ventricular contractility in patients with sepsis by hemofiltration.

Acta Radiol, 1999 Sep, 40(5), 552 - 5
Impact of CT in patients with sepsis of unknown origin; Barkhausen J et al.; PURPOSE: To evaluate the diagnostic relevance of CT in patients with sepsis of unknown origin . MATERIAL AND METHODS: Sixty-three consecutive intensive care patients with suspicion of an abscess and negative or inconclusive previous radiological examinations were included . CT was performed using the helical technique . A total of 45 abdominal and 38 chest examinations were evaluated . RESULTS: 5/38 examinations of the chest revealed the source of sepsis (pleural empyema 2, lung abscess 1, mediastinitis 1, retrosternal abscess 1) . 7/45 abdominal CT examinations showed the source of sepsis (intraabdominal abscess 2, hepatic abscess 3, intestinal perforation 1, gangrenous colitis 1) . CONCLUSION: CT is useful for the evaluation of patients with fever or sepsis without a known source . Due to the detection of a septic focus by CT, 19% of the patients in our study could be immediately referred to causal therapy as percutaneous drainage or surgery.

Am J Physiol, 1999 Sep, 277(3 Pt 2), H1036 - 44
Pentoxifylline prevents the transition from the hyperdynamic to hypodynamic response during sepsis; Yang S et al.; The cardiovascular response to sepsis includes an early, hyperdynamic phase followed by a late, hypodynamic phase . Although administration of pentoxifylline (PTX) produces beneficial effects in sepsis, it remains unknown whether this agent prevents the transition from the hyperdynamic to the hypodynamic response during the progression of sepsis . To study this, male adult rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) . At 1 h after CLP, PTX (50 mg/kg body wt) or vehicle was infused intravenously over 30 min . At 20 h after CLP (i.e., the late stage of sepsis), cardiac output and organ blood flow were measured by radioactive microspheres . Systemic and regional (i.e., hepatic, intestinal, and renal) oxygen delivery (DO2) and oxygen consumption (VO2) were determined . Moreover, plasma levels of lactate and alanine aminotransferase (ALT) were measured, and histological examinations were performed . In additional animals, the necrotic cecum was excised at 20 h after CLP, and mortality was monitored for 10 days thereafter . The results indicate that cardiac output, organ blood flow, and systemic and regional DO2 decreased by 36-65% (P < 0.05) at 20 h after CLP . Administration of PTX early after the onset of sepsis, however, prevented reduction in measured hemodynamic parameters and increased systemic and regional DO2 and VO(2) by 50-264% (P < 0.05) . The elevated levels of lactate (by 173%, P < 0.05) and ALT (by 718%, P < 0.05), as well as the morphological alterations in the liver, small intestine, and kidneys during sepsis were attenuated by PTX treatment . In addition, PTX treatment decreased the mortality rate from 50 to 0% (P < 0.05) after CLP and cecal excision . Because PTX prevents the occurrence of hypodynamic sepsis, this agent appears to be a useful adjunct for maintaining hemodynamic stability and preventing lethality from sepsis.

Minerva Anestesiol, 1999 Jul-Aug, 65(7-8), 529 - 40
Sepsis and organ dysfunction/failure . An overview; Gullo A; Sepsis is a condition at high risk for the patients to develop organ(s) or system dysfunction/failure and represent a very limiting process for survival . Researchers and clinicians proposed standardization of terminology for sepsis and related problems to improve communication and to evaluate the efficacy of preventive measures and therapeutic interventions . Interrelationship among systemic inflammatory response syndrome (SIRS), infection and sepsis are surrounded by non infectious satellite events such as trauma, burns, pancreatitis, haemorrhagic shock, immune-mediated organ injury and infectious cause such as fungemia, parasitemia, viremia . The prevalence of infections among intensive care patients has been reported to vary from 15 to 40% . Usually indicators of sepsis are persistent hyperlactatemia and supranormal level of DO2 . These conditions may progress as a sort of dynamic process known as endotoxaemia condition which is mediated by derangement of biohumoral factors inducing immunological dissonance and ultimately concomitant or sequential organs dysfunction/failure . Multiple sources of sepsis is a phenomenon clearly associated with poor prognosis and all the sepsis trials managed in the last decades have failed on reducing mortality rate in enrolled patients . Development of scoring system routinely used at bedside represent an important method to establish cost-effectiveness in this exiting area of study and clinical management . Controversial results on sepsis need a sort of consensus at different level from researchers to clinician experiencing new strategies for prevention and more appropriately therapeutic approach for the management of this syndrome.

