Sepsis

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 procoagulant effects of granulocyte macrophage colony-stimulating factor) . Resolution of these issues will require carefully designed clinical studies with meticulous monitoring of immunologic parameters.

Semin Nephrol, 1999 May, 19(3), 272 - 6
Nitric oxide, sepsis, and the kidney; Schwartz D et al.; Although excess nitric oxide (NO) production plays a major role in the hypotension characteristic of sepsis, concurrent constitutive NO generation in the kidney during sepsis is essential for preservation of renal perfusion and prevention of glomerular thrombosis . The authors have shown that although all nitric oxide synthase (NOS) inhibitors restore normal blood pressure in lipopolysaccharide (LPS) treated rats, only selective inducible NOS (iNOS) inhibition prevents the reductions in glomerular filtration rate (GFR), whereas nonselective inhibition of NOS further decreases GFR . Glomerular endothelial NOS (eNOS) activity was found to be inhibited by LPS . The decrease in eNOS activity was completely prevented by selective iNOS inhibition in vivo and in vitro . The adverse renal outcomes after LPS administration correlated with decreased glomerular eNOS activity rather than elevated NO production . These findings suggest that the decrease in GFR after LPS is caused by local inhibition of eNOS by iNOS possibly via NO autoinhibition . Selective inhibition of iNOS could represent a substantially superior approach for the treatment of the sepsis syndrome.

J Immunoassay, 1999 Feb-May, 20(1-2), 1 - 11
The detection of pyrogens in sera from patients with symptoms of sepsis using an ex vivo whole blood culture assay; Pool EJ et al.; The aim of this study was to investigate whether the ex vivo whole blood culture (WBC) assay system can be used to detect pyrogens in blood from patients with symptoms of sepsis . Blood samples from 35 patients with symptoms of sepsis were assayed for bacterial contamination using the radiometric blood culture assay . Serum from the same patients were screened for IL-6, C-reactive protein (CRP) and pyrogens using the whole blood culture assay . Serum samples from 26 patients tested positive for pyrogens . Of the 26 patients with pyrogenic serum, 15 had elevated serum IL-6 levels and 19 had elevated CRP levels . Only two of the samples had positive blood cultures as detected by the routine radiometric assay . Both of these patients had high serum CRP and pyrogen levels, while only one of them had an elevated serum IL-6 level . These results show that the WBC is very sensitive in detecting pyrogens in serum of patients . This technique can be a useful tool to quantitate pyrogens in sera from patients with symptoms of sepsis and to determine whether their clinical symptoms are caused by pyretic substances in their circulatory system.

Dis Colon Rectum, 1999 Mar, 42(3), 421 - 3
Life-threatening retroperitoneal sepsis after hemorrhoid injection sclerotherapy: report of a case; Barwell J et al.; We present a case of life-threatening retroperitoneal sepsis after injection sclerotherapy for first-degree hemorrhoids.

Pharmacotherapy, 1999 Mar, 19(3), 346 - 8
Anticonvulsant hypersensitivity syndrome occurring as sepsis with multiorgan dysfunction; Marik P; Phenytoin is a highly effective and widely prescribed anticonvulsant agent . However, it is associated with both dose-related side effects and hypersensitivity reactions . Life-threatening anticonvulsant hypersensitivity syndrome in one patient was characterized by a skin eruption and multisystem organ dysfunction.

Shock, 1999 Apr, 11(4), 298 - 301
Sepsis produces depression of testosterone and steroidogenic acute regulatory (StAR) protein; Sam AD 2nd et al.; The hypothesis that induction of chronic peritoneal sepsis would produce depression of serum testosterone due to a decrease in Leydig cell steroidogenic acute regulatory (StAR) protein or P450c17 steroidogenic enzyme was tested . Male Sprague-Dawley rats (350-400 g) were randomized to septic and nonseptic groups . Sepsis was induced with a cecal slurry (200 mg/kg in 5 mL of 5% dextrose in water (D5W); intraperitoneal) while nonseptic rats received only sterile D5W . Animals (n = 6, in each group) were killed by CO2 asphyxiation and blood samples were collected by direct cardiac puncture at 24 h after induction of sepsis/sham sepsis . The serum concentration of corticosterone, progesterone, estradiol, and testosterone was determined using radioimmunoassay . Western blot analysis was utilized to quantify Leydig cell StAR protein and P450c17 enzyme . Sepsis produced a significant decrease in the serum concentration of testosterone, a down-regulation of StAR protein, and an increase in serum estradiol 24 h after induction of sepsis (as compared with the nonseptic group) . Protein levels of P450c17 in Leydig cells and serum concentrations of progesterone and corticosterone 24 h after induction of sham sepsis or sepsis were not different . It is concluded that the decreases in serum testosterone after 24 h of chronic peritoneal sepsis correlated with reductions in StAR protein.

Shock, 1999 Apr, 11(4), 229 - 34
Evaluation of Fc-receptor positive (FcR+) and negative (FcR-) monocyte subsets in sepsis; Schinkel C et al.; The monocyte/macrophage (Mphi is central in the regulation of the immune response in states of trauma and sepsis . Because monocyte subsets, characterized by expression of the Fc-receptor (FcR), were shown to play distinct immunologic roles in trauma, it was the objective of this study to assess insights into the functional role of FcR positive (FcR+) and negative (FcR-) subclasses in surgical sepsis . In a prospective study, peripheral blood Mphi from 20 septic patients and 10 healthy volunteers were evaluated on consecutive days after the onset of sepsis . FcR+/- subsets were separated by rosetting with antibody-coated human erythrocytes . Receptor expression and synthesis of proinflammatory cytokines were used to evaluate the functional role of these cells . We demonstrated a significant monocytosis (350%; p<.01) and suppression of human lymphocyte antigen (HLA-DR) expression (35%; p<.05) . Synthesis of Interleukin-1beta (IL-1beta; e.g., Day 1: 230+/-30 pg/mL) and Interleukin-6 (IL-6; e.g., Day 1: 1920+/-350 U/mL) were significantly higher (p<.05) in FcR+ subsets than in controls (IL-1beta: 100+/-5 pg/mL; IL-6: 353+/-75 U/mL) . Tumor necrosis factor-alpha (TNF-alpha) was elevated in FcR+ monocytes but did not reach a significant value . Interleukin-8 (IL-8) synthesis showed only on Day 1 and in controls significant differences in FcR+ and FcR- cells (Day1: FcR-: 19.6+/-4.1 nM; FcR+: 9+/-4.3 nM) . Sepsis results in a significant shift toward FcR+ monocytes . This cell population is characterized by high proinflammatory cytokine synthesis . The extent of this shift seems to identify a group of high risk septic patients that might benefit from immunomodulatory therapy.

Pediatr Emerg Care, 1999 Apr, 15(2), 113 - 5
Persistent crying as predominant manifestation of sepsis in infants and newborns; Ruiz-Contreras J et al.; Acute episodes of unexplained crying in infants may be due to serious and even life-threatening conditions . We present six infants in whom excessive crying was the predominant initial manifestation of sepsis for a period of time that ranged from 2 to 10 hours, before other symptoms or signs became evident . This led to a diagnostic delay in two patients who were considered initially to have infant colic . Sepsis should be considered in the differential diagnosis of acute unexplained crying in infants.

J Trauma, 1999 Apr, 46(4), 590 - 6
Early activation of pulmonary nuclear factor kappaB and nuclear factor interleukin-6 in polymicrobial sepsis; Browder W et al.; BACKGROUND: Transcription factor activation may be a pivotal step in the pathophysiology of sepsis syndrome and adult respiratory distress syndrome . This study investigated the activation of lung nuclear factor kappaB (NFkappaB) and nuclear factor interleukin-6 (NF-IL6) and how they correlate to proinflammatory cytokine expression and mortality in a murine model of cecal ligation and puncture (CLP) . METHODS: Polymicrobial sepsis was induced by CLP . Transcription factor activation was assessed at 0, 1, 2, 3, 4, 5, 6, 8, and 24 hours after CLP by the electrophoretic mobility-shift assay . Lung cytokine mRNA levels were established by reverse transcriptase-polymerase chain reaction . RESULTS: CLP induced pulmonary NFkappaB activation at 3, 4, and 8 hours (p < 0.05) . Lung NFkappaB activation peaked at 3 hours (533% vs . no surgery, 2,900% vs . sham treatment) after CLP . Supershift analysis revealed a predominance of p50 subunits in the lung nuclear extracts of septic mice 3 hours after CLP, indicating the presence of p50 homodimer . In contrast, liver nuclear extracts from septic mice indicated the presence of both p65 and p50 subunits at 3 hours . Lung NF-IL6 activation (p < 0.05) was observed at 4 hours (649% vs . no surgery, 296% vs . sham treatment) and 6 hours after CLP . Lung tumor necrosis factor-alpha mRNA levels were increased (p < 0.05) at all time intervals after CLP . Lung IL-6 mRNA levels were increased at 3, 6, and 8 hours after CLP . CONCLUSION: Early activation of lung NFkappaB and NF-IL6 and lung cytokine mRNA expression correlated with mortality in polymicrobial sepsis . Although IL-6 mRNA levels correlated with NFkappaB and NF-IL6 activation, tumor necrosis factor-alpha mRNA levels did not, in that they preceded transcription factor activation . These data suggest a potential role for NFkappaB and NF-IL6 activation in the initiation and propagation of acute lung injury.

Biochim Biophys Acta, 1999 Apr 19, 1427(2), 315 - 21
Pulmonary clearance of adrenomedullin is reduced during the late stage of sepsis; Ornan DA et al.; Polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase . Although upregulation of adrenomedullin (ADM), a novel potent vasodilatory peptide, plays an important role in producing cardiovascular responses during the progression of sepsis, it remains unknown whether the clearance of this peptide is altered under such conditions . To determine this, male adult rats were subjected to sepsis by cecal ligation and puncture (CLP) followed by fluid resuscitation . At 5 h (i.e., the hyperdynamic phase of sepsis) or 20 h (the hypodynamic phase) after CLP, the animals were injected with 125I-labeled ADM through the jugular vein . Blood and tissue samples (including the lungs, kidneys, gastrointestinal tract, pancreas, spleen, mesentery, liver, brain, skeletal muscle, heart, and skin) were harvested 30 min after the injection and the radioactivity was determined . The results indicate that there were no significant alterations in tissue {125I}ADM distribution at 5 h after CLP compared to shams . At 20 h after CLP, however, there was a significant decrease in radioactivity in the lungs . In contrast, a significant increase of radioactivity was observed in all other organs except the liver and kidneys . The pulmonary distribution of {125I}ADM was found to be far greater than in any other organs tested, irrespective of the effect of sepsis . In separate groups of animals, injection of {125I}ADM into the left ventricle resulted in a significant decrease in radioactivity in the lungs of both sham and septic animals at 20 h after surgery . These results suggest that the lungs are the primary site of ADM clearance, which is significantly diminished during the late stage of sepsis . The decreased clearance of ADM by the lungs may play an important role in maintaining the sustained levels of plasma ADM under such conditions.

Br J Surg, 1999 Apr, 86(4), 562 - 5
Chronic groin sepsis following tension-free inguinal hernioplasty; Taylor SG et al.; BACKGROUND: Chronic groin sepsis requiring mesh removal is said to be a rare complication of tension-free inguinal hernioplasty . The aim of this study was to determine the number of surgeons performing tension-free inguinal hernioplasty in the West of Scotland and assess the frequency with which chronic groin sepsis was encountered . METHODS: A questionnaire was sent to all consultant surgeons performing inguinal hernia repair in the region and follow-up of patients with chronic groin sepsis following tension-free inguinal hernioplasty was undertaken . RESULTS: Of 80 consultants who replied to the questionnaire, 79 were performing tension-free hernioplasty . Of these, 76 were performing only open repairs while three were also undertaking laparoscopic repairs . Sixteen consultants reported 20 patients with groin sepsis after mesh repair . Twelve patients were traced; eight had chronic sinuses and four had groin abscesses . The median interval between repair and presentation was 4 months (range from 2 weeks to 39 months) . All have required complete (11 patients) or partial (one) removal of mesh to resolve the symptoms . CONCLUSION: Tension-free inguinal hernioplasty has become the operation of choice for surgeons in the region . Chronic groin sepsis may be more frequent than reported previously . Complete removal of mesh is required to treat this condition.

J Surg Res, 1999 May 1, 83(1), 36 - 43
Splenic immune suppression in sepsis: A role for IL-10-induced changes in P38 MAPK signaling; Song GY et al.; BACKGROUND: Studies have indicated that following the induction of sepsis, there is a late (24 h) generalized suppression of the immune response which is associated with increased anti-inflammatory mediator release (e.g., IL-10) . However, the mechanisms by which this occurs are unknown . In this regard, recent studies indicate that p38 mitogen-activated protein kinase (p38 MAPK) may play a central role in transducing the signals from immunosuppressive agents which in turn may alter lymphoid cytokine release . The aim of this study, therefore, was to determine whether the anti-inflammatory mediator IL-10 alters splenocyte IL-2 and IFN-gamma release, as well as the expression and activation of p38 MAPK in septic animals . MATERIALS AND METHODS: Splenocytes (SPL) (or for some experiments purified T cells) were harvested from mice subjected 24 h earlier to either sepsis by cecal ligation and puncture (CLP) or Sham-CLP and stimulated with 2.5 microg concanavalin A (ConA)/ml in the presence or absence of either monoclonal antibody (Mab) to IL-10 (4 microg/ml) or IgG control . In subsequent studies, sepsis was induced in C57BL/6J and C57BL/6 IL-10 knockout mice, and SPL harvested and stimulated with ConA . SPL cytokine release was measured by ELISA, and the expression and phosphorylation of p38 MAPK were measured by Western analysis . RESULTS: The results indicate that Th1 cytokine (IL-2, IFN-gamma) release was depressed by sepsis, while p38 MAPK expression and activity were increased in SPL as well as in T-cells . Neutralization of IL-10 by in vitro use of anti-IL-10 Mab and in the IL-10 knockout animal restored the Th1 response and caused a downregulation of p38 MAPK expression and activity after CLP . Thus, IL-10 appears to contribute to the increase in p38 MAPK activity and expression and the corresponding suppression of Th1 response seen in late sepsis .

J Immunol, 1999 Apr 1, 162(7), 4148 - 56
Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis; Hotchkiss RS et al.; In sepsis there is extensive apoptosis of lymphocytes, which may be beneficial by down-regulating the accompanying inflammation . Alternatively, apoptosis may be detrimental by impairing host defense . We studied whether Bcl-2, a potent antiapoptotic protein, could prevent lymphocyte apoptosis in a clinically relevant model of sepsis . Transgenic mice in which Bcl-2 was overexpressed in T cells had complete protection against sepsis-induced T lymphocyte apoptosis in thymus and spleen . Surprisingly, there was also a decrease in splenic B cell apoptosis in septic Bcl-2 overexpressors compared with septic HeJ and HeOuJ mice . There were marked increases in TNF-alpha, IL-1beta, and IL-10 in thymic tissue in sepsis in the three species of mice, and the increase in TNF-alpha and IL-10 in HeOuJ mice was greater than that in Bcl-2 mice . Mitotracker, a mitochondrial membrane potential indicator, demonstrated a sepsis-induced loss of membrane potential in T cells in HeJ and HeOuJ mice but not in Bcl-2 mice . Importantly, Bcl-2 overexpressors also had improved survival in sepsis . To investigate the potential impact of loss of lymphocytes on survival in sepsis, Rag-1-/- mice, which are totally deficient in mature T and B cells, were also studied . Rag-1-/- mice had decreased survival compared with immunologically normal mice with sepsis . We conclude that overexpression of Bcl-2 provides protection against cell death in sepsis . Lymphocyte death may be detrimental in sepsis by compromising host defense.

Crit Care Med, 1999 Mar, 27(3), 565 - 75
Acadesine during fluid resuscitation from shock and abdominal sepsis; Melton SM et al.; OBJECTIVE: To determine properties of acadesine, the prototype adenosine regulating agent, in an experimental model in which abdominal sepsis is superimposed onto hemorrhagic shock . DESIGN: Randomized, blinded animal study . SETTING: University-based animal research facility . SUBJECTS: Twenty-eight anesthetized mongrel pigs (35.5 +/- 1.1 kg) . INTERVENTIONS: The cecum was ligated and punctured to produce abdominal sepsis . To produce hemorrhagic shock, 45% to 47% of the estimated blood volume was withdrawn . After 1 hr, shed blood plus supplemental crystalloid (twice the shed blood volume) plus either acadesine (5 mg/kg bolus + 1 mg/kg x 60 min, n = 10) or its vehicle (n = 10) was administered . All animals were awakened and observed for 48 hrs . At 48 hrs, cardiac function, bacterial cultures from the septic focus, and inflammatory changes in the abdomen were quantified . MEASUREMENTS AND MAIN RESULTS: After resuscitation with acadesine vs . vehicle, we observed the following: a) arterial blood pressure and cardiac filling pressures were similar but cardiac index, systemic oxygen delivery, and systemic oxygen consumption were increased; b) plasma lactate was higher, systemic vascular resistance was lower, but ileal mucosal blood flow was not measurably altered; c) lipopolysaccharide-evoked tumor necrosis factor production in whole blood ex vivo was reduced; d) in those animals that survived 48 hrs (10/10 vs . 8/10), sepsis-induced cardiac depression, amount of free intraperitoneal fluid, extra abscess inflammatory reaction, abscess wall formation, abscess bacterial counts, and peritoneal bacterial counts, were all similar, but blood bacterial counts were higher . CONCLUSIONS: Fluid resuscitation with acadesine produced no adverse hemodynamic consequences and probably improved washout of metabolites from the reperfused microcirculation in sites other than the small intestine or heart . Taken together, these observations suggest that adenosine regulating agents might have therapeutic potential during fluid resuscitation from trauma . However, at least in these extreme conditions, the acute salutary effects of acadesine were probably overwhelmed by polymicrobial sepsis . Further studies must determine whether supplemental adjuvants to boost host defense during recovery from trauma will optimize adenosine-based resuscitation solutions.

Am J Physiol, 1999 Apr, 276(4 Pt 1), E611 - 9
TNF-binding protein ameliorates inhibition of skeletal muscle protein synthesis during sepsis; Cooney R et al.; We examined the effects of TNF-binding protein (TNFBP) on regulatory mechanisms of muscle protein synthesis during sepsis in four groups of rats: Control; Control+TNFBP; Septic; and Septic+TNFBP . Saline (1 . 0 ml) or TNFBP (1 mg/kg, 1.0 ml) was injected daily starting 4 h before the induction of sepsis . The effect of TNFBP on gastrocnemius weight, protein content, and the rate of protein synthesis was examined 5 days later . Sepsis reduced the rate of protein synthesis by 35% relative to controls by depressing translational efficiency . Decreases in protein synthesis were accompanied by similar reductions in protein content and muscle weight . Treatment of septic animals with TNFBP for 5 days prevented the sepsis-induced inhibition of protein synthesis and restored translational efficiency to control values . TNFBP treatment of Control rats for 5 days was without effect on muscle protein content or protein synthesis . We also assessed potential mechanisms regulating translational efficiency . The phosphorylation state of p70(S6) kinase was not altered by sepsis . Sepsis reduced the gastrocnemius content of eukaryotic initiation factor 2Bepsilon (eIF2Bepsilon), but not eIF2alpha . The decrease in eIF2Bepsilon content was prevented by treatment of septic rats with TNFBP . TNFBP ameliorates the sepsis-induced changes in protein metabolism in gastrocnemius, indicating a role for TNF in the septic process . The data suggest that TNF may impair muscle protein synthesis by reducing expression of specific initiation factors during sepsis.

Crit Care Med, 1999 Mar, 27(3), 639 - 60
Practice parameters for hemodynamic support of sepsis in adult patients in sepsis . Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine; Serum leptin concentrations and their relation to metabolic abnormalities in human sepsis; North Western Injury Research Centre, University of Manchester, Hope Hospital, Salford M6 8HD, United Kingdom . gcarlson@fs1.ho.man.ac.uk

Circulating leptin concentrations are raised in animal models of inflammation and sepsis . The purpose of this study was to determine the effect of sepsis on serum leptin concentration in humans and to examine the relationship between leptin and the metabolic consequences of sepsis . Resting energy expenditure, insulin sensitivity, and fasting serum leptin, plasma insulin, and cortisol concentrations were measured in 20 subjects with intra-abdominal sepsis and 20 healthy control subjects, before and during a 2-h period of euglycemic hyperinsulinemia . Fasting serum leptin concentrations were similar in septic and control subjects . In simple regression analysis, serum leptin concentrations correlated significantly with percent body fat in both septic patients (r = 0 . 64, P < 0.005) and healthy subjects (r = 0.75, P < 0.0001) . Multiple regression analyses additionally indicated that percent body fat, fasting plasma insulin, and plasma cortisol, but not sepsis, were significant and independent determinants of serum leptin concentration . No relationship between leptin and resting energy expenditure or insulin sensitivity was identifiable . A major metabolic role for leptin in human sepsis therefore appears unlikely.

Haematologica, 1999 Mar, 84(3), 254 - 9
Inflammation, sepsis, and coagulation; Esmon CT et al.; The molecular links between inflammation and coagulation are unquestioned . Inflammation promotes coagulation by leading to intravascular tissue factor expression, eliciting the expression of leukocyte adhesion molecules on the intravascular cell surfaces, and down regulating the fibrinolytic and protein C anticoagulant pathways . Thrombin, in turn, can promote inflammatory responses . This creates a cycle that logically progresses to vascular injury as occurs in septic shock . Most complex systems are regulated by product inhibition . This inflammation-coagulation cycle seems to follow this same principle with the protein C pathway serving as the regulatory mechanism . The molecular basis by which the protein C pathway functions as an anticoagulant is relatively well established compared to the mechanisms involved in regulating inflammation . As one approach to identifying the mechanisms involved in regulating inflammation, we set out to identify novel receptors that could modulate the specificity of APC in a manner analogous to the mechanisms by which thrombomodulin modulates thrombin specificity . This approach led to the identification of an endothelial cell protein C receptor (EPCR) . To understand the mechanism, we obtained a crystal structure of APC (lacking the Gla domain) . The crystal structure reveals a deep groove in a location analogous to anion binding exosite 1 of thrombin, the location of interaction for thrombomodulin, platelet thrombin receptor and fibrinogen . Thrombomodulin blocks the activation of platelets and fibrinogen without blocking reactivity with chromogenic substrates or inhibitors . Similarly, in solution, EPCR blocks factor Va inactivation without modulating reactivity with protease inhibitors . Thus, these endothelial cell receptors for the protein C system share many properties in common including the ability to be modulated by inflammatory cytokines . Current studies seek to identify the substrate for the APC-EPCR complex as the next step in elucidating the mechanisms by which the protein C pathway modulates the response to injury and inflammation.

Shock, 1999 Mar, 11(3), 211 - 7
Does Fas ligand or endotoxin contribute to thymic apoptosis during polymicrobial sepsis?
Ayala A, Xu YX, Chung CS, Chaudry IH.
Recent studies have shown that with the onset of sepsis there is an increase in apoptosis (Ao) in the thymus, mediated in part by steroids, which may contribute to a loss of T-cell progenitors, thereby, reducing immune functions . However, reports also suggest that these steroid effects could be mediated by Fas ligand (FasL) and/or by endotoxin (ETX) . Thus, our study was to determine: 1) if polymicrobial sepsis (cecal ligation and puncture; CLP) alters thymocyte Fas antigen/receptor (Fas+) expression and 2) if the increase in Ao in septic ETX-sensitive C3H/HeN mice is seen in thymocytes from ETX-tolerant, C3H/HeJ, or the FasL-deficient/ETX-tolerant, C3H/HeJ-FasL(gld), male mouse strains subjected to CLP or sham-CLP (Sham) 12 or 24 h before they were killed . The results of flow cytometric analysis indicated that increased %Ao+ seen in thymocytes of CLP C3H/HeN mice was associated with either no change (12 h) or a decrease in %Fas+ expression at 24 h, although the %Bcl-2+ (an antiapoptotic protein) cells was depressed at both times . Additional studies examining C3H/HeJ or C3H/HeJ-FasL(gld) mice subjected to CLP show that as with the ETX-sensitive mouse, thymocyte Fas and Bcl-2 antigen expression as well as Bcl-2/Bcl-X(L/S) mRNA levels decreased although the %Ao+ increased after CLP in both ETX-tolerant and ETX-tolerant/FasL-deficient mice . Furthermore, if ETX-tolerant/FasL-deficient CLP animals were administered the steroid receptor antagonist RU-38486 (s.c., immediately after CLP) the increase in Ao was markedly attenuated, along with restoration of the percentage of cells expressing Bcl-2 and Fas antigen as well as Bcl-2/Bcl-X(L/S) mRNA levels . Thus, we concluded that increased septic thymocyte Ao is not regulated through either Fas mediated pathway or ETX, but is a result of the release of endogenous steroids possibly acting directly or indirectly on Bcl-2 expression.

Drugs, 1999 Feb, 57(2), 127 - 32
Treatment of sepsis: past and future avenues; Baumgartner JD et al.; In recent years, the concept has emerged that the host's inflammatory response contributes substantially to the development of septic shock and organ failure . Experimental observations prompted large scale randomised clinical trials with a variety of agents such as glucocorticoids, ibuprofen, antiendotoxin monoclonal antibodies, antagonists of platelet-activating factor, of bradykinin or of interleukin-1 receptor, and monoclonal anti-tumour necrosis factor (TNF) antibodies or soluble dimeric TNF receptor fusion proteins . All these major studies of immunomodulators in sepsis have yielded disappointing results despite showing promise during preliminary clinical studies . However, these recent failures do not mean that septic shock will forever remain an insurmountable medical challenge . Many lessons have been learned from these studies . and certain mistakes in their study design will be avoided in the future . Our understanding of the pathophysiology of sepsis and septic shock is increasing markedly; potential new treatment strategies are available and could be explored to improve the outcome of patients with sepsis.

Anaesthesist, 1999 Feb, 48(2), 63 - 79
{Oxygen delivery in sepsis . After 10 years more questions than answers}; Bone HG et al.; Object of this review is to present the physiological principles, diagnostic techniques and therapeutic options that are related to modifications of oxygen delivery in sepsis . Despite intense research activities in this area, many topics regarding oxygen transport and oxygen consumption in sepsis are still not clear . For example, the often discussed shift of the critical value of oxygen delivery to higher values in sepsis has not been proven, yet . Beside an impaired regional perfusion also disturbances in the cellular oxygen utilization may be responsible for organ failure in sepsis . Until now, it was not shown, whether the increase of oxygen delivery to supranormal levels reduces mortality in septic patients . It is also unknown, which catecholamine and which infusion solution is suitable for the treatment of septic patients . In future further research is necessary to solve the problems associated with sepsis therapy.

J Surg Res, 1999 Apr, 82(2), 172 - 9
End-diastolic pressure-volume relationship in sepsis: relative contributions of compliance and equilibrium chamber volume differ; Farias S et al.; BACKGROUND . Compliance is a complex parameter to measure both clinically and in the laboratory . Investigations in recent years have interpreted changes in the end-diastolic pressure-volume relationship (EDPVR) as changes in compliance . However, without considering the equilibrium chamber volume (LV volume when transmural pressure = 0), changes in the EDPVR may not reflect changes in left ventricular chamber compliance . In the present study, chamber compliance was differentiated from equilibrium chamber volume to determine their respective contributions to the EDPVR in a clinically relevant animal model of chronic sepsis . MATERIALS AND METHODS . Rats were made septic by intraperitoneal injection of a cecal slurry (200 mg/kg; 5 ml/kg of 5% dextrose in water) . At 1, 3, and 7 days post-sepsis induction, hearts were perfused on an isolated heart apparatus . A latex balloon was placed in the left ventricle to record peak systolic and end-diastolic pressures at various volumes, and the starting volume in the balloon was recorded . Systolic performance was evaluated by calculating the developed pressure (systolic pressure minus end-diastolic pressure) and peak dP/dt at end-diastolic pressures of 5 and 10 mm Hg . RESULTS . Developed pressure and peak dP/dt were impaired 3 days after sepsis induction and continued to be so through Day 7 of sepsis . The diastolic data were fitted to an exponential equation, the results of which indicated a strong leftward shift in the EDPVR through 7 days of sepsis with a concomitant decrease in equilibrium chamber volume . The LV chamber compliance decreased at 1 day after sepsis induction, as indicated by significant changes in regression coefficients for the curves, transiently returned toward control by Day 3, but decreased again by 7 days of sepsis . CONCLUSIONS . Our data indicate that early in sepsis, compliance changes contribute to a left-shifting EDPVR, but at later times in the course of the disease, unstressed chamber volume becomes an important determinant of the left shift . The decrease in compliance (suggesting diastolic dysfunction) occurred prior to systolic impairment, which may have valuable prognostic implications for septic patients.

Cytokine, 1999 Feb, 11(2), 173 - 8
Relation of ex vivo stimulated blood cytokine synthesis to post-traumatic sepsis; Flach R et al.; The cytokine production in endotoxin stimulated blood of patients immediately after polytrauma with high risk for developing sepsis or multi organ failure was analysed . Forty patients sustaining traumatic injury with >/=317 pts according to the Injury Severity Score (ISS), 10 of whom developed severe sepsis (ACCP/SCCM conference 1992) were included in the study . Levels of interleukin 8 (IL-8), IL-6 and tumour necrosis factor (TNF) were measured by ELISA in endotoxin-stimulated whole blood and IL-10 and IL-6 in serum . The allotype for the bi-allelic Nco I restriction length polymorphism in the TNF locus was determined for each patient.Two to four hours after polytrauma endotoxin-stimulated synthesis of TNF and IL-6 was found to be reduced in whole blood from patients compared to healthy donors, whereas no such differences were found for IL-8 synthesis . At this time, however, the patients who developed sepsis at a later stage (day 4-6) showed significantly (P<0.05) enhanced IL-8 synthesis in endotoxin stimulated whole blood in comparison to healthy donors . The IL-6 and TNF production of their blood was significantly enhanced compared to patients with uncomplicated recovery . Ninety per cent of the patients developing sepsis were of the TNFB2/TNFB2 allotype, whereas this was the case for only 30% of the non-septic group . Assessment of endotoxin-stimulated cytokine synthesis may provide a prognostic indicator for patients at high risk for developing a sepsis syndrome .

Int J Mol Med, 1999 Apr, 3(4), 401 - 4
Expression of heat shock protein 70 in leukocytes of patients with sepsis; Martins GA et al.; The heat shock proteins are known to protect cells against diverse injuries such as cytotoxicity by TNFalpha acting mainly as chaperones for denatured proteins . Lipopolysaccharide stimulates the production and the release of numerous endogenous mediators of sepsis: tumor necrosis factor alpha, interleukin-1, and interleukin-6 that induce fever production . Moreover, temperature at 40 degrees C is sufficient to induce heat shock and attenuate both TNFalpha and IL-1 expression . We demonstrate a distinct profile in gene expression of HSP 70 family in leukocytes obtained from different phases of septic patients . Our findings strongly suggest that HSP 70 may play a role in the outcome of septic shock patients.

Acta Anaesthesiol Scand, 1999 Mar, 43(3), 275 - 88
The role of nitric oxide in sepsis--an overview; Kirkeboen KA et al.; Nitric oxide (NO) is normally produced in the endothelium by the constitutive isoform of the NO synthase . This physiological production of NO is important for blood pressure regulation and blood flow distribution . Several lines of evidence suggest that a hyperproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock . Lipopolysaccarides and cytokines, such as tumor necrosis factor, interleukin-1 and interferon-gamma, have been shown to induce iNOS in the endothelium, vascular smooth muscle cells, macrophages and different parenchymal cells . Treatment with inhibitors of NO synthesis has been shown to improve hemodynamic variables and survival in several animal models of septic shock . In human septic shock, inhibition of NO synthesis has been shown to alter hemodynamic variables in short-term studies, but it is uncertain whether this treatment has beneficial long-term effects . The aim of this review is to give an overview of the physiological role of NO and to discuss the role of NO in sepsis and the potential therapeutic implications of NO as a target in treatment of human septic shock . A main new aspect of this review is a critical discussion of previous reports measuring plasma nitrite/nitrate during septic shock and an evaluation of the validity of interpreting these data as evidence for a hyperproduction of NO . This review also emphasizes that many septic patients have preexisting endothelial dysfunction and lung diseases, which may contribute to adverse effects by systemic inhibition of NO synthesis . Another new aspect of the present review is a focus on the lack of direct evidence of iNOS expression in human septic shock.

Klin Khir, 1998, (11), 15 - 6
{Lipid peroxidation and the function of the antioxidant system in sepsis in patients with soft-tissue suppurative and inflammatory lesions}; Shapoval SD; While sepsis present in 73 patients with purulent-inflammatory affection of soft tissues and in 76 patients with local purulent inflammation the dynamics of processes of peroxidal oxidation of lipids (POL) and of antioxidant system (AOS) was studied up . In patients of both groups the trustworthy increase of the POL products in a blood plasma and pre- and postoperative AOS suppression was noted.

