Shock, 1999 Aug, 12(2), 118 - 26 Immunopathologic responses to non-lethal sepsis; Ebong SJ et al.; Although sepsis causes significant morbidity and mortality, its basic pathology is still not well understood . We investigated the inflammatory and physiologic alterations of non-lethal sepsis using cecal ligation and puncture (CLP), a model that induces peritonitis due to mixed intestinal flora, reproducing the complex immunology of sepsis . Groups of mice were subjected to CLP (25G needle) or sham surgery, had minimitters implanted to continuously monitor temperature and activity, and were sacrificed daily for 6 days . There was significant hypothermia (6-13 hrs post-surgery), and decreases in activity (to day 4) and weight (to day 3) but no mortality in the CLP group . Blood analyses of the CLP-treated mice showed reduced hemoglobin, platelets, lymphocytes, monocytes, and neutrophils, compared to sham animals . Both groups had nearly equivalent neutrophil influx into the peritoneum . Plasma and peritoneal G-CSF, IL-6, as well as the murine chemokines KC and MIP2-alpha were significantly higher in the CLP-treated mice at day 1 . Plasma and peritoneal TNF were low (<70 pg/mL) . While there was elevated IL-1beta in the peritoneum of the CLP-treated mice, this cytokine was not detected in the plasma in either treatment group . Cytokines were not detected in the pulmonary airspace of the CLP-treated mice and PMNs were not recruited to this site . Our data shows altered immunopathology in non-lethal sepsis with significant blood and cytokine alterations . Since there was 100% survival, the inflammatory response was appropriate and probably even protective. Crit Care Med, 1999 Jul, 27(7), 1369 - 77 Microcirculatory oxygenation and shunting in sepsis and shock; Ince C et al.; OBJECTIVE: To review optical spectroscopic techniques for assessment of the determinants of tissue oxygenation and to evaluate the notion that the disturbances in oxygen pathways in sepsis can be accounted for by enhanced functional shunting of parts of the microcirculation . DATA RESOURCES: Experimental data from previous research and the literature were analyzed . STUDY SELECTION: The data selected pertained to a) whether cellular distress in sepsis is caused by tissue hypoxia or disturbed metabolic pathways, b) optical spectroscopic techniques used to study microcirculatory oxygenation, and c) possible mechanisms underlying shunting of the microcirculation in hypoxemia and sepsis . STUDY SYNTHESIS: Despite resuscitation of oxygen-derived variables, signs of regional tissue hypoxia persist in sepsis . The mechanisms underlying this condition are expected to be associated with oxygen pathways in the microcirculation . Optical spectroscopic techniques are providing new insights into these mechanisms . These include absorption spectroscopy for hemoglobin saturation of erythrocytes, reduced nicotinamide adenine dinucleotide fluorescence for tissue mitochondrial bioenergetics, and palladium-porphyrin phosphorescence for microvascular PO2 . Reduced nicotinamide adenine dinucleotide videofluorescence studies have shown the heterogeneous nature of hypoxia . Measurement of gut microvascular PO2 in pigs has shown the development of a PO2 gap between microvascular PO2 and venous PO2 during hemorrhage and endotoxemia, with a larger gap occurring in sepsis than in hemorrhage . It is hypothesized that this difference is caused by the enhanced shunting of the microcirculation present in sepsis . CONCLUSIONS: Microcirculatory distress may form one of the earliest stages in the progress of sepsis to multiple organ failure, and shunting of the microcirculation may be an important contributing factor to this development . To evaluate the severity of microcirculatory distress and the effectiveness of resuscitation strategies, new clinical technologies aimed at the microcirculation will need to be developed . It is anticipated that optical spectroscopy will play a major role in the development of such tools. Crit Care Med, 1999 Jul, 27(7), 1330 - 4 Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis; Fang XM et al.; OBJECTIVES: To determine whether the allele frequencies and genotype distribution of an interleukin (IL)-1beta TaqI polymorphism and an interleukin-1 receptor antagonist polymorphism are associated with susceptibility to and outcome of severe sepsis . In addition, we analyze a possible linkage disequilibrium between a previously described NcoI polymorphism within the tumor necrosis factor (TNF) locus and the two IL-1 gene family polymorphisms . DESIGN: Prospective, consecutive entry study of patients with diagnosis of severe sepsis . SETTING: Intensive care unit (ICU) of a university hospital . PATIENTS: Ninety-three patients with diagnosis of severe sepsis admitted to the ICU between June 1993 and June 1996 . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: The polymorphic region within intron 2 of the IL-1ra gene containing variable numbers of a tandem repeat of 86 base pairs was amplified by means of the polymerase chain reaction . Alleles A1-5 are identified according to the size of the amplified DNA product . The region that contains the biallelic TaqI site within exon 5 of the IL-1beta gene was analyzed by polymerase chain reaction amplification and subsequent digestion using the TaqI restriction enzyme . A NcoI TNF-beta polymorphism was determined . The allele frequency of the allele IL-1raA2 was increased in 93 patients with severe sepsis compared with normal individuals (p < .01) . No association with patients' outcome was observed . Allele frequencies or genotype distribution of the IL-1beta TaqI polymorphism did not differ between patients and controls . In addition, the allele TNFB2 of the NcoI TNF-beta polymorphism was associated with nonsurvival . Occurrence of the TNFB1 and TNFB2 alleles and genotypes was unrelated to alleles and genotypes of the two IL-1 gene family polymorphisms . CONCLUSION: In contrast to the TNF-beta NcoI polymorphism, which has been associated with patients' nonsurvival, the allele IL-1raA2 of the polymorphism within the intron 2 of IL-1ra may contribute to susceptibility to sepsis. Crit Care Med, 1999 Jul, 27(7), 1303 - 8 Time course and prognostic significance of hemostatic changes in sepsis: relation to tumor necrosis factor-alpha; Martinez MA et al.; OBJECTIVES: To describe the time course and prognostic significance of tumor necrosis factor-alpha (TNF-alpha) levels and hemostatic abnormalities in clinical sepsis . DESIGN: Prospective, observational study with sequential measurements in an inception cohort . SETTING: An emergency department in a university teaching hospital . Patients were followed up until they either left the hospital or died . PATIENTS: During a 1-yr period, 43 adult patients were selected from all emergency department patients who met the established criteria for sepsis . Excluded were patients with either organ dysfunction or septic shock at the time of admission . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Blood samples were collected serially (day of admission and on days 3, 5, and 7) to determine TNF-alpha, platelet count, fibrinogen, factor VII, antithrombin III, tissue-type plasminogen activator activity, plasminogen activator inhibitor activity, plasminogen, and alpha2-antiplasmin . Fibrinopeptide A was measured only on the day of admission . Data were analyzed to determine whether admission values or serially obtained values within 7 days were useful in predicting outcome . Thirteen patients died and 30 survived . On admission, assay values indicated that platelet count and antithrombin III were significantly lower than normal (as observed in 50 healthy adults) . Fibrinogen, plasminogen activator inhibitor type 1, tissue-type plasminogen activator, fibrinopeptide A, and TNF-alpha were higher than normal, whereas concentrations of factor VII, plasminogen, and alpha2-antiplasmin were in the normal range . No differences were detected in the admission values between survivors and nonsurvivors, except for antithrombin III . However, subsequent values of some variables demonstrated a difference between survivors and nonsurvivors . Survivors showed increasing platelet count and antithrombin III values compared with nonsurvivors, in whom the values remained low, with no significant changes during the study period . High TNF-alpha levels were found in both groups, but only survivors experienced progressive decrease during the observation period . CONCLUSIONS: Early clinical sepsis is characterized by high plasma levels of TNF-alpha and by activation of the coagulation and fibrinolysis systems . Longitudinal analysis of some variables (antithrombin III, platelet count, and TNF-ea) showed some differences with time between the survivor and nonsurvivor groups, but we feel that such differences were not large enough to be predictive in individual patients. Crit Care Med, 1999 Jul, 27(7), 1295 - 302 Components of energy expenditure in patients with severe sepsis and major trauma: a basis for clinical care; Uehara M et al.; OBJECTIVE: To obtain accurate values for the components of energy expenditure in critically ill patients with sepsis or trauma during the first 2 wks after admission to the intensive care unit . DESIGN: Prospective study . SETTING: Critical care unit and university department of surgery in a single tertiary care center . PATIENTS: Twelve severely septic (median Acute Physiology and Chronic Health Evaluation II Score, 23; range, 15 to 34) and 12 major trauma patients (median Injury Severity Score, 33.5; range, 26 to 50) . Interventions: Total body fat, total body protein, and total body glycogen were measured as soon as hemodynamic stability had been reached and repeated 5 and 10 days later . Resting energy expenditure (REE) was measured daily by indirect calorimetry . MEASUREMENTS AND MAIN RESULTS: Changes in total body fat, total body protein, and total body glycogen in critically ill patients provide data for the accurate construction of an energy balance . Energy intake minus energy balance gives a direct measurement of total energy expenditure (TEE) and, when combined with measurements of REE, activity energy expenditure can be obtained . TEE, REE, and activity energy expenditure were calculated for two sequential 5-day study periods . REE progressively increased during the first week after the onset of severe sepsis or major trauma, peaking during the second week at 37 +/- 6% (SEM) and 60 +/- 13% greater than predicted, respectively . For both the sepsis and trauma patients, TEE was significantly higher during the second week than during the first week (3257 +/- 370 vs . 1927 +/- 370 kcal/day, p < .05, in sepsis; 4123 +/- 518 vs . 2380 +/- 422 kcal/day, p < .05, in trauma) . During the first week after admission to the hospital, TEE in sepsis and trauma patients, respectively, averaged 25 +/- 5 and 31 +/- 6 kcal/kg of body weight/day, and during the second week, 47 +/- 6 and 59 +/- 7 kcal/kg/day (p < .03, for comparison of first and second weeks) . For the first week, the ratio of TEE to REE was 1.0 +/- 0.2 and 1.1 +/- 0.2 but during the second week rose to 1.7 +/- 0.2 and 1.8 +/- 0.2 in patients with sepsis (p < .05, for comparison of weeks) and trauma (p = .09), respectively . CONCLUSIONS: Total energy expenditure is maximal during the second week after admission to the critical care unit, reaching 50 to 60 kcal/kg/day. Crit Care Med, 1999 Jul, 27(7), 1265 - 70 Analysis of two human leukocyte antigen-linked polymorphic heat shock protein 70 genes in patients with severe sepsis; Schroeder S et al.; OBJECTIVE: To determine whether the genotype and allelic frequencies of two human leukocyte antigen-linked bi-allelic 70-kilodalton heat shock protein (HSP70) gene polymorphisms are associated with susceptibility to and outcome of severe sepsis . Furthermore, we investigated a possible linkage between HSP70 gene polymorphisms and the previously reported and mortality-related tumor necrosis factor-beta (TNF-beta) NcoI gene polymorphism . DESIGN: Consecutive entry study of patients with severe sepsis . SETTING: Surgical intensive care unit in a university hospital . PATIENTS: Eighty-seven patients with a diagnosis of severe sepsis . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: We studied two bi-allelic polymorphisms within the coding region of the constitutively expressed HSP70-HOM C/T, and the stress-inducible HSP70-2 G/A in patients with severe sepsis . The HSP70-HOM Ncol, HSP70-2 Pstl, and TNF-beta NcoI polymorphisms were identified by means of the polymerase chain reaction followed by restriction analysis of the polymerase chain reaction product . No significant differences in genotype and allelic frequencies were observed for both HSP70 gene polymorphisms between the 87 patients and the 110 healthy Caucasians serving as the control group . In addition, no differences in genotype and allelic frequencies between surviving and nonsurviving patients were detected . The allelic frequencies in the group of nonsurvivors were 0.8 for the HSP70-HOM C allele and 0.2 for the HSP70-HOM T allele vs . 0.87 and 0.13 for the survivors (p > .05) . The frequency for the HSP70-2 G allele was 0.36 and 0.64 for the HSP70-2 A allele in the group of nonsurvivors vs . 