Sepsis

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 induced by cecal ligation and puncture (CLP) . The results show that phosphorylation of troponin I (TnI) was increased by 268% during the early phase (9 h after CLP) but decreased by 46% during the late phase (18 h after CLP) of sepsis . Phosphorylation of C protein was increased by 76% during the early phase but decreased by 41% during the late phase of sepsis . Phosphorylation of myosin light chain-2 (MLC-2) remained unaltered during the early phase but was decreased by 38% during the late phase of sepsis . Phosphorylation of TnT was unaffected during the progression of sepsis . The increases in the phosphorylation of TnI and C protein during early sepsis were associated with the decrease in the Ca(2+) sensitivity of myofilaments and the increases in myocardial changes in tension development (+dP/dt(max)) and cAMP level . The decreases in the phosphorylation of TnI and C protein during late sepsis coincided with the declines in the activities of myofibrillar ATPase, Ca(2+) sensitivity of myofilaments, myocardial +/-dP/dt(max), and cAMP content . The increases and the decreases in the phosphorylation of TnI and C protein, +/-dP/dt(max), and the tissue cAMP level were sensitive to isoproterenol stimulation and propranolol inhibition . These findings suggest that alterations in the phosphorylation of myofibrillar proteins, such as TnI, C protein, and MLC-2, and changes in the activities and the Ca(2+) sensitivity of myofibrillar ATPase may contribute to the altered cardiac function during the progression of sepsis . Furthermore, the sepsis-induced alterations in the phosphorylation and Ca(2+) sensitivity of cardiac myofibrillar proteins were mediated via a beta-adrenergic receptor pathway.

Crit Care Med, 2001 Jul, 29(7 Suppl), S126 - 9
Tissue factor pathway inhibitor activity in severe sepsis; Creasey AA et al.; OBJECTIVE: To review the preclinical and clinical evidence that provides the therapeutic rationale for recombinant human tissue factor pathway inhibitor (rTFPI) as a novel treatment for human sepsis . DATA SOURCES: A summary of published English-language literature regarding preclinical studies and limited information published about three phase II clinical studies for the evaluation of rTFPI safety in sepsis patients . DATA SUMMARY: Tissue factor pathway inhibitor, the physiologic inhibitor of the tissue factor pathway, interrupts activation of coagulation at multiple steps, including tissue factor VIIa activity, Xa activity, prothrombinase complex, and thrombin generation . Recombinant human TFPI exhibits anticoagulant and anti-inflammatory activities in animal models and humans with sepsis . These activities appear to have an important therapeutic role in protecting the microvasculature from injury and preventing multiple organ failure in sepsis . CONCLUSIONS: Tissue factor pathway inhibitor is a potent inhibitor of clotting in the microvasculature, which is thought to protect organs from injury . Recombinant TFPI improved survival of septic animals in multiple models . Recent phase II results suggest that rTFPI is well tolerated, and they show a trend toward reduction in 28-day all-cause mortality in rTFPI-treated patients; in addition, rTFPI demonstrated significant reduction in thrombin generation . These results suggest that a powered study is indicated to further evaluate rTFPI utility for the adjunctive management of severe sepsis.

Crit Care Med, 2001 Jul, 29(7 Suppl), S121 - 5
Anti-tumor necrosis factor therapy in sepsis: update on clinical trials and lessons learned; Reinhart K et al.; OBJECTIVE: Tumor necrosis factor (TNF) is an important mediator involved in the pathogenesis of sepsis . We review clinical studies investigating the efficacy of anti-TNF therapy in decreasing mortality rates in septic patients . DATA SOURCES: We conducted a computerized bibliographic search of randomized, clinical, multicenter trials studying the effects of anti-TNF therapy in the treatment of sepsis . We included all primary studies, reviewed all published meta-analyses, and contacted primary investigators of multicenter trials where necessary . DATA SYNTHESIS: Almost all randomized studies targeting TNF during sepsis show a small, albeit nonsignificant, benefit in decreasing mortality . Strategies using monoclonal antibodies are more effective than are strategies using TNF receptor proteins . Analysis of randomized multicenter trials shows a small but significant benefit with anti-TNF therapeutic strategies . Furthermore, a recent study in 2634 septic patients using a murine anti-TNF antibody shows a 3.6% significant benefit in reducing mortality . CONCLUSIONS: Anti-TNF strategies are only partially effective in patients with sepsis . Although individual studies show small, nonsignificant benefits, analysis of all trial data as well as data from a recent trial in a large population of septic patients show that anti-TNF strategies may confer a small survival benefit . Better characterization of patients and a more multimodal approach by concomitantly targeting other mediators involved in sepsis may be helpful in enlarging the clinical benefit of anti-TNF therapy.

Crit Care Med, 2001 Jul, 29(7 Suppl), S90 - 4
Rationale for restoration of physiological anticoagulant pathways in patients with sepsis and disseminated intravascular coagulation; Levi M et al.; OBJECTIVE: In the pathogenesis of disseminated intravascular coagulation, dysfunctional natural anticoagulant pathways appear to play a pivotal role . In this article, we will address the mechanisms that contribute to this defect in the regulation of coagulation activation . Furthermore, we will explore the experimental and clinical evidence that restoration of these anticoagulant pathways results in clinical improvement . DATA SOURCES: We have searched and reviewed published articles on experimental studies of disseminated intravascular coagulation models in animals and clinical studies in patients with disseminated intravascular coagulation . DATA SYNTHESIS: All three major anticoagulant pathways, that is, the antithrombin pathway, the protein C system, and tissue factor pathway inhibitor, are defective in sepsis and disseminated intravascular coagulation . Several mechanisms contribute to this defect . Restoration of these pathways, in principle, by administration of coagulation inhibitor concentrates or recombinant anticoagulant factors, appears to ameliorate the coagulation disorder and, more important, result in improvement of clinically relevant outcomes, such as a reduction of organ failure and mortality . CONCLUSIONS: Restoration of disrupted physiologic anticoagulant pathways in disseminated intravascular coagulation is not only a logical point of impact in patients with sepsis and an activated coagulation system, but also is associated with an improved outcome in experimental and (initial) clinical studies.

Crit Care Med, 2001 Jul, 29(7 Suppl), S69 - 74
Activated protein C versus protein C in severe sepsis; Yan SB et al.; OBJECTIVE: To delineate critical differences between activated protein C (APC) and its precursor, protein C, with regard to plasma levels in health and in severe sepsis, and to discuss the implications of these differences as they relate to treatment strategies in patients with severe sepsis . DATA SOURCE/STUDY SELECTION: Published literature including abstracts, manuscripts, and review articles reporting studies in both experimental animal models and humans that provide an understanding of the relationship and the critical differences between circulating levels of APC and protein C . DATA EXTRACTION AND SYNTHESIS: The protein C pathway represents one of the major regulatory systems of hemostasis, exhibiting antithrombotic, profibrinolytic and anti-inflammatory properties . This pathway also plays a critical role in the pathophysiology of severe sepsis . Central to this pathway is the vitamin K-dependent serine protease, APC, and its precursor, protein C . The conversion of protein C to APC is dependent on the complex of thrombin and thrombomodulin, an integral endothelial surface receptor . The conversion of protein C to APC is further augmented by another endothelial surface protein, the endothelial protein C receptor . There are limited published data on APC levels in health and disease, probably due to the complexity of the assay methodology for measuring APC and the absence of commercially available diagnostic kits . In animals and humans with normal functioning endothelium, circulating levels of APC (1-3 ng/mL) are positively correlated with protein C (4000-5000 ng/mL) concentration and the amount of thrombin generated . In patients with severe sepsis, there is a generalized endothelial dysfunction, contributing to multiple organ failure with increased morbidity and mortality . Persistently low protein C levels are related to poor prognosis . Key to understanding the treatment strategy with APC or protein C is knowledge of the functional status of the endothelium and, specifically, whether the microvasculature in patients with severe sepsis can support the conversion of protein C to APC . To date, only APC (drotrecogin alfa {activated}) has been shown to reduce mortality in severe sepsis in a large, phase 3, placebo-controlled, double-blind international trial . In contrast, no data, other than open-label case studies, are available for evaluation of the effects of protein C in the treatment of severe sepsis . CONCLUSION: The limited data available indicate that lower levels of protein C in sepsis occur in the absence of appreciable conversion to APC . These observations indicate that treatment with APC may be more efficacious than protein C in severe sepsis, where generalized endothelial dysfunction may impair conversion of protein C to APC . Additional research is required to confirm these observations.

Crit Care Med, 2001 Jul, 29(7 Suppl), S62 - 7; discussion S67-8
Coagulation in severe sepsis: a central role for thrombomodulin and activated protein C; Faust SN et al.; OBJECTIVES: To review the mechanisms that cause coagulation abnormalities in sepsis, focusing on the interaction between the vascular endothelium and the circulating coagulation factors, particularly the role of the protein C pathway and thrombomodulin . DATA SOURCES/STUDY SELECTION: Published research abstracts and review articles on the experimental and clinical investigation of the pathophysiology of disseminated intravascular coagulation in sepsis . DATA EXTRACTION AND SYNTHESIS: The data provide increasing evidence that the coagulopathy seen in sepsis is a result of a complex imbalance of pro- and anticoagulant pathways . Whereas previous research has largely studied events in the plasma, it is now apparent that reactions on cell surfaces such as the vascular endothelium are important in the control of the regulatory pathways . CONCLUSIONS: The plasma components of the protein C pathway are down-regulated in sepsis . Decreased thrombomodulin expression may cause defective function of the endothelial component of this pathway in septic patients . Treatments must be designed to overcome any functional defect.

Crit Care Med, 2001 Jul, 29(7 Suppl), S53 - 60; discussion S60-1
Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis; Grinnell BW et al.; OBJECTIVE: To review the mechanisms of action and rationale for the use of recombinant human activated protein C in the treatment of severe sepsis . Specifically, we focus on the mechanisms of action in the protein C pathway that converge to modulate the pathophysiology of severe inflammatory disease and sepsis . This analysis includes a discussion of the role of activated protein C in directly modulating cell system biology, independent of antithrombotic activity . DATA SOURCES/STUDY SELECTION: Published research and review articles relating to the protein C pathway, recombinant human protein C, and the role of protein C in sepsis . Data were also derived from broad gene profiling in model systems of endothelial dysfunction . DATA EXTRACTION AND SYNTHESIS: Relevant studies were included to support discussion of the unique mechanistic aspect of protein C and its role in the pathogenesis of severe sepsis . We discuss the potential of activated protein C as a unique system modulator for the treatment of severe sepsis and other systemic inflammatory responses that result in microvascular coagulopathy, endothelial dysfunction, and vascular bed failure . CONCLUSIONS: The protein C pathway plays a unique role in modulating vascular function . As an antithrombotic/profibrinolytic agent, it plays a clear role in maintaining vascular patency . Moreover, it has anti-inflammatory properties and appears to play a unique role as an antiapoptotic and endothelial cell survival factor . In states of systemic inflammatory activation, loss of protein C due to consumptive processes results in a compromised ability to modulate coagulation as well as inflammatory and cell survival functions . This compromise leads to vascular dysfunction, end-organ failure, and death . Replacement with recombinant human activated protein C offers a system-modulating approach to improved outcome.