J Vasc Surg, 1999 Sep, 30(3), 509 - 17
Intermediate-term outcome of primary digit amputations in patients with diabetes mellitus who have forefoot sepsis requiring hospitalization and presumed adequate circulatory status; Nehler MR et al.; PURPOSE: The intermediate success and outcome of primary forefoot amputations in patients with diabetes mellitus who have sepsis limited to the forefoot and presumed adequate forefoot perfusion, as determined by means of noninvasive methods, was studied . METHODS: Cases of a university hospital-based practice from January 1984 to April 1998 were retrospectively reviewed . Patients included had diabetes mellitus with forefoot sepsis requiring immediate hospitalization for digit amputations who had adequate arterial circulation for healing based on noninvasive and clinical assessment: palpable pedal pulses (29%), "compressible" ankle pressure of 70 mm Hg or higher (48%), pulsatile metatarsal waveforms (67%), and/or toe pressure higher than 55 mm Hg (36%) . All patients underwent a primary single- or multiple-digit amputation (through the interphalangeal joint, metatarsal head, or metatarsal shaft) . Additional forefoot procedures (debridement, digit amputation) were performed during the follow-up period as needed for persistent or recurrent infection . The main outcome variables were recurrent or persistent foot infection (defined as requiring rehospitalization for antibiotics, wound care, and/or reoperation), the number of repeat operations and hospitalizations for salvage of limbs with recurrent or persistent infections, and time to complete forefoot healing or foot amputation . RESULTS: Ninety-two patients who had diabetes mellitus with 97 forefoot infections comprised the study group . Ninety-seven primary digit amputations (34 through interphalangeal joints, 28 through metatarsal heads, 35 through metatarsal shafts) were performed . The median length of hospital stay was 10 days . There were no operative deaths . The mean follow-up period was 21 months (range, 3 days to 105 months) . The primary amputation healed (without persistent infection) in only 38 limbs (39%), at a mean time of 13 +/- 10 weeks . Twenty-three limbs (24%) had not healed the primary amputation without evidence of persistent infection at last follow-up (mean, 12 weeks) . Infection persisted in 35 limbs (36%), and infection recurred in 15 of 38 (40%) healed limbs . An average of 1.0 reoperations (range, 0 to 3) and 1.6 rehospitalizations (range, 1 to 4) were involved in salvage attempts in these recurrent/persistent infections . Five persistent and five recurrent infections ultimately healed (mean, 53 weeks) . Complete healing was achieved in only 33 of 97 limbs (34%) . Twenty-two foot amputations (20 transtibial, two Syme's) were performed (mean, 49 +/- 74 weeks; 20 for persistent infection) . Eighteen persistent/recurrent infections remained unhealed at the last follow-up examination (mean, 105 weeks) . CONCLUSION: Patients with diabetes mellitus who have sepsis limited to the forefoot requiring acute hospitalization and undergoing primary digit amputations have a high incidence of intermediate-term, persistent, and recurrent infection, leading to a modest rate of limb loss, despite having apparently salvageable lesions and noninvasive evidence of presumed adequate forefoot perfusion.

Vox Sang, 1999, 77(1), 1 - 5
Reduction of platelet transfusion- associated sepsis by short-term bacterial culture; Liu HW et al.; BACKGROUND AND OBJECTIVES: There is as yet no suitable routine laboratory test for a blood transfusion service to detect bacterial contamination in platelets . This study evaluates the effectiveness and the applicability of short-term bacterial culture for such a purpose . MATERIALS AND METHODS: Samples from 5-unit platelet pools were inoculated into an aerobic culture bottle, then monitored for 48 h at 35 degrees C in an automated monitoring and detection system . RESULTS: 26,210 whole-blood-derived platelet components were tested, of which 14 (0.053%) platelet units were found to be contaminated . In addition, nine of the associated red cell units and 4 fresh-frozen plasma units grew the same organisms on culture . CONCLUSION: Short-duration bacterial culture by an automated system is effective and suitable for routine screening in a regional transfusion center.