0.41 and 0.59 for the survivors (p > .05) . Analysis of a possible linkage between HSP70 and TNF-beta genotypes resulted in a significant association (odds ratio, 4.15; p < .01) of the HSP70-2 A/A homozygous genotype and the TNFB2/B2 homozygous genotype, which is reported to be a genomic marker for a poor prognosis in severe sepsis . CONCLUSIONS: Our data show that the bi-allelic NcoI and PstI polymorphisms within the HSP70-HOM and HSP70-2 locus, respectively, are associated with neither susceptibility to nor outcome of severe sepsis . Moreover, we found a linkage between HSP70-2 A homozygotes and the previously reported and mortality-related homozygous genotype, TNFB2/B2, in patients suffering from severe sepsis. Crit Care Med, 1999 Jul, 27(7), 1230 - 51 Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction; Hotchkiss RS et al.; OBJECTIVES: The purpose of this study was to determine whether apoptosis is a major mechanism of cell death in patients with sepsis . The activities of caspase-3 and the antiapoptotic protein, BCL-2, were investigated also . DESIGN: A prospective study of 20 patients who died of sepsis and multiple organ dysfunction was performed . The control group of 16 patients consisted of critically ill, nonseptic patients who were evaluated either prospectively (7) or retrospectively (9) . In addition, normal colon sections from seven patients who had bowel resections were included . Apoptosis was evaluated in hematoxylin and eosin-stained specimens by deoxyuridine triphosphate nick end-labeling (TUNEL) and by DNA gel electrophoresis . SETTING: Two academic medical centers . PATIENTS: Critically ill patients . MEASUREMENTS AND MAIN RESULTS: In septic patients, apoptosis was detected in diverse organs by all three methods with a predominance in lymphocytes and intestinal epithelial cells . Hematoxylin and eosin-stained specimens from septic patients demonstrated at least focal apoptosis in 56.3% of spleens, 47.1% of colons, and 27.7% of ileums . Indirect evidence of lymphocyte apoptosis in septic patients included extensive depletion of lymphocytes in white pulp and a marked lymphocytopenia in 15 of 19 patients . Hematoxylin and eosin from nonseptic patients' tissues revealed a low level of apoptosis in one patient only . The TUNEL method increased in positivity with a delay in tissue fixation and was highly positive in many tissues from both septic and nonseptic patients . Immunohistochemical staining for active caspase-3 showed a marked increase in septic vs . nonseptic patients (p < .01), with >25% to 50% of cells being positive focally in the splenic white pulp of six septic but in no nonseptic patients . CONCLUSIONS: We conclude that caspase-3-mediated apoptosis causes extensive lymphocyte apoptosis in sepsis and may contribute to the impaired immune response that characterizes the disorder. Am J Physiol, 1999 Aug, 277(2 Pt 2), R434 - 40 Activity and expression of the 20S proteasome are increased in skeletal muscle during sepsis; Hobler SC et al.; Recent studies suggest that sepsis stimulates ubiquitin-dependent protein breakdown in skeletal muscle . In this proteolytic pathway, ubiquitinated proteins are recognized, unfolded, and degraded by the multicatalytic 26S protease complex . The 20S proteasome is the catalytic core of the 26S protease complex . The role of the 20S proteasome in the regulation of sepsis-induced muscle proteolysis is not known . We tested the hypothesis that sepsis increases 20S proteasome activity and the expression of mRNA for various subunits of this complex . Proteolytic activity of isolated 20S proteasomes, assessed as activity against fluorogenic peptide substrates, was increased in extensor digitorum longus muscles from septic rats . The proteolytic activity was inhibited by specific proteasome blockers . Northern blot analysis revealed an approximately twofold increase in the relative abundance of mRNA for the 20S alpha-subunits RC3 and RC9 and the beta-subunit RC7 . However, Western blot analysis did not show any difference in RC9 protein content between sham-operated and septic rats . The increased activity and expression of the 20S proteasome in muscles from septic rats lend further support for a role of the ubiquitin-proteasome-pathway in the regulation of sepsis-induced muscle proteolysis. Arch Surg, 1999 Aug, 134(8), 831 - 6; discussion 836-8 Abdominal computed tomography for the diagnosis of intra-abdominal sepsis in critically injured patients: fishing in murky waters; Velmahos GC et al.; HYPOTHESIS: Abdominal computed tomographic (ACT) scans are useful in the evaluation of sepsis of unknown origin in patients with major trauma . DESIGN: Prospective case series of consecutive patients . SETTING: Intensive care unit of level I academic trauma center . PATIENTS: Eighty-five critically injured patients admitted to the intensive care unit in 32 months (6% of all intensive care unit admissions) who developed sepsis of unknown origin . INTERVENTIONS: One hundred sixty-one ACT scans . MAIN OUTCOME MEASURES: Sensitivity and specificity of the ACT scans, number of patients subjected to changes in treatment following an ACT scan . RESULTS: Forty-nine patients (58%) had an intraabdominal focus of infection identified on ACT scan . Penetrating trauma and emergent laparotomy were the only independent factors associated with abnormal findings on ACT scan . The sensitivity and specificity of the test were 97.5% and 61.5%, respectively . Overall, 59 patients (69%) benefited from treatment changes after an ACT scan . CONCLUSION: Abdominal computed tomographic scans reliably identify intra-abdominal foci of infection in patients with major trauma evaluated for sepsis of unknown origin. Burns, 1999 Aug, 25(5), 425 - 30 Prophylactic treatment with growth hormone and insulin-like growth factor I improve systemic bacterial clearance and survival in a murine model of burn-induced gut-derived sepsis; Fukushima R et al.; The purpose of this investigation was to evaluate the effects of GH and IGF-I administration in a murine model of burn-induced gut-derived sepsis . BALB/C mice were treated with 4.8 mg/kg/day of GH, 24 mg/kg/day of IGF-I or saline for 4 days . They were then administered 10(10) E . coli by gavage and subjected to 20% full thickness flame burn . All mice received allogeneic blood transfusion 5 days before burn injury to induce mild immunosuppression . Seventy-three mice were observed for survival and 51 mice were sacrificed at 4 and 20 h postburn . Blood, mesenteric lymph nodes (MLN), spleen and liver were harvested aseptically, and viable bacterial counts in the organs were determined . The small intestine was harvested for the evaluation of villus height and mitoses in the crypts . GH and IGF-I groups showed a significantly better survival than the control group . GH and IGF-I groups had significantly greater villus height and mitoses/crypt than the control group . Translocation of bacteria was not significantly different among groups, however, the relation between the numbers of viable bacteria in MLN and blood suggests that both GH and IGF-I reduced systemic spread of translocated bacteria . It is concluded that GH and IGF-I had positive effects on outcome in this model of burn-induced gut-derived sepsis . It appears that GH and IGF-I may have immune-enhancing effects and that administration of these agents may be useful for burn injury. J Infect Dis, 1999 Sep, 180(3), 908 - 11 Relationship of plasma leptin to plasma cytokines and human survivalin sepsis and septic shock; Arnalich F et al.; Leptin production is increased in rodents by administration of endotoxin or cytokines . To investigate whether circulating leptin is related to cytokine release and survival in human sepsis, plasma concentrations of leptin, interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, soluble TNF receptor type I, IL-1 receptor antagonist (IL-1ra), and the inflammatory modulator IL-10 were measured as soon as severe sepsis (n=28) or septic shock (n=14) developed and every 6 h for 24 h . Patients with sepsis or septic shock had leptin concentrations 2.3- and 4.2-fold greater, respectively, than the control group . There was an independent association for leptin with IL-1ra and IL-10 in both patient groups . By discriminant analysis, leptin and IL-6 were independent predictors of death . These findings suggest that increases in leptin levels may be a host defense mechanism during sepsis. J Clin Anesth, 1999 May, 11(3), 251 - 3 Anesthesia in a patient with undiagnosed salicylate poisoning presenting as intraabdominal sepsis; Chui PT; An 81-year-old woman with unintentional salicylate intoxication presented with features of sepsis, abdominal pain, and tenderness . Laparotomy was performed to rule out acute cholecystitis . Anesthesia was complicated by severe hypercarbia despite hyperventilation, and progressive cardiovascular and neurologic deterioration postoperatively . The adverse neurologic, respiratory, and hepatic effects of abdominal surgery and general anesthesia probably potentiated salicylate toxicity and increased patient morbidity . Anesthesiologists should be aware of the protean manifestations of salicylate poisoning and consider it as a cause of "medical abdomen." FASEB J, 1999 Aug, 13(11), 1435 - 43 Sepsis stimulates release of myofilaments in skeletal muscle by a calcium-dependent mechanism; Williams AB et al.; Sepsis is associated with a pronounced catabolic response in skeletal muscle, mainly reflecting degradation of the myofibrillar proteins actin and myosin . Recent studies suggest that sepsis-induced muscle proteolysis may reflect ubiquitin-proteasome-dependent protein breakdown . An apparently conflicting observation is that the ubiquitin-proteasome pathway does not degrade intact myofibrils . Thus, it is possible that actin and myosin need to be released from the myofibrils before they can be ubiquitinated and degraded by the proteasome . We tested the hypothesis that sepsis results in disruption of Z-bands, increased expression of calpains, and calcium-dependent release of myofilaments in skeletal muscle . Sepsis induced in rats by cecal ligation and puncture resulted in increased gene expression of micro-calpain, m-calpain, and p94 and in Z-band disintegration in the extensor digitorum longus muscle . The release of myofilaments from myofibrillar proteins was increased in septic muscle . This response to sepsis was blocked by treating the rats with dantrolene, a substance that inhibits the release of calcium from intracellular stores to the cytoplasm . The present results provide evidence that sepsis is associated with Z-band disintegration and a calcium-dependent release of myofilaments in skeletal muscle . Release of myofilaments may be an initial and perhaps rate-limiting component of sepsis-induced muscle breakdown. Arch Med Res, 1999 May-Jun, 30(3), 198 - 202 Amniotic fluid interleukin-6 and the risk of early-onset sepsis among preterm infants; Figueroa-Damian R et al.; BACKGROUND: High concentrations of interleukin-6 (IL-6) have been demonstrated in amniotic fluid (AF) from women with intra-amniotic infection . Recent studies have reported that IL-6 levels in AF were related to an increase in neonatal morbidity; moreover, higher IL-6 plasma levels have been observed in neonates with sepsis . METHODS: A cohort study was carried out at the National Institute of Perinatology in Mexico City . Inclusion criteria were the following: 1) preterm singleton pregnancy; 2) intact membranes at time of enrollment, and 3) written informed consent . Women with other complications of pregnancy were excluded . Newborn sepsis during the first 72 h was defined as early-onset sepsis . Amniotic fluid was obtained at the moment of delivery . Amniotic fluid IL-6 (AF IL-6) was determined by enzyme-linked immunoassays . RESULTS: Ninety-three women met the criteria for enrollment in the study and 31 (33%) of their newborns had early-onset neonatal sepsis . The mean AF IL-6 in mothers of septic newborns was 5779 +/- 2804 pg/ml compared to 729 +/- 382 pg/ml in mothers with non-infected neonates (p < 0.001) . AF IL-6 concentrations higher than 1250 pg/ml were significantly associated with early-onset sepsis (OR 33.3; 95% CI 9.4-117.3) (p < 0.001) . Gestational age under 32 weeks was also associated with neonatal sepsis (OR 2.56; 95% CI 1.2-9) (p = 0.002) . Women whose infants developed neonatal sepsis had a higher frequency of clinical chorioamnionitis (p = 0.02) . CONCLUSIONS: IL-6 determination in AF may be a useful indicator to identify neonates with higher risk of in utero bacterial infection. Acta Paediatr, 1999 Jun, 88(6), 647 - 50 Evaluation of interleukin-6, tumour necrosis factor-alpha and interleukin-1beta for early diagnosis of neonatal sepsis; Silveira RC et al.; The objective of this study was to assess the contribution of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) to an early diagnosis of early-onset neonatal sepsis . A cohort of 117 newborn infants delivered during a 1-y period had IL-6, TNF-alpha and IL-1beta, blood and cerebrospinal fluid (CSF) cultures, leucocyte and platelet count collected on