Crit Care Med, 2001 Jul, 29(7 Suppl), S42 - 7
Hepatic response to sepsis: interaction between coagulation and inflammatory processes; Dhainaut JF et al.; OBJECTIVES: a) To review the hepatic response to sepsis and to establish how this response contributes to coagulation and inflammatory processes; b) to review the physiologic and biochemical mechanisms that suggest hepatic dysfunction may occur during sepsis, enhance procoagulant and proinflammatory activities, and participate in the potential evolution to multiple organ dysfunction syndrome . DATA SOURCES: A summary of published medical literature from MEDLINE search files and published reviews on liver function in experimental and human sepsis . DATA SUMMARY: In sepsis, the liver plays a major role in host defense mechanisms . Kupffer cells are responsible for bacterial scavenging, bacterial products inactivation, and inflammatory mediators clearance and production . Hepatocytes, via receptors for many proinflammatory cytokines, modify their metabolic pathway toward gluconeogenesis, amino-acid uptake, and increased synthesis of coagulant and complement factors and protease inhibitors . The acute-phase protein (APP) response also contributes to the procoagulant state, especially by enhancing the inhibition of protein C (alpha1-antitrypsin and alpha2-macroglobulin) and by decreasing liver synthesis of protein C and antithrombin (negative APPs) . Elevated C-reactive protein levels (positive APPs) promote the expression of tissue factor by mononuclear cells . Increased liver production of thrombin-activatable fibrinolytic inhibitor (positive APPs) enhances fibrinolysis inhibition . Conversely, such hepatic inflammatory and coagulation processes in sepsis may alter the function of this organ . Indeed, the liver can be injured by activated Kupffer cells that release chemokines, attract blood neutrophils into the liver, and activate them . Neutrophils up-regulate their surface adhesion molecules, tissue factor, and Kupffer cells, whereas tissue factor pathway inhibitor and thrombomodulin are almost undetectable in endothelial cells . This may lead to microcirculatory disturbances, fibrin deposition, hepatocyte injury, endotoxin and bacteria spillover, and multiple organ failure . CONCLUSIONS: In sepsis, the liver participates in host defense and tissue repair through hepatic cell cross-talk that controls most of the coagulation and inflammatory processes . When this control is not adequate, a secondary hepatic dysfunction may occur and may sometimes lead to bacterial products spillover, enhanced procoagulant and inflammatory processes, and in turn, multiple organ failure and death.

Crit Care Med, 2001 Jul, 29(7 Suppl), S28 - 34; discussion S34-5
Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis; Aird WC; OBJECTIVES: To examine the role of vascular bed-specific pathways in determining the hemostatic phenotype in sepsis . DATA SOURCES/STUDY SELECTION: Published research and review articles related to hemostasis and endothelial cell biology . DATA EXTRACTION AND SYNTHESIS: The results of published studies have been used to generate a hypothesis of vascular bed-specific hemostasis in sepsis . CONCLUSIONS: In sepsis, coagulation is initiated by the extrinsic pathway and is amplified through the intrinsic pathway . In addition, the body's natural anticoagulant mechanisms are significantly dampened . Together, these changes result in a net imbalance of hemostasis . The nature of this imbalance varies from one vascular bed to the next according to the local set point of the endothelium . These concepts lay an important foundation for understanding the pathophysiology of sepsis.

Crit Care Med, 2001 Jul, 29(7 Suppl), S21 - 7
The endothelium in sepsis: source of and a target for inflammation; Hack CE et al.; OBJECTIVE: To discuss a possible role of the endothelium in sepsis . DATA SOURCES: Studies published in biomedical journals and our own experimental results . STUDY SELECTION: Studies on endothelial mechanisms in the context of sepsis . DATA EXTRACTION AND SYNTHESIS: Changes in endothelial cells on activation by inflammatory stimuli are reviewed briefly; potential mechanisms that lead to endothelial damage during sepsis are discussed . CONCLUSIONS: The endothelium is a key organ involved in the pathogenesis of sepsis . Dysfunction of or injury to the endothelium may be involved in the pathogenesis of multiple organ failure and should be discriminated from activation resulting from stimulation with inflammatory stimuli . Identification of the molecular mechanisms that contribute to endothelial dysfunction or damage is likely to provide novel targets for the treatment of sepsis.

Crit Care Med, 2001 Jul, 29(7), 1423 - 30
Attenuation of sepsis-related immunoparalysis by continuous veno-venous hemofiltration in experimental porcine pancreatitis; Yekebas EF et al.; OBJECTIVES: In light of evidence suggesting that hemofiltration favorably influences septic diseases by removing sepsis mediators, the impact of different modalities of continuous veno-venous hemofiltration (CVVH) on outcome and immunologic derangements in porcine pancreatogenic sepsis was evaluated . DESIGN: Randomized, controlled intervention trial . SUBJECTS: Forty-eight minipigs of either sex . INTERVENTIONS: Pancreatitis was induced by intraductal injection of sodium taurocholate (4%, 1 mL/kg body weight {BW}) and enterokinase (2 U/kg BW) . Animals were allocated either to untreated controls-group 1-or to one of three treatment groups-group 2: low-volume CVVH (20 mL/kg BW), no change of hemofilters; group 3: low-volume CVVH, filters changed every 12 hrs; and group 4: high-volume CVVH (100 mL/kg BW), filters changed every 12 hrs . Survival represented the major parameter of the study . Serum cytokine levels, sepsis-related down-regulation of major histocompatibility complex II and CD14 expression on leukocytes, bacterial translocation, and endotoxemia were further parameters evaluated in the study . MEASUREMENTS AND MAIN RESULTS: High-volume CVVH combined with periodic filter change was significantly superior compared with less intensive treatment modalities (low-volume CVVH, no filter change) in sepsis protection . Long-term survival (>60 hrs) was found in 67% of group 4 and 33% of group 3 animals (p <.05), whereas in controls and group 2 no animal survived . CVVH ameliorated the initial serum tumor necrosis factor-alpha response and prevented sepsis-induced in vitro endotoxin hyporesponsiveness . Down-regulation of major histocompatibility complex II and CD14 expression on monocytes was significantly improved by CVVH . Improved oxidative burst and phagocytosis capacity in polymorphonuclear leukocytes suggested that leukocyte function was stabilized by CVVH . Also, CVVH significantly reduced bacterial translocation and endotoxemia . CONCLUSIONS: Hemofiltration reversed sepsis-induced immunoparalysis in a porcine model of bile acid-induced pancreatitis . Implications for human pancreatitis must be validated in prospective, clinical protocols.

Crit Care Med, 2001 Jul, 29(7), 1380 - 5
Cardiac variability in critically ill adults: influence of sepsis; Korach M et al.; OBJECTIVE: To evaluate, in critically ill adults, factors associated with impaired sympathovagal balance . DESIGN: One-month inception cohort study . SETTING: Twenty-six-bed medical intensive care unit of a teaching hospital . PATIENTS: Critically ill adults with an expected duration of intensive care unit stay of > or =48 hrs were enrolled . Patients with permanent arrhythmia or cardiac pacing were not included . INTERVENTIONS: None . MEASUREMENT AND MAIN RESULTS: Sympathovagal balance was assessed on the day after intensive care unit admission by the low-frequency/high-frequency ratio obtained from spectral components of heart rate signal: overall variability, low frequency, and high frequency . RESULTS: Forty-one patients, 13 with sepsis and 28 without sepsis, were assessed . Predictors of low-frequency/high-frequency ratio with the automatic interaction detection method were sepsis and age . Binary logit analysis adjusted for age showed that sepsis remained a strong and independent factor of a low-frequency/high-frequency ratio of <1.50, with an odds ratio of 3.63 (95% confidence interval, 1.47-9.01, p =.005) . Use of mechanical ventilation, catecholamines, or sedation did not add any information . The use of the low-frequency/high-frequency ratio in diagnosing sepsis may be supported by a likelihood ratio for low frequency/high frequency <1 at 6.47 . CONCLUSIONS: This work suggests that impaired cardiac variability and notably sympathovagal balance (i.e., a low-frequency/high-frequency ratio <1.0) may be a diagnostic test for sepsis.

Crit Care Med, 2001 Jul, 29(7), 1343 - 9
Tissue oxygenation and perfusion in patients with systemic sepsis; Sair M et al.; OBJECTIVE: Multiple organ dysfunction is associated with systemic sepsis . To investigate whether this is attributable to peripheral tissue hypoperfusion and/or cellular hypoxia, simultaneous measurements of tissue perfusion and oxygenation were made in patients with severe sepsis and in controls . DESIGN: Prospective, observational study . SETTING: Adult intensive care unit, tertiary referral center . PATIENTS: Volunteers (group C, n = 7), patients undergoing cardiopulmonary bypass (group B, n = 6), and patients with severe sepsis (group S, n = 6) . INTERVENTIONS: Limb ischemia and reperfusion . MEASUREMENTS AND MAIN RESULTS: Tissue oxygenation and microvascular flow were measured by using microelectrodes inserted into brachoradialis muscle and overlying subcutaneous tissue . Forearm cutaneous red cell flux and regional blood flow were measured simultaneously . Responses to 20 mins of limb ischemia and subsequent reperfusion were observed . Baseline muscle tissue oxygenation was greater in sepsis (1.7 +/- 0.2, 1.5 +/- 0.7, and 4.4 +/- 0.6 kPa for groups C, B, and S, respectively, mean +/- sem, p <.05), although baseline subcutaneous tissue oxygenation did not vary between groups . During ischemia tissue oxygenation, values decreased in muscle (to 1.3 +/- 0.2, 1.0 +/- 0.4, and 1.5 +/- 0.4 kPa for groups C, B, and S, respectively) and subcutaneous tissue (to 2.0 +/- 0.3, 1.7 +/- 0.5, and 2.3 +/- 0.2 kPa for groups C, B, and S, respectively) . Decline in tissue oxygen tension was initially more rapid in septic muscle compared with controls (25% decrease, 68 +/- 23 vs . 176 +/- 38 for group S vs . group C, p <.05, and 50% decrease, 126 +/- 34 vs . 398 +/- 72 secs for group S vs . group C, p <.01) . However, overall rate of tissue decline was similar (95% decrease, 444 +/- 122 vs . 614 +/- 96 for group S vs . group C, p >.05) . After reperfusion, significant differences in muscle tissue oxygenation reappeared between groups (2.0 +/- 0.3, 1.5 +/- 0.7, and 4.0 +/- 0.4 kPa for groups C, B, and S, respectively, p <.05) . There were no differences in time to 25%, 50%, or 95% tissue oxygen recovery . Whole limb reperfusion was significantly less in patient groups compared with controls (10.6 +/- 0.9, 4.5 +/- 1.2, and 4.3 +/- 1.6 mL x 100 mL(-1) x min(-1) for groups C, B, and S, respectively, p <.05) . CONCLUSIONS: Significant differences in tissue oxygenation distribution between muscle and subcutaneous tissues occur in patients with severe sepsis . High baseline muscle tissue oxygen levels are accompanied by rapid extraction of oxygen during stagnant ischemia.

