Ulus Travma Derg, 2001 Apr, 7(2), 82 - 6 {The effectiveness of hemopoietic growth factors in sepsis}; Yilmaz G et al.; In this experimental study, consist of 54 Sprague-Dawley rats, we tried to observe the effectiveness of haemopoietic growth factors such as G-CSF and GM-CSF in treatment of sepsis and see if they have any effects on phagocytic activity of macrophages when are administered after establishment of sepsis . In first phase of this study, twenty one rats were randomly divided into three groups of 7 animals each . Cecal ligation and perforation were carried out in each rat and sepsis made up . The Control group received 2 x 0.2 cc %5 dextrose injection subcutaneous (s.c.). . The G-CSF group received 2 x 1 g G-CSF with 0.2 cc %5 dextrose s.c . The GM-CSF received 1 x 2 g GM-CSF with 0.2 cc %5 dextrose s.c . Seventh day survival was considered as criterion in the three groups . In second phase of this study, thirty three rats were randomly divided into three groups of 11 animals each . The same procedures were carried out also in these groups . Leukocyte counts and peripheric spread were analyzed in postoperative 24th and 72th hours, alveolar and peritoneal macrophages were Investigated in postoperative 72nd hour . There was significantly neutrophilic leukocytosis in the G-CSF group according to the control group . Nevertheless, there was no change in the phagocytic activity of alveolar and peritoneal macrophages . GM-CSF brought about positive effect of phagocytic activity of macrophages without change of leucocyte count in the sepsis, but it caused neutrophilic, monocytosis and lymphocytopenia . The seventh day survival rates in control, G-CSF, GM-CSF groups were as; 42.8%, 71.4%, 28.5% respectively . As a result, we saw that G-CSF has no effect on the phagocytic activity of macrophages, while increases the survival by enhancing the count and probably the function of neutrophils . GM-CSF fails to increase survival while effects the phagocytic activities of macrophages positively and enhances the peripheral neutrophil and monosit counts without changing the total number of leukocytes. Am J Respir Crit Care Med, 2001 Oct 15, 164(8 Pt 1), 1444 - 7 A global approach to energy metabolism in an experimental model of sepsis; L'Her E et al.; Disturbances in energy metabolism during sepsis are not clearly understood . The aim of the study was to globally assess the energy drive in septic rat myocytes, studying both glycolysis rates and mitochondrial maximal activities together, using recent in vitro techniques . Measurements were assessed before (H0) and 4 h after sepsis induction (H4) . Hyperlactatemia was observed in all septic animals ({lactate} = 1.2 +/- 0.3 mmol/L at H0 versus 3.3 +/- 0.6 mmol/L at H4; p < 0.001) . An enhanced glycolysis rate was observed in both aerobic ( J(A) = 7.2 +/- 0.9 at H0 versus 18.2 +/- 4.1 nmol glucose/min/g at H4; p < 0.05) and anaerobic ( J(B) = 7.5 +/- 1.2 at H0 versus 15.4 +/- 3.4 micromol glucose/min/g at H4; p < 0.05) fluxes, associated with a selective significant pyruvate-malate-dependent oxygen consumption rate decrease (V O(2)-PM = 0.144 +/- 0.008 at H0 versus 0.113 +/- 0.007 micromol O(2)/h/mg at H4; p < 0.05) . This oxygen consumption decrease can be interpreted either as a complex I and/or a complex I-ubiquinone relation alteration . Our results are consistent with the hypothesis that an altered mitochondrial function during sepsis is responsible, at least in part, for hyperlactatemia, which is thus a consequence of an increased glycolysis rate. J Hepatobiliary Pancreat Surg, 2001, 8(5), 449 - 52 Abdominal zippers for temporary abdominal closure in planned relaparotomies for peripancreatic sepsis: experience in a developing country; Perez A et al.; BACKGROUND: Planned relaparotomies have generated renewed interest because of the high mortality rates associated with conventional management techniques in severe intraabdominal sepsis . The use of abdominal zippers for temporary abdominal closure was devised to facilitate repeated explorations, allowing daily cleansing of the peritoneal cavity and the detection and management of septic complications . METHODS: In our institution, eight patients were managed in a 4-year period, using abdominal zippers for peripancreatic sepsis . RESULTS: In all eight patients, subsequent laparotomies allowed the detection of progressive necrosis . Repeated explorations successfully controlled the sepsis in five patients . In three patients, the condition deteriorated, and they died of multiple organ failure . CONCLUSIONS: The technique warrants further prospective controlled trials in the local setting to ascertain its role in the management of severe intraabdominal sepsis, and in other patients who may require "second-look" operations. Crit Care Med, 2001 Nov, 29(11), 2051 - 9 Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis; Bernard GR et al.; OBJECTIVES: To assess the safety and effect on coagulopathy of a range of doses of recombinant human activated protein C (rhAPC) . To determine an effective dose and duration of rhAPC for use in future clinical trials . DESIGN: Double-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential), phase II clinical trial . SETTING: Forty community or academic medical institutions in United States and Canada . PATIENTS: One hundred thirty-one adult patients with severe sepsis . INTERVENTIONS: Intravenous infusion of rhAPC (12, 18, 24, or 30 microg/kg/hr) or placebo for 48 or 96 hrs . MEASUREMENTS AND MAIN RESULTS: No significant differences in incidence of serious bleeding events (4% rhAPC, 5% placebo, p >.999) or incidence of serious adverse events (39% rhAPC, 46% placebo, p = 0.422) between rhAPC- and placebo-treated patients were observed . One of 53 rhAPC-treated patients with suitable immunogenicity samples had a low level, transient, non-neutralizing anti-APC antibody response not associated with any clinical adverse event . Significant dose-dependent decreases in both D-dimer (p <0.001) and end of infusion interleukin 6 levels (p =.021) were demonstrated . No statistically significant effects on fibrinogen or platelet counts were observed . A nonstatistically significant 15% relative risk reduction in 28-day all-cause mortality was observed between rhAPC- and placebo-treated patients . CONCLUSIONS: rhAPC was safe and well-tolerated and demonstrated a dose-dependent reduction in D-dimer and interleukin 6 levels relative to placebo . The dose of 24 microg/kg/hr for 96 hrs was selected for use in future clinical studies. Acta Paediatr, 2001 Oct, 90(10), 1176 - 81 Cord blood levels of cytokines as predictors of early neonatal sepsis; Santana C et al.; AIM: To investigate whether cord blood levels of C-reactive protein, interleukin-1beta, interleukin-6, interleukin-8, tumour necrosis factor-alpha and the soluble receptor of interleukin-2, are useful markers in the diagnosis of early neonatal sepsis . DESIGN: Umbilical cord blood samples were obtained at birth from 261 neonates, but 5 of these newborns were excluded from the study . Group I included 10 newborns that developed early neonatal sepsis with a positive blood culture; Group II included 11 newborns with non-infectious perinatal diseases; Group III, which served as the control group, included 10 randomly selected patients, matched for gestational age, among the 235 healthy newborn babies . RESULTS: There were no differences among the three study groups in levels of C-reactive protein . interleukin-1beta, tumour necrosis factor-alpha and the soluble receptor of interleukin-2 . Interleukin-6 was significantly elevated in Group I (360.4+/-157.8 pg/ml) and Group II (158.8+/-122.3 pg/ml), when compared with Group III (8.6+/-3.12 pg/ml) (p < 0.01), whereas interleukin-8 was significantly elevated in Group I (389.3+/-115.9 pg/ml) compared with Groups II (30.2+/-5.1 pg/ml) (p < 0.05) and III (33.9+/-8.6 pg/ml) (p < 0.05) . A cut-off of 100.8 pg/ml for interleukin-6 obtained by the ROC (receiver operating characteristic) method gave a sensitivity of 50% and a specificity of 87%, and a cut-off of 111.7 pg/ml for interleukin-8 showed a sensitivity of 78% and a specificity of 91% . CONCLUSION: While cord blood levels of interleukin-6 appear to be related to pathological conditions in the perinatal period (infectious and non-infectious), interleukin-8 seems to be a good predictor of early bacterial neonatal infection. Arthroscopy . 2001 Nov-Dec;17(9):E39. Medulloscopy for sepsis or nonunion: Early clinical experience with the tibia and femur; Roberts CS et al.; We report the clinical use of "medulloscopy" for the visualization and irrigation of sepsis or nonunion of the tibia and femur in 7 cases . Included were 2 cases of aseptic femoral nonunion, 1 infected femoral nonunion with chronic osteomyelitis, 2 cases of healed tibia fracture with chronic osteomyelitis, 1 aseptic nonunion of the tibia, and 1 case of tibial osteomyelitis secondary to intravenous drug use . Visualization of the nonunion site or pathologic lesion was achieved in 86% of cases (6 of 7) and additional diagnostic information was obtained by medulloscopy in 86% of cases (6 of 7) . A representative case is presented . Medulloscopy appears to be clinically useful for the treatment of sepsis or nonunion of the tibia and femur when access to the intramedullary canal is necessary. Pediatrics, 2001 Nov, 108(5), 1099 - 102 Maternal epidural use and neonatal sepsis evaluation in afebrile mothers; Goetzl L et al.; OBJECTIVE: Epidural use has been associated with a higher rate of neonatal sepsis evaluation . Epidural-related fever explains some of the increase but not the excess of neonatal sepsis evaluations in afebrile women METHODS: We studied 1109 women who had singleton term pregnancies and who presented in spontaneous labor and were afebrile during labor (<100.4 degrees F) . Neonatal sepsis evaluation generally was performed on the basis of the presence of 1 major or 2 minor criteria . Major criteria included rupture of membranes for >24 hours or sustained fetal heart rate of >160 beats per minute . Minor criteria included a maternal temperature of 99.6 degrees F to 100.4 degrees F, rupture of membranes for 12 to 24 hours, maternal admission white blood cell count of >15 000 cells/mL(3), or an Apgar score of <7 at 5 minutes . RESULTS: Infants of afebrile women with epidural analgesia were more likely to be evaluated for sepsis than infants of women without epidural (20.4% vs 8.9%), although not more likely to have neonatal sepsis . An increased risk of sepsis evaluation persisted in regression analysis (odds ratio: 3.1; 95% confidence interval: 2.0, 4.7) after controlling for confounders and was not explained by longer labors with epidural . Women with epidural were significantly more likely to have major and minor criteria for sepsis evaluation, including fetal tachycardia (4.4% vs 0.4%), rupture of membranes for >24 hours (6.2% vs 3.4%), low-grade fever of 99.6 degrees F to 100.4 degrees F (24.3% vs 5.2%), and rupture of membranes for 12 to 24 hours (21.4% vs 5.2%) than women without epidural . CONCLUSIONS: Epidural analgesia is associated with increased rates of major and minor criteria for neonatal sepsis evaluations in afebrile women. Aesthetic Plast Surg, 2001 Sep-Oct, 25(5), 347 - 9 A case of life-threatening sepsis after breast augmentation by fat injection; Valdatta L et al.; A case is presented in which an aesthetic breast augmentation by fat injection led a young woman to a life-threatening sepsis due to bilateral mammary abscesses . Immediate and late complications of this procedure are considered; infection is the frightful complication that can lead to septic shock, affecting survival, aesthetic outcome, and reconstruction possibilities of the patient's breasts. Ann Clin Lab Sci, 2001 Oct, 31(4), 365 - 8 Clinical commentary: granulocytic fragments in sepsis; Dalton RR et al.; Granulocytic fragments have been described in the peripheral blood of patients with sepsis and the systemic inflammatory response syndrome (SIRS) . Although initially proposed as a morphologic clue for distinguishing the leukoerythroblastosis of sepsis from that of myelophthisis or marrow replacement by tumor, granulocyte-derived fragments may be part of a spectrum of cellular fragmentation associated with pathological inflammation and thrombosis, and thus play an important role in the pathophysiology of sepsis and SIRS . Pathologists, hematologists, and medical technologists should be aware of their existence, the morphologic features that distinguish them from macrothombocytes and schistocytes, and their potential significance. JAMA, 2001 Oct 17, 286(15), 1869 - 78 Caring for the critically ill patient . High-dose antithrombin III in severe sepsis: a randomized controlled trial; Warren BL et al.; CONTEXT: Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock . Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock . Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients . OBJECTIVE: To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock . DESIGN AND SETTING: Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000 . PATIENTS: A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin) . MAIN OUTCOME MEASURE: All-cause mortality 28 days after initiation of study medication . RESULTS: Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P =.94) . Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups . In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P =.08) . This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P =.03) . In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001) . CONCLUSIONS: High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset . High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin . There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin. Curr Opin Hematol, 2001 Nov, 8(6), 380 - 6 Transfusion-related bacterial sepsis; Reading FC et al.; Transfusion-associated bacterial sepsis is a persistent problem in transfusion medicine, posing a greater threat than the combined risks of receiving a blood product contaminated with HIV-1 or 2, hepatitis C virus (HCV), hepatitis B virus (HBV), and human T-cell lymphtrophic virus (HTVL) -I or -II . This article provides a brief overview of the current incidence, clinical presentation, associated blood products and organisms, and the most feasible and effective methods available to reduce the potential risk of transfusion-associated sepsis . Because bacterial contamination of blood products is the most frequent cause of transfusion-transmitted infectious disease, and as no single existing strategy can completely eliminate its risk, it is important that clinical suspicion be high, and any partial solutions additively be implemented. BioDrugs, 2001, 15(10), 645 - 54 Innovative therapies for sepsis; Krishnagopalan S et al.; Sepsis and septic shock continue to be a major cause of morbidity and mortality . Despite numerous advances in the supportive care of patients with sepsis, the overall mortality has changed little in the past 20 years . Many innovative therapies have been attempted in the field of sepsis, primarily aimed at stopping the cycle of cytokine activation which is part of the systemic inflammatory response . Therapies have also targeted other molecular mediators of inflammation and coagulation . Despite encouraging preliminary preclinical results, most of the early trials in sepsis research have failed to offer hope of improving survival with the use of these innovative therapies . Postulated reasons for the failure of clinical trials include the disparity between animal models and clinical reality, the heterogeneous nature of patient populations and sepsis, and the complexity of the inflammatory cascade . On a more hopeful note, three recent trials assessing corticosteroids, anti-tumour necrosis factor strategy and drotrecogin alfa (rhAPC), respectively, have proclaimed positive results . However, only the drotrecogin alfa trial has been peer reviewed and published. Ann Acad Med Singapore, 2001 Sep, 30(5), 528 - 31 Plasma procalcitonin in sepsis and organ failure; Yukioka H et al.; INTRODUCTION: Because the use of procalcitonin (PCT) as a marker of bacterial infection has been advocated, this study was carried out to determine the usefulness of plasma PCT in the early diagnosis and differentiation of patients with non-infectious systemic inflammatory response syndrome (SIRS) from those with sepsis, and the relationship between plasma PCT level and severity of organ failure . MATERIALS AND METHODS: Thirty-five patients with non-septic SIRS (n = 16), sepsis (n = 7) or septic shock (n = 12) were included in this study . PCT and C-reactive protein (CRP) levels were measured and sepsis-related organ failure assessment (SOFA) score was calculated for these patients . Plasma PCT was measured by immunoluminometric assay . RESULTS: The median (minimum, maximum) plasma PCT levels were 0.6 (0.1, 3.4) ng/mL in non-septic SIRS, 5.4 (0.9, 47.7) ng/mL in sepsis and 73.4 (9.6, 824.1) ng/mL in septic shock, and significant differences existed in plasma PCT levels among the three groups . The median (minimum, maximum) CRP levels were 13.8 (0.3, 48.8) mg/dL in non-septic SIRS, 23.3 (1.4, 26.6) mg/dL in sepsis and 17.4 (2.2, 34.1) mg/dL in septic shock, without significant differences among the three groups . A good correlation was found between plasma PCT level and SOFA score (rs = 0.766, P < 0.0001), although no correlation was found between CRP level and SOFA score . CONCLUSIONS: CRP is increased by inflammatory disease as well as infection and is therefore not a good indicator of infection in patients with severe SIRS . On the other hand, PCT is a good indicator of severity of sepsis and organ failure in patients with severe SIRS since PCT levels correlated with sepsis and SOFA scores . PCT level is useful for diagnosis of sepsis and as an indicator of severity of organ failure in patients with SIRS. Surgery, 2001 Oct, 130(4), 748 - 51; discussion 751-2 Differences in arterial and mixed venous IL-6 levels: the lungs as a source of cytokine storm in sepsis; Tyburski JG et al.; BACKGROUND: Several investigators have shown that blood levels of interleukin 6 (IL-6) correlate with the severity of illness in critically ill or injured patients . However, little is known about differential arterial and venous blood levels of the cytokine, especially across the lungs . METHODS: We measured differences in IL-6 levels in pulmonary and systemic arterial blood and then documented the production or elimination of IL-6 by the lungs in 19 patients with severe illness . Prospective data were obtained from multiple, simultaneous systemic arterial (ART) and mixed venous (MV) blood samples that were drawn for IL-6 analysis from systemic arterial and pulmonary artery catheters in 7 patients awaiting vascular operation and in 12 trauma patients being treated in the intensive care unit . RESULTS: A lung disorder was present in 5 patients (pneumonia {n = 1}, lung trauma {n = 4}) and absent in the remaining 14 patients . The following data were obtained (mean +/- SD) from the highest MV IL-6 levels (pg/mL) in each patient . In patients with a lung disorder (n = 5) compared with those with no disorder (n = 14), ART IL-6 was 9309 +/- 12,521 versus 134 +/- 128 (P =.010), MV IL-6 was 5516 +/- 7420 versus 137 +/- 129 (P =.011), the absolute difference was 3793 +/- 5271 versus -3 +/- 15 (P =.011), and the percentage difference was 37.4% +/- 29.8% versus 1.5% +/- 12.3% (P =.001) . The ART and MV IL-6 levels tended to be much higher in the 5 patients with pneumonia (n = 1) and lung injuries (n = 4) than in the patients without apparent pulmonary problems . In addition, the patients with a primary lung disorder demonstrated a net increase in IL-6 levels across the lungs, whereas there was no increase, but rather, a net reduction of IL-6 levels across the lungs in patients without a lung disorder . CONCLUSIONS: The lung appears to be a major producer of IL-6 in patients with an inflammatory lung process . There is a 39% increase in the level of IL-6 as it passes through inflamed lung, producing a marked difference in ART and MV IL-6 levels . Normal lung demonstrated little effect on either ART or MV IL-6 levels. Am J Physiol Endocrinol Metab, 2001 Nov, 281(5), E1045 - 53 Insulin fails to stimulate muscle protein synthesis in sepsis despite unimpaired signaling to 4E-BP1 and S6K1; Vary TC et al.; Induction of sepsis in rats causes an inhibition of protein synthesis in skeletal muscle that is resistant to the stimulatory actions of insulin . To gain a better understanding of the underlying reason for this lack of response, the present study was undertaken to investigate sepsis-induced alterations in insulin signaling to regulatory components of mRNA translation . Experiments were performed in perfused hindlimb preparations from rats 5 days after induction of a septic abscess . Sepsis resulted in a 50% reduction in protein synthesis in the gastrocnemius . Protein synthesis in muscles from septic rats, but not controls, was unresponsive to stimulation by insulin . The insulin-induced hyperphosphorylation response of the translation repressor protein 4E-binding protein 1 (4E-BP1) and of the 70-kDa S6 kinase (S6K1) (1), two targets of insulin action on mRNA translation, was unimpaired in gastrocnemius of septic rats . Hyperphosphorylation of 4E-BP1 in response to insulin resulted in its dissociation from the inactive eukaryotic initiation factor (eIF)4E . 4E-BP1 complex in both control and septic rats . However, assembly of the active eIF4F complex as assessed by the association of eIF4E with eIF4G did not follow the pattern predicted by the increased availability of eIF4E resulting from changes in the phosphorylation of 4E-BP1 . Indeed, sepsis caused a dramatic reduction in the amount of eIF4G associated with eIF4E in the presence or absence of insulin . Thus the inability of insulin to stimulate protein synthesis during sepsis may be related to a defect in signaling to a step in translation initiation involved in assembly of an active eIF4F complex. Anesteziol Reanimatol, 2001 Jul-Aug, (4), 26 - 7 {Disorders of purine metabolism and the antioxidant system in obstetrical-gynecologic sepsis}; Lukach VN; Results of examinations of 360 patients with obstetrical gynecological sepsis are analyzed on the basis of ACCP/SCCM conference recommendations on the diagnosis and classification of sepsis . The patients were divided into 3 groups: with sepsis, severe sepsis, and septic shock . Parameters characterizing purine metabolism and lipid peroxidation were studied . Disorders in purine metabolism and activation of lipid peroxidation were detected in all patients and were the most severe in severe sepsis and septic shock. Pediatrics . 2001 Oct;108(4):E61. Reactive hyperemia and interleukin 6, interleukin 8, and tumor necrosis factor-alpha in the diagnosis of early-onset neonatal sepsis; Martin H et al.; OBJECTIVE: To evaluate the diagnostic value of peripheral circulatory reactive hyperemia and serum levels of interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-alpha) in early-onset neonatal sepsis . METHODS: Reactive hyperemia in the dorsal hand and serum levels of IL-6, IL-8, and TNF-alpha were studied in newborn infants (n = 32; gestational age 39 +/- 3 weeks) who had been admitted to the neonatal unit because of suspected sepsis <48 hours after birth . On admission, reactive hyperemia after a standardized arterial occlusion was measured with laser Doppler technique, and blood samples were taken for cytokine analyses . On the basis of predetermined criteria, the infants subsequently were classified as septic (n = 12) or not (n = 20) . RESULTS: The degree of reactive hyperemia was higher in the group with sepsis (median + 170% perfusion increase) than in that without (+37%) . On admission, serum levels of IL-6, IL-8, and TNF-alpha all were higher in septic (median values: 1620, 331, and 22 pg/mL, respectively) than in nonseptic neonates (median values: 42, 63, and 13 pg/mL, respectively) . In the group with sepsis, the degree of reactive hyperemia correlated to log IL-6 (r = 0.80) and log IL-8 values (r = 0.71) . CONCLUSION: Newborn infants with septicemia have increased reactive hyperemia and elevated cytokine levels very early in their disease . Reactive hyperemia in skin can be analyzed at the bedside and noninvasively and therefore may serve as an additional diagnostic tool in neonatal sepsis. Shock, 2001 Oct, 16(4), 298 - 303 The involvement of multiple protease-antiprotease systems and gut origin sepsis in zymosan-associated endothelial barrier injury and multiple organ dysfunction in rats; Deng X et al.; Multiple organ dysfunction syndrome is a dominant cause of mortality in the intensive care unit . Experimentally, a condition similar to the multiple organ dysfunction syndrome can be induced by the intraperitoneal injection of sterile zymosan . In the present study we investigate potential alterations in multiple organ functions, endothelial permeability, and antiproteinases after intraperitoneal injection of zymosan at various doses . Zymosan-induced generalized inflammation lead to endothelial barrier injury in multiple organs/tissues, a decrease in systemic arterial pressure, impaired organ function and gut defence function, and consumption of protease inhibitors, particularly the consumption of alpha2 antiplasmin . Endothelial barrier injury appears to present a dose- and organ-dependent pattern in multiple organs/tissues, and the increase in endothelial barrier permeability occurred prior to organ dysfunction . Zymosan induced the development of multiple organ dysfunction syndrome, probably initiating multiple protease-antiprotease systems, particularly the fibrinolytic system, leading to endothelial barrier injury, tissue edema, parenchymal cell damage, and eventual organ dysfunction, potentially augmented by a secondary bacterial infection. J Child Neurol, 2001 Sep, 16(9), 704 - 6 Concentrations of nucleotides, nucleosides, purine bases, oxypurines, uric acid, and neuron-specific enolase in the cerebrospinal fluid of children with sepsis; Rodriguez-Nunez A et al.; To determine the effects of sepsis on cerebral energy metabolism, the cerebrospinal fluid adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, hypoxanthine, xanthine, and urate concentrations were determined by high-performance liquid chromatography and the neuron-specific enolase levels by means of an enzyme immunoassay method in 32 children with sepsis, without meningitis, aged between 2 months and 13 years, and in 160 age-matched controls . The septic group had significantly higher cerebrospinal fluid concentrations of inosine, adenosine, xanthine, and urate than controls . These results suggest that sepsis could provoke some degree of neuronal hypoxia and significant alterations of cerebral energy metabolism homeostasis. Blood Purif, 2001, 19(4), 361 - 8; discussion 368-9 Newly developed immobilized polymyxin B fibers improve the survival of patients with sepsis; Nemoto H et al.; BACKGROUND: Sepsis and septic shock are still major causes of morbidity and mortality in spite of the availability of powerful and broadly active antibiotics . METHODS: A prospective, open and randomized trial of the effect of immobilized polymyxin fibers (PMX-F) on the survival of patients with sepsis throughout a follow-up period of 28 days or until discharge, if earlier, was carried out . Ninety-eight patients were included who met at least 4 of the criteria for systemic inflammatory response syndrome due to infection . The patients were classified into three groups based on their Acute Physiology and Chronic Health Evaluation (APACHE) II score . RESULTS: The overall survival rate was significantly improved by using PMX-F compared to the control group (41 vs . 