Crit Care Med, 1999 Feb, 27(2), 394 - 400
Dopexamine attenuates flow motion in ileal mucosal arterioles in normotensive sepsis; Madorin WS et al.; OBJECTIVES: Injury to the small intestine is thought to play a crucial role in the development and propagation of sepsis . Cellular hypoxia, caused by hypoperfusion, may result in increased mucosal permeability, thus allowing the translocation of bacteria and endotoxin to the circulation . The purpose of this study was to assess the effect of the synthetic catecholamine, dopexamine, on the mucosal microcirculation of the septic rat ileum . DESIGN: Randomized, crossover study . SETTING: Teaching hospital animal laboratory . SUBJECTS: Sprague-Dawley male rats . INTERVENTIONS: Sepsis was induced by cecal ligation and perforation in 11 male Sprague-Dawley rats . Six sham animals were also studied . At 24 hrs, rats were anaesthetized, intubated, ventilated, and prepared for intravital microscopy of the mucosal surface of the ileum . Dopexamine (8 microg/kg/min) and saline were infused intravenously into each rat using a randomized crossover design . MEASUREMENTS AND MAIN RESULTS: Observations were videotaped for later analysis of arteriolar flow patterns, red cell velocity, arteriolar diameter, and intercapillary area . All values are expressed as mean +/- SEM . The main effect of dopexamine infusion in the sepsis group was the attenuation of the rhythmic blood flow patterns (flow motion) observed during saline infusion . In each subject, dopexamine decreased the absolute number of arterioles exhibiting flow motion by 35.93+/-6.81% (p<.001, paired t-test) . Dopexamine decreased the amount of time red cell flow was stopped in marginal and central arterioles by 11.83+/-2.49% (p<.001, paired t-test) . Dopexamine did not alter significantly the diameter of the marginal arterioles, the intercapillary area, or the red cell velocity compared with saline in the sepsis group . The sham group displayed marked microvascular differences compared with the sepsis group with respect to arteriolar diameter (13.32+/-0.05 vs . 9.46+/-0.24 mm, p<.001), intercapillary area (975.93+/-60.60 vs . 1256.03+/-43.88 mm2, p<.05 ), red cell velocity (611.40+/-38.77 vs . 289.15+/-36.45, p<.001), and blood flow patterns (% displaying flow motion, 15.89+/-6.09 vs . 58.22+/-9.63, p<.01; % time stopped flow, 1.96+/-0.89 vs . 20.21+/-3.92, p<.005) . CONCLUSIONS: These results indicate that dopexamine increased overall blood flow and possibly oxygen delivery to the mucosa by altering patterns of blood flow within the villi . The observation that the diameter of the marginal arterioles is not affected by dopexamine indicates that dopexamine influences the mucosal microcirculation at the level of higher order arterioles . We conclude that sepsis results in abnormal microvascular villus blood flow and that dopexamine can partially restore these changes towards normal.

J Clin Microbiol, 1999 Apr, 37(4), 1193 - 6
Central line sepsis in a child due to a previously unidentified mycobacterium; Hogg GG et al.; A rapidly growing mycobacterium similar to strains in the present Mycobacterium fortuitum complex (M . fortuitum, M . peregrinum, and M . fortuitum third biovariant complex {sorbitol positive and sorbitol negative}) was isolated from a surgically placed central venous catheter tip and three cultures of blood from a 2-year-old child diagnosed with metastatic hepatoblastoma . The organism's unique phenotypic profile and ribotype patterns differed from those of the type and reference strains of the M . fortuitum complex and indicate that this organism may represent a new pathogenic taxon.

Int Immunol, 1999 Feb, 11(2), 217 - 27
Mechanisms of acute inflammatory lung injury induced by abdominal sepsis; Neumann B et al.; Sequestration of neutrophils and release of histotoxic mediators are considered important for the development of pathologic alterations of the lung defined as adult respiratory distress syndrome . Mechanisms of inflammatory lung injury caused by abdominal sepsis were investigated using the colon ascendens stent peritonitis (CASP) model that closely mimics the human disease . In the CASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending colon, generating a septic focus . In contrast to the cecal ligation and puncture model of peritonitis, survival of mice following CASP surgery is dependent on IFN-gamma, but independent of tumor necrosis factor (TNF) . Here we show that the systemic inflammation induced by CASP surgery results in a rapid and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung . Activation of circulating granulocytes was characterized by increased production of serine proteinases and reactive oxygen metabolites, as well as elevated expression of cell surface Mac-1 . Expression of MIP-2, KC, MIP-1alpha and E-selectin mRNA in lung was strongly increased within 3 h following CASP surgery, whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed . In contrast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not detectable after CASP surgery . Importantly, recruitment of leukocytes to the lung was normal in lipopolysaccharide-resistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.

J Arthroplasty, 1999 Feb, 14(2), 175 - 81
Cementless fixation in 2-stage reimplantation for periprosthetic sepsis; Fehring TK et al.; Twenty-five patients with documented infection of the hip were reviewed . All patients underwent reconstruction in a 2-stage fashion with cementless implants . The average follow-up in this group was 41 months . The average time to reimplantation was 4.8 months . Of the 25 living patients, 22 retained their implants . There were 2 recurrences of infection, for an infection recurrence rate of 8% (2 of 25) . The average postoperative Harris Hip Score was 81 . Bone ingrowth was confirmed radiographically via the Engh fixation score in all but 1 of the surviving implants . Cementless fixation in 2-stage reimplantation can result in acceptable eradication rates, while supplying predictable fixation, provided that appropriate cementless revision implants are used.

Intensive Care Med, 1999 Jan, 25(1), 106 - 9
T helper cell subset ratios in patients with severe sepsis; Ferguson NR et al.; BACKGROUND: T helper 1 (Thl) lymphocytes produce interferon gamma (IFNgamma), favouring cell mediated immunity; Th2 cells secrete interleukin-4 (IL-4), favouring humoral immunity . Cytokines produced in sepsis may effect Th subset predominance and subsequent immune responses . METHODS: We measured Th subsets in ten patients with severe sepsis, seven APACHE II score-matched non-septic critically ill control patients, and ten healthy subjects . Mononuclear leukocytes were isolated and Th subsets identified by flow cytometry . RESULTS: The median (range) Th1/Th2 ratio was 0.46 (0.2-2.5) in patients with sepsis, which was significantly lower than both non-septic controls (median 2.5 (0.2-5.9), p = 0.050) and healthy subjects (median 3.9 (1.2-10.8), p = 0.01) . CONCLUSIONS: In patients with sepsis, Th2 antibody mediated (humoral) immune responses predominate . This type of response may lead to fibroblast activation and ultimately immunosuppression . Modulation of Th cell subset predominance may present a novel therapeutic option in the treatment of severe sepsis.

Anesteziol Reanimatol, 1998 Nov-Dec, (6), 72 - 6
{Criteria of systemic inflammatory response syndrome are unacceptable in the diagnosis of sepsis in patients with leukopenia}; Galstian GM et al.; Twenty-two patients with hemoblastosis were examined in order to evaluate the possibility of using the criteria of the total system's inflammatory response syndrome (TSIRS) for the diagnosis of sepsis in hemoblastosis patients with leukopenia . The patients were examined before and after chemotherapy . Twelve patients with myelotoxic leukopenia developed TSIRS in response to a concomitant infection . No intensive care and resuscitation were needed in 9 of them; antibiotic therapy rapidly improved the clinical status . Three of these patients had to be transferred to intensive care wards . These patients differed from patients with TSIRS who needed no intensive care and from patients without TSIRS by higher fever (39.6 +/- 0.9, 39.1 +/- 0.4, and 36.5 +/- 0.7 degrees C, respectively), tachycardia (114.1 +/- 19.1, 105.3 +/- 12.8, and 84.0 +/- 10.0 stroke/min, respectively), thrombocytopenia (35.4 +/- 33.2.10(9), 55.1 +/- 34.5.10(9), and 89.2 +/- 95.1.10(9)/liter, respectively), prolongation of XIIa-dependent fibrinolysis (161.0 +/- 67.5 . 64.7 +/- 57.0, and 46.2 +/- 45.8 min, respectively), decreased content of antithrombin III (79.6 +/- 8.1, 102.0 +/- 16.2, and 98.9 +/- 11.9%, respectively), and a more grave status according to the APACHEII score (20.4 +/- 5.2, 15 +/- 2.0, and 10.8 +/- 3.2, respectively) . The APACHEII score and XIIa-dependent fibrinolysis were in direct correlation . We consider that the TSIRS/sepsis criteria are highly sensitive but not specific . They just permit singling out the group of patients part of whom may have sepsis.

Anesteziol Reanimatol, 1998 Nov-Dec, (6), 58 - 62
{Hemodynamics and oxygen transport in patients with surgical sepsis during hemofiltration}; Bobrinskaia IG et al.; Effects of hemofiltration (HF) on central hemodynamics and oxygen transport are studied in 35 patients with surgical sepsis and multiple organ failure . HF is paralleled by development of hypovolemia and decrease of myocardial contractility, determining a decrease in cardiac output and oxygen transport . As a result, oxygen utilization by tissues decreases and hypoxia progresses . The only compensatory mechanism of oxygen supply in such patients is maintenance of cardiac output, which should be borne in mind when carrying out HF.

Biochim Biophys Acta, 1999 Feb 24, 1453(2), 273 - 83
Adrenomedullin is upregulated in the heart and aorta during the early and late stages of sepsis; Zhou M et al.; Although circulating levels of adrenomedullin (ADM), a newly reported vasodilatory peptide with 52 amino acid residues in the human and 50 amino acid residues in the rat, are elevated during the early and late stages of sepsis, ADM levels in cardiovascular tissues and its precise localization remain to be determined . To study this, rats were subjected to sepsis by cecal ligation and puncture (CLP), followed by administration of 3 ml/100 g b.wt . normal saline to these and sham-operated animals . The heart and thoracic aorta were harvested at 5 h (i.e . the early stage of sepsis) and 20 h (late sepsis) after CLP . Tissue levels of ADM were determined by radioimmunoassay . The localization of ADM in the left ventricle and thoracic aorta was examined by using immunohistochemistry and electron microscopy techniques . The results indicated that ADM levels in the heart and thoracic aorta increased significantly at 5 h after CLP and remained elevated at 20 h after the onset of sepsis . Immunohistochemistry findings showed that ADM immunoreaction products were localized in the cytoplasm of the cardiac myocytes and aortic endothelial cells . Using electron microscopy, ADM immunoreaction products were found in the cytoplasmic matrixes . The immunostainings were also associated with the outer membranes of mitochondria and vesicles of the myocytes as well as vascular endothelial cells . It appears that the cardiovascular tissues, among other organ systems, contribute to the increased levels of plasma ADM under those conditions . Since ADM is localized in different cell populations in the heart and the large blood vessel (i.e . myocytes versus vascular endothelial cells), this peptide may play a differential role in regulating cardiac and vascular functions during sepsis as an autocrine and/or paracrine mediator.

Biochim Biophys Acta, 1999 Feb 24, 1453(2), 207 - 15
Transcriptional regulation of alpha1-adrenoceptor gene in the rat liver during different phases of sepsis; Dong LW et al.; Changes in alpha1-adrenoceptor (alpha1AR) 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 phase (9 h after CLP, early sepsis) followed by a hypoglycemic phase (18 h after CLP; late sepsis) . The {3H}prazosin binding studies show that the density of alpha1AR was increased by 30% during the early phase while it was decreased by 24% during the late phase of sepsis . Western blot analyses reveal that alpha1AR protein level was elevated by 48% during early sepsis but was decreased by 55% during late sepsis . Northern blot analyses depict that the steady-state level of alpha1bAR mRNA was enhanced by 21% during the early phase but was declined by 29% during the late phase of sepsis . Nuclear run-off assays show that the transcription rate of alpha1bAR gene transcript was increased by 76% during early sepsis while it was decreased by 29% during late sepsis . The actinomycin D pulse-chase studies indicate that the half-life of alpha1bAR mRNA remained unaffected during the early and the late phases of sepsis . These findings demonstrate that during the early phase of sepsis, the increase in the rate of transcription of alpha1bAR gene paralleled with the elevations in the alpha1bAR mRNA abundance and alpha1AR protein level, while during the late phase of sepsis, the decrease in the rate of transcription of alpha1bAR gene coincided with the declines in the alpha1bAR mRNA abundance and the alpha1AR protein level in the rat liver . These observations indicate that the altered expression of alpha1AR genes in the rat liver during the progression of sepsis was regulated transcriptionally.

Digestion, 1999, 60 Suppl 1, 52 - 6
The novel carboxamide derivative IS-741 reduces neutrophil chemoattractant production by bronchoalveolar macrophages in rats with cerulein-induced pancreatitis complicated by sepsis; Yamaguchi Y et al.; BACKGROUND/AIMS: The priming mechanism of macrophages to secrete cytokines in acute pancreatitis is important for remote organ failure following septic complication . The effects of novel carboxamide derivative, IS-741, on neutrophil chemoattractant production by bronchoalveolar macrophages were studied in rats with cerulein-induced pancreatitis complicated by sepsis . METHODS: Pancreatitis was induced by four intramuscular injections of cerulein (50 microg/kg at 1-hour intervals) . Pancreatitis rats were injected intraperitoneally with 10 mg/kg of lipopolysaccharide (LPS) 6 h following the first cerulein injection as a septic challenge . Pancreatitis rats received a continuous intravenous injection of IS-741 (3 mg/kg/h) 30 min before the septic challenge . RESULTS: Intense mononuclear cell infiltration and lung hemorrhage occurred in untreated pancreatitis rats complicated with sepsis, but hemorrhage was not seen in septic pancreatitis rats receiving a continuous intravenous injection of IS-741 shortly before sepsis induction . The IS-741-treated rats had lower serum concentrations of cytokine-induced neutrophil chemoattractant (CINC), as well as fewer the pulmonary neutrophils and infiltrates immunoreactive for CINC or Mac-1 (CD11b/CD18) . CONCLUSION: The novel carboxamide derivative IS-741 reduced CINC production by bronchoalveolar macrophages and effectively prevented pancreatitis-associated lung injury following the septic challenge.

Chest, 1999 Feb, 115(2), 453 - 61
A randomized and controlled trial of the effect of treatment aimed at maximizing oxygen delivery in patients with severe sepsis or septic shock; Alia I et al.; OBJECTIVE: To evaluate the effects of increased oxygen delivery on mortality and morbidity . DESIGN: Randomized, controlled trial . SETTING: Medical-surgical ICU of a tertiary care hospital . PATIENTS: Sixty-three patients classified according to predetermined criteria as having severe sepsis or septic shock . INTERVENTIONS: The patients were randomly assigned to one of two groups: the control group (n = 32) received conventional therapy with a normal targeted value of oxygen delivery, and the treatment group (n = 31) received therapy with a targeted oxygen delivery index (DO2I) value of > 600 mL/min/m2 . The therapeutic approach to maintain BP, arterial saturation, hemoglobin concentration, and pulmonary artery occlusion pressure was similar in both groups . MEASUREMENTS AND MAIN RESULTS: The hemodynamic, oxygen transport, and gastric intramucosal pH measurements were recorded at the time of admission to the study and every 6 h for the next 96 h . The outcome measures were the rate of patient mortality and the number of organ dysfunctions occurring during the ICU stay . The study groups were similar with respect to demographics and admission hemodynamic variables, but the percentage of patients with positive blood cultures was significantly higher in the control group than in the treatment group, respectively: 34 vs 13% (p = 0.04) . The average cardiac index was significantly higher in the treatment group than in the control group, respectively: 3.96 vs 3.05 L/min/m2 (p = 0.01) . This factor did not significantly affect the DO2I . Nine of the 31 treatment group patients reached an average DO2I value of > 600 mL/min/m2 . The rate of mortality in the control group patients up to the time of ICU discharge (66%) was similar to that seen in the treatment group (74%), respectively: 21 of 32 vs 23 of 31 (p = 0.46) . The number of dysfunctional organs per patient was also similar in the control and treatment groups, respectively: 2.1+/-1.1 vs 2.6+/-1.2 (p = 0.12) . CONCLUSION: Treatment aimed at maximizing oxygen delivery in patients with severe sepsis or septic shock does not reduce mortality or morbidity.

Infection, 1999 Jan-Feb, 27(1), 44 - 5
A case of cryptic miliary tuberculosis mimicking cholecystitis with sepsis; Siemann M et al.; Miliary tuberculosis is a rare form of tuberculosis in industrialized countries . We report on a 69-year-old woman presenting a sepsis syndrome caused by cryptic miliary tuberculosis clinically mimicking a case of cholecystitis with sepsis . The patient died of a multi-organ failure on day 6 of her hospital stay.

Acta Anaesthesiol Scand, 1999 Feb, 43(2), 196 - 201
Sepsis attenuates the intensity of the neuromuscular blocking effect of d-tubocurarine and the antagonistic actions of neostigmine and edrophonium accompanying depression of muscle contractility of the diaphragm; Narimatsu E et al.; BACKGROUND: Prolonged effects of non-depolarizing muscle relaxants in septic patients have been reported, although the influence of sepsis on neuromuscular transmission has not yet been clarified satisfactorily . These studies were intended to elucidate the influence of sepsis on neuromuscular transmission and on the action of drugs being utilized for regulation of muscle tone (a neuromuscular blocker and anti-cholinesterase (anti-ChE) drugs) . METHODS: The effect of d-tubocurarine (dTc) on neuromuscular transmission and the antagonistic action of anti-ChE drugs (neostigmine and edrophonium) on dTc-induced twitch depression were estimated using sham control and septic rat nerve-hemidiaphragm preparations in vitro . Isometric twitch tension elicited by indirect (phrenic nerve) or direct (muscle) stimulation at 0.1 Hz was evaluated . RESULTS: Sepsis induced by panperitonitis attenuated the twitch tension elicited by indirect or direct stimulation (P < 0.01) without obvious morphological inflammatory damage to the diaphragm . dTc dose-dependently decreased twitch tension elicited by indirect stimulation (P < 0.01) less intensely in the septic group than in the sham group (P < 0.01) . The antagonistic actions of the anti-ChE drugs on dTc (1 microM)-induced twitch depression were less intense in the septic group (P < 0.01 or 0.05) . CONCLUSION: These results demonstrate that sepsis in the acute phase attenuates the effects of a neuromuscular blocker and anti-ChE drugs and depresses muscle contractility simultaneously.

Infect Immun, 1999 Mar, 67(3), 1079 - 85
A sustained rat model for studying the long-lasting catabolic state of sepsis; Breuille D et al.; Most animal models of sepsis induced high mortality or early recovery and do not mimic the long-lasting catabolic state observed in patients . The purpose of this study is to develop a model of sepsis which reproduces these disorders, especially the long-lasting muscle wasting . This report summarizes our observations in a series of seven experiments using this model with rats to study the route of live Escherichia coli administration, dose of bacteria, reproducibility of the model, bacterial count in tissues, comparison of injection of live or dead bacteria, metabolic perturbations linked to infection, and potential role of tumor necrosis factor alpha (TNF-alpha) in muscle wasting . After intravenous infection, animals were anorexic and the catabolic state was long-lasting: body weight loss for 2 to 3 days followed by a chronic wasting state for several days . Liver, spleen, lung protein content, and plasma concentration of alpha2-macroglobulin were increased 2 and 6 days after infection . At 6 days, muscle protein content was substantially (-40%) reduced . The plasma TNF-alpha level measured 1.5 h after infection correlated with body weight loss observed 9 days later . The inhibition of TNF-alpha secretion by administration of pentoxifylline 1 h before infection reduced muscle wasting and activation of proteolysis at day 2 and abolished them at day 6 . This septic model mimics in rats the prolonged protein metabolism alterations and muscle atrophy characteristics of infected patients and thus is useful for studying the impact of nutritional support on outcome.

Khirurgiia (Sofiia), 1998, 51(2), 25 - 9
{Hemodynamic changes and nitric oxide production in an experimental model of sepsis}; Vasilev D et al.; Nitric {correction of Nitrous} oxide is most likely a queer "end mediator" giving rise to vasoplegia in septic shock patients . The study is aimed at comparative assessment of kinetic changes in the synthesis of nitric {correction of nitrous} oxide in experimentally induced sepsis model with the corresponding hemodynamic parameters . The laboratory animals--pigs--are divided up in two groups, and exposed to general narcosis induction, orotracheal intubation and mechanical ventilation under controlled regimen . The hemodynamic parameters studied include: MAP, CO and SVR . Additional endotoxin (1 mg/50 ml) in the form of infusion is given to the animals in the sepsis group . Nitrate production mirrors NO synthesis, insofar as there are no other relevant mechanisms of nitrate synthesis . The kinetic parameters of nitrate production are estimated using stable nitrate isotopes--N15 . The theory of compartment models and appropriate computerized simulation are used to calculate the respective constants . In the endotoxin treated group (n = 5) a significantly higher level of synthesis of induced NO production is documented--26 +/- 9 mumol/h, as compared to production in the control group--6 +/- 7 mumol/h, as well as a significant increase in cardiac output and systemic vascular resistance reduction . The good correlation between enhanced NO production and hemodynamic response (increase in cardiac output and decrease in systemic vascular resistance) corroborates the validity of the method.

J Immunol, 1999 Feb 15, 162(4), 2341 - 6
Expression and function of the chemokine receptors CXCR1 and CXCR2 in sepsis; Cummings CJ et al.; Neutrophils (polymorphonuclear neutrophils; PMN) and a redundant system of chemotactic cytokines (chemokines) have been implicated in the pathogenesis of the acute respiratory distress syndrome in patients with sepsis . PMN express two cell surface receptors for the CXC chemokines, CXCR1 and CXCR2 . We investigated the expression and function of these receptors in patients with severe sepsis . Compared with normal donors, CXCR2 surface expression was down-regulated by 50% on PMN from septic patients (p < 0.005), while CXCR1 expression persisted . In vitro migratory responses to the CXCR1 ligand, IL-8, were similar in PMN from septic patients and normal donors . By contrast, the migratory response to the CXCR2 ligands, epithelial cell-derived neutrophil activator (ENA-78) and the growth-related oncogene proteins, was markedly suppressed in PMN from septic patients (p < 0.05) . Ab specific for CXCR1 blocked in vitro migration of PMN from septic patients to IL-8 (p < 0.05), but not to FMLP . Thus, functionally significant down-regulation of CXCR2 occurs on PMN in septic patients . We conclude that in a complex milieu of multiple CXC chemokines, CXCR1 functions as the single dominant CXC chemokine receptor in patients with sepsis . These observations offer a potential strategy for attenuating adverse inflammation in sepsis while preserving host defenses mediated by bacteria-derived peptides such as FMLP.

Am J Physiol, 1999 Feb, 276(2 Pt 2), R468 - 73
Sepsis is associated with increased ubiquitinconjugating enzyme E214k mRNA in skeletal muscle; Hobler SC et al.; Previous studies provided evidence that sepsis is associated with increased ubiquitin-proteasome-dependent protein breakdown in skeletal muscle . The 14-kDa ubiquitin-conjugating enzyme (E214k) has been proposed to be a key regulator of the ubiquitin proteolytic pathway . We tested the hypothesis that E214k message and protein levels are increased in skeletal muscle during sepsis . Sepsis was induced in rats by cecal ligation and puncture (CLP) . Control rats were sham operated . E214k mRNA and protein levels were quantitated after Northern and Western blot analysis, respectively, 16 h after CLP or sham operation . Sepsis resulted in a 70% increase in the 1 . 2-kb E214k transcript in the fast-twitch extensor digitorum longus muscle, whereas no changes were seen in the slow-twitch soleus muscle . E214k protein levels were not influenced by sepsis in any of the muscles studied . Although the changes in the expression of the E214k 1.2-kb transcript paralleled the differential effect of sepsis on protein breakdown in fast- and slow-twitch muscle, the potential role of E214k in the regulation of sepsis-induced muscle proteolysis needs to be interpreted with caution, because the results demonstrated that increased message levels were not associated with increased E214k protein levels.

Crit Care Med, 1999 Jan, 27(1), 137 - 41
Arginine-nitric oxide pathway in plasma membrane of rat hepatocytes during early and late sepsis; Hwang TL et al.; OBJECTIVE: To study the transported L-arginine in rat hepatocytes during different stages of sepsis . DESIGN: A prospective, controlled study . Subjects: Thirty-six Sprague-Dawley male rats (250 to 300 g) were anesthetized and studied . INTERVENTIONS: Early sepsis was produced 9 hrs after cecal ligation and puncture (CLP) and late sepsis developed 18 hrs after CLP . The control group underwent sham operation . Plasma membrane of rat hepatocytes was prepared by differential centrifugation . The {3H} L-arginine uptake of plasma membrane vesicles during sepsis was measured and inhibition studies employing omega-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine were performed . MEASUREMENTS AND MAIN RESULTS: L-arginine transport was saturable, increased linearly with plasma membrane protein concentration, and increased with uptake time up to 5 mins . {3H} L-arginine uptake increased by 77% to 121% (p < .05) during early sepsis, with no significant changes during late sepsis . Comparing inhibitors of nitric oxide synthase, L-NAME was effective in inhibiting L-arginine transport while aminoguanidine was not . CONCLUSIONS: L-arginine transport was enhanced in rat hepatocytes during the early stage of sepsis . The increased uptake of L-arginine could contribute to the increase production of nitric oxide by hepatocyte during sepsis.

Crit Care Med, 1999 Jan, 27(1), 113 - 9
Effect of pentoxifylline on survival and intestinal cytokine messenger RNA transcription in a rat model of ongoing peritoneal sepsis; Nelson JL et al.; OBJECTIVE: Septic animals receiving high-protein liquid diets have increased mortality and increased production of cytokines by the gut compared with animals receiving low-protein diets . The purpose of this study was to evaluate the ability of pentoxifylline to alter gut cytokine production in a rat model of prolonged acute peritonitis, to determine its effect on survival in such animals, and to determine whether alteration of gut cytokine production was associated with survival . DESIGN: Prospective, randomized animal study . SETTING: Research laboratory . SUBJECTS: Male Lewis rats weighing between 250 and 300 g . INTERVENTIONS: Anesthetized rats had placement of a gastrostomy, followed 1 wk later by implantation of a bacteria-filled osmotic minipump into the peritoneal cavity . Rats were fed a high-protein (20% total energy) enteral diet . Saline or pentoxifylline (5 or 20 mg/kg im) was administered daily beginning at the time of pump implantation . MEASUREMENTS AND MAIN RESULTS: Septic rats fed the high-protein liquid diet and given pentoxifylline in a dose of 5 mg/kg/day demonstrated improved survival compared with saline-treated animals or animals given the high dose (20 mg/kg/day) of pentoxifylline (p< .05) . Administration of pentoxifylline at 5 mg/kg/day also down regulated the production of IL-6 messenger RNA (mRNA) in liver and lipopolysaccharide binding protein mRNA in the liver and intestine of septic animals given the high-protein liquid diet . CONCLUSION: Low-dose (but not high-dose) pentoxifylline administration reduced production of some, but not all, cytokines studied in the gut and liver in a rat model of acute peritonitis and this reduced production was associated with an improved survival in such animals.

Crit Care Med, 1999 Jan, 27(1), 82 - 9
Compositional, structural, and functional alterations in pulmonary surfactant in surgical patients after the early onset of systemic inflammatory response syndrome or sepsis; Raymondos K et al.; OBJECTIVES: Sepsis is one of the most important predisposing factors for the development of the acute respiratory distress syndrome (ARDS) . Alterations of pulmonary surfactant contribute in the pathogenesis of ARDS . However, little is known about surfactant in patients with less severe grades of lung injury related to sepsis or systemic inflammatory response syndrome (SIRS) . Therefore, the purpose of this study was to characterize endogenous surfactant in surgical intensive care patients with sepsis or SIRS . DESIGN: Prospective, observational study . SETTING: University-affiliated, interdisciplinary intensive care unit . PATIENTS: Eleven patients after major surgery with SIRS or sepsis included within 12 hrs of onset and 11 controls without infection or lung disease . INTERVENTIONS: Operating room and standard intensive care unit management . MEASUREMENTS AND MAIN RESULTS: Four serial bronchoalveolar lavage samples (BAL) were recovered over 7 days from the patients and single BAL samples were obtained from controls . BAL cells, total protein, surfactant-associated protein A (SP-A), surfactant alveolar transition forms, and surface activity were analyzed . Two of 11 patients met criteria for acute lung injury and six of the 11 patients met ARDS consensus conference criteria but acute lung injury or ARDS was not persistent . The mean Pao2/F(IO)2 for the patients over 7 days was 253.2+/-15.1 (SEM) and Murray's lung injury score was 1.12+/-0.12, indicating mild-to-moderate lung injury . BAL neutrophil counts were increased (p< .01), and the ratio of poorly functioning light aggregate surfactant to superiorly functioning heavy aggregate surfactant was increased compared with controls (0.32+/-0.06 vs . 0.09+/-0.01, p < .05) . SP-A was decreased (1.9+/-0.4 vs . 3.5+/-0.6 microg/mL of BAL, p< .05) and there were increases in the ratios of phospholipid to SP-A (p < .05), protein to SP.A (p < .01), and protein to phospholipid (p < .05) . The surface tension-lowering ability of purified heavy aggregate surfactant was significantly impaired (15.6+/-1.6 vs . 2.8+/-0.6 milliNewtons/m, p< .05) . CONCLUSIONS: These observations show that surgical patients with SIRS or sepsis who have mild-to-moderate lung injury develop surfactant dysfunction detectable within 7 days of onset . We propose, therefore, that therapeutic strategies to modulate these severe surfactant abnormalities should be considered, as these strategies may have the potential to reduce lung injury, which is associated with a high mortality in sepsis.

Langenbecks Arch Chir Suppl Kongressbd, 1998, 115, 1067 - 70
{Induction of early endotoxin tolerance with atoxic endotoxin--a new method for preventing sepsis syndrome}; Staubach KH et al.; The induction of early-phase endotoxin tolerance in a procine endotoxin shock model by atoxic LPS from Rhodobacter sphaeroides led to a significant extension of the survival time (p < 0.0179) . The protective effect of the non-specific tolerant state also led to an enhancement of cardiorespiratory parameters during the continuous endotoxin challenge . Non-specific stimulation of host defense mechanisms with atoxic endotoxin as prophylactic agent in surgical patients at risk may prove to be beneficial in the future.

Horm Metab Res, 1998 Dec, 30(12), 726 - 9
Leptin and interleukin-6 in sepsis; Torpy DJ et al.; Both leptin and interleukin-6 (IL-6) are hypersecreted in acute critical illness, such as sepsis . Leptin is produced by adipocytes, it inhibits appetite and stimulates the sympathetic nervous system, thereby reducing adipose mass . IL-6 is produced by immune cells and adipocytes, it reduces the production of other inflammatory cytokines and stimulates release of acute phase proteins by the liver, participating in the control of inflammation . Leptin inhibits, whereas IL-6 stimulates, the hypothalamic-pituitary-adrenal axis . While high IL-6 levels are associated with poor outcome in critically ill patients, the role of leptin in critical illness and its importance for survival are not known . To examine the relation between IL-6, leptin and cortisol in critical illness, we performed frequent 4 h plasma sampling in eight patients on day 1 of intensive care unit admission for acute sepsis . Sampling was repeated on days 3 and 5 in the five survivors . The levels of all three hormones were markedly elevated; there was a lack of the normal diurnal rhythmicity of leptin and IL-6 and a blunted diurnal rhythmicity of cortisol secretion . A strong negative correlation between mean 24 h plasma IL-6 and leptin was revealed . Although such a relationship could possibly be explained by the negative and positive effects of cortisol hypersecretion on each hormone respectively, a negative correlation between leptin and cortisol was detected, whereas there was no significant correlation between IL-6 and cortisol . Mean IL-6 values were higher (1389.5+/-644.9 vs . 658.8+/-250.5) and leptin levels were lower (2.73+/-1.1 vs . 26.5+/-11.6) in the non-survivors than in the survivors . These findings suggest that IL-6 is not the principal stimulus of leptin hypersecretion in critically ill patients with sepsis . The negative relation between IL-6 and leptin is of potential importance, as high IL-6 levels have been associated with poor outcome in critically ill patients, and relatively low leptin levels may impair sympathetic system and immune functions.

Thorac Cardiovasc Surg, 1998 Dec, 46(6), 348 - 51
Diagnostic value of procalcitonin: the influence of cardiopulmonary bypass, aprotinin, SIRS, and sepsis; Boeken U et al.; BACKGROUND: The reasons for a systemic inflammatory response syndrome (SIRS) following ECC are not yet fully understood . Procalcitonin (PCT) blood levels may distinguish between bacterial infections and a non-bacterial systemic inflammation . We investigated the influence of ECC, ECC modified by application of aprotinin, systemic inflammation, and bacterial infection on the PCT values . METHODS: 20 CABG patients were randomized and divided in two groups . Group A served as the control group, while group B perioperatively received a high dose of aprotinin . Blood samples for measurement of PCT were taken 6 times perioperatively . Furthermore, blood samples were taken from 20 preoperatively comparable patients who suffered from bacterial infection (n = 10) (group C) or a SIRS (n = 10) (group D) after ECC; in these groups PCT was determined daily after the onset of inflammation . RESULTS: There was no significant elevation of PCT in group A or B at any time . In sepsis patients a significant elevation of PCT was seen, with the peak level of 18.6+/-6.3 ng/ml on the second day after diagnosis; the PCT level of SIRS patients remained constantly low (<0.9 ng/ml) . CONCLUSIONS: In this study it was demonstrated that ECC and the use of aprotinin did not have any influence on the secretion of PCT . A systemic bacterial infection caused a significant increase of PCT, whereas PCT values remained normal in case of a SIRS . So it seems to be possible to distinguish between a primary SIRS and a bacterial sepsis by means of PCT.

Am J Emerg Med, 1999 Jan, 17(1), 15 - 8
Superoxide production of neutrophils after severe injury: impact of subsequent surgery and sepsis; Shih HC et al.; To evaluate the early variations of superoxide production of neutrophils (SPN) in injured patients, SPN was serially measured on the first, third, and seventh day after severe injury (injury severity score of >16) . For patients receiving subsequent surgery, SPN was measured again on the first postoperative day . Eighteen patients were studied . Six had subsequent surgery within 1 day (early operation); 6 had surgery 3 days after injury (late operation); 6 did not have surgery (nonoperation) . SPN increased on the first day and recovered from the third day after injury in all three groups . In patients who had surgery, SPN did not significantly increase on the first postoperative day . Eight patients developed sepsis, 4 of whom had early multiple organ dysfunction (EMOD) . On the last measurement, mean SPN was suppressed in septic patients with EMOD, whereas it was elevated in septic patients without EMOD . Patients with EMOD also had a higher injury severity score . In conclusion, subsequent surgery after injury has no effect on the priming of neutrophils . While late priming of neutrophils in injured patients coincides with the development of sepsis, suppression of SPN is found in septic patients with EMOD that frequently results from severe injury.

Shock, 1999 Jan, 11(1), 39 - 43
Alterations of G-protein and adenylate cyclase signaling in rat liver during the progression of sepsis; Wu LL et al.; Changes in the protein level of various subunits of G-protein and the activity of adenylate cyclase in rat liver plasma membranes during different metabolic phases of sepsis were studied . Sepsis was induced by cecal ligation and puncture (CLP) . The results show that the protein levels of Galphai-2 and Galphai-3 were unchanged during the early hypermetabolic (hyperglycemic) phase (9 h after CLP), whereas Galphaai-2 and Galphaai-3 were increased by 32.4 and 59.1%, respectively, during the late hypometabolic (hypoglycemic) phase (18 h after CLP) of sepsis . The protein levels of Galphas and Gbeta remained unaltered during both the early and the late phases of sepsis . The activity of adenylate cyclase remained unchanged during the early phase, whereas it was decreased by 26% (p < .05) during the late phase of sepsis . Since the G-protein/adenylate cyclase signaling system mediates hormonal control of hepatic glucose metabolism, the observed increases in the Galphai-2 and Galphai-3 protein levels coupled with a decrease in the activity of adenylate cyclase may contribute to the development of the hypoglycemia during the late stage of sepsis.

