Crit Care Med, 1998 May, 26(5), 895 - 904 Exogenous interleukin-10 fails to decrease the mortality or morbidity of sepsis; Remick DG et al.; OBJECTIVE: To determine if exogenous interleukin (IL)-10 will decrease the morbidity or mortality of sepsis induced by cecal ligation and puncture . DESIGN: Prospective, randomized, controlled study . SETTING: University research laboratory . SUBJECTS: Adult, female, Balb inverted question markc mice . INTERVENTIONS: Balb inverted question markc mice were subjected to cecal ligation and puncture with an 18- or 23-gauge needle and treated with triple antibiotics . Mice were injected subcutaneously with recombinant human IL-10 (diluted in normal saline with 0.1% mouse serum albumin) and followed until death . In a separate experiment, IL-10 was also injected subcutaneously and lipopolysaccharide (LPS) injected intraperitoneally and plasma tumor necrosis factor concentrations measured 90 mins later . MEASUREMENTS AND MAIN RESULTS: In the LPS experiments, IL-10 decreased tumor necrosis factor (TNF) production by nearly 90% . For the cecal ligation and puncture experiments, temperature and movement were recorded continuously via implanted transmitters . Studies on mortality indicated that exogenous IL-10 given at 0, +6 and +12 hrs after surgery failed to increase survival when using an 18-gauge needle (alive:total cecal ligation and puncture alone 4:21; IL-10 10 microg/mouse 2:12; 1 microg/mouse 8:25; 0.1 microg/mouse 1:12) or a 23-gauge needle (cecal ligation and puncture alone 13:29; IL-10 1 microg 18:30) . There was no difference in the number of hours to death between the groups . IL-10 did not prevent the hypothermia after cecal ligation and puncture or increase the animals' activity . To examine parameters of inflammation, mice were killed 8 hrs after 18-gauge cecal ligation and puncture . IL-10 (1 microg/mL) failed to reduce pulmonary neutrophil sequestration (lung myeloperoxidase, cecal ligation and puncture 107 +/- 10 {SEM}, IL-10 107 +/- 5) or recruitment of neutrophils to the peritoneum (neutrophils x 10(6), cecal ligation and puncture 3.72 +/- 0.62; IL-10 3.49 +/- 0.37) . IL-10 also failed to reduce the appearance of TNF or IL-6 in the plasma or peritoneal fluid . The chemokine KC was reduced in the peritoneal fluid but not the plasma and endogenous IL-10 production was not reduced in the peritoneum . CONCLUSION: Our data indicate that exogenous IL-10 fails to improve morbidity or mortality in the clinically relevant cecal ligation and puncture model of sepsis. Baillieres Clin Endocrinol Metab, 1997 Dec, 11(4), 645 - 57 Substrate utilization/insulin resistance in sepsis/trauma; Wolfe RR; Endogenous substrate metabolism is markedly altered in critically ill patients . Glucose production is elevated not only in the post-absorptive state, but the normal suppressive effect of exogenous glucose and glucose production is greatly diminished . In the post-absorptive state, glucose clearance is generally elevated, potentially causing hypoglycaemia in extreme cases . Somewhat paradoxically, the ability of insulin to stimulate glucose uptake is diminished, so that hyperglycaemia is often evident during nutritional intake . Lipolysis, the breakdown of peripheral fat, is accelerated, meaning that free fatty acids are released into plasma at a rate far exceeding their oxidation . Some of the excess fatty acids are re-esterified in the liver, leading to accelerated hepatic triglyceride formation . A large increase in hepatic triglyceride stores can ensue if the rate of excretion of triglycerides in very low density lipoproteins is not accelerated commensurately with the increased triglyceride production . Indirect calorimetry measurements support the notion that the large increase in availability of fatty acids may lead to a greater reliance on fatty acids as energy substrates . Nonetheless, carbohydrates should be the predominant source of non-protein calories, because the accompanying insulin response effectively enhances protein synthesis . There is already ample fat available via endogenous lipolysis, and more fat given exogenously provides little further benefit. Semin Thromb Hemost, 1998, 24(2), 183 - 94 Therapeutic use of antithrombin concentrate in sepsis; Balk R et al.; Sepsis and its associated complications of disseminated intravascular coagulation (DIC) and multiple organ dysfunction syndrome (MODS) continue to be a major cause of morbidity and mortality . Improved detection of all forms of DIC is essential to assure earlier diagnosis . Studies already indicate that the therapeutic use of antithrombin (AT) concentrate may produce a more positive outcome for sepsis-associated DIC . If DIC could be identified earlier and AT concentrate could then be given earlier in the sepsis continuum, study results for the use of AT concentrate in humans might reveal a statistically significant difference versus placebo, and the efficacy of AT concentrate for this syndrome is more likely to be proved . Fixed-bolus doses of AT concentrate based on body weight are currently preferred, but improved, user-friendly assays for plasma AT levels would permit more rapid turnaround time for AT results and could help fine-tune the use of AT concentrate to the specific needs of each patient . Clinical trials involving the therapeutic use of AT concentrate in sepsis should continue, and it can be hoped that their design will reflect the concepts and conclusions offered by this panel of investigators. Z Geburtshilfe Neonatol, 1998 Jan-Feb, 202(1), 30 - 4 {Sepsis and SIRS (systemic inflammatory response syndrome) in the puerperium--pathogenesis and clinical management}; Sauer I et al.; PURPOSE: We report about 5 cases of "puerperal sepsis" to elucidate the clinical significance and resulting therapeutic management of Sepsis, SIRS (Systemic inflammatory response syndrome) and MODS (Multiple organ dysfunction syndrome), whose definitions were introduced at the Consensus Conference of the American College of Chest Physicians/Society of Critical Care Medicine in 1992 . RESULTS: All patients had documented endomyometritis, 3 of them in combination with ovarian vein thrombosis . None of the patients responded adequately to conservative treatment with antibiotics and intravenously applied Heparin . After 12 to 72 hours, because of clinical deterioration, all women underwent laparotomy with hysterectomy combined with an ovarectomy in 3 cases . Although the inflammatory "septic" source was removed by the surgical intervention, the clinical condition of 3 of the patients further deteriorated; they were suffering from SIRS, and 2 developed MODS . Symptoms of MODS were DIC, hypotension, kidney failure and encephalopathy . CONCLUSIONS: Our results support the theory that infection or trauma may initiate an endogenous inflammatory response which could progress to MODS even after removal of the initial source . Our findings, however, do not support the view that septic endomyometritis and postpartum ovarian vein thrombosis should be treated nonsurgically, because the clinical course in our patients was less complicated the earlier the surgical intervention was initiated. G Chir, 1998 Mar, 19(3), 96 - 102 {Rare complications of biliary sepsis}; Fimmano A et al.; The surgical approach to the acute biliary pathologies also today is often controversial . The choice of the right time to operate an acute patient is based either on personal clinical experiences, either under the statement that waiting for the resolution of the acute process could be preferable in the aim of reduce the surgical risk . This is the almost general tendency . Recently, some interesting articles issued by Swedish and German schools conducted as controlled trials on a great base of cases, try to emphasize the advantages of an early surgical therapy, particularly in the elderly patients . In these ones, in fact, the concomitance of cardiovascular, metabolic and immunodepressive pathologies makes more serious the complications too . In this article, the Authors refer on three clinical cases, all of which were quite different, and in which it was possible to identify a former septic hepato-biliary pathology . All the patients, upon hospital admission showed an acute pattern . In two cases it was an hepatic abscess, accompanied in one case by a "satellite" pulmonary abscess on the right lung . These two were treated conservatively, although by a TC-guided drainage of the liver abscesses . The third case, a localized choleperitoneum (biloma saccatus), underwent an operation . The accurate investigation on the clinical records of Authors' Department since 1980 to 1995 and in particular on the three referred cases seems to confirm that the importance of some complications after acute biliary pathology and their great morbidity must stimulate the surgeons to investigate always on the real causes of all clinical patterns, even if uncommon. Am J Physiol, 1998 Apr, 274(4 Pt 2), R1078 - 86 Phosphorylation of beta-adrenergic receptor leads to its redistribution in rat heart during sepsis; Tang C et al.; The role of receptor phosphorylation on the redistribution of beta-adrenergic receptors (beta-ARs) in rat hearts during different phases of sepsis was investigated . Sepsis was induced by cecal ligation and puncture (CLP) . Changes in the distribution of beta-ARs in the sarcolemmal and light vesicle fractions were studied using (-)-{4,6-propyl-3H}dihydroalprenolol ({3H}DHA) . Phosphorylation of beta-ARs was studied by perfusing hearts with {32P}H3PO4 followed by identification of the phosphorylated beta-ARs with immunoprecipitation using anti-beta 1-AR antibody . The results show that septic rat hearts exhibit an initial hypercardiodynamic (9 h after CLP; early sepsis) and a subsequent hypocardiodynamic (18 h after CLP; late sepsis) state . {3H}DHA binding studies show that, during early sepsis, the maximum binding capacity (Bmax) was increased by 26% in sarcolemma but was decreased by 30% in light vesicles, whereas, during late sepsis, the Bmax was decreased by 39% in sarcolemma but increased by 31% in light vesicles . These data indicate that beta-ARs in the rat heart were externalized from light vesicles to sarcolemma during early sepsis but were internalized from surface membranes to intracellular sites during late sepsis . The immunoprecipitation studies reveal that the externalization of beta-ARs during early sepsis was coupled with a concomitant decrease (-28.5 to -30.6%, P < 0.01) in the receptor phosphorylation, whereas the internalization of beta-ARs during late sepsis was accompanied by a simultaneous increase (30.3 to 33.8%, P < 0.01) in the receptor phosphorylation . Because the phosphorylation/dephosphorylation of beta 1-ARs regulate their functional coupling and may reflect their subcellular distribution, it is suggested that the increase in receptor phosphorylation seen in late sepsis leads to the receptor internalization observed in late sepsis; similarly, externalization of (dephosphorylated) receptors in early sepsis may give rise to the apparent decrease in sarcolemmal receptor phosphorylation observed during this interval. Am J Physiol, 1998 Apr, 274(4 Pt 2), R956 - 62 Role of central IL-1 in regulating peripheral IGF-I during endotoxemia and sepsis; Lang CH et al.; Inflammatory cytokines may mediate the host response to infection via central nervous system, endocrine, and/or paracrine/autocrine signaling mechanisms . Previous studies have shown that intravenous administration of interleukin (IL)-1 beta alters the concentration of the anabolic hormone insulin-like growth factor (IGF)-I in plasma and various tissues . The purpose of the present study was to determine 1) whether the intracerebroventricular injection of IL-1 beta can influence peripheral IGF-I levels in control animals and 2) whether the central administration of a IL-1 receptor antagonist (IL-1ra) can prevent the changes in peripheral IGF-I induced by endotoxin {lipopolysaccharide (LPS)} or sepsis produced by cecal ligation and puncture . In the first experiment, injection of IL-1 beta (100 ng/rat) decreased IGF-I levels in plasma, liver, and gastrocnemius muscle 28-36% by 1.5 h in conscious fasted rats . IGF-I levels remained reduced at 3 h, but returned to baseline by 6 h . IGF-I content was not altered in soleus, kidney, spleen, intestine, or whole brain after IL-1 beta . In the second series of experiments, LPS injected intravenously decreased IGF-I levels in plasma, liver, and gastrocnemius at 1.5 h, and levels were even further reduced at 3 and 6 h in these tissues (59, 57, and 48%, respectively) . Moreover, the IGF-I content was also decreased in soleus (30-35%) and increased in kidney (2- to 3-fold) after LPS . In the third experiment, changes in IGF-I levels in plasma and tissues, similar to those seen in LPS-treated rats, were detected 24 h after induction of peritonitis . Intracerebroventricular infusion of IL-1ra did not alter any of the changes in IGF-I produced by either LPS or sepsis, although it did attenuate the concomitant changes in growth hormone levels . These data suggest that, although central IL-1 beta is capable of modulating peripheral IGF-I levels, central administration of IL-1ra was unable to modulate the changes in peripheral IGF-I in blood and tissues produced by either endotoxemia or peritonitis. Infect Immun, 1998 May, 66(5), 2300 - 9 Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis; Zantl N et al.; Despite considerable progress, peritonitis and sepsis remain life-threatening conditions . To improve the understanding of the pathophysiology encountered in sepsis, a new standardized and highly reproducible murine model of abdominal sepsis termed colon ascendens stent peritonitis (CASP) was developed . In CASP, a stent is inserted into the ascending colon, which generates a septic focus . CASP employing a stent of 14-gauge diameter (14G stent) results in a mortality of 100% within 18 to 48 h after surgery . By inserting stents of small diameters, mortality can be exactly controlled . Thus, CASP surgery with insertion of a 22G or 18G stent (22G or 18G CASP surgery) results in 38 or 68% mortality, respectively . 