the initial evaluation of possible early-onset sepsis . They were divided into four groups: I, positive blood and/or CSF cultures; II, probably infected with clinical sepsis but negative cultures; III, same as group II but mother received antibiotic antepartum; and IV, newborn infants that did not receive any antibiotic therapy . There were no differences among the four groups with respect to mean gestational ages and birthweights, median Apgar scores, type of delivery, or number of newborn infants with leucocyte count <5000 mm(-3) or >25000 mm(-3), platelet count <100000 mm(-3), immature/total neutrophil ratio >0.2, absolute neutrophil count <1000mm(-3) and median IL-1beta levels . Median IL-6 and TNF-alpha levels were significantly higher in groups with patients with a diagnosis of clinical sepsis than in controls . The optimal cut-off point was 32 pg ml(-1) for IL-6 and 12 pg ml(-1) for TNF-alpha . The combination of both provided a sensitivity of 98.5% . In conclusion, the combination of IL-6 and TNF-alpha is a highly sensitive marker of sepsis in the immediate postnatal period. Surgery, 1999 Jul, 126(1), 54 - 65 Inhibiting early activation of tissue nuclear factor-kappa B and nuclear factor interleukin 6 with (1-->3)-beta-D-glucan increases long-term survival in polymicrobial sepsis; Williams DL et al.; BACKGROUND: Recent data implicate the activation of nuclear factor-kappa B (NF-kappa B) and nuclear factor interleukin 6 (NF-IL6) as important steps in the pathophysiologic mechanisms of adult respiratory distress syndrome and systemic inflammatory response syndrome . METHODS: This study evaluated the effect of immunomodulating polysaccharides on transcription factor activation, cytokine expression, and mortality in a murine cecal ligation and puncture (CLP) model . ICR/HSD mice were treated with glucan (50 mg/kg) 1 hour before or 15 minutes after CLP . Liver and lung tissue were harvested at 3 hours and mortality trends were observed for 20 days . RESULTS: CLP increased liver and lung NF-kappa B and NF-IL6 nuclear binding activity as well as tumor necrosis factor-alpha and interleukin 6 messenger RNA levels at 3 hours . Pretreatment or posttreatment with glucans inhibited tissue NF-kappa B and NF-IL6 nuclear binding activity and tissue cytokine messenger RNA levels . Prophylaxis with glucan phosphate or scleroglucan increased (P < .001) long-term survival (20% CLP vs 65% glucan phosphate, 75% scleroglucan) . Posttreatment with glucan phosphate also increased (P < .05) long-term survival (20% vs 65%) . CONCLUSIONS: Pretreatment or posttreatment with biologic response modifiers decreased tissue transcription factor nuclear binding activity and cytokine message in liver and lung of septic mice . Inhibiting early transcription factor activation and cytokine message expression correlates with improved outcome in polymicrobial sepsis as denoted by increased long-term survival. Intensive Care Med, 1999 Jun, 25(6), 620 - 4 IV milrinone for cardiac output increase and maintenance: comparison in nonhyperdynamic SIRS/sepsis and congestive heart failure; Heinz G et al.; OBJECTIVE: To characterize the effect of the phosphodiesterase inhibitor (PDEI) milrinone in adult patients with a non-hyperdynamic condition during the course of the systemic inflammatory response syndrome (SIRS) or sepsis when compared with patients with congestive heart failure (CHF) . PDEIs are potent inhibitors of cytokine production and expression . We hypothesized that there might be an outstanding beneficial effect of PDEIs in the setting of SIRS/sepsis . DESIGN: Prospective, open labeled, protocol-driven pilot study . PATIENTS: Nine patients with a nonhyperdynamic hemodynamic condition during SIRS/sepsis (group 1) and seven patients with CHF (group 2) requiring inotropic support . All patients were having heart disease . All patients had a combination of various catecholamines at the time of inclusion in the study and had received fluid resuscitation to an extent that left ventricular stroke work index (LVSWI) did not increase further . INTERVENTION: Milrinone infusion at a rate of 0.5 microg/kg per min in addition to preexisting catecholamine therapy . MEASUREMENTS AND RESULTS: Measurements of cardiac index (CI; thermodilution) and calculation of vascular resistance and LVSWI was done every 8 h for at least 40 h during milrinone infusion . CI and LVSWI significantly increased in both groups (p < 0.001 and p = 0.006, respectively) . There were no significant differences between groups in these parameters (p > 0.11 and p > 0.13, respectively) . The LVSWI increase occurred while there was a decrease in pulmonary capillary wedge pressure, suggesting a true and comparable improvement in cardiac function relatively independent of loading conditions . Preexisting catecholamines had to be increased in both groups (NS) . Milrinone had to be discontinued in one patient due to hypotension . CONCLUSION: Milrinone administration is feasible in selected patients with a non-hyperdynamic condition during SIRS/sepsis and with preexisting heart disease . Under the conditions of this study, milrinone was no better in terms of CI and LVSWI maintenance in septic cardiac dysfunction when compared with CHF . These results do not necessarily extend to other cohorts with no preexisting heart disease. Nurs Crit Care, 1999 Mar-Apr, 4(2), 63 - 6 Nursing care of a patient with fever due to sepsis/SIRS; Thompson S; The pathophysiology of fever in sepsis/Systemic Inflammatory Response Syndrome (SIRS) is outlined . The three phases of fever are explored using a patient case study . The conclusion recommends further research is needed on the nursing management of critically ill patients with a fever. Am J Physiol, 1999 Jul, 277(1 Pt 2), R132 - 9 Transcriptional and posttranscriptional regulation of beta(2)-adrenergic receptor gene in rat liver during sepsis; Yang J et al.; Changes in beta(2)-adrenergic receptor (beta(2)-AR) gene expression in the rat liver during different phases of sepsis were studied . Sepsis was induced by cecal ligation and puncture (CLP) . Septic rats exhibit two metabolically distinct phases: an initial hyperglycemic (9 h after CLP; early sepsis) followed by a hypoglycemic phase (18 h after CLP; late sepsis) . The {(3)H}dihydroalprenolol binding studies show that the density of beta(2)-AR was decreased by 12 and 35% during the early and late phases of sepsis, respectively . Western blot analyses depict that the beta(2)-AR protein level was reduced by 37 and 72% during early and late sepsis, respectively . The reverse transcription polymerase chain reaction and Southern blot analyses reveal that the steady-state level of beta(2)-AR mRNA was decreased by 37% during early phase and 77% during late phase of sepsis . Nuclear run-off assays show that the rate of transcription of beta(2)-AR mRNA was reduced by 36% during early sepsis and 64% during late sepsis . The stability assays indicate that the half-life of beta(2)-AR mRNA was shortened by 21 and 50% during the early and late phases of sepsis, respectively, indicating that the rate of degradation of beta(2)-AR mRNA was progressively enhanced during sepsis . These findings demonstrate that the beta(2)-AR gene was underexpressed in the liver during the progression of sepsis, and, furthermore, the underexpression of the beta(2)-AR gene was the result of a reduction in the rate of transcription coupled with an enhancement in the rate of degradation of beta(2)-AR gene transcripts . Thus our findings that the transcriptional and posttranscriptional regulation of beta(2)-AR gene associated with decreases in beta(2)-AR number and its protein expression may provide a molecular mechanistic explanation for the development of hypoglycemia during the late stage of sepsis. Przegl Epidemiol, 1999, 53(1-2), 205 - 9 {Ischemic stroke during sepsis and bacterial meningoencephalitis: a case report}; Kepa L et al.; A case of acute ischaemic stroke in a woman aged 49 years during sepsis and purulent, bacterial meningoencephalitis was described . Diagnosis was based on clinical examination and repeatedly CT scans . Attention is called to diagnostic difficulties in this complication of central nervous system bacterial infections. J Lab Clin Med, 1999 Jul, 134(1), 49 - 55 Procalcitonin expression in human peripheral blood mononuclear cells and its modulation by lipopolysaccharides and sepsis-related cytokines in vitro; Oberhoffer M et al.; Procalcitonin (PCT), the precursor of calcitonin, was recently put forward as a diagnostic marker of systemic bacterial infection and sepsis . The major PCT production site in sepsis still remains unclear . Because of a certain association between increased levels of PCT and leukocyte-derived cytokines during sepsis, we assessed the possible expression of PCT in human peripheral blood mononuclear cells (PBMCs) and the modulation of PCT by lipopolysaccharides (LPS) and various sepsis-related cytokines by reverse transcriptase-polymerase chain reaction (RT-PCR) by using a novel primer set and flow cytometric analysis with intracellular staining with antibodies to the PCT components calcitonin and katacalcin . RT-PCR and flow cytometric analysis demonstrated that PBMCs express PCT both on mRNA and on protein levels . LPS and various proinflammatory cytokines (interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), IL-2) had pronounced stimulatory effects on the expression of PCT mRNA . Under identical experimental conditions the anti-inflammatory cytokine IL-10 had no effect on the expression of mRNA for PCT . Flow cytometric analysis demonstrated increased intracellular amounts of PCT components after LPS stimulation . Thus we demonstrate for the first time that PCT is expressed in PBMCs . This expression is modulated by bacterial LPS and sepsis-related cytokines . Therefore PBMCs may be among the sources of elevated PCT levels in patients with sepsis. Intensive Care Med, 1999 May, 25(5), 435 - 44 Relationship of antibodies to endotoxin core to mortality in medical patients with sepsis syndrome; Strutz F et al.; OBJECTIVES: To assess the prognostic value of determining anti-endotoxin core antibodies (EndoCab) immunoglobulin (Ig)G and IgM in medical patients with sepsis syndrome in order to identify patient subgroups that may profit from endotoxin-neutralizing therapy . The findings were correlated with clinical outcome, endotoxin levels and sepsis score . DESIGN: Cohort study with a follow-up period of 30 days . SETTING: Medical intensive care units (2) of a university hospital . PATIENTS AND METHODS: Twenty-nine patients who fulfilled the criteria of sepsis syndrome and did not present with septic shock or had not been treated with antibiotics for more than 3 days were included in the study . Twenty-one intensive care patients without infections served as controls for antibody concentrations . INTERVENTIONS: Blood samples were obtained from indwelling arterial catheters or direct venipuncture on admission and daily thereafter until transfer to a regular unit . Sepsis scores were determined daily . RESULTS: The mortality rate at 30 days was 44.8% (13 out of 29) . Sepsis patients had significantly lower initial EndoCab IgM and IgG concentrations than controls . Initial EndoCab IgG concentrations were significantly lower in non-survivors of sepsis syndrome but not in survivors compared to controls (median concentrations 51.5 vs 110.1 vs 245.4 MU/ml) . EndoCab IgM and IgG were lower in non-survivors compared to survivors, though that difference failed to reach significance (p = 0.11 in both cases) . Depletion of initial EndoCab IgM concentrations (defined as a value below the 10th percentile of a control population) was present in 15 patients, 9 of whom died, and depletion of IgG in five patients, four of whom died . EndoCab IgM and IgG concentrations rose concordantly in survivors and non-survivors in the course of the disease . Endotoxin levels were significantly higher in non-survivors compared to controls but not in survivors . A sepsis score of 21 and higher was associated with 90.9% mortality (specificity 93.8%, sensitivity 76.9%) . CONCLUSIONS: Decreased EndoCab IgG concentrations are associated with increased mortality in medical patients with sepsis syndrome . The measurement of initial anti-endotoxin antibodies may provide a useful tool to identify septic patients who profit potentially from endotoxin neutralizing therapy, however considerable overlap of antibody concentrations warrants additional parameters . The sepsis score is easy to determine and useful in the evaluation of medical patients with sepsis. Crit Care Med, 1999 Jun, 27(6), 1080 - 4 Impaired inducibility of heat shock protein 70 in peripheral blood lymphocytes of patients with severe sepsis; Schroeder S et al.; OBJECTIVE: To determine the extent of the potentially protective heat shock protein 70 response in peripheral blood lymphocytes of patients with severe sepsis after ex vivo lipopolysaccharide stimulation . DESIGN: Entry study of consecutive patients with severe sepsis, those who were critically ill or nonseptic after major surgery, and healthy blood donors . SETTING: Surgical intensive care unit in a university hospital . PATIENTS: Ten patients with diagnoses of severe sepsis; ten critically ill, nonseptic patients after major surgery; and ten healthy blood donors . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: We investigated the ex vivo endotoxin-inducible expression of heat shock protein 70 in peripheral blood lymphocytes of patients with severe sepsis by means of flow cytometry . Only negligible amounts of inducible intracellular heat shock protein 70 accumulation (<4.2% of lymphocytes) could be detected in peripheral blood lymphocytes without lipopolysaccharide stimulation . The proportion of cells accumulating heat shock protein 70 after treatment with lipopolysaccharide was distinctly lower in patients with severe sepsis (p < .05) than in critically ill, nonseptic patients after major surgery and healthy blood donors (38.3+/-3.3%, 82.2+/-4.5%, and 70.9+/-3.9%, respectively; mean +/- SEM; n = 10) . Patients with clinical signs of recovery from severe sepsis showed an increase in heat shock protein 70 expression . CONCLUSIONS: Inducibility of ex vivo heat shock protein 70 was impaired in peripheral blood lymphocytes of patients with severe sepsis . The impaired expression of the potentially protective heat shock protein 70 may contribute in vivo to immune dysfunction, because intact functioning of T and B lymphocyte responses is of central importance in resisting infection in severe sepsis . Monitoring of inducible heat shock protein 70 in peripheral blood lymphocytes may contribute to the evaluation of the immune consequences of severe sepsis. Minerva Anestesiol, 1999 Jun, 65(6), 419 - 26 Present and future options in continuous renal replacement therapies of sepsis and MOF; Tetta C et al.; Conventional continuous extracorporeal treatments such as hemofiltration and hemodiafiltration have not achieved significant reduction in cytokine plasma levels, in spite of their increasing popularity mainly related to the unnecessary fluid restriction thereby rendering adequate caloric intake possible (Actualites Nephrologiques, 1994) . This is mainly due to reduced filtration, to saturability of the adsorption-related phenomena and to the absence of a convective mass transfer . New approaches have been more recently introduced . The concept of blood purification has been applied in some new innovative techniques that use non-selective or selective sorbents . We will focus on the criteria used by others and us to assess the efficiency in vitro and in animal models of sepsis of more recently introduced non-selective and selective devices . Among the innovative techniques, modalities aimed at the plasma treatment will receive emphasis . These modalities that are based on plasma filtration with the use of different sorbents . The preliminary results obtained from ongoing clinical trials will be presented . We will also expand on the technical, biological and clinical aspects that should be addressed in order to establish a new modality as innovative in the treatment of sepsis. Minerva Anestesiol, 1999 Jun, 65(6), 410 - 8 Immunomodulation in sepsis: the role of hemofiltration; Kellum JA; Inflammation is a normal and biologically important process essential for host defense and repair of tissue injury . However, given the cyto-destructive capacity of inflammation, it is tightly controlled even in severe sepsis . There are both pro- and anti-inflammatory components of the inflammatory response, which are initiated simultaneously and co-exist in a single organism . Significant morbidity and mortality results when the inflammatory response becomes unstable and its components uncoupled . Restoring immune stability likely requires reestablishing a balance between pro- and anti-inflammatory processes as well as restoring the normal feedback mechanisms necessary for systemic control . Selective manipulation of inflammation by augmenting or blocking specific components continues to fail as a therapeutic approach to human sepsis, perhaps because such targeted manipulation of the immune response is unable to restore balance and immune stability . It has been recently shown that continuous veno-venous hemofiltration (CVVH) can nonselectively affect the plasma concentrations of immune mediators in patients with sepsis and multiple organ dysfunction syndrome (MODS) . Hemofiltration offers tremendous potential advantages over other forms of immunomodulation because it is both non-specific and self-regulating . CVVH can remove both soluble pro- and anti-inflammatory substances and does so in direct relationship to the circulating mediator concentrations . The ultimate value of this technique will depend on whether immunomodulation is an appropriate goal for patients with sepsis . The avoidance of unintended immunomodulation is also an important issue, and evidence already suggests that this should be a priority. Acad Emerg Med, 1999 Jun, 6(6), 588 - 95 Alterations in hepatic gluconeogenesis, prostanoid, and intracellular calcium during sepsis; Maitra SR et al.; OBJECTIVE: The metabolic alterations observed during sepsis may be associated with changes in local concentrations of intracellular calcium (Ca2+) and prostanoid synthesis in the liver . The authors studied hepatocyte intracellular Ca2+ and the release of glucose and prostanoid in an in-vivo murine liver perfusion model . METHODS: Sepsis was induced in anesthetized, fasted rats by cecal ligation and puncture (CLP, n = 42) . Hepatic glucose release was studied in control (n = 10) and CLP (n = 10) groups using a non-recirculating liver perfusion model with and without lactate as gluconeogenic substrate . Hepatocyte intracellular Ca2+ (n = 11) was measured using the selective indicator Fura-2 under basal and epinephrine (10(-5) M) stimulated conditions . 6-Keto-prostaglandin F1alpha (6-Keto) and thromboxane B2 (TxB2) were determined from liver perfusate by radioimmunassay (n = 11) . Data were analyzed using t-tests and repeated-measures ANOVA . RESULTS: Plasma glucose was significantly lower in CLP groups compared with controls (74.9+/-6.6 vs 115.7+/-4.6 mg/dL, p < 0.05) . Plasma lactate was significantly higher in CLP vs controls (3.7+/-0.4 vs 1.4+/-0.1 mM, p < 0.05) . Glucose release in isolated perfused livers was significantly lower in CLP vs controls (8.5 vs 16+/-1.2 microM/g/hr, p < 0.001) . With the addition of lactate + pyruvate to the perfusate, glucose output in CLP livers was significantly lower following 5 (9.9+/-0.7 vs 17.7+/-1.1 microM/g/hr, p < 0.05) and 10 (11.9+/-1.2 vs 20.6+/-1.3 microM/g/hr, p < 0.001) minutes of perfusion . The basal level of intracellular calcium ({Ca2+}i) in CLP rats (460.1+/-91.6 nM) was significantly higher than in control rats (196.3+/-35.5 nM) (p < 0.05) . A significant increase (p < 0.05) in {Ca2+}i occurred after the addition of epinephrine in hepatocytes in control (196.3+/-35.5 vs 331.8+/-41.4 nM) but not CLP (460.1+/-91.6 vs 489.4+/-105 nM) rats . 6-Keto was significantly lower in CLP compared with controls at 30 minutes (25.7+/-3.9 vs 33.4+/-5.5 pg/mL, p < 0.05), whereas TxB2 was not significantly altered (52.1+/-34.7 vs 87.5+/-43.2 pg/mL) . CONCLUSION: These results demonstrate that CLP sepsis is associated with an increase in hepatocyte intracellular free Ca2+ concentration along with attenuation of hormone-mediated Ca2+ mobilization and hepatic gluconeogenesis. Clin Exp Pharmacol Physiol Suppl, 1999 Apr, 26, S23 - 8 Renal-dose (low-dose) dopamine for the treatment of sepsis-related and other forms of acute renal failure: ineffective and probably dangerous; Power DA et al.; 1 . Low-dose ('renal-dose') dopamine (i.e . 1-3 micrograms/kg per min) is used widely for the treatment of acute renal failure induced by ischaemia, toxins and/or sepsis . Here we review the scientific rationale, experimental studies and clinical trials evaluating its use in these settings . 2 . Renal-dose dopamine augments renal blood flow, sodium excretion and probably glomerular filtration rate in healthy humans and experimental animals and limits ATP utilization and oxygen requirements in nephron segments at risk of ischaemic injury . Renal-dose dopamine is renoprotective in several ischaemic and nephrotoxic models of acute renal failure . 3 . However, most studies in humans have not demonstrated prevention of acute renal failure in high-risk patients or improved outcome in those with established acute renal failure . While the safety profile of dopamine in these settings has not been extensively defined, it is known the drug may precipitate serious cardiovascular and metabolic complications in the critically ill . Therefore, we suggest that renal-dose dopamine should not be used for selective renal vasodilatory and natriuretic actions in those patients with acute renal failure until its efficacy is established in randomized control trials . 4 . Renal-dose dopamine may be most valuable when combined with agents targeting other events in acute renal failure, such as cast formation, epithelial cell injury and tubule regeneration . These recommendations should not preclude the use of dopamine for its systemic effects in heart failure and septic shock. J Surg Res, 1999 Jul, 85(1), 59 - 65 Reduction in vascular responsiveness to adrenomedullin during sepsis; Wang P et al.; BACKGROUND: Although sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase, the mechanism responsible for the transition from the hyperdynamic to the hypodynamic state remains unknown . Since recent studies have shown that adrenomedullin (ADM), a novel potent vasodilatory peptide, is upregulated during sepsis, the aim of this study was to determine whether the reduced vascular responsiveness to ADM is associated with the transition from the hyperdynamic phase to the hypodynamic phase of sepsis . MATERIALS AND METHODS: Adult male Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP) . At 5 and 10 h (i.e., the hyperdynamic phase of sepsis) or 20 h (the hypodynamic phase) after CLP, the thoracic aorta or small intestine was harvested and preconstricted with norepinephrine . Adrenomedullin (10(-7) M) was applied and the percentage of ADM-induced vascular relaxation in the aortic ring and isolated small intestine was determined . RESULTS: The responsiveness to ADM in the thoracic aorta was not altered at 5-10 h, but decreased significantly at 20 h after CLP . Although ADM-induced relaxation in resistance blood vessels of the small intestine did not change at 5 h, it decreased markedly at 10 and 20 h after the onset of sepsis . CONCLUSIONS: Since the transition from hyperdynamic to hypodynamic sepsis takes place between 10 and 20 h after CLP, it is likely that reduced vascular responsiveness to ADM may be responsible for such an event during the course of polymicrobial sepsis . In view of this, maintenance of vascular ADM responsiveness by pharmacologic agents appears to be a novel approach for preventing or delaying the occurrence of hypodynamic sepsis and septic shock . Br J Surg, 1999 Jun, 86(6), 813 - 21 Selective impairment of glucose storage in human sepsis; Saeed M et al.; BACKGROUND: Glucose utilization in sepsis is impaired but the mechanisms are unclear . This study examined the effect of sepsis on total glucose utilization, oxidation and storage, and the energetic costs of these metabolic processes . METHODS: Glucose infusion rate (GIR), glucose oxidation rate (GOR), non-oxidative disposal rate and the energetic cost of glucose storage were studied in 24 patients with abdominal sepsis and in 26 healthy controls, using indirect calorimetry and the euglycaemic hyperinsulinaemic clamp with insulin infusion rates of 40 and 240 mU m-2 min-1 . RESULTS: Basal GOR was significantly lower in septic patients than in controls (1.5 versus 2.3 mg per kg fat-free mass (FFM) per min, P < 0.001) . Septic patients had a significantly lower GIR at 40 mU m-2 min-1 (4.2 versus 9.1 mg per kg FFM per min) and at 240 mU m-2 min-1 (7.5 versus 11.8 mg per kg FFM per min), relative to controls (P < 0.001) . GOR was similar in septic and control subjects at both rates of insulin infusion whereas non-oxidative disposal was significantly lower in septic patients (P < 0.001) and accounted entirely for the reduction in GIR . The energetic cost of glucose disposal was unaffected by sepsis . CONCLUSION: Sepsis is associated with selective impairment of glucose storage but the energetic cost of non-oxidative disposal is unaffected. J Crit Care, 1999 Jun, 14(2), 78 - 83 Comparison between intrathoracic blood volume and cardiac filling pressures in the early phase of hemodynamic instability of patients with sepsis or septic shock; Sakka SG et al.; PURPOSE: The purpose of this study was to analyze three different variables of cardiac preload; central venous pressure (CVP), pulmonary artery occlusion pressure (PAOP), and intrathoracic blood volume index (ITBVI) that served as the best indicator of cardiac function, that is, cardiac index (C1) or stroke index (SI) . MATERIALS AND METHODS: This was a prospective study in 57 critically ill patients with sepsis or septic shock in whom 581 hemodynamic profiles were analyzed . One patient was included a second time after a period of 6 weeks . All patients were sedated and mechanically ventilated . Each patient had a 7.5-Frfive-lumen