Pediatrics, 1999 Jan, 103(1 Suppl E), 360 - 73
The neonatal "sepsis work-up": personal reflections on the development of an evidence-based approach toward newborn infections in a managed care organization; Escobar GJ; "Rule out sepsis" may be the most common discharge diagnosis among infants admitted to the neonatal intensive care unit . Although the frequency of sepsis, meningitis, and other confirmed bacterial infections has remained constant (between 1 and 5/1000 live births) for many years, the number of infants evaluated and treated is much higher . Each year in the United States, as many as 600 000 infants experience at least one evaluation for suspected bacterial infection during the birth hospitalization . The number treated is estimated at 130 000 to 400 000 per year . Despite massive overtreatment, delayed diagnosis still occurs . The Kaiser Permanente Medical Care Program (KPMCP) considers developing and implementing an evidence-based approach to "rule out sepsis," a research and operational priority . To achieve these goals, it is essential to consider two key aspects of the problem . First, it is important to adopt a phenomenologic approach that takes clinicians' personal experience into account . This must include reflection on those aspects of experience often considered "irrational" or "subjective." Second, incorporation of a phenomenologic approach needs to be tempered with sound epidemiologic methods . If one considers these two aspects-physician experience and sound epidemiology-it is clear that much of the existing literature on "rule out sepsis" is of limited utility . Consequently, the KPMCP has conducted its own studies . These are aimed at characterizing the "sepsis work-up," developing electronic datasets that would permit clinicians to simulate various strategies, and developing techniques for ongoing electronic monitoring . This article summarizes the approach taken by the KPMCP Division of Research . It describes the results of a pilot study as well as the development and use of a dedicated neonatology outcomes database, the Kaiser Permanente Neonatal Minimum Data Set (NMDS) . The NMDS database includes the Score for Neonatal Acute Physiology and permits ongoing monitoring of sepsis "work-ups" as well as confirmed cases of neonatal infection . The article also describes how the experience from the pilot as well as the NMDS was incorporated in the design of a much larger study on "rule out sepsis." Finally, the article describes some important theoretic issues affecting decision rule development and the use of computer simulations in neonatology . These issues are 1) how one handles possible overanalysis of a dataset; 2) how one handles data points that are unstable (eg, the absolute neutrophil count, which can vary considerably depending on age and sampling conditions); and 3) the limitations of decision rules based on computer simulations.

Burns, 1998 Dec, 24(8), 745 - 50
Procalcitonin--a sepsis parameter in severe burn injuries; von Heimburg D et al.; Procalcitonin (PCT) levels increase in patients with systemic infections; the highest levels have been found in sepsis . This study tested whether plasma procalcitonin level was related to sepsis, CRP, burn size, inhalation injury or mortality in severely burned patients over the entire clinical course . In 27 patients with 51 (20-91)% TBSA, PCT was measured three times weekly from admission over the entire course of stay in a single ICU . Daily scoring by the "Baltimore Sepsis Scale" was performed . The patients were assigned to three groups depending on the clinical course and outcome: A = no septic complications, B = septic complications-survivors, C = septic complications non-survivors . PCT levels were elevated slightly at admission (mean 2.1 ng/ml) except in three patients who suffered electrical burns (mean 15.7 ng/ml) . PCT peak levels correlated well with the Scoring values (r = 0.84) while CRP did not (r = 0.64) . Peak PCT levels were significantly higher (p < 0.005) in septic patients (B and C) who averaged 49.8+/-76.9 ng/ml, than in non-septic patients (A) who averaged peak levels of 2.3+/-3.7 ng/ml . The highest PCT levels were found immediately before death (86.8+/-97 ng/ml) . Seven patients had an inhalation injury 3rd degree . In these patients at 24 h postburn, there was no relationship between PCT levels and inhalation injury but during the later days postburn there were significant differences in PCT levels in patients with versus without inhalation injury . All patients with inhalation injury 3rd degree developed septic complications . There was no positive correlation between the PCT-admission-levels and the TBSA, but there was a positive correlation between the TBSA and the mean peak PCT levels during the later days postburn (r = 0.73; p < 0.05) . The cut-off value of 3 ng/ ml we found reliable to indicate severe bacterial or fungal infection . PCT values over 10 ng/ml increasing over the following days were found only in life-threatening situations due to systemic infections . The individual course of PCT in one patient is more important than absolute values . PCT presented in this study as a useful diagnostic parameter in severely burned patients.

Intensive Care Med, 1998 Dec, 24(12), 1315 - 22
Beta-adrenergic receptor-dependent and -independent stimulation of adenylate cyclase is impaired during severe sepsis in humans; Bernardin G et al.; OBJECTIVES: a) To investigate the functional consequences of sepsis on the beta-adrenergic signal transduction in human circulating lymphocytes; b) to appreciate sepsis-associated catecholamine and cytokine release . DESIGN: Experimental, comparative study . SETTING: Research laboratory in a university hospital . SUBJECTS: Healthy controls (n = 10); critically ill patients who were not septic (n = 7); septic patients with severe sepsis or septic shock (n = 11) . MEASUREMENTS AND MAIN RESULTS: Experiments were carried out using freshly isolated peripheral blood mononuclear cells (PBMC) . We measured beta-adrenergic receptor (betaAR) number and affinity, and intracellular cAMP content at baseline and after the pharmacological stimulation of each component of the beta-adrenergic complex: betaAR with isoproterenol, Gs-protein with sodium fluoride (NaF), adenylate cyclase with forskolin . Catecholamine (adrenaline, noradrenaline) and cytokine (TNFalpha, IL-1alpha, IL-1beta, IL-6) serum levels were measured . In both septic and non-septic patients we observed a similar 40 % down-regulation of betaARs compared to controls, and a reduced basal and isoproterenol-stimulated cAMP accumulation (p < 0.05) . The cAMP production elicited by NaF or forskolin was lower in septic patients than in the controls (p < 0.01) . Forskolin-stimulated cAMP accumulation was significantly lower in septic patients than it was in non-septic ones (p < 0.001) . Catecholamine serum concentrations were increased in the two patient groups without any significant difference . Elevated cytokine serum levels were detected in 45% of the septic patients (versus 14% of non-septic patients p < 0.05) . CONCLUSIONS: Patients presenting with severe sepsis or septic shock have extended postreceptor defects of the beta-adrenergic signal transduction . This finding suggests a heterologous desensitization of adenylate cyclase stimulation.

Mol Cell Biochem, 1998 Dec, 189(1-2), 55 - 61
GTP-binding protein mediated phospholipase A2 activation in rat liver during the progression of sepsis; Tong LJ et al.; Effects of GTP-binding proteins on the activation of secretory phospholipaseA2 (sPLA2) and cytosolic phospholipaseA2 (cPLA2) in rat liver during two different phases of sepsis were studied . Sepsis was induced by cecal ligation and puncture (CLP) . Experiments were divided into three groups: control, early sepsis, and late sepsis . Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after CLP . The results show that in the absence of G-protein modulator, hepatic sPLA2 and cPLA2 activities were activated by 40.8-46 and 91.6-105.8%, respectively, during early and late phases of sepsis . GTPgammaS and fluoroaluminate (AlF4-) stimulated sPLA2 and cPLA2 activities within each experimental group, i.e., control, early sepsis, and late sepsis . The GTPgammaS and AlF4(-)-stimulated sPLA2 and cPLA2 activities remained significantly elevated during early phase (22.3-65.6% increase) and late phase (32.5-109.1% increase) of sepsis . Further analyses demonstrate that cholera toxin significantly stimulated sPLA2 and cPLA2 activities within each experimental group, and that the cholera toxin stimulated sPLA2 and cPLA2 activities remained significantly higher during early phase (23.5-37% increase) and late phase (56.7-70% increase) of sepsis . In contrast, pertussis toxin significantly inhibited sPLA2 and cPLA2 activities within each experimental group, and that the pertussis toxin-inhibited sPLA2 and cPLA2 activities remained significantly higher in early septic (57-68.5% increase) and late septic (34.6-45.5% increase) experiments . These data demonstrate that cholera toxin-sensitive G alpha s and pertussis toxin-sensitive G alpha i were both involved in the activation of sPLA2 and cPLA2 activities in rat liver during the progression of sepsis.

J Surg Res, 1998 Dec, 80(2), 326 - 32
Adenosine receptor antagonism affects regional resting vascular resistance during rat peritoneal sepsis; Motew SJ et al.; BACKGROUND . To identify vascular beds where endogenous adenosine plays a significant role as a mediator of resting perfusion alterations associated with sepsis, we tested the hypothesis that adenosine receptor blockade would cause differential regional increases in vascular resistance during intraperitoneal (ip) sepsis in the rat . MATERIALS AND METHODS . Rats (250-350 g) were catheterized and randomized to septic or nonseptic groups . Sepsis was induced with an ip injection of cecal slurry (150 mg/kg in D5W; 5 ml/kg), and baseline hemodynamics, cardiac output (CO), and blood flows (microspheres) were measured 24 h later . Animals then received the adenosine receptor antagonist 8-phenyltheophylline (8-PTH; 10 mM, 1.5 ml/kg), its vehicle (1.5 ml/kg), or normal saline (1.5 ml/kg), iv, and measurements were repeated . RESULTS . Septic animals treated with 8-PTH had a significant increase in skeletal muscle, hepatic portal, and cerebral vascular resistance with concomitant decreases in CO when compared with vehicle at 1 min . No significant resistance changes were observed in the renal, adipose, or coronary vasculatures . Adenosine receptor blockade caused a significant increase in +dP/dt and -dP/dt during sepsis, indicating that the reduced CO was not secondary to myocardial depression . CONCLUSIONS . These data suggest that adenosine receptor-mediated actions during sepsis affect vascular beds selectively and indicate a significant role for adenosine in resting perfusion redistribution in sepsis .

Crit Care Med, 1998 Dec, 26(12), 2005 - 9
Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock; Gando S et al.; OBJECTIVES: To obtain systematic information on the extrinsic coagulation pathway, as well as to investigate the time course of the coagulation abnormalities in sepsis . DESIGN: Prospective observational study . SETTING: General intensive care unit . PATIENTS: Nineteen patients with the diagnosis of severe sepsis or septic shock and nine control patients . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Tissue factor antigen concentration (tissue factor antigen), prothrombin fragment F1+2, thrombin antithrombin III complex, fibrinopeptide A, D-dimer, and antithrombin III concentrations were measured on the day of diagnosis of severe sepsis and septic shock, and on days 1, 2, 3, and 4 after diagnosis . The concentrations of tissue factor antigen, prothrombin fragment F1+2, fibrinopeptide A, and D-dimer were significantly increased in patients with severe sepsis and septic shock compared with control subjects . However, the concentrations of thrombin antithrombin III complex showed no statistical differences between the septic patients and the control subjects . Significantly, low antithrombin III concentrations were observed in the septic patient groups compared with control subjects . With the exception of D-dimer, the concentrations of the hemostatic markers were similar between severe sepsis and septic shock patients . Significant correlations were noted between tissue factor antigen and the disseminated intravascular coagulation score (r2=.236, p< .0001) and the number of dysfunctioning organs (r2=.229, p=.035) . CONCLUSIONS: We systematically elucidated coagulation disorders in newly defined sepsis . The extrinsic coagulation pathway is activated in patients with severe sepsis and septic shock . In these patients, enhanced thrombin generation and activation, and fibrin formation were demonstrated when compared with the control subjects . Furthermore, the thrombin generated appears not to be fully neutralized by antithrombin III.

Nurs Crit Care, 1997 Mar-Apr, 2(2), 83 - 7
The metabolic changes associated with trauma and sepsis; Say J; Developments in critical care medicine have increased the chances of survival of those patients with severe trauma or established sepsis . However, such patients often have a prolonged critical illness, and the ensuing catabolic response can have detrimental effects causing a depletion of body weight, tissue mass and stored nutrients . In order to facilitate treatment and minimise the effects of these catabolic changes, both the mediators of this response and the response itself have been studied . This paper explores the current understanding of the metabolic changes that occur in trauma and sepsis, and how these changes alter carbohydrate, fat and protein metabolism.

J Crit Care, 1998 Dec, 13(4), 169 - 76
Role of neurosympathetic pathways in the vascular response to sepsis; Magder S et al.; PURPOSE: The aim of this study was to determine the role of sympathetic neural activity in the hemodynamic adaptations to sepsis in pigs with an emphasis on circuit adaptations . A fall in resistance to venous return (RVR) was predicted in contrast to what was previously observed in sympathetically intact animals that had no change in RVR . MATERIALS AND METHODS: We anesthetized and ventilated 13 pigs and gave 5 mg/kg of indomethacin . We measured cardiac output (CO) by thermodilution and measured pulmonary arterial (PAP), pulmonary capillary wedge (Pcw), right atrial pressure (Pra), and arterial pressure (MAP) . Intermittent inflation of a 50-mL balloon in the right atrium was used to transiently arrest the circulation for the measurement of mean circulatory filling pressure (MCFP) . RVR was calculated from (MCFP - Pra)/CO . Animals were divided into two groups; 6 received 10 mg/kg of the ganglionic blocker, hexamethonium and norepinephrine to maintain MAP; 7 had their spinal cords cut at C-2 . After baseline measurements, all animals received 10 microg/kg/h of endotoxin for 2 hours, and hemodynamic measurements were repeated . Plasma samples were obtained for measurements of immunoreactive endothelin-1 (ET-1), which was assayed by a radioimmunoassay . RESULTS: Hexamethonium had no significant effect on hemodynamics except for an increase in heart rate . After endotoxin, MAP and SVR fell, PAP rose, and CO and RVR did not change . Spinal section resulted in an increase in heart rate and small increase in PAP and MCFR After endotoxin, there was a further increase in heart rate, PAP, and MCFP with a marked fall in MAP and CO . RVR increased from 2.1 +/- 0.46 after spinal section to 3.6 +/- 54 mm x min/L (P < .05) . ET-1 in the hexamethonium group (n = 2) rose from 2.21 +/- .14 to 11.5 +/- 2.1 pg/ml at 2 hours, and in the spinal group (n = 7) from 2.04 +/- 0.77 to 6.85 +/- 3.9 pg/mL at 45 minutes . CONCLUSION: Spinal section resulted in a more profound fall in blood pressure and less increase in MCFP than in previously studied animals with sympathetic nervous system intact, but there was still an increase in RVR and PAP ET-1 is a possible mediator of the increase in RVR and PAP.

Arch Surg, 1998 Dec, 133(12), 1347 - 50
Multivariate analysis of 9 disease-associated variables for outcome prediction in patients with sepsis; Calvano SE et al.; OBJECTIVE: To assess the ability of 9 clinical or biological variables to predict outcome (survival or nonsurvival) using multiple regression and classification analyses . DESIGN: Prospective, descriptive cohort study with no interventions . SETTING: Surgical intensive care unit of a tertiary care hospital and a medical school research laboratory . PATIENTS: Eighteen patients with a documented source of infection who met currently accepted criteria for sepsis syndrome or septic shock . MAIN OUTCOME MEASURES: Prediction of survival or nonsurvival based on analysis of clinical (Multiple Organ Dysfunction score, Acute Physiology and Chronic Health Evaluation III scores) and biological (plasma levels of cortisol, interleukin 6, interleukin 10, phospholipase A2, soluble tumor necrosis factor receptor p75, and monocyte membrane tumor necrosis factor receptor levels) variables, with comparison of predicted and actual outcomes . RESULTS: Plasma interleukin 6, interleukin 10, and phospholipase A2 concentrations were not significantly (P>.05) different between survivors and nonsurvivors . By standard, forward stepwise, and backward stepwise multiple regression analyses, only monocyte membrane tumor necrosis factor receptor levels measured at the onset of sepsis significantly predicted outcome in all 3 analyses . However, by both standard and backward stepwise analyses, Multiple Organ Dysfunction scores based on evaluation at the onset of sepsis and 24 hours later were also significant predictors of outcome . Classification analysis showed that assignment to outcome group was statistically significant when based on monocyte membrane tumor necrosis factor receptor levels determined at the onset of sepsis or on Multiple Organ Dysfunction scores assessed 24 hours after sepsis was diagnosed . CONCLUSION: Although these findings were based on a relatively small cohort, both multiple regression and classification analyses indicated that only monocyte membrane tumor necrosis factor receptor levels are able to discriminate survivors from nonsurvivors at the onset of sepsis.

Arch Surg, 1998 Dec, 133(12), 1316 - 21
Skeletal muscle phosphocreatine depletion depresses myocellular energy status during sepsis; Lara TM et al.; OBJECTIVE: To determine the effects of phosphocreatine (PCr) depletion on myocellular energetics . DESIGN: Randomized controlled study . SETTING: University laboratory . MATERIALS: Thirty-eight adult male Wistar rats (110-121 g) . METHODS: The poorly metabolized creatine analogue beta-guanidinopropionic acid, (beta-GPA, 2% of a gel diet) was fed to the rats for 14 days to replace (75%) endogenous PCr stores before cecal ligation and puncture (CLP) . Rats were randomized to receive sham operation and gel diet (sham-gel group {n=10}), sham operation and beta-GPA diet (sham-beta-GPA group {n=9}), CLP and gel diet (CLP-gel group {n=10}), and CLP and beta-GPA diet (CLP-beta-GPA group {n=9}) . On day 14, all animals underwent operation . Twenty-four hours later, in vivo phosphorus 31-labeled magnetic resonance spectroscopy (31P-MRS) of the gastrocnemius muscle was performed . Muscle samples were collected to determine enzyme activities of beta-hydroxyacyl-CoA dehydrogenase, phosphofructokinase, citrate synthase, and the metabolites adenosine triphosphate (ATP), PCr, inorganic phosphate, and creatine . Free adenosine diphosphate levels, the phosphorylation potential, and free energy change of ATP hydrolysis were then calculated . RESULTS: All animals undergoing CLP but no controls had positive results of blood cultures . Although sham-beta-GPA animals had altered bioenergetics, CLP-beta-GPA rats experienced a greater deterioration of energy state compared with CLP-gel controls . Glycolytic and oxidative enzyme activities were not significantly different between groups and therefore could not explain the observed differences . CONCLUSIONS: There is an overall decrease in energy availability during sepsis, which is worsened by PCr depletion . These changes support the contention that PCr plays an important role as an ATP buffer during systemic infection.

Arch Surg, 1998 Dec, 133(12), 1298 - 304
The pivotal role of adrenomedullin in producing hyperdynamic circulation during the early stage of sepsis; Wang P et al.; BACKGROUND: Initial cardiovascular responses during sepsis are characterized by hyperdynamic circulation . Although studies have shown that a novel potent vasodilatory peptide, adrenomedullin (ADM), is up-regulated under such conditions, it remains unknown whether ADM is responsible for initiating the hyperdynamic response . OBJECTIVE: To determine whether increased ADM release during early sepsis plays any major role in producing hyperdynamic circulation . DESIGN, INTERVENTION, AND MAIN OUTCOME MEASURE: Synthetic rat ADM (8.5 microg/kg of body weight) was infused intravenously in normal rats for 15 minutes at a constant rate . Cardiac output, stroke volume, and microvascular blood flow in various organs were determined immediately as well as 30 minutes after ADM infusion . At 30 minutes after infusion, plasma ADM level was also measured . In additional groups, rats were subjected to sepsis by cecal ligation and puncture . At 1.5 hours after cecal ligation and puncture, specific anti-rat ADM antibodies were infused, which completely neutralized the circulating ADM . Various hemodynamic variables were measured 5 hours after cecal ligation and puncture (ie, the early stage of sepsis) . RESULTS: Cardiac output, stroke volume, and microvascular blood flow in the liver, small intestine, kidney, and spleen increased, and total peripheral resistance decreased 0 and 30 minutes after ADM infusion . In addition, plasma levels of ADM increased from the preinfusion level of 92.7+/-5.3 to 691.1+/-28.2 pg/mL 30 minutes after ADM infusion, which was similar to ADM levels observed during early sepsis . Moreover, 5 hours after the onset of sepsis, cardiac output, stroke volume, and microvascular blood flow in various organs increased and total peripheral resistance decreased . Administration of anti-ADM antibodies, however, prevented the occurrence of the hyperdynamic response . CONCLUSIONS: The results suggest that increased ADM production and/or release plays a major role in producing hyperdynamic responses during early sepsis . Since our previous studies have shown that vascular responsiveness to ADM decreases in late sepsis, maintenance of ADM vascular responsiveness by pharmacological agents during the course of sepsis may prevent transition from the hyperdynamic to the hypodynamic state.

Arch Surg, 1998 Dec, 133(12), 1281 - 8
Dehydroepiandrosterone: an inexpensive steroid hormone that decreases the mortality due to sepsis following trauma-induced hemorrhage; Angele MK et al.; BACKGROUND: Recent studies suggest that male sex steroids play a role in producing immunodepression following trauma-hemorrhage . This notion is supported by studies showing that castration of male mice before trauma-hemorrhage or the administration of the androgen receptor blocker flutamide following trauma-hemorrhage in noncastrated animals prevents immunodepression and improves the survival rate of animals subjected to subsequent sepsis . However, it remains unknown whether the most abundant steroid hormone, dehydroepiandrosterone (DHEA), protects or depresses immune functions following trauma-hemorrhage . In this regard, DHEA has been reported to have estrogenic and androgenic properties, depending on the hormonal milieu . OBJECTIVE: To determine whether administration of DHEA after trauma-hemorrhage has any salutary or deleterious effects on immune responses, and whether it improves the survival of animals subjected to subsequent sepsis . DESIGN: Male C3H/HeN mice underwent laparotomy (ie, trauma-induced) and hemorrhagic shock (blood pressure, 35+/-5 mm Hg for 90 minutes) followed by fluid resuscitation, or sham operation . The animals then received 100 mg of DHEA (4 mg/kg) or propylene glycol (hereafter referred to as vehicle) . At 24 hours after trauma-hemorrhage and resuscitation, the animals were killed and blood, spleens, and peritoneal macrophages were harvested . Splenocyte proliferation and interleukin (IL) 2 release and splenic and peritoneal macrophage IL-1 and IL-6 release were determined . In a separate set of experiments, sepsis was induced by cecal ligation and puncture at 48 hours after trauma-hemorrhage and resuscitation . For those studies, the animals received vehicle, a single 100-microg dose of DHEA, or 100 microg/d DHEA for 3 days following hemorrhage and resuscitation . Survival was monitored for 10 days after the induction of sepsis . RESULTS: Administration of DHEA restored the depressed splenocyte and macrophage functions at 24 hours after trauma-hemorrhage . Moreover, daily administration of DHEA for 3 days significantly increased the survival of animals subjected to subsequent sepsis (P=.01) . CONCLUSION: The finding that DHEA markedly improves the depressed immune functions and survival of animals subjected to subsequent sepsis suggests that short-term treatment with DHEA after trauma-hemorrhage is a safe and novel approach for preventing immunodepression and for decreasing the mortality rate due to subsequent sepsis.

Acad Emerg Med, 1998 Dec, 5(12), 1169 - 76
Severe sepsis in the emergency department and its association with a complicated clinical course; Smith SW et al.; OBJECTIVE: Infection severity as determined by clinical criteria has been recently classified and studied in hospitalized inpatients . The objective of the study was to use modified criteria to determine the clinical course associated with three levels of infection severity in infected patients admitted from the ED . METHODS: This was a retrospective cohort study involving all patients 18 years of age and older admitted through the ED of an urban teaching hospital during a four-month period whose primary reason for requiring hospitalization was an infection that was recognized in the ED . ED records were reviewed for criteria used to classify patients by three levels of infection severity: no systemic inflammatory response syndrome, sepsis, and severe sepsis (SS) . The relationships between these classifications as well as certain clinical characteristics and any complicated clinical course as measured by death and/or admission to an intensive care unit (ICU), and/or prolonged hospitalization, were analyzed . RESULTS: Of 408 patients entered into the study, 138 (33.8%) fulfilled the criteria of SS in the ED . Patients with SS in the ED had a mortality of only 4.3%, though with an increased risk of dying compared with that of the other groups combined {relative risk (RR) = 11.64, 95% confidence interval (CI) = 1.43 to 96.53}, an increased risk of ICU stay (RR = 7.65, 95% CI = 4.08 to 14.36), and an increased risk of prolonged hospitalization (RR = 1.99, 95% CI = 1.38 to 2.88) . Although age over 60 years and several comorbid conditions also were identified by univariate analysis as risk factors, multivariate analysis revealed that only SS and diabetes mellitus (DM) were independent predictors of a complicated course . In the authors' institution, the positive predictive value (PPV) of SS for complicated clinical course was 0.48 and the negative predictive value (NPV) of no SS for no complicated course was 0.77 . The PPV of {SS + DM} was 0.83, and the NPV of {SS, DM, or both} was also 0.83 . CONCLUSION: Although the strongest correlate of a complicated clinical course identified in the ED is SS as defined by the study criteria, its specificity and PPV are low . The mortality of ED patients with SS is much lower than the mortality rates reported for inpatients with SS . SS as defined by the study criteria is too sensitive and therefore lacks utility in the ED setting.

Anesthesiology, 1998 Dec, 89(6), 1313 - 21
Systolic pressure variation as a guide to fluid therapy in patients with sepsis-induced hypotension; Tavernier B et al.; BACKGROUND: Monitoring left ventricular preload is critical to achieve adequate fluid resuscitation in patients with hypotension and sepsis . This prospective study tested the correlation of the pulmonary artery occlusion pressure, the left ventricular end-diastolic area index measured by transesophageal echocardiography, the arterial systolic pressure variation (the difference between maximal and minimal systolic blood pressure values during one mechanical breath), and its delta down (dDown) component (= apneic - minimum systolic blood pressure) with the response of cardiac output to volume expansion during sepsis . METHODS: Preload parameters were measured at baseline and during graded volume expansion (increments of 500 ml) in 15 patients with sepsis-induced hypotension who required mechanical ventilation . Each volume-loading step (VLS) was classified as a responder (increase in stroke volume index > or = 15%) or a nonresponder . Successive VLSs were performed until a nonresponder VLS was obtained . RESULTS: Thirty-five VLSs (21 responders) were performed . Fluid loading caused an overall significant increase in pulmonary artery occlusion pressure and end-diastolic area index, and a significant decrease in systolic pressure variation and delta down (P < 0.01) . There was a significant difference between responder and nonresponder VLSs in end-diastolic area index, systolic pressure variation, and dDown, but not in pulmonary artery occlusion pressure . Receiver-operator curve analysis showed that dDown was a more accurate indicator of the response of stroke volume index to volume loading than end-diastolic area index and pulmonary artery occlusion pressure . A dDown component of more than 5 mmHg indicated that the stroke volume index would increase in response to a subsequent fluid challenge (positive and negative predictive values: 95% and 93%, respectively) . CONCLUSION: The dDown component of the systolic pressure variation is a sensitive indicator of the response of cardiac output to volume infusion in patient with sepsis-induced hypotension who require mechanical ventilation.

Am J Kidney Dis, 1998 Dec, 32(6), 953 - 61
Effect of hemoperfusion with polymyxin B-immobilized fiber on plasma endothelin-1 and endothelin-1 mRNA in monocytes from patients with sepsis; Ebihara I et al.; Hemoperfusion using polymyxin B-immobilized fiber (PMX-F) is reported to be an effective treatment for sepsis . The aim of the present study is to assess whether plasma endothelin-1 (ET-1) and ET-1 messenger RNA (mRNA) levels in peripheral-blood monocytes are altered in patients with sepsis and whether PMX-F treatment affects plasma ET-1 and monocyte ET-1 mRNA levels . Sixteen patients with sepsis and 20 healthy volunteers were included in this study . Plasma ET-1 concentration was measured by radioimmunoassay (RIA), and plasma levels of transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) were measured by enzyme-linked immunosorbent assay (ELISA) . Sixteen patients with sepsis were treated with direct hemoperfusion using PMX-F columns . Blood endotoxin levels decreased significantly from 35 to 10 pg/mL after two treatments of direct hemoperfusion, each for 2 hours . Patients with sepsis showed significantly increased levels of plasma ET-1 (P < 0.001) and monocyte ET-1 mRNA (P < 0.001) compared with healthy volunteers . However, no differences in plasma levels of TGF-beta, TNF-alpha, and IL-1beta existed between patients with sepsis and healthy volunteers . Increased plasma ET-1 levels and monocyte ET-1 mRNA levels in patients with sepsis decreased significantly after PMX-F treatment (P < 0.01) . These data suggest that the secretion of ET-1 from peripheral-blood monocytes may be stimulated by endotoxin, and PMX-F treatment may be effective in reducing ET-1 secretion in patients with sepsis.

Am J Respir Crit Care Med, 1998 Dec, 158(6), 1990 - 8
Reversal of hypocalcemia and decreased afterload in sepsis . Effect on myocardial systolic and diastolic function; Kovacs A et al.; Sepsis is a major cause of death in intensive care units . Clinically, sepsis induces a number of physiologic and metabolic abnormalities, including decreased myocardial contractility and decreased plasma ionized calcium . There is debate about the proper therapy of hypocalcemia in sepsis because calcium administration may worsen cell function by causing intracellular Ca2+ overload . We investigated the effect of Ca2+ administration on myocardial systolic and diastolic function in an extensively utilized rat model of sepsis, i.e., the cecal ligation and puncture model (CLP) . Approximately 24 h after CLP or sham surgery, rats were anesthetized and myocardial function assessed in vivo by a left ventricular Millar catheter and simultaneous two-dimensional guided M-mode echocardiography . Septic rats had a 28% decrease in peak left ventricular developed pressure, a 30% decrease in +dP/ dt, and a 23% decrease in -dP/dt (p < 0.05) . Plasma ionized Ca2+ was decreased in septic compared with that in sham rats: 4.9 +/- 0.9 and 5.6 +/- 0.01 mg/dl, respectively (p < 0.05) . CaCl2 improved both systolic and diastolic function and there was no evidence of adverse effects of Ca2+ even at supraphysiologic levels . Surprisingly, correction of decreased afterload in septic rats, using the pure alpha-agonist phenylephrine, caused normalization of all indices of cardiac contractility, indicating that the presumed decrease in cardiac function was due entirely to an effect of the decreased afterload to "unload" the left ventricle . We conclude that Ca2+ administration is not detrimental to cardiac function in the rat CLP model . Although the rat CLP model is widely utilized and reproduces many of the clinical hallmarks of sepsis, it does not cause intrinsic myocardial depression and, therefore, it may not be an appropriate model to investigate the clinical cardiac dysfunction that occurs in patients with sepsis.

Am J Physiol, 1998 Dec, 275(6 Pt 2), R1983 - 91
Sepsis in mice stimulates muscle proteolysis in the absence of IL-6; Williams A et al.; We tested the role of interleukin-6 (IL-6) in sepsis-induced muscle proteolysis by determining ubiquitin mRNA levels and protein breakdown rates in incubated extensor digitorum longus muscles from septic and sham-operated IL-6 knockout and wild-type mice . In addition, the effect of treatment of mice with human recombinant IL-6 on muscle protein breakdown rates was determined . Finally, protein breakdown rates were measured in myotubes treated for up to 48 h with different concentrations of IL-6 . Sepsis in wild-type mice resulted in an approximately ninefold increase in plasma IL-6 levels, whereas IL-6 was not detectable in plasma of sham-operated or septic IL-6 knockout mice . Total and myofibrillar muscle protein breakdown rates were increased by approximately 30% and threefold, respectively, in septic IL-6 wild-type mice with an almost identical response noted in septic IL-6 knockout mice . Ubiquitin mRNA levels determined by dot blot analysis were increased during sepsis in muscles from both IL-6 knockout and wild-type mice, although the increase was less pronounced in IL-6 knockout than in wild-type mice . Treatment of normal mice or of cultured L6 myotubes with IL-6 did not influence protein breakdown rates . The present results suggest that IL-6 does not regulate muscle proteolysis during sepsis.

Am J Physiol, 1998 Dec, 275(6 Pt 1), G1423 - 9
Intrahepatic STAT-3 activation and acute phase gene expression predict outcome after CLP sepsis in the rat; Andrejko KM et al.; Interleukin-6 (IL-6) regulates hepatic acute phase responses by activating the transcription factor signal transducer and activator of transcription (STAT)-3 . IL-6 also may modulate septic pathophysiology . We hypothesize that 1) STAT-3 activation and transcription of alpha2-macroglobulin (A2M) correlate with recovery from sepsis and 2) STAT-3 activation and A2M transcription reflect intrahepatic and not serum IL-6 . Nonlethal sepsis was induced in rats by single puncture cecal ligation and puncture (CLP) and lethal sepsis via double-puncture CLP . STAT-3 activation and A2M transcription were detected at 3-72 h and intrahepatic IL-6 at 24-72 h following single-puncture CLP . All were detected only at 3-16 h following double-puncture CLP and at lower levels than following single-puncture CLP . Loss of serum and intrahepatic IL-6 activity after double-puncture CLP correlated with mortality . Neither intrahepatic nor serum IL-6 levels correlated with intrahepatic IL-6 activity . STAT-3 activation following single-puncture CLP inversely correlated with altered transcription of gluconeogenic, ketogenic, and ureagenic genes . IL-6 may have both beneficial and detrimental effects in sepsis . Fulminant sepsis may decrease the ability of hepatocytes to respond to IL-6.

J Infect Dis, 1999 Jan, 179(1), 136 - 41
Detection of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta during experimental endotoxemia and human sepsis; O'Grady NP et al.; Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta regulate leukocyte activation and trafficking . To assess the role of MIP-1alpha and MIP-1beta in human inflammation, healthy subjects were studied during experimental endotoxemia with prior administration of ibuprofen, a cyclooxygenase inhibitor, or dimeric p75 tumor necrosis factor (TNF)-alpha receptor, a TNF antagonist; septic patients were also studied . Following endotoxin, blood levels of both MIP-1 molecules rose acutely and fell to baseline by 6 h (P= . 001) . While MIP-1 mediates fever in animals independent of cyclooxygenase blockade, in subjects given endotoxin and ibuprofen, MIP-1 levels increased and fever was suppressed . MIP-1 levels were not diminished by inhibiting circulating TNF-alpha in humans . In septic patients, elevated levels of MIP-1alpha and MIP-1beta were detected within 24 h of sepsis and fell in parallel with TNF-alpha and interleukin-6 (P<.01) . MIP-1alpha and MIP-1beta increase during acute inflammation but are not associated with fever in endotoxemic humans during cyclooxygenase blockade.