14G CASP surgery leads to a rapid invasion of bacteria into the peritoneum and the blood . As a consequence, endotoxemia occurs, inflammatory cells are recruited, and a systemic inflammatory response syndrome develops . Interestingly, the most pronounced upregulation of inflammatory cytokines (gamma interferon {IFN-gamma}, tumor necrosis factor alpha {TNF-alpha} and interleukin-12) is observed in spleen and lungs . CASP surgery followed by stent removal at specific time intervals revealed that all animals survived if intervention was performed after 3 h, whereas removal of the septic focus after 9 h did not prevent death, suggesting induction of autonomous mechanisms of a lethal inflammatory response syndrome . 18G CASP surgery in IFN-gamma receptor-deficient (IFNgammaR-/-) mice revealed an essential role of IFN-gamma in survival of sepsis, whereas TNF receptor p55-deficient (TNFRp55-/-) mice did not show altered survival rates . In summary, this study describes a novel animal model that closely mimics human sepsis and appears to be highly suitable for the study of the pathophysiology of abdominal sepsis . Importantly, this model demonstrates a protective role of IFN-gamma in survival of bacterial sepsis. Ann Surg, 1998 Apr, 227(4), 474 - 80 Hemodynamic effects of the laparoscopic pneumoperitoneum during sepsis in a porcine endotoxic shock model; Greif WM et al.; OBJECTIVE: The authors compared the hemodynamic effects of laparoscopic intervention with conventional laparotomy in an endotoxic shock model in the pig . SUMMARY BACKGROUND DATA: Laparoscopic techniques are being applied more frequently to severely ill patients to evaluate potential abdominal sources of sepsis . Although hemodynamic effects of laparoscopy are minimal in healthy patients, recent studies have shown more significant changes in patients with chronic cardiopulmonary disease . It is unclear whether these effects are applicable to acutely septic patients . METHODS: Twelve domestic pigs received intravenous lipopolysaccharide (LPS) injection and underwent surgical abdominal exploration using either laparoscopy or conventional laparotomy . For baseline comparison, four pigs underwent exploratory laparoscopy without intravenous LPS injection . Hemodynamic measurements and blood gas analyses were obtained using Swan-Ganz and arterial catheters . RESULTS: After LPS exposure, animals undergoing laparoscopic evaluation were significantly more hypercarbic (p < 0.01) and acidotic (p < 0.01) than those undergoing conventional laparotomy . Their mean pulmonary arterial pressure and pulmonary vascular resistance were greater as well (not significant) . The cardiac index (p < 0.05) and stroke volume (p < 0.05) were decreased in the laparoscopic group . Their oxygen delivery was decreased and oxygen consumption increased, although these were not significantly different from those of the laparotomy group . The degree of acidosis was highly correlated with the cardiac index (correlation coefficient, r = 0.82) . CONCLUSIONS: Animals exposed to LPS tolerate laparoscopy but with significant hemodynamic compromise . Much of this effect seems to be mediated by a cardiodepressive effect of acidosis . This study suggests that laparoscopic intervention, when used in septic patients, should be used with caution. Clin Cardiol, 1998 Apr, 21(4), 304 - 7 Ticlopidine-induced neutropenia mimicking sepsis early after intracoronary stent placement; Ochoa AB et al.; We report a case of ticlopidine-induced profound neutropenia early in the course of therapy, which was manifest as a febrile systemic illness mimicking sepsis . This clinical presentation was potentially indicative of a contaminated intracoronary stent . The patient's signs and symptoms of illness promptly resolved with removal of ticlopidine, and no infection was documented . Review of indications for ticlopidine use, potential adverse effects, and monitoring recommendations are discussed. Mol Cell Biochem, 1998 Apr, 181(1-2), 181 - 9 Inactivation of protein kinase C in rat liver during late hypoglycemic phase of sepsis; Hsu C et al.; Changes in protein kinase C (PKC) (calcium- and phospholipid-dependent protein kinase) activity in rat liver during different metabolic 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 . Hepatic PKC was extracted and partially purified by ammonium sulfate fractionation and DEAE-cellulose chromatography . PKC activity was assayed based on the rate of incorporation of 32p from {gamma-32P}ATP into histone . The results show that during early sepsis, both membrane-associated and cytosolic PKC activities remained relatively unaltered . During late sepsis, membrane-associated PKC was unaffected while cytosolic PKC activity was decreased by 19.5-34.4% . Kinetic analysis of the data on cytosolic PKC during late phase of sepsis reveals that the Vmax values for ATP, histone, Ca2+, phosphatidylserine, and diacylglycerol were decreased by 23.4, 22.1, 19.5, 25, and 34.4%, respectively, with no changes in their Km values . These data indicate that cytosolic PKC activity was inactivated in rat liver during late hypoglycemic phase of sepsis . Since PKC-mediated phosphorylation plays an important role in regulating hepatic glucose metabolism, an inactivation of cytosolic PKC may contribute to the development of hypoglycemia during late phase of sepsis. J R Coll Surg Edinb, 1998 Feb, 43(1), 43 - 4 Does early wound infection after elective orthopaedic surgery lead on to chronic sepsis? Benger JR, Kelly AJ, Winson IG. Infection is an uncommon, but occasionally devastating, complication of orthopaedic surgery . The definition of post-operative infection remains problematic . A high rate of early post-operative sepsis has previously been reported using a clinical definition of wound infection as recommended by the Surgical Infection Study Group . The purposes of this study is to determine the rate of ongoing wound problems and deep sepsis 1 year after these early wound infections . Of 1131 consecutive orthopaedic procedures, there were 70 wound infections occurring within 30 days of surgery . Adequate follow-up data were obtained in 67 (97%) of the 69 patients alive at 1 year . Of these 67, three had definite evidence and two possible evidence of ongoing wound problems and/or deep sepsis . It is concluded that early post-operative wound infection as defined by the Surgical Infection Study Group is a poor predictor (4-10%) of ongoing wound problems and deep sepsis at 1 year . All of the confirmed cases of late sepsis were found to be associated with revision arthroplasty and/or pin tract sepsis. Crit Care Med, 1998 Apr, 26(4), 705 - 9 Total plasma antioxidant capacity is not always decreased in sepsis; Pascual C et al.; OBJECTIVE: To compare total plasma antioxidant capacity and selected individual antioxidants in patients with varying degrees of severity of sepsis . DESIGN: A prospective, observational, consecutive case study . SETTING: A 16-bed intensive care unit (ICU) in a university teaching hospital . INTERVENTIONS: None . PATIENTS: Forty-six healthy controls, ten ICU patients, nine patients with systemic inflammatory response syndrome (SIRS), 11 septic patients, and 14 septic shock patients . Plasma was obtained in healthy patients scheduled for minor surgery immediately before anesthesia and in ICU patients within 24 hrs of admittance to the unit or diagnosis of SIRS, sepsis, or septic shock . MEASUREMENTS AND MAIN RESULTS: Using the total peroxyl radical trapping method, we found plasma antioxidant capacity to be lower in septic patients but higher in septic shock patients, as compared with controls . Bilirubin was the greatest contributor to the increase with shock, followed by uric acid . Neopterin also correlated with the peroxyl radical trapping antioxidant parameter values . CONCLUSION: Although total plasma antioxidant capacity is decreased from normal levels in septic patients, an increase in some oxidants contributes to an increased total antioxidant capacity in septic shock patients. Wiad Lek, 1997, 50(10-12), 312 - 20 {Sepsis in surgery: pathogenesis, new therapeutic approaches}; Chmiel B et al.; Sepsis and septic shock are phenomena with a characteristic clinical picture and etiologically related to injury . Chains of events from injury (e.g., infection) through activation of immunological system to multiple organ failure are responsible for sepsis . Neutralization of endotoxins, TNF, interleukins and so on, can improve the treatment of sepsis in the future. J Burn Care Rehabil, 1998 Mar-Apr, 19(2), 102 - 5 Efficacy of a rise in C-reactive protein serum levels as an early indicator of sepsis in burned children; Neely AN et al.; C-Reactive protein serum levels were measured in 57 pediatric patients with 3% to 92% total body surface area burns to determine whether a defined rise in C-reactive protein serum levels could indicate sepsis earlier in burn patients . A rise in C-reactive protein serum levels was defined as an increase of at least 3 mg/dL for 2 days or 10 mg for 1 day . Increases the first 2 days after the burn or the day after surgery were excluded, since these injuries increase C-reactive protein serum levels . Patients were defined as septic when they were on systemic antibiotics and exhibited at least two of 16 specific clinical parameters . C-Reactive protein serum levels correctly predicted sepsis 82% of the time (efficiency=82%) . Nonseptic patients generally did not show increased C-reactive protein serum levels (specificity=69%) . When sepsis did occur, it always was preceded by increased C-reactive protein (sensitivity=100%), and the increased C-reactive protein occurred 2.3+/-0.5 days before the patient was deemed septic clinically . Hence, a defined rise in C-reactive protein serum levels can predict sepsis sooner in burned children. Chest, 1998 Apr, 113(4), 1055 - 63 Serum cardiac troponin T as a prognostic marker in early sepsis; Spies C et al.; STUDY OBJECTIVE: Sepsis is the leading cause of death in the noncardiologic ICU . Maldistributed nutritive blood flow and altered convective and diffusive oxygen transport during sepsis can lead to organ dysfunction and multiple organ failure . One of the causes of myocardial dysfunction is thought to be myocardial ischemia in sepsis; however, conventional biochemical parameters to detect myocardial ischemia lack sensitivity and specificity . Serum cardiac troponin T (S-TnT) was reported to have higher sensitivity and specificity in diagnosing minor myocardial injury . The aim of this study was to investigate if and how often S-TnT is pathologically elevated in patients with sepsis and to evaluate whether S-TnT might be a prognostic marker in early sepsis . DESIGN: Prospective study . SETTING: Surgical ICU . PATIENTS: Twenty-six patients with sepsis were included in this study within 24 h of the onset of sepsis . The patients were allocated a priori to a high S-TnT group (S-TnT > or = 0.2 microg/L) and a low S-TnT group (S-TnT<0.2 microg/L) . MEASUREMENT: Blood samples for the determination of S-TnT and conventional myocardial ischemia markers as well as for adhesion molecules were drawn . Hemodynamic measurements were performed every 4 h during the first 24 h and then once per day over 7 days . S-TnT was determined by enzyme-linked immunosorbent sandwich assay . RESULTS: Eighteen patients had pathologically high S-TnT values . High S-TnT values were associated with an increased mortality rate (15/18 in the high S-TnT group vs 3/8 in the low S-TnT group; p=0.02) . Significant differences between the two groups were found in the norepinephrine dosages at maximum values of S-TnT . Soluble intercellular adhesion molecule-1 was significantly elevated in the high S-TnT group . CONCLUSIONS: As high S-TnT values were associated with an increased mortality rate, it seems reasonable to further evaluate S-TnT as a prognostic marker of myocardial ischemia in patients with sepsis under different therapeutic regimens. Pediatrics, 1998 Apr, 101(4 Pt 1), 654 - 7 Candida sepsis and association with retinopathy of prematurity; Mittal M et al.; OBJECTIVE: To assess the association of Candida sepsis with retinopathy of prematurity (ROP) in extremely low birth weight infants . METHODS: We prospectively identified 253 infants admitted to the Critical Care Nursery at Georgetown University Hospital with birth weights </=1000 g born between January 1, 1994, and June 30, 1996 . Of these 253 infants, 62 died and 55 were transferred to other institutions before ophthalmologic screening for ROP . Clinical data on 98% (133/136) infants were reviewed . Candida sepsis was defined as a positive blood culture for Candida species . Severity of ROP was staged by the International Classification for ROP . Data were analyzed using the chi2 test for nominal data, unpaired t test for continuous data, Mann-Whitney U test for ordinal data, and logistic regression . RESULTS: The mean birth weight (+/-SD) of the population studied was 777 g (+/-136 g), and the mean gestational age at birth was 26.0 weeks (+/-1.8 weeks) . The overall incidence of ROP was 74%, and it correlated significantly with birth weight, gestational age, days on supplemental oxygen, and 5-minute Apgar scores . The incidence of ROP was significantly higher in the infants who had Candida sepsis (21/22 {95%}) compared with those who did not (77/111 {69%}) . Using logistic regression to control for the influence of birth weight, gestational age, days on supplemental oxygen, and 5-minute Apgar scores, Candida sepsis was an independent predictor of stage 3 or worse ROP . In addition, 9 (41%) of 22 infants with Candida sepsis required laser surgery compared with 10 (9%) of 111 infants without Candida sepsis . This difference was significant independent of birth weight, gestational age, days on supplemental oxygen, and 5-minute Apgar scores . CONCLUSIONS: Candida sepsis is independently associated with increased severity of ROP and the need for laser surgery in extremely low birth weight infants. Mol Cell Biochem, 1998 Jan, 178(1-2), 81 - 6 Reduced 40S initiation complex formation in skeletal muscle during sepsis; Vary TC et al.; Severe muscle wasting is a characteristic feature of sepsis . We have previously established that the rate of protein synthesis in muscles composed of fast-twitch fibers is severely diminished in response to sepsis . The present studies investigate the biochemical reactions responsible for the decreased rate of protein synthesis using gastrocnemius from control and septic rats perfused in situ . Analysis of free ribosomal subunits indicated peptide-chain initiation was impaired by infection . To characterize biochemical reactions in the pathway of peptide-chain initiation affected, the effect of sepsis on the incorporation of initiator {35S}methionyl-tRNA (met-tRNA(imet)) into the 40S initiation complex was examined . Sepsis caused a 65% decrease in the binding of radiolabelled met-tRNA(imet) to the 40S initiation complex compared with controls . The binding of met-tRNA(met) to the 40S ribosome is regulated by eukaryotic initiation factor eIF-2B, whose activity can be modulated in part by the redox state of pyridine dinucleotides . The mean cytoplasmic NADH/NAD+ ratio was increased 2 fold in sepsis, while the NADPH/NADP+ ratio was unchanged . These findings identify the formation of the 40S initiation complex as a defect in the protein synthesis machinery during sepsis . The decreased formation of the 40S initiation complex in muscle could not be explained by changes in the cytoplasmic redox state. Int J Clin Pract, 1998 Jan-Feb, 52(1), 60 - 1 Retroperitoneal perforation of duodenal ulcer presenting as scrotal sepsis; Rajasekar A et al.; Retroperitoneal extravasation is an extremely uncommon complication of duodenal ulcer perforation . The preoperative diagnosis is difficult and may even by missed at operation . There were 25 cases reported in the literature . Only one patient was correctly diagnosed preoperatively and only seven patients survived . We describe the first case of retroperitoneal extravasation from perforated duodenal ulcer presenting as scrotal sepsis. Pediatr Infect Dis J, 1998 Mar, 17(3), 231 - 6 Sepsis evaluations in hospitalized infants with bronchiolitis; Antonow JA et al.; OBJECTIVES: To define variation in the decision to perform a sepsis evaluation in hospitalized infants with bronchiolitis, to define predictors of the decision and to measure the clinical and cost outcomes . METHODS: Retrospective chart review of all nonintensive care unit infants < or = 60 days with any discharge diagnosis of bronchiolitis (n = 282 from 1993 to 1995 in a 232-bed pediatric hospital . Process variables included temperature at sepsis work-up or Tmax if no sepsis workup . Outcome variables were charges, length of stay, sepsis workup and serious bacterial infection . RESULTS: There was no difference in mean temperature between groups with or without sepsis evaluation (38.1 degrees C, P = 0.75) . Of 282 infants 140 had a sepsis workup; 5 (1.8%) had serious bacterial infection . Infants with sepsis workup had an average total charge of $4507 and length of stay of 3.4 days compared with $2998 and 2.8 days for those without (P = 0.0001 and P = 0.002, respectively) . A multivariate logistic regression model was constructed with sepsis workup as the dichotomous dependent variable . Significant (P < or = 0.05) predictor variables with a positive coefficient were: higher bronchiolitis score and normal chest roentgenogram . Significant variables with a negative coefficient were: admission diagnosis of bronchiolitis, chest roentgenogram typical for bronchiolitis and age > 28 days . CONCLUSIONS: Temperature was not a predictor of sepsis evaluation . Infants with respiratory distress and normal chest roentgenogram were more likely to receive sepsis evaluations; those with recognized typical bronchiolitis and those > 28 days of age were less likely . Risk of serious bacterial infection is low; the costs of a sepsis evaluation outweigh the benefits in infants with obvious bronchiolitis. J Appl Physiol, 1998 Mar, 84(3), 837 - 44 Capillary and arteriolar responses to local vasodilators are impaired in a rat model of sepsis; Tyml K et al.; Although sepsis is known to affect vascular function, little is known about changes at the capillary level . We hypothesized that sepsis attenuates the "upstream" arteriolar response to vasoactive agents applied locally to capillaries . Sepsis in rats was induced by cecal ligation and perforation . After 24 h, extensor digitorum longus muscle was prepared for intravital microscopy . Phenylephrine (PE, 10 mM) and acetylcholine (ACh, 10 mM) were applied iontophoretically on terminal arterioles and on their downstream daughter capillaries (300 micron from arteriole) . There was no significant difference between control and septic rats in baseline arteriolar diameters {8.0 +/- 0.6 vs . 9.8 +/- 0.8 (SE) micron- or baseline red blood cell velocity (VRBC) in perfused daughter capillaries (255 +/- 10 vs . 264 +/- 13 micron/s) . Application of PE onto arterioles resulted in comparable constrictions (i.e., -22% diameter change) and VRBC reductions (-100%) in control and septic rats . In contrast, arteriolar diameter and VRBC increases after application of ACh were attenuated in sepsis (diameter: from 41 to 14%; VRBC: from 67 to 24%) . Application of PE onto the capillary reduced VRBC to the same level (-100%) in both groups, whereas application of ACh increased VRBC less in septic than in control rats (20 vs . 73%) . On the basis of arteriolar-capillary pair stimulations, sepsis affected VRBC responses to ACh more in the capillary than in the arteriole . When the adenosine analog 5'-N-ethylcarboxamidoadenosine (0.1 mM) was used instead of ACh, similar effects of sepsis were seen . To test for a possible involvement of inducible NO synthase (iNOS) in sepsis-induced attenuated ACh responses, arterioles and capillaries in septic animals were locally pretreated with the iNOS blocker aminoguanidine (10 mM) . In both microvessels, aminoguanidine restored the ACh response to the control level . We conclude that impaired capillary VRBC and arteriolar diameter responses to vasodilators applied to capillaries in septic rat skeletal muscle were due to dysfunction at arteriolar and capillary levels . The study underscores the significant role iNOS/NO may play in sepsis-induced alteration of vascular reactivity in vivo. Zentralbl Bakteriol, 1998 Jan, 287(1-2), 117 - 23 Acridine-orange leucocyte cytospin (AOLC) test as an in-situ method for the diagnosis of central venous catheter (CVC)-related sepsis in adult risk patients; von Baum H et al.; The AOLC method for the in-situ diagnosis of catheter-associated septicemia was evaluated in adult intensive care patients . 55 blood samples and corresponding CVC tips were examined using the AOLC method, the semiquantitative roll plate method and the broth immersion method . In 4 patients (7.3%), a CVC-related septicemia was diagnosed, 10 patients (18.2%) showed a colonisation of their central venous access . The AOLC method was positive in 50% of the cases with CVC-related septicemia and in 20% of the colonized patients . Thus, we do not recommend the AOLC test as a routine method for the diagnosis of suspected CVC-related infection but as a facultative additional diagnostic measure for certain risk patients. J Trauma, 1998 Mar, 44(3), 460 - 8 Effects of trauma and sepsis on soluble L-selectin and cell surface expression of L-selectin and CD11b; Maekawa K et al.; OBJECTIVES: To examine (1) the effects of trauma on changes in neutrophil L-selectin and CD11b expression and on the levels of soluble L-selectin and (2) whether these alterations are different on leukocyte subpopulations in those patients who develop multiple organ dysfunction syndrome . MATERIALS AND METHODS: Twenty patients with Injury Severity Score (ISS) > or = 16 and 15 patients with ISS score < 16 were studied . Arterial blood were collected serially after injury . The staining of leukocyte surface adhesion molecules was performed with antibodies against L-selectin and CD11b . Positive cell count and mean fluorescence intensity were determined by flow cytometry . Soluble L-selectin was measured using enzyme-linked immunosorbent assay . RESULTS: In patients with ISS > or = 16, neutrophil L-selectin expression showed an immediate increase, reaching peak levels between 3 to 4 hours after injury (p < 0.05 vs . patients with ISS < 16), followed by a gradual decrease . Plasma levels of soluble L-selectin reached peak levels at 6 hours after injury . However, in patients with ISS < 16, minimal changes in L-selectin expression and soluble L-selectin were observed . Neutrophil CD11b expression showed an immediate increase for the first 3 hours followed by a gradual increase up to 24 hours after injury . In patients who developed multiple organ dysfunction syndrome, CD11b both on neutrophils and lymphocytes remained elevated for 120 hours . CONCLUSIONS: These findings suggest that acute neutrophil activation is an early event after trauma and may be implicated as "a vulnerable window" for leukocyte-mediated end organ injury. Am J Med, 1998 Jan, 104(1), 40 - 7 Prevalence of hypophosphatemia in sepsis and infection: the role of cytokines; Barak V et al.; BACKGROUND: Sepsis occurs following the presence of bacteria in the circulation and is associated with fever, hyperthermia, and hypotension . Hypophosphatemia develops in the early stages of sepsis . High levels of inflammatory cytokines also characterize early sepsis . AIM: The aim of the present study was to correlate hypophosphatemia with cytokines and cytokine receptor levels during early sepsis . We aimed to reestablish the results obtained from patients in an in vivo experimental model, in order to understand the mechanism of hypophosphatemia induction in early sepsis . METHODS: Ninety-nine patients were enrolled in this study and their clinical condition was classified as the presence of infection, sepsis, and bacterial growth in blood cultures . Phosphate levels and cytokine levels were recorded . In order to determine whether hypophosphatemia is correlated to the increased inflammatory cytokines, we injected normal mice with recombinant cytokines and studied their effect on phosphate levels . RESULTS: Our results revealed that 80% of the septic patients had hypophosphatemia associated with very high levels of tumor necrosis factor (TNF)alpha and interleukin (IL)-6 and of soluble IL receptor (sIL)-2R and IL-6R, especially in those patients with positive blood cultures . Injection of IL-6, TNFalpha and IL-1beta in mice markedly decreased the phosphate serum levels . CONCLUSIONS: Significant associations were demonstrated between high levels of inflammatory cytokines and their receptors and between serum phosphate levels, especially in patients with positive blood culture . Our results point to a correlation between the high inflammatory cytokines levels and hypophosphatemia during early sepsis . Cytokine levels and hypophosphatemia may be included in sepsis evaluation and prognosis . Anticytokine strategies might, therefore, reverse hypophosphatemia and other parameters of sepsis. Shock, 1998 Mar, 9(3), 199 - 203 Protein kinase C activity is increased in rat heart during the early hyperdynamic phase of sepsis; Yang SL et al.; Changes in protein kinase C (PKC) (calcium- and phospholipid-dependent protein kinase) activity in rat heart during different cardiodynamic phases of sepsis were studied in an attempt to understand the pathophysiology of altered myocardial function during sepsis . Sepsis was induced by cecal ligation and puncture . 