pulmonary artery catheter (PAC) and a 4-Fr catheter with an integrated thermistor and fiberoptic that was advanced into the descending aorta via a femoral artery sheath . The study was performed in the surgical intensive care unit of a university hospital . RESULTS: Linear regression analysis of the first profile for each case (n = 58) revealed a significant correlation between ITBVI and SI (r = 0.66) . For comparison, correlations for PAOP/SI (r = 0.06) and CVP/SI (r = 0.10) were poor . The analysis of all second profiles showed that only the change in ITBVI reflected the change in SI (r = 0.67), whereas PAOP (r = 0.07) and CVP (r = 0.05) failed . Furthermore, a positive change in SI (n = 265) was most often associated with an increase in ITBVI (n = 189, 71.3%), less for PAOP (n = 122, 46.0%) and CVP (n = 137, 51.7%) . A reduction in SI (n = 256) was accompanied by a decrease in ITBVI (n = 176, 68.8%), PAOP (n = 119, 46.5%), and CVP (n = 118, 46.1%) . An increase in ITBVI (n = 269) was accompanied by an increase in SI in 189 cases (70.3%) . In these, PAOP increased only in 91 (48.1%) and CVP in 101 cases (53.4%), respectively . Accordingly, a positive change in PAOP (n = 218) was associated with an increase in SI in 122 cases (56.0%) . ITBVI increased in 91 (74.6%) and CVP in 84 (68.9%) of these cases . A decrease in ITBVI (n = 250) was associated with a decrease in SI in 176 cases (70.4%) . Decreases in PAOP (n = 89, 50.6%) and CVP (n = 91, 51.7%) did not reflect these changes . However, when PAOP (n = 229) and SI decreased (n = 119, 52.0%), ITBVI decreased in 89 (74.8%) and CVP in 73 cases (61.3%) . CONCLUSIONS: In comparison with cardiac filling pressures, ITBVI seems to be the more reliable indicator of cardiac preload in patients with sepsis or septic shock. J Crit Care, 1999 Jun, 14(2), 69 - 72 IL-1ra administration does not improve cardiac function in patients with severe sepsis; Vincent JL et al.; PURPOSE: The purpose of this study was to investigate the effects of interleukin-1 receptor antagonist (IL-1ra) on myocardial function in septic patients . MATERIALS AND METHODS: A subgroup of patients from a prospective, randomized, double-blind, placebo-controlled, multicenter trial was studied from 63 academic medical centers in the United States, Canada, and Europe . A subgroup of 71 patients with severe sepsis in whom vasoactive support was little altered during the study was included . The patients were randomized to receive either placebo (n = 29) or IL-1ra at a dose of 1 mg/kg/h (n = 20) or 2 mg/kg/h (n = 22) . RESULTS: Hemodynamic measurements were taken at baseline, and 1, 2, 3, 4, 8, and 12 hours after placebo or IL-1ra administration . No significant differences in hemodynamic parameters were observed between the groups or over time during the study period . CONCLUSIONS: IL-1ra administration has no effect on cardiac function in septic patients. J Crit Care, 1999 Jun, 14(2), 63 - 8 Interleukin 1 receptor antagonist and E-selectin concentrations: a comparison in patients with severe acute pancreatitis and severe sepsis; Hynninen M et al.; PURPOSE: This prospective clinical study was designed to compare interleukin 1 receptor antagonist (IL-1ra) and E-selectin concentrations in patients with severe acute pancreatitis to those with severe sepsis . MATERIALS AND METHODS: Nine consecutive patients with severe acute pancreatitis and 11 consecutive patients with severe sepsis admitted to a medical/surgical intensive care unit were included in the study . Plasma concentrations of IL-1ra and E-selectin were serially measured daily for 7 days or throughout their stay in the intensive care unit if shorter . RESULTS: The concentrations of IL-1ra were significantly higher on admission in patients with severe sepsis compared with the patients with severe pancreatitis (median levels 10,500 and 2,600 pg/mL, respectively, P = .007) . When the data from the first 3 days were analyzed using analysis of variance (ANOVA), the levels of IL-1ra and E-selectin were similar in both groups . The concentrations of IL-1ra and E-selectin correlated to the development of multiorgan dysfunction as assessed by sequential organ failure assessment (SOFA) score (P = .032 and .043, respectively) . CONCLUSION: This study shows that IL-1ra and E-selectin are released in acute severe pancreatitis, and the levels seem to be comparable to those in patients with severe sepsis . Concentrations of IL-1ra and E-selectin correlate to the development of multiorgan failure as indicated by high SOFA scores during the first week of disease. Metabolism, 1999 Jun, 48(6), 779 - 85 Leukocyte glycolysis and lactate output in animal sepsis and ex vivo human blood; Haji-Michael PG et al.; Lactate is released in large quantity from sites of sepsis and inflammation . We asked whether the increased lactate production found in sepsis can be explained by the augmented glycolysis of inflammatory cells . The glycolytic metabolism of rat peritoneal leukocytes was measured following cecal ligation and perforation (CLP) or sham laparotomy . CLP augmented glucose uptake, the pentose phosphate pathway, and glucose oxidation . Lactate output increased from 1.03 +/- 0.05 to 1.20 +/- 0.05 fmol x cell(-1) x min(-1) (P < .001) . Total lactate output of peritoneal lavage fluid increased from 7.94 +/- 2.59 to 28.12 +/- 5.60 nmol L x min(-1) (P < .005) . The effect of lipopolysaccharide (LPS) on the lactate output of whole blood from 31 critically ill patients was measured . Leukocyte lactate production was calculated by multiple linear regression analysis . Following exposure to LPS, human leukocyte lactate output increased from 0.20 +/- 0.09 to 1.22 +/- 0.14 fmol x cell(-1) x min(-1) (P < .001) . This rate of production is so high that it suggests that the lactate output of different tissue beds in sepsis may be affected by their different cell populations and state of activation . This study supports the hypothesis that lactate may be more a product of inflammation than a marker of tissue hypoxia in sepsis. Am J Obstet Gynecol, 1999 Jun, 180(6 Pt 1), 1345 - 8 Neonatal sepsis and death caused by resistant Escherichia coli: possible consequences of extended maternal ampicillin administration; Terrone DA et al.; OBJECTIVE: Our goal was to evaluate the relationship between neonatal death caused by sepsis associated with ampicillin-resistant organisms and length of antibiotic exposure . STUDY DESIGN: All neonatal deaths from culture-positive sepsis over a 3-year period were examined . Infants who were delivered at either the University of Mississippi Medical Center or at Saint Barnabas Medical Center at >/=24 weeks' gestation and died within 7 days of life were included . Information on the organism causing sepsis and its sensitivities was collected, and the number of doses of ampicillin administered to the mother before delivery was determined . RESULTS: Of the 78 neonatal deaths, 35 met the inclusion criteria . There were 8 cases of sepsis from ampicillin-resistant Escherichia coli and 27 cases caused by other organisms . There was a statistically significant difference between the mean number of doses of ampicillin received by the ampicillin-resistant Escherichia coli group (17.6 +/- 5.5) compared with the other organisms group (4.9 +/- 3.6) (P <.001) . CONCLUSION: A relationship exists between neonatal death caused by ampicillin-resistant Escherichia coli and prolonged antepartum exposure to ampicillin. Eur J Clin Nutr, 1999 Apr, 53 Suppl 1, S143 - 7 Limitations of nutrient intake . The effect of stressors: trauma, sepsis and multiple organ failure; Campbell IT; The response to injury includes a diminution in appetite, a decrease in nutrient intake, an acute mobilisation of endogenous energy stores (glucose and fat), but an impaired ability to use them . Lean tissue is broken down to its constituent amino acids, which provide precursors for the synthesis of glucose in the liver (gluconeogenesis) . Glucose is used as a source of energy by the brain and red blood cells, as well as by wound tissue . After a discrete injury normal function is normally resumed with a reduced body mass . In very severe injury or sepsis, in those who are physiologically or immunologically impaired or those with a genetic predisposition to the condition, organ failure may develop due to an apparent ongoing inflammatory process . The origin of this process is not always apparent, but loss of integrity of the gastrointestinal tract has been suggested . Apparently adequate nutritional support in the presence of a severe inflammatory stimulus only attenuates the gluconeogenic process, and the breakdown of lean tissue continues . Supply of protein (amino acids) stimulates protein synthesis, but it also stimulates breakdown . Nutrient intake via the enteral route may be limited by gastrointestinal symptoms and via the parenteral route by fluid overload, although this can be circumvented by fluid removal by haemofiltration . It is probable that, if nutritional support in severe trauma/sepsis/multiple organ failure is to be effective, satisfactory pharmacological methods of controlling metabolism will have to be found. Eur J Clin Nutr, 1999 Apr, 53 Suppl 1, S136 - 42 Sepsis as a modulator of adaptation to low and high carbohydrate and low and high fat intakes; Wolfe RR; Catabolism of lean body mass (particularly muscle) occurs in sepsis and other forms of critical illness despite apparently adequate nutritional support . The determination of the optimal balance of carbohydrate and fat intake in this circumstance should be based on the resulting effect on the maintenance of lean body mass, and the nature and extent of any side effects . The general stress response involves a disruption in normal glucoregulation, in that hepatic glucose production is accelerated and the normal blood glucose lowering action of insulin is diminished . Nonetheless, the capacity to oxidize glucose once inside the cells is not impaired . Lipolysis, or the breakdown of peripheral triglycerides to free fatty acids (FFA) and glycerol, is accelerated in critical illness, to a greater extent than fat oxidation . Provision of exogenous fat maintains fat stores, but has minimal effect on the direct oxidation of plasma FFA . From the results of oxidation studies, it seems that about 5 mg kg x min of glucose can be readily oxidized, and the balance of energy will be supplied by the oxidation of fat, either endogenous or exogenous . However, an additional consideration in determining the optimal caloric substrate is that insulin is a potent anabolic hormone and stimulates muscle protein synthesis . Consequently, provision of exogenous insulin enhances retention of muscle . This procedure dictates that almost all non-protein calories be provided as carbohydrate to avoid hypoglycemia . Preliminary studies suggest this may be the optimal approach in critically ill patients . Glucose and fatty acids are the major energy substrates in the body . The oxidative metabolism of these substrates provides the ATP needed for physiological function, including protein synthesis . Over the past 20 y, development of new techniques in nutritional support have made it possible to provide large amounts of carbohydrate and fat to critically-ill patients, along with protein or amino acids . However, despite providing such patients with what should be more than adequate caloric and protein intake, critically ill patients lose lean body mass (Streat et al, 1987), largely because of persistent muscle catabolism (Sakurai et al, 1995) . The general relation between energy substrate metabolism and maintenance of lean body mass has been recognized for many years (Calloway & Spector, 1954), so it is important to examine the alterations in energy substrate metabolism that occur in response to critical illness that may play a role in causing the persistent catabolism of muscle protein. Mol Biol Rep, 1999 Apr, 26(1-2), 71 - 6 Role of the ubiquitin-proteasome pathway in sepsis-induced muscle catabolism; Hasselgren PO; Several lines of evidence suggest that the ubiquitin-proteasome pathway is involved in sepsis-induced muscle catabolism . The gene expression of ubiquitin and several of the proteasome subunits was increased in muscle from both septic rats and patients . In other studies, the activity of isolated 20S proteasomes was stimulated in septic muscles . Sepsis-induced increase in muscle total and myofibrillar protein breakdown was inhibited with specific proteasome blockers . Although the ubiquitin-proteasome pathway is upregulated in septic muscle, it is still unclear how the myofibrillar proteins actin and myosin are ubiquitinated and become substrates for the 26S proteasome . Recent studies suggest that a calcium-dependent, calpain-mediated process releases myofilaments from the Z-disks during sepsis . It is possible that this process exposes destabilizing N-terminal residues on actin and myosin, making them suitable substrates for the N-end rule pathway involving the 14 kD ubiquitin-conjugating enzyme E214k and the ubiquitin-protein ligase E3alpha. Crit Care Med, 1999 May, 27(5), 959 - 64 Salutary effects of ATP-MgCl2 on the depressed endothelium-dependent relaxation during