Thromb Haemost, 1998 Nov, 80(5), 816 - 21
Recombinant antitrypsin Pittsburgh undergoes proteolytic cleavage during E . coli sepsis and fails to prevent the associated coagulopathy in a primate model; Harper PL et al.; During severe sepsis there is dramatic activation of both contact proteases and the coagulation pathway . These processes contribute to the development of shock and disseminated intravascular coagulation (DIC) respectively . The Pittsburgh mutant of antitrypsin (358Met-Arg) is a novel protease inhibitor with activity against both thrombin and the contact proteases and should therefore prove beneficial as a therapeutic agent in the management of septic shock . This hypothesis was supported by an earlier study in a pig model where recombinant antitrypsin Pittsburgh (rAT Pittsburgh) at a concentration of 1 microM alleviated some of the features of shock, but did not improve survival . In order to reduce the lethal effects of E . coli sepsis we postulated that a higher concentration of antitrypsin Pittsburgh would be necessary . To test this hypothesis we used rAT Pittsburgh in a primate model . This was chosen in preference to another species as E . coli sepsis in the primate has been well characterised and closely resembles the changes seen in man . Surprisingly this treatment did not alleviate the features of shock and unexpectedly appeared to exacerbate the associated coagulopathy . We propose two possible mechanisms for this unforeseen outcome . The first results from the broad spectrum of activity of antitrypsin Pittsburgh . As well as inhibiting thrombin and the contact proteases, the Pittsburgh mutant also inhibits activated protein C . Inhibition of the protein C system is known to exacerbate septic shock . Secondly, a significant quantity of inactive antitrypsin Pittsburgh, cleaved at the reactive centre, was detected in the plasma of the treated animals . Proteolytically altered serpins, including antitrypsin . have been shown to enhance the inflammatory process . Therefore the accumulation of cleaved rAT Pittsburgh might be expected to exacerbate septic shock.

Intensive Care Med, 1998 Oct, 24(10), 1052 - 6
C-reactive protein as an indicator of sepsis; Povoa P et al.; OBJECTIVE: To determine the use of plasma C-reactive protein (CRP) concentrations, body temperature (BT) and white blood cell count (WBC) in the detection of sepsis in critically ill patients . DESIGN: All patients admitted for more than 24 h in the intensive care unit (ICU) were prospectively included . Patients were followed up to ICU discharge and each patient-day was classified in one of four categories according to the infectious status: 1) Negative, patient-day without systemic inflammatory response syndrome (SIRS); 2) Definite, patient-day with SIRS and a positive culture; 3) SIRS, patient-day with SIRS and negative or no cultures . The last group was subdivided according to the following criteria: a) new, or persistence of, pulmonary infiltrates, b) the presence of pus in a place known to be sterile . Patient-days without these criteria were classified as SIRS with improbable sepsis (Unlikely), and with one criteria or more as SIRS with probable sepsis (Probable) . SETTING: Medical/surgical intensive care unit . PATIENTS: Twenty-three patients were followed . MEASUREMENTS AND RESULTS: A total of 306 patient-days were analysed: 20 Negative, 15 Definite, 63 Unlikely and 208 Probable . The median (range) CRP values for Negative, Unlikely, Probable and Definite groups were as follows: 24.5 (7-86), 34 (5-107), 143 (39-544), and 148 (52-320) mg/l . The plasma CRP levels were significantly related to the infectious status (Negative, Unlikely, Probable or Definite) of the patient-day classification (p < 0.05) . Concentrations of CRP in the Negative and Unlikely groups were significantly lower than in the Probable and Definite ones (p < 0.05) . A plasma CRP of 50 mg/l or more was highly suggestive of sepsis (sensitivity 98.5%, specificity 75%) . CONCLUSIONS: Daily measurement of CRP is useful in the detection of sepsis and it is more sensitive than the currently used markers, such as BT and WBC.

Kaohsiung J Med Sci, 1998 Nov, 14(11), 664 - 72
Heat shock treatment decreases the mortality of sepsis in rats; Yang RC et al.; Sepsis is an increasingly common and lethal diagnosis in hospitalized patients . In spite of the advances in antibiotics and medical equipment, the mortality rate has not been improved in the last decade . Recently, heat shock proteins (Hsps) have been well documented to play a self-protective role in almost all living cells under various pathological and physiological stresses through a mechanism known as thermotolerance or cross tolerance . The present study was designed to investigate the expression of Hsp72 and the protective role of pre-induction of Hsps in the mortality during different phases of sepsis . Adult male Sprague-Dawley rats were employed in the study . Sepsis was induced by cecal ligation and puncture (CLP) . Heat shock treatment was performed 16 hrs before sepsis induction by heating the rats whole-bodily with an electric heating pad under general anesthesia . The mortality rates with time in both control and preheated groups were monitored . Hsp72 was detected by SDS-PAGE, Western blotting and immunostaining in the brain, heart, liver, kidney, lung, adrenal gland, muscle and lymphocytes . The results show that both early (9 hrs post-CLP) and late (18 hrs post-CLP) sepsis failed to increase the synthesis of Hsp72 . Previous induction of Hsps by heat shock treatment significantly decreased the mortality rate of late sepsis . Applying a sufficient inducer to lymphocytes of late sepsis reversed the synthesis of Hsp72 from inactive state into an over-expressive situation in vitro . These results suggest that Hsps are involved in the pathogenesis of sepsis and the involvement of Hsps during the progression of sepsis could add to a first line of host defense against invasive pathogens . Searching for an acceptable agent or less invasive method that leads to increased Hsps expression may provide a means for better treatment of severe infection.

Anasthesiol Intensivmed Notfallmed Schmerzther, 1998 Oct, 33(10), 681 - 4
{Emphysematous pyelonephritis--a rare cause of sepsis}; Schaal M; A 66-year old female was admitted to our ICU in septic shock with accompanying signs of gastroenteritis and diabetic-related hyperglycemia . Computer tomography of the abdomen revealed the rare diagnosis of emphysematous pyelonephritis . Immediate nephrectomy led to a favourable outcome in this dramatic case . Although abscess drainage and broad-based antibiotic therapy are generally the first-line therapy today, emergency surgery would seem to be indicated in selected cases.

J Infect, 1998 Sep, 37(2), 194 - 6
Severe sepsis caused by Mobiluncus curtisii subsp . curtisii in a previously healthy female: case report and review; Hill DA et al.; We present the case of a 54-year-old female with life-threatening septicaemia due to Mobiluncus curtisii subsp . curtisii . Her admission was complicated by septic shock, renal failure, disseminated intravascular coagulation, the adult respiratory distress syndrome and spontaneous splenic rupture . The patient survived with full intensive care support and intravenous ceftriaxone . Extra-genital infection with Mobiluncus species is rarely diagnosed and has been confined to breast abscesses and non-life-threatening bacteraemia . A review of extra-genital infections with Mobiluncus species is presented.

Crit Care Med, 1998 Nov, 26(11), 1829 - 33
Diastolic filling in human severe sepsis: an echocardiographic study; Munt B et al.; OBJECTIVE: To determine if nonsurvivors have a more abnormal pattern of left ventricular relaxation than survivors with severe sepsis . DESIGN: Prospective, observational, cohort study . SETTING: Intensive care unit in a university-affiliated tertiary care hospital . PATIENTS: Twenty-four adults with severe sepsis . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Baseline clinical and hemodynamic variables, Acute Physiology and Chronic Health Evaluation (APACHE) II scores and Doppler echocardiographic mitral inflow pattern (analyzed for normalized peak early filling rate {E/VTI, systolic volumes/sec}, deceleration time {msec}, and early to atrial filling velocity ratio {E/A}) . There were seven deaths . The patients did not differ in baseline demographics, inotropic infusions, hemodynamic measurements or ventilatory settings or variables . Nonsurvivors had a more abnormal pattern of left ventricular relaxation (E/VTI, 4.7 {range 3.8 to 5.8} vs . 5.8 {range 3.8 to 8.9}, p= .04; deceleration time, 235 {range 209 to 367} vs . 182 {range 155 to 255}, p = .002) . E/A showed a nonsignificant trend in the same direction (0.9 {range 0.8 to 1.6} vs . 1.2 {range 0.7 to 1.9}, p = .12) . In a multivariate analysis, deceleration time (p< .004) and APACHE II score (p < .02) were the only independent predictors of mortality . CONCLUSION: Severe sepsis nonsurvivors have a more abnormal echocardiographic pattern of left ventricular relaxation than survivors.

Crit Care Med, 1998 Nov, 26(11), 1793 - 800
Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study . Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine; Vincent JL et al.; OBJECTIVE: To evaluate the use of the Sequential Organ Failure Assessment (SOFA) score in assessing the incidence and severity of organ dysfunction in critically ill patients . DESIGN: Prospective, multicenter study . SETTING: Forty intensive care units (ICUs) in 16 countries . PATIENTS: Patients admitted to the ICU in May 1995 (n = 1,449), excluding patients who underwent uncomplicated elective surgery with an ICU length of stay <48 hrs . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: The main outcome measures included incidence of dysfunction/failure of different organs and the relationship of this dysfunction with outcome . In this cohort of patients, the median length of ICU stay was 5 days, and the ICU mortality rate was 22% . Multiple organ dysfunction and high SOFA scores for any individual organ were associated with increased mortality . The presence of infection on admission (28.7% of patients) was associated with higher SOFA scores for each organ . The evaluation of a subgroup of 544 patients who stayed in the ICU for at least 1 wk showed that survivors and nonsurvivors followed a different course . This subgroup had greater respiratory, cardiovascular, and neurologic scores than the other patients . In this subgroup, the total SOFA score increased in 44% of the nonsurvivors but in only 20% of the survivors (p < .001) . Conversely, the total SOFA score decreased in 33% of the survivors compared with 21% of the nonsurvivors (p < .001) . CONCLUSIONS: The SOFA score is a simple, but effective method to describe organ dysfunction/failure in critically ill patients . Regular, repeated scoring enables patient condition and disease development to be monitored and better understood . The SOFA score may enable comparison between patients that would benefit clinical trials.

Clin Exp Immunol, 1998 Nov, 114(2), 220 - 7
Levels of soluble Fc gammaRIII correlate with disease severity in sepsis; Muller Kobold AC et al.; Neutrophil activation is thought to play a crucial role in the pathogenesis of sepsis . During activation, neutrophils adhere to and migrate through the endothelium . Therefore, the amount of circulating neutrophils does not adequately reflect the total amount of neutrophils that are involved in the pathophysiologic process of this condition . In this study we test the hypothesis that the severity of sepsis is associated with the total body mass of neutrophils as reflected in the plasma concentration of soluble Fc gamma receptor type III (sFc gammaRIII) . Nineteen patients with sepsis (12 male, seven female, median age of 69 years, range 29-87 years) were included in this study . Ten healthy volunteers served as controls . Plasma sFc gammaRIII concentrations were measured by ELISA . Other parameters that were studied were leucocyte count, plasma concentrations of lactoferrin and soluble L-selectin, and surface expression of CD11b and CD66b on circulating neutrophils . Disease activity was measured using the Acute Physiology and Chronic Health Evaluation (APACHE) II score . Soluble Fc gammaRIII levels were elevated in sepsis patients whereas soluble L-selectin levels were moderately decreased compared with healthy controls . Markers of cell activation were significantly increased in sepsis patients . Soluble Fc gammaRIII correlated with disease severity as measured by the APACHE score (P<0.05, r=0.53), whereas the other parameters did not correlate with the APACHE score . In conclusion, this study demonstrates that soluble Fc gammaRIII is a useful marker for disease severity in patients with sepsis.

Scand J Immunol, 1998 Nov, 48(5), 509 - 14
Anti-TNF treatment of baboons with sepsis reduces TNF-alpha, IL-6 and IL-8, but not the degree of complement activation; Bengtsson A et al.; The activation of complement and the release of TNF-alpha, IL-6 and IL-8 are important pathogenic factors behind organ dysfunction in sepsis . The aim of this study was to determine whether infusion of anti-TNF antibodies alters complement activation and plasma concentrations of pro-inflammatory cytokines at high doses of Escherichia coli . Six baboons received intravenously 2 x 10(9) live E . coli bacteria per kg body weight (group 1), in addition five received pretreatment with 1 mg per kg body weight anti-TNF antibodies (group 2), and seven received 5 x 10(8) live E . coli bacteria per kg body weight (group 3) . Two hours after the start of infusion of the bacteria, plasma concentrations of C3 activation products, C5a and the terminal SC5b-9 complement complex were increased in groups 1 and 2 (P < 0.05), but there was no significant difference between the groups . At 2 h the levels of TNF-alpha, IL-6 and IL-8 were lower in group 2 compared with group 1 (P<0.05) . In group 2 compared with group 1 the TNF-alpha concentrations were, however, higher at 4, 8 and 24 h . The explanation for this phenomenon is probably that TNF-alpha binds to the anti-TNF antibody complex and is released slowly after it has been bound . The study showed that infusion of anti-TNF antibodies reduced the concentrations of TNF-alpha, IL-6 and IL-8, without any detectable influence on complement activation.

Arch Surg, 1998 Nov, 133(11), 1213 - 20
Is Fas ligand or endotoxin responsible for mucosal lymphocyte apoptosis in sepsis?
Chung CS, Xu YX, Wang W, Chaudry IH, Ayala A.
BACKGROUND: Apoptosis (Ao) is a normal constitutive process that seems to have pathological effects in diseases of immune deficiency and autoimmune disorders, as well as in certain lymphoid tissues during sepsis . Little is known about this process in mucosal lymphoid tissue, such as intestinal intraepithelial lymphocytes (IELs) . OBJECTIVES: To determine whether sepsis induces increased Ao in small intestinal IEL, whether this was associated with functional changes in cytokine gene expression in the IEL, and which mediators control this process and their impact on the survival of the mouse with sepsis . DESIGN: Male C3H/HeN (endotoxin-sensitive), C3H/HeJ (endotoxin-tolerant), and C3H/HeJ-FasLgld (endotoxin-tolerant/Fas ligand {FasL}-deficient) mice were subjected to sepsis (cecal ligation and puncture {CLP}) and IELs were harvested at 4 (early) or 24 hours (late sepsis) . Alterations in the cell phenotype and Ao (TUNEL {terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling} assay) were determined by 3-color flow cytometry . Cytokine gene expression was assessed by multiprobe RNase protection assay . RESULTS: At 4 hours after CLP, only the frequency of IEL which was CD8+ decreased markedly . By 24 hours after CLP, the number of CD8+ and CD4+ cells decreased while the proportion of double-negative cells showed a marked increase when compared with sham-controls . The percentage of Ao positive in CD8+ and CD4+ double-positive and double-negative cells increased markedly 24 hours after CLP concomitant with a significant (P<.05 vs sham-controls, Mann-Whitney U test) increase in expression of the IL-2, IL-10, and IL-15 gene . These data collectively suggest that sepsis causes lymphocyte activation-induced Ao that may be mediated by FasL . Additional studies were done to determine if the increased Ao was due to either endotoxin or FasL . The results of studies with endotoxin-tolerant C3H/HeJ or FasL-deficient C3H/HeJ-FasLgld mice showed an increase in A,, in CD4+ and CD8+ cells from septic C3H/HeJ but not C3H/HeJ-FasLgld mice . With regard to septic mortality, our results indicated that there was a marked reduction in mortality in C3H/HeJ-FasLgld vs C3H/HeJ mice . CONCLUSIONS: We conclude that the phenotypic changes associated with increased Ao may be a reflection of localized immune cell activation due to a FasL-mediated process and not endotoxin . Thus, FasL directly and/or indirectly contributes to higher septic mortality.

Arch Surg, 1998 Nov, 133(11), 1200 - 5
Gender differences in human sepsis; Schroder J et al.; BACKGROUND: In animal studies, gender differences were related to hormonal and immunologic changes that were associated with an increased susceptibility to sepsis in males . OBJECTIVE: In a prospective study, gender differences in patients with surgical sepsis were evaluated in terms of survival, sex hormones, and proinflammatory as well as anti-inflammatory mediators . SETTING: Surgical intensive care unit of a university hospital . PATIENTS: Fifty-two patients (19 women and 33 men) with surgical sepsis . MEASUREMENTS AND MAIN RESULTS: In a prospective study, tumor necrosis factor alpha and interleukin 6 bioactivity and plasma levels of interleukin 10 (using enzyme-linked immunosorbent assay), total testosterone, and 17-beta estradiol (using radioimmunoassay) were determined on days 1, 3, 5, 7, 10, and 14 after diagnosis of sepsis . There were no differences in characteristics of patients in age (mean age, 55.4 years for women and 53.1 years for men) or cause and severity of sepsis (Acute Physiology and Chronic Health Evaluation II score, 17.3 for women and 18.5 for men; multiple organ dysfunction score, 9.9 vs 10.8, respectively) . Although no difference could be found in the multiple organ dysfunction score from day 1 to day 28, the prognosis of sepsis was significantly different in women compared with men . Hospital-mortality rate was 70% (23 of 33 patients) in male and 26% (5 of 19) in female patients (P<.008, log-rank test) . Bioactivity of tumor necrosis factor continuously increased in men after diagnosis of sepsis, with significantly elevated levels on day 10 (P<.05, Mann-Whitney U test with Bonferroni correction), whereas no difference was found for interleukin 6 bioactivity . Women displayed enhanced interleukin 10 levels compared with men from day 1 to day 10 that reached a significant difference on days 3 and 5 (P<.05) . Total testosterone levels were below the normal range for men, and estradiol levels were initially increased in both men and postmenopausal women, with higher levels for women . CONCLUSIONS: In this prospective study, gender differences were confirmed in human sepsis, with a significantly better prognosis for women, which may be related to increased levels of anti-inflammatory mediators . The hypothetical different ratio of proinflammatory and anti-inflammatory mediators may be important for further therapeutic interventions in sepsis.

Am J Respir Crit Care Med, 1998 Nov, 158(5 Pt 1), 1656 - 63
Diaphragm sarcolemmal injury is induced by sepsis and alleviated by nitric oxide synthase inhibition; Lin MC et al.; Endotoxemia is associated with impaired diaphragm contractility, and increased nitric oxide (NO) production has recently been implicated in this phenomenon . However, the precise nature of sepsis-related alterations in diaphragm myofiber function remains unclear . We tested the hypothesis that enhanced NO synthesis during sepsis produces diaphragm sarcolemmal injury with attendant abnormalities of myofiber membrane electrophysiology . Two different rat sepsis models were employed: acute (4 h) intraarterial endotoxin (LPS; 20 mg/kg) and subacute (24 h) peritonitis induced by cecal ligation and perforation (CLP) . Diaphragm damage occurred after both LPS and CLP, as indicated by hyperpermeability of myofibers to a low molecular weight tracer dye, which is normally unable to penetrate the sarcolemma . Sarcolemmal injury was significantly correlated with reductions in the resting membrane potential (Em) of single diaphragm myofibers . Western analysis revealed increased diaphragmatic expression of the inducible isoform of NO synthase (iNOS) after LPS and CLP . An inhibitor of NOS activity, LNMMA, significantly decreased morphologic as well as electrophysiologic signs of myofiber membrane injury and dysfunction . Therefore, we conclude that both acute endotoxemia and subacute peritonitis models of sepsis lead to significant sarcolemmal damage and altered Em in diaphragm myofibers . These changes appear to be mediated, at least in part, through the pathway of increased nitric oxide production.

J Intraven Nurs, 1998 Sep-Oct, 21(5), 275 - 81
Treatment of sepsis in the neonate; Sater KJ; Sepsis is a complication that can present during the neonatal period . Diagnosis and treatment of the septic newborn presents clinical and psychosocial challenges for the healthcare team, family, and reimbursement source . The challenges associated with the identification and treatment of neonatal sepsis are explored.

Sheng Li Xue Bao, 1997 Apr, 49(2), 191 - 6
{Changes of calcium transport in rat liver nuclei during sepsis}; Wang PY et al.; Calcium transport changes in rat liver nuclei were observed on the model of early sepsis (9 h after operation of cecal ligation and puncture) . Calcium content in hepatocytes and nuclei were significantly increased by 20% and 36% respectively (P < 0.05) during sepsis . The activity of Ca(2+)-ATPase in hepatocytic nuclei was increased by 94% (P < 0.01) and 45Ca2+ transport accelerated by 32% (P < 0.01) . There was a positive correlation between nuclear 45Ca2+ transport and nuclear Ca(2+)-ATPase activity (r = 0.914, P < 0.01) . Calmodulin stimulated the activity of nuclear Ca(2+)-ATPase and 45Ca2+ transport; while calmodulin inhibitor trifluoperazine exerted an opposite effect . The above results suggest that liver nuclear calcium transport is strengthened during early sepsis as a result of changes of Ca(2+)-ATPase activity.

Horm Metab Res, 1998 Sep, 30(9), 570 - 4
Dissociation of ACTH, beta-endorphin and cortisol in graded sepsis; Legakis I et al.; The function of the hypothalamic-pituitary-adrenal axis as related to the degree of severity of a septic process was assessed by measuring plasma levels of beta-endorphin, ACTH and cortisol . Sixty-one cases of postoperative patients treated at the intensive care unit were classified into four groups according to the severity of infection: Group 1 (control) included patients who did not show any sign of infection, group 2 patients with sepsis, group 3 patients with septic syndrome and group 4 patients with septic shock . Compared to G1 patients' ACTH values (4.16+/-2.6pg/ml), a statistically significant increase in ACTH values in various stages of septicemia (p < 0.005) with a noticeable difference also between G3 (7.11 +/-3.7pg/ml) and G4 (11.5+/-6.6pg/ml) (p<0.05) was found . Differences were also observed in beta-endorphin (with a level of significance between the several groups of p = 0.0001) . Also, beta-endorphin values in G4 (40.6+/-30.3 pg/ml) differed significantly from each of G1 (17.5 +/-6.6 pg/ml), G2 (21.1+/-11.3 pg/ml) and G3 (23.5+/-12 pg/ ml) (p<0.05) . A progressive hypercortisolemia was obvious, with values of G4 (37.2+/-15.6 microg/dl) differing significantly from those of G1 (18+/-4.6microg/dl) and G2 (24-/+8.4microg/dl) (p<0.05) and of G3 (28.5+/-12.3 microg/dl) from that of G1 (p < 0.05) . Interestingly, a dissociation of ACTH, beta-endorphin and cortisol was observed, in that the increased values of beta-endorphin and cortisol, detected in the G3 were not associated with a parallel increase in ACTH . These findings might be interpreted in the sense of an impairment of the stress stimulation of the hypothalamic pituitary adrenal axis . Provided that such a situation can be lethal, our results further confirm the idea that a low-dose, steroid replacement might be beneficial to critical illness.

Early Hum Dev, 1998 Oct, 52(3), 251 - 61
Increased serum concentrations of soluble tumor necrosis factor receptors p55 and p75 in early onset neonatal sepsis; Doellner H et al.; Sepsis and pneumonia are major causes of morbidity and mortality in the neonatal period . The symptoms are variable and unspecific . So far, no reliable diagnostic test for neonatal infection has been found . In this study we measured serum levels of soluble tumor necrosis factor receptors (sTNFR) p55 and p75 in non-infected and infected neonates, and evaluated the diagnostic value of these mediators as tests for early detection of neonates with sepsis or pneumonia . Blood was collected on admission and after 3-4 days from 161 neonates consecutively admitted to the Neonatal Intensive Care Unit (NICU) during the first week of life . Twenty two neonates suffered from infection and 127 were classified as non-infected (controls) . Samples were analyzed for p55 and p75, C-reactive protein (CRP) and white blood cell count with differential . Both preterm and term infected neonates had initially higher concentrations of p55 (both p <0.01) and p75 (p = 0.01 and p = 0.05, respectively) than controls . In non-infected neonates p55 levels decreased in the perinatal period, whereas p75 levels remained stable . Levels of both p55 and p75 decreased in neonates with infection during the perinatal period . CRP was a more specific parameter than p55 and p75 (CRP: 97%, p55: 65% and p75: 75%) whereas the sensitivity of all three parameters was at similar levels (CRP: 59%, p55: 70% and p75: 67%) . We conclude that assessment of sTNFR may not improve accuracy in the diagnosis of early onset neonatal sepsis compared to the use of CRP.

Clin Exp Pharmacol Physiol, 1998 Nov, 25(11), 951 - 4
Myocardial dysfunction in sepsis; Piper RD; 1 . Sepsis is the leading reversible cause of death in patients requiring modern intensive care services . 2 . In this group of patients, death usually results from progressive multiple organ failure, rather than overwhelming primary infection . 3 . The pathophysiology of sepsis-induced remote organ dysfunction is incompletely understood, although it is believed to result from a systemic inflammatory process that causes tissue injury in the absence of septic shock . 4 . As septic shock is the most common early manifestation of severe sepsis, an understanding of mechanisms of myocardial dysfunction is of clinical relevance . In the present review, we will discuss mechanisms of remote organ failure in sepsis, focusing in particular on the pathogenesis of myocardial dysfunction.

Pharmacol Res, 1998 Nov, 38(5), 405 - 11
Effects of nitric oxide synthase inhibition in lipopolysaccharide-induced sepsis in mice; Tunctan B et al.; In the present study, we have investigated the effects of nitric oxide (NO) synthase inhibition on mortality in lipopolysaccharide (LPS)-induced sepsis in mice . Serum nitrite levels peaked at 15 h after an injection of LPS (10 mg kg-1, i.p.) . Aminoguanidine, a selective inducible NO synthase (iNOS) inhibitor, at a dose of 100 mg kg-1 significantly reduced the LPS-induced increase in nitrite levels and improved mortality . Econazole, iNOS inhibitor, calmodulin antagonist, 5-lipoxygenase and a specific thromboxane synthase inhibitor, at a 1 mg kg-1 dose significantly decreased the LPS-induced increase in nitrite levels, but increased mortality 4 . 9-fold when compared to the LPS group (control) . Indomethacin, a putative iNOS and non-selective cyclo-oxygenase (COX) inhibitor, of 1, 10 and 100 mg kg-1, dose dependently decreased the LPS-induced increase in nitrite levels . This decrease was significantly different from the control at 10 and 100 mg kg-1 dose levels . When indomethacin (100 mg kg-1) was combined with aminoguanidine (100 mg kg-1), LPS-induced nitrite levels were significantly attenuated . NO precursor, L-arginine, was added to this combination in order to test the inhibition of iNOS activity which resulted in no change in nitrite levels . An indomethacin and aminoguanidine combination increased mortality twofold when compared to the control . The addition of L-arginine to the combination enhanced the mortality rate to 1.5-fold . These results suggest that NO appears to play a role in the LPS-induced septic shock model in mice . The improvement in sepsis-induced mortality enhanced by aminoguanidine by the inhibition of iNOS but not with the other agents or combinations should be re-evaluated in order to make an appropriate choice of the therapeutic target . In addition, it may also suggest that other mediators, such as arachidonic acid products and cytokines play a role in septic shock pathogenesis as well . (c) 1998 The Italian Pharmacological Society.

J Appl Physiol, 1998 Nov, 85(5), 1693 - 701
Histamine H3 activation depresses cardiac function in experimental sepsis; Li X et al.; In the heart, histamine (H3) receptors may function as inhibitory presynaptic receptors that decrease adrenergic norepinephrine release in conditions of enhanced sympathetic neural activity . We hypothesized that H3-receptor blockade might improve cardiovascular function in sepsis . In a canine model of Escherichia coli sepsis, we found that H3-receptor blockade increased cardiac output (3.6 to 5.3 l/min, P < 0.05), systemic blood pressure (mean 76 to 96 mmHg, P < 0.05), and left ventricular contractility compared with pretreatment values . Plasma histamine concentrations increased modestly in the H3-blocker-sepsis group compared with values obtained in a nonsepsis-time-control group . In an in vitro preparation, histamine H3 activation could be identified under conditions of septic plasma . We conclude that activation of H3 receptors may contribute to cardiovascular collapse in sepsis.

Indian J Med Res, 1998 Sep, 108, 88 - 92
The effects of prostaglandin E2 indomethacin & Ginkgo biloba extract on resistance to experimental sepsis; Canturk NZ et al.; We investigated the effect of 16,16-dimethyl prostaglandin E2 indomethacin and Ginkgo biloba extract on the survival in two experimental sepsis models in rats due to administration of 1 x 10(7) cfu and 1 x 10(9) cfu Escherichia coli . Animals in each model were then randomly divided (10/group) into four groups, administered saline, indomethacin, G . biloba extract and prostaglandin E2 respectively . When compared, there was no significant difference in the survival period between the two sepsis models (P > 0.05) . The best survival rate was observed in the PGE2-administered animals in the first major model (P < 0.05) . Indomethacin appeared not to decrease the mortality rates . There was no significant difference in PGE2 levels between two sepsis models (P > 0.05) . Our results suggest that elevated prostaglandin E2 levels following major trauma are not responsible for the postinjury increased susceptibility to infectious complications . Our observations should also discourage aggressive use of cyclo-oxygenase inhibitors for protection against infectious complications after major trauma.

Diabet Med, 1998 Oct, 15(10), 858 - 62
Serious hand sepsis and diabetes mellitus: specific tropical syndrome with western counterparts; Gill GV et al.; Infection in the extremities of diabetic patients most commonly involves the feet and, at least in western societies, is often associated with chronic complications of diabetes . Severe hand infection, often culminating in amputation and even death, is, however, well-described in tropical countries, where it may not be associated with any evidence of neuropathy or arterial insufficiency . Similar cases are described in the western literature but are more often associated with more severe antecedent trauma . The literature describing hand sepsis in diabetic patients both in tropical and in western practice is reviewed and we draw some conclusions about pathogenesis and treatment from the literature and from original data documenting the varying experience of hand sepsis in diabetic practice throughout Africa.

Int J Clin Pract Suppl, 1998 Jun, 95, 44 - 8
Sepsis: definitions and diagnosis; Karzai W et al.; There have been many attempts to provide a uniform definition for the diagnosis of sepsis that can be used for research and clinical purposes . Several definitions are too broad and, as a result, clinicians are unable to direct appropriate therapies to patients . Disappointing immunomodulatory trials have led many researchers to the conclusion that the current diagnostic criteria of sepsis fails to identify patients who could benefit from immunomodulatory therapies . In order to restore clinical and experimental relevance, many researchers and clinicians believe that sepsis should be defined as an inflammatory response to infection with signs of remote organ dysfunction . However, because common clinical signs of systemic inflammation are neither specific nor sensitive for sepsis, other markers may be helpful . Markers of the systemic inflammatory response to infection could include cytokines such as tumour necrosis factor alpha, interleukin 1, 6 and 8 and the propeptide procalcitonin . As well as identifying patients who may benefit from pro- or anti-inflammatory therapies, these markers may gauge the extent of the inflammatory response and could be used for monitoring the immune status of the patient.

Pediatrics, 1998 Nov, 102(5), 1107 - 11
Preliminary report: rhG-CSF may reduce the incidence of neonatal sepsis in prolonged preeclampsia-associated neutropenia; Kocherlakota P et al.; OBJECTIVES: To determine whether adjunctive therapy with recombinant human granulocyte colony-stimulating factor (rhG-CSF) could reverse the neutropenia and reduce the incidence of sepsis (</=28 days postnatal age) in neonates with prolonged preeclampsia-associated neutropenia compared with conventional therapy . STUDY DESIGN: An intravenous infusion of rhG-CSF (10 microgram/kg/day x 3 days for 10 neonates or 5 microgram/kg/day x 3 days for 5 neonates) was administered to ventilated patients with prolonged (>/=3 consecutive days in the first postnatal week) preeclampsia-associated neutropenia (absolute neutrophil count {ANC} <1500/mm3) . Neutrophilic responses and the incidence of neonatal sepsis in the next 28 postnatal days were compared with 13 case-matched control neonates who also had prolonged preeclampsia-associated neutropenia . Sepsis was defined as at least one positive blood culture in a newly symptomatic neonate treated with antibiotics for >/=7 days . RESULTS: No significant differences existed among the three groups in the birth weight, gestational age, sex, growth retardation, method of delivery, magnitude of respiratory support, use of surfactant, usage of intravascular catheters, or in the initial (pretreatment) ANC . The average baseline ANC (pretreatment) in the 10 microgram rhG-CSF group was 815 +/- 169/mm3 (mean +/- SEM), in the 5 microgram group it was 786 +/- 165/mm3, and in the conventional group it was 965 +/- 283 . Eighteen of 28 (64%) neonates with preeclampsia-associated neutropenia were neutropenic at birth, the other 10 (36%) had normal neutrophil counts at birth but subsequently developed >/=3 days of neutropenia between 24 and 120 hours after birth . The ANC increased by 2-fold at 24 hours, by 4-fold at 72 hours, and 14-fold by the 7th day in the 10-microgram group . In the 5-microgram group, a 2-fold and 5-fold increase occurred at 72 hours and 7 days, respectively . In the conventionally-treated group, only a 4-fold increase was seen as late as 7 days after achieving entry criteria . Sepsis was observed in 13% (2/15) of the rhG-CSF-treated neonates compared with an incidence of 54% (7/13) in the conventionally-treated neonates . Conclusions . rhG-CSF increases the ANC significantly (at 10 microgram/kg/day x 3 days) and reduces the incidence of neonatal sepsis in critically ill ventilated neonates with prolonged preeclampsia-associated neutropenia when compared with conventional therapy . A future prospective, randomized, and blinded trial is needed to validate the beneficial effects of prophylactic rhG-CSF therapy in neonates with prolonged preeclampsia-associated neutropenia.