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 cecal ligation and puncture . Cardiac PKC was extracted and partially purified by ammonium sulfate fractionation and diethylaminoethyl-cellulose chromatography . PKC activity was assayed on the basis of the rate of incorporation of 32P from {gamma-32P}adenosine triphosphate into histone . The results show that during early sepsis, cytosolic PKC activity was increased by 42-73%, whereas membrane associated PKC activity was unchanged . During late sepsis, both cytosolic and membrane associated PKC activities remained unchanged . Kinetic analysis of the data on cytosolic PKC during the early phase of sepsis reveals that the Vmax (maximal velocity) values for Ca2+, phosphatidylserine, and diacylglycerol were increased by 58, 42, and 50%, respectively, with no changes in their Km (substrate concentration required for half-maximal enzyme activity) values . These data indicate that cytosolic PKC activity was activated in rat heart during the early hyperdynamic phase of sepsis . Because PKC mediated phosphorylation plays an important role in regulating myocardial contractility, an activation in cytosolic PKC may contribute to the development of a hypercardiodynamic state during the early phase of sepsis. Shock, 1998 Mar, 9(3), 184 - 92 Mesenteric and skeletal muscle microvascular responsiveness in subacute sepsis; Cameron EM et al.; This study was performed to assess the effects of subacute sepsis in rats on the in vitro reactivity of arterioles (internal diameter, 100-150 microm) to alpha1- and alpha2-adrenergic stimulation and to angiotensin II . Male Sprague-Dawley rats were rendered septic by intraperitoneal implantation of a gelatin capsule containing sterile rat feces and 1 x 10(6) viable colony forming units of Escherichia coli . Control rats underwent sham laparotomy and implantation of a gelatin capsule containing only sterile feces . In vitro reactivity of arterioles from mesentery and skeletal muscle were studied 48 h later in a pressurized (50 mmHg) no flow state using videomicroscopy . Subacute sepsis decreased the contractile response of nonprecontracted microvessels from both anatomical sites to phenylephrine (both p < .01 versus control) and blunted the relaxation response to staurosporine (both p < .01), an inhibitor of protein kinase C . The small contraction to angiotensin II of mesenteric vessels was inhibited by sepsis (p < .05) but was unaltered in the skeletal muscle microcirculation . In the precontracted mesenteric microvessels from septic rats, endothelium-dependent relaxation to clonidine and to adenosine 5'-diphosphate were decreased (both p < .01 versus control), whereas in skeletal muscle microvessels, clonidine and adenosine 5'-diphosphate elicited constriction (both p < .01) . Relaxation to the endothelium independent vasodilators sodium nitroprusside and pinacidil was preserved across all vessels . In conclusion, mesenteric and skeletal muscle microvascular responses to angiotensin II and alpha1- and alpha2-adrenergic stimulation are altered in subacute sepsis . This may in part lead to systemic hypotension and altered organ perfusion during states of chronic sepsis. Clin Infect Dis, 1998 Mar, 26(3), 664 - 72 Reliability of procalcitonin concentrations for the diagnosis of sepsis in critically ill neonates; Chiesa C et al.; We evaluated the reliability of serum concentrations of procalcitonin for the diagnosis of early- and late-onset sepsis in a neonatal intensive care unit (NICU) setting . Timed procalcitonin determinations were prospectively obtained during two postnatal periods: 0-48 hours of age (period 1) and 3-30 days of age (period 2) . In period 1, we measured procalcitonin concentrations in 83 healthy newborns (group 0) and in 120 NICU patients (14 with culture-proven sepsis, group 1A; 14 with clinical septicemia, group 1B; 75 with no evidence of infection, group 2; and 17 with uncertain findings, group 3) . After we established 95% hour-specific reference ranges for group 0, we performed multiple linear regression analyses to determine which maternal, intrapartum, and neonatal complications would affect normal procalcitonin values . Maternal diabetes was the only variable identified in group 2 patients that induced a significant deviation from procalcitonin reference ranges . Analyses of the pooled procalcitonin values obtained for group 1 patients over the 48-hour period after birth yielded a sensitivity of 92.6% and a specificity of 97.5% for procalcitonin concentrations in the detection of early-onset sepsis . In period 2, blood samples from 23 cases with systemic infections were analyzed for procalcitonin concentrations at the onset of signs of infection . The control group was formed by matching four uninfected NICU patients to each infected case . None of the procalcitonin values for the 92 controls overlapped those for the cases (sensitivity and specificity, 100%) . Procalcitonin is a promising marker for the diagnosis of early- and late-onset sepsis in neonates at high risk for this infection. Pediatrics . 1997 Jul;100(1):E6. Human granulocyte colony-stimulating factor may improve outcome attributable to neonatal sepsis complicated by neutropenia; Kocherlakota P et al.; OBJECTIVES: To determine whether adjunctive therapy with recombinant human granulocyte colony-stimulating factor (rhG-CSF) could reverse sepsis-associated neonatal neutropenia and improve neonatal survival compared with conventional therapy in a phase I/II-type trial . Study DESIGN: An intravenous infusion of rhG-CSF (10 microg/kg/d x 3 d) was administered to 14 septic neutropenic neonates . Neutrophilic responses and outcome of these neonates were compared with 11 concurrently treated, retrospectively selected, case-matched control septic patients identified by using a search of medical records coded for sepsis with neutropenia (>/=24 hours) . RESULTS: Seven neonates with early-onset sepsis with neutropenia at birth and seven neonates with late-onset sepsis plus neutropenia (all with necrotizing enterocolitis) were entered in the rhG-CSF treatment group . Results were compared with a conventional therapy control group (five early onset, six late onset) . No significant differences existed in the birth weight, gestational age, use of antibiotic therapy, magnitude of respiratory support, severity of metabolic acidosis, use of vasopressors, or other supportive therapy between the two groups . In the rhG-CSF-treated group and in the conventionally treated control group, the absolute neutrophil count (ANC) (mean +/- SEM) was 585 +/- 138 and 438 +/- 152, respectively . The ANC increased to more than baseline in the rhG-CSF-treated group by 10-fold versus 2-fold at 24 hours, 18-fold versus 4-fold at 48 hours, 24-fold versus 5-fold at 72 hours (significant by one-way analysis of variance in the rhG-CSF group only), and 29-fold versus 16-fold at 7 to 10 days when compared with the conventional therapy group . There were no nonresponders in the rhG-CSF group by 24 hours after the first dose of study drug . Monocyte cell counts also increased significantly in both groups by 7 days after entry into this protocol but remained within normal range for age . No clinically significant effect on lymphocytes, erythrocytes, or platelet counts was noted . Thirteen patients in the rhG-CSF-treated group (92%; 13 out of 14) and five in the conventionally treated group (55%; 5 out of 11) survived to 28 days after the onset of the signs of sepsis . No adverse effects were noted in the rhG-CSF-treated group . CONCLUSIONS: rhG-CSF can increase the neutrophil count in critically ill septic neutropenic neonates . This finding suggests that rhG-CSF may be effective in a therapeutically useful time frame to treat septic neonates with neonatal neutropenia attributable to bone marrow suppression or neutrophil consumption . Future randomized trials are needed to validate the beneficial effects of rhG-CSF and to determine whether any significant side effects of therapy exist. Semin Thromb Hemost, 1998, 24(1), 61 - 9 Antithrombin III in animal models of sepsis and organ failure; Dickneite G; Antithrombin III (AT III) is the physiological inhibitor of thrombin and other serine proteases of the clotting cascade . In the development of sepsis, septic shock and organ failure, the plasma levels of AT III decrease considerably, suggesting the concept of a substitution therapy with the inhibitor . A decrease of AT III plasma levels might also be associated with other pathological disorders like trauma, burns, pancreatitis or preclampsia . Activation of coagulation and consumption of AT III is the consequence of a generalized inflammation called SIRS (systemic inflammatory response syndrome) . The clotting cascade is also frequently activated after organ transplantation, especially if organs are grafted between different species (xenotransplantation) . During the past years AT III has been investigated in numerous corresponding disease models in different animal species which will be reviewed here . The bulk of evidence suggests, that AT III substitution reduces morbidity and mortality in the diseased animals . While gaining more experience with AT III, the concept of substitution therapy to maximal baseline plasma levels (100%) appears to become insufficient . Evidence from clinical and preclinical studies now suggests to adjust the AT III plasma levels to about 200%, i.e., doubling the normal value . During the last few years several authors proposed that AT III might not only be an anti-thrombotic agent, but to have in addition an anti-inflammatory effect. Semin Thromb Hemost, 1998, 24(1), 33 - 44 Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock; Vervloet MG et al.; In patients with sepsis and septic shock, both coagulation and fibrinolysis are activated frequently leading to the syndrome of diffuse intravascular coagulation (DIC) . The different mechanisms leading to abnormalities in coagulation and fibrinolysis are discussed in detail . The coagulation and fibrinolytic system appear to be influenced by the septic process largely independently, leading to a procoagulant imbalance between these systems . Coagulation is initiated by mediator-induced expression of tissue factor and is associated with consumption of the natural coagulation inhibitors antithrombin III, protein C, and protein S . As a result, high plasma levels of thrombin-antithrombin complex (TAT) can be found . The effects on fibrinolysis are dominated by (highly) increased levels of plasminogen activator inhibitor type 1 (PAI-1), leading to inadequate fibrinolysis . Although levels of plasminogen activator antigen are increased, its activity is almost completely inhibited by PAI-1 . The resulting effects predispose to a procoagulant state, with widespread fibrin deposition, which may be an important mechanism contributing to multiple organ failure . A thorough understanding of the pathophysiological mechanisms underlying the DIC-syndrome is a prerequisite for a rational approach and future therapy for this severe complication of sepsis. Eur J Gastroenterol Hepatol, 1998 Jan, 10(1), 95 - 8 Sclerosing peritonitis complicated by sepsis: a potential cause of portal hypertension; Jones EA et al.; A 27-year-old woman with chronic renal failure, who had been treated with chronic ambulatory peritoneal dialysis and had developed sclerosing peritonitis, was admitted to the hospital with intra-abdominal sepsis . In spite of antibiotic therapy, sepsis recurred and was associated with intrahepatic cholestasis . In addition, over a period of about 4.5 weeks she developed hepatomegaly and portal hypertension unassociated with occlusion of the portal vein or one of its main extrahepatic branches . A wedge biopsy of the liver revealed extensive thick fibrosis of the liver capsule, intrahepatic cholestasis, diffuse swelling of hepatocytes, central veins that were difficult to visualize and small portal tracts . It is suggested that the sepsis was responsible for the intrahepatic cholestasis, swelling of hepatocytes and hepatomegaly . It is also suggested that the rigidity of the fibrotic liver capsule provided resistance to the development of hepatomegaly, with the result that intrahepatic pressure increased (compressing intrahepatic branches of the portal vein as well as portal tracts and central veins) and portal hypertension developed. Anesteziol Reanimatol, 1997 Nov-Dec, (6), 54 - 5 {A rare case of BCG vaccinal sepsis in a patient with bladder cancer}; Gorobets ES et al.; Immunotherapy consisting in intravesical injection of BCG vaccine to a 44-year-old patient with surface relapsing cancer of the bladder resulted in development of sepsis . The vaccine in a dose of 120 mg was injected directly after bougienage of the urethra and catheterization of the bladder . As soon as in 2 