11%) (p = 0.002) . In patients with an APACHE II score less than 20, treatment with PMX-F was shown to improve outcome (65 vs . 19%) (p = 0.01) . In cases of more severe sepsis with an APACHE II score of 20-29, PMX-F still maintained efficacy in improving outcome (40 vs . 11%) (p = 0.04) . However, PMX-F treatment did not improve the survival rate in patients with an APACHE II score of greater than 30 (survival rate 7 vs . 0%) (p = 0.59) . CONCLUSION: From these results, it is concluded that treatment with PMX-F in patients with sepsis is effective and prolongs the survival rate when applied at an early stage of sepsis . However, in severe sepsis, this therapy does not improve the survival rate . Ned Tijdschr Geneeskd, 2001 Sep 8, 145(36), 1718 - 22 {Adjuvant therapies for sepsis and shock: which are more effective?}; Groeneveld AB et al.; Adjuvant therapy for severe sepsis and shock can be divided into 4 groups . The first group comprises those compounds with proven efficacy in human studies (activated protein C and recombinant bacterial permeability-increasing protein) . The second group includes compounds with potential efficacy (heparin), while the third group represents those with no demonstrated efficacy in randomised clinical trials (tumour necrosis factor and interleukin-1 antibodies and receptor antagonists) . The fourth group includes those drugs which have been found to be potentially effective in animal studies, but which have not yet been evaluated in humans (i.e., tyrosine kinase inhibitors, selective inducible nitric oxide synthase inhibitors, polyadenosine-diphosphate-ribose-polymerase and caspase III (apoptosis) inhibitors) . Formal clinical comparisons between the various treatment options are necessary to assist the clinician in selecting the appropriate form of therapy. Biochim Biophys Acta, 2001 Sep 28, 1537(2), 167 - 74 The role of lipopolysaccharide in stimulating adrenomedullin production during polymicrobial sepsis; Yang S et al.; Previous studies have shown that adrenomedullin (AM), a potent vasodilatory peptide, is upregulated during sepsis . However, it remains unknown whether the increased AM observed under such conditions is solely due to the elevated levels of circulating lipopolysaccharide (LPS) . To determine this, an Alzet micro-osmotic pump, containing a low dose of Escherichia coli LPS or vehicle (sterile normal saline), was implanted in the peritoneal cavity of the normal male adult rat . At 10 h after the pump implantation, samples of blood and small intestine were harvested for the determination of AM by radioimmunoassay . In additional groups, rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) . LPS binding agent polymyxin B was administrated intramuscularly at 1 h prior to as well as 5 h after the onset of sepsis . At 10 h after CLP or sham-operation, blood and intestinal samples were harvested and levels of AM were then determined . Plasma levels of LPS were also measured by Limulus amebocyte lysate assay . The results indicate that administration of a low dose of LPS via the peritoneal cavity in normal animals (which did not significantly alter cardiac output, blood pressure or heart rate) markedly increased plasma and intestinal levels of AM . In addition, plasma and tissue levels of AM increased significantly at 10 h after CLP . Administration of polymyxin B, however, attenuated the increase in AM levels under such conditions . Similarly, the increased plasma levels of LPS was significantly reduced by polymyxin B during sepsis . These results, taken together, suggest that the upregulated AM observed during polymicrobial sepsis is at least in part due to the increase in circulating levels of endotoxin. J Dermatol, 2001 Aug, 28(8), 442 - 7 Epstein-Barr virus-associated recurrent necrotic papulovesicles with repeated bacterial infections ending in sepsis and death: consideration of the relationship between Epstein-Barr virus infection and immune defect; Yoon TY et al.; The disease of Epstein-Barr virus (EBV) -associated recurrent necrotic papulovesicles is a distinct clinicopathologic entity different from classic hydroa vacciniforme (HV) . A few patients have been reported as atypical HV with systemic involvement, development of lymphoma, and poor prognosis . We describe a patient with recurrent necrotic papulovesicles and multiple varioliform scars in both sun-exposed and covered areas . In contrast to cases of previously reported atypical HV, our patient suffered from repeated bacterial infections on various sites ending in sepsis and death, but without malignant transformation . EBV was detected in the lymphoid cells from the skin lesions by anti-latent membrane protein (LMP) antibody and in situ hybridization . We suggest that the repeated bacterial infections in this case raise the possibility of an association of EBV infection with increased susceptibility to bacterial infections. Am J Physiol Regul Integr Comp Physiol, 2001 Oct, 281(4), R1177 - 85 Acute G-CSF therapy is not protective during lethal E . coli sepsis; Quezado Z et al.; We investigated whether decreases in circulating polymorphonuclear neutrophils (PMN) during lethal Escherichia coli (E . coli) sepsis in canines are related to insufficient host granulocyte colony-stimulating factor (G-CSF) . Two-year-old purpose-bred beagles had intraperitoneal E . coli-infected or -noninfected fibrin clots surgically placed . By 10 to 12 h following clot, both infected survivors and nonsurvivors had marked increases (P = 0.001) in serum G-CSF levels (mean peak G-CSF ng/ml +/- SE, 1,931 +/- 364 and 2,779 +/- 681, respectively) compared with noninfected controls (134 +/- 79), which decreased at 24 to 48 h . Despite increases in G-CSF, infected clot placement caused delayed (P = 0.06) increases in PMN (mean +/- SE change from baseline in cells x 10(3)/mm(3) at 24 and 48 h) in survivors (+3.9 +/- 3.9 and +13.8 +/- 3.6) compared with noninfected controls (+13.1 +/- 2.8 and +9.1 +/- 2.5) . Furthermore, infected nonsurvivors had decreases in PMN (-1.4 +/- 1.0 and -1.1 +/- 2.3, P = 0.006 compared with the other groups) . We next investigated whether administration of G-CSF immediately after clot placement and continued for 96 h to produce more rapid and prolonged high levels of G-CSF after infection would alter PMN levels . Although G-CSF caused large increases in PMN compared with control protein from 2 to 48 h following clot in noninfected controls, it caused much smaller increases in infected survivors and decreases in infected nonsurvivors (P = 0.03 for the ordered effect of G-CSF comparing the three groups) . Thus insufficient host G-CSF is unlikely the cause of decreased circulating PMN in this canine model of sepsis . Other factors associated with sepsis either alone or in combination with G-CSF itself may reduce increases or cause decreases in circulating PMN. Am J Physiol Gastrointest Liver Physiol, 2001 Oct, 281(4), G1014 - 21 Norepinephrine-induced hepatocellular dysfunction in early sepsis is mediated by activation of alpha2-adrenoceptors; Yang S et al.; Gut-derived norepinephrine (NE) has been shown to play a critical role in producing hepatocellular dysfunction in early sepsis, but it is not known whether alpha2-adrenoceptor activation mediates this dysfunction . We infused normal male adult rats with NE, NE plus the specific alpha2-adrenergic antagonist rauwolscine (RW), or vehicle (normal saline) for 2 h . Hepatocellular function was determined by in vivo indocyanine green (ICG) clearance . An isolated perfused liver preparation was also used to assess hepatocellular function by in vitro ICG clearance; NE alone or with RW was added to the perfusate . Rats were subjected to sepsis by cecal ligation and puncture (CLP) . At 1 h after CLP, RW was infused for 15 min . At 5 h after CLP, we measured hepatocellular function and serum tumor necrosis factor-alpha (TNF-alpha) levels . Intraportal NE infusion in normal rats produced hepatocellular dysfunction, which was prevented by RW and NE infusion . This is confirmed by findings with the isolated perfused liver preparation . RW administration in early sepsis maintained hepatocellular function and downregulated TNF-alpha production at 5 h after CLP . These results suggest that NE-induced hepatocellular dysfunction in early sepsis is mediated by alpha2-adrenoceptor activation, which appears to upregulate TNF-alpha production . Modulation of hepatic responsiveness to NE by alpha2-adrenergic antagonists should provide a novel approach for maintaining cell and organ functions during sepsis. Blood Coagul Fibrinolysis, 2001 Sep, 12(6), 459 - 67 Treatment of porcine sepsis with high-dose antithrombin III reduces tissue edema and effusion but does not increase risk for bleeding; Dickneite G et al.; We evaluated the effectiveness of antithrombin III (AT III) infusions designed to achieve supraphysiologic plasma levels of this serine protease inhibitor in preventing vascular permeability and disseminated intravascular coagulation in a pig model of sepsis . In addition, we determined whether high AT III doses were associated with increased bleeding risk . Sepsis was induced in 18 pigs by injection of lipopolysaccharide (LPS) (0.25 microg/kg per h for 3 h) . At 90 min after the start of LPS infusion, pigs were randomized (n = 6 per group) to receive either human serum albumin as a placebo, AT III 120/5 (120 U/kg, 30-min bolus + 5 U/kg per h for 240 min), or AT III 250/10 (250 U/kg + 10 U/kg per h) . Three additional animals served as negative controls (no LPS, no AT III) . Treatment with AT III significantly reduced the amount of effluents in body cavities and fibrin monomers . AT III did not significantly increase bleeding risk as determined by organ hemorrhage . An additional assessment of AT III's bleeding risk {skin bleeding time (SBT)} was carried out in 35 nonseptic pigs treated with either AT III alone (120/5 or 250/10) or in the combination with heparin . Heparin administration alone produced a dose-dependent increase in SBT, but AT III alone did not . Addition of AT III 120/5 to heparin did not induce a further increase in bleeding time over heparin alone . These results indicate that administration of AT III in doses designed to achieve very high plasma concentrations significantly ameliorates symptoms of sepsis-induced vascular leakage and disseminated intravascular coagulation without increasing bleeding risk. Chest, 2001 Sep, 120(3), 915 - 22 Low levels of protein C are associated with poor outcome in severe sepsis; Yan SB et al.; STUDY OBJECTIVE: To investigate whether protein C levels predict 30-day mortality rate, shock status, duration of ICU stay, and ventilator dependence in patients with sepsis . DESIGN: Retrospective analysis of a subset of a previously published, prospective, randomized, double-blind, placebo-controlled trial ("Effects of Ibuprofen on the Physiology and Survival of Patients With Sepsis" {ISS}) . SETTING: A multicenter study performed in the United States and Canada (seven sites) . PATIENTS: Seventy hospitalized patients with acute severe sepsis and failure in one or more organs at entry into the ISS trial . MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained from all patients at baseline and at 20, 44, 72, and 120 h after the initiation of study drug (ibuprofen or placebo) infusion . Data obtained at these times included platelet count, prothrombin time, and partial thromboplastin time . The results described in this article are based on a subset of the total ISS population for whom additional coagulation assays were performed on the blood samples obtained at baseline and 44 h . These assays included protein C antigen, D-dimer, and fibrinogen levels . A total of 63 of the 70 patients (90%) studied in this report had acquired protein C deficiency at entry to the ISS trial (baseline) . The presence and severity of acquired protein C deficiency were associated with poor clinical outcome, including lower survival rate, higher incidence of shock, and fewer ICU-free and ventilator-free days . CONCLUSIONS: Acquired protein C deficiency may be useful in predicting clinical outcome in patients with sepsis . Clinical studies are warranted to determine whether the replacement of protein C in sepsis patients may improve outcome. Eur J Anaesthesiol, 2001 Oct, 18(10), 673 - 8 The effects of sepsis on gut mucosal blood flow in rats; Sielenkamper AW et al.; BACKGROUND AND OBJECTIVE: The effects of sepsis on gut mucosal blood flow have not been fully clarified . We designed an experiment to explicitly describe the effects of sepsis on gut mucosal blood flow in rats using an advanced intravital microscopy technique . METHODS: This work was performed as a prospective, controlled laboratory experiment . Twenty-four hours after sham laparotomy or laparotomy and caecal ligation and perforation to create sepsis, rats were anaesthetized and their lungs mechanically ventilated (n=7 per group) . Intravital videomicroscopy was performed on 6-12 villi of ileum mucosa . Video recordings were analysed off-line using computerized image analysis . RESULTS: Intercapillary area size (inversely related to capillary density) was increased in sepsis as compared with the control group (941 +/- 92 vs . 