Schweiz Med Wochenschr, 1998 Sep 26, 128(39), 1444 - 52
Myocardial dysfunction in sepsis: clinical and experimental investigations; Suffredini AF; OBJECTIVE: To review the clinical manifestations and mechanisms of cardiac dysfunction in septic shock . METHODS: Literature review of selected clinical studies and animal models . RESULTS: Depressed myocardial contractile function is a common consequence of severe infections . Bacterial factors, in conjunction with host inflammatory mediators, produce a profile of reversible cardiac dysfunction manifested by a decrease in ventricular ejection fraction, ventricular dilatation, and increased cardiac output . Global ischemia is not the major mechanism that mediates cardiac dysfunction during sepsis . Inflammatory mediators contribute to myocardial dysfunction by damaging the coronary microcirculation and contributing to myocardial edema and cardiocyte damage . However, trials of anti-inflammatory agents have not prevented or increased the rate of reversal of septic shock or improved survival . The link between nitric oxide and clinical myocardial depression remains unclear, as nonselective nitric oxide synthase inhibition does not block the development of ventricular dysfunction . CONCLUSIONS: Serious bacterial infections result in inflammatory injury to the heart manifested by a common profile of cardiac dysfunction . Therapy remains limited to treatment of the infection with antibiotics and supportive care, with fluid resuscitation and selective use of inotropes and vasopressors . Experimental models suggest that new anti-inflammatory strategies (e.g . tyrosine kinase inhibitors) may offer some advantages over those that target a single mediator; these agents remain to be clinically evaluated.

Am J Physiol, 1998 Nov, 275(5 Pt 2), R1412 - 9
Cytokine modulation by PX differently affects specific acute phase proteins during sepsis in rats; Voisin L et al.; To explore the regulation of the acute phase response in vivo, the effects of pentoxifylline (PX) treatment (100 mg/kg ip 1 h before infection) were investigated in infected and pair-fed rats 2 and 6 days after an intravenous injection of live bacteria (Escherichia coli) . PX treatment prevented the increase in plasma tumor necrosis factor (TNF)-alpha (peak 1.5 h after the infection) and resulted in an 84 and 61% inhibition of plasma interleukin (IL)-1beta and IL-6, respectively (peaks at 3 h) . Plasma corticosterone kinetics were not modified by the treatment . Infection increased alpha1-acid glycoprotein (AGP), alpha2-macroglobulin (A2M), and fibrinogen plasma concentrations and decreased albumin levels . PX significantly reduced AGP plasma concentration as early as day 2 in infected animals but reduced A2M and fibrinogen plasma levels only at day 6 . The treatment had no effect on the albumin plasma concentration . Hepatic AGP and fibrinogen mRNA levels increased in infected rats, whereas those of A2M were unchanged and those of albumin were decreased . Two days after infection, AGP and fibrinogen mRNA levels were reduced in treated infected animals . PX was ineffective in modifying those of A2M and albumin . These data demonstrate, in vivo, that different acute phase proteins are individually regulated in sepsis . The in vivo effects of PX treatment support the hypothesis that TNF-alpha plays an important role in the regulation of AGP production, whereas other factors seem to be involved in the regulation of A2M, fibrinogen, and albumin expression.

J Surg Res, 1998 Nov, 80(1), 75 - 9
Does neutrophil-mediated oxidative stress play any significant role in producing hepatocellular dysfunction during early sepsis?
Molnar RG, Wang P, Chaudry IH.
BACKGROUND: Although previous studies have indicated that hepatocellular dysfunction during early sepsis can be prevented by prior neutrophil depletion, it remains unknown whether the changes in hepatic oxidative stress induced by activated neutrophils are responsible for the salutary effect of neutropenia on hepatocellular function . MATERIALS AND METHODS: Neutropenia was induced in the rat by intravenous injection of immunoglobulins directly against rat neutrophils (anti-neutrophil Ig) at 16 and 2 h prior to the initiation of cecal ligation and puncture (CLP, i.e., an animal model of polymicrobial sepsis) or sham operation . Neutropenia was confirmed by peripheral blood smears . Neutrophil-competent control animals were given nonimmunized Ig prior to the onset of sepsis . Sham animals received anti-neutrophil Ig or control Ig . The levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) in the liver were determined at 5 h after CLP (i.e., the early, hyperdynamic stage of sepsis) or sham operation by high performance liquid chromatography . RESULTS: Although the levels of hepatic GSH and GSSG decreased significantly at 5 h after CLP, irrespective of neutropenia, the ratio of GSSG/GSH was not significantly altered under such conditions . The decrease in hepatic glutathione concentrations in septic animals may represent the decreased synthesis or increased efflux into the bile or circulation . CONCLUSION: Since neutrophil depletion did not significantly affect hepatic levels of GSH and GSSG as well as the GSSG/GSH ratio but prevented the occurrence of hepatocellular dysfunction, factors other than oxidative stress are likely to be the mechanism responsible for depressing hepatocellular function during the early, hyperdynamic stage of sepsis .

Lancet, 1998 Oct 17, 352(9136), 1271 - 7
Interleukin-1 receptor antagonist and interleukin-6 for early diagnosis of neonatal sepsis 2 days before clinical manifestation; Kuster H et al.; 9ACKGROUND: Neonatal sepsis is a common and life-threatening disorder, particularly among preterm infants . Early initiation of antibiotic therapy is frequently delayed because the first clinical signs of sepsis are non-specific and there are no reliable early laboratory indicators . We investigated the time course of expression and the prognostic power of the early inflammatory mediators interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), and circulating intercellular adhesion molecule-1 (cICAM-1) before clinical diagnosis of sepsis . METHODS: In a prospective multicentre study, we monitored 182 very-low-birthweight infants in six intensive-care units for occurrence of sepsis . During routine or clinically indicated blood sampling, an additional sample was collected for measurement of IL-1ra, IL-6, cICAM-1, and C-reactive protein (CRP) . Infants were grouped into those with proven sepsis, no infection, or unclassified . The mean study duration was 34 days . Whenever sepsis occurred, a study period of 10 days was defined: day 0 was the day of clinical diagnosis of sepsis; days -4 to -1 were the 4 days before diagnosis; days +1 to +5 were the 5 days after . We compared the concentrations of the immune mediators during the 10-day study period with group-specific baseline values from before day -4 . FINDINGS: 101 infants were included in the analysis: 21 with proven sepsis, 20 with no infection, and 60 unclassified . We excluded 57 because of incomplete datasets and 24 who had early-onset sepsis . IL-1ra and IL-6 increased significantly 2 days before diagnosis of sepsis; maximum median increases within the study period were 15-fold for IL-1ra and 12-fold for IL-6 . The diagnostic sensitivities of IL-1ra, IL-6, and CRP concentrations on day 0 of diagnosis were 93%, 86%, and 43%, respectively; corresponding values on day -1 were 64%, 57%, and 18% . The specificities of IL-1ra, IL-6, and CRP concentrations were 92%, 83%, and 93% . cICAM-1 had a specificity of only 64% . INTERPRETATION: IL-1ra and IL-6 are superior to cICAM-1 and CRP as predictors of sepsis 1 or more days before clinical diagnosis . Ad-hoc measurement of these cytokines could allow earlier initiation of antibiotic therapy with corresponding improvement in outcome in very-low-birthweight infants with sepsis.

Crit Care Med, 1998 Oct, 26(10), 1650 - 9
Effect of a chimeric antibody to tumor necrosis factor-alpha on cytokine and physiologic responses in patients with severe sepsis--a randomized, clinical trial; Clark MA et al.; OBJECTIVES: Tumor necrosis factor (TNF)-alpha appears central to the pathogenesis of severe sepsis, but aspects of the cytokine cascade and the link to physiologic responses are poorly defined . We hypothesized that a monoclonal antibody to TNF-alpha given early in the course of severe sepsis would modify the pattern of systemic cytokine release and, as a consequence, resuscitation fluid requirements, net proteolysis, and hypermetabolism would be reduced . DESIGN: Randomized, double-blind, placebo-controlled trial . SETTING: Critical Care Unit and University Department of Surgery in a single tertiary care center . PATIENTS: Fifty-six patients (from 92 eligible patients) with severe sepsis . Twenty-eight patients were randomized to treatment, and were comparable with the placebo group for age, gender, race, Acute Physiology and Chronic Health Evaluation II score, and site and type of infection . INTERVENTIONS: A 300-mg single dose of cA2 (a chimeric neutralizing antibody to TNF-alpha) was given intravenously within 12 hrs of the onset of severe sepsis . Standard surgical and intensive care therapy was otherwise delivered . MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of TNF-alpha, interleukin (IL)-1beta IL-6, IL-8, IL-10, soluble 75-kilodalton TNF-alpha receptor (sTNFR-75), and IL-1beta receptor antagonist (IL-1ra) were measured by sandwich enzyme-linked immunosorbent assay before cA2 infusion, 8 hrs later, and then daily for a minimum of 4 days . Sequential changes in total body protein, body water spaces, and resting energy expenditure over 21 days were measured, as soon as patients achieved hemodynamic stability, by in vivo neutron activation analysis, tritium and bromide dilution, and indirect calorimetry, respectively . Twenty-one patients died, ten having received cA2 . Suppression of measurable TNF-alpha was observed at 8 hrs with subsequent rebound by 24 hrs after cA2 treatment . The concentrations of other cytokines were high, were not reduced by intervention, and decreased logarithmically over 5 days . Both groups reached hemodynamic stability at similar times (57.5 +/- 11.8 hrs in controls vs . 58.6 +/- 9.2 hrs in the cA2 group) and following similar volumes of infused fluids (29.1 +/- 3.4 L vs . 28.9 +/- 4.4 L) . No differences in net proteolysis, resolution of body water expansion, or alteration in resting energy expenditure were demonstrated . CONCLUSION: A single dose of cA2 did not alter the overall pattern of cytokine activation or the profound derangements in physiologic function that accompany severe sepsis.

Rev Chir Orthop Reparatrice Appar Mot, 1998 Jul, 84(4), 358 - 62
{Importance of intertibio-peroneal graft in pseudoarthrosis of the leg at risk for sepsis . Apropos of 21 cases}; Moyikoua A et al.; PURPOSE: The purpose of our study was to analyze the use of intertibio-fibular bone grafting (I.T.F.G.) in non-union presenting a septic risk . MATERIAL AND METHODS: Twenty one non-unions of the tibial diaphysis presenting a septic risk were treated by intertibio-fibular bone grafting through a postero-lateral approach, over a seven year period (1988-1995) . There were 2 septic non-unions and 19 non-unions following open fractures, all treated initially by external fixation . Seventeen patients were male, four were female . Mean age was 33 years (range 19 to 70 years) . RESULTS: Healing was obtained in 20 cases, only one patient had a second bone grafting . Postoperative complications included two infections (one deep and one superficial) without consequences on bone healing . Functional results were good and excellent in 18 cases (85.7 per cent) . DISCUSSION-CONCLUSION: Our study showed that among techniques for the treatment of non-union presenting a septic risk, the I.T.F.G . is one of the most reliable, with low morbidity and low cost . The authors recommend this type of surgery particularly in developing countries.

Pediatr Res, 1998 Oct, 44(4), 469 - 77
Plasma levels and gene expression of granulocyte colony-stimulating factor, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, and soluble intercellular adhesion molecule-1 in neonatal early onset sepsis; Berner R et al.; Bacterial sepsis is still a leading cause of neonatal morbidity and mortality . Early onset sepsis in particular, presents with a different clinical course and involves other pathogens than sepsis later in life . In this study, plasma concentrations and mRNA expression of granulocyte colony-stimulating factor (G-CSF), tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, IL-8, and soluble intercellular adhesion molecule-1 (sICAM-1) of neonates with early onset sepsis were evaluated in cord blood and during the first days of life . Irrespective of prematurity, plasma levels of G-CSF, TNF-alpha, IL-1beta, IL-6, and IL-8, but not sICAM-1, were excessively elevated in septic neonates when compared with both healthy infants and infants with clinically suspected but not confirmed sepsis . Compared with the corresponding maternal levels, neonatal cytokine cord plasma levels were likewise highly elevated, indicating the endogenous cytokine production by the neonate . With the exception of TNF-alpha, mRNA expression in blood cells from septic infants was, however, not more frequently detectable than in those from nonseptic patients . Cytokine levels decreased significantly within the first days of life, whereas levels of sICAM-1 and C-reactive protein increased during the same time period . In summary, in contrast to C-reactive protein and sICAM-1, cord blood plasma levels, but not the presence of mRNA, of G-CSF, TNF-alpha, IL-1beta, IL-6, and IL-8 can predict neonatal early onset sepsis with a high sensitivity and specificity . Cell types other than blood cells are likely to contribute considerably to the high cytokine production in septic newborns.

J Vet Intern Med, 1998 Sep-Oct, 12(5), 317 - 24
The sepsis-coagulant axis: a review; Weiss DJ et al.; Activation of coagulation is a normal component of the acute inflammatory response . Inflammatory cytokines initiate coagulation events locally at sites of inflammation by converting endothelium from an antithrombotic surface to a prothrombotic surface; by stimulating tissue factor production, which activates both the extrinsic and intrinsic coagulation systems; and by stimulating production of platelet-activating factors . The fibrinolytic system is initially activated but is subsequently inhibited . This results in a marked imbalance in coagulation and fibrinolysis resulting in a net procoagulant state . When thrombin generation and platelet activation exceed the body's capacity to inactivate or remove these factors, disseminated intravascular coagulation (DIC) results . DIC directly contributes to multiple organ failure and death associated with sepsis . Presently available treatments (i.e., heparin and aspirin) are relatively ineffective in treating DIC; however, newer, more potent drugs may soon be available for clinical use.

J Drug Target, 1998, 5(5), 353 - 64
Distribution of free and liposomal cefoxitin in plasma and peritoneal fluid in a porcine intra-abdominal sepsis model; Shek PN et al.; The plasma and peritoneal fluid pharmacokinetic parameters obtained after the intravenous administration of free and liposomal cefoxitin were studied in a porcine model of intraabdominal sepsis . No prior assumptions were made to predict the number of compartments pertaining to drug clearance from the administration of either cefoxitin formulation . The experimental data obtained were applied to fit mathematical models of multiexponential drug clearance and the pharmacokinetic data were found to best fit a two-compartment open model . Liposomal encapsulation significantly altered the plasma drug distribution pattern resulting in changes in the magnitude of a number of pharmacokinetic parameters examined . The mean post-distributive half-life of liposomal cefoxitin was substantially longer than that of free cefoxitin by at least 3 times . The peritoneal cavity appeared to provide a reservoir for the initial distributive phase of rapid drug clearance from the plasma compartment followed by a less-rapid post-distributive phase . The cumulative drug level, as determined by the area under the concentration curve (AUC) as a function of time, in the plasma of animals treated with liposomal cefoxitin was about 3-4 fold as high as that of animals treated with free cefoxitin . The differences in pharmacokinetic parameters appeared to account for the improved therapeutic efficacy of liposomal cefoxitin in this animal model.

Clin Infect Dis, 1998 Sep, 27(3), 500 - 3
Total parenteral nutrition via multilumen catheters does not increase the risk of catheter-related sepsis: a randomized, prospective study; Ma TY et al.; The purpose of this study was to determine in a randomized, prospective manner whether administration of total parenteral nutrition (TPN) via multilumen catheters increases the risk of catheter-related sepsis (CRS) . All patients receiving hyperalimentation during a 24-month period were randomized to receive either a double-lumen catheter (DLC) or a triple-lumen catheter (TLC) . A total of 101 catheters were placed in 79 patients, of which 49 were DLCs and 52 were TLCs . The patients with DLCs received a total of 784 days of TPN, whereas patients with TLCs received a total of 754 days of TPN . CRS was associated with one (2.0%) of the 49 DLCs vs . one (1.9%) of the 52 TLCs . In comparison, the rate of CRS associated with single-lumen catheters (historical control) at our institution was 1.4% (P > .90) . We conclude that the use of multilumen catheters in TPN therapy does not result in an increased risk of CRS.

Biochim Biophys Acta, 1998 Sep 30, 1407(3), 225 - 33
Progressive internalization of beta-adrenoceptors in the rat liver during different phases of sepsis; Tang C et al.; Changes in the distribution of beta-adrenoceptors (beta ARs) in the plasma membrane and the light vesicle fractions of rat liver during different phases of sepsis were studied using {3H}dihydroalprenolol binding and photoaffinity labeling with {125I}iodocyanopindolol diazirine . Sepsis was induced by cecal ligation and puncture (CLP) . Septic rats exhibit an initial hypermetabolic (hyperglycemic) phase (9 h after CLP; early sepsis) followed by a hypometabolic (hypoglycemic) phase (18 h after CLP; late sepsis) . The radioligand studies show that in the plasma membranes, the density of beta ARs was decreased by 28-32% and 46-69% during the early and the late phases, respectively, of sepsis . In the light vesicles, the density of beta ARs was increased by 25-30% and 30-35% during the early and the late phases, respectively, of sepsis . The total number of the receptor binding sites (the sum of that in plasma membrane plus light vesicle) was decreased by 11-12% and 21-35% during the early and the late phases, respectively, of sepsis . These results indicate that beta ARs were progressively internalized from surface membranes to the intracellular sites and, furthermore, they were underexpressed in the rat liver during the progression of sepsis . Since hepatic glucose metabolism is known to be regulated by catecholamines, in part, through beta AR mediation, an internalization/underexpression of hepatic beta ARs may play a role in the altered glucose homeostasis during sepsis, particularly in the late hypometabolic phase of sepsis.

Clin Sci (Lond), 1998 Oct, 95(4), 459 - 65
Administration of albumin to patients with sepsis syndrome: a possible beneficial role in plasma thiol repletion; Quinlan GJ et al.; 1.Albumin is often administered intravenously to critically ill patients as a volume expander, to combat hypoalbuminaemia, and to decrease hyperbilirubinaemia . There is, however, an ongoing debate concerning the therapeutic benefit of the former which is an expensive form of treatment.2.Albumin has several biological functions, in particular as a ligand binder . It also acts as an extracellular transition metal ion-binding and radical-scavenging antioxidant . These functions are influenced by the presence of an exposed thiol group (cys 34) on the surface of the albumin molecule . 3.The ability of infused albumin to influence the plasma thiol pool, and hence antioxidant potential, was investigated in patients with sepsis syndrome.4.Plasma thiol levels rose rapidly after albumin infusion and remained elevated even after plasma albumin levels had declined significantly, due to interstitial leakage . Data are suggestive of some form of thiol exchange in the plasma of these patients between albumin and molecules containing oxidized thiol groups.5.Administration of albumin to patients with sepsis syndrome leads to a sustained increase in plasma thiols . Thiols have several important antioxidant functions, and thiol repletion in these patients, who are known to suffer from oxidative stress, may have beneficial antioxidant effects . Antioxidant repletion may represent an important facet of clinically administered albumin.

J Clin Endocrinol Metab, 1998 Sep, 83(9), 3296 - 301
Serum calcitonin precursors in sepsis and systemic inflammation; Whang KT et al.; High serum levels of the calcitonin (CT) prohormone, procalcitonin (pro-CT), and its component peptides occur in systemic inflammation and sepsis . Using two different assays, we undertook a prospective study to determine the utility of serum precalcitonin peptides (pre-CT) as markers in this condition . Twenty-nine patients meeting criteria for the systemic inflammatory response syndrome were studied daily in two intensive care units . Sera were collected, and APACHE II scores were determined until recovery or death . All patients had markedly elevated serum pre-CT . Prognostically, peak values were the most important . The highest values portended mortality, and a lower level could be ascertained below which all patients survived . Peak pre-CT levels were significantly higher in patients with infection documented by blood cultures than in those patients with no documented infection from any source (P < 0.05) . Mature CT remained normal or only moderately elevated . Compared with the serum pre-CT levels, receiver operating characteristic curve analysis revealed that the APACHE II scores, although more cumbersome, were better overall predictors of mortality . Thus, pre-CT is an important serum marker for systemic inflammatory response syndrome and is predictive of outcome . It also provides data concerning the presence of severe infection and may prove to be clinically useful for proactive patient care.

Chest, 1998 Sep, 114(3), 854 - 60
The hemodynamic derangements in sepsis: implications for treatment strategies; Marik PE et al.; The incidence of the sepsis syndrome has increased dramatically in the last few decades . During this time, we have gained new insights into the pathophysiologic mechanisms leading to organ dysfunction in this syndrome . Yet, despite this increased knowledge and the use of novel therapeutic approaches, the mortality associated with the sepsis syndrome has remained between 30% and 40% . Appropriate antibiotic selection and hemodynamic support remain the cornerstone of treatment of patients with sepsis . Recent studies have failed to demonstrate a global oxygen debt in patients with sepsis . Furthermore, therapy aimed at increasing systemic oxygen delivery has failed to consistently improve patient outcome . The primary aim of the initial phase of resuscitation is to restore an adequate tissue perfusion pressure . Aggressive volume resuscitation is considered the best initial therapy for the cardiovascular instability of sepsis . Vasoactive agents are required in patients who remain hemodynamically unstable or have evidence of tissue hypoxia after adequate volume resuscitation.

Anaesthesist, 1998 Jul, 47(7), 581 - 7
{Procalcitonin . A new diagnostic parameter for severe infections and sepsis}; Oberhoffer M et al.; Procalcitonin (PCT), a glycoprotein consisting of 116 amino acids, has been proposed as a new marker of severe infection . The site of production under this condition remains unknown . The serum PCT concentration is determined by an immunoluminometric assay of 40 microliters serum or plasma requiring approximately two hours . Elevations of PCT are for instance associated with levels of lipopolysaccharide and the cytokines TNF-alpha and IL-6 . Bacterial, parasitic or fungal infections developing septic complications in contrast to local infections, often show values exceeding 2 ng/ml . The specificity of the parameter in this context increases with its concentrations . Therapeutic actions that confine the infection locally are reflected by a decrease of the PCT value . PCT may be elevated within the first days after extended surgery or polytrauma, in some malignancies, heat-stroke and during treatment of some hematologic diseases without an existing sepsis or severe infection . Previous studies indicate certain benefits of PCT compared to traditional markers of inflammation or sepsis, where the ability to indicate a generalized infection is the primary advantage.

Biochim Biophys Acta, 1998 Sep 16, 1404(3), 377 - 84
Upregulation of Kupffer cell beta-adrenoceptors and cAMP levels during the late stage of sepsis; Hahn PY et al.; Although a burst of immunoresponsiveness may occur during the early stage of sepsis, late sepsis is characterized by severe immunodepression . In addition, although studies have shown that stimulation of macrophage beta-adrenoceptors results in an increase in cAMP and an associated reduction in macrophage phagocytic activity, it remains unknown whether Kupffer cell beta-adrenoceptor characteristics and cAMP levels are altered during polymicrobial sepsis . To study this, Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP) . At 5 h (i.e., the early stage of sepsis) or 20 h (late sepsis) after CLP or sham operation, the liver was perfused with collagenase solution and Kupffer cells were isolated . beta-Adrenoceptor characteristics of the isolated Kupffer cells were determined using {125I}iodopindolol, and basal levels of cAMP were measured by radioimmunoassay . The results indicate that while maximum binding capacity (Bmax) of Kupffer cell beta-adrenoceptors was not altered at 5 h, it increased significantly at 20 h after CLP . Similarly, basal levels of cAMP in Kupffer cells did not change at 5 h but increased markedly at 20 h after the onset of sepsis . In contrast, the dissociation constant (Kd, 1/affinity) of Kupffer cell beta-adrenoceptors was not significantly affected by sepsis at both 5 h and 20 h after CLP . Thus, upregulation of beta-adrenoceptors and increase in cAMP levels in Kupffer cells occur during the late stage of polymicrobial sepsis, and this may contribute to the depression of macrophage phagocytic function under such conditions.

Endocr Res, 1998 May, 24(2), 141 - 57
Effects of rhG-CSF on neutrophil functions and survival in sepsis induced diabetic rats; Canturk Z et al.; Diabetic patients are more prone to infection and evidence for an immunologic defect superimposed upon the metabolic abnormalities of diabetes is convincing . Neutrophils play a critical role in the host defense mechanism against various bacterial infections, and it is suggested that impaired neutrophil functions cause susceptibility to infections in diabetic patients . To explore the possibility that Granulocyte colony-stimulating factor (G-CSF) may be useful to prevent the morbidity and mortality caused by infections in diabetics . We studied the effect of G-CSF against septicemia in diabetic rats . Forty eight rats were divided into seven equal groups . The IInd, IVth-VIth groups were made diabetic by single intraperitoneal injection of streptozotocin . Fourth, VIth and VIIth groups were made septicemic by cecal ligation and perforation at the end of the second week of streptozotocin injection . G-CSF was subcutaneously injected into IIIrd, Vth and VIth groups . White blood cell count, neutrophil counts and function were determined . Rats in all groups were also observed for seven days for survival . White blood cells, neutrophil and lymphocyte counts and the neutrophil phagocytosis index decreased but neutrophil adherence rate was not different in diabetic group II (p<0.05) . All these variables were significantly diminished in diabetes and sepsis-induced group IV (p<0.05) . G-CSF injections improved all variables except neutrophil adherence . Cumulative survival ratio was better in G-CSF-injected group VI than in ceftriaxon-administrated group VII (p<0.05) . In conclusion, G-CSF increased neutrophil counts, developed neutrophil functions and improved survival . These results suggest that G-CSF may be useful as a drug to prevent bacterial infection in diabetic patients.

J Surg Res, 1998 Aug, 78(2), 108 - 17
Tumor necrosis factor binding protein improves incisional wound healing in sepsis; Maish GO 3rd et al.; BACKGROUND: Sepsis is associated with poor wound healing; however, the exact role of tumor necrosis factor (TNF) as a mediator of sepsis-induced alterations in different types of tissue repair is unknown . This study examines the effects of a specific TNF antagonist (TNFbp) on the healing of intestinal anastomoses, incisional wounds, and polyvinyl (PVA) sponge implants in chronic abdominal sepsis . METHODS: Three groups of male Sprague-Dawley rats were studied: control, sepsis, and sepsis + TNFbp . Jejunal resection and anastomosis were performed through a 4-cm upper midline incision on day 1 . On day 3, sepsis was induced by creation of a chronic abdominal abscess . Saline (0.1 ml) or TNFbp (1.0 mg/kg, 0.1 ml) was injected subcutaneously every day starting 4 h prior to sepsis . On day 7, the wound-breaking strength (WBS) of the skin incision and intestinal anastomoses was determined using a tensiometer . Wound histology and collagen deposition were evaluated by comparison of Sirius red-stained sections . The hydroxyproline content of PVA sponges was used to quantitate collagen content under the different experimental conditions . RESULTS: Septic mortality (20% vs 26%) was not significantly altered by TNFbp . Septic animals demonstrated a reduction in food consumption on days 3 to 5 that was not affected by TNFbp administration . Neither sepsis nor TNFbp altered the breaking strength or histologic appearance of intestinal anastomoses . However, the breaking strength of incisional wounds was decreased by 40% in septic rats (P < 0.001 vs controls) . Administration of TNFbp to septic rats significantly improved incisional WBS (P < 0.01 vs sepsis), but not to control levels . Serius red staining of incisional wounds and PVA sponges demonstrated a decrease in collagen organization and deposition in septic rats that was ameliorated by TNFbp . Similarly, the reduction in hydroxyproline content of PVA sponges from septic animals was prevented by TNFbp . CONCLUSIONS: The process of tissue repair in intestine and skin wounds appears to be significantly different following the septic insult . The healing of jejunal anastomoses was refractory to the catabolic effects of sepsis . In contrast, collagen deposition and organization are significantly decreased in cutaneous wounds during chronic sepsis . TNFbp significantly ameliorated the inhibitory effects of sepsis on cutaneous wound healing . These results suggest that TNF is an important mediator of the decrease in collagen deposition observed in cutaneous wounds during the septic state .

J Surg Res, 1998 Jul 15, 78(1), 18 - 22
Sepsis increases lung glutamine synthetase expression in the tumor-bearing host; Elgadi KM et al.; Acute stresses such as trauma or endotoxemia augment GLN demand and are associated with increased release of this amino acid from skeletal muscle and lung as well as increased expression of glutamine synthetase (GS, the principal enzyme of GLN synthesis) in these tissues . Muscle GLN release is also increased during chronic catabolic states which are associated with depletion of lean body mass, such as starvation or malignancy . We hypothesized that the expression of GS in response to an acute stress would be altered in tumor-bearing rats (TBR) experiencing severe cachexia and therefore a previously heightened GLN demand . Male Fischer 344 rats were implanted with methylcholanthrene-induced fibrosarcoma tumors or underwent sham operations and pair-feeding (sham) with TBR partners . When tumor burden reached approximately 15% of carcass weight, animals received injections of either Escherichia coli lipopolysaccharide (LPS, 1 mg/kg body wt) or saline vehicle . Rats were sacrificed 8 h after injection and lung and muscle tissue were analyzed for GS mRNA and protein via Northern and Western blot techniques, respectively . LPS injection caused an equivalent 4- to 6-fold increase in lung and muscle GS mRNA in both TBR and sham rats (P < 0.01) . LPS did not produce a significant increase in GS protein level in muscle tissue of either group or in lung tissue of sham rats . In contrast, endotoxin did lead to a 3.5-fold increase in GS protein levels in lung tissue of TBRs (P < 0.05) . This increase in lung GS protein may signify the importance of the lung in maintaining GLN homeostasis during chronic catabolic states where muscle mass is diminished .

Ann Fr Anesth Reanim, 1997, 16(3), 234 - 8
{Malignant hyperthermia and appendicular sepsis . Can they be differentiated during surgical procedure?}; Strecker G et al.; OBJECTIVE: To assess the possibility to differentiate clinically intraoperative malignant hyperthermia (MH) and sepsis . STUDY DESIGN: Comparative retrospective study of clinical cases . PATIENTS: Sixteen patients operated on for acute appendicitis and developing clinical signs of MH confirmed or not by in vitro caffeine halothane contracture tests (IVCT) . METHOD: To isolate the patients' characteristics with regard to the diagnosis of sepsis and MH crisis . To compare both groups of clinical features with results of IVCT . RESULTS: The diagnosis of MH sensitivity has been excluded in ten hyperthermic patients and confirmed in four others with IVCT . No correlation was existing between the importance of perioperative sepsis, MH features and IVTC results . CONCLUSIONS: This study confirmed the difficulty to differentiate clinically MH and sepsis during surgery . Considering the severe outcome of MH crisis, it is recommended to start the specific therapy even in case of appendicular sepsis.

Obes Surg, 1998 Apr, 8(2), 211 - 4
Periprosthesis sepsis: an undesirable complication of silicone gastric banding; Lucchese M et al.; BACKGROUND: Gastric banding is a very satisfactory procedure for the treatment of morbid obesity . The significant incidence of skin suppuration in these patients makes the laparoscopic approach a suitable technique . Regardless of this, in some cases, suppuration can still rarely result . METHODS AND RESULTS: In four patients the authors observed diffusion of suppuration in both directions along the catheter which connects the port to the band, necessitating band removal and thus invalidating the procedure . CONCLUSIONS: Suppuration of port location is an undesirable complication that must be avoided because it may contaminate the entire device system . This complication must be carefully evaluated for a correct diagnosis and an eventual removal of the band.

J Immunol, 1998 Sep 1, 161(5), 2655 - 9
Increased susceptibility to postoperative sepsis in patients with impaired monocyte IL-12 production; Hensler T et al.; IL-12 is a potent immunoregulatory cytokine that is essential for the development of protective immunity, as demonstrated by numerous animal models of infection . Here, we provide evidence for a critical role of IL-12 in human sepsis . The results of a prospective study of 184 patients undergoing major elective surgery of the upper and lower gastrointestinal tract revealed that, in contrast to patients showing uneventful recovery, monocyte IL-12 production was severely and selectively impaired in patients developing postoperative sepsis . Moreover, the extent of monocyte IL-12 suppression correlated with the severity of postoperative sepsis . Monocyte IL-12 secretion was suppressed before surgery and remained low until the onset of sepsis . Therefore, the suppression of IL-12 secretion preceded the onset of postoperative sepsis but did not occur as a consequence of major surgery . In contrast, IL-1beta production was only reduced during the late postoperative course in patients developing postoperative sepsis, and TNF-alpha release was even increased at different time intervals before the onset of sepsis . Thus, reduced IL-12 release does not reflect a general defect in monocyte cytokine production . Consequently, these results establish a critical role for IL-12 in early resistance to postoperative infection and may allow for the development of novel therapeutic strategies designed to stimulate host defense mechanisms and to reduce the incidence and severity of septic complications.

Am J Physiol, 1998 Sep, 275(3 Pt 1), G467 - 72
PAF and CD18 mediate neutrophil infiltration in upper gastrointestinal tract during intra-abdominal sepsis; Beyer AJ et al.; Neutrophil infiltration is a critical event in the development of multiple organ failure during sepsis . We hypothesized that platelet-activating factor (PAF) release contributes to neutrophil infiltration in the gastrointestinal tract during sepsis . In the first experiments we administered exogenous PAF (1.56, 6.25, 25, and 100 ng . kg-1 . min-1 for 30 min) to urethan-anesthetized Sprague-Dawley rats . PAF was administered alone or in combination with either the PAF antagonist WEB-2086 (250 microg . kg-1 . min-1), a monoclonal antibody (MAb) to CD18, or a MAb to intercellular adhesion molecule 1 (ICAM-1) . In separate groups of rats, cecal ligation and incision (CLI) was performed to create intra-abdominal sepsis, which we hypothesized would stimulate the release of endogenous PAF . CLI was performed in rats given either saline, WEB-2086, anti-CD18, or anti-ICAM-1 MAb . After these experiments, tissue myeloperoxidase (MPO) levels were determined as a marker of neutrophil infiltration . Both exogenous PAF and CLI induced significant increases in MPO activity in the stomach and duodenum . These increases were significantly attenuated by WEB-2086, anti-CD18 MAb, and anti-ICAM-1 MAb in both PAF- and CLI-treated rats . These results suggest that both the inflammatory mediator PAF and the CD18 integrins play a major role in neutrophil infiltration in the upper gastrointestinal tract during sepsis.

Shock, 1998 Aug, 10(2), 123 - 8
The role of endothelin-1 in circulatory changes during hypodynamic sepsis in the rat; Szalay L et al.; Our objective was to investigate the significance of endogenous endothelin-1-induced systemic circulatory reactions during hypodynamic sepsis . In the first part of this study, we observed the changes in global hemodynamic parameters in Wistar rats after exogenous endothelin-1 administration in order to test an intervention strategy aimed at preventing the development of hypodynamic cardiovascular derangement during intraabdominal sepsis . Cardiac output, mean arterial blood pressure, and peripheral vascular resistance were recorded, and the endothelin-A receptor antagonist BQ-610 and the endothelin-B receptor antagonist IRL-1038 were used to investigate the role of receptor subtypes in circulatory changes . In addition, the effects of treatment with the novel endothelin-A receptor inhibitor ETR-P1/fl peptide were examined in endothelin-1-treated anesthetized rats . The injection of 1 nmol/kg endothelin-1 induced a significant rise in peripheral vascular resistance, a transient increase in mean arterial pressure, and a decrease in cardiac output . Administration of the endothelin-A receptor antagonist BQ-610 and ETR-P1/fl peptide increased cardiac output and decreased systemic vascular resistance in the controls and in animals treated with exogenous endothelin . In the second part of the study, the animals were instrumented for hemodynamic monitoring and randomized to undergo cecal ligation and perforation for 8 h or control laparotomy . Septic animals with cecal ligation and puncture were normotensive and hypodynamic, with a significantly increased total peripheral resistance throughout the 8 h observation period . ETR-P1/fl peptide treatment started after the induction of sepsis significantly increased cardiac output and decreased systemic vascular resistance almost to control levels . We conclude that endogenous endothelin-1 contributes significantly to the systemic hemodynamic alterations during hypodynamic circulatory response, and the inhibition of endothelin-A receptors may improve global hemodynamic status in this phase of sepsis.