h the patient developed chill, fever (38.5 degrees C), and felt bad . The condition progressed, but only in 15 days did the patient applied for medical care . Intensive care including antibiotics and antituberculous drugs in massive doses and repeated sessions of hemoperfusion were of no avail . The patient died with signs of progressive hepatorenal failure . Autopsy confirmed vaccinal mycobacterial sepsis . Intravesical immunotherapy after injury to the urethra was an error, promoting generalization of the infection; another cause of lethal outcome was late application for medical care. J Antimicrob Chemother, 1998 Jan, 41 Suppl A, 95 - 102 Design of clinical trials in sepsis: problems and pitfalls; Finch RG; The pathophysiology of sepsis has been studied intensively in recent years and a variety of opportunities for therapeutic intervention have been identified . A number of biological products including endotoxin antibodies, cytokine inhibitors and receptor antagonists have been evaluated after the failure of pharmacological doses of steroids to influence survival in septic shock . Despite a number of large, international multi-centre studies, the therapeutic promise of these various interventions remains unfulfilled . These trials have largely been conducted in intensive care units in a heterogeneous population of patients with various entry criteria and end-points of response . While the clinical trial must remain the standard for assessing safety and efficacy of new interventions there are opportunities to improve on the design, execution and analysis of these studies . Factors such as the appropriateness of antibiotic therapy, the adequacy of medical and surgical management, and the issue of withdrawal or withholding of life support are discussed in relation to these studies . Furthermore the role of an independent scientific extramural review committee is stressed, particularly in relation to the impact of confounding events of an unforeseen nature . The potential for improving the quality of the analyses of clinical trials of sepsis is illustrated by a recently completed study of the efficacy of a murine monoclonal antibody to human tumour necrosis factor-alpha. J Antimicrob Chemother, 1998 Jan, 41 Suppl A, 81 - 94 Therapeutic options directed against platelet activating factor, eicosanoids and bradykinin in sepsis; Fink MP; Various autacoids, including the eicosanoids, platelet activating factor (PAF) and bradykinin, have been implicated in the pathogenesis of sepsis and septic shock . The precise role of these compounds as mediators of the diffuse inflammatory state characteristic of sepsis remains to be determined, but, in animal models, beneficial effects have been observed as a result of treatment with various inhibitors of eicosanoid biosynthesis or antagonists of PAF or bradykinin receptors . To date, however, it has been impossible to translate these encouraging results from animal models into convincingly positive results in the clinical setting. J Antimicrob Chemother, 1998 Jan, 41 Suppl A, 65 - 9 Experimental therapies for sepsis directed against tumour necrosis factor; Read RC; Tumour necrosis factor (TNF) has been identified as an important mediator involved in the generation of sepsis syndrome . Two major strategies have evolved for counteracting the effects of TNF in patients with severe manifestations of sepsis: neutralization by anti-TNF antibodies and competitive antagonism of TNF with synthetic soluble TNF receptors . Clinical trials with murine monoclonal antibodies against TNF have shown that this agent is able to reduce early morbidity and mortality, but with no reduction in 28 day mortality . A clinical study with a synthetic 75 kDa soluble TNF receptor failed to show any benefit with this drug and indeed there was higher mortality at higher doses . Trials of a 55 kDa soluble TNF receptor are continuing and this drug is apparently safe . Drugs that modify TNF in vivo may be a useful component of future management of sepsis, either as monotherapy or as part of a combined strategy of immunomodulation. J Antimicrob Chemother, 1998 Jan, 41 Suppl A, 51 - 63 Acute pancreatitis as a model of sepsis; Wilson PG et al.; Severe acute pancreatitis has many similarities to sepsis syndrome and septic shock . The haemodynamic features of cardiovascular instability, reduced ejection fraction and decreased systemic vascular resistance are indistinguishable in each of these conditions . In addition there are many striking similarities in the cytokine and inflammatory mediator profiles, suggesting that the haemodynamic abnormalities may result from the same pathogenic mechanisms, albeit as a result of different inflammatory stimuli . Although septic complications of severe acute pancreatitis do arise these are usually late features and in the early phase of a severe attack there is sterile pancreatic necrosis . Evidence suggests that the important cytokines in the development of complications and multiple organ failure in severe acute pancreatitis are tumour necrosis factor-alpha, interleukin-1, interleukin-6 and interleukin-8 . In addition, endotoxin and other important inflammatory mediators including platelet activating factor and phospholipase A2 are implicated in the development of complications in both severe acute pancreatitis and sepsis . Patients with severe acute pancreatitis are not an entirely homogeneous group but in terms of pathogenesis and complications of their disease they have much more in common with each other than the patients who are collected under the unifying diagnosis of 'sepsis' . The similar clinical and biochemical features between severe acute pancreatitis and sepsis make the former an excellent model for studying the pathogenesis of the sepsis syndrome. J Antimicrob Chemother, 1998 Jan, 41 Suppl A, 47 - 9 The value of animal models in the development of new drugs for the treatment of the sepsis syndrome; Michie HR; The sepsis syndrome has proved to be one of the most difficult clinical situations to replicate in animal models . The outcome of sepsis in patients depends not only on the pathogens, sizes of bacterial challenge and adequacy of treatment, but also on age, host defence mechanisms and individual response to septic shock and multiple organ failure . Novel immunomodulatory agents may control endotoxaemia or bacteraemia in animal models but they have not proved effective in septic patients . This article considers whether the principal problem lies in our interpretation of the data from animal studies, or whether such models are unsuitable for assessing new treatments for the sepsis syndrome. J Antimicrob Chemother, 1998 Jan, 41 Suppl A, 17 - 24 The haematological manifestations of sepsis; Mammen EF; Haematological changes in the septic patient are, primarily, neutropenia or neutrophilia, thrombocytopenia and disseminated intravascular coagulation (DIC) . Thrombocytopenia frequently arises from DIC although inhibition of thrombopoiesis or immunological platelet damage also occur . DIC contributes to bleeding and microvascular thrombosis, leading to multiple organ failure . Tissue factor release, primarily mediated by tumour necrosis factor, activates the clotting system; fibrinolysis is initially activated, but later becomes inhibited by the release of plasminogen-activator inhibitor (PAI-1), further fostering multiple organ failure . Most septic patients have compensated, chronic DIC, detectable by assays of molecular markers; the earliest signs are already found during the systemic inflammatory response syndrome . Compensated DIC later becomes decompensated with rapid consumption of factors including inhibitors such as antithrombin III (AT III) and proteins C and S . AT III concentrations of < 60-70% of the normal values predict outcome . Management of DIC must address the underlying disease, interrupt the activated haemostasis system and replace consumed coagulation constituents . Interruption of haemostasis with heparin may be attempted, but bleeding may worsen . Administration of a natural anticoagulant, such as AT III, may arrest clotting without concomitant risk of bleeding . In several animal models of DIC, AT III concentrates shortened the duration of DIC and reduced multiple organ failure and mortality . Similar benefits have been reported in early studies of patients with DIC, especially in the absence of sepsis . Studies are under way to determine whether outcome will improve if patients with sepsis are treated before the development of shock and plasma AT III concentrations are maintained at 100-150% of normal. Crit Care Med, 1998 Mar, 26(3), 465 - 9 Immunoglobulin E and eosinophil counts are increased after sepsis in trauma patients; DiPiro JT et al.; OBJECTIVES: To determine the time course of plasma immunoglobulin E (IgE) concentration increases after traumatic injury, if increased IgE concentrations were related to clinical events or complications, and if increased peripheral eosinophil counts could be related to trauma, sepsis, or organ-specific complications . DESIGN: Data relating to severity of injury, clinical complications, plasma concentrations of IgE, and peripheral eosinophil counts were prospectively collected . SETTING: Trauma service, tertiary-care medical center . PATIENTS: One hundred adult trauma patients admitted to the intensive care unit . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Plasma IgE concentrations increased in most patients . However, the greatest increases were observed in patients with sepsis (p = .03), renal dysfunction (p = .04), or pneumonia (p = .02) . IgE increases were not related to severity or mechanism of injury, allergy history, or age . The day of highest observed IgE concentration was related to the day of onset of sepsis (p = .012, r = .39), and occurred a mean of 3.8 days after sepsis . Most patients had increased peripheral eosinophil counts and eosinophil percentages of white blood cells during their intensive care unit stays . Eosinophil counts were greater in patients with sepsis (p < .0001), severe sepsis (p < .0001), or pneumonia (p < .002) . CONCLUSIONS: Increased IgE concentrations and eosinophil counts were found after sepsis and do not appear to be related to the initial injury . Since IgE and eosinophil production are enhanced by interleukin-4 and interleukin-5, respectively, these findings suggest that T-helper lymphocyte type 2 cytokines are activated in response to sepsis after traumatic injury. J Pediatr, 1998 Feb, 132(2), 295 - 9 Interleukin-6 concentrations in neonates evaluated for sepsis; Doellner H et al.; OBJECTIVES: This study was performed to determine serum concentrations of interleukin-6 (IL-6) during bacterial infections in the first week of life and to evaluate the usefulness of IL-6 as a diagnostic test for perinatal bacterial infections, alone and in combination with C-reactive protein (CRP) . STUDY DESIGN: Blood was obtained from 241 newborn children on admission to the neonatal intensive care unit and at 3 to 4 days after admission . Both samples were analyzed for IL-6, CRP, and white blood cell count with differential . RESULTS: Twenty-four newborns were classified as having an infection . Increased serum IL-6 levels were detected in infected compared with noninfected newborns on admission (p < 0.0001) . Detection of IL-6 (> or = 20 pg/ml) alone yielded a sensitivity of 78%, a specificity of 71%, a positive predictive value of 40%, and a negative predictive value of 93% . A combined parameter of IL-6 (> or = 50 pg/ml) and CRP (> or = 10 mg/L) yielded a sensitivity of 96%, a specificity of 74%, a positive predictive value of 49%, and a negative predictive value of 99% . CONCLUSIONS: Used in combination with CRP, IL-6 seems to be a valuable parameter in the early diagnosis of neonatal infections. Infection, 1998 Jan-Feb, 26(1), 54 - 7 A case of BCG sepsis with bone marrow and liver involvement after intravesical BCG instillation; Dederke B et al.; The case described concerns a 68-year-old male patient, who received intravesical BCG instillations for non-resectable urothelial carcinoma (stage pT1, G2) . After the third instillation, which was complicated by hematuria during catheterization, he had a high temperature, dyspnoea, a weight-loss of 15 kg and critical recurrent hypotension for 3 weeks . On admission to the clinic he presented with high serum liver enzymes and pancytopenia . The suspected diagnosis of BCG sepsis was confirmed by the detection of typical granulomas in liver and bone marrow histology . After initiation of tuberculostatic therapy, the patient's condition improved and laboratory results returned to normal . This case shows the potential of a life-threatening systemic side effect after intravesical BCG instillation. Arch Pathol Lab Med, 1998 Feb, 122(2), 197 - 8 A rare common hepatic duct diverticulum causing fatal biliary obstruction and sepsis; Flowers MB et al.; The case of a 59-year-old woman who presented with signs and symptoms of biliary obstruction and cholangitis is reported . The patient's clinical course was punctuated by recurring sepsis and acute hemorrhagic pancreatitis . Computed tomography revealed extrinsic