Am J Respir Crit Care Med, 1999 Sep, 160(3), 852 - 7
Impact of immunomodulating therapy on morbidity in patients with severe sepsis; Pittet D et al.; We assessed the impact, over a 28-d period, of therapy with the tumor necrosis factor (TNF) neutralizing receptor fusion protein (p55-IgG) on the incidence of end-organ failures in patients with severe sepsis or early septic shock in a subgroup of 165 patients recruited into a randomized, multicenter clinical trial to receive placebo (n = 78) or a single infusion of p55-IgG, 0.083 mg/kg (n = 87) . At study entry, distribution of organ dysfunctions and other baseline characteristics were similar for the two study groups . Treatment with p55-IgG was associated with a trend toward reduced 28-d mortality (p = 0.07), a decreased incidence of new organ dysfunctions (relative risk {RR}, 0.57; 95% confidence interval {95% CI} 0.29 to 1.10, p = 0.10), and a decreased overall incidence-density of organ failures (RR 0.65; 95% CI 0.60 to 0.71, p = 0.0001) . Patients treated with p55-IgG had more organ failure-free days after study entry than those who received placebo . Average intensive care unit (ICU) stay was 2.6 d shorter (95% CI 0.2 to 5.0) for patients who received p55-IgG than for those who received placebo . For those patients who survived, this difference was 4.1 d (95% CI 1.6 to 6.6) . Duration of ventilatory support was 3.2 d shorter (95% CI 0.1 to 6.3) among 28-d survivors who received p55-IgG, compared with placebo . In conclusion, in the population of septic patients studied, treatment with p55-IgG was associated with a trend toward shorter need for mechanical ventilatory support, a decreased length of stay (LOS), and a decreased incidence and duration of organ failure.

Intensive Care Med, 1999 Jul, 25(7), 686 - 96
The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care . Results of a prospective, multicentre study . Working Group on Sepsis related Problems of the ESICM; Moreno R et al.; OBJECTIVE: To evaluate the performance of total maximum sequential organ failure assessment (SOFA) score and a derived measure, delta SOFA (total maximum SOFA score minus admission total SOFA) as a descriptor of multiple organ dysfunction/failure in intensive care . DESIGN: Prospective, multicentre and multinational study . SETTING: Forty intensive care units (ICUs) from Australia, Europe, North and South America . PATIENTS: Data on 1,449 patients, evaluated at admission and then consecutively every 24 h until ICU discharge (11,417 records) during May 1995 . Excluded from data collection were all patients with a length of stay in the ICU less than 2 days following uncomplicated scheduled surgery . MAIN OUTCOME MEASURE: Survival status at ICU discharge . INTERVENTIONS: The collection of raw data necessary for the computation of a SOFA score on admission and then every 24 h, and basic demographic and clinical statistics . MEASUREMENTS AND MAIN RESULTS: Mean total maximum SOFA score presented a very good correlation to ICU outcome, with mortality rates ranging from 3.2% in patients without organ failure to 91.3% in patients with failure of all the six organs analysed . A maximum score was reached 1.1 +/- 0.2 days after admission for all the organ systems analysed . The total maximum SOFA score presented an area under the ROC curve of 0.847 (SE 0.012), which was significantly higher than any of its individual components . The cardiovascular score (odds ratio 1.68) was associated with the highest relative contribution to outcome . No independent contribution could be demonstrated for the hepatic score . No significant interactions were found . Principal components analysis demonstrated the existence of a two-factor structure that became clearer when analysis was limited to the presence or absence of organ failure (SOFA score > or = 3 points) during the ICU stay . The first factor comprises respiratory, cardiovascular and neurological systems and the second coagulation, hepatic and renal systems . Delta SOFA also presented a good correlation to outcome . The area under the receiver operating characteristic (ROC) curve was 0.742 (SE 0.017) for delta SOFA, lower than the total maximum SOFA score or admission total SOFA score . The impact of delta SOFA on prognosis remained significant after correction for admission total SOFA . CONCLUSIONS: The results show that total maximum SOFA score and delta SOFA can be used to quantify the degree of dysfunction/failure already present on ICU admission, the degree of dysfunction/failure that appears during the ICU stay and the cumulative insult suffered by the patient . These properties make it a good instrument to be used in the evaluation of organ dysfunction/failure.