Crit Care Med, 2001 Jul, 29(7), 1303 - 10
Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care; Angus DC et al.; OBJECTIVE: To determine the incidence, cost, and outcome of severe sepsis in the United States . DESIGN: Observational cohort study . SETTING: All nonfederal hospitals (n = 847) in seven U.S . states . PATIENTS: All patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification of Diseases, Ninth Revision, Clinical Modification . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: We linked all 1995 state hospital discharge records (n = 6,621,559) from seven large states with population and hospital data from the U.S . Census, the Centers for Disease Control, the Health Care Financing Administration, and the American Hospital Association . We defined severe sepsis as documented infection and acute organ dysfunction using criteria based on the International Classification of Diseases, Ninth Revision, Clinical Modification . We validated these criteria against prospective clinical and physiologic criteria in a subset of five hospitals . We generated national age- and gender-adjusted estimates of incidence, cost, and outcome . We identified 192,980 cases, yielding national estimates of 751,000 cases (3.0 cases per 1,000 population and 2.26 cases per 100 hospital discharges), of whom 383,000 (51.1%) received intensive care and an additional 130,000 (17.3%) were ventilated in an intermediate care unit or cared for in a coronary care unit . Incidence increased >100-fold with age (0.2/1,000 in children to 26.2/1,000 in those >85 yrs old) . Mortality was 28.6%, or 215,000 deaths nationally, and also increased with age, from 10% in children to 38.4% in those >85 yrs old . Women had lower age-specific incidence and mortality, but the difference in mortality was explained by differences in underlying disease and the site of infection . The average costs per case were $22,100, with annual total costs of $16.7 billion nationally . Costs were higher in infants, nonsurvivors, intensive care unit patients, surgical patients, and patients with more organ failure . The incidence was projected to increase by 1.5% per annum . CONCLUSIONS: Severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those from acute myocardial infarction . It is especially common in the elderly and is likely to increase substantially as the U.S . population ages.

Am J Physiol Cell Physiol, 2001 Aug, 281(2), C662 - 9
MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis; Song GY et al.; Although studies indicate that a shift from a Th1 to a Th2 response contributes to a marked suppression of cell-mediated immunity during sepsis, the mechanism by which this occurs remains unknown . Given that the mitogen-activated protein kinase (MAPK) p38 plays a critical role in the activation and function of immune cells, the aim of this study was to determine the contribution of MAPK p38 activation to the immune dysfunction seen in polymicrobial sepsis . To study this, polymicrobial sepsis was induced in C3H/HeN male mice by cecal ligation and puncture (CLP) . Splenic lymphocytes and purified T cells were harvested 24 h post-CLP, pretreated with the specific MAPK p38 inhibitor SB-203580, and then stimulated with a monoclonal antibody against the T cell marker CD3 . The results indicate that interleukin (IL)-2 release is markedly depressed while the release of the immunosuppressive mediator, IL-10, as well as mRNA levels of IL-10 and IL-4, are augmented after CLP . Inhibition of MAPK p38 suppressed in vitro IL-10 levels as well as IL-10 and IL-4 gene expression while restoring the release of IL-2 . To determine whether these in vitro findings could be translated to an in vivo setting, mice were given 100 mg of SB-203580/kg body wt or saline vehicle (intraperitoneal) at 12 h post-CLP . Examination of ex vivo lymphocyte responsiveness indicated that, as with the in vitro finding, septic mouse Th1 responsiveness was restored . In light of our recent finding that delayed in vivo SB-203580 treatment also improved survival after CLP, we believe that these results not only illustrate the role of MAPK p38 in the induction of immunosuppressive agents in sepsis but demonstrate that SB-203580 administration after the initial proinflammatory state of sepsis significantly prevents the morbidity from sepsis.

Shock, 2001 Jul, 16(1), 40 - 3
Progressive decrease in constrictor reactivity of the non-absorbing intestine during chronic sepsis; Zhao H et al.; Chronic sepsis leads to an impaired intestinal microcirculation, which might reflect altered microvascular control . We hypothesized that intestinal microvascular sensitivity to norepinephrine (NE) is decreased during chronic sepsis . Chronic sepsis was induced by a polymicrobial inoculation of implanted subcutaneous sponges in rats . Septic rats were studied either 24 or 72 h after a single inoculation (1-hit) of bacteria . Other rats received a second inoculation (2-hit) of bacteria 48 h later and were studied at 24 h after the second inoculation . NE (0.01-1.0 microM) responses in the non-absorbing terminal ileal arterioles (inflow A1, proximal-p and distal-d premucosal A3) were measured by video microscopy . NE threshold sensitivity (pD(T20) = -log of 20% response dose) was analyzed . pD(T20) was significantly decreased in A1, pA3, and dA3 of 1-hit 24-h septic rats (P < 0.05), and was further decreased in all vessels of 2-hit 72-h septic rats (P < 0.05) . In contrast, the pDT(T20) of all three vessels significantly returned toward normal values after 72 h in rats that had only 1 bacteria inoculation . We conclude that an initial bacterial challenge decreases vasoconstrictor reactivity of the intestinal microcirculation and that subsequent repeated bacterial challenge exacerbates this defect in vasoconstrictor control in the non-absorbing intestine.

Shock, 2001 Jul, 16(1), 33 - 9
Impairment of the ryanodine-sensitive calcium release channels in the cardiac sarcoplasmic reticulum and its underlying mechanism during the hypodynamic phase of sepsis; Dong LW et al.; Changes in Ca2+-induced Ca2+ release in cardiac sarcoplasmic reticulum (SR) during different phases of sepsis were studied . Sepsis was induced by cecal ligation and puncture (CLP) . The 45Ca2+ release studies show that the amount of Ca2+ released from the passively and the actively loaded SR vesicles was unaffected during the early sepsis (9 h after CLP), but it was significantly decreased during the late phase (18 h after CLP) of sepsis . The {3H}ryanodine binding assays reveal that the Bmax for ryanodine binding was unaffected during the early phase, but was decreased by 32.1% during the late phase of sepsis . The affinity of ryanodine receptor for Ca2+ remained unchanged during sepsis . ATP, AMP-PCP, and caffeine stimulated binding, while MgCl2 and ruthenium red inhibited {3H}ryanodine binding in control, early sepsis, and late sepsis groups . The EC50 and IC50 values for these regulators were unaffected during the progression of sepsis . Digestion of control SR with phospholipase A2 decreased {3H}ryanodine binding and the decrease was reversible by the addition of phosphatidylcholine (PC), phosphatidylethanolamine (PE), or phosphatidylserine (PS) . Addition of PC, PE, or PS to the SR isolated from septic rats stimulated {3H}ryanodine binding . These data demonstrate that Ca2+-induced Ca2+ release from cardiac SR remained relatively unaffected during the early phase, but was significantly impaired during the late phase of sepsis . The sepsis-induced impairment in SR Ca2+ release is a result of a quantitative reduction in the number of Ca2+ release channels . Furthermore, the reduction is associated with a mechanism involving a modification of membrane lipid profile in response to certain stimuli such as activation of phospholipase A2.

Shock, 2001 Jul, 16(1), 25 - 7
Possible role of TNF on procalcitonin release in a baboon model of sepsis; Redl H et al.; Procalcitonin (PCT) has been described as an early and discriminating marker of bacteria-associated sepsis in patients . However, little is known of its source and actions, especially with regard to its relation to tumor necrosis factor (TNF) . TNF is responsible for the release of several other mediators of sepsis e.g., chemokines . We tested the hypothesis that plasma PCT levels during sepsis differ with regard to the degree of TNF availability . Severe hyperdynamic sepsis was induced in baboons (n = 14) by i.v . infusion of live E . coli (approximately 2 x 10(9) colony-forming units/kg) over 2 h . Animals were pretreated 2 h before E . coli either with 1 mg/kg humanized anti-TNF antibody (CDP571) or placebo (Ringer solution) . Plasma PCT levels at baseline was barely detectable, but increased to about 4000 pg/mL at 4 h after E . coli infusion . Levels were maximal between 8 and 24 h and had returned nearly to baseline at 72 h . Although no TNF could be measured in the treated group, PCT levels were not different between the placebo and the TNF antibody treatment group . We conclude that PCT levels are not dependent on the systemic presence of TNF in an E . coli sepsis model in baboons . Such sepsis induced PCT release is clearly different from the previously reported PCT release during infusion of rhTNF in volunteers or chimpanzees.

J Immunol, 2001 Jul 15, 167(2), 1053 - 9
Adenoviral delivery of human and viral IL-10 in murine sepsis; Minter RM et al.; Adenovirus (Ad) gene therapy has been proposed as a drug-delivery system for the targeted administration of protein-based therapies, including growth factors and biological response modifiers . However, inflammation associated with Ad transduction has raised concern about its safety and efficacy in acute inflammatory diseases . In the present report, intratracheal and i.v . administration of a first-generation adenoviral recombinant (E1,E3 deleted) either containing an empty cassette or expressing the anti-inflammatory cytokines viral or human IL-10 (IL-10) was administered to mice subjected to zymosan-induced multisystem organ failure or to acute necrotizing pancreatitis . Pretreatment of mice with the intratracheal instillation of Ad expressing human IL-10 or viral IL-10 reduced weight loss, attenuated the proinflammatory cytokine response, and reduced mortality in the zymosan-induced model, whereas pretreatment with a control adenoviral recombinant did not significantly exacerbate the response . Pretreatment of mice with pancreatitis using adenoviral vectors expressing IL-10 significantly reduced the degree of pancreatic and liver injury and liver inflammation when administered systemically, but not intratracheally . We conclude that adenoviral vectors can be administered prophylactically in acute inflammatory syndromes, and expression of the anti-inflammatory protein IL-10 can be used to suppress the underlying inflammatory process.

Am J Surg, 2001 Apr, 181(4), 301 - 8
Limits of peritoneal cytokine measurements during abdominal lavage treatment for intraabdominal sepsis; Scheingraber S et al.; BACKGROUND: Monitoring of peritoneal cytokine concentrations of tumor necrosis factor (TNF)-alpha was recommended for early detection of severe postoperative complications . In the present study the clinical application of cytokine monitoring was examined in the treatment course of severe peritonitis . METHODS: Nineteen patients with secondary peritonitis were followed up during 75 abdominal lavages . Serum and peritoneal interleukin (IL)-6, IL-8, and IL-10 and TNF-alpha were measured before the surgical intervention, after 1 hour, 3 hours, 6 hours, and 24 hours . Additionally, cardiorespiratory parameters, osmolarity, C-reactive protein, and total leucocyte count were recorded . RESULTS: Serum and peritoneal cytokine concentrations did not correlate to each other as well as to the observed cardiorespiratory parameters . Peritoneal cytokine concentrations were 10- to 1000-fold higher to serum concentrations and showed an intermittent wash out . There were no differences in determined cytokine concentrations between survivors and nonsurvivors . CONCLUSIONS: Once elevated, peritoneal cytokine measurements offer no new diagnostic or prognostic tool in abdominal lavage peritonitis treatment.