compression of the common hepatic duct, which was nonfilling on cholangiography, thus raising the suspicion of a solid tumor; the common hepatic duct diverticulum was not revealed until autopsy . Diverticula in this region of the biliary tract are extremely rare and may, as in this case, present a diagnostic challenge and result in a fatal outcome. Trop Med Int Health, 1997 Mar, 2(3), 284 - 8 Evaluation of neonates with risk for infection/suspected sepsis: is routine lumbar puncture necessary in the first 72 hours of life? Ajayi OA, Mokuolu OA. To determine whether lumbar puncture is necessary in the evaluation of neonates with risk for infection or suspected sepsis in the first 72 hours of life, we reviewed the laboratory and medical records of 506 infants who had lumbar punctures between January 1988 and December 1990 . Neonates < 72 hours of age accounted for 52% of all lumbar punctures, but no case of meningitis . This led to a policy shift from routinely performing lumbar punctures to reserving them for infants with signs of severe sepsis (i.e . lethargy, hypothermia, hypotonia, poor perfusion or apnoea), specific neurological signs or clinical deterioration . This new policy was monitored prospectively from July 1991 to December 1993 . Three times fewer procedures were performed in neonates < 72 hours, and there was no diagnosed or missed case of meningitis . Given that meningitis is rare within the first 72 hours of life and the yield of lumbar puncture virtually zero, we recommend that lumbar punctures be reserved for selected infants. Blood, 1998 Feb 15, 91(4), 1362 - 72 Increased mucosal B-lymphocyte apoptosis during polymicrobial sepsis is a Fas ligand but not an endotoxin-mediated process; Ayala A et al.; Sepsis is reported to induce an increase in the rate of apoptosis (Ao), in immature lymphoid cells residing in hematopoietic tissues such as the thymus and bone marrow . Alternatively, secondary lymphoid tissue, such as the spleen exhibit little innate (unstimulated) Ao . However, it is unknown whether or not polymicrobial sepsis has any effects on the frequency of Ao in mucosal lymphoid tissue and what, if any, are the functional consequences of such a change . To assess this, Peyer's patch cells were harvested from C3H/HeN (endotoxin-sensitive) mice killed 12 or 24 hours after the onset of polymicrobial sepsis (cecal ligation and puncture {CLP}) . The results indicate that the percentage of cells that were Ao+ as determined by flow cytometry were markedly increased at 24 hours, but not at 12 hours post-CLP . This correlates well with evidence of increased DNA fragmentation as well as histological changes observed both at a light and transmission electron microscopic level of the Peyer's patch Ao . Phenotypically, these changes were restricted to the B220+ (B-cell) population that also exhibited a marked increase of Fas/Apo-1 antigen expression . The functional consequence of this increased apoptosis appears to be associated with the endogenous stimulation (activation) of IgA production by mucosal B lymphocytes and increased nuclear c-Rel expression . Furthermore, we found that Peyer's patch lymphocytes isolated from C3H/HeJ-Faslgld (endotoxin-tolerant/Fas ligand- {FasL} deficient) as opposed to C3H/HeJ (endotoxin-tolerant) inbred mice did not exhibit increased Ao after CLP . These findings indicate that increased B-cell Ao appears to be a FasL-Fas antigen-mediated process, but is not due to endotoxin sensitivity . In conclusion, we speculate that the increased Fas-associated apoptosis detected in mucosal B cells (as opposed to splenic or bone marrow B cells) may be due to increased luminal antigens other than endotoxin, released due to gut barrier integrity breakdown during sepsis. Infect Immun, 1998 Mar, 66(3), 1135 - 41 Endotoxin binding and elimination by monocytes: secretion of soluble CD14 represents an inducible mechanism counteracting reduced expression of membrane CD14 in patients with sepsis and in a patient with paroxysmal nocturnal hemoglobinuria; Hiki N et al.; Little is known about the role of peripheral blood mononuclear cells (PBMCs) in lipopolysaccharide (LPS) elimination . We studied the endotoxin elimination capacities (EEC) of PBMCs of 15 healthy volunteers, 13 patients with sepsis, and 1 patient suffering from paroxysmal nocturnal hemoglobinuria (PNH) . Although expression of CD14, the best-characterized receptor for LPS to date, was reduced from 93.6% +/- 0.8% in healthy subjects to 50.5% +/- 6.5% in patients with sepsis and was 0.3% in a patient with septic PNH, EEC were found to be unchanged . There was no difference in the amount of tumor necrosis factor alpha (TNF-alpha) released by PBMCs of healthy donors and patients with sepsis . Anti-CD14 antibodies (MEM-18) completely suppressed EEC, binding of fluorescein isothiocyanate-labeled LPS to monocytes as determined by FACScan analysis, and TNF-alpha release in all three groups studied . The concentrations of soluble CD14 (sCD14) secreted by endotoxin-stimulated PBMCs from healthy donors and patients with sepsis amounted to 4.5 +/- 0.4 and 20.1 +/- 1.8 ng/ml, respectively . Based on our results, we suggest that PBMCs eliminate LPS by at least two different mechanisms; in healthy subjects, the membrane CD14 (mCD14) receptor is the most important factor for LPS elimination, while in patients with sepsis (including the septic state of PNH), increased sCD14 participates in LPS elimination . Secretion of sCD14 is strongly enhanced under conditions of low expression of mCD14 in order to counteract the reduction of mCD14 and maintain the function of monocytes . This sCD14 may substitute the role of mCD14 in LPS elimination during sepsis . The elimination of LPS by PBMCs correlates with the binding reaction and the secretion of TNF-alpha. Shock, 1998 Feb, 9(2), 135 - 7 Increased mesenteric, diaphragmatic, and pancreatic interstitial albumin content in rats with acute abdominal sepsis; Shostak A et al.; This study was designed to evaluate the decreased permselectivity of the capillary wall and the resultant higher permeability to macromolecular anionic albumin in septic rats, by quantitative estimation of Evans blue-albumin complexes in interstitial tissue . Septic peritonitis was induced by intraperitoneal injection of Escherichia coli-O6 KS H16 . Twenty-four hours after induction of septic peritonitis, intact (healthy, noninoculated animals) and septic rats were perfused with 5 mL/Kg of a solution of Evans blue in normal saline (20 mg/mL in .9% NaCl) . In septic rats, the interstitial concentration of Evans blue in mesentery, pancreas, and diaphragmatic muscle was significantly higher than that observed in intact animals . The present observations were made in the same experimental model of abdominal sepsis that showed a substantial reduction in the endothelial negative charge of the mesenteric, pancreatic, and diaphragmatic capillary beds . The evidence obtained from this experiment confirms that the loss of the permselective properties of capillary wall for macromolecular anionic albumin derives from a drastic reduction of its normally present and regularly distributed fixed electronegative charges. Ter Arkh, 1997, 69(11), 38 - 9 {Tumor necrosis factor-alpha kinetics during renal replacement therapy in patients with sepsis and multiple organ failure}; Timokhov VS et al.; Peptide TNF-alpha (tumor necrosis factor alpha) secreted by monocytes and resident macrophages is a key proinflammatory mediator . It can generate response systemic inflammation leading to shock and polyorganic insufficiency . Elimination of circulating TNF-alpha is pathogenetically perspective in respect to therapy of septic shock . Plasma level of TNF-alpha and its elimination with the filter/dialysate was traced in 23 patients with sepsis and polyorganic insufficiency receiving substitute renal therapy (continuous hemodiafiltration, intermittent hemodialysis) for acute renal failure . Sepsis and polyorganic insufficiency was associated with elevated plasma levels of TNF-alpha correlating in many cases with the disease severity . TNF-alpha was for the most part eliminated with the filter/dialysate . The degree of this elimination was related to the technique of blood perfusion and characteristics of the procedure. Am J Respir Crit Care Med, 1998 Feb, 157(2), 421 - 7 Red blood cell deformability in sepsis; Baskurt OK et al.; The microcirculatory disturbances in sepsis have prompted micropore bulk-filtration studies of red blood cell (RBC) mechanical behavior (i.e., deformability) . However, these prior reports may not solely reflect RBC behavior because of possible white blood cell (WBC) occlusion of the filter pores . The present study was designed to examine RBC mechanical alterations in human and experimental sepsis using techniques that are not affected by WBC artifacts . RBC were obtained from adult patients with sepsis and from healthy control donors . RBC were also obtained from Swiss-albino rats in which experimental sepsis was induced via cecal ligation-puncture . Red cell mechanical behavior was tested using a computerized micropore filtration system (CTA) and a laser-diffraction shearing device (LORCA); the latter provides the extent of RBC deformation at various stresses and the time constant for RBC shape recovery . Salient findings include: (1) for human RBC, significantly decreased deformability at fluid shear stresses < 5 Pa (LORCA) yet no differences from control with the CTA; (2) for rat RBC in experimental sepsis, significant decreases of deformability and shape-recovery time constant (LORCA) but no differences with the CTA . We conclude that RBC deformability is reduced in sepsis but that micropore bulk-filtration methods may not be appropriate for detecting these changes. Histol Histopathol, 1998 Jan, 13(1), 121 - 8 Histochemical and ultrastructural study of skeletal muscle in patients with sepsis and multiple organ failure syndrome (MOFS); Diaz NL et al.; Muscle biopsies for histochemical and ultrastructural analysis were obtained from seven critically ill patients admitted to the Intensive Care Unit of the "Domingo Luciani" Hospital, Caracas, Venezuela . The sample included two patients with sepsis of abdominal origin, and five that presented sepsis/MOFS, with renal, hepatic, and respiratory disturbances and muscular weakness . Sections were examined for myosin adenosine triphosphatase (ATPase) after pre-incubation with both acid buffer (pH 4.37 and 4.6) and alkaline buffer (pH 10.3), for reduced nicotinamide dinucleotide diaphorase (NADHd), and for alpha-glycerophosphate dehydrogenase (alpha-GPDH) . Sections were stained with hematoxilin and eosin to look for pathological changes and examined with a transmission electron microscope . Skeletal muscle of patients in early stage of sepsis showed a normal aspect with light microscopy, but at the ultrastructural level some of the fibres showed atrophy and some capillaries looked altered . Patients with sepsis/MOFS exhibited an evident muscle disorder with oedema, infiltrate, atrophy and segmental necrosis . All fibre types showed decrease in diameter; specially fibre types IIA and IIB . Intramuscular capillaries were thickened and occluded, indexes of capillarity were slightly reduced, and fibre oxidative activity was decreased . At ultrastructural level fibres showed severe atrophy, contractile system disorganization and segmental necrosis . Capillaries were also altered and the mononuclear cell infiltrate was abundant and represented by macrophages, lymphocytes and mastocytes. Kidney Int Suppl, 1998 Feb, 64, S80 - 3 Positive role of immune nutrition on metabolism in sepsis and multi-organ failure; Georgieff M et al.; Critically ill patients with systemic inflammatory response syndrome (SIRS) and multi-organ failure are at great risk of nosocomial infections due to a reduced immune status . There is growing evidence from in vitro studies and animal models that the reduced immune response might be improved by the so-called immunomodulatory nutrition . Based on these studies there are now some commercially available enteral or parenteral solutions with immunomodulatory substrates, such as n-3 polyunsaturated fatty acids (PUFAs), arginine and nucleotides . Recently, enteral nutrition with this experimental formula reduced the hospital length of stay and the frequency of acquired infections in critically ill patients . The increasing knowledge about the metabolic effects of these nutritions offers therapeutic potential for the future, and might reduce the mortality of critically ill patients from nosocomial infections . However, at present, studies are necessary to find the best time for beginning and duration of the feeding . In addition, the optimal dosage and composition of these pharmacologically active substances has to be investigated. Kidney Int Suppl, 1998 Feb, 64, S27 - 30 Nitric oxide in sepsis-syndrome: potential treatment of septic shock by nitric oxide synthase antagonists; Ketteler M et al.; Nitric oxide (NO) is an effector molecule with multiple effects on various organ systems . The most prominent physiological actions of NO as a biological mediator include