Acta Physiol Scand, 1999 Aug, 166(4), 293 - 300
Differentiation of the peptidergic vasoregulatory response to standardized splanchnic hypoperfusion by acute hypovolaemia or sepsis in anaesthetized pigs; Aneman A et al.; This study was performed to integratively investigate the vasoregulatory response during standardized splanchnic hypoperfusion in pigs . Splanchnic perfusion was reduced to 50% of baseline by: haemorrhage by 20 and 40% of the estimated total blood volume; femoral venous infusion of live E . coli to establish sepsis of systemic origin; portal venous infusion of live E . coli to establish sepsis of splanchnic origin . Invasive haemodynamic monitoring and radioimmunoassay analyses of arterial plasma concentrations of angiotensin II, endothelin-1 and atrial natriuretic peptide were carried out . Acute hypovolaemia reduced systemic and splanchnic vascular resistances following transient increases and increased angiotensin II levels (+587%), whereas endothelin-1 and atrial natriuretic peptide levels did not change significantly . Systemic sepsis following femoral venous infusion of E . coli resulted in increased splanchnic vascular resistance and increased levels of angiotensin II (+274%), endothelin-1 (+134%) and atrial natriuretic peptide (+185%) . Infusion of E . coli via the portal venous route induced an increase in splanchnic vascular resistance associated with particularly elevated levels of angiotensin II (+1770%) as well as increased endothelin-1 (+201%) and atrial natriuretic peptide (+229%) concentrations . Hypovolaemia and sepsis, although standardized with a predefined level of splanchnic hypoperfusion, elicited differentiated cardiovascular and vasopeptidergic responses . Sepsis, particularly of portal origin, notably increased splanchnic vascular resistance related to increased production of the vasoconstrictors angiotensin II and endothelin-1 . The role of atrial natriuretic peptide as a vasodilator seems to be of subordinate importance in hypovolaemia and sepsis.

Shock, 1999 Jul, 12(1), 63 - 8
Evidence of multi-step regulation of HSP72 expression in experimental sepsis; Chen HW et al.; Heat shock proteins (Hsps) are a family of highly conserved proteins induced in response to various stresses . Hsps protect cells against subsequent lethal circumstances . Previous work from our laboratory has indicated that Hsp72 is not induced during experimental sepsis in rats, but the regulation of the induction of Hsp72 synthesis in this disease cascade has not been investigated . In the present study, we evaluated the expression of the hsp72gene, focusing on the activation and DNA-binding ability of heat shock factor 1 (HSF1), hsp mRNA accumulation, and Hsp72 synthesis in animal sepsis models induced by cecal ligation and puncture procedure . The results were compared with those of sham-treated and heat-shocked rats . It was shown that the expression of the hsp72 gene in sepsis was a multi-step process, as previously documented in in vitro studies . Hsp72 synthesis was not induced during sepsis, whereas DNA binding of HSF was detectable, suggesting that the induction of Hsp72 is blocked downstream to HSF-DNA complex formation by the metabolic alteration occurring during sepsis . The dissociation failure of the constitutive heat shock element binding factor (CHBF) from the heat shock element may play an important role in this negative regulation.

Shock, 1999 Jul, 12(1), 17 - 24
Influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) on whole blood endotoxin responsiveness following trauma, cardiopulmonary bypass, and severe sepsis; Flohe S et al.; Major surgery, multiple injury, and severe sepsis lead to an impaired immune response . The suppressed status of the immune system is reflected by a reduced TNFalpha production of whole blood after stimulation with endotoxin in vitro and by a decreased HLA-DR expression on monocytes . In the present study, the effect of the immunostimulating hematopoetic growth factor GM-CSF on whole blood cultures of multiple injury, cardiac surgery, and severe sepsis patients was investigated . Endotoxin-induced TNFalpha production and HLA-DR expression was reduced in blood cultures of these patients compared to healthy donors . Preincubation with GM-CSF in vitro increased cytokine production in volunteers' and all patients' blood specimens in a dose-dependent manner . The elevation of cytokine response in cardiopulmonary bypass patients' blood, caused by in vitro preincubation with GM-CSF, equaled that of normal patients, whereas GM-CSF caused a lower rise of TNFalpha-producing capacity in blood of multiple-injury and sepsis patients . Further, GM-CSF treatment in vitro increased the down-regulated HLA-DR expression on monocytes prepared after cardiac surgery to a degree comparable to preoperative levels . Finally, GM-CSF incubation in vitro elevated TNFalpha synthesis in normal monocytes and in cells treated with a combination of the anti-inflammatory mediators IL-10, TGFbeta, and PGE2 . These experiments show that hyporesponsiveness of whole blood induced by trauma, sepsis, or cardiac surgery is not irreversible but can be, at least in vitro, overridden by the immunostimulating compound GM-CSF.