669 +/- 79 microm(2), P < 0.05) . In the central villus arteriole, blood flow was similar between groups (control: 3.5 +/- 0.4 nL min(-1); caecal ligation and perforation group: 3.6 +/- 0.5 nL min(-1)) . There were no relevant changes in arteriolar red cell velocity and diameter . CONCLUSIONS: In the gut mucosa of rats, sepsis resulting from caecal ligation and perforation depressed the perfused capillary density without affecting blood flow in the central villus arteriole . Mucosal hypoperfusion at the level of the capillary networks may occur in the presence of precapillary shunting in the villus microcirculation. Am J Respir Crit Care Med, 2001 Sep 1, 164(5), 891 - 5 Characterization of a hyperdynamic murine model of resuscitated sepsis using echocardiography; Hollenberg SM et al.; A small animal model of sepsis that reproduces the vasodilation, hypotension, increased cardiac output, and response to treatment seen in patients with septic shock would be useful for studies of pathophysiology and treatment, but no current models replicate all of these features . Mice were made septic by cecal ligation and puncture and resuscitated with fluids and antibiotics every 6 h . Blood pressure was measured in anesthetized mice with manometric catheters, and echocardiography was performed in these animals every 6 h . Survival in treated septic mice was improved compared with untreated mice (44% versus 0%, p < 0.01) . In control mice, heart rate (HR, 420 +/- 31 beats/min), mean arterial pressure (Pa, 100 +/- 8 mm Hg), stroke volume (SV, 26 +/- 4 microl), and cardiac output (12.5 +/- 6.6 ml/min) were unchanged over 48 h . In septic mice Pa was significantly decreased (102 +/- 14 to 65 +/- 19 mm Hg, p < 0.02), starting at 12 h . HR and cardiac output increased significantly (HR, 407 +/- 70 to 524 +/- 76 beats/min, cardiac output, 11.6 +/- 2.0 to 17.1 +/- 1.5 ml/min, p < 0.01) . SV (24 +/- 5 microl) remained constant . This fluid-resuscitated, antibiotic-treated model replicates the mortality, hypotension, and hyperdynamic state seen in clinical sepsis . Precise determination of serial hemodynamics in this model may be useful to elucidate pathophysiologic mechanisms and to evaluate new therapies for septic shock. Eur J Med Res, 2001 Aug 27, 6(8), 351 - 8 Parameters influencing membrane CD14 expression and soluble CD14 levels in sepsis; Gluck T et al.; INTRODUCTION: Membrane (mCD14) and soluble (sCD14) CD14 are pattern recognition receptors for bacterial cell wall fragments . They play an important role in the generation of the innate immune response against bacterial pathogens . Differential expression of these receptors may be relevant for the clinical course of patients with sepsis . PATIENTS AND METHODS: 32 patients with an early onset of sepsis (duration of symptoms < 24h) were examined repeatedly by flow cytometry for expression of mCD14, and by ELISA for levels of sCD14, leukocyte elastase and C-reactive Protein (CRP) . RESULTS: At study entry, mCD14 expression was reduced in all patients with sepsis, but returned to normal levels during the course of the disease in survivors only . mCD14 was found to be inversely correlated with severity of disease, leukocyte elastase, and C-reactive protein . Among patients with severe disease and Apache II scores >or= 20, sCD14 levels at study entry were significantly higher in those who survived by day 28, as compared to non-survivors (p = 0.02) . CONCLUSION: The data presented are compatible with a recently published hypothesis derived from in vitro experiments suggesting that leukocyte elastase may be responsible for cleavage of mCD14 from the monocyte surface . The data also suggest that higher sCD14 levels may be beneficial in sepsis . Persistently reduced mCD14 expression seems to be a marker for severity of disease in patients with sepsis. Eur J Pediatr, 2001 Aug, 160(8), 478 - 82 Natural killer cell cytotoxicity is deficient in newborns with sepsis and recurrent infections; Georgeson GD et al.; We investigated natural killer (NK) cell cytotoxicity in healthy preterm and full-term newborns in comparison to adults, to elucidate the possible role of delivery mode in influencing the NK activity and to evaluate the NK activity in severe neonatal pathological conditions such as bacterial sepsis and recurrent infections . NK cell cytotoxicity was investigated using a 4 h 51Cr release assay with K562 cells as targets expressed as percentage kill in the following study groups: full-term normal spontaneous vaginal delivery (n = 55), full-term caesarean section (n = 51), preterm normal spontaneous vaginal delivery (n = 34), preterm caesarean section (n = 28), bacterial sepsis (n = 15), recurrent neonatal infections (n = 8) and healthy adults aged between 22-42 years (n = 89) . NK activity for the normal newborns was determined in paired cord and 2-4 day-old neonate blood . The NK cell cytotoxicity in healthy newborns was significantly lower than in adults (P < 0.01) . Prematurity was associated with a significant decrease in NK cell activity compared to full-term neonates (P < 0.05) . The mode of delivery did not influence the NK cytotoxicity . In sepsis and recurrent infections, a dramatic decrease in NK cell cytotoxicity was seen related to healthy newborns (P < 0.01) . CONCLUSION: Natural killer cell cytotoxicity is deficient in both neonatal sepsis and recurrent infections. Crit Care Med, 2001 Sep, 29(9), 1720 - 5 Sepsis is associated with reciprocal expressional modifications of constitutive nitric oxide synthase (NOS) in human skeletal muscle: down-regulation of NOS1 and up-regulation of NOS3; Lanone S et al.; OBJECTIVE: To study the expression (mRNA and protein) and activity of the constitutive isoforms of nitric oxide synthase (NOS1 and NOS3) in a skeletal muscle of septic patients . DESIGN: Prospective study . SETTING: An adult trauma/surgical intensive care unit in an urban teaching hospital . PATIENTS: Sixteen septic patients and 21 controls . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Samples of the rectus abdominis muscle were obtained during surgical procedure . NOS mRNA, protein, and activity were detected by reverse-transcriptase polymerase chain reaction, Western blot, and the conversion of {3H}L-arginine to {3H}L-citrulline, respectively . The main results of this study are as follows: a) Levels of NOS1 mRNA and protein were significantly higher than those of NOS3 in the rectus abdominis muscle of control patients; b) NOS1 expression was down-regulated in septic patients, whereas NOS3 was up-regulated; c) these modulations were associated with a reduction in constitutive NOS activity; and d) modifications of NOS1 and NOS3 protein expression were correlated significantly with the severity of sepsis, assessed by the Simplified Acute Physiology Score II . CONCLUSIONS: Sepsis induces reciprocal expressional modifications of NOS1 and NOS3 in human skeletal muscle, which decreases muscular constitutive NOS activity . These modifications may have implications for muscle impairment in septic patients. J Magn Reson Imaging, 2001 Sep, 14(3), 254 - 60 Evaluation of perianal sepsis: comparison of anal endosonography and magnetic resonance imaging; Maier AG et al.; The purpose of this study was to compare prospectively the diagnostic yield of anal endosonography (AES) and magnetic resonance imaging (MRI) in the assessment of perianal fistulae and abscesses . There were 39 patients (14 men, 25 women; mean age, 40 years) who underwent AES, performed with a 10-MHz rotating endoanal probe and MRI at 1.0 T (axial and coronal T2-weighted turbo spin-echo (TSE) and turbo-STIR sequences) . Fistulae were classified as subcutaneous, intersphincteric, transsphincteric, high (i.e., high extrasphincteric or suprasphincteric), rectovaginal, and horseshoe and were compared with the surgical findings in all patients . Overall, 58 fistulae (subcutaneous, N = 7; intersphincteric, N = 9; transsphincteric, N = 16; high, N = 17; rectovaginal, N = 5; and horseshoe, N = 4) were detected at surgery . MRI showed a sensitivity of 84% and AES of 60% (P <.05) . False-positive diagnoses were made in 6 patients (15%) with MRI and in 15 patients (26%) with AES, for a specificity of 68% and 21%, respectively (P <.05) . Our findings show that MRI is superior to AES in the assessment of fistula-in-ano before major surgery . AES should be used only for orientation before minor procedures, such as incision or drainage of subcutaneous fistulae . J Trauma, 2001 Sep, 51(3), 452 - 6; discussion 456-7 Early trauma polymorphonuclear neutrophil responses to chemokines are associated with development of sepsis, pneumonia, and organ failure; Adams JM et al.; OBJECTIVES: The modulation of polymorphonuclear neutrophil (PMN) function by injury is unpredictable, and can predispose either to hyperimmune states (adult respiratory distress syndrome {ARDS}, multiple organ failure) or to immune dysfunction, infection, and sepsis . Such outcomes have been related to excess production of the CXC chemokine interleukin (IL)-8, but PMN responses to IL-8 are mediated by both the relatively stable and IL-8 specific CXC receptor 1 (CXCR1) and the labile, promiscuous CXCR2 . We hypothesized that progression to septic and multiple organ failure outcomes could be related to early differences in PMN CXC receptor status . METHODS: PMNs were isolated 12 +/- 3 hours after injury from 15 major trauma patients (Injury Severity Score of 34 +/- 2, 11 men and 4 women, age 36 +/- 4 years) who survived at least 7 days . Volunteer normal PMNs (n = 6 donors) were studied for comparison . Cells were stimulated either with the CXCR2 specific agent growth-related oncogene-alpha, or with IL-8, which stimulates CXCR1 and CXRR2 . Receptor response was assessed as the mobilization of cell calcium . The development of ARDS, sepsis, and pneumonia was assessed according to standardized criteria . Day 1 receptor activity in the clinical groups was then compared by analysis of variance with Tukey's or t tests as appropriate . RESULTS: In patients that were otherwise comparable, CXCR2 responses were markedly diminished in the PMNs of patients who went on to sepsis and pneumonia, but were elevated in PMNs from the patients who went on to ARDS . CXCR1 responses were modestly lower in trauma patients than volunteers, but showed no significant variations among the various clinical outcome groups . CONCLUSION: The activity of PMN CXCR2 receptors soon after injury may be reflected in the later clinical sequelae of PMN activity . High CXCR2 activity may correlate with PMN hyperfunction and outcomes such as ARDS, whereas the loss of CXCR2 function in inflammatory environments may impair PMN functions in a manner that predisposes to pneumonia or sepsis . Early responses of PMN CXC receptors to injury may influence the clinical course of trauma patients. Intensive Care Med, 2001 Jul, 27(7), 1231 - 4 Dysfunction of vasomotor reactivity in severe sepsis and septic shock; Terborg C et al.; OBJECTIVE: Perfusion abnormalities are an overall phenomenon in severe sepsis and septic shock, leading to organ dysfunction . We investigated whether carbon dioxide (CO2)-induced vasomotor reactivity (VMR) is impaired in septic patients, compared with values obtained outside sepsis . DESIGN: Prospective, clinical study . SETTING: Six-bed neurologic critical care unit of a university hospital . PATIENTS AND PARTICIPANTS: Eight consecutive patients with severe sepsis and septic shock . MEASUREMENTS AND RESULTS: CO2-reactivity was measured during and outside a period of severe sepsis or septic shock according to ACCP/SCCM criteria by means of transcranial Doppler sonography and near-infrared spectroscopy (NIRS) . VMR was calculated as the percentage change of cerebral blood flow velocity (normalized CO2-reactivity, NCR) and absolute changes in concentration of oxygenated hemoglobin, deoxygenated hemoglobin, total hemoglobin (HbO2, Hb, HbT) and Hbdiff (difference between HbO2 and Hb) in micromol/l per 1% increase in end-tidal CO2 (CR-HbO2, CR-Hb, CR-HbT, CR-Hbdiff) . NCR and NIRS-reactivities were significantly reduced during severe sepsis and septic shock compared with values outside sepsis (mean, SD, Wilcoxon): NCR 11.0 (7.1) versus 30.7 (13.0), p < 0.02; CR-HbO2 0.70 (0.61) versus 2.33 (1.11), p < 0.02; CR-Hb -0.17 (0.74) versus -1.42 (1.28), p < 0.04; CR-HbT 0.53 (0.48) versus 1.05 (0.40), p < 0.03; CR-Hbdiff 0.91 (1.33) versus 3.75 (2.33), p < 0.02 . This indicates a severely disturbed VMR . CONCLUSIONS: In the advent of a disturbed cerebral autoregulation, critical drops in blood pressure during sepsis are transferred directly into the vascular bed, leading to cerebral hypoperfusion . This mechanism might contribute to the pathogenesis of septic encephalopathy. J Perinatol, 2001 Jun, 21(4), 242 - 7 Association of postnatal dexamethasone use and fungal sepsis in the development of severe retinopathy of prematurity and progression to laser therapy in extremely low-birth-weight infants; Haroon Parupia MF et al.; OBJECTIVE: The objective of this study was to evaluate the role of postnatal dexamethasone use and fungal sepsis in the development of severe retinopathy and progression to laser therapy . BACKGROUND: Postnatal steroids have been frequently used in the management of infants with chronic lung disease, airway edema, and hypotension, but their use is not free from adverse effects . Postnatal dexamethasone use has been associated with increased risk for the development of fungal sepsis, but the influence of glucocorticoid therapy on retinopathy of prematurity (ROP) is controversial . Candida sepsis has been shown to be associated with severe ROP and the need for laser therapy in some studies but not in others . STUDY DESIGN: Medical records of all <1000 g birth weight infants (n=158) admitted to Louisiana State University Health Sciences Center between July 1, 1996 and June 30, 1999 were reviewed . After exclusion of those infants who either died (n=25) or transferred (n=3) before eye examination, demographic and clinical data of 130 infants were analyzed by chi-squared analysis, Mann-Whitney U test, t-test, analysis of variance, and logistic regression . All data are mean+/-SD . RESULTS: Gestational age was 26.4+/-1.7 weeks; birth weight was 797+/-130 g . Twenty-six infants were Caucasian, the rest African-American . Seventy-five (58%) received antenatal steroids . Eighty-eight (68%) of the infants received postnatal steroids . All infants were exclusively fed premature infant formulae . Sepsis developed in 44 (34%) infants and fungal sepsis in 14 (11%) . Incidence of ROP was 77% (100/130), severe ROP (stage > or =3) 52% (68) . Severe ROP was more frequent in Caucasian infants (p=0.005) and in infants who received postnatal dexamethasone (p< or =0.0001) . The development of threshold ROP (zone 1 or 2 with stage 3+, five contiguous or eight total clock hours of the retina) and requirement for laser therapy were higher in Caucasians (p=0.0002) and in infants with fungal sepsis (p=0.001) . Antenatal steroids had no effect on the severity of ROP or the need for laser treatment . Postnatal dexamethasone use was significantly associated with fungal sepsis 13/14 (93%) . After controlling for gestational age, race, days on supplemental oxygen, and fungal sepsis, cumulative postnatal dexamethasone use was independently associated with severe ROP {OR 1.2 (1.04-1.33)}, and fungal sepsis {OR 8.2 (2.0-33.0)} was independently associated with the need for laser therapy . CONCLUSIONS: Postnatal steroid use is an independent risk factor for development of severe ROP . The risk of threshold ROP requiring laser treatment was higher in infants who developed fungal sepsis. J Nutr, 2001 Sep, 131(9 Suppl), 2535S - 8S; discussion 2550S-1S Glutamine metabolism in sepsis and infection; Karinch AM et al.; Severe infection causes marked derangements in the flow of glutamine among organs, and these changes are accompanied by significant alterations in regional cell membrane transport and intracellular glutamine metabolism . Skeletal muscle, the major repository of glutamine, exhibits a twofold increase in glutamine release during infection, which is associated with a significant increase in endogenous glutamine biosynthesis . Despite an increase in glutamine synthetase activity in skeletal muscle, the intracellular glutamine pool becomes depleted, indicating that release rates exceed rates of synthesis . Simultaneously, the circulating pool of glutamine does not increase, indicating accelerated uptake by other organs . The liver appears to be the major organ of glutamine uptake in severe infection; studies in endotoxemic rodents have shown net hepatic glutamine uptake to increase by as much as 8- to 10-fold . This increase is due partially to increases in liver blood flow, but also to a three- to fourfold increase in hepatocyte System N activity in the liver . Cytokines and glucocorticoids mediate the increased uptake of glutamine by the liver in septic states as well as other compounds . Sepsis does not appear to induce an increase in System N gene expression, indicating that the increase in hepatic glutamine transport observed during severe infection is probably regulated at the protein level . The bowel displays a decrease in glutamine utilization during sepsis, a response that may be related to the decrease in circulating insulin-like growth factor-1 (IGF-1) levels that is characteristic of sepsis . Recent studies suggest that IGF-1 has a direct effect on stimulating glutamine transport across the gut lumen and thus may represent a therapeutic avenue for improving gut nutrition during severe infection . The cells of the immune system (lymphocytes, macrophages) are also major glutamine consumers during inflammatory states in which cell proliferation is increased . Under these conditions, glutamine availability can become rate limiting for key cell functions, such as phagocytosis and antibody production. Clin Sci (Lond), 2001 Sep, 101(3), 295 - 304 Sequential changes in in vivo muscle and liver protein synthesis and plasma and tissue glutamine levels in sepsis in the rat; O'Leary MJ et al.; We have investigated sequential changes in skeletal muscle and hepatic protein synthesis following sepsis, and their relationship to changes in circulating and tissue glutamine concentrations . Male Wistar rats underwent caecal ligation and puncture (CLP) or sham operation, with starvation, and were killed 24, 72 or 96 h later . A group of non-operated animals were killed at the time of surgery . Protein synthesis was determined using a flooding dose of L-{4-(3)H} phenylalanine, and glutamine concentrations were measured by an enzymic fluorimetric assay . Protein synthesis in gastrocnemius muscle fell in all groups . Gastrocnemius total protein content was reduced after CLP and at 72 and 96 h after sham operation . After CLP, protein synthesis was lower at 24 h, and total protein content was lower at 72 and 96 h, than in sham-operated animals . CLP was associated with increased liver protein synthesis at all time points, whereas there was no change after sham operation . Liver protein content did not change after CLP, but was lower at 72 and 96 h after sham operation than in non-operated animals . Plasma glutamine concentrations were reduced at 24 h after sham operation, and at 72 and 96 h after CLP . Muscle glutamine concentrations were reduced in all groups, with the decrease being greater following CLP than after sham operation . In the liver, glutamine concentrations were unchanged after CLP, but increased after sham operation . In rats with sepsis, decreases in muscle protein synthesis and content are associated with markedly reduced muscle glutamine concentrations . Plasma glutamine concentrations are initially maintained, but fall later . In liver, protein synthesis is increased, while glutamine concentrations are preserved . These results support a peripheral-to-splanchnic glutamine flux in sepsis. J Endotoxin Res, 2001, 7(2), 85 - 93 Immunodepression in sepsis and SIRS assessed by ex vivo cytokine production is not a generalized phenomenon: a review; Cavaillon JM et al.; Sepsis and non-infectious systemic inflammatory response syndrome (SIRS) are paradoxically associated with an exacerbated production of cytokines, as assessed by their presence in biological fluids, and a diminished ability of circulating leukocytes to produce cytokine upon in vitro activation . In this review, we depict that the observed cellular hyporeactivity is not a global phenomenon and that some signalling pathways are unaltered and allow the cells to respond normally to certain stimuli . Furthermore, we illustrate that during sepsis and SIRS, cells derived from tissues are either fully responsive to ex vivo stimuli or even primed, in contrast to cells derived from hematopoietic compartments (blood, spleen, etc.) which are hyporeactive . In addition to cytokine production, nuclear factor-kappa B (NF-kappa B) status within leukocytes can be used as a useful marker of hypo- or hyper-reactivity . We illustrate that the immune-depression reported in sepsis and SIRS patients, often revealed by a diminished capacity of leukocytes to respond to lipopolysaccharide, is not a generalized phenomenon and that SIRS is associated with a compartmentalized responsiveness which involves either anergic or primed cells. J Endotoxin Res, 2000, 6(6), 463 - 9 Clinically-oriented therapies in sepsis: a review; Dubois MJ et al.; Our insight of the sepsis response has evolved to encompass not only the pro-inflammatory but also an anti-inflammatory reaction following infection . Clinical trials have been designed to target either bacterial products, endotoxin in particular, or mediators involved in the sepsis response, but until recently the majority of them have given unfavorable results . In this article, we provide a scope of clinical trials that have been done in immunomodulation during sepsis whether or not they provide positive results . We will also discuss some of the reasons why those studies have been disappointing . Current and future trials with a better assessment of inflammatory status of patients and better-defined outcomes such as organ dysfunction are now underway. J Endotoxin Res, 2000, 6(6), 421 - 30 The lipemia of sepsis: triglyceride-rich lipoproteins as agents of innate immunity; Harris HW et al.; Bacterial endotoxin (LPS) elicits dramatic responses in the host including elevated plasma lipid levels due to the increased synthesis and secretion of triglyceride (TG)-rich lipoproteins by the liver, and the inhibition of lipoprotein lipase . This cytokine-induced hyperlipoproteinemia, clinically termed the "lipemia of sepsis", was customarily thought to represent the mobilization of lipid stores to fuel the host response to infection . However, since lipoproteins can also bind and neutralize LPS, we hypothesize that TG-rich lipoproteins (VLDL and chylomicrons) are also components of an innate, non-adaptive host immune response to infection . Herein we review data demonstrating the capacity of lipoproteins to bind LPS, protect against LPS-induced toxicity, and modulate the overall host response to this bacterial toxin . Lastly, we propose a pathway whereby lipoprotein-bound LPS may represent a novel, endogenous mechanism for regulating the hepatic acute phase response. Infect Dis Obstet Gynecol, 2001, 9(3), 147 - 8 Candida sepsis following transcervical chorionic villi sampling; Paz A et al.; BACKGROUND: The use of invasive devices and broad spectrum antibiotics has increased the rate of candidal superinfections . Candida sepsis associated with pregnancy is rare . Candida sepsis following chorionic villi sampling (CVS) has never been reported . CASE: A 31 -year-old pregnant woman presented with signs of sepsis one day after undergoing transcervical CVS . Blood culture and curettage material yielded C . albicans . She was treated with 400 mg of fluconazole daily for 4 weeks and completely recovered . CONCLUSION: Candida sepsis should be considered in the differential diagnosis of sepsis following CVS. Intensive Care Med, 2001 Aug, 27(8), 1412 - 5 Plasma levels of macrophage migration inhibitory factor are elevated in patients with severe sepsis; Lehmann LE et al.; OBJECTIVE: To investigate the role of macrophage migration inhibitory factor (MIF) as a marker of