Shock, 1998 Aug, 10(2), 118 - 22
Up-regulation of a novel potent vasodilatory peptide adrenomedullin during polymicrobial sepsis; Wang P et al.; A large number of studies have been and are being carried out to examine the role of nitric oxide in the hyperdynamic and hypodynamic stages of sepsis . It remains unknown, however, whether adrenomedullin (ADM), a novel potent vasodilatory peptide, is up-regulated during hyperdynamic sepsis and, if so, whether its production is sustained during hypodynamic sepsis . To determine this, rats were subjected to sepsis by cecal ligation and puncture (CLP), followed by administration of 3 mL/100 g body weight normal saline to these and sham-operated animals . Blood samples were taken at 1, 1.5, 2, 5, and 10 h (2-10 h post-CLP represents the hyperdynamic stage of sepsis) or at 20 and 30 h after CLP (i.e., the hypodynamic stage) . Plasma levels of ADM were measured by radioimmunoassay . Adrenomedullin gene expression in various tissues was examined at 2, 10, or 20 h after CLP by reverse transcription-polymerase chain reaction (RT-PCR) . The results indicated that plasma levels of ADM did not increase at 1 and 1.5 h after CLP but increased significantly at 2 h after the onset of sepsis . Moreover, circulating ADM increased progressively at 5-20 h and remained elevated at 30 h after CLP . The increased levels of plasma ADM during sepsis were correlated with up-regulation of ADM mRNA in the small intestine, left ventricle, and thoracic aorta . In contrast, ADM gene expression in renal and hepatic tissues was not significantly altered following the onset of sepsis . The association between the up-regulated ADM and the occurrence of hyperdynamic circulation during the early stage of sepsis (both occur at 2 h after CLP) may indicate a possible cause and effect relationship between the two events . Since we have previously shown that ADM-induced vascular relaxation decreased at 20 h after CLP, it appears that the down-regulation of ADM receptors may be responsible for the transition from the hyperdynamic stage to the hypodynamic stage of sepsis.

Shock, 1998 Aug, 10(2), 90 - 6
Effect of antithrombin III supplementation on inflammatory response in patients with severe sepsis; Inthorn D et al.; Antithrombin III (AT III) is an important inhibitor of thrombin activity, as well as of many other proteases of the coagulation system . AT III administration showed beneficial effects on septic multiple organ dysfunction in clinical and experimental studies . It was the aim of this study to determine whether continuous long-term AT III supplementation alters the systemic inflammatory response in patients with severe sepsis . In a prospective study, 29 surgical patients with severe sepsis were randomly assigned to receive either conventional intensive care treatment (n = 15, control group) or additional AT III supplementation to achieve a plasma AT III activity >120% during a 14 day study period (n = 14, AT III group) . Plasma concentrations of interleukin (IL)-6 and IL-8 and of the circulating soluble adhesion molecules sICAM-1 and sE-selectin, as well as of PMN elastase, were determined daily . Additionally, total leukocyte count and C-reactive protein (CRP) were measured daily, and body temperature was registered . Compared to control patients, a down-regulation of plasma IL-6 was observed in the AT III group (p < or = .01) . AT III supplementation prevented the continuous increase in sICAM-1 plasma concentration observed in control patients and led to a significant fall in soluble sE-selectin and CRP concentration (p < or = .01) . This fall corresponded to a down-regulation of body temperature over time (p < or = .01) . There was no AT III effect on IL-8, PMN-elastase concentration, or total leukocyte count . Our results show that long-term AT III supplementation attenuates the systemic inflammatory response in patients with severe sepsis . The down-regulation of IL-6 may also explain the fall in endothelium-derived adhesion molecules and may represent the molecular basis by which AT III exerts its beneficial effects on organ function.

Ann Ital Chir, 1998 Mar-Apr, 69(2), 165 - 7
{Connection between the type of drainage and sepsis in thyroid surgery}; De Salvo L et al.; Drainage in thyroid surgery, although still controversial, is used at our service routinely, as it guarantees the output of serum, sometimes abundant after thyroidectomy, and allows the immediate check of hemorrhage . It is nevertheless known that the presence of drainage can favour the occurrence of infection of the surgical bed . Through a randomized trial, we tested the incidence of sepsis after thyroidectomy, using in one group a double open Silastic drain and in another group a double aspirative drain . We registered 3 cases of wound infection and 4 cases of seroma in the group treated with open drainage versus one case of wound infection and 2 cases of seroma in the group treated with aspirative drainage . Such difference, although evident, did not result significant . Nevertheless, it is our opinion to conclude that the aspirative draining system guarantees a better sterility of the surgical wound, and therefore a lower incidence of wound complications.

S Afr J Surg, 1998 May, 36(2), 52 - 6
Relaparotomies for abdominal sepsis--why, when, how? A collective review; Velmahos GC et al.; Despite numerous reports in the recent literature, the indications for relaparotomies for abdominal sepsis are still not clear cut . In particular there is no consensus concerning the decision or the optimal time to reoperate . There is more benefit than hazard in a low threshold for surgically exploring the critically ill patient, especially the one who cannot easily be assessed clinically . Exclusive reliance on radiological confirmation of ongoing sepsis might delay diagnosis and treatment . Relaparotomy at regular intervals (preferably every 24-48 hours) should be done until complete eradication of sepsis is achieved.

Am J Obstet Gynecol, 1998 Jul, 179(1), 80 - 6
Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis; Sacks GP et al.; OBJECTIVE: Our aim was to seek evidence for circulating leukocyte activation in preeclampsia . STUDY DESIGN: Whole blood flow cytometric techniques were used to analyze surface markers of activation (CD11b, CD14, CD23, CD49d, CD62L, CD64, CD66b, HLA-DR) and intracellular reactive oxygen species . Samples were taken from 21 women with preeclampsia, 21 matched normal pregnant women, 21 healthy nonpregnant controls, and 6 nonpregnant patients with septicemia . Ten preeclamptic cases were followed up 6 weeks post partum . RESULTS: The leukocytes of healthy pregnant women differed substantially and significantly from those of nonpregnant women (increased CD11b, CD14, and CD64 and increased intracellular reactive oxygen species) . In preeclampsia there was, in addition to these changes, reduced expression of L-selectin and further increases in intracellular reactive oxygen species . The changes found in normal pregnancy and preeclampsia were similar, but not identical, to those found in sepsis . CONCLUSIONS: Normal third-trimester pregnancy is characterized by remarkable activation of peripheral blood leukocytes, which is further increased in preeclampsia.

Placenta, 1998 Jul-Aug, 19(5-6), 385 - 9
Two fetal deaths associated with maternal sepsis and with thrombosis of the intervillous space of the placenta; Bendon RW et al.; The placental pathology in two second trimester fetal losses associated with mild maternal disseminated intravascular coagulation are reported . Case one had a dental abscess, a leukocytosis of 36300 white blood cells/m, and evidence of mild consumptive coagulopathy at 20 weeks . Case two had septic findings including disseminated intravascular thrombosis associated with pyelonephritis . The placentae had extensive intervillous thrombosis at the periphery of spiral arterial flow . It is hypothesized that in mild disseminated intravascular coagulation, the trophoblast inhibits fibrinolysis, favouring thrombosis perhaps due to production of plasminogen activator inhibitor.

MMWR Morb Mortal Wkly Rep, 1998 Jul 31, 47(29), 610 - 2
Clinical sepsis and death in a newborn nursery associated with contaminated parenteral medications--Brazil, 1996; Sepsis induces increased apoptosis in lamina propria mononuclear cells which is associated with altered cytokine gene expression; Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, Rhode Island, 02903, USAStudies indicate that lymphoid tissue (e.g., thymus, bone marrow, and Peyer's patches) shows evidence of increase apoptosis (Ao, a form of nonnecrotic cell death) during sepsis . However, it is not known if mucosal lymphoid tissue, such as lamina propria (LP), also shows evidence of increased Ao and if so, is this associated with functional changes, i.e., cytokine gene expression in the LP . To examine this, male C3H/HeN mice were subjected to cecal ligation and puncture (CLP) and lamina propria mononuclear cells (LPMC) were harvested at 4 h (early sepsis) or 24 h (late sepsis) . Alterations in the cell phenotype as well as Ao (Tunel assay) were determined by three-color flow cytometry . Cytokine gene expression was assessed by multiprobe RNase protection assay . Sham LPMC preparations were found to be 34.4 +/- 2.4% B220(+) (B-cells), while 12.4 +/- 2.1% were CD8(+) (cytotoxic T-cells), 22.0 +/- 0.8% were CD4(+) (helper T-cells), and 6.4 +/- 0.7% were F4/80(+) (macrophages) . The frequency of B220(+) (9%* upward arrow) and CD8 (6%* upward arrow) populations increased markedly at 4 h after CLP; however, this increase was not seen at 24 h . The percentage of Ao+ in CD8(+), B220(+), and F4/80(+) cells increased markedly at both 4 and 24 h . CD4(+) cells showed a marked increase in Ao only at 24 h after CLP . When LPMC mRNA expression was examined, a significant increase in IL-2, -10, and -15 gene expression was observed only at 24 h but not 4 h after CLP . Thus, the early phenotypic changes associated with increased Ao may be a reflection of localized immune cell activation in early sepsis contributing to the increased cytokine gene expression seen in late sepsis . This localized activation may contribute to gastrointestinal inflammation and/or immune dysfunction in sepsis .

J Surg Res, 1998 May, 76(2), 165 - 73
Does hepatocellular injury in sepsis involve apoptosis?
Ayala A, Evans TA, Chaudry IH.
Apoptosis (AO) is a process by which cells typically undergo a form of nonnecrotic cellular suicide . AO normally allows the host to selectively delete cells from a given tissue site without producing bystander injury associated with necrosis . However, inappropriate induction of AO has been associated with a variety of acute as well as chronic pathological states and may contribute to the therapeutic nonresponsiveness frequently encountered in the septic animal/patient's organ function . In this respect, while AO has been demonstrated in a variety of immune cell tissues of septic animals it is unclear if it is present in the septic liver . Therefore, it was the aim of our study to determine if AO is evident in hepatocytes of polymicrobial septic animals . To assess this, C3H/HeN male mice were subjected to polymicrobial sepsis (cecal ligation and puncture) or sham- CLP (Sham) . Hepatocytes were then harvested at 4 h (early hyperdynamic phase) or 24 h (late hypodynamic state) later, and indices of AO were assessed {cell cycle analysis of Annexin V/propidium iodide (PI) staining for flow cytometric analysis, DNA extracted, and cell death ELISA} . Plasma glutamic pyruvic transaminase (GPT) was also colorimetrically assessed as well as total viable cell yield as an index of hepatocellular necrosis . The results indicate that indices of hepatocellular AO, as determined by cell cycle analysis and cell death ELISA, were markedly increased in polymicrobial septic mice at 24 h . However, while an increase in DNA fragmentation/degradation could be consistently detected, the pattern was typically faint . Similarly, although there was an increase in Annexin V staining it was not dissociated from that of PI (necrotic index) . Alternatively, necrosis (as evidenced by increased GPT levels at both 4 and 24 h) preceded the induction of all the indices of AO . Taken together, these data suggest a role for both necrosis and apoptosis in the evolution of hepatocellular injury encountered in the polymicrobial septic animal/patient which may represent a unique pattern of cell death under such conditions.

Gynecol Oncol, 1998 Jul, 70(1), 100 - 4
Necrosis of myometrial choriocarcinoma with fulminating sepsis complicating chemotherapy for trophoblastic tumor; Odunsi KO et al.; We report a patient who developed metastatic gestational choriocarcinoma following delivery of a normal, healthy child that, however, was anemic and required blood transfusion . The patient developed secondary postpartum hemorrhage over a period of several weeks and required curettage and myometrial contractants to control the bleeding . At the time of diagnosis the patient had extensive pulmonary metastases and ultrasound showed full penetration of the myometrium by tumor . Immediately following the second course of chemotherapy with etoposide, methotrexate, and actinomycin D, alternating with cyclophosphamide and vincristine, the patient developed sepsis associated with a uteroperitoneal fistula and required hysterectomy . The sepsis was associated with disseminated intravascular coagulopathy and adult respiratory distress syndrome . However, the patient's tumor was exquisitely sensitive to chemotherapy and with good intensive care unit support and chemotherapy the survived without residual scar except for the loss of reproductive function . There are two lessons to be learned from these events: (1) The syndrome of secondary postpartum hemorrhage with a fetus that is anemic spells a diagnosis of choriocarcinoma; and (2) color Doppler flow vaginal ultrasound performed at the time of presentation of trophoblastic tumors may be useful to show full penetration of the myometrium by tumor which may be a warning of possible scar rupture in a subsequent pregnancy.

J Infect Dis, 1998 Aug, 178(2), 471 - 7
Granulocyte colony-stimulating factor and antibiotics in the prophylaxis of a murine model of polymicrobial peritonitis and sepsis; Villa P et al.; Infections that occur after intraabdominal surgery still cause considerable morbidity and mortality despite the administration of prophylactic antibiotics . Increasing the number of neutrophils may also be a prophylactic approach, and granulocyte colony-stimulating factor (G-CSF) has been found to be beneficial in different animal models of peritonitis and sepsis . It is the combination of G-CSF and antibiotics, however, that is clinically relevant . Treatment of mice with G-CSF that was started before cecal ligation and puncture and continued afterward with antibiotics improved survival, decreased splenic bacterial colony-forming units and serum tumor necrosis factor, and increased serum interleukin-10, compared with treatment with antibiotics alone or with saline . Compared with saline, antibiotics alone increased tumor necrosis factor and did not affect interleukin-10 . Thus, G-CSF confers onto antibiotics beneficial antiinfectious and antiinflammatory properties . A prophylactic regimen combining G-CSF and antibiotics may help prevent severe infectious complications following intraabdominal surgery.

Eur J Cancer Care (Engl), 1998 Jun, 7(2), 99 - 101
The sepsis syndrome and the cancer patient: respiratory management and active physiotherapy; Thompson N et al.; Cancer and its treatment place heavy physical and metabolic demands on a patient . Sepsis exacerbates this and may lead to hypoxia . Timely physiotherapy can help improve respiratory function and, together with other members of the multidisciplinary team, in the long-term will help to return the patient to previous levels of function.

J Surg Res, 1998 Apr, 76(1), 67 - 73
Tissue coexpression of LBP and CD14 mRNA in a mouse model of sepsis; Wang SC et al.; BACKGROUND: Lipopolysaccharide binding protein (LBP) markedly increases the sensitivity of immune cells to LPS and CD14 expression correlates with cellular responsiveness to LPS . LBP gene expression can be induced in multiple organs following injury and CD14 upregulation on monocytes correlates with the infection and mortality rates in severely injured patients . We sought to determine the time-course induction of LBP and CD14 gene expression following experimental peritonitis . MATERIAL AND METHODS: BALB/c mice were subjected to laparotomy alone or laparotomy with cecal ligation and puncture and treated with Imipenem . At serial time points, animals were sacrificed and tissues harvested for isolation of RNA and protein . LBP, CD14, and cytokine mRNAs were analyzed by Northern blot analysis and TaqMan fluorescent quantitative RT-PCR . RESULTS: LBP and CD14 mRNA levels were significantly increased in all three organs from CLP mice compared to sham-operated mice . IL-1 mRNA levels increased in all three organs following CLP with significantly higher levels found in the lungs compared to the kidney and liver . No significant differences were noted in local TNF mRNA levels . CONCLUSIONS: LBP, CD14, and IL-1 mRNA levels are induced concurrently in the lung, kidney, and liver after cecal ligation and puncture . Given the synergistic affect of LBP and CD14 in potentiating LPS-induced production of inflammatory cytokines and the hypothesized role of such cytokines in the etiology of MSOF following injury and sepsis, our findings suggest a mechanism by which these organs may be rendered more susceptible to a "second hit" from endotoxemia after initial injury.

Clin Exp Dermatol, 1998 Mar, 23(2), 84 - 6
Ofuji's papuloerythroderma following choledocholithiasis with secondary sepsis: complete resolution with surgery; Azon-Masoliver A et al.; We describe a case of Ofuji's papuloerythroderma (PE) in a 72-year-old man with biliary sepsis induced by choledocholithiasis . The PE disappeared completely after surgery with no relapse . This aetiology for PE does not appear to have been described previously, while its resolution after treatment of the primary process supports the idea that it may be a reactive disorder of multifactorial origin.

Anasthesiol Intensivmed Notfallmed Schmerzther, 1998 Jun, 33 Suppl 2, S60 - 9
{Aspects in monitoring and treatment of gastrointestinal underperfusion in sepsis . Diagnosis and therapy of gastrointestinal underperfusion in sepsis}; Meier-Hellmann A et al.; Tissue hypoxia, especially in the splanchnic area, is still considered to be an important cofactor in the pathogenesis of multiple organ failure . Thus, in the treatment of septic shock the specific effects of ino-tropic drugs on the splanchnic perfusion are of particular interest . To give strict recommendations for monitoring and for therapeutic strategies in the treatment of gastrointestinal failure in patients with sepsis is difficult not only due to the lack of data on clinical outcome and organ dysfunction, but also due to some limitations in the methods applied to assess splanchnic perfusion and oxygenation . A reasonable approach in the management of splanchnic underperfusion in septic patients includes: Measurement of gastric mucosal pH or CO2-gap because it is the only method for the assessment of splanchnic perfusion which can be useful in the clinical routine . Adequate volume loading likely is the most important step in the supportive treatment of patients with septic shock . Unfortunately, what kind of fluids, endpoints, and monitoring techniques should be used is still controversial . Nevertheless, techniques allowing us to achieve and tightly control volume loading and regional perfusion, e.g . the measurement of pHi or CO2-gap, may be helpful . Patients with high DO2 have had better outcome . However, measurement of parameters assessing global and regional oxygenation may be superior than to guide therapy by DO2 . To maximize DO2 by the use of very high dosages of catecholamines can be harmful . The recommendation to use dobutamine as catecholamine of first choice seems to be justified . In critically ill patients, no negative effects of norepinephrine on regional perfusion have been demonstrated provided the patient is adequately volume resuscitated and the DO2 is normal or slightly elevated . Therefore, after volume resuscitation and treatment with dobutamine, norepinephrine should be used for achieving an adequate perfusion pressure . Epinephrine and dopamine should be avoided because they seem to restribute 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 . These recommendations are limited by the lack of outcome studies and optimal methods for the assessment of splanchnic perfusion/oxygenation.

Acta Anaesthesiol Scand, 1998 Jul, 42(6), 713 - 6
Elevated methemoglobin in patients with sepsis; Ohashi K et al.; BACKGROUND: It has been reported that large amounts of nitric oxide (NO) are released in patients with sepsis . NO is converted to methemoglobin and nitrate . This study was designed to determine whether blood methemoglobin levels were increased in patients with sepsis or septic shock . METHODS: Forty-five critically ill patients including 8 with sepsis but without shock, 6 with septic shock and 31 non-septic patients were enrolled in the study . For septic and septic shock patients, blood methemoglobin concentrations were measured during sepsis or septic shock and at the time of recovery or just before the onset of sepsis . For the remaining non-septic patients, methemoglobin concentrations were measured at ICU admission and discharge . RESULTS: Blood methemoglobin levels in the presence of sepsis or septic shock were significantly (P < 0.05) higher than those in non-septic patients and those at recovery or just before the onset of sepsis in both septic and septic shock patients . CONCLUSIONS: Blood methemoglobin concentration may be useful as a marker of the onset of sepsis or septic shock.

Am J Physiol, 1998 Jul, 275(1 Pt 2), R269 - 77
Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice; Leon LR et al.; Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) have been implicated as key mediators in inflammation, morbidity, and mortality associated with sepsis . We examined the role of IL-6 and TNF-alpha signaling on hypothermia, fever, cachexia, anorexia, and survival during sepsis induced by cecal ligation and puncture (CLP) in male and female gene knockout mice . Male wild-type mice developed an initial hypothermia and subsequent fever during sepsis . Male IL-6 knockout mice did not develop fever; rather, they maintained a profound hypothermia during sepsis . Male TNF p55/p75 receptor (TNFR) knockout mice had attenuated hypothermia, but developed a virtually identical fever as wild-type mice . Cachexia did not differ between male wild-type and IL-6 or TNFR knockout mice, whereas anorexia was prolonged in IL-6 knockout mice . Due to the rapid lethality of sepsis in female mice, survival was the only variable we were able to statistically compare among female genotypes . Female wild-type mice had significantly decreased survival compared with male wild-type mice . Survival was significantly enhanced in male and female TNFR knockout mice compared with their wild-type controls . Lack of IL-6 did not affect male or female lethality . These data support the hypothesis that IL-6 is a key mediator of fever and food intake, whereas TNF is responsible for the initial hypothermia and lethality of sepsis in both sexes of mice . The enhanced lethality of CLP-treated female mice supports a role for sex steroids during sepsis.

Am J Physiol, 1998 Jul, 275(1 Pt 1), L139 - 44
Mitochondrial respiration after sepsis and prolonged hypoxia; Taylor DE et al.; Recently, marked oxygen dependence of respiration by isolated mitochondria after exposure to prolonged hypoxia has been described . Because mitochondrial oxygen-dependent respiration could significantly influence oxygen consumption during critical illness, we sought to confirm the oxygen-dependent behavior of mitochondria . We hypothesized that mitochondria isolated during sepsis would exhibit increased oxygen dependence . We isolated rat liver mitochondria 16 h after cecal ligation and puncture and found a 30-40% greater oxygen uptake compared with control rats under state 3 conditions . Mitochondria incubated in deoxygenated buffer were studied for oxygen dependence at 10-min intervals for 90 min . Mitochondrial respiration after reoxygenation was stable over a 60-min period of hypoxia for control rats and decreased slightly for septic rats (10-15%) . State 3 respiration was 10% lower when mitochondria were reoxygenated at low (15-25 Torr) versus high (90-100 Torr) and low (10-15 Torr) versus intermediate (40-45 Torr) oxygen tension . Oxygen consumption with ascorbate+N, N, N', N'-tetramethyl-p-phenylenediamine was 20% lower at low versus high oxygen tension . No increase in oxygen dependence was observed during 1 h of hypoxic incubation . Our data indicate only a modest oxygen dependence of respiration between 10 and 100 Torr, which is similar for septic and control mitochondria . Additionally, oxygen dependence did not increase significantly during a 1-h hypoxic exposure for well-coupled mitochondrial preparations.

Arch Surg, 1998 Jul, 133(7), 745 - 51
Prolonged overexpansion of extracellular water in elderly patients with sepsis; Cheng AT et al.; OBJECTIVE: To compare the sequential changes in extracellular water (ECW) expansion in elderly patients receiving intensive care for severe sepsis with those in a similar group of younger patients . DESIGN: Inception cohort study . SETTING: Critical Care Unit and University Department of Surgery in a single tertiary care center . PATIENTS: A consecutive series of 14 patients older than 60 years (n=8) or younger than 40 years (n=6) with severe sepsis who completed sequential measurements of body composition during a 21-day period . MAIN OUTCOME MEASURE: Sequential measurements of body composition including ECW by bromide dilution, total body water by tritium dilution, and fat-free body mass by dual-energy x-ray absorptiometry were performed during 21 days after resuscitation . Excess ECW was estimated from the difference between measured ECW and ECW predicted from fat-free body mass corrected to normal hydration . RESULTS: On the first study day, ECW was overexpanded by 9.05+/-1.87 L (mean+/-SEM) and 10.33+/-1.79 L in the young and elderly groups, respectively (P=.66) . Whereas the young group excreted most of this excess ECW by day 5 (P=.008), the elderly group remained overexpanded until day 10 before mobilization of ECW occurred (P=.003) . The changes over time of ECW excess were significantly different (P=.02 for group x time interaction) . The elderly group required more prolonged inotropic (P=.009) and ventilatory (P=.004) support and remained in intensive care longer (P=.008) than the young group . CONCLUSIONS: The period of ECW expansion is more prolonged in elderly patients with sepsis and contributes to a poorer outcome from critical illness . This new finding is of fundamental importance to the treatment of elderly patients recovering from severe sepsis.

Pediatrics . 1998 Aug;102(2):e18.
Decline in sepsis-associated neonatal and infant deaths in the United States, 1979 through 1994; Stoll BJ et al.; BACKGROUND: Infant mortality in the United States has continued to decline in recent years, but changes in sepsis-associated deaths among infants have not been evaluated previously . METHODS: Data from US death records were analyzed for the period 1979 through 1994 to assess trends in sepsis-associated deaths among newborns and older infants . RESULTS: Annual neonatal mortality associated with sepsis declined by 25% from 50.5 deaths per 100 000 live births in 1979 through 1981 to 38.0 deaths per 100 000 live births in 1992 through 1994 . Although infant mortality associated with sepsis declined from 71.7 to 56.4 per 100 000 live births over the same period, this decline was attributable to lower sepsis-related mortality among newborns . The rates of sepsis-associated deaths declined for both preterm and term deliveries . Approximately 2260 infants (1521 of whom were newborns) died of sepsis per year in 1992 through 1994 . Sepsis-associated death was more likely to occur among infants who were male, black, preterm, or born in the South . Among black infants, the racial gap in sepsis-associated mortality was greater for term than for preterm infants . CONCLUSIONS: Despite declines in the overall sepsis-related mortality among newborns, racial and regional gaps in mortality persisted over the 16-year study period . Almost half of the sepsis-related deaths occurred among infants who were born prematurely . Disproportionate rates of prematurity among blacks and infants born in the South may have contributed to persistently high sepsis-related mortality in these groups . Future efforts to reduce the incidence of sepsis-associated deaths will depend on targeting higher risk populations and reducing prematurity.

ASAIO J, 1998 Jul-Aug, 44(4), 263 - 6
Use of extracorporeal life support for adult patients with respiratory failure and sepsis; Rich PB et al.; Traditionally, adult sepsis has been considered a contraindication to extracorporeal life support (ECLS) . The objective of this study was to review the authors' institutional experience with a subgroup of adult patients requiring ECLS for severe respiratory failure and sepsis . Hospital records from 100 consecutive adult patients with respiratory failure placed on ECLS between 1990 and 1996 were retrospectively reviewed . Patients with sepsis as a primary indication were identified, and blood culture data reviewed . Data were analyzed with t tests and chi-square and are presented as mean +/- standard deviation . Multiple logistic regression determined the impact of sepsis and positive blood cultures (PBCs) on survival . Fourteen patients required ECLS for sepsis; 36 had PBCs during hospitalization (15 before or during ECLS) . Septic patients had lower pre-ECLS PaO2/FIO2 ratios (septic: 53 +/- 14 mmHg, nonseptic: 70 +/- 68 mmHg, p = 0.04) . Patients with PBCs before or during ECLS were younger (PBC: 29 +/- 6 years, no PBC: 35 +/- 13 years, p = 0.003), remained on ECLS longer (PBC: 485 +/- 336 hours, no PBC: 232 +/- 212 hours, p = 0.01), and were more frequently cannulated within 12 hours (PBC: 15/15, no PBC 60/85 p = 0.02) . Neither group differed in organ dysfunction (incidence or type), frequency of respiratory recovery, or survival . Neither sepsis nor positive blood cultures were independently predictive of mortality . Sepsis and positive blood cultures do not adversely affect outcome in adult patients with respiratory failure requiring ECLS.

Acta Med Croatica, 1998, 52(2), 127 - 32
Therapeutic plasma exchange in severe sepsis or septic shock; Kes P; Endotoxic shock with multiorgan dysfunction syndrome (MODS) is fatal in more than 80% of cases and is the leading cause of death in patients admitted to intensive care units . The incidence has increased to more then 100% in the last 10 years and there has been no significant decreases in its morbidity and mortality . The systemic inflammatory response to infection, e.g . sepsis, develops when the endotoxins activate various cascade systems . The activation of the cascade systems triggers further release of various active substances and cytokines . The progress may result in consumption coagulopathy, which may further generate an acute septic shock, disseminated intravascular coagulation, and MODS . When more than 3 organs are involved, the risk of fatal outcome exceeds 80% . The use of plasma exchange may be a beneficial adjunct to therapy during a progressive septic shock with MODS, when the patient does not respond to classical intensive care unit therapy . The beneficial effect, recently reported for plasma exchange procedures in patients with sepsis, may be due to the removal of various toxins and waste products from the blood, and administration of plasma from healthy subjects.

Clin Infect Dis, 1998 Jul, 27(1), 185 - 90
The dynamics of disease progression in sepsis: Markov modeling describing the natural history and the likely impact of effective antisepsis agents; Rangel-Frausto MS et al.; We conducted a 9-month prospective cohort study of 2,527 patients with systemic inflammatory response syndrome in three intensive care units and three general wards in a tertiary health care institution . Markov models were developed to predict the probability of movement to and from more severe stages--sepsis, severe sepsis, or septic shock--at 1, 3, and 7 days . For patients with sepsis, severe sepsis, and septic shock, the probabilities of remaining in the same category after 1 day were .65, .68, and .61, respectively . The probability for progression after 1 day was .09 for sepsis to severe sepsis and .026 for severe sepsis to shock . The probability of patients with sepsis, severe sepsis, and septic shock dying after 1 day was .005, .009, and .079, respectively . The model can be used to predict the reduction in end organ dysfunction and mortality with use of increasingly effective antisepsis agents.

Chest, 1998 Jul, 114(1), 207 - 13
Central vein catheter-related thrombosis in intensive care patients: incidence, risks factors, and relationship with catheter-related sepsis; Timsit JF et al.; OBJECTIVE: To evaluate the incidence and risk factors for catheter-related central vein thrombosis in ICU patients . DESIGN: Observational prospective multicenter study . SETTING: An 8-bed surgical ICU, a 10-bed surgical cardiovascular ICU, and a 10-bed medical-surgical ICU . PATIENTS: During an 18-month period, 265 internaljugular or subclavian catheters were included . Veins were explored by duplex scanning performed just before or < 24 h after catheter removal . Suspected risk factors of catheter-related central vein thrombosis were recorded . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Fifty-seven catheters were excluded from the analysis . Therefore 208 catheters were analyzed . Mean age of patients was 64+/-15 years, simplified acute physiologic score was 12+/-5, organ system failure score at insertion was 1+/-1, and mean duration of catheterization was 9+/-5 days . A catheter-related internal jugular or subclavian vein thrombosis occurred in 33% of the cases (42% {95% confidence interval (CI), 34 to 49%} and 10% {95% CI, 3 to 18%}, respectively) . Thrombosis was limited in 8%, large in 22%, and occlusive in 3% of the cases . Internal jugular route (relative risk {RR}, 4.13; 95% CI, 1.72 to 9.95), therapeutic heparinization (RR 0.47; 95% CI, 0.23 to 0.99), and age >64 years (RR, 2.44; 95% CI, 2.05 to 3.19) were independently associated with catheter-related thrombosis . Moreover, the risk of catheter-related sepsis was 2.62-fold higher when thrombosis occurred (p=0.011) . CONCLUSIONS: Catheter-related central vein thrombosis is a frequent complication of central venous catheterization in ICU patients and is closely associated with catheter-related sepsis.

Infect Immun, 1998 Aug, 66(8), 3569 - 78
Pulmonary and hepatic gene expression following cecal ligation and puncture: monophosphoryl lipid A prophylaxis attenuates sepsis-induced cytokine and chemokine expression and neutrophil infiltration; Salkowski CA et al.; Polymicrobial sepsis induced by cecal ligation and puncture (CLP) reproduces many of the pathophysiologic features of septic shock . In this study, we demonstrate that mRNA for a broad range of pro- and anti-inflammatory cytokine and chemokine genes are temporally regulated after CLP in the lung and liver . We also assessed whether prophylactic administration of monophosphoryl lipid A (MPL), a nontoxic derivative of lipopolysaccharide (LPS) that induces endotoxin tolerance and attenuates the sepsis syndrome in mice after CLP, would alter tissue-specific gene expression post-CLP . Levels of pulmonary interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), granulocyte colony-stimulating factor (G-CSF), IL-1 receptor antagonist (IL-1ra), and IL-10 mRNA, as well as hepatic IL-1beta, IL-6, gamma interferon (IFN-gamma), G-CSF, inducible nitric oxide synthase, and IL-10 mRNA, were reduced in MPL-pretreated mice after CLP compared to control mice . Chemokine mRNA expression was also profoundly mitigated in MPL-pretreated mice after CLP . Specifically, levels of pulmonary and hepatic macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, MIP-2, and monocyte chemoattractant protein-1 (MCP-1) mRNA, as well as hepatic IFN-gamma-inducible protein 10 and KC mRNA, were attenuated in MPL-pretreated mice after CLP . Attenuated levels of IL-6, TNF-alpha, MCP-1, MIP-1alpha, and MIP-2 in serum also were observed in MPL-pretreated mice after CLP . Diminished pulmonary chemokine mRNA production was associated with reduced neutrophil margination and pulmonary myeloperoxidase activity . These data suggest that prophylactic administration of MPL mitigates the sepsis syndrome by reducing chemokine production and the recruitment of inflammatory cells into tissues, thereby attenuating the production of proinflammatory cytokines.