Rev Invest Clin, 1999 May-Jun, 51(3), 159 - 65
{Bayesian prediction of chloramphenicol blood levels in children with sepsis and malnutrition}; Lares-Asseff I et al.; OBJECTIVE: To validate the population pharmacokinetic parameters of chloramphenicol in pediatric patients with sepsis and malnutrition (PPSM) using a bayesian forecasting program . DESIGN: Retrospective evaluation of predictive performance of a bayesian program in PPSM . SETTING: Tertiary care center . PATIENTS: Fifteen MPSP and ten NMPSP that receiving treatment with chloramphenicol . METHODS AND MAIN RESULTS: In the first part of the study, the medical records of 10 MPSP and 10 NMPSP who had received treatment with chloramphenicol were reviewed . The population pharmacokinetic parameter values for each group were estimated using a nonparametric expectation maximization algorithm (NPEM) . In the second part, data gathered from five other MPSP receiving chloramphenicol were entered into a bayesian program . Chloramphenicol pharmacokinetic values for each of these five patients were estimated, first using the values of NMPSP as a priori distribution and then repeating the analysis using the MPSP values . The bayesian serum chloramphenicol concentrations predicted for each population model were compared with the actual peaks and troughs . The specific model for MPSP permitted forecasting the peak and trough serum chloramphenicol concentrations with less bias and a better precision compared with the NMPSP population model . CONCLUSIONS: These data indicate that chloramphenicol pharmacokinetics in PPSM can be predicted with minimal bias and good precision using a bayesian forecasting program, allowing a better control of the chloramphenicol serum concentrations . In addition, the limited number of samples required by the bayesian method may represent an important economical benefit for the patient.

Korean J Intern Med, 1999 Jul, 14(2), 72 - 7
The imbalance between coagulation and fibrinolysis is related to the severity of the illness and the prognosis in sepsis; Park KJ et al.; OBJECTIVES: The coagulation and fibrinolytic system appears to be activated by the septic process independently, leading to the syndrome of disseminated intravascular coagulation (DIC) . In this study, we investigated the changes within the hemostatic system related to the severity of the illness and the prognosis in patients with sepsis . METHODS: Plasma thrombin-antithrombin III (TAT) and plasmin-alpha 2-antiplasmin (PAP) complexes were measured using ELISA methods in 32 patients with sepsis and 20 controls and were analyzed according to the APACHE III scores and survival of the patients . RESULTS: Plasma TAT and PAP in patients with sepsis were significantly higher than controls . Nonsurvivors showed greater levels of TAT (21.7 +/- 22.3 ng/mL) and lower levels of PAP (628.4 +/- 378.1 ng/mL) than survivors (TAT: 11.1 +/- 11.2 ng/mL; PAP: 857.1 +/- 364.1 ng/mL) . The imbalance between coagulation and fibrinolysis described as TAT/PAP ratio was closely related with APACHE III scores in patients with sepsis (r = 0.47) and the TAT/PAP ratio in nonsurvivors was significantly higher compared with survivors (34.4 +/- 21.4 vs . 14.4 +/- 13.8) . CONCLUSION: In sepsis, both coagulation and the fibrinolysis system are activated and the imbalance between coagulation and fibrinolysis predisposes to the hypercoagulation state and is closely related to the severity of the disease and the prognosis.

Anesteziol Reanimatol, 1999 May-Jun, (3), 59 - 60
{Use of octagam and pentaglobin in the treatment of severe sepsis in the neonatal period}; Barinov AV et al.; Many patients with sepsis are immunocompetent . They respond well to standard combinations of antibiotics and cardiovascular support . However, immunocompetent patients, particularly small-for-date newborns, are in need of stronger immune protection . Although the mechanisms due to which antibody preparations yield positive effects are not quite clear, clinical studies carried out in many countries and our own results indicate a high protective effect of intravenous immunoglobulins and necessitate their use at least in intensive care departments.

Curr Opin Clin Nutr Metab Care, 1999 May, 2(3), 235 - 42
Inter-organ protein and carbohydrate metabolic relationships during sepsis: necessary evils or uncanny coincidences?
Vary TC.
Sepsis alters the dynamic flux of metabolic substrates between skeletal muscle and liver . Derangements in skeletal muscle glucose metabolism evoked by sepsis to a certain extent determine the rate of gluconeogenesis in the liver . In contrast, accelerated rates of gluconeogenesis do not drive net catabolism in skeletal muscle, nor does the upregulation of hepatic protein metabolism in sepsis or inflammation appear to be contingent or dependent upon the catabolism of muscle proteins during sepsis.