hyperdynamic sepsis; Wang P et al.; OBJECTIVES: Studies have shown that endothelium-dependent relaxation (mediated by endothelium-derived nitric oxide) is depressed during the early, hyperdynamic stage of sepsis . Although it is known that ATP-MgCl2 produces beneficial effects following various adverse circulatory conditions, it remains unknown whether this agent attenuates the depressed endothelium-dependent relaxation during early sepsis . The aim of this study, therefore, was to determine whether or not the administration of ATP-MgCl2 early after the onset of sepsis improves or maintains endothelium-dependent relaxation . DESIGN: Prospective, controlled animals study . SETTING: A university research laboratory . SUBJECTS: Adult male Sprague-Dawley rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP), followed by administration of 3 mL/100 g body weight normal saline to these and sham-operated rats . INTERVENTIONS: At 1 hr after CLP, ATP-MgCl2 (50 micromol/kg body weight) or an equivalent volume of normal saline was infused intravenously over 90 mins . MEASUREMENTS AND MAIN RESULTS: At 5 hrs or 10 hrs after CLP (i.e., the early, hyperdynamic stage of sepsis), the thoracic aorta was isolated, cut into rings, and placed in organ chambers . Norepinephrine was used to preconstrict vessel rings . Dose responses for an endothelium-dependent vasodilator, acetylcholine (ACh, via endothelium-dependent nitric oxide), and an endothelium-independent vasodilator, nitroglycerin, were determined . These results indicate that endothelium-dependent relaxation induced by ACh was significantly depressed at 5 and 10 hrs after CLP . Administration of ATP-MgCl2 after the onset of sepsis, however, maintained ACh-induced vascular relaxation . In contrast, no significant difference in nitroglycerin-induced vascular relaxation as well as norepinephrine-induced contraction was observed, irrespective of administration of ATP-MgCl2 . CONCLUSION: Since administration of ATP-MgCl2 prevents the impaired vascular relaxation to the endothelium-dependent vasodilator ACh, this agent may be a useful adjunct for maintaining endothelial cell function during the hyperdynamic stage of sepsis. Zentralbl Chir, 1999, 124(4), 318 - 26 {Clinical guidelines as part of total quality management . Analysis of heterogenous treatment concepts of sepsis in various clinics with computer assisted generation, logical testing and complexity assessment of clinical algorithms}; Sitter H et al.; Generation, local tailoring, implementation and evaluation of clinical guidelines is an integral part of quality management . Clinical guidelines are intimately related to the independency of physicians' decisions . By this the physicians should be responsible for guideline development and guarantee the use of adequate methods of total quality management and outcome assessment . Formal consensus finding and transparency of evidence are necessary to guarantee the use of guidelines . Clinical algorithms are highly formalized and they are well suited for generation and analysis by the software ALGO . Determination of complexity and comparison of the clinical contents of algorithms is done by the scores CASA (Clinical Algorithm Structural Analysis) and CAPA (Clinical Algorithm Patient Abstraction) . In a study of 22 clinical departments on treatment management concepts in sepsis following anastomotic insufFiciency in colorectal carcinoma a considerable heterogeneity was shown using this program. Shock, 1999 May, 11(5), 347 - 55 Hepatic gene expression and cytokine responses to sterile inflammation: comparison with cecal ligation and puncture sepsis in the rat; Bazel S et al.; Inflammatory stimulation of hepatic acute phase protein expression is, in part, modulated by tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-beta), and IL-6 . These cytokines also may mediate some aspects of the persistent inflammation and metabolic dysregulation of sepsis . Cecal ligation and puncture (CLP) sepsis in male Sprague-Dawley rats inappropriately decreases hepatocellular transcription of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), carnitine palmitoyltransferase II (CPTII), acetyl CoA acyltransferase (ACA), and ornithine transcarbamylase (OTC) . We hypothesize that 1) transcriptional reprogramming does not occur after simple inflammation induced by subcutaneous turpentine injection, 2) the pattern of acute phase gene expression after CLP differs from that following turpentine injection, and 3) the different responses reflect differences in the intrahepatic activity of TNFalpha/IL-1beta or IL-6 . Gene expression, transcription factor activity, and cytokine abundance were determined after either a subcutaneous injection of turpentine or CLP . After turpentine injection, PEPCK, G6Pase, CPTII, ACA, and OTC expression were unchanged, different from previously reported data following CLP . Both turpentine injection and CLP increased expression of TNFalpha/IL-1beta-regulated alpha1-acid glycoprotein, and IL-6-regulated alpha2-macroglobulin and decreased expression of transthyretin (a negative acute phase protein) . However, the magnitude and temporal pattern of expression differed . Turpentine injection increased the activity of the TNFalpha/IL-1beta-linked transcription factor NF-kappaB and the intrahepatic abundance of TNFalpha in a manner similar to that observed after CLP but only slightly altered the activity of the IL-6-linked transcription factor Stat-3 and intrahepatic IL-6 abundance . This differed significantly from observations after CLP . We conclude that CLP-induced alterations in hepatic gene expression may reflect differences in IL-6 activity. Clin Chem Lab Med, 1999 Mar, 37(3), 363 - 8 Outcome prediction by traditional and new markers of inflammation in patients with sepsis; Oberhoffer M et al.; Patients (n=242) admitted to intensive care unit for longer than 48 hours were categorised for sepsis according to American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference criteria . Body temperature, leukocyte count, C-reactive protein (CRP) and procalcitonin (PCT) as well as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8, IL-10 and HLA-DR expression on monocytes were determined . Data of one randomly chosen day per patient entered analysis . Immunologic mediators contributing significantly to outcome were determined by logistic regression analysis . Area under the curves (AUC) of receiver operating characteristic curves of clinical markers of inflammation predicting prognosis were compared with AUC of relevant immunologic mediators . TNF-alpha, IL-6 and HLA-DR expression on monocytes were significantly associated with outcome; the AUC's were 0.835, 0.844 and 0.761 respectively . AUC's for clinical markers were 0.878, 0.811, 0.620 and 0.614 for PCT, CRP, leukocyte count and body temperature respectively . PCT had the highest AUC compared to other clinical markers . These data indicate that PCT might be a better marker than the classic criteria of inflammation, CRP, leukocyte count, and body temperature to identify patients endangered by severe infection or sepsis. Clin Chem Lab Med, 1999 Mar, 37(3), 357 - 62 Reduction of circulating cholesterol and apolipoprotein levels during sepsis; Fraunberger P et al.; Sepsis with multiple organ failure is frequently associated with a substantial decrease of cholesterol levels . This decrease of cholesterol is strongly associated with mortality suggesting a direct relation between inflammatory conditions and altered cholesterol homeostasis . The host response during sepsis is mediated by cytokines and growth factors, which are capable of influencing lipid metabolism . Conversely lipoproteins are also capable of modulating cytokine production during the inflammatory response . Therefore the decrease in circulating cholesterol levels seems to play a crucial role in the pathophysiology of sepsis . In this review the interaction between cytokines and lipid metabolism and its clinical consequences will be discussed. Clin Chem Lab Med, 1999 Mar, 37(3), 333 - 9 Supportive therapy of the sepsis syndrome; Meier-Hellmann A et al.; Adequate volume loading may be the most important step in the treatment of patients with septic shock . Techniques allowing us to achieve and tightly control volume loading and regional perfusion are considered to be helpful . An elevated oxygen delivery may be beneficial in some patients but the increase of oxygen delivery should be guided by the measurement of parameters assessing global and regional oxygenation . Forcing an increase in oxygen delivery by the use of very high dosages of catecholamines can be harmful . Vasopressors should be used for achieving an adequate perfusion pressure . For norepinephrine, no negative effects on regional perfusion have been demonstrated . Epinephrine and dopamine should be avoided because they seem to redistribute blood flow away from the splanchnic region . There are no convincing data yet to support the routine use of low dose dopamine or dopexamine in patients with sepsis . Neither low dose dopamine nor dopexamine has been proven to prevent renal failure in septic patients . Furthermore, there is evidence that low dose dopamine may reduce mucosal perfusion in the gut in some patients . There is some suggestion that dopexamine can improve splanchnic perfusion but since these effects remain somewhat controversial, there is no reason for a general recommendation for dopexamine in septic patients. Clin Chem Lab Med, 1999 Mar, 37(3), 327 - 32 Apheresis of plasma compounds as a therapeutic principle in severe sepsis and multiorgan dysfunction syndrome; Stegmayr B; During sepsis there is an increase in the plasma content of several compounds, e.g., bacterial toxins, cytokines, cell debris, free hemoglobin and myoglobin . In blood, these compounds activate various cascade systems, which in large amounts or in more vulnerable patients lead to a disseminated intra-vascular coagulopathy (DIC) with multiorgan dysfunction syndrome (MODS) and death, despite conventional intensive care unit therapy . Therapeutic attempts to reverse these conditions have so far been of limited benefit . These effects have mainly been focused on lowering the blood concentration of single substances such as tumor necrosis factor . By the use of low-and high-flux hemodialysis filters, usually only small amounts of these substances are removed . By the use of plasmapheresis or plasma exchange, the extent of removal is considerably increased . The efficacy varies between the techniques (centrifugation vs . filtration or adsorption) and has also different influences on e.g . the complement system . This report describes these techniques and the therapeutical possibilities given by them . In small trials, blood or plasma exchange has been used as rescue therapy in critically ill patients with a progressive MODS and DIC . A survival of about 80% of the patients has been reported in these studies and the use of combined therapy will be discussed . Controlled trials are required in this field. Anasthesiol Intensivmed Notfallmed Schmerzther, 1999 Apr, 34(4), 237 - 8 Lactate in sepsis and trauma--hindrance or help? Sladen RN. Physiologic hyperlactatemia must be distinguished from lactate acidosis (lactate > 5 mM/L, pH < 7.32) . Sustained lactic acidosis, or changes in lactate in response to inotropic support, are useful predictors of mortality in severe sepsis and trauma, and superior to hemodynamic markers such as DO2 and VO2 . Base deficit is a readily available surrogate for plasma lactate, and the addition of gastric tonometry enhances its predictive ability. Am J Respir Crit Care Med, 1999 Jun, 159(6), 1696 - 702 Increased rigidity and priming of polymorphonuclear leukocytes in sepsis; Drost EM et al.; It has been proposed that abnormal mechanical properties may contribute to capillary retention of polymorphonuclear leukocytes (PMN) in sepsis, leading to the development of organ dysfunction . The present study was designed to determine whether PMN rigidity is increased in severe sepsis, and whether changes in the rheologic behavior of PMN correlate with the clinical course in sepsis . Eighteen adults with severe sepsis were studied over a period of 14 d; 11 survived and seven died . PMN deformation behavior was investigated via micropore filtration, using the cell transit analyzer . On Day 0, PMN rigidity was 2.5-fold greater for sepsis patients than for five normal controls (p < 0.001) . PMN rigidity progressively improved over the 14 d study period for patients who recovered, but not for those who died; clinical indicators correlated with PMN rigidity . Patient PMN also exhibited a 5-fold greater increase in rigidity in response to formyl-methionylleucylphenylalanine (fMLP) than did control PMN . Both the increased rigidity and enhanced response to fMLP could be simulated in vitro by incubation of normal PMN with tumor necrosis factor-alpha (TNF-alpha) . We conclude that circulating PMN are more rigid in severe sepsis, and are "primed" for an augmented response to chemotactic stimuli . These findings support the hypothesis that cytokine-mediated increases of PMN rigidity may lead to sequestration of these cells in capillaries