Ann Surg, 1998 Jul, 228(1), 131 - 9
Growth hormone and insulinlike growth factor 1 promote intestinal uptake and hepatic release of glutamine in sepsis; Balteskard L et al.; OBJECTIVE: To study the effects of growth hormone (GH) and insulinlike growth factor 1 (IGF-1) on whole body and gastrointestinal (GI), hepatic, femoral, and renal glutamine (GLN) uptake and release in septic piglets . SUMMARY BACKGROUND DATA: The GI metabolism of GLN is impaired during sepsis, and this may contribute to a breakdown of the gut's mucosal barrier . GH treatment has produced increased GI GLN uptake in surgical stress . Little is known about the effects of GH and IGF-1 in sepsis . METHODS: Twenty-four piglets were randomized to three groups of eight each: a GH group received a bolus of 16 IU of Genotropin; an IGF-1 group received a continuous infusion of 1.3 mg/hour of IGF-1; and a control group received saline . After surgical preparation, sepsis was induced with live Escherichia coli bacteria . Using isotope technique, whole body turnover and organ-specific absolute uptake and release were measured before and 4 hours after sepsis . RESULTS: After sepsis, both GH and IGF-1 treatment increased GI GLN uptake compared with controls and induced hepatic release of GLN . GLN release from skeletal muscle was diminished in all groups after sepsis . Whole body GLN turnover was increased in the GH and IGF-1 groups compared with the controls, before and after sepsis . CONCLUSIONS: GH and IGF-1 treatment induced increased GI net uptake of GLN . GH and IGF-1 treatment also promoted absolute and net release of GLN from the liver . This release might facilitate increased GI uptake despite reduced hindleg release in the early phase of sepsis.

Br J Surg, 1998 Jun, 85(6), 818 - 25
Proinflammatory mediator activity, endogenous antagonists and the systemic inflammatory response in intra-abdominal sepsis . Scottish Sepsis Intervention Group; Wakefield CH et al.; BACKGROUND: Severe intra-abdominal sepsis continues to carry a high mortality rate . The physiological response to sepsis in this condition and its relationship with proinflammatory mediators and their endogenous antagonists require further clarification . METHODS: Fifty-seven patients were stratified by Acute Physiology And Chronic Health Evaluation (APACHE) II score at the time of admission to an intensive care unit (group 1, score of less than 20; group 2, score of 20 or more) . Serial measurements of clinical and immunological variables were made . RESULTS: Non-survivors from group 2 had a raised acute physiology score (P = 0.01), a higher peak serum interleukin (IL) 6 concentration (P = 0.03) and a depressed level of endogenous immunoglobulin (Ig) G class antiendotoxin core antibody (P = 0.005) . In group 1, although organ failure score increased progressively in non-survivors, physiology score and peak IL-6 level were similar to those in survivors, and endogenous IgG class antiendotoxin core antibody titre rose (P = 0.02) . In both groups IL-1 and tumour necrosis factor alpha were detected infrequently, but their natural antagonists were present in much higher concentrations in both survivors and non-survivors . Levels of C-reactive protein were raised in both but were not significantly different between survivors and non-survivors . CONCLUSION: During the development of organ failure and death, the pattern of proinflammatory mediators and their endogenous antagonists can vary markedly and may in part be determined by the extent of the initial physiological disturbance.

An Esp Pediatr, 1998 Jun, 48(6), 639 - 43
{Prospective study of Candida-related sepsis in the neonate}; Jaraba Caballero S et al.; OBJECTIVE: Our objective was to carry-out a prospective study of newborns with systemic candidiasis admitted to our Neonatology Unit in a teritiary hospital during the period of March 1994-September 1997 . PATIENTS AND METHODS: To be included in the study the patient had to have Candida sp recovered from a normally sterile body fluid and clinical signs of sepsis . We analyzed perinatal and neonatal antecedents, risk factors, clinical course, diagnosis, treatment and outcome . RESULTS: The incidence of systemic candidiasis was 0.62% (14 newborns) . Two were term infants and 12 preterm infants, 9 of which weighed less than 1500 g . All of the patients had as predisposing factors the use of broad spectrum antibiotics, prolonged intravascular catheterization and parenteral nutrition, while 64% had mechanical ventilation . The mean age at onset of sepsis was 22 days, with non-specific clinical presentation . Four infants were treated with intravenous amphotericin B and 9 with liposomal amphotericin B in association with fluconazole in one patient and with flucytosine and fluconazole in another . No adverse effects were observed . Mortality was 21% . C . parapsilosis was isolated in 7 cases and C . albicans in another 7 patients, with an important increase in C . parapsilosis in the last few years . CONCLUSIONS: Clinical suspicion of invasive candidiasis requires the removal of indwelling catheters and early initiation of systemic ungal therapy to reduce mortality . The increased incidence of species with more epidemic presentation like C . parapsilosis reinforce the importance of control measures such as handwashing for all personnel and aseptic management of intravascular catheters and solutions in order to prevent infections.

JPEN J Parenter Enteral Nutr, 1998 Jul-Aug, 22(4), 217 - 23
Use of intravenous lipids in critically ill patients with sepsis without and with hepatic failure; Druml W et al.; BACKGROUND: Fat is the preferred energy fuel both in patients with sepsis and with hepatic failure . Thus lipid emulsions should serve as an ideal nutritional substrate in parenteral nutrition . However, previous studies have generated conflicting results on the utilization of artificial lipids in these disease states, and systematic studies in critically ill patients with combined organ dysfunctions and additional complications are lacking . We compared the elimination, hydrolysis, and oxidation of a 20% lipid emulsion in critically ill patients on respiratory support with sepsis and with sepsis plus hepatic failure and in healthy control subjects . SETTING: Medical critical care unit of a university hospital . SUBJECTS AND METHODS: Eight critically ill patients with sepsis, 8 patients with sepsis and decompensated chronic hepatic failure, and 10 healthy volunteers were investigated . Elimination and hydrolysis was evaluated during constant i.v . infusion of 4.5 mg.kg body wt-1.min-1 of triglycerides during 120 minutes . Concentrations of plasma triglycerides, free fatty acids, and glycerol were measured, and elimination parameters were analyzed from plasma curves of triglycerides by using a two-compartment model . Resting energy expenditure and substrate oxidation were measured by indirect calorimetry . RESULTS: In patients with sepsis without and with hepatic failure the rise in plasma triglycerides was blunted and the clearance of triglycerides was enhanced by 20% and 40% (p < .05), respectively, compared with healthy controls . Basal free fatty acid concentrations were elevated, and the rise of free fatty acids and glycerol was comparable to healthy subjects . Energy expenditure was increased and lipid oxidation (as fraction of total energy expenditure) was slightly elevated in both patient groups; the rise in lipid oxidation during lipid infusion was comparable to controls . No side effects or impairment of gas exchange was seen . CONCLUSIONS: In a clinically relevant dosage range, the utilization of an i.v . lipid emulsion, the elimination and hydrolysis of triglycerides, and the lipid oxidation is not impaired in ventilated critically ill patients with sepsis or sepsis and chronic hepatic failure . Lipid emulsions thus are efficiently metabolized in critically ill patients with combined organ dysfunctions and associated sepsis.

Crit Care Med, 1998 Jun, 26(6), 1001 - 6
Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis; Nylen ES et al.; OBJECTIVES: Procalcitonin (ProCT), the precursor to the calcitonin hormone, is abnormally increased in experimental and clinical systemic inflammation, including sepsis . Initially, we investigated the effects of supraphysiologic amounts of ProCT administered to animals with septic peritonitis . Subsequently, we evaluated the efficacy of prophylactic and therapeutic immune blockade of ProCT in this lethal model of sepsis . DESIGN: Prospective, experimental, controlled study . SETTING: Animal research laboratory approved by the American Association for the Accreditation of Laboratory Animal Care at a Veterans Affairs Medical Center . SUBJECTS: Young male Golden Syrian hamsters, weighing 90 to 120 g . INTERVENTIONS: In the first study, serum ProCT concentrations were measured in animals at 0, 3, 6, 12, and 24 hrs after induction of sepsis by intraperitoneal implantation of pellets containing Escherichia coli (5 x 10(8) colony-forming units/pellet) . In the second study, with mortality as the end point, 30 microg/kg of isolated, purified human ProCT in 10% hamster serum (experimental) or an equal volume of 10% hamster serum (control) were administered intravenously at the time of the E . coli peritoneal implantation . In the third study, experimental animals received intraperitoneal injections of a multiregion-specific goat antiserum reactive to hamster ProCT 1 hr before and 24 hrs after E . coli implantation, while control animals received nonimmune goat serum at the same time points . In the final study, the same antiserum was administered in five divided doses during the 24 hrs after the insertion of E . coli . MEASUREMENTS AND MAIN RESULTS: In the initial study, ProCT concentrations were increased shortly after induction of sepsis and peaked at 12 hrs . Administration of exogenous ProCT to septic animals significantly increased mortality compared with control animals (93% vs . 43%, p=.02) . Prophylactic blockade of ProCT almost completely protected the animals from the lethal effects of sepsis: the 102-hr mortality rate in the experimental group was 6% compared with 62% in the control group (p < .003) . In the therapeutic trial, the 102-hr mortality rate was 54% in experimental animals compared with 82% in control animals (p < .045) . CONCLUSIONS: These results demonstrate that increased ProCT exacerbates mortality in experimental sepsis, whereas neutralization of ProCT increases survival . Thus, ProCT, in addition to being an important marker of severity of systemic inflammation and mortality, is an integral part of the inflammatory process and directly affects the outcome.

Rozhl Chir, 1998 Apr, 77(4), 146 - 9
{The significance of cytokines in the early diagnosis of postoperative intraabdominal sepsis}; Gurlich R et al.; The objective of the investigation was to evaluate the possible use of selected cytokines and cytokine receptors in the early diagnosis of postoperative intraabdominal sepsis . The investigation was focused on the dynamics of plasma levels of tumour necrotizing factor-alfa (TNFalfa), interleukin (IL)-1beta, IL-2, IL-6, IL-8, IL-10, soluble receptors IL-2 and IL-6 (sIL-2R and sIL-6R) and the receptor antagonist IL-1 (IL-1ra) . The investigated parameters were tested on model operations (resection of large bowel and resection of pancreas) . These two groups were compared with values recorded in patients with sepsis and with healthy subjects . Based on the assembled results the authors recommend to use for postoperative investigations the first 48 hours and to follow up the following parameters: IL-6, IL-ra or sIL-2R . During the first 48 hours these indicators differentiate sufficiently specifically incipient sepsis from an uncomplicated postoperative condition . During the subsequent period, i.e . more than 48 hours after surgery, it is useful to include in the examination pattern also some acute stage proteins (C reactive protein, alfa1-antitrypsin and haptalobin) which differentiate sepsis between the 3rd and 5th day after surgery.

J Surg Res, 1998 Mar, 75(2), 170 - 6
Visceral ischemia and neutrophil activation in sepsis and organ dysfunction; Foulds S et al.; BACKGROUND: It has previously been shown that a rise in intraoperative neutrophil CD11b expression during supracoeliac cross-clamping is a marker for subsequent development of postoperative organ dysfunction . Prolonged visceral ischemia and increased aneurysm extent are associated with higher risks of morbidity and mortality after TAAA repair . This study investigates the relationship between visceral ischemia and neutrophil activation in sepsis and organ dysfunction following visceral reperfusion . METHOD: Fifty-one patients undergoing supracoeliac cross-clamping, 5 patients undergoing suprarenal clamping, and 8 patients undergoing infrarenal clamping for repair of aortic aneurysms were studied . Perioperative neutrophil CD11b expression was measured by flow cytometry . RESULTS: There was significant correlation between visceral clamp time and intraoperative CD11b expression . More extensive aneurysms resulted in increased visceral clamp times and CD11b expression . There were no differences between bypass and non-bypass-assisted surgery with regard to neutrophil expression . There were increased clamp time in patients who developed severe sepsis and postoperative organ dysfunction . Differences in preoperative levels of CD11b expression were observed between groups and high levels of preoperative CD11b expression were observed in patients who died intraoperatively, in type II patients who went on to develop severe sepsis and organ failure, and in patients who developed multiple organ failure rather than single organ failure . CONCLUSION: Longer periods of visceral ischemia are associated with higher levels of intraoperative CD11b expression, severe sepsis, and organ failure . High preoperative levels of CD11b may identify an "at-risk" subset of patients.

J Surg Res, 1998 Mar, 75(2), 165 - 9
Phospholipase A2 activities are decreased during early but increased during late phases of sepsis in rat heart; Tong LJ et al.; BACKGROUND: Changes in the activities of secretory phospholipase A2 (sPLA2) and cytosolic phospholipase A2 (cPLA2) in the rat heart during early hyperdynamic and late hypodynamic phases of sepsis were studied in an attempt to understand the pathophysiology of cardiac dysfunction during sepsis . METHODS: Sepsis was induced by cecal ligation and puncture (CLP) . Experiments were divided into three groups: control, early sepsis, and late sepsis . Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after CLP . PLA2 activity was measured based on the rate of hydrolysis of 1-palmitoyl-2-{1-(14)C}-oleoyl phosphatidylcholine . RESULTS: The results show that under physiological conditions, sPLA2 and cPLA2 activities were time and protein dependent . The optimal Ca2+ concentrations for sPLA2 and cPLA2 activities were 3 mM and 40 microM, respectively . During sepsis, sPLA2 activity was decreased by 25% (P < 0.01) during early phase while it was increased by 49% (P < 0.01) during late phase of sepsis . Similarly, cPLA2 activity was decreased by 23% (P < 0.01) during early sepsis while it was increased by 60% (P < 0.01) during late sepsis . CONCLUSIONS: Since PLA2 functions to maintain cell membrane integrity and function, a biphasic change in sPLA2 and cPLA2 activities may contribute to the development of the two cardiodynamically distinct phases during the progression of sepsis.

J Surg Res, 1998 Mar, 75(2), 97 - 102
The central response to ovarian carcinoma simulates the response to sepsis; Carson LF et al.; BACKGROUND: Animal models of stress and sepsis demonstrate increased hypophyseal gene expression of the transcription factor c-fos and the cytokines interleukin-1 and interleukin-6 . Chronic central nervous system exposure to interleukin-1 results in hypermetabolism, accelerated nitrogen loss, anorexia, and cachexia . We test the hypothesis that the host response to ovarian carcinoma recapitulates the host response to sepsis regarding the elaboration of the transcription factors and cytokines in the central nervous system, liver, and lung . MATERIALS AND METHODS: Nude mice were seeded intraperitoneally with either ovarian carcinoma (MA-148) or vehicle . The animal subjects were observed for 5 weeks and sacrificed for brain, pituitary, lung, and liver mRNA . We studied the mRNA accumulation of the transcription factors c-fos, c-jun, and C/EBP alpha and the cytokines interleukin-1 and interleukin-6 using reverse-transcriptase polymerase chain reaction . RESULTS: Compared with the control, ovarian carcinoma in the mouse model resulted in the following: (1) Pituitary c-fos and c-jun mRNA increased 3-fold (P = 0.012) and 6-fold (P < 0.001), respectively; (2) pituitary IL-1 and IL-6 mRNA increased 4-fold (P < 0.001) and 8-fold (P = 0.037), respectively; (3) liver c-fos mRNA increased > 8-fold (P < 0.001); and (4) lung C/EBP alpha mRNA decreased greater than 10-fold (P < 0.001) . CONCLUSIONS: We conclude that the host response to ovarian carcinoma in this animal model recapitulates many aspects of the host response to bacterial sepsis especially concerning pituitary gene expression . These data suggest that, as in sepsis, a hypothalamic-hypophyseal-mediated cytokine response in ovarian carcinoma may result in hypermetabolism, accelerated nitrogen loss, anorexia, and cachexia.

New Horiz, 1998 May, 6(2), 194 - 200
Potential protective role of the heat shock response in sepsis; Wong HR; The heat shock response, a primitive and highly conserved cellular defense mechanism, has broad protective effects against sepsis-induced injury . In various models of sepsis, induction of the heat shock response protects against sepsis-induced mortality, organ injury, cardiovascular dysfunction, and apoptosis . The mechanisms by which the heat shock response protects against sepsis-induced injury are currently under investigation . One potential mechanism involves the ability of the heat shock response to inhibit proinflammatory responses . The heat shock response has been demonstrated to inhibit expression of the cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta . The heat shock response has also been demonstrated to inhibit cytokine-mediated expression of inducible nitric oxide synthase . Recent studies demonstrated that the heat shock response inhibits nuclear translocation of nuclear factor-kappaB (NF-kappaB), a transcription factor involved in the regulation of many proinflammatory responses . Heat shock response-mediated inhibition of NF-kappaB nuclear translocation involves stabilization of an NF-kappaB inhibitory protein called I-kappaBalpha . The heat shock response also increases expression of I-kappaBalpha, thus providing another potential mechanism by which the heat shock response can modulate proinflammatory responses . Future studies designed to further understand the protective role of the heat shock response against sepsis-induced injury may allow for the development of rational pharmacologic agents or gene therapy methods to safely induce the heat shock response as a strategy to treat patients with sepsis.

New Horiz, 1998 May, 6(2 Suppl), S97 - 102
Therapeutic immunomodulatory approaches for the control of systemic inflammatory response syndrome and the prevention of sepsis; Faist E et al.; In the sequelae of massive traumatic stress, substantial impairment of immunologic reactivity has been demonstrated to correlate clinically with increased susceptibility to serious infection . Posttraumatic immune abnormalities consist basically of two coexistent mechanisms: Hyperinflammation and depression of cell-mediated immune responses . It is our understanding that the endogenous ability of the organism to survive overwhelming trauma is insufficient and requires exogenous support to prevent the conversion from systemic inflammatory response syndrome to bacterial sepsis and septic shock . The objectives of immunomodulatory interventions, which should be started as early as possible after tissue destruction, include a) prevention of excessive macrophage stimulation via neutralization of circulating endotoxins and exotoxins with high doses of polyvalent immunoglobulin and soluble complement receptors, b) global short-term (<72 hrs) down-regulation of inflammatory monocyte/macrophage and polymorphonuclear neutrophil activity, and c) restoration of cell-mediated immune performance to overcome posttraumatic functional paralysis . Among recent promising strategies, the use of granulocyte-macrophage colony-stimulating factor, pentoxifylline, and recombinant human interleukin-13 has been suggested, all of them predominantly down-regulating the Mphi (monocyte/macrophage) inflammatory potential . Cyclooxygenase inhibitors such as indomethacin and thymomimetic peptides can help normalize the immunoreactivity by restoring the forward-regulatory pathway of cell-mediated immunity responses . The efficacy of interferon to reduce infection and deaths in severely injured patients has been assessed in clinical trials . Still other compounds, i.e., CNI-1493, interleukin-11, tissue factor pathway inhibitors, and PGG-Glucan represent auspicious immunomodulatory approaches for control of posttraumatic or postoperative infections.

Pediatrics, 1998 Jul, 102(1 Pt 1), 6 - 13
A randomized, placebo-controlled trial of granulocyte colony-stimulating factor administration to newborn infants with neutropenia and clinical signs of early-onset sepsis; Schibler KR et al.; OBJECTIVE: To determine whether recombinant human granulocyte colony-stimulating factor (G-CSF) administration: 1) accelerates production of neutrophils; 2) increases bone marrow stored and precursor neutrophils; and 3) is safe in newborn infants with neutropenia and clinical signs of early-onset sepsis . STUDY DESIGN: We randomized 20 infants with neutropenia and clinical signs of early-onset sepsis in the first 3 days of life to receive G-CSF (10 microg/kg/d) or placebo for 3 days . Entry criteria included neutropenia as defined by Manroe criteria, an elevated immature to total neutrophil ratio {(I/T) >/=0.25}, and a requirement for ventilatory support . Cultures were obtained and antibiotics initiated on all study infants . Circulating absolute neutrophil count (ANC), I/T ratio, bone marrow neutrophil storage pool (NSP) and neutrophil proliferative pool (NPP), and plasma G-CSF concentrations were evaluated . Also, severity of illness as determined using the Score for Neonatal Acute Physiology (SNAP), morbidity, and mortality were recorded . RESULTS: Circulating ANC increased in both G-CSF and placebo recipients by day 1 . Also, the I/T neutrophil ratio decreased in both G-CSF and placebo recipients . There were no significant differences in the ANC or I/T ratio between the two groups during the study period . Similarly, bone marrow NSP and NPP did not differ between G-CSF and placebo recipients at study entry or day 2 . No differences were observed in the secondary outcome measures including severity of illness, morbidity, and mortality . CONCLUSIONS: Administration of recombinant G-CSF to infants with neutropenia and clinical signs of early-onset sepsis did not increase circulating ANC, or bone marrow NSP and NPP compared with placebo . No differences were observed between G-CSF and placebo recipients in severity of illness, morbidity, or mortality . No adverse effects of G-CSF administrations were noted.

J Perinat Med, 1998, 26(2), 94 - 101
Risk factors for neonatal sepsis in offspring of women with prelabor rupture of the membranes at 34-42 weeks; Ladfors L et al.; One thousand three hundred eighty-five women with PROM (prelabor rupture of the membranes) participated in a prospective randomized study . Women with PROM were randomized to induction the following morning after PROM (early induction group) or induction two days later (late induction group) . If contractions started within 2 hours after admission these women were included in the short latency group . All neonatal infections were classified as verified sepsis (positive culture) or clinical sepsis . The aim of the study was to compare the perinatal infectious outcome between the groups with different expectant managements in women with PROM and to study the association between demographic, intrapartum and postpartum variables and neonatal sepsis . In the short latency group one neonate had a proven sepsis while four neonates with proven sepsis were found in the early induction group . No proven sepsis was detected in the late induction group . Univariate analyses showed a significant association between clinical sepsis and: induction of labor (OR = 2.94, 95% CI 1.30-6.68), established labor 24.1-32 hours after ROM (OR = 5.89, 95% CI 1.68-20.63), established labor > 32 hours after ROM (OR = 4.59, 95% CI 1.52-13.87), time from ROM to delivery > 32 hours (OR = 5.07, 95% CI 1.40-18.39), cesarean section (OR = 11.03, 95% CI 4.10-29.68), chorioamnionitis before or during delivery (OR = 27.14, 95% CI 2.38-309.16), endometritis (OR = 18.08, 95% CI 1.82-179.87), CRP over 20 mg/l in the umbilical cord (OR = 17.12, 95% CI 5.68-52.12) and Apgar score < 7 after 1, 5 or 10 minutes . In a stepwise logistic regression analysis a significant association was found between clinical sepsis and cesarean section (OR = 10.08, 95% CI = 3.26-31.20), time from ROM to delivery > 32 h (OR = 3.74, 95% CI 1.62-8.62), gestational age 34-36 weeks (OR = 3.16, 95% CI 1.11-8.96) and parous women (OR = 2.41, 95% CI 1.04-5.57) . In conclusion, this study indicates that that there was no difference in the incidence of neonatal infections between those with early and late induction . Clinical neonatal sepsis was associated with time from PROM to delivery over 32 hours, cesarean section, parous women and gestational age between 34 and 36 weeks.

Nutrition, 1998 Jun, 14(6), 554 - 6
Anabolic agents in trauma and sepsis: repleting body mass and function; Saito H; Both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are potent anabolic agents . Exogenous GH improves nitrogen metabolism in patients undergoing surgery; however, the anabolic effects of GH in cases of multiple injury, burn, and sepsis are equivocal . Moreover, few data are available concerning the effects of GH in organ failures . Exogenous IGF-1 attenuates catabolism in animal trauma models . A clinical trial, however, did not confirm the anabolic actions of IGF-1 . Further knowledge of the interaction between the GH/IGF-1 axis in critical illness is essential for GH and IGF-1 therapy . Theoretically, the improved nitrogen metabolism achieved with exogenous anabolic agents may provide functional benefits . However, only a few studies have confirmed the beneficial effects of GH on body function in trauma and sepsis . GH treatment decreases the postoperative depression of hand grip strength . GH also stimulates wound healing . Both GH and IGF-1 exert their effects on immune system, suggesting that these anabolic agents are potentially beneficial for the prevention and treatment of sepsis . On the contrary, inhibition of polymorphonuclear neutrophil apoptosis and the potentiation of PMNs by GH may have harmful effects on the systemic responses . Further studies are required to determine the safety and clinical benefits of GH administration in critical illness.

Shock, 1998 Jun, 9(6), 416 - 21
Effect of NG-nitro-L-arginine methyl ester on testicular blood flow and serum steroid hormones during sepsis; Sharma AC et al.; Production of nitric oxide (NO) via NO synthase (NOS) has been implicated in the regulation of steroidogenesis in normal physiology and septic pathophysiology . The hypothesis that blockade of NOS by NG-nitro-L-arginine methyl ester (L-NAME) would affect testicular blood flow and circulating levels of steroid reproductive hormones was tested . Male Sprague-Dawley rats (350-450 g) were randomized to septic and nonseptic groups . Sepsis was induced with an intraperitoneal (i.p.) injection of a cecal slurry (200 mg/kg in 5 mL 5% dextrose in water (D5W)) in rats, while nonseptic rats received only sterile D5W . The rats (n = 6 per group) were catheterized in the jugular vein, left ventricle (via right carotid artery), and tail artery to determine blood flow and systemic hemodynamics and to collect blood at 24 h after induction of sepsis/sham sepsis . After baseline (24 h post-cecal slurry challenge) measurement, L-NAME (.50 mg/ kg x min) was infused through the jugular vein for 10 min, blood flow was determined using a radioactive microsphere technique, and blood samples were collected . The serum concentrations of corticosterone, progesterone, and testosterone were determined using radioimmunoassay . Plasma concentrations of NO byproducts (NOx) were determined using the Greiss reaction . After 24 h, heart rate, testicular blood flow, and NOx levels were significantly increased, whereas the serum concentration of testosterone was significantly decreased in the septic group as compared with the nonseptic group . However, serum concentrations of progesterone and corticosterone at 24 h after induction of sham-sepsis or sepsis were not statistically different . Infusion of L-NAME significantly reduced the testicular blood flow and serum NOx levels in septic rats as compared with their baseline values . The administration of L-NAME significantly increased the concentration of testosterone in nonseptic and septic rats as compared with their respective basal values . However, testosterone levels in septic rats were still significantly lower than in nonseptic rats . The results of this study indicate that the synthesis of NO through NO synthase may play a role in the regulation of testicular blood flow and the serum levels of testosterone, associated with chronic peritoneal sepsis in the rat.

Rinsho Byori, 1998 Mar, 46(3), 265 - 70
{Measurement of levels of plasma endothelin-1 and serum nitrate anion in patients with sepsis}; Hara K et al.; Recently much attention has been paid to the circulatory disturbance and peripheral vascular damage in patients with sepsis and septic shock . We intended to elucidate the interaction between nitric oxide (NO) and endothelin (ET)-1 under various pathological conditions by measuring the concentrations of NO3-, the principal metabolite of NO and immunoreactive ET-1 . In cases with good prognosis after the septic shock, ET-1 was significantly higher as compared with these in sepsis without shock . In lethal cases with septic shock, these parameters were abnormally high as compared with the survived case . These levels elevated as the degree of severity progressed . When patients recovered from the septic shock, plasma ET-1 levels rapidly decreased . These results may mean that the level of the concentration of ET-1 plays a key role for prevention of the multiple organ failure even after the recovery from septic shock . The elevated level of NO3- during the initial several days in septic shock will mean that NO is acting to prevent platelet aggregation and to keep blood flow by dilating the arteries during septic shock . On the contrary, it may also be suggested that the elevated level of NO3- and ET-1 leads to the dysfunction of vascular endothelial cells and the apoptosis.

Clin Sci (Lond), 1998 Apr, 94(4), 413 - 23
Sustained modifications of protein metabolism in various tissues in a rat model of long-lasting sepsis; Breuille D et al.; 1 . Sepsis was induced in rats by an intravenous injection of live bacteria . Infected and pair-fed animals were studied before the infection, in an acute septic phase (day 2 post-infection), in a chronic septic phase (day 6) and in a late septic phase (day 10) . Protein synthesis rates were measured in vivo after administration of a flooding dose of L{1-13C}valine . 2 . During the acute phase, muscle protein loss associated with infection resulted from both a decrease in protein synthesis and an increase in proteolysis . During the chronic phase and the late phase, the increase of proteolysis in infected rats as compared with pair-fed animals persisted, worsening muscle atrophy . Skin protein synthesis rates were not significantly modified by infection . However, skin protein content decreased 6 and 10 days after infection, suggesting an increased proteolysis in response to sepsis . 3 . Protein synthesis in liver of infected rats was twice that of pair-fed animals . Liver protein synthesis remained elevated in infected rats compared with pair-fed animals until day 10 . Hypoalbuminaemia and high plasma concentrations of fibrinogen were evident at all periods studied . alpha 2-Macroglobulin and alpha 1-acid glycoprotein reached peak concentrations during the acute phase (concentrations increased 50 times in infected rats) . On day 10, the levels of these proteins were still about 12-fold higher . 4 . Protein synthesis rates were significantly increased in the digestive tract and lung of infected rats compared with pair-fed groups on days 2 and 6, but were similar in the two groups on day 10 post-infection . The fractional protein synthesis rate was increased 3-fold over the entire experimental period in the spleen . 5 . The results show that sepsis stimulates protein synthesis in various tissues over a long time, and that skin, like muscle, can provide amino acids to the rest of the body.

Exp Lung Res, 1998 May-Jun, 24(3), 253 - 68
Differential expression of arginase and iNOS in the lung in sepsis; Carraway MS et al.; The primary metabolic fates of L-arginine are conversion to L-citrulline by nitric oxide synthase (NOS) and to L-ornithine by arginase . In the lung, arginine utilization is increased after the inducible form of NOS (iNOS) is expressed during inflammation . The expression of arginase in normal lung and after sepsis, and its potential relationships with iNOS, however, are not known . Since arginase and iNOS share the substrate L-arginine, we tested the hypothesis that lung arginase would be co-induced with iNOS in sepsis and its cellular distribution would be related to that of iNOS in the lung . Lungs from cecal ligation and puncture (CLP) and sham-operated (S) rats were harvested 6 or 16 hours after the procedures . Lung wet-to-dry weight ratio, myeloperoxidase content, and lipid peroxidation products were measured as indices of lung injury . Western blot analyses were performed with polyclonal antibodies against two isoforms of rat arginase (I and II) and iNOS . Additional lungs from CLP and S animals were inflation-fixed for immunohistochemistry using the same antibodies . We found by Western blot that arginase II at 39 kDa was the main isoform present in normal rat lung . The enzyme was distributed diffusely in alveolar and bronchial epithelial cells, endothelial cells, and alveolar macrophages . After CLP, arginase II was almost undetectable in rat lungs at 16 hours . In contrast, in normal lung, the iNOS was not detectable by Western blot or immunohistochemistry . After CLP, strong expression of iNOS was found in similar cell types to arginase II . These data demonstrate loss of constitutive expression of arginase II in rat lung as iNOS is upregulated by the response to sepsis.

Artif Cells Blood Substit Immobil Biotechnol, 1998 May, 26(3), 273 - 84
Influence of sepsis on the plasma elimination pharmacokinetics of diaspirin crosslinked hemoglobin in rats; d'Almeida MS et al.; Septic shock is characterized by abnormalities in microcirculatory O2 delivery (QO2) and profound tissue O2 debt . Administration of crosslinked hemoglobin may be a means of augmenting the QO2 and tissue O2 availability . Sepsis is associated with hemodynamic and metabolic alterations which may affect the pharmacokinetics of crosslinked hemoglobin . The objective of this study was to determine the effect of sepsis on the plasma elimination of diaspirin crosslinked hemoglobin (DCLHb) . Twenty-four hours after the induction of sepsis by cecal ligation and perforation, septic (n = 9) and sham rats (n = 8) received an intravenous infusion of 300 mg of DCLHb and arterial blood samples were taken at regular intervals to determine free plasma hemoglobin concentration . DCLHb elimination in septic and sham rats was consistent with first-order elimination kinetics . The half life (t1/2) for septic rats was 4.2 +/- 0.7 h and was significantly shorter than the t1/2 of non-septic rats (5.4 +/- 0.9 h) . In all rats, free plasma hemoglobin returned to basal levels by 24 hours after DCLHb administration . The volume of distribution for DCLHb in the septic and non-septic rats was not significantly different and suggests that DCLHb is not influenced by altered gut permeability . Despite significant changes in some elimination parameters the differences were small . Consequently, dosing regimens for this compound may not need to be altered in sepsis.

Chest, 1998 Jun, 113(6), 1632 - 9
Expression of inducible nitric oxide synthase and inflammatory cytokines in alveolar macrophages of ARDS following sepsis; Kobayashi A et al.; STUDY OBJECTIVE: The objective of this study was to evaluate the role of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines in alveolar macrophages (AMs) in the pathogenesis of ARDS following sepsis . SETTING: ICU in a university hospital . DESIGN: Prospective exploratory, open-labeled study was carried out . PATIENTS: A total of 24 patients were investigated: 8 patients diagnosed as having ARDS following sepsis (ARDS group); 8 patients under general anesthesia in the operating room whose lung functions were normal (control group); and 8 patients who were intubated and artificially ventilated for 1 week in the ICU whose lung functions were not deteriorated without fulfilling the ARDS criteria and whose general state fulfilled the sepsis criteria (long-term ventilation group, or LTV group) . MEASUREMENTS AND RESULTS: The expression of iNOS, interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and interleukin-8 (IL-8) in AMs obtained from BAL fluid (BALF) was determined by the immunofluorescent technique . We observed the significant expression of iNOS, IL-6, and IL-8 only in the ARDS group . Meanwhile, NOx (the sum of NO2- + NO3-) was elevated in the BALF supernatant, and IL-6 and IL-8 levels in both the BALF supernatant and the serum were also elevated in the ARDS group . No significant expressions were detected in the control and the LTV group . CONCLUSIONS: The result that iNOS was detected only in ARDS patients following sepsis suggests that iNOS together with proinflammatory cytokines produced by AMs might play a pivotal role in the pathogenesis of acute lung injury and be useful for monitoring disorders in the lung in such conditions.