Surgery, 1999 Aug, 126(2), 438 - 42
Inducible nitric oxide synthase (iNOS) gene deficiency increases the mortality of sepsis in mice; Cobb JP et al.; BACKGROUND: Nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS or NOS2) has been implicated in the hypotension, organ failure, and death that complicate sepsis . To avoid the confounding effects and limitations of iNOS inhibitors, we used iNOS gene "knockout" mice to examine the effect of inducible NO production in a model of polymicrobial abdominal sepsis treated with antibiotics . We hypothesized that iNOS gene deficiency would significantly alter outcome . METHODS: C57BL6 wild-type (control) and congenic iNOS knockout mice were studied concurrently . Under halothane anesthesia, the ceca were ligated with 4-0 silk suture and punctured twice with a 26-gauge needle (cecal ligation and puncture, CLP) . Survival was followed for 7 days, after which necropsies were performed in surviving animals . In an accompanying study examining the acute effects of sepsis, organ injury at 18 hours after CLP as determined by histology and the degree of cell death by apoptosis were examined with the use of hematoxylin and eosin (H&E) and TUNEL staining and two-channel fluorescence-activated cell sorter (FACS) analysis . RESULTS: Sham laparotomy produced no lethality in either knockout (n = 3) or wild-type (n = 3) animals . Compared with survival in controls (n = 20), survival after CLP in iNOS knockout mice (n = 21) was significantly decreased (P < .01 at 2 days, P = .080 at 7 days, Mantel-Haenszel log-rank test) . CLP-induced apoptotic cell death was significantly less in the thymus of iNOS knockout mice compared with wild-type mice . CONCLUSIONS: We conclude that iNOS gene function provides a survival benefit in septic mice and is associated with increased sepsis-induced thymocyte apoptosis . To our knowledge, this is the first survival study examining the effect of iNOS gene deficiency in a clinically relevant model of sepsis.

Surgery, 1999 Aug, 126(2), 378 - 83
What is the role of interleukin 10 in polymicrobial sepsis: anti-inflammatory agent or immunosuppressant?
Song GY, Chung CS, Chaudry IH, Ayala A.
BACKGROUND: Controversy exists concerning the role of interleukin 10 (IL-10) in sepsis . When IL-10 is used in models of endotoxemia, it appears to protect (by anti-inflammatory effects), whereas in models of polymicrobial sepsis it seems to be deleterious (by immunosuppression?) . However, little direct evidence for such an immunosuppressive role is available for polymicrobial sepsis . Thus the aim of this study was to determine whether IL-10 contributes to lymphocyte immunosuppression in a model of cecal ligation and puncture (CLP) and whether neutralization of IL-10 has any salutary effects on survival after sepsis . METHODS: To assess the former, polymicrobial sepsis was induced in male C57BL/6J wild-type (+/+) and C57BL/6J-IL-10 knockout(-/-) mice by CLP . Splenocytes were harvested 24 hours later and stimulated with concanavalin A to assess their proliferative capacity and their ability to release the Th1 lymphokines interleukin 2 and interferon gamma (by enzyme-linked immunosorbent assay, nanograms/millilter) . To further verify the immunosuppressive role of IL-10, splenocytes were obtained from male C3H/HeN mice 24 hours after CLP and then stimulated in the presence or absence of anti-IL-10 monoclonal antibody (Mab, 4 micrograms/mL) . To assess the in vivo effects of IL-10 neutralization on survival after CLP, C3H/HeN mice (16 per group) were given 250 micrograms of anti-IL-10 Mab (intraperitoneally) either immediately after CLP (before the initiation of the hyperdynamic phase) or 12 hours after CLP (the beginning of the hypodynamic state) . Control mice were given nonspecific rat immunoglobulin G . RESULTS: These data indicate that IL-10 deficiency (-/-) prevents the depression of the proliferative capacity and Th1 lymphokine production after sepsis . Analysis of the interleukin 2-interferon gamma production patterns and proliferative capacity in lymphocytes treated with anti-IL-10 Mab confirmed the role of IL-10 in suppressing lymphocyte responsiveness in CLP . Interestingly, however, only delayed administration (12 hours after CLP) of anti-IL-10 markedly increased survival of mice (Fisher's exact test, P < .05) . CONCLUSION: The results not only illustrate IL-10's role in septic immune dysfunction but document that anti-IL-10 administration beyond the initial proinflammatory hyperdynamic state of polymicrobial sepsis improves survival of animals subjected to sepsis.