Nippon Jinzo Gakkai Shi, 2001 May, 43(4), 362 - 6
{Tubulointerstitial nephritis in the case of acute renal failure from sepsis after a cat bite}; Aihara H et al.; Acute tubulointerstitial nephritis is associated with a variety of causes, such as drug interaction, and infectious or immunological mechanisms . We describe a patient who suffered from sepsis, septic shock, disseminated intravascular coagulation(DIC), hepatic failure and renal failure after receiving a bite from her house cat . The causes of her acute renal failure were initially thought to be due to circulatory failure with hypotensive shock, decrease in renal blood flow with fibrin formation by DIC, or microangiopathy such as hemolitic uremic syndrome . However, the renal biopsy on the 60th hospital day indicated tubulointerstitial nephritis, which was recognized by the presence of patchy and focal mononuclear small cell infiltration with invasion to the tubular epithelium . We concluded that prolonged renal failure was caused by tubulointerstitial nephritis . The cause of tubulointerstitial nephritis was not identified . Tubulointerstitial nephritis should be taken into consideration when the recovery from acute renal failure is slow.

Transpl Infect Dis, 1999 Sep, 1(3), 146 - 52
Low HLA-DR expression on peripheral blood monocytes predicts bacterial sepsis after liver transplantation: relation with prednisolone intake; Haveman JW et al.; Bacterial sepsis remains a frequent complication after liver transplantation . We previously reported the results of a pilot study that suggested that low expression of HLA-DR on monocytes is a predictive marker for the occurrence of sepsis . We have studied the value of this marker in an additional cohort of patients, and have analyzed the relation of HLA-DR expression with the use of immunosuppressive agents . 20 adult liver transplantation patients were prospectively monitored during the first 4 weeks after transplantation . All were treated according to standard protocols . The percentage of monocytes expressing HLA-DR was measured by flow cytometry . In addition, the effects of incubation of monocytes with prednisolone in vitro on the expression of HLA-DR was determined in 7 healthy volunteers . Seven patients developed bacterial sepsis after a median 15 (range 10-20) days after transplantation . HLA-DR expression was significantly lower in these patients on days 7, 14, 21, and 28 after transplantation compared with non-septic patients . The percentage of HLA-DR positive monocytes was 30% or less, 3 (1-8) days before onset of sepsis . On day 7 after transplantation, HLA-DR expression on 50% or less of monocytes had a positive predictive value for sepsis of 71%, whereas the negative predictive value was 85% . Patients who developed sepsis received significantly more prednisolone . Incubation with prednisolone in vitro lowered the expression of HLA-DR in a dose-dependent manner . We conclude that low HLA-DR expression on monocytes is a marker for a high risk of subsequent sepsis in liver transplantation patients . This high risk may be (at least partly) related to the dose of prednisolone.

Eur J Pediatr, 2001 Jun, 160(6), 345 - 50
Plasma levels of interleukin-6 and interleukin-10 in preterm neonates evaluated for sepsis; Romagnoli C et al.; In a prospective study, plasma interleukin-6 (IL-6) and interleukin-10 (IL-10) levels were measured by enzyme-linked immunosorbent assay in 45 premature neonates (25-34 weeks gestational age) with signs and symptoms of suspected sepsis at 0, 12 and 24 h; C-reactive protein (CRP) was measured at 0-24 h after enrolment . Six subjects were excluded due to insufficient blood sampling . The remaining 39 neonates were assigned to one of three groups: 25 newborns with sepsis (blood culture positive), seven with pneumonia (positive results on broncho-alveolar lavage fluid culture and characteristic chest radiography) and seven with necrotising enterocolitis (NEC) (characteristic intestinal and radiological signs according to the criteria of Bell et al.) . A group of 20 healthy preterm neonates represented control subjects . On admission, higher levels of IL-6, IL-10 and CRP were observed in neonates with sepsis: IL-6 (median 1500 pg/ml, range 487-10000 pg/ml), IL-10 (median 113 pg/ml, range 70-196 pg/ml), CRP (median 22 mg/l, range 4-80 mg/l); pneumonia: IL-6 (median 1500 pg/ml, range 747-8000 pg/ml, IL-10 (median 84 pg/ml, range 76-92 pg/ml), CRP (median 10 mg/l, range 8-33 mg/l) and NEC: IL-6 (median 6650 pg/ml, range 1595-7950 pg/ml), IL-10 (median 80 pg/ml, range 61-147 pg/ml), CRP (median 3 mg/l, range 2.8-8 mg/l) as compared to controls (IL-6 median 208 pg/ml, range 198-349 pg/ml; IL-10 median 36 pg/ml, range 19-50 pg/ml; CRP median < 2 mg/l) (P < 0.05) . In neonates with sepsis, IL-6 levels were significantly correlated with IL-10 levels (r = 0.65; P = 0.04) at the time of the second sample . The highest IL-6 levels were observed at onset, while IL-10 was predominant 12 h later . On admission, IL-10 and CRP levels were significantly higher in non-survivors (IL-10 median 507 pg/ml, range 422-753 pg/ml; CRP median 123 mg/l, range 20-219 mg/l) than in survivors (IL-10 median 76 pg/ml, range 61-143 pg/ml; CRP median 8 mg/l range 3-46 mg/l), while IL-10 levels were significantly higher (P < 0.05) also 12 h after admission (non-survivors: IL-10 median 600 pg/ml, range 538-800 pg/ml; survivors: IL-10 median 74 pg/ml, range 53-161 pg/ml) . IL-6 and IL-10 levels were significantly correlated with CRP levels on admission (r = 0.45; P = 0.05) . CONCLUSION: Preterm neonates with sepsis, pneumonia or necrotising enterocolitis showed increased interleukin-6, interleukin-10 and C-reactive protein levels . High interleukin-10 concentration was associated with mortality and could be an early indicator of prognosis.

Rev Med Chil, 2001 Apr, 129(4), 347 - 58
{Study of cytokines kinetics in severe sepsis and its relationship with mortality and score of organic dysfunction}; Dougnac A et al.; BACKGROUND: The Infectious Systemic Inflammatory Response syndrome and multiple organic dysfunction have common physiopathological mechanisms . Multiple organic dysfunction can be assessed using severity scores . AIM: To relate cytokine kinetics with a multiple organic dysfunction score during sepsis . MATERIAL AND METHODS: Tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL6) kinetics were studied in 25 patients with severe sepsis with less than 48 h of evolution and interleukin 1 beta (IL beta) kinetics was studied in 13 patients . Measurements were made at 0, 12, 24 and 48 hours after admission to the study, using an ELISA technique . These parameters were correlated with the Marshall multiple organic dysfunction score and survival . RESULTS: Mean age of study subjects was 70 years, the APACHE II score was 16.9 +/- 6 and the Marshall score was 6.8 +/- 3.6 . Sepsis was of pulmonary origin in 56% of patients and intra abdominal in 32% . Mortality was 36% . TNF alpha increased during the study period (24.1 pg/ml initially and 37.8 pg/ml at 24 hours, with a slight posterior reduction, p < 0.02) . These levels had no association with mortality or organic dysfunction . IL6 remained elevated during the first hours and had a tendency to decrease thereafter . Decreased patients had higher values than survivors (306 pg/ml and 55.4 pg/ml respectively, p = 0.011) . Its values were tightly correlated with Marshall score, with the number of failing organs, with the presence of shock and with probability of dying during hospitalization . IL1 beta remained low and was not associated with clinical parameters . CONCLUSIONS: There is a tight correlation between the elevation of IL6 and the severity of the Systemic Inflammatory Response and mortality in these patients with sepsis.

J Leukoc Biol, 2001 Jun, 69(6), 928 - 36
TSG-14 transgenic mice have improved survival to endotoxemia and to CLP-induced sepsis; Dias AA et al.; Tumor necrosis factor-stimulated gene 14 (TSG-14)/PTX3 was identified originally as a TNF-alpha and IL-1beta-stimulated gene from normal, human foreskin fibroblasts and vascular endothelial cells, respectively . TSG-14 gene encodes a 42-kDa-secreted glycoprotein with a carboxy-terminal half that shares homology with the entire sequence of C-reactive protein (CRP) and serum amyloid P component (SAP), acute-phase proteins of the pentraxin family . Some experimental evidence suggests that TSG-14 plays a role in inflammation, yet its function and mechanism of action remain unclear . We have generated transgenic mice that overexpress the murine TSG-14 gene under the control of its own promoter . From eight transgenic founders, two lineages were derived and better characterized: Tg2 and Tg4, carrying two and four copies of the transgene, respectively . TSG-14 transgenic mice were found to be more resistant to the endotoxic shock induced by LPS and to the polymicrobial sepsis caused by cecal ligation and puncture (CLP) . Moreover, macrophages derived from the transgenic mice produced higher amounts of nitric oxide in response to IFN-gamma, TNF-alpha, and LPS as compared with macrophages from wild-type animals, and the augmented response appears to be the consequence of a higher responsiveness of transgenic macrophages to IFN-gamma . The data shown here are the first in vivo evidence of the involvement of TSG-14 in the inflammatory process and suggest a role for TSG-14 in the defense against bacterial infections.

Eur Surg Res, 2001, 33(2), 71 - 6
Effect of CO2 pneumoperitoneum on the systemic and peritoneal cytokine response in a LPS-induced sepsis model; Matsumoto T et al.; We studied the effect of carbon dioxide (CO2) pneumoperitoneum on the systemic and peritoneal cytokine response in a rat model of intraperitoneal sepsis . After intraperitoneal injection of bacterial lipopolysaccharide (LPS, 10 mg/kg), rats were divided into 3 groups (n = 49 in each group): control (abdominal puncture); CO2 pneumoperitoneum, and laparotomy . Blood and peritoneal lavage fluid (PLF) were sampled at 0, 1, 2, 3, 4, 6, and 8 h after LPS challenge . Blood cell counts, plasma endotoxin level, and the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in the plasma and PLF were measured . Blood cell counts did not differ between the 3 groups . Plasma endotoxin levels in the pneumoperitoneum group were significantly increased immediately after the procedure (p < 0.05) . Although peak plasma TNF-alpha levels in the pneumoperitoneum group were seen immediately after the procedure, other changes in plasma cytokine levels did not differ significantly between the 3 groups . PLF TNF-alpha and IL-1beta levels in the pneumoperitoneum group were significantly lower than levels in the control and laparotomy groups soon after the procedure (p < 0.05) . PLF IL-6 levels in the pneumoperitoneum group tended to be lower than those in the laparotomy group . In conclusion, CO2 pneumoperitoneum might induce different responses between systemic and peritoneal cytokines soon after the procedure in a rat model of intraperitoneal sepsis .