and to the consequent impairment of microvascular perfusion in sepsis. Brain Res, 1999 May 29, 830(1), 94 - 100 Sepsis facilitates brain serotonin activity and impairs learning ability in rats; Shimizu I et al.; Sepsis often provokes various neurological disorders . Because many neurologic symptoms are caused by changes in neurotransmissions, we investigated the relationship between behavioral alterations and changes in activities of the monoaminergic systems in rats . Sepsis was induced by cecal ligation and puncture . A step-through passive avoidance test was used for the behavioral evaluation . Passive avoidance retention in animals subjected to learning immediately before the septic or sham operation was examined after 24 or 48 h . Retention performance in animals subjected to learning 24 h after the operation was also examined after a further 24 h . Plasma concentrations of amino acids were determined 24 h after the operation . The activities of the brain monoaminergic systems were evaluated by ratios of metabolites to monoamines . Marked damage was found in the septic rats in the blood analysis 24 h after the operation . The plasma concentrations of tyrosine and arginine in the septic rats were decreased to 69% and 70% of those in the sham-operated animals, respectively . Retention performance was impaired in the septic rats when they were subjected to learning 24 h after the operation, but it was not impaired when animals were subjected to learning before the septic operation . The brain concentration of serotonin was increased in the cerebral cortex, striatum, and hippocampus 48 h after the septic operation, but not after 24 h . The concentration of 5-hydroxyindoleacetic acid, a metabolite of serotonin, was increased in the above three regions both 24 and 48 h after the operation, but not in the hypothalamus . Facilitation of the serotonergic activity in the telencephalon and hippocampus is suggested to be involved in the impairment of learning ability in sepsis . J Neurochem, 1999 Jun, 72(6), 2617 - 20 Sepsis increases intracellular free calcium in brain; Anderson SA et al.; Using magnetic resonance methods and a clinically relevant rodent model of sepsis, we have made in vivo measurements of increased intracellular calcium in a pathologic state in the CNS . The intracellular calcium concentration was increased nearly twofold in septic rat brain compared with controls (p < 0.0001) . This result, in a fully intact functioning mammalian system, ties together a previous spectrum of indirect evidence from numerous laboratories suggesting an important role for elevated intracellular calcium in sepsis . In addition, levels of the proinflammatory cytokine tumor necrosis factor-a were elevated threefold in septic rat brain (p < 0.02), and electron microscopic examination revealed scattered injury in approximately 0.25% of glial cells . These findings are discussed in light of the current understanding of the pathophysiology of sepsis. Infect Dis Clin North Am, 1999 Jun, 13(2), 495 - 509 Current therapy for sepsis; Dellinger RP; The treatment of severe sepsis and septic shock remains a challenge as we approach the next millennium . Although more attention is being given to guidelines and care pathways for sepsis, these are unfortunately based primarily on consensus opinion . Additional research into supportive interventions in this potentially devastating disease is needed . Priorities in the management of sepsis include rapid reversal of hypotension and hypoperfusion, followed by empiric antibiotic therapy and definitive localization and treatment of infection nidus . A wide variety of adrenergic agents may be useful in sepsis . Initial therapy for hypoperfusion, however, should be targeted toward establishing adequate intravascular volume and left ventricular preload . Adjunctive therapy to prevent complications during the intensive care unit stay is important. Infect Dis Clin North Am, 1999 Jun, 13(2), 483 - 94, xi Rapid diagnostic methods in the detection of sepsis; Carlet J; Any delay in the management of infection is deleterious, especially in patients whose illness is severe . It is of paramount importance to shorten this delay . This article emphasizes the different ways to reach this goal, including the use of new biologic markers, such as cytokines or procalcitonin. Infect Dis Clin North Am, 1999 Jun, 13(2), 449 - 63, x Nitric oxide in the pathogenesis of sepsis; Symeonides S et al.; In sepsis and septic shock, inflammatory mediators result in the production of increased concentrations of nitric oxide (NO) from the enzymatic breakdown of the amino acid L-arginine . The increased amounts of NO are responsible for changes in vasomotor tone, decreased vasopressor responsiveness, and decreased myocardial function, characteristic of septic insult . Therapeutic strategies designed to reduce the concentration of NO by inhibiting the action of the nitric oxide synthase enzyme, or by scavenging the excess NO, offer the potential to treat directly the vasomotor abnormalities and myocardial depression seen in sepsis and other inflammatory states . This article reviews the biology of NO in sepsis and discusses strategies for neutralization of the increased NO production, in the setting of severe sepsis and septic shock. Infect Dis Clin North Am, 1999 Jun, 13(2), 413 - 26, ix Cytokines and anticytokines in the pathogenesis of sepsis; van der Poll T et al.; Clinical trials with anti-inflammatory agents in patients with sepsis are based on the assumption that excessive proinflammatory activity of the cytokine network negatively influences the outcome of severe bacterial infections . The failure of these trials to show clinical benefit, in conjunction with recent experimental data, raises doubt about the validity of this assumption . This article reevaluates the role of cytokines in the pathogenesis of sepsis and severe bacterial infections . The cytokine network is discussed as consisting of proinflammatory cytokines, antiinflammatory cytokines, and soluble inhibitors of proinflammatory cytokines. Infect Dis Clin North Am, 1999 Jun, 13(2), 299 - 312, vii The epidemiology of bacterial sepsis; Rangel-Frausto MS; As a result of better understanding of pathogenesis, new definitions of sepsis have been proposed, and the complexity of this syndrome is clearer . Population-based studies of bloodstream infections--what now is called sepsis--have helped us to understand the natural history of this very frequent problem . The mortality and morbidity of each of the systemic inflammatory response syndrome stages have been described; our ability to better understand and predict these stages will help us to make better therapeutic decisions. Infect Dis Clin North Am, 1999 Jun, 13(2), 285 - 97, vii Clinical trials for severe sepsis . Past failures, and future hopes; Opal SM et al.; Recent clinical trials with experimental immunotherapeutic agents for severe sepsis and septic shock have been largely unsuccessful despite seemingly convincing preclinical evidence of significant benefit of these antisepsis therapies . This article reviews basic therapeutic rationale, preclinical evaluation, and clinical trial design of past clinical trials of innovative sepsis treatments . Lessons learned from past failures should provide insights into the design and implementation of successful clinical trials for new anti-sepsis agents in the future. J Matern Fetal Med, 1999 May-Jun, 8(3), 88 - 94 Maternal chorioamnionitis and umbilical vein interleukin-6 levels for identifying early neonatal sepsis; Smulian JC et al.; OBJECTIVE: The purpose of this study was to determine whether elevated levels of umbilical vein IL-6 would be a better marker for early neonatal sepsis than the clinical signs of maternal chorioamnionitis . METHODS: Patients delivering preterm because of spontaneous preterm labor or premature rupture of the membranes were evaluated for clinical signs of chorioamnionitis, which was defined as a temperature of > or =100.4 degrees F along with > or =2 of the following: significant maternal tachycardia (> or = 120 bpm), fetal tachycardia (> or =160 bpm), purulent discharge, uterine tenderness, and leukocytosis (WBC > or =18,000 cells/mm3) . Umbilical vein blood was assayed for interleukin-6 . An elevated interleukin-6 level was determined to be 25 pg/mL . Infants were evaluated for evidence of early neonatal sepsis . The abilities of clinical chorioamnionitis and interleukin-6 levels > or =25 pg/mL to predict early neonatal sepsis were compared . RESULTS: There were 28 patients delivering 14 (50%) neonates with evidence for early neonatal sepsis . The incidence of suspected neonatal sepsis in women with and without clinical chorioamnionitis was 6/10 (60%) vs . 8/18 (44.4%), P = 0.43 . Using receiver operator characteristic curves, the best cutoff for interleukin-6 was found to be 25 pg/mL . The compared sensitivity, specificity, and positive and negative predictive values of clinical chorioamnionitis vs . interleukin-6 levels > or =25 pg/mL for predicting early neonatal sepsis were 42.9% vs . 92.9%, 71.4% vs . 92.9%, 60% vs . 92.9%, and 55.6% vs . 92.9%, respectively . CONCLUSIONS: Elevated umbilical vein levels of interleukin-6 predict those preterm infants with early sepsis better than the presence of clinical chorioamnionitis. Chest, 1999 May, 115(5), 1390 - 6 Persistent gastric intramucosal ischemia in patients with sepsis following resuscitation from shock; Oud L et al.; STUDY OBJECTIVES: (1) To determine the effects of resuscitation of patients with severe sepsis to conventional hemodynamic end points and normal blood lactate levels on postresuscitation sequential assessments of gastric intramucosal pH (pHi) . (2) To determine whether trends in pHi are reflected in trends in systemic hemodynamic, oxygen utilization, and acid-base assessments . DESIGN: Prospective cohort study . SETTING: Medical ICU in an inner-city, university-based medical center . PATIENTS: Twelve recently admitted patients with severe sepsis and signs of circulatory shock who were successfully resuscitated to normal hemodynamic end points and lactate levels and who were also monitored with pulmonary artery catheters and gastric tonometers . INTERVENTIONS: Because of the observational nature of this study, no specific interventions were employed . The physician staff administered i.v . fluids and pharmacologic agents, during and after the resuscitative period, to treat infection and to achieve and maintain hemodynamic stability . Mechanical ventilation and supplemental oxygen were provided as needed . The hemodynamic and physiologic monitoring employed was determined by the managing physicians and established medical ICU routines . MEASUREMENTS AND RESULTS: A total of 12 patients were studied . Systemic hemodynamic, oxygen utilization, and acid-base assessments and pHi were recorded following resuscitation, and every 12 h thereafter . pHi decreased from 7.33 +/- 0.08 (mean +/- SD) following resuscitation to 7.26 +/- 0.04 at 24 h, 7.20 +/- 0.07 at 36 h (p < 0.05), and 7.24 +/- 0.08 at 48 h . Corresponding statistically significant and clinically relevant changes in systemic hemodynamic, oxygen utilization, and acid-base variables were not observed . The hospital mortality of this patient group was high (10 of 12; 83%) . CONCLUSIONS: Gastric intramucosal acidosis develops and persists for at least 48 h in patients resuscitated from septic shock to conventional resuscitative end points, including the normalization of lactate levels . These regional changes were not reflected in corresponding changes in systemic acid-base and oxygen utilization variables . Direct determinations of pHi and therapy directed toward the resolution of splanchnic ischemia may be required to improve the outcome in these patients. J Surg Res, 1999 May 15, 83(2), 151 - 7 Kupffer cells are responsible for producing inflammatory cytokines and hepatocellular dysfunction during early sepsis; Koo DJ et al.; BACKGROUND: Although hepatocellular dysfunction occurs early after the onset of sepsis, the mechanism responsible for this remains unknown . We tested the hypothesis that the reduction in Kupffer cell (KC) numbers prior to the onset of sepsis prevents the occurrence of hepatocellular dysfunction and reduces levels of the proinflammatory cytokines IL-1beta and IL-6 during the early stage of polymicrobial sepsis . MATERIALS AND METHODS: The number of KC in male adult rats was reduced in vivo by intravenous injection of gadolinium chloride 48 h before the induction of sepsis . KC-reduced and KC-normal rats were then subjected to cecal ligation and puncture (CLP, i.e., a model of polymicrobial sepsis) or sham operation followed by administration of normal saline solution . At 5 h after CLP (the early stage of sepsis), hepatocellular function {i.e., the maximal velocity of clearance (Vmax) and efficiency of active transport (Km) of indocyanine green} was measured using a fiber-optic catheter and in vivo hemoreflectometer . Whole blood was drawn to measure plasma levels of IL-1beta and IL-6 using enzyme-linked immunosorbent assays . RESULTS: Hepatocellular function was depressed and the circulating levels of IL-1beta and IL-6 