cGMP-dependent vasodilation and cytotoxicity against pathogens in the unspecific immune defense . Sepsis syndrome is a complex disease entity mostly caused by overwhelming bacterial infections . It has a high mortality rate of 40 to 60% . Catecholamine-resistant hypotension and myocardial depression are regarded as major factors contributing to death in septic patients . In septic shock, a pathophysiologically increased NO production occurs due to an excessive induction of the inducible NO synthase (iNOS) . Inducible nitric oxide synthase up-regulation is probably caused by bacterial endo- and exotoxins as well as by an increase of circulating pro-inflammatory cytokines . It may be a key factor leading to pronounced vasodilation and myocardial toxicity . Experimental studies have confirmed that NO overproduction causes severe hypotension in septic animals . Treatment with competitive NOS-inhibitors abolishes this hypotension in animals as well as in septic patients . However, their use is complicated by concomitant decreases in cardiac index and oxygen delivery . Conclusive data on mortality in animals and patients with sepsis-syndrome treated by NOS antagonists are not available . This article discusses current concepts concerning the L-arginine/NO system in the pathophysiology of and as a potential therapeutic target in septic shock. Pediatr Res, 1998 Feb, 43(2), 276 - 82 Elevated circulating calcitonin gene-related peptide in umbilical cord and infant blood associated with maternal and neonatal sepsis and shock; Parida SK et al.; The role of the sensory neuropeptide calcitonin gene-related peptide (CGRP) was studied in preterm and term neonates with sepsis and shock . CGRP levels in blood were measured by RIA . The identity of immunoreactive CGRP (irCGRP) in adult and infant human blood was confirmed by reverse phase-HPLC . CGRP levels were analyzed in a total of 189 samples (95 from cord blood and 94 from neonates) . The gestational ages ranged from 24 to 43 wk, and the birth weights ranged from 520 to 4445 g . Cord samples were collected immediately after delivery and infant blood samples were collected within 12 h of birth . Samples were coded, and the data were assigned to groups after determination of CGRP levels . There was a weight- and gestation-dependent increase in irCGRP in the newborn population . The direct correlation of circulating CGRP with ascending birth weight and gestation may have significance in the development of the fetus . Infants with and without certain complications were grouped in 500-g intervals . CGRP levels in cord blood were significantly elevated when certain stressful situations existed in the mother . These included culture-positive chorioamnionitis, placental abruption, and severe preeclampsia . There was a similar elevation in CGRP in patient blood in infants with culture-positive sepsis and/or shock with blood pressure <2 SD from the mean for corresponding gestation . CGRP levels did not differ between male and female infants and did not appear to be influenced by type of delivery (vaginal versus cesarean section) . There was no significant difference in CGRP level between cord and patient blood in preterm neonates, but at term gestation cord blood levels were slightly higher than those in the patient blood . These results suggest that inflammation and hemodynamic imbalance (e.g . shock) are associated with increased in CGRP levels in the circulation in neonates . Future studies will focus on the biologic effects of elevated CGRP during neonatal complications and will examine the utility of CGRP measurement for diagnosis and treatment of disease in preterm infants. J Med Assoc Thai, 1997 Dec, 80(12), 760 - 6 Hypoglycemia in sepsis: risk factors and clinical characteristics; Rattarasarn C; To determine risk factors for the development and clinical characteristics of hypoglycemia in patients with sepsis, a case-control study was performed in 52 case-patients who developed spontaneous hypoglycemia (plasma glucose < 50 mg/dl) during episodes of sepsis compared with 49 nondiabetic, control-patients who had sepsis as an immediate cause of death and did not develop hypoglycemia . The presence or absence of potential risk factors for the development of hypoglycemia which consisted of the state of starvation, malnutrition, renal insufficiency, acute or chronic liver disease and malignancy were evaluated in both groups as well as the clinical characteristics of hypoglycemia . The mean of the lowest plasma glucose levels in hypoglycemic patients was 23.4 +/- 14.9 (SD) mg/dl (range 3-47) . One-third of patients were found having hypoglycemia since the time of arrival to the hospital . About 90 per cent had septic shock at the time of hypoglycemia . The mortality rate was 90 per cent; 80 per cent died within 48 hours after the first episode of hypoglycemia . Among those risk factors, starvation and liver disease were independently associated with the development of hypoglycemia with odd ratios of 6.38 (95% confidence interval 1.95-20.86; P = 0.002), and 3.59 (95% confidence interval 1.09-11.81; P = 0.035), respectively . In conclusion, hypoglycemia in patients with sepsis was associated with a grave prognosis . The risk of developing hypoglycemia increased significantly in patients who had been fasted for more than 24 hours or had acute or chronic liver disease at the time of sepsis. Crit Care Med, 1998 Feb, 26(2), 315 - 21 Enhancement of peritoneal leukocyte function by granulocyte colony-stimulating factor in rats with abdominal sepsis; Zhang P et al.; OBJECTIVE: To investigate the therapeutic effects of granulocyte colony-stimulating factor (G-CSF) on the functional activities of circulating and peritoneal neutrophils during intra-abdominal sepsis . DESIGN: Placebo, controlled study, using a rat model of intra-abdominal sepsis . SETTING: Animal research facility . SUBJECTS: Male specific pathogen-free Sprague-Dawley rats . INTERVENTIONS: Abdominal sepsis was produced in rats by cecal ligation and puncture . The control animals received a sham operation . G-CSF (subcutaneous injection at 50 microg/kg) or vehicle (100 microL of 5% dextrose) treatment was initiated at 1 hr after cecal ligation and puncture or sham operation and repeated at 12-hr intervals thereafter . MEASUREMENTS AND MAIN RESULTS: Six hours after cecal ligation and puncture, CD11b/c and CD18 expression on circulating neutrophils was significantly up-regulated when compared with those in the sham operated control animals . Peritoneal neutrophils exhibited a further up-regulation of these adhesion molecules than did the circulating neutrophils . A sustained up-regulation of CD11b/c and CD18 was found in peritoneal neutrophils even at 24 hrs after cecal ligation and puncture . G-CSF treatment increased CD11b/c expression on circulating neutrophils in 6-hr sham-operated rats, but did not further up-regulate CD11b/c or CD18 expression on circulating or peritoneal neutrophils in cecal ligation and puncture rats . Phagocytic activities of circulating neutrophils assessed by uptake of fluorescent latex microspheres were lower in 24-hr cecal ligation and puncture rats when compared with the sham-operated controls . G-CSF treatment prevented this inhibition . Furthermore, G-CSF enhanced the phagocytic activities of peritoneal neutrophils in both 6- and 24-hr cecal ligation and puncture rats when compared with those of the vehicle-treated animals . Spontaneous hydrogen peroxide generation by circulating neutrophils was increased in 6-hr cecal ligation and puncture rats, but not in 24-hr cecal ligation and puncture rats . Peritoneal neutrophils exhibited an inhibition of phorbol myristate acetate-stimulated hydrogen peroxide generation . G-CSF treatment did not up-regulate neutrophil hydrogen peroxide generation . CONCLUSIONS: Circulating and peritoneal neutrophils exhibit marked polymorphism in their functional activities during the host response to abdominal sepsis . G-CSF treatment significantly enhanced the phagocytic function of both circulating and peritoneal neutrophils which may be one mechanism underlying its protective effect in abdominal sepsis. Shock, 1998 Jan, 9(1), 46 - 51 Sequential alterations in tissue lipoprotein lipase, triglyceride secretion rates, and serum tumor necrosis factor alpha during Escherichia coli bacteremic sepsis in relation to the development of hypertriglyceridemia; Lanza-Jacoby S et al.; The time sequence and the mechanisms leading to the development of the hypertriglyceridemia of bacteremic sepsis are not fully understood . This study was conducted to determine the mechanisms leading to the early rise in serum triglycerides (TG) . Bacteremic sepsis was induced in fasted and parenterally fed rats by intravenous infusion of live Escherichia coli colonies over a 1 h period every 24 h up to 96 h . Body temperature was elevated from 12 to 48 h after E . coli infusion in fasted rats and from 24 to 72 h after E . coli infusion in fed rats . The initial rise in serum TG was observed at 3 h after E . coli infusion; in fasted rats this elevation was maintained over 72 h . In the parenterally fed rats, hypertriglyceridemia was evident only at the 3 h time point . Serum concentrations of tumor necrosis factor alpha (TNF-alpha) were elevated significantly at 60 min after initiating the E . coli infusion, peaked at 90 min, and declined by 120 min . Immunization with neutralizing goat anti-TNF-alpha IgG did not block the initial increase in serum TG induced by E . coli . This early rise in TG in fasted E . coli-treated rats was accompanied by a 33% increase in TG secretion in comparison with control rats . TG secretion declined by 27% at 9 h and remained depressed at 12 and 24 h in comparison with time-matched control rats . By 24 h lipid accumulation was evident in the livers of the fasted and fed E . coli-treated rats . Most of the fasted E . coli-treated rats died by 72 h . Parenteral feeding extended survival of E . coli-treated rats until 120 h . These findings along with the observation that two mechanisms are involved in maintaining the elevation of serum TG during E . coli sepsis suggests that the hypertriglyceridemia may be important in host survival. Shock, 1998 Jan, 9(1), 1 - 11 Animal models of sepsis and shock: a review and lessons learned; Deitch EA; Over the past decade, the biotechnology/pharmaceutical industry has been diligently working on the development of immunomodulatory agents for the treatment of shock and sepsis, and the literature is rife with descriptions of novel and innovative molecules that promise to become the panacea for these conditions . Unfortunately, despite promising preclinical evidence, dozens of these new agents have failed to demonstrate clinical efficacy in controlled, randomized clinical trials, abandoning the bedside physician to the traditional armamentarium of drugs and therapeutics for the treatment of patients with these complex, progressive, and life-threatening conditions . The reasons for this quandary are controversial, complex, and multifactorial . This review focuses on the concept that the preclinical trials of many of these agents were conducted using models of sepsis and shock that do not adequately reflect the clinical realities of these conditions . As a result, it is not surprising that clinical trials of agents based on clinically flawed models failed to demonstrate clinical efficacy . The lack of clinical insight during preclinical development of these agents has contributed to the current impasse of the development of safe, efficacious, and potentially lifesaving agents for the treatment of shock and sepsis . Thus, the goal of this review article is to review the advantages and disadvantages of commonly used sepsis and shock models in light of lessons learned from these clinical trials. Eur J Clin Invest, 1997 Dec, 27(12), 1044 - 8 Granulocyte colony-stimulating factor enhances protection by anti-K1 capsular IgM antibody in murine Escherichia coli sepsis; Hustinx W et al.; Combined prophylactic treatment with recombinant murine granulocyte colony-stimulating factor (G-CSF) and a suboptimal dose of anti-K1 capsular IgM monoclonal antibody (MAb) significantly enhanced survival in an experimental mouse Escherichia coli O7:K1 peritonitis model compared with untreated animals (67% vs . 11% survival; P < 0.001) and with either treatment alone (67 vs . 