ILAR J, 1999 Sep, 40(4), 142 - 150
New Frontiers in Cytokine Involvement during Experimental Sepsis; Steinhauser ML et al.; Despite significant advances in the antibiotic arsenal and in intensive care unit technology, including mechanical ventilation, sepsis-related morbidity and mortality remain unacceptably high . Ultimately, 25 to 50% of all septic episodes end in death . However, various subsets of septic patients, including those who experience septic peritonitis, and various secondary sequelae like the acute respiratory distress syndrome or nosocomial infections, demonstrate much higher mortality rates ranging from 60 to 95% . Although a number of strategies have been utilized to curb the progression of systemic inflammatory response syndrome with immune or inflammatory modulating therapies, none of these interventions has resulted in significant improvement in survival, and some have proven deleterious . The inability to utilize immune-modulating strategies effectively to treat septic patients likely reflects the inherent conflict that is illustrated by the two diagnostic criteria for the syndrome . The very immune/inflammatory response that has evolved to eliminate infection results in severe and life-threatening damage to host tissues . This review outlines the inflammatory pathways utilized by the host during a septic response . The basis of early immune-modulating therapies and possible reasons these approaches have failed in the treatment of sepsis are discussed . A picture of the ideal therapeutic approach for acute inflammatory diseases like sepsis is also created, and the reason therapies targeting chemokine pathways may more closely approximate the ideal therapy is proposed.

Cytokine, 2001 May 7, 14(3), 162 - 9
Gender differences in the inflammatory response and survival following haemorrhage and subsequent sepsis; Diodato MD et al.; Studies have shown gender dimorphism in cell-mediated immune responses following haemorrhage, with depressed responses in young males and maintained or enhanced responses in proestrus females . However, it remains unknown whether or not the sexually dimorphic immune response to haemorrhage provides any protection against a subsequent in vivo polymicrobial septic challenge . To study this, male and proestrus female C3H/HeN mice were subjected to haemorrhage (35+/-5 mmHg for 90 min followed by fluid resuscitation) or sham operation . Twenty-four hours thereafter, all mice were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) and survival was assessed over a 10 day period . Haemorrhage prior to CLP significantly increased mortality in males as compared to shams . In contrast, mortality in females following CLP was comparable between the sham and haemorrhage groups . Plasma levels of interleukin (IL-)6, tumour necrosis factor (TNF)-alpha and prostaglandin E(2)(PGE(2)) at 5 h after CLP were significantly increased in males subjected to prior haemorrhage . In contrast, plasma levels of IL-6 and TNF-alpha in females did not increase under such conditions . PGE(2)levels were comparable in males and females following CLP, however prior haemorrhage significantly reduced PGE(2)levels in females, whereas no change was observed in males . Liver and splenic expression of cyclooxygenase-2 protein paralleled the changes in plasma PGE(2) . Female sex hormones, therefore, appear to play an important role not only in maintaining immune function following haemorrhage, but also provide a survival advantage against subsequent septic challenge .

Contrib Nephrol, 2001, (132), 367 - 74
Extracorporeal blood purification therapy for sepsis and systemic inflammation: its biological rationale; Bellomo R et al.; EBPTs represent a promising new approach to the adjuvant treatment of severe sepsis, septic shock and MODS . Their technology is rapidly evolving and pilot animal and human studies are now taking place to prepare the territory for the first large randomized controlled trial . The rationale for EBPT is reasonable and the initial data are encouraging . The correct technology and molecular targeting, however, are still being explored . Once the best technology has been determined, it is likely that phase II and phase III trials will be performed to test the hypothesis that these therapies can indeed alter mortality in severe inflammatory multiorgan dysfunction.

Contrib Nephrol, 2001, (132), 354 - 66
Sepsis: a pro- and anti-inflammatory disequilibrium syndrome; Pinsky MR; Severe sepsis and probably most prolonged critical illnesses reflect a paradox of combined increased activation and depression of the immune apparatus . The increased activation of the inflammatory response is evidenced from the increased levels of circulating proinflammatory cytokines in the blood, increased endothelial activation with increased expression of inducible nitric oxide synthase, and increased de novo CD11b expression on circulating immune effector cells, such as PMNs, monocytes and lymphocytes . However, coexisting with this proinflammatory process is a profound anti-inflammatory state characterized by increased circulating levels of anti-inflammatory species that both directly block the binding of proinflammatory stimuli to their cell surface receptors (IL-1ra, soluble TNF receptors) and also induce an anti-inflammatory state on their own (IL-10, TFG-beta) . This humoral anti-inflammatory state is mirrored at the cellular levels by decreased monocyte ability to process antigen, characterized by a reduced HLA-DR expression and impaired PMN upregulation in response to clearly proinflammatory stimuli . Accordingly, severe sepsis reflects a combined pro- and anti-inflammatory state . Both the pro- and anti-inflammatory arms have protective and destructive aspects, making their modulation by treatment less predictable than if their actions were purely beneficial or detrimental.

Crit Care Med, 2001 Jun, 29(6), 1201 - 6
Glycine attenuates hepatocellular depression during early sepsis and reduces sepsis-induced mortality; Yang S et al.; OBJECTIVES: To determine whether administration of glycine, a nonessential amino acid, early after the onset of polymicrobial sepsis has any beneficial effects on hepatocellular function and the survivability of septic animals and, if so, whether the beneficial effects of glycine are associated with down-regulation of proinflammatory cytokine tumor necrosis factor-alpha production . DESIGN: Prospective, controlled, and randomized animal study . SETTING: A university research laboratory . SUBJECTS: Male adult rats were subjected to polymicrobial sepsis by cecal ligation and puncture or sham operation followed by the administration of normal saline solution . MEASUREMENTS AND MAIN RESULTS: At 1 hr after cecal ligation and puncture, glycine (0.6 mmol/kg) or vehicle (normal saline solution) was administered intravenously over 15 mins . At 5 hrs after cecal ligation and puncture (i.e., early stage of sepsis), hepatocellular function (i.e., the maximal velocity and efficiency of in vivo indocyanine green clearance) was determined and hepatocyte injury was assessed by measuring plasma concentrations of alpha-gluthathione S-transferase . Serum tumor necrosis factor-alpha was measured by enzyme-linked immunosorbent assay . In additional animals, the necrotic cecum was excised at 20 hrs after cecal ligation and puncture, the peritoneal cavity was irrigated with saline, and the midline incision was closed in layers . Mortality was monitored for 10 days thereafter . The results indicate that hepatocellular function was depressed in the early stage of sepsis (i.e., 5 hrs after cecal ligation and puncture) as indicated by significant decreases in both maximal velocity and transport efficiency of in vivo indocyanine green clearance . Plasma concentrations of alpha-gluthathione S-transferase and tumor necrosis factor-alpha were elevated significantly at that interval after cecal ligation and puncture . Administration of glycine 1 hr after cecal ligation and puncture, however, increased maximal velocity and maximal efficiency by 60% and 101% (p <.05), respectively . Glycine administration in septic animals decreased alpha-gluthathione S-transferase and tumor necrosis factor-alpha by 43% and 80% (p <.05) . In addition, glycine treatment decreased the mortality rate from 50% to 0% (p <.05) at 10 days after cecal ligation and puncture and cecal excision . CONCLUSIONS: It appears that the beneficial effect of glycine on hepatocyte function and integrity in sepsis may be mediated via down-regulation of tumor necrosis factor-alpha . Because administration of glycine attenuated hepatocellular depression and injury during early sepsis and decreased sepsis-induced mortality rates, this amino acid appears to be a useful adjunct for maintaining cellular functions and preventing lethality from polymicrobial sepsis.

Ceska Gynekol, 2000 Dec, 65 Suppl 1, 29 - 33
{Interleukin-6, procalcitonin, C-reactive protein and the immature to total neutrophil ratio (I/T) in the diagnosis of early-onset sepsis in low birth weight neonates}; Janota J et al.; OBJECTIVE: To determine the influence of early-onset neonatal sepsis on interleukin-6 (IL-6) and procalcitonin (PCT) levels in cord blood . To evaluate the significance of usually used infection markers--C-reactive protein (CRP) and immature to total neutrophil ratio (I/T)--and new markers (PCT, IL-6) for the diagnosis of early-onset neonatal sepsis . DESIGN: Prospective clinical study . SETTING: Institute for the Care of Mother and Child, Prague . METHODS: The serum levels of IL-6 and PCT were measured in cord blood in 37 low birht weight infants less than 35 week of gestation born in our institute . IL-6 and PCT levels were further evaluated together with CRP and I/T in neonatal blood within 2 hours after delivery . Neonatal sepsis within the first 72 hours of life was monitored . RESULTS: Differences in mean values of CRP, I/T, IL-6, and PCT between "sepsis proven" and "sepsis not proven" groups were not statistically significant . Only the difference between groups in cord blood PCT was of borderline significance (p = 0.06, higher in "sepsis proven" group) . Fisher test showed significant dependence on sepsis in cord blood PCT only (cut-off point 0.4 ng/ml, p < or = 0.05) . Other parameters did not show significant dependence on sepsis . Sensitivity for early onset sepsis above 50% was found in cord blood PCT only (sensitivity 60%, specificity 85.2%) . PCT predictive accuracy for sepsis expressed as AUC value was 0.74 +/- 0.06 . CONCLUSION: The only relatively sensitive marker and moderate predictor of early-onset sepsis in premature low birthweight infant was in our study cord blood PCT.

Mayo Clin Proc, 2001 Jun, 76(6), 653 - 6
Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept; Baghai M et al.; Patients with long-standing, severe, erosive rheumatoid arthritis who have extra-articular manifestations and have undergone joint replacement surgery are at increased risk for serious infection and premature mortality . New therapies, including cytokine antagonists, hold great promise for improving the course of rheumatoid arthritis . However, they have powerful anti-inflammatory effects that may mask symptoms of serious infection . We report a case of fatal pneumococcal sepsis occurring in a 37-year-old woman with rheumatoid arthritis treated with the tumor necrosis factor antagonist etanercept and suggest management strategies for early detection and management of this complication.

Curr Opin Pediatr, 2001 Jun, 13(3), 247 - 53
Pediatric sepsis and multiple organ dysfunction syndrome; Despond O et al.; Systemic inflammatory response syndrome may be viewed as the systemic expression of cytokine signals that normally function on an autocrine or paracrine level . Sepsis is defined as systemic inflammatory response syndrome caused by an infection . Multiple organ dysfunction syndrome may represent the end stage of severe systemic inflammatory response syndrome or sepsis . Many cells are involved, including endothelial cells and leukocytes and multiple proinflammatory and antiinflammatory mediators (cytokines, oxygen free radicals, coagulation factors, and so forth) . Various pathophysiologic mechanisms have been postulated . The most popular theory is that the inflammatory process loses its autoregulatory capacity; however, microcirculatory dysregulation and apoptosis may also be important, and a new paradigm posits a complex nonlinear system . Many new treatments have been studied recently . The usefulness of immune modulating diets remains to be evaluated . Molecular immunomodulation is still of unclear value . The therapy of sepsis and multiple organ dysfunction syndrome remains mainly supportive.