Surgery, 1999 Aug, 126(2), 305 - 13
Granulocyte colony-stimulating factor and neutrophil-related changes in local host defense during recovery from shock and intra-abdominal sepsis; Davis KA et al.; BACKGROUND: We have reported that treatment with exogenous granulocyte colony-stimulating factor (G-CSF) improves abscess localization and reduces mortality without aggravating neutrophil (PMN)-mediated reperfusion injury in a model of septic abdominal trauma . The purpose of this study was to determine actions of G-CSF on PMN function in the peritoneum . METHODS: Anesthetized swine were pretreated with broad-spectrum antibiotics and underwent cecal ligation and incision and 35% hemorrhage (trauma) . After 1 hour they were resuscitated with shed blood, crystalloid, and either G-CSF (n = 10) or saline solution vehicle (n = 9) . The animals were observed for 72 hours . RESULTS: After trauma, saline solution treatment increased PMN infiltration into the peritoneum within 2 hours (P = .035), increased peritoneal PMN elastase production (i.e., cytotoxicity) by 24 hours (P = .004), and decreased adherence of peritoneal PMNs to an artificial substrate from 4 to 72 hrs (P = .043) . The mean autopsy score was 7.0 +/- 0.5 . With G-CSF treatment peritoneal neutrophilia was enhanced (maximum 48 hours, P = .002) and PMN cytotoxicity was augmented and delayed (maximum 48 hours, P = .004) . Despite these changes, adherence of peritoneal PMNs was not significantly changed and there was no evidence for PMN-mediated damage in the lung as judged by bronchoalveolar lavage protein, bronchoalveolar lavage PMNs, lung tissue myeloperoxidase, or histologic changes . The mean autopsy score was improved to 4.1 +/- 0.3 (P < .001) . CONCLUSIONS: G-CSF in resuscitation fluids improved localization of an intra-abdominal septic focus by increased production of circulating PMNs, increased PMN extravasation into the peritoneal cavity, and increased PMN cytotoxicity at the abdominal septic focus, without exaggerating PMN-dependent reperfusion injury in the lung . Therefore these data further support the idea that G-CSF in resuscitation fluids might reduce septic complications in the multiply injured trauma patient.

Curr Opin Clin Nutr Metab Care, 1999 Mar, 2(2), 155 - 60
Pathways of muscle protein breakdown in injury and sepsis; Hasselgren PO; The purpose of this article is to review evidence that the ubiquitin-proteasome proteolytic pathway plays an important role in injury- and sepsis-induced muscle catabolism . Such evidence includes upregulated gene expression of several of the components of the ubiquitin-proteasome pathway as well as energy-dependency of the injury- and sepsis-induced muscle protein breakdown . Although the ubiquitin-proteasome pathway is the predominant mechanism of muscle breakdown in various catabolic conditions, other proteolytic mechanisms, in particular calcium-dependent, calpain-mediated protein degradation, probably participate as well.

Biochim Biophys Acta, 1999 Aug 30, 1454(3), 289 - 95
Is gut the major source of proinflammatory cytokine release during polymicrobial sepsis?
Koo DJ, Zhou M, Jackman D, Cioffi WG, Bland KI, Chaudry IH, Wang P.
Although studies have shown that the gut is capable of being a cytokine-producing organ and that the proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6 are upregulated following the onset of sepsis, it remains unknown whether the gut is indeed the major source of the increased cytokine production under such conditions . To determine this, male rats were subjected to cecal ligation and puncture (CLP, a model of polymicrobial sepsis) or sham operation followed by the administration of normal saline solution subcutaneously (i.e., fluid resuscitation) . Systemic and portal blood samples were taken simultaneously at 2, 5, 10, or 20 h after CLP or sham operation . Plasma levels of TNF-alpha, IL-1beta, and IL-6 were determined using an enzyme-linked immunosorbent assay . In additional animals, the small intestine was harvested at 10 h after CLP or sham operation and examined for TNF-alpha, IL-1beta, and IL-6 gene expression by RT-PCR . The results indicate that the levels of TNF-alpha, IL-1beta, and IL-6 in both systemic and portal blood samples were significantly elevated during sepsis with the exception that the increase in IL-1beta was not significant at 2 h after CLP . However, there were no significant differences in the levels of those proinflammatory cytokines between systemic and portal blood at any points after the onset of sepsis . Moreover, there were no significant alterations in the proinflammatory cytokine gene expression in the small intestine at 10 h after CLP . Since the levels of TNF-alpha, IL-1beta, and IL-6 were not significantly increased in portal blood as compared to systemic blood and since there was no upregulation of gene expression for these cytokines, it appears that organs other than the gut are responsible for the upregulated proinflammatory cytokines during polymicrobial sepsis.