29% and 27% survival, respectively; P < 0.01), which suggests synergism between these agents . Enhanced survival by combined treatment was associated with increased neutrophil counts in blood and peritoneal lavage fluid, lower systemic and higher levels of local tumour necrosis factor (TNF) and lower bacterial counts in blood cultures . Mouse neutrophils treated with G-CSF but not infected with E . coli showed enhanced phagocytic and respiratory burst capacity, down-regulation of L-selectin receptors and enhanced expression of Fc RII-III receptors but not of complement receptors. Am J Physiol, 1998 Jan, 274(1 Pt 2), R30 - 7 Sepsis-induced increase in muscle proteolysis is blocked by specific proteasome inhibitors; Hobler SC et al.; Recent studies suggest that sepsis stimulates ubiquitin-dependent protein breakdown in skeletal muscle . The 20S proteasome is the catalytic core of the ubiquitin-dependent proteolytic pathway . We tested the effects in vitro of the proteasome inhibitors N-acetyl-L-leucinyl-L-leucinal-L-norleucinal (LLnL) and lactacystin on protein breakdown in incubated muscles from septic rats . LLnL resulted in a dose- and time-dependent inhibition of protein breakdown in muscles from septic rats . Lactacystin blocked both total and myofibrillar muscle protein breakdown . In addition to inhibiting protein breakdown, LLnL reduced muscle protein synthesis and increased ubiquitin mRNA levels, probably reflecting inhibited proteasome-associated ribonuclease activity . Inhibited muscle protein breakdown caused by LLnL or lactacystin supports the concept that the ubiquitin-proteasome pathway plays a central role in sepsis-induced muscle proteolysis . The results suggest that muscle catabolism during sepsis may be inhibited by targeting specific molecular mechanisms of muscle proteolysis. Khirurgiia (Mosk), 1997, (7), 44 - 7 {Influence of hemosorption on hemostasis in patients with sepsis}; Kruchinskii NG et al.; The changes in the system of hemostasis were studied in 36 patients with sepsis managed with sorptive detoxication . The starting status of the system of hemostasis in patients with favorable outcome of the disease can be considered as the 2d stage of the disseminated intravascular coagulation (DIC), and in patients with the unfavorable outcome--as the 3d (hypocoagulative) stage . The sorptive detoxication provides the treatment of the DIC syndrome in favorable outcome, as well as further progression of the process in unfavorable outcome of sepsis . Conservative treatment provides stabilization of the hemostatic system and gives opportunity to perform delayed hemosorption with a positive clinical result. Rev Med Chir Soc Med Nat Iasi, 1996 Jul-Dec, 100(3-4), 44 - 7 {The current pathogenetic aspects of MODS in the sepsis patient}; Dorobat C et al.; MODS, a phenomenon observed in many critically ill patients, is the progressive failure of two or more organ system which results from nonspecific systemic responses to abnormal intravascular inflammation . It is triggered by a number of cellular humoral and biochemical mediators (more than 100) . This article takes up the role of individual organ system dysfunction in the development of MODS . Cardiopulmonary, renal and hepatic responses to injury and infection and the relation of these responses to the subsequent development of MODS have been the subject of intense investigations; recently the gastrointestinal tract was identified as another target organ in such patients. J Surg Res, 1997 Dec, 73(2), 117 - 22 The role of neutrophils in producing hepatocellular dysfunction during the hyperdynamic stage of sepsis in rats; Molnar RG et al.; Although studies have shown that hepatocellular function is depressed during the early, hyperdynamic stage of sepsis, the mechanism responsible for this remains unknown . To determine whether neutrophils play any role in producing this depression, hepatocellular function was measured in neutrophil-competent and neutropenic animals subjected to sepsis . Neutropenia was induced by tail vein injection of an immunoglobulin directly against rat neutrophils (anti-neutrophil Ig) at 16 and 2 h prior to the initiation of cecal ligation and puncture (CLP, i.e., a model of polymicrobial sepsis) . Neutropenia was confirmed by peripheral blood smears . Neutrophil-competent controls were given nonimmunized Ig before the onset of sepsis . Sham-operated animals received anti-neutrophil Ig or control Ig . Hepatocellular function {i.e., the maximal velocity of indocyanine green clearance (Vmax) and efficiency of the clearance (Km)} was determined by a fiber-optic catheter and in vivo hemoreflectometer at 5 h after CLP (i.e., early, hyperdynamic sepsis) or sham operation . Serum alanine aminotransferase (ALT) levels were also determined . The results indicate that although circulating levels of ALT were not elevated, hepatocellular function was significantly depressed during early sepsis . The depression in Vmax and Km was, however, prevented by neutrophil depletion, suggesting an integral role of the neutrophils in depressing hepatocellular function under such conditions . The results suggest that the prudent modulation of neutrophil function during the early stage of polymicrobial sepsis may be beneficial for preventing or delaying the occurrence of hepatocellular dysfunction . World J Surg, 1998 Feb, 22(2), 203 - 8 Sepsis: stimulation of energy-dependent protein breakdown resulting in protein loss in skeletal muscle; Hasselgren PO et al.; Muscle catabolism is a characteristic metabolic response to sepsis, severe infection, and injury . In patients with severe and protracted sepsis, the catabolic response results in muscle wasting and fatigue, which may adversely affect the outcome in these patients . An understanding of the regulation of muscle protein breakdown during sepsis and the mechanisms involved is important from a clinical standpoint and is essential for the development of new therapeutic modalities to prevent protein loss from muscle tissue . Studies in septic patients and experimental animals have provided evidence that the myofibrillar proteins actin and myosin are particularly sensitive to the effects of sepsis . Among the factors that regulate muscle protein breakdown during sepsis, the proinflammatory cytokines tumor necrosis factor and interleukin-1, together with glucocorticoids, are the principal mediators . Intracellular protein breakdown is regulated by multiple proteolytic pathways . Among these, the energy-ubiquitin-dependent pathway accounts for a major portion of muscle protein breakdown during sepsis . The development of specific proteasome inhibitors may make it possible in the future to target the molecular mechanisms of sepsis-induced increase in muscle proteolysis . Such treatment may prove an important avenue to reduce the metabolic cost in patients with severe infection or sepsis. J Appl Physiol, 1998 Jan, 84(1), 107 - 15 Cardiopulmonary effects of inhaled nitric oxide in normal dogs and during E . coli pneumonia and sepsis; Quezado ZM et al.; We investigated the effect of inhaled nitric oxide (NO) at increasing fractional inspired O2 concentrations (FIO2) on hemodynamic and pulmonary function during Escherichia coli pneumonia . Thirty-eight conscious, spontaneously breathing, tracheotomized 2-yr-old beagles had intrabronchial inoculation with either 0.75 or 1.5 x 10(10) colony-forming units/kg of E . coli 0111:B4 (infected) or 0.9% saline (noninfected) in one or four pulmonary lobes . We found that neither the severity nor distribution (lobar vs . diffuse) of bacterial pneumonia altered the effects of NO . However, in infected animals, with increasing FIO2 (0.08, 0.21, 0.50, and 0.85), NO (80 parts/million) progressively increased arterial PO2 {-0.3 +/- 0.6, 3 +/- 1, 13 +/- 4, 10 +/- 9 (mean +/- SE) Torr, respectively} and decreased the mean arterial-alveolar O2 gradient (0.5 +/- 0.3, 4 +/- 2, -8 +/- 7, -10 +/- 9 Torr, respectively) . In contrast, in noninfected animals, the effect of NO was significantly different and opposite; NO progressively decreased mean PO2 with increasing FIO2 (2 +/- 1, -5 +/- 3, -2 +/- 3, and -12 +/- 5 Torr, respectively; P < 0.05 compared with infected animals) and increased mean arterial-alveolar O2 gradient (0.3 +/- 0.04, 2 +/- 2, 1 +/- 3, 11 +/- 5 Torr; P < 0.05 compared with infected animals) . In normal and infected animals alike, only at FIO2 < or = 0.21 did NO significantly lower mean pulmonary artery pressure, pulmonary artery occlusion pressure, and pulmonary vascular resistance index (all P < 0.01) . However, inhaled NO had no significant effect on increases in mean pulmonary artery pressure associated with bacterial pneumonia . Thus, during bacterial pneumonia, inhaled NO had only modest effects on oxygenation dependent on high FIO2 and did not affect sepsis-induced pulmonary hypertension . These data do not support a role for inhaled NO in bacterial pneumonia . Further studies are necessary to determine whether, in combination with ventilatory support, NO may have more pronounced effects. J Nutr, 1998 Jan, 128(1), 97 - 105 Metabolism of cysteine is modified during the acute phase of sepsis in rats; Malmezat T et al.; In vivo cysteine metabolism during the inflammatory state has been studied minimally . We investigated cysteine metabolism (i.e . taurine, sulfate and glutathione formation) using a single dose of {35S} cysteine in septic rats that had been injected with live Escherichia coli into the tail vein and in control, pair-fed rats . Cysteine metabolites were separated by ion exchange chromatography, and radioactivity was counted in the different fractions . Radioactivity incorporated in tissue proteins was also measured after protein precipitation . {35S}Sulfate production was significantly lower in septic rats than in pair-fed rats . {35S}Taurine contents were significantly lower only in kidneys, spleen and gastrointestinal tract of septic rats . The higher production of {35S} taurine in the livers (the major site of taurine production) of septic rats could have a protective effect against oxidation . Glutathione concentrations were also significantly greater in liver, spleen, kidneys and gastrocnemius muscle of septic rats, presumably in order to combat oxidative stress induced by sepsis . {35S}Cysteine incorporation in glutathione was significantly higher in spleen and kidneys but not in liver of septic rats compared to pair-fed rats . This could be explained by the fact that, in liver, a greater amount of labeled glutathione had been utilized for host defense, or by a high level in glutathione turnover . Finally, {35S}cysteine incorporation into protein, in septic rats, was significantly greater than in pair-fed rats in spleen, lung and particulary in whole plasma proteins other than albumin, which mainly represent the acute-phase proteins . These data suggest an increased requirement for cysteine during sepsis in rats. Pediatr Surg Int, 1998 Jan, 13(1), 8 - 9 Hepatic duct stone associated with chlamydia sepsis: a rare condition in childhood; Celayir S et al.; Stone formation in the biliary system is a rare condition in infants . A few cases of bile stones in the biliary tree have been reported with underlying predisposing factors, such as sepsis and antibiotic usage . This article describes a surgically treated 16-week-old infant with recurrent cholangitis who had a bile stone in the hepatic duct after chlamydia sepsis. Am J Respir Crit Care Med, 1998 Jan, 157(1), 129 - 34 Leukocyte activation and flow behavior in rat skeletal muscle in sepsis; Piper RD et al.; In animal models of endotoxemia, sepsis is associated with the accumulation of leukocytes and altered microvascular perfusion . In order to test the hypothesis that bacterial sepsis upregulates leukocyte-endothelial adhesion, we used intravital microscopy to examine the flow behavior of leukocytes in the postcapillary venules (PCV) of rats made septic by cecal ligation and perforation (CLP) . Animals were randomized to CLP or sham study groups and studied 6 h, 24 h, or 48 h later . In postcapillary venules of the extensor digitorum longus muscle, we found that: (1) over the course of the study, leukocyte adhesion and extravasation increased in both experimental groups (analysis of variance {ANOVA}, significant time effect: adhesion, p < 0.001; extravasation, p < 0.05); (2) leukocyte adhesion was decreased by CLP treatment (ANOVA, sepsis effect, p = 0.05), particularly after 24 to 48 h of sepsis (ANOVA, sepsis x time interaction, p < 0.05); and (3) the reduction in leukocyte adhesion in CLP animals was associated with a decrease in leukocyte extravasation (ANOVA, sepsis effect, p < 0.01) . After correction for the reduction in systemic leukocyte count associated with CLP, the effect of sepsis on leukocyte adhesion and extravasation no longer reached statistical significance . These findings suggest that chronic (6 to 48 h) bacterial sepsis does not upregulate leukocyte adhesion in a manner similar to that seen in models of acute endotoxemia . These data suggest that the increased microcirculatory flow heterogeneity seen in this and other models of bacterial sepsis may not be explained by leukocyte entrapment in postcapillary venules. Am J Respir Crit Care Med, 1998 Jan, 157(1), 50 - 6 Determination of total effective vascular compliance in patients with sepsis syndrome; Stephan F et al.; Changes in capacitance vessels have important consequences on cardiac filling pressure and fluid volume distribution in patients with sepsis syndrome . Vascular compliance may be evaluated from the slope of the relationship between changes in total blood volume (deltaTBV) and changes in central venous pressure (deltaCVP) during acute volume expansion (450 ml of gelatin fluid over 6 min), i.e., from the deltaTBV/deltaCVP ratio . The mean ratio (ml x mm Hg-1 x kg-1) was 2.03 +/- 0.21 in control subjects, 1.43 +/- 0.25 in mechanically ventilated patients without sepsis syndrome, and 0.