Chest, 1998 Jun, 113(6), 1625 - 31
The compensatory anti-inflammatory cytokine interleukin 10 response in pediatric sepsis-induced multiple organ failure; Doughty L et al.; STUDY OBJECTIVES: To determine the circulating anti-inflammatory cytokine interleukin 10 (IL-10) response during the development of sepsis-induced multiple organ failure in children . DESIGN: Prospective study . SETTING: University pediatric ICU . PATIENTS: Fifty-three consecutive children with sepsis and 15 critically ill children without sepsis . INTERVENTIONS: Plasma IL-10, interleukin 6 (IL-6), and nitrite+nitrate (stable end products of nitric oxide) levels and an organ failure index (OFI indicating the number of failing organ systems) were determined in 53 children on days 1 to 3 of sepsis and in control children on day 1 . The effect of exogenous human IL-10 or neutralizing IL-10 antibody on supernatant IL-6 levels in ex vivo whole blood culture from 17 children on day 1 of sepsis . MEASUREMENTS AND RESULTS: Children with three or more organ failures had higher plasma IL-10 levels than children with less than 3 organ failures (days 1 and 3; p<0.05) . Children who developed sequential pulmonary/hepatic/renal failure had higher IL-10 levels (days 1 to 3; p<0.05) . Nonsurvivors had higher IL-10 levels (day 3; p<0.05) . IL-10 levels correlated with IL-6 levels (days 1 and 2) and nitrite+nitrate levels (days 1 and 3; p<0.05) . Whole blood samples incubated ex vivo with exogenous recombinant human IL-10 had decreased supernatant IL-6 levels (p<0.05) and neutralizing IL-10 antibody showed no significant effect . CONCLUSION: A persistent compensatory anti-inflammatory cytokine response characterizes sepsis-induced multiple organ failure . Administration of exogenous IL-10 may inhibit the early proinflammatory response; however, identification of individual immune responsiveness and possibility of persistent infection could be important to rational use in the later stages of pediatric sepsis.

Langenbecks Arch Surg, 1998 Mar, 383(1), 44 - 8
Outcome of patients with sepsis and septic shock after ICU treatment; Schoenberg MH et al.; OBJECTIVE: Today, sepsis syndrome is the leading cause of death in adult, non-coronary intensive care units (ICUs) and is of great clinical importance . The purpose of this review was to evaluate recent prospective studies concerning the short- and long-term prognosis of patients suffering from systemic inflammatory-response syndrome (SIRS), sepsis, severe sepsis and septic shock . It has been shown in multicentre prospective surveys that 1% and 0.3% of all patients admitted to hospitals suffer, respectively, from bacteraemia alone and bacteraemia with severe sepsis . This rate increases, of course, when only admissions to the ICUs are considered: the above-mentioned rates increase then by a factor of 8 and 30, respectively . Thus, approximately 10% of patients in the ICU suffer from sepsis, 6% from severe sepsis and 2-3% from septic shock . SIRS occurs more frequently and its occurrence ranges from 40% to 70% of all patients admitted to ICUs . Thereby, 40-70% suffering from SIRS progress to a more severe septic-disease state . The overall prognosis is still poor, despite the recent advances in ICU treatment . The mortality rate of SIRS ranges from 6% to 7% and in septic shock amounts to over 50% . In particular, abdominal sepsis exhibits the highest mortality rate with 72% . The long-term prognosis is equally poor; only approximately 30% survived the first year after hospital admission . CONCLUSION: The prognosis of sepsis and septic shock remains poor, despite the advances in ICU treatment . Although prognostic factors have been identified for some patients, groups have not yet been able to identify the immediate or long-term prognosis for the majority of these septic patients.

Langenbecks Arch Surg, 1998 Mar, 383(1), 26 - 34
Thirty years of anti-mediator treatment in sepsis and septic shock--what have we learned?
Neugebauer E, Rixen D, Raum M, Schafer U.
Sepsis, the systemic response (specific and non-specific) of the body to an infection, is an increasing clinical problem . During the last 30 years, nearly 50 clinical trials involving more than 10,000 patients have failed to demonstrate improvement of patients' outcome with different "anti-mediator" strategies . The wrong conceptional approaches to interact with the complex mediator network and flaws in study design and conduct are the main reasons for this disappointing situation . We learned, however, that the systemic host response is more than persistent uncontrolled inflammation; it is also a stimulation of the counter regulatory network . Although it is important to analyse the complex picture, we have now reached a point where more sophisticated strategies for describing complexity and novel attempts for synthesis are needed . Along this line, improved study designs (decrease of "signal-to-noise ratio") are mandatory . In addition, secondary preventive strategies are emphasised.

Langenbecks Arch Surg, 1998 Mar, 383(1), 11 - 4
Clinical relevance of sepsis scores; van Nieuwenhoven EJ et al.; In this article sepsis scoring systems commonly used are presented as regards their results and shortcomings . Furthermore, in a more general context, the direct and indirect effect on the individual patients is discussed and recommendations are given on how to use scoring systems.

Langenbecks Arch Surg, 1998 Mar, 383(1), 2 - 10
Molecular mechanisms of sepsis; Woltmann A et al.; Today a great number of problems in the field of bacterial sepsis remain to be solved . Understanding the molecular mechanisms of one of the most important bacterial products in the pathogenesis of sepsis - endotoxin may contribute to innovative and more effective therapies . Therefore, this review focuses on the structural and functional elements of endotoxin, its interaction with immune cells, and its biological activity . Finally, other bacterial components and their impact on sepsis are discussed.

Shock, 1998 Apr, 9(4), 304 - 9
Anti-intercellular adhesion molecule-1 antibody and intercellular adhesion molecule-1 gene deficiency do not prevent pulmonary neutrophil recruitment in polymicrobial sepsis; Que LG et al.; The intercellular adhesion molecule (ICAM)-1 is expressed constitutively in normal lungs and increased in pulmonary inflammation . Whether increased ICAM-1 expression in the lung contributes to neutrophil sequestration during lung inflammation in sepsis is unclear . We tested this hypothesis in mice after systemic sepsis from cecal ligation and puncture (CLP) . ICAM-1 expression in mouse CLP lung tissue was found to increase with time . The time course of lung ICAM-1 up-regulation correlated with increases in lung myeloperoxidase (MPO) activity and neutrophil sequestration by light microscopy . The monoclonal IgG2b rat anti-mouse antibody, an anti-ICAM-1 antibody (YN1/1.7), administered intravenously at doses of 3, 10, or 30 mg/kg, however, did not decrease the lung MPO levels compared with nonimmune rat IgG . In support of these findings, lung MPO content in ICAM-1-deficient mice that underwent CLP was significantly higher than similarly treated ICAM-1-sufficient mice . Our results suggest that neutrophil sequestration in the mouse lung after CLP is not dependent on ICAM-1.

Shock, 1998 Apr, 9(4), 289 - 95
Effect of aminoguanidine on plasma nitric oxide by-products and blood flow during chronic peritoneal sepsis; Alden KJ et al.; We hypothesized that plasma nitric oxide (NO), generated via inducible NO synthase (iNOS) or endothelial constitutive NO synthase and measured via its by-products NO2- and NO3- (NO2- + NO3- = NOx) would increase and remain elevated during chronic peritoneal sepsis . We further hypothesized that treatment with aminoguanidine (AG; 50 mg/kg), a selective iNOS inhibitor, would decrease NO production and alter blood flow . Sprague Dawley rats were randomized to septic and nonseptic groups . Septic rats received an intraperitoneal cecal slurry (200 mg of cecal material/5 mL 5% dextrose-H2O/kg); control rats received sterile 5% dextrose-H2O (5 mL/kg) only . Plasma NOx and hemodynamics were measured 0, 4, 12, 24, and 48 h after sepsis or sham induction . We also examined the effect of AG, an iNOS inhibitor, on plasma NOx levels and tissue blood flow at 24 h . Septic rats uniformly displayed signs of sepsis, including lethargy, piloerection, and diarrhea . NOx levels were significantly elevated compared with controls at 4, 12, 24, and 48 h (p < or = .05) . Septic rats also demonstrated hypotension (t = 12, 24, and 48 h) and tachycardia (t = 4, 12, 24, and 48 h) . The infusion of AG (50 mg/kg intravenously for 30 min) at 24 h significantly decreased plasma NOx in septic animals . Plasma NOx concentrations returned to basal levels by 90 min after infusion of AG . In addition, blood flow studies demonstrated that AG treatment in nonseptic rats resulted in a significant decrease in blood flow to the stomach, skin, and adipose tissue, whereas AG infusion did not significantly alter the regional perfusion profile in septic animals . Furthermore, treatment with AG did not significantly alter mean arterial pressure in either group; however, nonseptic animals exhibited a decrease in stroke volume, and septic animals demonstrated an increase in heart rate . In contrast to the rise and fall of NOx levels in endotoxemia, this study demonstrates that the initial rise is sustained during 48 h of peritoneal sepsis . This sustained increase in NOx levels in this model correlated with the observable signs of systemic infection and may relate to enhanced iNOS activity . AG infusion demonstrated variable effects on regional tissue blood flow profiles in septic and nonseptic animals and attenuated the increase in plasma NOx levels in septic animals, an index of iNOS activity.

Vojnosanit Pregl, 1998 Mar-Apr, 55(2 Suppl), 75 - 8
The significance of immunoglobulins in the treatment of patients with sepsis and septic shock; Bojic I et al.; Inappropriate body response is, besides the infectious agent, responsible for the genesis of sepsis and septic shock . It is non-specific and in cascade of events it can hardly be controlled . The results of immunoglobulins administration compared to the disease course and outcome have been compared and analyzed in 135 patients with sepsis and septic shock . A hundred and four patients were treated for sepsis . Immunoglobulins were administered to 18, of whom 17 patients (94.55%) were cured, while one (5.55%) developed septic shock with lethal outcome . Out of the other 86 patients who did not receive immunoglobulins, 82 (95.35%) were cured, while in 4 (4.65%) patients the outcome was lethal . No difference was observed between studied groups . Among 31 patients with septic shock, 13 received immunoglobulins . Seven (53.85%) patients were cured, and 6 (46.15%) died . In relation to the favorable disease outcome the difference was observed (statistically non-significant) in the group that received immunoglobulins, compared to the group that did not (53.85% vs . 44.45%) . The importance of immunoglobulins administration, in sepsis and septic shock should be emphasized.

Vojnosanit Pregl, 1998 Mar-Apr, 55(2 Suppl), 71 - 4
High doses of immunoglobulins decrease mortality rate of surgical patients with severe intraabdominal infections and sepsis; Marenovic T et al.; Two groups of 40 surgical Intensive Care Unit patients each, were included in the study . All patients had severe intraabdominal infections and sepsis, and septic score higher than 20 . All were treated with individual specified conventional symptomatic therapy, and 40 of them received high doses of intravenous immunoglobulins . Significantly lower mortality rate was noticed in IVIG group (40%) than in control group (63.7%) . Immunoglobulin therapy also decreased mortality rate in patients with septic shock, but it was no more effective than conventional therapy in patients with multiple organ failure (MOF).

Orv Hetil, 1998 May 17, 139(20), 1229 - 33
{The role of elective hemofiltration in the management of sepsis and multiple organ failure}; Molnar Z et al.; Septic shock and the multiple organ dysfunction syndrome carries a very high risk of mortality . The exact pathomechanism of the development of multiorgan dysfunction is yet to be revealed and its treatment remains the biggest challenge in intensive care . In order to prevent the development of multiple organ dysfunction new therapeutic modalities have been investigated over the last years . One promising intervention is the exchange of large volumes of ultrafiltrate during haemofiltration termed as "elective" haemofiltration . By removing several middle molecular weight inflammatory mediators from the circulation, currently thought to be responsible for a number of complications due to sepsis, it as been suggested, that it might improve survival in theses patients.

J Mol Cell Cardiol, 1998 May, 30(5), 967 - 78
Cardiac myofilament protein function is altered during sepsis; Powers FM et al.; Male Sprague-Dawley rats (350-500 g) were made septic by intraperitoneal injection of 200 mg/kg cecal material in 5% dextrose in water (D5W; 5 ml/kg) . Control rats (n = 11) received D5W . Preparations were studied on days 1 (n = 7), 3 (n = 7), and 7 (n = 8) of sepsis . In isolated hearts, ventricular function was depressed on days 3 and 7 of sepsis . Densitometric analysis of myofilament proteins from septic rats separated by SDS-PAGE showed no differences in relative amounts of actin, troponin, tropomyosin and myosin light chains compared to control . Myofilament function, assessed by measuring ATPase activities, was altered during sepsis . CA(2+)-independent Mg-ATPase activity was elevated on days 1 and 3 of sepsis, returning toward control by day 7 . Maximal ATPase activity was unchanged on day 1, but was increased on days 3 and 7 sepsis . Myofibrillar myosin K(EDTA)-, Ca(2+)-, and Mg(2+)-ATPase activities were not altered, nor were there any apparent changes in myosin heavy chain isoform populations . Our data are the first to demonstrate alterations in minimal and maximal ATPase activities and myofilament CA(2+)-sensitivity during chronic peritoneal sepsis . These alterations may contribute to observed changes in ventricular function.

Shock, 1998 May, 9(5), 352 - 8
Cardiac contractility and structure are not significantly compromised even during the late, hypodynamic stage of sepsis; Zhou M et al.; Although cardiac function is depressed during endotoxic shock, it remains controversial whether the ventricular contractility and structure are altered during sepsis . To resolve this issue, rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) . At 2, 5, and 10 h after CLP (i.e., the early, hyperdynamic stage of sepsis) or 20 h after CLP (the late, hypodynamic stage of sepsis, based on the depressed tissue perfusion), in vivo left ventricular contractility parameters such as maximal rate of the left ventricular pressure increase (+dP/dtmax) and decrease (-dP/dtmax), maximal rate of "pressure-normalized" change in ventricular pressure (dP/dtmax/P), and ventricular peak systemic pressure were determined using a Digi-Med Heart Performance Analyzer . In additional groups of animals, ultrastructure of the cardiac muscle in the left ventricle was examined at 5, 10, or 20 h after CLP, using a transmission electron microscope . The results indicate that +dP/dtmax and dP/dtmax/P increased significantly at 2-10 h after CLP . The values of -dP/dtmax and ventricular peak systemic pressure increased significantly at 2 and 5 h after the onset of sepsis, respectively . These in vivo ventricular contractility parameters, however, were not significantly different from shams at 20 h after CLP . Ultrastructural examination showed that enlarged T-tubules were prominent during the hyperdynamic stage of sepsis, which was correlated with the increased cardiac contractility . Although focal and moderate hypertrophy as well as expanded intermyocyte junctions could be observed occasionally, myocardial cells did not appear to be compromised at 20 h after CLP . Thus, the transition from the hyperdynamic to hypodynamic circulation during sepsis does not appear to be due to any depression in myocardial function because cardiac contractility and structure are not compromised even during the late, hypodynamic stage of sepsis . However, further investigation is required to determine whether cardiac function is depressed at the terminal stage of polymicrobial sepsis.

Mol Cell Biochem, 1998 Feb, 179(1-2), 125 - 34
Respiratory muscle dysfunction in sepsis; Hussain SN; It became evident in the past 12 years that venitlatory muscle contractile performance is significantly impaired during the course of septic shock . In animal models of septic shock, depression of ventilatory muscle contractile performance has been shown to cause hypercapneic ventilatory failure and respiratory arrest . Failure of ventilatory muscle contractility in septic shock has never been attributed to a single factor, but two groups of factors are likely to be involved: (a) increased ventilatory muscle metabolic demands due to augmentation of ventilation, hypoxemia and increased pulmonary impedance; and (b) specific cellular, metabolic, immune and hemodynamic defects which interfere with several processes necessary for normal force generation . These defects are mediated by complex interactions between several local and systematic mediator such a bacterial endotoxin, proinflammatory cytokines, prostaglandins, platelet activating factor, reactive oxygen species and nitric oxide . This is a summary of how these interactions are likely to interfere with ventilatory muscle contractile performance in septic shock with particular emphasis on the newly described role of nitric oxide.

Intensive Care Med, 1998 Apr, 24(4), 336 - 42
Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study; Baudo F et al.; BACKGROUND: ATIII is decreased in sepsis and/or shock and its baseline value correlates with mortality . The efficacy of ATIII therapy on mortality was assessed in a selected group of patients admitted to the intensive care unit (ICU) in a double-blind, randomized, multicenter study . METHODS: 120 patients admitted to the ICU with an ATIII concentration < 70% were randomized to receive ATIII (total dose 24000 units) or placebo treatment for 5 days; 56 patients had septic shock . RESULTS: ATIII concentrations in the treated group remained constant throughout the treatment period (range 97-102%) . The Kaplan-Meier analysis showed no difference in overall survival between the two groups: 50 and 46% for ATIII and placebo, respectively . Septic shock and hemodynamic support were unbalanced in the two groups at admission . Therefore the Cox analysis was carried out after adjusting for these two variables . Treatment with ATIII decreases the risk of death with an odds ratio (OR) of 0.56 . Of the covariates analyzed, septic shock and the baseline multiple organ failure score were negatively associated with survival and plasma activity level was positively associated with survival with an OR of 0.97 for each 1% increase in the ATIII plasma concentration at baseline . CONCLUSIONS: The results of ATIII treatment in this population of patients suggests that replacement therapy reduces mortality in the subgroup of septic shock patients only.

J Pediatr Surg, 1998 May, 33(5), 714 - 6
A prospective randomized trial of urokinase as an adjuvant in the treatment of proven Hickman catheter sepsis; Atkinson JB et al.; BACKGROUND/PURPOSE: Chronic vascular access catheters have become an important adjunct to the treatment of children with complex medical diseases, particularly malignancy . One of the major complications of chronic venous access devices is bacterial infection of the catheter site and bloodstream . Infusion of systemic antibiotics directly into the catheter has been the standard initial therapy with failure leading to catheter removal and replacement . It has been suggested by a number of investigators that the addition of urokinase as a thrombolytic agent to lyse any accumulated thrombus or fibrin would increase the successful catheter clearance by antibiotics . This study was designed as a prospective, randomized trial to compare treatment of children with positive catheter blood cultures with either antibiotics alone or in combination with urokinase 5,000 U boluses 12 and 24 hours after study entry . METHODS: A total of 63 patients were entered in the study . Thirty-three received antibiotics and urokinase, and 30 received antibiotics alone . RESULTS: A total of 45 catheters (71%) were cleared of infection and salvaged . Treatment failures leading to catheter removal occurred in 9 of 33 in the experimental group and 9 of 30 in the control population (no significant difference) . CONCLUSIONS: Urokinase could not be shown to act as an adjuvant in the clearance of infection from chronic central venous access catheters that had no evidence of clot or thrombus . This study required the performance of a dye study and excluded any patient with a known thrombus . This conclusion must therefore be limited to patients with no evidence of a clot or fibrin sheath.

J Perinatol, 1998 Mar-Apr, 18(2), 135 - 7
Placental blood sampling: an aid to the diagnosis of neonatal sepsis; Herson VC et al.; OBJECTIVE: To determine the usefulness of placental blood cultures in establishment of the diagnosis of early onset sepsis . STUDY DESIGN: Babies born to mothers with suspected intraamniotic fluid infection had blood cultures obtained from a branch of the umbilical vein on the fetal surface of the placenta immediately after delivery . The babies at highest risk (n = 35) had subsequent neonatal blood cultured from a peripheral vein (group 1), whereas 26 newborns at a lower risk did not (group 2) . A group of 20 term babies born after uncomplicated labor and vaginal delivery or by elective cesarean delivery served as control subjects . RESULTS: Placental blood cultures were more often positive for pathogens in group 1 (7 of 35; 20%; 0.09 to 0.36) than in group 2 (0 of 26; 0 to 0.11) or control subjects (0 of 20; 0 to 0.14; p < 0.02) . Within group 1, placental blood cultures were more often positive (7 of 35; 20%; 0.09 to 0.36) than subsequent neonatal blood cultures (1 of 35; 3%; 0 to 0.15; p < 0.05) . Contaminants were cultured in 3 of 81 (4%; 01 to 0.11) placental samples (all from group 1) compared with 1 of 35 (3%; 0 to 0.11) neonatal samples (difference not significant) . CONCLUSIONS: A carefully obtained culture of placental blood may be a useful addition or substitute for neonatal blood culturing in newborns at risk for early-onset sepsis by virtue of maternal risk factors.

J Perinatol, 1998 Mar-Apr, 18(2), 112 - 5
Nosocomial sepsis in the neonatal intensive care unit; Mullett MD et al.; OBJECTIVE: To evaluate the risk factors for nosocomial sepsis among infants hospitalized in 23 neonatal intensive care units . METHODS: Risk factors for nosocomial sepsis among 5760 admissions are analyzed by birth weight groups, <1 kg, 1 to 1.5 kg, and >1.5 kg . A Cox hazard regression model was used to evaluate further detail in the two lower weight groups . RESULTS: Use of corticosteroids had no effect on the incidence of nosocomial sepsis in the two lower weight categories although it was significant among the >1.5 kg infants . In a simple Cox model, significant risk factors included lowest birth weight category, ventilatory support, and presence of a central venous catheter . The complex Cox model revealed that an increase in total days of presence of central arterial catheter, use of antibiotics, and ventilatory support were significant but that total days of presence of a central venous catheter was not . A model for Candida sepsis revealed as a risk factor an increase in total days of use of antibiotics before infection . CONCLUSIONS: The risk for infection associated with presence of a central venous catheter is the same for each day of exposure (i.e., the same risk on day 5 of presence of the line as on day 30), but the risk associated with ventilatory support increases over time . Candida sepsis is associated with prolonged antibiotic use before the first episode of nosocomial sepsis and not with birth weight group.

J Trauma, 1998 May, 44(5), 750 - 8; discussion 758-9
Granulocyte colony-stimulating factor improves host defense to resuscitated shock and polymicrobial sepsis without provoking generalized neutrophil-mediated damage; Patton JH Jr et al.; BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) increases production and release of neutrophil precursors and activates multiple functions of circulating polymorphonuclear neutrophils (PMNs) . G-CSF has therapeutic effects in many experimental models of sepsis; its actions with superimposed reperfusion insults are unknown . In traumatic conditions, G-CSF could exacerbate unregulated, PMN-dependent injury to otherwise normal host tissue or, it could partially reverse trauma-induced immune suppression, which may improve long-term outcome . This study tested whether stimulating PMN proliferation and function with G-CSF during recovery from trauma+sepsis potentiated reperfusion injury or whether it improved host defense . METHODS: Anesthetized swine were subjected to cecal ligation and incision, 35% hemorrhage, and 1 hr of hypotension . Resuscitation consisted of intravenous G-CSF (5 microg/kg) or placebo followed by shed blood and 40 mL/kg of lactated Ringer's solution . The control group received laparotomy only . G-CSF or placebo was given daily . Animals were killed at 4 days . Observers, blind to the protocol, graded autopsy samples for localization of infection and quality of abscess wall formation . Data included complete blood count, granulocyte oxidative burst after phorbol myristate acetate stimulation in vitro (GO2B), bronchoalveolar lavage (BAL) cell count, BAL noncellular protein, lipopolysaccharide-stimulated tumor necrosis factor production in whole blood in vitro (lipopolysaccharide-tumor necrosis factor), and lung tissue myeloperoxidase (MPO) . RESULTS: Neutrophilia and localization of infection, were significantly improved by G-CSF . Variables altered by G-CSF, though not significantly, showed GO2B potential increased by 50%, lipopolysaccharide-tumor necrosis factor decreased by 50%, and improved survival versus placebo (100% vs . 70%) . G-CSF did not increase lung MPO, BAL cell count, or BAL protein . Both arterial and venous O2 saturations were unaltered . CONCLUSIONS: Our data show that G-CSF initiated at the time of resuscitation reduced the sequelae of posttrauma sepsis by increasing PMN proliferation and function without potentiating PMN-mediated lung reperfusion injury.

J Trauma, 1998 May, 44(5), 777 - 81; discussion 781-2
Prostaglandin E2 alterations during sepsis are partially mediated by endotoxin-induced inhibition of prostaglandin 15-hydroxydehydrogenase; Hahn EL et al.; Prostaglandin E2 (PGE2) is significantly elevated in the plasma of septic or injured patients and is thought to be a component of the resultant immune suppression associated with augmented rates of infection and mortality . Many studies have examined the effect of burn injury and sepsis on PGE2 synthesis . However, the effect of sepsis or burn injury on the expression of prostaglandin 15-hydroxydehydrogenase (PGDH), the key enzyme responsible for PGE2 degradation, has not been explored . The aim of this study was to examine the effect of endotoxin treatment and/or burn injury on the expression of PGDH . Male BDF1 mice were assigned to four groups (n = 4/group): sham, lipopolysaccharide (LPS) (2.5 mg/kg, Escherichia coli LPS, i.p.), burn (15% body surface area scald injury), and burn + LPS (15% body surface area + 2.5 mg/kg LPS, i.p.) . Lung tissue was harvested at specific time points after treatment and subsequently was processed for total RNA and protein . Northern and Western blot analyses were used to examine differences in PGDH protein and mRNA expression . Total RNA was probed with the riboprobe for murine PGDH, and the 100,000 g protein fraction was immunoblotted using an rabbit antimurine PGDH antibody . PGDH was expressed in lung at t = 0 in both the saline and LPS-treated animals . A decrease in mRNA expression was initially observed at 2 hours after LPS treatment . The decrease was also significant (p < 0.05) at 3 hours after LPS and maximal decrease in mRNA and protein expression was observed at 6 hours . At 24 hours after LPS administration, the PGDH mRNA and protein expression was still significantly depressed to 49% of control expression . PGDH expression was similar and not statistically different in both burn and burn + LPS treatment at t = 0 . At 2 hours after LPS, PGDH mRNA expression in the burn + LPS treatment group had significantly decreased to 47% in comparison with the burn alone group . Maximal decrease in PGDH mRNA and protein expression in lung from burn + LPS was observed at 6 hours after LPS treatment . This change represents a 73% decrease in mRNA in comparison with the time-matched burn control . At 24 hours after LPS administration, PGDH mRNA but not protein expression in the lung from burn + LPS treated mice was still significantly decreased . In summary, LPS treatment alters PGDH mRNA expression at the transcriptional and protein levels . Consequently, sepsis-induced increases in PGE2 levels may not be only due to increased PGE2 synthesis but also due to decreased PGDH expression and, hence, PGE2 degradation.

J Trauma, 1998 May, 44(5), 743 - 8; discussion 748-9
Functional analysis of monocyte subsets in surgical sepsis; Schinkel C et al.; BACKGROUND: Sepsis still remains a major cause of death after surgery . Impaired monocyte (Mphi) function and disruption of monocyte (Mphi/T-cell interaction were shown to be crucial for the development of septic complications in these patients . It was the objective of the study to assess more insights in Mphi behavior in surgical sepsis by means of analysis of Fc receptor- and human leukocyte antigen DR (HLA-DR) expression in Mphi subsets, and to evaluate the kinetics of these changes . METHODS: In a prospective study, 20 septic patients and 10 healthy control subjects were included . Peripheral Mphi were isolated on consecutive days after onset of sepsis, and FcR positive (FcR+) and negative (FcR-) subsets were separated by rosetting with antibody-coated human erythrocytes . Cell surface receptor expression and in vitro cytokine production were used to determine the clinical importance of these subsets . RESULTS: A significant monocytosis (3.5-fold; p < 0.01) and suppression of HLA-DR receptor expression (35%, p < 0.01) which correlate with sepsis severity and outcome could be demonstrated . There was a significant increase of FcR+ subsets in sepsis compared with control subjects (60% vs . 24%; p < 0.05) . In vitro stimulation of Mphi subsets and peripheral blood mononuclear cells revealed suppressed interferon-gamma synthesis (p < 0.05 up to 0.01) from day 1 to day 5, elevated neopterin release (p < 0.05) on day 14 and increased synthesis rates of proinflammatory cytokines (e.g., interleukin-1beta); p < 0.05) predominantly in FcR+ subsets . CONCLUSIONS: Sepsis results in a significant monocytosis and suppression of HLA-DR receptor expression, which are correlating with sepsis severity and outcome . A significant shift toward FcR+ Mphi subsets can be found . This subpopulation resembles the previously described "angry macrophage" that is characterized by high proinflammatory cytokine synthesis and suppressed antigen presentation and that contributes to a disruption of adequate Mphi/T-cell interaction, rendering the host anergic toward opportunistic infections . The extend of HLA-DR suppression and the shift toward FcR+ Mphi might characterize a high risk patient subpopulation, which could benefit from immunomodulatory strategies.

Burns, 1998 Feb, 24(1), 72 - 3
Successful cure of an extensive burn injury complicated with mucor wound sepsis; Tang D et al.; Mucormycosis is an opportunistic infection occurring in the severely immunocompromised patient . A case of mucormycosis occurring in a patient who sustained an 85 per cent TBSA burn injury is reported . Diagnosis and management is reported in the paper.

Can J Anaesth, 1998 Apr, 45(4), 360 - 6
Anaesthesia affects outcome of sepsis in mice; Imai T et al.; PURPOSE: To determine whether the survival curves and rates differ between a mutant strain of mice (C3H/HeJ: endotoxin-resistant) and an endotoxin-susceptible strain (C3H/HeN) when severe sepsis (caecal ligation and puncture: CLP) is performed with different anaesthetics (ketamine or varied exposure to halothane) . METHODS: The CLP was performed under a randomly chosen anaesthetic method out of inhalation of halothane in oxygen (15 min, 2 hr, or 6 hr) (100, 120, and 103 mice respectively) or a single injection of ketamine im (127 mice) in paired fashion in eight-week-old male mice of each strain . The daily survival rates were compared between the two strains until the 10th day after CLP for each anaesthetic and among the four anaesthetic methods for each strain using multiple comparisons . RESULTS: The C3H/HeJ had delayed death relative to the C3H/HeN with every anaesthetic method except a two hours halothane (P < 0.01 at day 1 and day 2-5 in halothane 15 min and 6 hr, P < 0.05 at day 4-6 in ketamine), however, the final survival rates for each method of anaesthesia were the same in the two strains . Regardless of the genetic susceptibility to endotoxin, short exposure to halothane resulted in the most rapid death compared with the other anaesthetic methods (P < 0.05), and two hours halothane showed the best survival . CONCLUSION: Endotoxin susceptibility affected the septic course for each anaesthetic method, and the anaesthetic methods influenced the survival from sepsis in both strains.

Stat Med, 1998 Apr 30, 17(8), 909 - 44
Development of a clinical prediction model for an ordinal outcome: the World Health Organization Multicentre Study of Clinical Signs and Etiological agents of Pneumonia, Sepsis and Meningitis in Young Infants . WHO/ARI Young Infant Multicentre Study Group; Harrell FE Jr et al.; This paper describes the methodologies used to develop a prediction model to assist health workers in developing countries in facing one of the most difficult health problems in all parts of the world: the presentation of an acutely ill young infant . Statistical approaches for developing the clinical prediction model faced at least two major difficulties . First, the number of predictor variables, especially clinical signs and symptoms, is very large, necessitating the use of data reduction techniques that are blinded to the outcome . Second, there is no uniquely accepted continuous outcome measure or final binary diagnostic criterion . For example, the diagnosis of neonatal sepsis is ill-defined . Clinical decision makers must identify infants likely to have positive cultures as well as to grade the severity of illness . In the WHO/ARI Young Infant Multicentre Study we have found an ordinal outcome scale made up of a mixture of laboratory and diagnostic markers to have several clinical advantages as well as to increase the power of tests for risk factors . Such a mixed ordinal scale does present statistical challenges because it may violate constant slope assumptions of ordinal regression models . In this paper we develop and validate an ordinal predictive model after choosing a data reduction technique . We show how ordinality of the outcome is checked against each predictor . We describe new but simple techniques for graphically examining residuals from ordinal logistic models to detect problems with variable transformations as well as to detect non-proportional odds and other lack of fit . We examine an alternative type of ordinal logistic model, the continuation ratio model, to determine if it provides a better fit . We find that it does not but that this model is easily modified to allow the regression coefficients to vary with cut-offs of the response variable . Complex terms in this extended model are penalized to allow only as much complexity as the data will support . We approximate the extended continuation ratio model with a model with fewer terms to allow us to draw a nomogram for obtaining various predictions . The model is validated for calibration and discrimination using the bootstrap . We apply much of the modelling strategy described in Harrell, Lee and Mark (Statist . Med . 15, 361-387 (1998)) for survival analysis, adapting it to ordinal logistic regression and further emphasizing penalized maximum likelihood estimation and data reduction.

Trop Doct, 1998 Apr, 28(2), 92 - 5
Puerperal sepsis: a preventable post-partum complication; Dare FO et al.; Patients with puerperal sepsis following delivery at Ife State Hospital (ISH) of Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC) Ile-Ife over a 10-year period spanning January 1986 to December 1995 were reviewed . One hundred and forty-six patients were diagnosed as having puerperal sepsis and there were 8428 deliveries giving an incidence of 1.7% . The incidence was higher among the unbooked patients 71.2% . Predisposing factors were: anaemia in pregnancy, 69.2%; prolonged labour (labour lasting up to 12 h or more), 65.7%; frequent vaginal examinations in labour (more than five), 50.7%; premature rupture of membranes, 31.5%; and non-adherence to asepsis during delivery . The case mortality rate was 4.1% . Antenatal care and supervised hospital delivery should be encouraged in order to prevent or reduce this serious post-partum morbidityPIP: This study of 146 consecutive cases of postpartum genital tract sepsis was undertaken to determine the characteristics and outcome of patients with puerperal sepsis . Included in the study were patients with puerperal sepsis admitted into Ife State Hospital of Obafemi Awolowo University Teaching Hospital Complex in Nigeria during the period of January 1986 to December 1995 . Findings revealed that 1.7% out of 8428 deliveries were diagnosed as having puerperal sepsis . The incidence was higher among unbooked patients (71.2%) . Predisposing factors of puerperal sepsis include anemia in pregnancy; prolonged labor (labor lasting up to 12 hours or more); frequent vaginal examination during labor (more than 5 times); premature rupture of membranes; and nonadherence to asepsis during delivery . In addition, the mortality rate was 4.1% . Thus, antenatal care and supervised hospital delivery should be encouraged in order to prevent or reduce the seriousness of postpartum morbidity .

Nephrologie, 1998, 19(2), 83 - 8
{Hemofiltration during severe sepsis or multiorgan failure syndrome}; Guenoun T et al.; Continuous renal replacement therapy (CRRT) has been used in intensive care units particularly in patients with sepsis or multiorgan failure . In comparison to intermittent haemodialysis, hemofiltration techniques offers an improved hemodynamic tolerance, related to the absence of osmotic pressure gradient . Indeed, hemofiltration is based on the physical principle of convection to remove substances from the plasma . The removal of substances that are released during sepsis, acute respiratory distress syndrome or multiorgan failure may be of particular interest . Several human studies have demonstrated that hemofiltration removes various inflammatory mediators, but the clinical significance of this removal remains questionable . If this removal occurs predominantly by convection, interest in hemofiltration will focus on high volume hemofiltration in order to obtain maximal ultrafiltrate flows . Patients with sepsis or multiorgan failure require close monitoring of most vital functions . The use of a CRRT technique emphasizes the importance of this monitoring and adds new monitoring issues relative to fluid balance, anticoagulation, hypothermia or drug removal.

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