Crit Care, 2001, 5(2), S1 - 5
Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology; Vincent JL; Severe sepsis, defined as sepsis associated with acute organ dysfunction, results from a generalized inflammatory and procoagulant host response to infection . Coagulopathy in severe sepsis is commonly associated with multiple organ dysfunction, and often results in death . The molecule that is central to these effects is thrombin, although it may also have anticoagulant and antithrombotic effects through the activation of Protein C and induction of prostacyclin . In recent years, it has been recognized that chemicals produced by endothelial cells play a key role in the pathogenesis of sepsis . Thrombomodulin on endothelial cells coverts Protein C to Activated Protein C, which has important antithrombotic, profibrinolytic and anti-inflammatory properties . A number of studies have shown that Protein C levels are reduced in patients with severe infection, or even in inflammatory states without infection . Because coagulopathy is associated with high mortality rates, and animal studies have indicated that therapeutic intervention may result in improved outcomes, it was rational to initiate clinical studies.

Am Surg, 2001 May, 67(5), 484 - 6
Management of perianal sepsis in immunosuppressed patients; Munoz-Villasmil J et al.; Despite improvements in the supportive care of immunosuppressed patients controversy still surrounds the surgical management and outcome of anorectal sepsis in these patients . We reviewed 83 immunocompromised patients with diagnosis of perianal sepsis from 1995 to 1997 . Sixty-six patients (80%) were followed for a mean of 15 months . Mean age was 44 years and 76 per cent were males . Twenty-eight per cent were HIV+, 34 per cent had inflammatory bowel disease on steroids, 20 per cent had malignancies, and 18 per cent had diabetes . Twenty-eight per cent had anal fistula, 2 per cent had perianal abscess, and 40 per cent had both . Primary sites of fistula were: transsphincteric (38%), intersphincteric (33%), superficial (20%), and suprasphincteric (3%), and multiple tracks (6%) . Horseshoeing was present in 14 per cent of cases . The most commonly practiced surgical procedures were primary fistulotomy (n = 23) and fistulotomy plus drainage (n = 28) . Seven patients underwent fistulotomy and ostomy and eight patients were treated with fistulectomy plus drainage . Most wounds (91%) healed within 8 weeks . Incontinence (6%) and recurrence (7%) were the most commonly observed complications . These results are similar to those seen in the general population . Perianal sepsis can be safely managed in immunocompromised patients, with high rates of healing and low complication rates . An aggressive sphincter-preserving approach in the management of these patients may be undertaken.

Minerva Anestesiol, 2001 Apr, 67(4), 298 - 301
Microthrombosis in sepsis; Vallet B; Normal endothelial cells express several membrane components with anticoagulant properties, which include: 1) tissue factor pathway inhibitors (TFPI), i.e . surface molecules able to accelerate the action of antithrombin (AT) on coagulation proteases; 2) thrombomodulin (TM), a thrombin binding surface protein able to inhibit thrombin activity; the complex TM-thrombin, also, activates protein C (PC); 3) endothelium derived factors such as nitric oxide and prostacyclin, which have antiadhesive properties and activate plasminogen . Exposure to inflammatory and/or septic stimuli can rapidly lead to a procoagulant response, activated by bacterial endotoxins, and to a decrease of endothelial anticoagulant membrane components . Activation of coagulation concomitant to impaired fibrinolysis is associated with fibrin deposition, tissue ischemia and necrosis . This review presents the results of different strategies aimed at reducing organ dysfunction and mortality in septic shock by modulating coagulation activity . In various animal models and in phase II clinical studies, the treatment with TFPI, AT and activated PC reduced organ dysfunction and mortality . Two phase III trials showed no efficacy of AT and a reduction of the relative risk of death with activated PC . In animal studies, supplementation with l-arginine and administration of perindopril were able to prevent septic shock-associated endothelial injury . A marked reduction of endothelial injury and improved survival of treated animals were also seen with antiglycoprotein IIb/IIIa which attenuated the role of monocytes in the disseminated intravascular coagulation process.

Minerva Anestesiol, 2001 Apr, 67(4), 290 - 1
Cytopathic hypoxia in sepsis: a true problem?
Fink MP.
It is increasingly apparent that organ dysfunction in sepsis is caused, at least in part, by an acquired intrinsic derangement in cellular oxidative adenosine triphosphate (ATP) production . We have termed this phenomenon "cytopathic hypoxia" . Although several different but mutually compatible mechanisms might account for the development of cytopathic hypoxia in sepsis, recent data from our laboratory point to activation of the nuclear enzyme, poly-ADP-ribosyl polymerase (PARP), as being the most important.

Crit Care Med, 2001 Apr, 29(4), 880 - 6
New strategies for clinical trials in patients with sepsis and septic shock; Cohen J et al.; OBJECTIVE: The difficulty in identifying new treatment modalities that significantly reduce the mortality and morbidity rates associated with sepsis has highlighted the need to reevaluate the approach to clinical trial design . The United Kingdom Medical Research Council convened an International Working Party to address these issues . DATA SOURCES: The subject areas that were to be the focus of discussion were identified by the co-chairs, and group leaders were nominated . Preconference reading material was circulated to group members . STUDY SELECTION AND DATA EXTRACTION: Small-group discussion fed into an iterative process of feedback from plenary sessions, followed by the formulation of recommendations . Finally, each working group prepared a summary of its recommendations and these are reported herein . DATA SYNTHESIS: There were five key recommendations . First, investigators should no longer rely solely on the American College of Chest Physicians/Society of Critical Care Medicine definitions of sepsis or sepsis syndrome as the basis of trial entry . Entry criteria should be based on three principles: a) All patients should have infection; b) there should be evidence of a pathologic process that represents a biologically plausible target for the proposed intervention, for example, an abnormal circulating level of a biological marker pertinent to the study drug; and c) patients should fall into an appropriate category of severity (usually severe sepsis) . Second, investigators should use a scoring system for organ dysfunctions that has been validated and that can be incorporated into all sepsis studies; agreement on the use of a single system would simplify comparisons between studies . Third, the primary outcome measure generally should be mortality rates, but under appropriate circumstances major morbidities could be considered as primary end points . Regardless of choice of the duration to primary end point, patients should be followed for > or =90 days . Fourth, sample size needs to be based on a realistic assessment of achievable effect size based on knowledge of the at-risk population . Fifth, subgroups should be few in number and should be defined a priori on the basis of variables present before randomization . CONCLUSIONS: Important changes in several aspects of trial design may improve the quality of clinical studies in sepsis and maximize the chance of identifying effective therapeutic agents.

Crit Care Med, 2001 Apr, 29(4), 765 - 9
Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study; Reinhart K et al.; OBJECTIVE: This study investigated whether treatment with the anti-tumor necrosis factor-alpha monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL . DESIGN: Multicenter, double-blind, randomized, placebo-controlled study . SETTING: Eighty-four intensive care units in academic medical centers in Europe and Israel . PATIENTS: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations . Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222) . Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days . INTERVENTIONS: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days . Standard surgical and intensive care therapy was otherwise delivered . MEASUREMENTS AND MAIN RESULTS: The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met . The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p <.001) than that found in the randomized patients (55.8%, 249 of 446) . The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs . 57.7% (128 of 222), respectively . Treatment with afelimomab was not associated with any particular adverse events . CONCLUSIONS: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates . A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients . The treatment difference did not reach statistical significance.

Crit Care Med, 2001 Apr, 29(4), 728 - 36
Increased incidence of sepsis and altered monocyte functions in severely injured type A- glucose-6-phosphate dehydrogenase-deficient African American trauma patients; Spolarics Z et al.; OBJECTIVE: To determine whether trauma patients with the common, type A- glucose-6-phosphate dehydrogenase (G6PD) deficiency have an aggravated inflammatory response, increased incidence of septic complications, and/or more profound alterations in leukocyte functions compared with nondeficient trauma patients . SETTINGS: Intensive and surgical care units of a trauma center and flow cytometry and experimental laboratories at a teaching university hospital . DESIGN: Prospective cohort clinical study with measurements on days 2 and 5 postinjury . Monocyte and neutrophil oxidant content, apoptosis, and CD11b expression and plasma cytokine levels were compared between G6PD-deficient and nondeficient patients . PATIENTS: A total of 467 male African American trauma patients were screened for the deficiency . Forty-four type A-202/376 G6PD-deficient patients were identified and enrolled in the study; 43 nondeficient patients were also enrolled and were matched by age, clinical criteria of injury severity, and type of trauma . MAIN RESULTS: After severe injury (Injury Severity Score, > or =16), 50% of the deficient and 6.2% of nondeficient patients developed sepsis with positive bacterial blood cultures . In deficient patients, the frequency of bronchial (75%) and wound infections (25%) was also increased compared with nondeficient patients (32% and 0%) . The durations of systemic inflammatory response syndrome, Sepsis Syndrome, and days on antibiotics were three times longer in deficient than in nondeficient individuals . However, adult respiratory distress syndrome occurred in 37% of both groups . Anemia was more severe in the deficient than nondeficient patients from day 10 posttrauma . On day 5, the peroxide content was doubled, apoptosis was decreased, and CD11b expression was increased in monocytes from deficient patients compared with cells from nondeficient patients . On day 5, the plasma interleukin (IL)-10 concentration was significantly lower in deficient than nondeficient patients, whereas tumor necrosis factor-alpha, IL-6, and IL-8 levels were similar . After moderate injuries (Injury Severity Score, 9-16), the deficiency was not associated with adverse clinical effects, and the trauma-induced changes in leukocyte function were similar in deficient and nondeficient patients . CONCLUSIONS: The common type A- G6PD deficiency predisposes septic complications and anemia in trauma patients after severe injuries as defined by an Injury Severity Score of > or =16 . This adverse clinical course is accompanied by altered monocyte functions manifested as augmented oxidative stress, a decreased apoptotic response, increased cell adhesion properties, and a diminished IL-10 response.

Crit Care Med, 2001 Mar, 29(3), 618 - 22
Adrenal insufficiency during the late stage of polymicrobial sepsis; Koo DJ et al.; OBJECTIVES: Although studies have indicated that adrenal insufficiency occurs after severe trauma and hemorrhagic shock, it remains controversial whether adrenal function is depressed during the late stage of polymicrobial sepsis . DESIGN: Prospective, controlled animal study . SETTING: A university research laboratory . SUBJECTS: Male rats (275-325 g) were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) or sham operation followed by the administration of normal saline solution . MEASUREMENTS AND MAIN RESULTS: Systemic blood samples were taken at 20 hrs after CLP (i.e., a late stage of sepsis) or sham operation to measure plasma levels of corticosterone and corticotropin as well as adrenal contents of corticosterone . Additional groups of animals were utilized to examine corticotropin-stimulated plasma corticosterone release as well as adrenal levels of cyclic adenosine monophosphate (cAMP, the second messenger of corticotropin action) . The results indicate that despite a 75% (p < .05) higher concentration in plasma corticotropin at 20 hrs after the onset of sepsis, plasma corticosterone levels were similar to those in sham-operated animals . In addition, adrenal contents of corticosterone were reduced by 42% (p < .05) in septic animals . Moreover, the plasma corticosterone and adrenal cAMP responses to corticotropin were reduced by 53% and 27% (p < .05), respectively, at 20 hrs after CLP . CONCLUSIONS: These findings suggest that, despite high plasma levels of endogenous corticotropin, adrenal dysfunction, as indicated by the reduction of corticotropin-induced plasma corticosterone release and adrenal contents of cAMP as well as the decreased adrenal levels of corticosterone, occurs during the late stage of polymicrobial sepsis . Therefore, the recognition of adrenal insufficiency and interventions to improve adrenal responsiveness may be beneficial in improving the outcome during late sepsis.