severity of systemic inflammation in patients with severe sepsis and critically ill postsurgical patients . DESIGN: Prospective observational study in consecutive patients with severe sepsis, critically ill nonseptic postsurgical patients, and healthy blood donors . SETTING: A surgical intensive care unit of a university hospital . PATIENTS AND PARTICIPANTS: 19 patients with severe sepsis, 18 critically ill nonseptic postsurgical patients, and 10 healthy blood donors . MEASUREMENTS AND RESULTS: MIF plasma levels of patients and participants were measured . Interleukin 6 plasma levels were monitored as a control marker of inflammation . The median MIF plasma level was four to five times higher in patients with severe sepsis (2.70 ng/ml, range 0.31-19.59) and in critically ill nonseptic postsurgical patients (2.43 ng/ml, range 0.49-4.31) than in healthy blood donors (0.56 ng/ml, range 0.16-1.68) . MIF plasma levels did not differ between the patient groups . CONCLUSIONS: MIF serves as a general marker for systemic inflammation in septic and nonseptic acute critical illness, but MIF does not discriminate for severity or differentiate between infectious and noninfectious origins of an acute critical illness. Intensive Care Med, 2001 Aug, 27(8), 1281 - 7 Variability of splanchnic blood flow in patients with sepsis; Sakka SG et al.; OBJECTIVES: Previous studies on therapeutic interventions in sepsis have assumed stability of the measure of splanchnic blood flow throughout the study . We assessed the variability of splanchnic blood flow during stable global hemodynamics in eight patients with sepsis requiring treatment with dobutamine and/or norepinephrine . DESIGN AND SETTING: Prospective clinical study in an intensive care unit of a university hospital . MEASUREMENTS AND RESULTS: Global and regional hemodynamics were measured at baseline, 2 h later, and 4 h later . Cardiac output was measured by transpulmonary thermodilution, intrathoracic blood volume as an indicator of cardiac preload, and total blood volume by the double indicator (thermo-dye) dilution technique . Total body oxygen consumption was assessed by indirect calorimetry using a metabolic cart . Splanchnic blood flow was measured by the continuous indocyanine green method, and gastric mucosal CO2 tension by gas tonometry . Neither absolute nor fractional splanchnic blood flow (as ratio of cardiac output) revealed significant global tendencies during the study period . However, variance component analysis showed that splanchnic blood flow determinations varied considerably within patients, for repeated measurements at 5-min intervals (standard error 31.1%) as well as for average values at 2-h intervals (25.6%) . CONCLUSION: Stable global hemodynamics during a 4-h period in septic patients does not exclude marked changes in splanchnic blood measured by a hepatic venous catheter technique. Shock, 2001 Aug, 16(2), 137 - 42 Does the activation of poly (ADP-ribose) synthetase mediate tissue injury in the sepsis induced by cecal ligation and puncture? Baechtold F, Scott JA, Markert M, Mehta S, McCormack DG, Anglada F, Galaud D, Vaglio M, Waeber B, Feihl F. Poly (ADP-ribose) synthetase (PARS) is a DNA protective enzyme activated by single-strand breakage . It is suspected that exaggerated PARS activation related to biochemical stress by reactive oxygen and nitrogen species contributes to cellular injury in sepsis . The main hypothesis is that PARS activation leads to massive ATP and NAD consumption and consequent cellular energy depletion . The PARS inhibitor 3-amino-benzamide (3AB) is protective in rodents challenged with either endotoxin or intraperitoneal zymozan . The present experiment was designed to test the effect of 3AB in a more clinically relevant model of sepsis, namely polymicrobial sepsis induced by cecal ligature and puncture (CLP) . Adult male Wistar rats were anesthetized, instrumented with catheters in the jugular vein and in the carotid artery, and then randomized into three groups: Sham (no laparotomy, n = 13), CLP (n = 15), and CLP/3AB (n = 18) . All animals were allowed to recover and they received a continuous intravenous infusion of saline (20 mL/kg/h) and fentanyl (20 microg/kg/h) . 3AB was administered to the CLP/3AB group as an intravenous bolus (10 mg/kg) followed by a continuous intravenous infusion (10 mg/kg/h) . After 24 h, blood was drawn for the determination of biological indicators of organ injury . Rats were then anesthetized and biopsies of the liver were quickly frozen into liquid nitrogen for the subsequent determination of NAD and ATP levels . Further organ samples were collected for the assay of myeloperoxidase (MPO) to indicate tissue infiltration by leukocytes, and nitrotyrosine to indicate the level of biochemical stress by reactive nitrogen species . Twenty-four-hour mortality was 0/13 (Sham), 1/15 (CLP), and 5/18 (CLP/3AB; p = NS) . In the surviving rats, CLP induced a clear elevation of liver enzymes, bilirubin, and pancreatic lipase, but not creatinine in the plasma, as well as a marked increase of MPO activity in liver, jejunum, and lung, but not kidney or heart . None of these variables was affected by treatment with 3AB . Furthermore, CLP did not cause depletion of NAD or ATP in the liver, nor any change in the nitrotyrosine content of any organ . These data argue against a general role of PARS activation in the pathogenesis of sepsis-induced tissue injury. Shock, 2001 Aug, 16(2), 116 - 21 Glycine reduces the inflammatory response and organ damage in a two-hit sepsis model in rats; Grotz MR et al.; The goal of this study was to investigate whether prefeeding of glycine reduces the immunoinflammatory response, the degree of distant organ injury (liver), and/or the mortality rate in a two-hit model using intestinal ischemia/reperfusion and endotoxin (ET) challenge 6 h later in rats . The liver damage was greatest at 24 h after ET challenge and completely inhibited by glycine . The early systemic increase of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL) -6 as well as the secretion of the antiinflammatory cytokine IL-10 was reduced by glycine . Tissue cytokine mRNA expression (TNF-alpha, IL-1beta, IL-10) was decreased in the lung and the liver but not in the mesenteric lymph node or ileum, in the glycine-fed group . However, glycine did not decrease the mortality rate . These results suggest that prefeeding of glycine reduces liver damage as well as the systemic and local (lung and liver) inflammatory response after intestinal ischemia/reperfusion and endotoxin challenge in rats. Shock, 2001 Aug, 16(2), 102 - 8 Overexpression of the high-affinity Fcgamma receptor (CD64) is associated with leukocyte dysfunction in sepsis; Hirsh M et al.; The morbidity and mortality from sepsis and multiple organ dysfunction syndrome (MODS) continues to be high . An increase in FcgammaRI+ (CD64+) monocytes was demonstrated in septic patients, and an association between cell number, their secretory activity, and poor outcome has been described . In the present investigation further characterization of CD64+ leukocytes has been attempted . The study was aimed at examining the phagocytic activity (PA) and reactive oxygen species (ROS) production by monocytes (Mo) and neutrophils (Neu) in sepsis and sepsis-induced acute respiratory distress syndrome (ARDS) related to the pattern of CD64 expression . Twenty-three post-traumatic or post-operative male and female patients with sepsis were enrolled . The control group consisted of 10 healthy volunteers . Arterial blood samples were taken during the septic episode for flow cytometric analysis of surface leukocyte antigens, phagocytosis, and ROS production . CD64 expression on Mo and Neu was markedly increased in septic patients (P = 0.029 and P = 0.0005), and even more in sepsis with ARDS (P = 0.011) . In healthy individuals, PA of CD64+ Neu was higher, than of CD64- cells (P = 0.021) . In septic patients, decreased PA was detected in CD64+ Mo and Neu (P = 0.013 and P = 0.040, respectively) . CD64+ Neu of patients in ARDS exhibited the most prominent PA depression (P = 0.048) . ROS production in non-separated Mo and Neu was increased in sepsis (P = 0.026 and P = 0.004, respectively) . In healthy individuals CD64+ Neu and stimulated CD64+ Mo demonstrated increased ROS synthesis compared to matched CD64- cells (P = 0.001 and P = 0.042, respectively) . Although ROS production by CD64+ leukocytes in sepsis was also increased compared to CD64- cells, significantly less ROS was generated compared to healthy subjects (P = 0.021) . In conclusion, overexpression of CD64 on blood Mo and Neu from patients with sepsis and ARDS is associated with depressed PA and decreased oxidative response. Ann Plast Surg, 2001 Aug, 47(2), 191 - 3 Superiorly based rectus abdominis wraparound flap for axillofemoral graft sepsis; Skoll PJ et al.; Prosthetic vascular graft sepsis, although uncommon, can lead to catastrophic sequelae for life and limb . Axillofemoral grafts are predisposed to sepsis and perigraft seromas because of their length, subcutaneous tunneling, and infrainguinal anastomosis, and are often performed in elderly, debilitated patients . The authors detail the use of a superiorly based rectus abdominis muscle flap, in combination with a sartorius muscle flap to salvage a Szilagy/Samson grade III septic axillounifemoral graft . The superiorly based rectus abdominis wraparound muscle flap should be considered a salvage option for select cases of sepsis involving axillofemoral grafts. Crit Care Med, 2001 Aug, 29(8), 1569 - 74 Effects of intravenous fat emulsions on lung function in patients with acute respiratory distress syndrome or sepsis; Suchner U et al.; OBJECTIVE: To investigate whether rapid or slowly infused intravenous fat emulsions affect the ratio of prostaglandin I2/thromboxane A2 in arterial blood, pulmonary hemodynamics, and gas exchange . DESIGN: Prospective, controlled, randomized, crossover study . SETTING: Operative intensive care unit of a university hospital . PATIENTS: Eighteen critically ill patients . Ten patients were stratified with severe sepsis, and eight patients had acute respiratory distress syndrome (ARDS) . INTERVENTIONS: Patients were assigned randomly to receive intravenous fat emulsions (0.4 x resting energy expenditure) over 6 hrs (rapid fat infusion) or 24 hrs (slow fat infusion) along with a routine parenteral nutrition regimen, by using a crossover study design . MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary hemodynamics as well as gas exchange measurements were recorded via respective indwelling catheters . Arterial thromboxane B2 and 6-keto-prostaglandin-F1alpha plasma concentrations were obtained by radioimmunoassay, and 6-keto-prostaglandin-F1alpha/thromboxane B2 ratios (P/T ratios) were calculated . Data were collected immediately before and 6, 12, 18, and 24 hrs after onset of fat infusion . In the ARDS group, P/T ratio increased by rapid fat infusion . Concomitantly, pulmonary shunt fraction, alveolar-arterial oxygen tension difference {P(a-a)o2}/Pao2, and cardiac index increased as well, whereas pulmonary vascular resistance and Pao2/Fio2 declined . After slow fat infusion, a decreased P/T ratio was revealed . This was accompanied by decreased pulmonary shunt fraction, lowered P(a-a)o2/Pao2, and increased Pao2/Fio2 . Correlations between plasma concentrations of 6-keto-prostaglandin-F1alpha or thromboxane B2 and measures of respiratory performance could be shown during rapid and slow fat infusion, respectively . In the sepsis group, the P/T ratio remained unchanged at either infusion rate, but pulmonary shunt fraction and P(a-a)o2/Pao2 decreased after rapid fat infusion, whereas Pao2/Fio2 increased . CONCLUSION: Pulmonary hemodynamics and gas exchange are related to changes of arterial prostanoid levels in ARDS patients, depending on the rate of fat infusion . In ARDS but not in sepsis patients clear of pulmonary organ failure, a changing balance of prostaglandin I2 and thromboxane A2 may modulate gas exchange, presumably via interference with hypoxic pulmonary vasoconstriction. Am J Respir Crit Care Med, 2001 Aug 1, 164(3), 396 - 402 Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis; Harbarth S et al.; To assess the diagnostic value of procalcitonin (PCT), interleukin (IL)-6, IL-8, and standard measurements in identifying critically ill patients with sepsis, we performed prospective measurements in 78 consecutive patients admitted with acute systemic inflammatory response syndrome (SIRS) and suspected infection . We estimated the relevance of the different parameters by using multivariable regression modeling, likelihood-ratio tests, and area under the receiver operating characteristic curves (AUC) . The final diagnosis was SIRS in 18 patients, sepsis in 14, severe sepsis in 21, and septic shock in 25 . PCT yielded the highest discriminative value, with an AUC of 0.92 (CI, 0.85 to 1.0), followed by IL-6 (0.75; CI, 0.63 to 0.87), and IL-8 (0.71; CI, 0.59 to 0.83; p < 0.001) . At a cutoff of 1.1 ng/ml, PCT yielded a sensitivity of 97% and a