Zhonghua Zheng Xing Shao Shang Wai Ke Za Zhi, 1997 Sep, 13(5), 357 - 60
{Serum neopterin levels after extensive burns and their relationship to endotoxemia and sepsis}; Yao Y et al.; The present study was performed to determine the kinetics of serum neopterin levels after major thermal injury and their relationship to endotoxemia and sepsis . This prospective study included 35 patients (32 males and three females) with total burn surface area (TBSA) greater than 30% (30%-98%), and 22 healthy volunteers who served as normal controls . The results showed that neopterin levels increased in most patients on day 3 postburn, but they were not significantly correlated with the extent of the burn surface (P > 0.05) . Patients with endotoxemia had much higher neopterin values than those who showed no endotoxemia from the second week onward (P < 0.05-0.01), and circulating endotoxin and neopterin levels were positively correlated in patients who developed endotoxemia on day 14 (r = 0.368, P < 0.05) and day 21 (r = 0.439, P < 0.01) after major burns . Moreover, a high serum neopterin level was found in patients with sepsis (n = 15), and the marked elevation persisted throughout the observation period . The difference between septic and non-septic patients (n = 20) became significant on 14 and 28 days postburn . These data suggest that extensive burns can lead to an elevation of serum neopterin independent of TBSA . The endotoxin release in the circulation may be involved in the continuous formation of neopterin during the late postburn stage . In addition, the presence of a constant high neopterin level is associated with a critical event in the development of burn sepsis.

Ann Surg, 1999 Aug, 230(2), 207 - 14
Relation of a TNF gene polymorphism to severe sepsis in trauma patients; Majetschak M et al.; OBJECTIVE: To investigate the relation of the biallelic Nco1 restriction fragment length polymorphism in the first intron of the tumor necrosis factor (TNF) beta gene with the development of severe sepsis in multiply injured patients . SUMMARY BACKGROUND DATA: The biallelic Nco1 polymorphism of the TNFbeta gene has been described to be associated with autoimmune diseases and with the mortality rate in severe sepsis . Therefore, the Nco1 polymorphism may be associated with the clinical finding that despite comparable risk factors, posttraumatic sepsis develops in some patients but not others . METHODS: The study group consisted of 110 patients with severe blunt trauma (Injury Severity Score > or = 17) . Typing of each patient for the biallelic Nco1 polymorphism was performed by analyzing restriction fragments of an Nco1-digested DNA fragment obtained using polymerase chain reaction . Genotypes were then related to the occurrence of severe posttraumatic sepsis and TNFalpha serum concentrations . RESULTS: Fifty-seven patients showed an uncomplicated posttraumatic recovery, and severe sepsis developed in 53 patients . The overall allele frequency (TNFB1 0.29, TNFB2 0.71) and genotype distribution (TNFB1 homozygous 7.3%, TNFB1/TNFB2 42.7%, TNFB2 homozygous 50%) were in agreement with the distribution in healthy volunteers . Genotype distribution in patients with an uncomplicated clinical course was significantly different from that in patients with severe posttraumatic sepsis . Development of severe posttraumatic sepsis was significantly increased in patients homozygous for the allele TNFB2 . In patients with severe posttraumatic sepsis, TNFalpha serum concentrations were significantly higher in TNFB2-homozygous individuals compared with heterozygous and TNFB1 -homozygous individuals . The age- and injury-matched odds ratio for the homozygous TNFB2 genotype compared with the heterozygous genotype was 5.22 (p = 0.007, 95% confidence interval 1.6 to 17.9) . CONCLUSIONS: In multiply injured patients, the Nco1 polymorphism within the TNFbeta gene is associated with the development of severe posttraumatic sepsis and with increased TNFalpha serum levels when severe sepsis has occurred . This suggests a genetic determination of the individual inflammatory response after infection or tissue damage, which significantly influences susceptibility to severe nosocomial infections.

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