Crit Care Med, 2001 Mar, 29(3), 473 - 81
Combination immunotherapy with soluble tumor necrosis factor receptors plus interleukin 1 receptor antagonist decreases sepsis mortality; Remick DG et al.; OBJECTIVE: Inhibition of tumor necrosis factor (TNF) or interleukin 1 (IL-1) alone has not improved sepsis survival in human clinical trials; therefore, it has been suggested that blockade of both may be successful . We tested whether combination immunotherapy would improve survival in mice subjected to a lethal lipopolysaccharide (LPS) challenge or the sepsis model of cecal ligation and puncture . DESIGN: Mice were treated with the combination immunotherapy and challenged with either a lethal dose of lipopolysaccharide or a septic challenge induced by cecal ligation and puncture . SETTING: University research laboratory . SUBJECTS: Adult, female Balb/c mice . INTERVENTIONS: Mice were treated with the combination of the IL-1 receptor antagonist plus a polyethylene glycol-linked dimer of the TNF soluble receptor . MEASUREMENTS AND MAIN RESULTS: LPS lethality was reduced in the treated mice with a decrease in biologically active TNF in the plasma and peritoneal fluid . In the cecal ligation and puncture (CLP) model of sepsis, this combination immunotherapy for 1 day decreased plasma and peritoneal levels of IL-6 and the murine chemokines KC and MIP-2 . However, treatment did not result in a reduction in the hypothermia or peripheral blood alterations that occur after CLP, and the 1-day therapy did not result in an improvement in survival . In contrast, when combination immunotherapy was extended to 3 days there was a significant improvement in survival . CONCLUSIONS: These data demonstrate that inhibition of both TNF and IL-1 will decrease the lethality of sepsis initiated by CLP if the combination immunotherapy is provided for a sufficient amount of time.

Thromb Haemost, 2001 May, 85(5), 810 - 20
Microparticles from patients with multiple organ dysfunction syndrome and sepsis support coagulation through multiple mechanisms; Joop K et al.; AIM: We investigated the occurrence and thrombin generating mechanisms of circulating microparticles (MP) in patients with multiple organ dysfunction syndrome (MODS) and sepsis . METHODS: MP, isolated from blood of patients (n = 9) and healthy controls (n = 14), were stained with cell-specific monoclonal antibodies (MoAbs) or anti-tissue factor (anti-TF) MoAb and annexin V, and analyzed by flow cytometry . To assess their thrombin-generating capacity, MP were reconstituted in normal plasma . The coagulation activation status in vivo was quantified by plasma prothrombin fragment F1+2- and thrombin-antithrombin (TAT) measurements . RESULTS: Annexin V-positive MP in the patients originated predominantly from platelets (PMP), and to a lesser extent from erythrocytes, endothelial cells (EMP) and granulocytes (GMP) . Compared to healthy controls, the numbers of annexin V-positive PMP and TF-exposing MP were decreased (p = <0.001 for both), EMP were decreased (E-selectin, p = 0.003) or found equal (CD144, p = 0.063), erythrocyte-derived MP were equal (p = 0.726), and GMP were increased (p = 0.008) . GMP numbers correlated with plasma concentrations of elastase (r = 0.70, p = 0.036), but not with C-reactive-protein or interleukin-6 concentrations . Patient samples also contained reduced numbers of annexin V-negative PMP, and increased numbers of erythrocyte-derived MP and GMP (p = 0.005, p = 0.021 and p <0.001, respectively) . Patient MP triggered thrombin formation, which was reduced compared to the healthy controls (p = 0.008) and strongly inhibited by an anti-factor XII MoAb (two patients), by anti-factor XI MoAb (eight patients) or by anti-TF MoAb (four patients) . Concentrations of F1+2 and TAT were elevated (p = 0.005 and p = 0.001, respectively) and correlated inversely with the number of circulating MP (and r = -0.51, p = 0.013, and r = -0.65, p = 0.001, respectively) and their thrombin generation capacity (F1+2: r= -0.62, p = 0.013) . CONCLUSIONS: In patients with MODS and sepsis relatively low numbers of MP are present that differ from controls in their cellular origin, numbers and coagulation activation mechanisms.

J Trauma, 2001 May, 50(5), 801 - 9
Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis; Ogura H et al.; BACKGROUND: Activated platelets have been recently reported to produce platelet microparticles and to enhance platelet-leukocyte interaction . The precise role of platelets in systemic inflammatory response syndrome (SIRS) has not been clarified . The objective of this study was to evaluate microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis . METHODS: Twenty-six patients with severe SIRS (SIRS criteria and serum C-reactive protein > 10 mg/dL) and 12 healthy volunteers were studied . The severe SIRS was caused by trauma in 12 patients and sepsis in 14 . Microparticle formation, P-selectin expression on platelets, platelet-monocyte binding, and platelet-polymorphonuclear leukocyte (PMNL) binding were measured by flow cytometry in the presence or absence of ionomycin, N-formyl-methionyl-leucyl-phenylalanine, or anti-CD62p monoclonal antibody . Soluble P-selectin, thrombomodulin, neopterin, and PMNL elastase in blood were also measured . RESULTS: Microparticle formation, P-selectin expression on platelets, platelet-monocyte binding with or without ionomycin, and platelet-PMNL binding with ionomycin significantly increased in patients with severe SIRS in comparison with values in normal volunteers . The increased platelet-leukocyte binding in severe SIRS patients was markedly inhibited by P-selectin blockade and was not enhanced by N-formyl-methionyl-leucyl-phenylalanine . Soluble P-selectin, thrombomodulin, neopterin, and PMNL elastase in blood also increased in these patients . CONCLUSION: Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis . Enhanced platelet-leukocyte interaction is dependent on P-selectin expression and may be involved in the systemic inflammatory response after severe inflammatory insult.

J Immunol, 2001 Jun 1, 166(11), 6952 - 63
Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans; Hotchkiss RS et al.; Patients with sepsis have impaired host defenses that contribute to the lethality of the disorder . Recent work implicates lymphocyte apoptosis as a potential factor in the immunosuppression of sepsis . If lymphocyte apoptosis is an important mechanism, specific subsets of lymphocytes may be more vulnerable . A prospective study of lymphocyte cell typing and apoptosis was conducted in spleens from 27 patients with sepsis and 25 patients with trauma . Spleens from 16 critically ill nonseptic (3 prospective and 13 retrospective) patients were also evaluated . Immunohistochemical staining showed a caspase-9-mediated profound progressive loss of B and CD4 T helper cells in sepsis . Interestingly, sepsis did not decrease CD8 T or NK cells . Although there was no overall effect on lymphocytes from critically ill nonseptic patients (considered as a group), certain individual patients did exhibit significant loss of B and CD4 T cells . The loss of B and CD4 T cells in sepsis is especially significant because it occurs during life-threatening infection, a state in which massive lymphocyte clonal expansion should exist . Mitochondria-dependent lymphocyte apoptosis may contribute to the immunosuppression in sepsis by decreasing the number of immune effector cells . Similar loss of lymphocytes may be occurring in critically ill patients with other disorders.

Am J Physiol Heart Circ Physiol, 2001 Jun, 280(6), H2848 - 56
Erythrocyte deformability is a nitric oxide-mediated factor in decreased capillary density during sepsis; Bateman RM et al.; Erythrocyte deformability has been recognized as a determinant of microvascular perfusion . Because nitric oxide (NO) is implicated in the modulation of red blood cell (RBC) deformability and NO levels increase during sepsis, we tested the hypothesis that a NO-mediated decrease in RBC deformability contributes to decreased functional capillary density (CD) in remote organs . With the use of a peritonitis model of sepsis in the rat {cecal ligation and perforation (CLP)} and aminoguanidine (AG) to prevent increases in NO, we measured CD in skeletal muscle (intravital microscopy), mean erythrocyte membrane deformability (; micropipette aspiration), systemic NO production {plasma nitrite/nitrate (NO(x)) chemiluminescence}, and NO accumulation in RBC {NO bound to hemoglobin (HbNO) detected by electron paramagnetic resonance spectroscopy} . In untreated CLP animals relative to sham, NO(x) increased 254% (P < 0.05), stopped flow capillaries increased 149% (P < 0.05), and decreased 12.7% (P < 0.05), with a subpopulation (5%) of RBC with deformabilities below the normal range . AG prevented increases in NO(x), accumulation of HbNO, and decreases in both and functional CD . We found no evidence of leukocyte plugging postcapillary venules . Our findings suggest that decreased functional CD during sepsis resulted from a NO-mediated decrease in erythrocyte deformability.

Int J Legal Med, 2001, 114(4-5), 291 - 4
Post-mortem markers of sepsis: an immunohistochemical study using VLA-4 (CD49d/CD29) and ICAM-1 (CD54) for the detection of sepsis-induced lung injury; Tsokos M et al.; The up-regulation of different adhesion molecules such as VLA-4 (CD49d/CD29) and ICAM-1 (CD54) on the pulmonary endothelium and leukocytes, is a key event in sepsis-induced lung injury leading to inflammatory tissue alterations . The value of VLA-4 and ICAM-1 as micromorphological post-mortem markers for the detection of sepsis-induced lung injury, was evaluated in a semiquantitative immunohistochemical study . VLA-4 was strongly expressed on intravascular, interstitial and intra-alveolar leukocytes in sepsis-associated fatalities, whereas in non-septic fatalities an irregular weak immunoreactivity was observed on interstitial leukocytes and no positive immunohistochemical expression was detected on intravascular or intra-alveolar leukocytes . ICAM-1 was strongly expressed on endothelial cells of the pulmonary microvasculature and on pulmonary macrophages and lymphocytes in sepsis-associated fatalities . In contrast, an infrequent weak immunohistochemical reaction for ICAM-1 was found on pulmonary endothelium and on perivascular leukocytes in non-septic fatalities . Based on the results of the present preliminary study, VLA-4 and ICAM-1 can be considered as useful immunohistochemical post-mortem markers of sepsis.