specificity of 78% to differentiate patients with SIRS from those with sepsis-related conditions . Median PCT concentrations on admission (ng/ ml, range) were 0.6 (0 to 5.3) for SIRS; 3.5 (0.4 to 6.7) for sepsis; 6.2 (2.2 to 85) for severe sepsis; and 21.3 (1.2 to 654) for septic shock (p < 0.001) . The addition of PCT to a model based solely on standard indicators improved the predictive power of detecting sepsis (likelihood ratio test; p = 0.001) and increased the AUC value for the routine value-based model from 0.77 (CI, 0.64 to 0.89) to 0.94 (CI, 0.89 to 0.99; p = 0.002) . In contrast, no additive effect was seen for IL-6 (p = 0.56) or IL-8 (p = 0.14) . Elevated PCT concentrations appear to be a promising indicator of sepsis in newly admitted, critically ill patients capable of complementing clinical signs and routine laboratory parameters suggestive of severe infection. Am J Respir Crit Care Med, 2001 Aug 1, 164(3), 389 - 95 Mitochondrial membrane potential and apoptosis peripheral blood monocytes in severe human sepsis; Adrie C et al.; Reduced mitochondrial membrane potential (Delta(Psi)m), which is considered as an initial and irreversible step towards apoptosis, as well as cell death regulating proteins, such as Fas, Hsp70, or Bcl-2, may play an important role in sepsis . We studied the relationship between sepsis severity and peripheral blood monocyte Delta(Psi)m, cell death (necrosis and apoptosis), soluble Fas ligand, Hsp70, and Bcl-2 expression over time in 18 patients with sepsis, and compared these data with those of a group of 17 healthy control subjects . All measurements were performed within 3 d of the onset of severe sepsis (T1), then 7 to 10 d later (T2), and finally at hospital discharge (T3) . Delta(Psi)m was expressed as the percent monocytes with altered Delta(Psi)m (%Delta(Psi)m) . Patients with sepsis had greater %Delta(Psi)m at T1 and T2 but not at T3 (14.6 +/- 2.6% and 15.9 +/- 2%, respectively, versus control 6.6 +/- 0.2%, p < 0.01) . Septic patients exhibited greater cell death in their monocytes and had greater Hsp70 expression only at T1 . Bcl-2 levels were similar in septic and control subjects . Comparing survivors with non-survivors of sepsis, nonsurvivors had a greater %Delta(Psi)m at T1 (26.4 +/- 5.3% versus 10.1 +/- 2.7%, p < 0.01) and a significant decrease in Bcl-2 expression, whereas no difference was found in Hsp70 levels . These results indicate that mitochondrial dysfunction and subsequent cell death occur in severe sepsis and suggest that %Delta(Psi)m is a marker of severity in human sepsis . Keywords: mitochondria; apoptosis; sepsis; heat-shock protein 70; proto-oncogene protein c-Bcl-2 Sheng Li Xue Bao, 1999 Jun, 51(3), 338 - 42 {Alteration of ryanodine receptors in cardiac sarcoplasmic reticulum and nuclear envelope of rats during sepsis}; Wang PY et al.; To investigate changes of ryanodine receptors in the sarcoplasmic reticulum (SR) and the nuclear envelope (NE) of rat cardiac myocytes during sepsis induced by cecal ligation and puncture (CLP), myocardial SR and NE were fractionated with density gradient centrifugation and the characteristic of ryanodine receptor was assayed with a method of radioreceptor binding assay . The result showed that Bmax of ryanodine receptors in cardiac SR was increased by 23% during early sepsis (9 h after CLP), but decreased by 38% during late sepsis (18 h after CLP) . Bmax of ryanodine receptors in cardiac NE, on the other hand, was increased by 100% and 160% during early and late sepsis respectively . Kd of ryanodine binding to SR and NE remained unchanged during sepsis . These results demonstrated up-regulation of ryanodine receptors in SR occurred during early sepsis and down-regulation of these receptors in SR occurred during late sepsis, while up-regulation of ryanodine receptors in NE occurred during both the early and the late sepsis. Cytokine, 2001 Jun 21, 14(6), 334 - 42 A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18; Novick D et al.; IL-18 binding protein (IL-18BP) is a circulating antagonist of the proinflammatory Th1 cytokine IL-18 . It effectively blocks IL-18 by forming a 1:1 high affinity (Kd=400 pM) complex, exhibiting a very low dissociation rate . We have developed a sandwich ELISA for IL-18BPa and determined its limit of detection (62 pg/ml) . Interference by IL-18 and related cytokines, as well as cross reactivity with other IL-18BP isoforms (b, c, and d) were determined . Using this ELISA, we measured serum IL-18BPa in large cohorts of healthy individuals and in septic patients . Serum IL-18BPa in healthy individuals was 2.15+/-0.15 ng/ml (range 0.5-7 ng/ml) . In sepsis, the level rose to 21.9+/-1.44 ng/ml (range 4-132 ng/ml) . Total IL-18 was measured in the same sera by an electrochemiluminescence assay and free IL-18 was calculated based on the mass action law . Total IL-18 was low in healthy individuals (64+/-17 pg/ml) and most of it ( approximately 85%) was in its free form . Total IL-18 and IL-18BPa were both elevated in sepsis patients upon admission (1.5+/-0.4 ng/ml and 28.6+/-4.5 ng/ml, respectively) . At these levels, most of the IL-18 is bound to IL-18BPa, however the remaining free IL-18 is still higher than in healthy individuals . We conclude that IL-18BPa considerably inhibits circulating IL-18 in sepsis . Yet, exogenous administration of IL-18BPa may further reduce circulating IL-18 activity . Intensive Care Med, 2001 Jun, 27(6), 970 - 7 Early prognosis in severe sepsis via analyzing the monocyte immunophenotype; Saenz JJ et al.; OBJECTIVE: To analyze the early discriminative predictive information regarding the immunophenotype components of patients with sepsis, and its potential use as a prognosis tool . DESIGN: Observational prospective clinical study . SETTING: Intensive care unit (ICU) in a University Hospital . PATIENTS: Thirty-five patients admitted with severe sepsis . MEASUREMENTS: Analysis of peripheral blood on admission and 48 h later of the absolute white cell count and the immunophenotype of lymphocyte (CD3, CD3-HLADR, CD4, CD8, CD4/CD8 ratio, CD19, and CD25) and monocyte (CD13, CD13-HLADR, CD14, CD14-HLADR, CD13-CD14, and CD4) subpopulations . RESULTS: Due to its high correlation, the immunophenotypic profile studied at admission and 48 h later showed the same prognosis power regardless of the time of performance . The univariate analysis between groups (survival versus death) confirmed the prognostic significance of the total monocyte count and its subpopulations; significant differences were observed from the beginning only in the CD19 lymphocyte subpopulation . Multivariate analysis was performed using logistic regression with survival as the dependent variable . The final model comprised monocytes beta = 0.002 (P = 0.025) and CD13-HLADR beta = 0.016 (P = 0.029) . The monocytes receiver operating characteristic (ROC) area obtained was 0.819 (confidence interval 0.663-0.976 at 95 %), the CD13-HLADR ROC area was 0.810 (confidence interval 0.658-0.963), and the monocytes + CD13-HLADR ROC area was 0.918 (confidence interval 0.807-1.000) . CONCLUSIONS: A single blood sample test obtaining the absolute monocyte and CD13-HLADR subpopulation count in the first days of admission could contribute to simplifying the classification of patients with severe sepsis into high- and low-mortality risk. Anesteziol Reanimatol, 2001 Mar-Apr, (2), 51 - 5 {Use of plasmapheresis for correction of metabolic disorders in patients with surgical sepsis}; Tolkach AB et al.; Twenty-four patients aged 16-67 years with surgical sepsis developing as a result of pancreonecrosis, gynecological diseases, urological sepsis . closed abdominal injury, and suppurative inflammation of soft tissues were examined . Endotoxemia caused pronounced disorders in metabolism, particularly purine metabolism, and the associated lipid peroxidation processes . Plasmapheresis exerted a positive effect in patients with high concentration of medium molecular-weight polypeptides (more than 0.32 arb . units) in the blood, decreasing the mortality by 40.5% . At lower concentrations of these polypeptides in the blood (less than 0.32 arb . units) plasmapheresis is inefficient. Anesteziol Reanimatol, 2001 Mar-Apr, (2), 46 - 8 {High-volume hemodiafiltration in the treatment of sepsis and multiple organ failure: 2 methods of the elimination of TNF-alpha}; Iakovleva II et al.; Permanent hemodiafiltration (PHDF) as a method for treating patients with sepsis and multiple organ failure (MOF) corrects the severity of generalized inflammatory reaction, which is caused by hyperproduction of bioactive substances . Cytokines can be eliminated from circulation by 2 methods of kidney-replacing therapy: convection and adsorption on hemofilter membrane . Despite the slight adsorption clearance, our results indicate that experimental data not always correspond to the clinical situation . Pronounced cytokinemia persists in patients with sepsis and MOF during PHDF . In addition to correction of the main hemostasis parameters, kidney-replacing therapy eliminates an appreciable amount of TNF-alpha and other proinflammatory cytokines . Estimation of TNF-alpha balance indicates its good adsorption on the surface of hemodiafilter membrane. Khirurgiia (Mosk), 2001, (4), 55 - 8 {Use of ozone therapy and hydro-pressure technologies in complex intensive therapy of surgical sepsis}; Parkhisenko IuA et al.; Results of treatment of 214 patients with severe sepsis and septic shock were analyzed . 125 patients treated with various methods of ozonotherapy and hydropressive sanation of infectious foci formed the study group . Control group consisted of 89 patients treated according to generally accepted principles . Comparative analysis of treatment efficacy was carried out with numerous laboratory and instrumental study methods . It is shown that ozonotherapy and hydropressive technologies reduced a lethality from 39.2% in the control group to 25.6% in the study group. Surgery, 2001 Aug, 130(2), 339 - 45 Inhibition of Fas signaling prevents hepatic injury and improves organ blood flow during sepsis; Chung CS et al.; BACKGROUND: Fas/Fas ligand (FasL) system is one of the major pathways triggering apoptosis that has been shown to play an important role in development and pathogenesis of various diseases including liver and gastrointestinal diseases . Studies indicate that FasL deficiency provides a survival advantage in mice subjected to polymicrobial sepsis . However, the extent to which Fas/FasL contributes to organ injury during sepsis is unclear . Thus, the aim of this study was to determine whether in vivo administration of a Fas-signaling inhibitor during sepsis preserves organ function . METHODS: Male adult C3H/HeN mice were subjected to cecal ligation and puncture (CLP) or sham CLP (sham) . Twelve hours after CLP, mice received either Fas-receptor fusion protein (FasFP) (200 microg/kg body weight) or the saline vehicle . Twenty-four hours after the onset of sepsis, cardiac output and organ blood flow were measured with radioactive microspheres . Plasma levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase were assessed as indexes of liver damage . Changes in systemic cytokines were measured by enzyme-linked immunosorbent assay . RESULTS . The data indicate that although cardiac output and organ blood flow in the liver, intestine, kidneys, spleen, and heart decreased markedly at 24 hours after CLP, treatment with FasFP maintained the measured hemodynamic parameters and improved hepatic, intestinal, and heart blood flow (P <.05) and partially restored spleen and renal blood flow . Moreover, FasFP treatment markedly attenuated the systemic rise in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and interleukin 10 (P <.05) . CONCLUSIONS: These results not only indicate that there is a role for Fas/FasL-mediated processes in the induction of organ injury but suggest that inhibition of Fas/FasL pathway may represent a novel therapeutic modality for maintaining organ perfusion and preventing liver injury during sepsis. Diabetologia, 2001 Aug, 44(8), 1011 - 4 Interleukin-6 and C-reactive protein as early markers of sepsis in patients with diabetic ketoacidosis or hyperosmosis; Gogos CA et al.; AIMS/HYPOTHESIS: An early diagnosis of sepsis in patients with diabetic ketoacidosis and hyperosmolar non-ketotic coma is crucial and could save lives . We studied serum C-reactive protein and interleukin-6 to find out how useful these might be for identifying sepsis . METHODS: Sixty one diabetic patients with ketoacidosis or hyperosmolar non-ketotic coma were enrolled . Patients with signs and symptoms of systemic inflammatory response syndrome were identified . Acute-phase reactants, including C-reactive protein and interleukin-6, the main cytokine responsible for the induction of acute-phase proteins, were measured on admission and when patients had clinically improved and were euglycaemic . RESULTS: A total of 49 out of 61 patients with diabetic ketoacidosis or hyperosmosis had signs of systemic inflammatory response syndrome . Another 27 patients had systemic