were increased significantly at 5 h after CLP . KC reduction by prior administration of gadolinium chloride, however, prevented the occurrence of hepatocellular dysfunction and the upregulation of IL-1beta and IL-6 . CONCLUSIONS: The KC-derived proinflammatory cytokines IL-1beta and IL-6 appear to be directly or indirectly responsible for producing hepatocellular dysfunction during early sepsis . Thus, pharmacologic agents that downregulate the production of one or both of these proinflammatory cytokines in the liver may be useful for maintaining hepatocellular function during the early stage of sepsis . Zentralbl Chir, 1999, 124(3), 176 - 80 {Surgical management of peritonitis and sepsis}; Bruch HP et al.; The intraabdominal sepsis is one of the major surgical problems today . The Systemic Inflammatory Response Syndrome in peritonitis often leads to multiple organ failure . The surgical eradication of the infectious focus is the most important prerequisite for a successful treatment . Dependent on the form and severity of the local inflammation, different forms of abdominal lavage can be applied . Using surgical and physiological as well as organ failure scores like the Mannheimer-Peritonitis-Index (MPI), the APACHE-II and the Septic-Severity-Score (SSS), the prognosis can be objectively assessed and different clinical studies can be compared . However, in 88 own patients suffering from diffuse purulent peritonitis with sepsis (May 1990 to December 1996), all the above mentioned scores significantly allowed to discriminate surviving (mean MPI: 25, APACHE-II day 1: 19, SSS day 1: 28) from non surviving patients (mean MPI: 31, APACHE-II day 1: 26, SSS day 1: 45) . Furthermore, mortality increased significantly with increasing score ranges (< 20, 20 to 30, and > 30 points) for MPI from 0% to 28% to 81%, for APACHE-II day 1 from 20% to 46% to 100%, and for SSS day 1 from 10% to 37% to 71%. Orv Hetil, 1999 Mar 7, 140(10), 515 - 20 {Latest results of intensive care of sepsis, septic shock and multiple organ injuries}; Incze F; Author is first discussing sepsis and its new categories (SIRS, MODS), its pathogenesis and symptoms . One axis of the events is the release of inflammatory and anti-inflammatory cytokines from the monocytes and macrophages, due to the precipitating injury . The other one is the activation of the polymorphonuclear leucocytes and the endothelial cells and their interaction . The basically non infectious SIRS is often maintained and worsened to MODS by the "translocation" of bacteria and endotoxins from the gut into the circulation . It is a new development the use of the serum procalcitonin level for the diagnosis, differential-diagnosis and for the evaluation of the success of the therapy . The causal therapy of the sepsis is still the surgical management of the septic focus, which should be supported by antibiotics and non-specific treatment (fluid-load, ventilation, inotropic, vasoactive and immunogenic drugs) . It is new knowledge the effect of antibiotics on the immuno-system . For the treatment of SIRS, it has been tried many anti-cytokine and immunomodulating therapy; author explains the presumable causes of the failure of their majority. Resuscitation, 1999 Jan, 40(1), 53 - 6 Effect of haemofiltration on pathological fibrinolysis due to severe sepsis: a case report; Perouansky M et al.; Bleeding due to coagulopathy is a frequent complication of severe sepsis, especially in burn patients . The primary treatment is aimed at the underlying cause but additional supportive measures, consisting mainly of coagulation factor replacement, are frequently necessary . We describe the salutary effect of continuous veno-venous haemofiltration (CVVH) with predilution on diffuse haemorrhage in a patient with severe septic shock and renal failure . The diffuse haemorrhage was initially treated with replacement of coagulation factors . Prothrombin time and partial thromboplastin time became normal while diffuse bleeding continued and the thrombelastogram showed evidence of fibrinolysis . A short period of CVVH lead to the cessation of bleeding which was reflected by a normal thrombelastogram. Am J Pathol, 1999 Apr, 154(4), 1057 - 65 Mechanisms of enhanced lung injury during sepsis; Czermak BJ et al.; A major complication in sepsis is progressively impaired lung function and susceptibility to intrapulmonary infection . Why sepsis predisposes the lung to injury is not clear . In the current studies, rats were rendered septic by cecal ligation/puncture and evaluated for increased susceptibility to injury after a direct pulmonary insult (deposition of IgG immune complexes or airway instillation of lipopolysaccharide) . By itself, cecal ligation/puncture did not produce evidence of lung injury . However, after a direct pulmonary insult, lung injury in septic animals was significantly enhanced . Enhanced lung injury was associated with increased accumulation of neutrophils in lung, enhanced production of CXC chemokines (but not tumor necrosis factor-alpha) in bronchoalveolar lavage fluids, and increased expression of lung vascular intercellular adhesion molecule-1 (ICAM-1) . Complement depletion or treatment with anti-C5a abolished all evidence of enhanced lung injury in septic animals . When stimulated in vitro, bronchoalveolar lavage macrophages from septic animals had greatly enhanced CXC chemokine responses as compared with macrophages from sham-operated animals or from septic animals that had been complement depleted . These data indicate that the septic state causes priming of lung macrophages and suggest that enhanced lung injury in the septic state is complement dependent and related to increased production of CXC chemokines. J Appl Physiol, 1999 May, 86(5), 1739 - 44 Selective in vivo inhibition of inducible nitric oxide synthase in a rat model of sepsis; Scott JA et al.; Elevated production of nitric oxide (NO) by the inducible NO synthase (type II, iNOS) may contribute to the vascular hyporesponsiveness and hemodynamic alterations associated with sepsis . Selective inhibition of this isoenzyme is a possible therapeutic intervention to correct these pathophysiological alterations . Aminoguanidine has been shown to be a selective iNOS inhibitor and to correct the endotoxin-mediated vascular hypocontractility in vitro . However, to date aminoguanidine has not been shown to selectively block iNOS activity in vivo . The in vivo effects of aminoguanidine were assessed in the cecal ligation and perforation model of sepsis in rats . Aminoguanidine (1.75-175 mg/kg) was administered to septic and sham-operated rats for 3 h before euthanasia and harvest of tissues . NOS activities were determined in the thoracic aorta and lung from these animals . Aminoguanidine (17.5 mg/kg) did not alter the mean arterial pressure; however, it did inhibit induced iNOS (but not constitutive NOS) activity in the lung and thoracic aorta from septic animals . Only the higher dose of aminoguanidine (175 mg/kg) was able to increase the mean arterial pressure in septic and sham-operated animals . Thus selective inhibition of iNOS in vivo with aminoguanidine is possible, but our data suggest that other mechanisms, in addition to iNOS induction, are responsible for the loss of vascular tone characteristic of sepsis. Eur Respir J, 1999 Mar, 13(3), 514 - 8 Empirical treatment with fibrinolysis and early surgery reduces the duration of hospitalization in pleural sepsis; Lim TK et al.; The efficacy of three different treatment protocols was compared: 1) simple chest tube drainage (Drain); 2) adjunctive intrapleural streptokinase (IP-SK); and 3) an aggressive empirical approach incorporating SK and early surgical drainage (SK+early OP) in patients with pleural empyema and high-risk parapneumonic effusions . This was a nonrandomized, prospective, controlled time series study of 82 consecutive patients with community-acquired empyema (n=68) and high-risk parapneumonic effusions (n=14) . The following three treatment protocols were administered in sequence over 6 years: 1) Drain (n=29, chest catheter drainage); 2) IP-SK (n=23, adjunctive intrapleural fibrinolysis with 250,000 U x day(-1) SK); and 3) SK+early OP (n=30, early surgical drainage was offered to patients who failed to respond promptly following initial drainage plus SK) . The average duration of hospital stay in the SK+early OP group was significantly shorter than in the Drain and IP-SK groups . The mortality rate was also significantly lower in the SK+early OP than the Drain groups (3 versus 24%) . It was concluded that an empirical treatment strategy which combines adjunctive intrapleural fibrinolysis with early surgical intervention results in shorter hospital stays and may reduce mortality in patients with pleural sepsis. Thromb Res, 1999 Apr 15, 94(2), 95 - 101 Endothelial cell and hemostatic activation in relation to cytokines in patients with sepsis; Lopez-Aguirre Y et al.; Sepsis is commonly associated with disturbances of the hemostatic balance . Most of the pathophysiological changes in sepsis are caused by endotoxin acting directly through endothelial injury or indirectly through release of cytokines with procoagulant effects . The relation between cytokines and hemostatic parameters was assessed in 32 patients with sepsis . Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III complexes (TAT), tissue type plasminogen activator (t-PA) functional and antigen, plasminogen activator inhibitor-1 (PAI-1), plasminalpha2-antiplasmin complexes (PAP), D-Dimer, thrombomodulin (TM) and von Willebrand factor (vWF) were measured in patients and in 30 healthy subjects . The levels of cytokines TNF-alpha and interleukin-6 (IL-6) also were determined . A significant increase of F1+2, TAT, PAI-1, PAP, and D-Dimer was observed in septic patients as compared with controls (p<0.0001), whereas t-PA activity was significantly reduced (p<0.01) . The markers of endothelial cell activation TM, vWF, and t-PA antigen also were elevated significantly as compared with the control group (p<0.01) . Finally, we found a marked increase of TNF-alpha and IL-6 (p<0.0001) . Whereas the increase of cytokine levels could be partially responsible for the hemostatic activation, it did not correlate with markers of endothelial activation in patients with sepsis. APMIS, 1999 Apr, 107(4), 359 - 64 The effect of surgical stress and endotoxin-induced sepsis on the NK-cell activity, distribution and pulmonary clearance of YAC-1 and melanoma cells; Toft P et al.; Following surgery the activity of natural killer (NK) cells is decreased in the blood . It is possible that sepsis with release of endotoxin will further decrease the NK-cell activity . The purpose of the present study was to investigate the NK-cell cytotoxicity, the clearance in the lungs of YAC-1 and melanoma cells, as well as the distribution of NK-cells in the liver, following abdominal surgery and intraperitoneally (i.p.) administered endotoxin . Ten mice in each group were allocated to abdominal surgery, i.p . endotoxin or anaesthesia alone . Following abdominal surgery, the cytotoxicity of NK-cells isolated from the spleen was decreased and 4 h after injection the clearance of YAC-1 cells from the lungs was only 79.5+/-6.1% compared to 99.5+/-0.3% in the control group . The number of NK-cells in the liver was also significantly reduced following abdominal surgery . In contrast, i.p . endotoxin increased the activity of NK-cells by 28.5% compared to 11.8% in the control group and 8.1% in the surgery group, lowered the number of melanoma metastases in extrapulmonary organs and significantly increased the number of NK-cells in the liver . Following abdominal surgery, activity of NK-cells, pulmonary clearance and number of NK-cells in the liver were decreased . The number of NK-cells in the liver correlated with the NK-cell activity throughout the study . The increased NK-cell cytotoxicity and the increased number of NK-cells in the liver following i.p . administered endotoxin might initially be an appropriate measure against intra-abdominal infection. Curr Opin Hematol, 1999 May, 6(3), 176 - 83 Role of hematopoietic growth factors in non-neutropenic infections and sepsis; Held TK et al.; Therapy with colony-stimulating factors has been extended beyond their use in accelerating myeloid cell recovery to take advantage of their immune function-enhancing properties . Studies in animal models and with human subjects suggest a potential role as adjunctive therapy in infections of non-neutropenic hosts, including those with sepsis . Granulocyte colony-stimulating factor may play a pivotal role in the induction of lipopolysaccharide desensitization by nontoxic lipid A analogues proposed for the prevention of sepsis; granulocyte macrophage colony-stimulating factor may be useful in reversing the immune paralysis described in later stages of sepsis . Significant issues of exogenous colony-stimulating factor therapy must be addressed, however: the optimal timing, dose, and clinical context (e.g., type of immunosuppression, duration of infection-inciting stimulus) as well as tissue-specificity of the activities and net effect of potentially conflicting responses (e.g., immune restorative and