inflammatory response syndrome and no signs of infection and 22 patients had systemic inflammatory response syndrome due to proven infection . We detected a significant increase in serum C-reactive protein and interleukin-6 values in patients infected compared with patients not infected with systemic inflammatory response syndrome SIRS . Patients who finally died had much higher levels of these proteins, while there was a prompt reduction of serum C-reactive protein and interleukin-6 early during remission . CONCLUSION/INTERPRETATION: Diabetic ketoacidosis and hyperosmolar non-ketotic coma can often cause a clinical syndrome resembling systemic inflammatory response syndrome . Determination of serum C-reactive protein and interleukin-6 levels is a useful way of excluding an underlying infection early on as well as confirming and monitoring sepsis. Clin Resour Manag, 2001 Jul, 2(7), 107 - 9 Breakthrough found in treatment of severe sepsis. Sepsis and mechanisms of inflammatory response: is exercise a good model? Faculty of Physical Education and Health and Department of Public Health Sciences, University of Toronto and Defence and Civil Institute of Environmental Medicine, Toronto, Ontario, Canada . royjshep@mountain-inter.net OBJECTIVES: The immune changes induced by a bout of prolonged and vigorous exercise have been suggested to be a useful experimental model of sepsis and the inflammatory response . Available literature was reviewed to evaluate this hypothesis . METHODS: Literature describing the immune response to various patterns of exercise was compared with data on the immune changes observed during sepsis and inflammation . RESULTS: Although there are qualitative similarities between the immune responses to exercise and sepsis, the magnitude of the changes induced by most forms of exercise remains much smaller than in a typical inflammatory response . Indeed, the exercise induced changes in some key elements such as plasma cytokine concentrations are too small to be detected reliably by current technology . CONCLUSIONS: If exercise is to provide a valid model of sepsis and the inflammatory response, it will be necessary to focus on subjects who are willing to exercise extremely hard, to use the pattern of exercise that has the greatest effect on the immune system, and to combine this stimulus with other psychological, environmental, or nutritional stressors. Eur J Pediatr, 2001 Jul, 160(7), 436 - 8 Congenital neuroblastoma mimicking early onset sepsis; Lindner W et al.; A newborn girl presented with symptoms of severe early onset sepsis but also with systemic hypertension (SH) at age 3 h . Plasma catecholamine (CAT) levels were extremely elevated, reflecting increased release of CAT from a congenital neuroblastoma (NB) . Clinical symptoms at time of admission were: prolonged capillary refill (5 s), tachycardia, tachydyspnoea, metabolic acidosis (pH 7.17, lactate 11.8 mmol/l), fever (38.4 degrees C) and SH: 90/50/65 mmHg (systolic/diastolic/mean) . The infant experienced organ failure (lung, heart, liver) . A retroperitoneal dumbbell tumour was detected . Plasma CAT levels at age 15 h were: noradrenaline 219 nmol/l; adrenaline 13 nmol/l; and dopamine 65.3 nmol/l . SH responded to intermittent alpha-adrenergic blockage . CAT-related symptoms ceased within 1 week . The intraspinal NB was surgically removed when cord compression became symptomatic . The neurological and developmental state is normal at age 17 months . The abdominal NB regressed spontaneously . CONCLUSION: A neuroblastoma should be considered in newborn infants presenting with a shock-like condition together with systemic hypertension. Biol Neonate, 2001 Jul, 80(1), 41 - 7 Inflammatory mediators in umbilical plasma from neonates who develop early-onset sepsis; Dollner H et al.; OBJECTIVES: To study whether early-onset neonatal sepsis is associated with a prenatal immune response with elevated umbilical plasma levels of inflammatory mediators, and to study whether mediator levels may be helpful in identifying infected neonates . SETTING: Nested case-control study . METHODS: Cord blood was sampled from 7,073 consecutively delivered neonates . After review of the medical records, neonates suspected to suffer from infection were classified as infected (n = 52) or noninfected but sick controls (n = 33) . We also included a group of healthy controls (n = 99) . Umbilical plasma levels of tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, IL-6, IL-8, soluble TNF receptors (p55 and p75), IL-1 receptor antagonist (IL-1RA) and C-reactive protein were measured by immunoassays . RESULTS: Infected neonates had higher levels of TNFalpha, IL-1beta, IL-6, IL-8, p55, p75 and IL-1RA than healthy controls (all p < 0.01) . Among preterm infants (GA <37 weeks), those with infection (n = 11) had higher levels of IL-1beta, IL-6, IL-8, p55 and p75 than noninfected sick controls (n = 13) (all p < 0.05), but among term infants, the infected did not differ from the noninfected sick controls . Receiver operator characteristic plots showed that IL-1beta, IL-6 and IL-8 identified preterm infected neonates accurately . CONCLUSIONS: Early-onset neonatal sepsis is associated with a prenatal immune response with increased TNFalpha, IL-1beta, IL-6, IL-8, p55, p75 and IL-1RA levels in umbilical plasma . Among neonates who present symptoms suggestive of infection, cytokine levels may be helpful in identifying preterm, but not term infected individuals . J Cell Physiol, 2001 Sep, 188(3), 313 - 20 Suppression of inducible nitric oxide generation by agmatine aldehyde: beneficial effects in sepsis; Satriano J et al.; The induction of inducible nitric oxide synthase (iNOS) serves an important immuno-protective function in inflammatory states, but ungoverned nitric oxide (NO) generation can contribute to a number of pathologic consequences . Delineation of the mechanisms that can downregulate iNOS-generated NO in inflammation could have therapeutic relevance . Here we show that agmatine, a metabolite of arginine, inhibits iNOS mediated nitric oxide generation in cytokine stimulated cell culture preparations . This effect was not cell type specific . Increased diamine oxidase (DAO) and decreased aldehyde dehydrogenase (AldDH) activities are also representative of inflammatory settings . Increasing the conversion of agmatine to an aldehyde form by addition of purified DAO or suppression of aldehyde breakdown by inhibition of AldDH activity increases the inhibitory effects of agmatine in an additive fashion . Inhibitors of DAO, but not monoamine oxidase (MAO), decreased the inhibitory effects of agmatine, as did the addition of AldDH or reacting aldehydes with phenylhydrazine . We examined rats given lipopolysaccharide (LPS) to evaluate the potential effects of agmatine in vivo . Endotoxic rats administered agmatine prevented the decreases in blood pressure and renal function normally associated with sepsis . Agmatine treatment also increased the survival of LPS treated mice . Our data demonstrate the capacity of agmatine aldehyde to suppress iNOS mediated NO generation, and indicate a protective function of agmatine in a model of endotoxic shock . How agmatine may aid in coordinating the early NO phase and the later repair phase responses in models of inflammation is discussed . Rev Gastroenterol Mex, 2001 Jan-Mar, 66(1), 6 - 13 {Prognostic index in wound infection and abdominal sepsis}; Chalita-Manzur A et al.; OBJECTIVE: To establish an abdominal surgical infection prognostic index with all risk factors . SUMMARY BACKGROUND DATA: Individuals, requiring abdominal surgery have an established surgical infection risk of 1% and this risk increases with several factors, such as age over 50 years, (4%), diabetes mellitus (12%), obesity (8%), hospitalization up to 10 days (4%), bad nutrition (2%), surgical time up to 3 h (6%) summer (4%) shock (6%) immunosuppression (6%), contaminated surgery (from 1%-40%), or emergency surgery (4%) . METHOD: We reviewed 199 patients and investigated previous disease, total white blood cells, oxygen saturation, albumin, body weight, type of surgery performed in regard to contamination, surgical time, hospitalization time, preoperative hair removal previous to surgery, presence of emergency surgery, and prevalence of remote site infections at time of surgery . All these parameters were reviewed for 48 h before and after the surgical procedure and every risk factor acquired a number with respect to the established risk in the world literature . An index called Prognostic index of surgical infections (PISI) was performed, made up of the addition of risk factors . Every patient was observed 10 days after the surgical procedure searching for abdominal or wound infection and correlating the index with the presence of surgical infection . RESULTS: Patients with a prognostic index of 12 or less did not show infections in any case; those with an index of 13 to 15 points had 30% of risk infection, 16 to 18 obtained 70%, 19 to 21 acquired 90%, and 22 or more obtained 100% of surgical risk infection . Sensitivity was 100% and specificity, nearby 75% . CONCLUSIONS: PISI is a reliable indicator of surgical infection risk because it takes into account all factors that cause troubles in the patients, and has high sensitivity and very good specificity. Anesteziol Reanimatol, 1999 Nov-Dec, (6), 28 - 33 {Inflammatory reaction and sepsis in pancreatic necrosis}; Savel'ev VS et al.; Analysis of clinical data, results of treatment, and the development of systemic inflammatory reaction (SIR) in 100 patients with sterile or infective pancreonecrosis and pancreatogenic necrosis demonstrated a phase-wise pattern in the development of inflammatory and septic process in pancreonecrosis . The development of inflammation and sepsis in such patients is determined by the extent of involvement, infection of necrotic zone, and disease duration . SIR, shock, and polyorgan failure are the cardinal components in the pathogenesis of various phases of pancreonecrosis . Detection of signs of SIR and sepsis are needed for individual and urgent evaluation of patient's state . The scale for evaluating the severity of patient's physiological condition and index of involvement of abdominal and retroperitoneal organs are the most accurate, sensitive, and quantitative characteristics for evaluating the patient's condition and the course and outcome in pancreonecrosis. Am J Physiol Regul Integr Comp Physiol, 2001 Aug, 281(2), R654 - 60 The small intestine is an important source of adrenomedullin release during polymicrobial sepsis; Zhou M et al.; Adrenomedullin (AM), a potent vasodilatory peptide, has recently been reported to be involved in the altered cardiovascular responses under various pathophysiological conditions . Although the increase in plasma AM levels is associated with upregulation of AM gene expression in various tissues, it remains unknown whether the gut is an important source of AM release under such conditions . To determine this, adult male rats were subjected to sepsis by cecal ligation and puncture (CLP) followed by fluid resuscitation . Systemic and portal blood samples were collected simultaneously at 10 and 20 h after CLP or sham operation . A portion of the jejunum was also harvested . Plasma and tissue levels of AM were then determined by RIA . The localization of AM in the intestinal tissue was examined using immunohistochemistry . In an additional group of normal rats, synthetic rat AM (8.5 microg/kg body wt) was infused for 15 min at a constant rate via the portal vein (which produces a similar level of AM as observed during sepsis) . Cardiac output, stroke volume, total peripheral resistance, and microvascular blood flow in various organs were determined before and 30 min after AM administration . The results indicate that AM levels in portal blood were significantly higher than in systemic blood at 10 and 20 h after CLP . Intestinal AM was also markedly elevated . Immunohistochemical visualization shows that AM immunostainings were localized in the mucosa, submucosa, and intestinal nerve fibers, and they were increased at 10-20 h post-CLP . Because AM-immunopositive nerve fibers increase in the gut during sepsis, a nerve pathway may be involved in the regulation of vascular reactivity by this peptide . Moreover, intraportal administration of AM increased cardiac output, stroke volume, and microvascular blood flow in the liver, kidney, small intestine, and spleen . In contrast, total peripheral resistance was significantly reduced . Thus the gut plays an important role in increasing the levels of circulating AM during the progression of sepsis . Gut-derived AM appears to be a major factor in initiating the hyperdynamic response after the onset of sepsis. Am J Physiol Regul Integr Comp Physiol, 2001 Aug, 281(2), R408 - 16 Altered phosphorylation and calcium sensitivity of cardiac myofibrillar proteins during sepsis; Wu LL et al.; Altered phosphorylation and Ca(2+) sensitivity of cardiac myofibrillar proteins during different phases of sepsis were investigated . Sepsis was in