Int J Legal Med, 2001, 114(4-5), 237 - 43
Serum procalcitonin (PCT): a valuable biochemical parameter for the post-mortem diagnosis of sepsis; Tsokos M et al.; The aim of this prospective study was to investigate whether serum procalcitonin (PCT) can be used as a post-mortem marker of sepsis and to determine whether this biochemical parameter can be employed in the forensic elucidation of death due to sepsis . At least three blood samples were collected between 0.3 and 139 h post-mortem from sepsis-related fatalities (n = 8) and control individuals (n = 53, where death was due to various natural and unnatural causes) . Additionally one ante-mortem blood sample was collected shortly before death from the patients in the sepsis group . In the sepsis group, serum PCT concentrations, determined by using an immunoluminometric assay, were elevated in all patients for the whole observation period, whereas in the control group serum PCT was not detectable in 94% of the cases . Measurement of PCT levels seems reasonable until at least approximately 140 h postmortem, depending on the ante-mortem levels . A linear regression model is presented that allows the serum PCT concentration of an individual at the time of death to be estimated on condition that at least two positive post-mortem PCT values have been determined . Ante-mortem PCT values correlated well with the predicted PCT values at the time of death in the sepsis group using the standardized PCT logarithms . According to the results of the present study, PCT is a valuable biochemical parameter for the post-mortem discrimination between sepsis and underlying non-septic causes of death.

Ther Apher, 2001 Apr, 5(2), 123 - 7
Apheresis as therapy for patients with severe sepsis and multiorgan dysfunction syndrome; Stegmayr BG; Progressive multiorgan dysfunction syndrome may occur in the course of sepsis and septic shock as well as after various intoxications, pancreatitis, crush injuries, and major surgery . Despite conventional intensive care therapies, the prognosis in these patients is still poor . Apheresis, which uses more selective adsorption techniques, can lower the extent of toxins and cytokines in blood . This is achieved in clinical practice by, e.g., using polymyxin B as adsorbent . Although significantly lowered, the mortality is still about 50% with this technique . By unselective plasma exchange, the mortality is reduced down to 20 to 40% . A controlled and randomized study has shown a significant benefit . The centrifugation technique may be favorable over plasma filtration . Not only removal but also replacement with plasma seems important . In the future, probably selective techniques will be used in the early stages of sepsis while unselective plasma exchange may be useful in a disseminated situation.

Forensic Sci Int, 2001 Jun 1, 119(1), 47 - 56
Interleukin-6 and C-reactive protein serum levels in sepsis-related fatalities during the early postmortem period; Tsokos M et al.; Postmortem interleukin-6 (IL-6) and C-reactive protein (CRP) serum levels were investigated prospectively in sepsis-related fatalities and non-septic fatalities by using a linear regression model . At least three blood samples were collected between 0.3 and 139 h postmortem from sepsis-related fatalities (n=8) and non-septic fatalities (n=16) . In addition, one antemortem blood sample was collected shortly before death from the septic patients . Antemortem and postmortem IL-6 and CRP levels were highly elevated in all individuals included in the sepsis group . An excessive postmortem increase of IL-6 serum levels associated with progressive time after death was observed in five out of the eight septic patients . Both, IL-6 and CRP serum concentrations seem to be suitable biochemical postmortem markers of sepsis . The determination of IL-6 serum levels above 1500 pg/ml in peripheral venous blood obtained in the early postmortem interval can be considered as a diagnostic hint towards an underlying septic condition . A more precise postmortem discrimination between sepsis and non-septic underlying causes of death is provided by the postmortem measurement of serum CRP in peripheral venous blood: on condition that at least two postmortem CRP values have been determined at different time points postmortem, the CRP level of a deceased at the time of death can be calculated by using linear regression analysis . When assessing postmortem IL-6 and CRP concentrations as biochemical postmortem markers of sepsis, various clinical conditions, such as a preceding trauma or burn injury going along with elevated IL-6 and/or CRP levels prior to death as a result of the systemic inflammatory response syndrome (SIRS) should be taken into consideration, thus adding relevant information for the practical interpretation of the results.

Arch Immunol Ther Exp (Warsz), 2001, 49(2), 155 - 61
Proinflammatory cytokine inhibitors, TNF-alpha and oxidative burst of polymorphonuclear leukocytes in the pathogenesis of sepsis in newborns; Sikora JP et al.; This study was to evaluate the levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) and the cytokine inhibitors soluble TNF-alpha receptor (sTNFR) and interleukin (IL-1) receptor antagonist (IL-1ra), as well as the intensity of oxidative metabolism of peripheral blood polymorphonuclear leukocytes in the course of sepsis in newborns . An increase of TNF-alpha, sTNFR and IL-1ra concentrations was found in the blood serum of the patients at the time of diagnosis . This was further accompanied by polymorphonuclear leukocyte stimulation and, as a consequence of prolonged bacterial antigen stimulation, functional exhaustion of these cells and their diminished oxidative metabolism was observed . Within the same time period, an enhanced expression of p55 and p75 TNF-alpha receptors on polymorphonuclear leukocyte cell surfaces was found . It was indicated that the applied pharmacotherapy caused a decrease of the initially elevated concentrations of TNF-alpha and proinflammatory cytokine inhibitors (sTNFR, IL-1ra) . The intensive therapy of sepsis was associated with the increased oxidative burst of polymorphonuclear leukocytes along with the decrease of p55 and p75 expression on their cell surfaces.

Int J Surg Investig, 2000, 1(5), 365 - 71
Autologous blood transfusion as an immunomodulator in experimental sepsis; Sousa R et al.; BACKGROUND: Homologous blood transfusion is associated with immunosuppressive consequences . Some clinical and experimental studies have suggested an immunostimulating action of autologous blood transfusion . The aim of this paper is to ascertain the effects of either homologous blood transfusion or autologous blood transfusion on the lymphocyte subsets and cytokines in a model of intra-abdominal sepsis . MATERIALS AND METHODS: There were three study groups . Group A: 10 Wistar-Furth (WF) rats underwent cecal ligation and puncture (CLP) aimed at causing an intra-abdomial sepsis; Group B: 10 WF rats underwent CLP plus 1 ml homologous blood perioperative transfusion obtained from Fisher-344 rat while Group C: 10 WF rats underwent CLP plus 1 ml autologous blood perioperative transfusion . Changes of peripheral lymphocyte subsets, percentages of total T-lymphocytes (CD3), Helper T-lymphocytes (CD4), supressor/cytotoxic T-lymphocytes (CD8), CD4/CD8 ratio, Interleukin-2 receptor expression (IL-2R) and cytokines IL-1 and TNF-alpha were measured in peripheral blood on the preoperative, 1st, 3rd and 7th postsepsis (PO) days . RESULTS: Rats in homologous transfused group showed a decrease of %CD4 on the 3rd PO (from preoperative to 3rd PO;p < 0.01; and from 1st to 3rd PO; p < 0.05) and on the 7th PO (from preoperative to 7th PO; p < 0.05); %CD8 increased from preoperative to 3rd PO (p < 0.05), from 1st to 3rd PO (p < 0.01) and from 1st to 7th PO (p < 0.05) . An initial decrease on day 1 (p < 0.01) followed by an increase on the 3rd PO (p < 0.01) with regard to IL-2R and a significant increase of IL-1 levels within the first 24h (p < 0.01) . Rats in autologous transfused group showed an increase of %CD3 from preoperative to 7th PO (p < 0.05), and from 3rd to 7th PO (p < 0.01) . CONCLUSIONS: We observed that homologous blood transfusions induce a greater alteration in the cellular immune response and of the cascade of cytokines than autologous transfusions . This modulates the variations of the immune response induced by sepsis.

Anesteziol Reanimatol, 2001 Jan-Feb, (1), 51 - 3
{Choice of the optimal scale for evaluation of the severity of sepsis in children}; Mironov PI et al.; Quantitative assessment of the severity of clinical status was carried out and prognostic values of PRISM III, PRISM, SOFA, APACHE II scores and scores proposed by A . Castellanos et al . and K . L . Goitein was evaluated in 105 children (2 months-14 years) with sepsis . Clinical status evaluated in score during the first day of intensive care was correlated to the disease outcome . Sensitivity, specificity, expected values of positive and negative results were evaluated for each score and their discrimination capacity was assessed by ROC analysis . Use of quantitative scores (PRISM, PRISM III, SOFA, APACHE II, and A . Castellanos') is permissible for prospective evaluation of the efficiency of intensive care in children with sepsis, PRISM being the most informative.

Perfusion, 2001 Mar, 16(2), 113 - 20
Treatment of sepsis in cardiac surgery: role of immunoglobulins; Sablotzki A et al.; Cardiopulmonary bypass (CPB) is associated with an injury that may cause pathophysiological changes such as systemic inflammatory response syndrome, multiple organ dysfunction syndrome, and mediator-induced multiorgan failure . Systemic endotoxinaemia, release of proinflammatory cytokines, and interactions between neutrophils and endothelium have been reported to correlate with a high incidence of organ dysfunction, infection and sepsis following cardiac surgery . This review discusses the dysregulation of the immune response as a major reason for the higher susceptibility to infections following cardiac surgery, various treatment strategies to reduce CPB-induced inflammation, and especially the prophylactic use of immunoglobulins in cardiac surgery.

Am J Clin Nutr, 2001 May, 73(5), 908 - 13
Amino acid kinetics in patients with sepsis; Druml W et al.; BACKGROUND: In patients with sepsis and systemic inflammatory response syndrome, amino acid extraction by the liver is enhanced, resulting in decreased plasma amino acid concentrations . Systematic investigations of the elimination of intravenously infused amino acids have not been performed . OBJECTIVE: The objective of this study was to compare the elimination of 17 amino acids in patients with sepsis and in healthy control subjects . DESIGN: Elimination of amino acids was evaluated in 9 patients with sepsis and in 8 healthy control subjects by using a combined loading and maintenance infusion of 375 mg amino acids/kg body wt for 60 min . Pharmacokinetic variables were analyzed from plasma curves . RESULTS: With the exception of lysine, methionine, glutamate, ornithine, phenylalanine, and tyrosine, plasma concentrations of amino acids were lower in the patients with sepsis than in the control subjects; phenylalanine was the only amino acid whose plasma concentration increased (P < 0.001) . In patients with sepsis, whole-body clearance (Cl(tot)) of total amino acids was 74% higher than in control subjects (x +/- SEM: 13,161 +/- 1659 and 7566 +/- 91 mL/min, respectively; P < 0.01), the Cl(tot) of essential amino acids was 64% higher (P < 0.02), that of nonessential amino acids was 82% higher (P < 0.01), and that of both branched-chain amino acids and glucogenic amino acids was 97% higher (P < 0.001) . With the exception of phenylalanine, ornithine, proline, and glutamate, the Cl(tot) of all amino acids was elevated . The Cl(tot) of phenylalanine and ornithine decreased slightly (NS) . CONCLUSIONS: In patients with sepsis, plasma concentrations of most amino acids are greatly decreased and the elimination of amino acids from the intravascular space during intravenous infusion is greatly enhanced.

An Esp Pediatr, 2001 May, 54(5), 439 - 43
{Adrenal function in children with sepsis and septic shock}; Garcia Garcia E et al.; OBJECTIVES: To assess adrenal function in children with sepsis and septic shock with petechiae and to investigate the possible relationship between adrenal hypofunction, sonographic diagnosis of massive bilateral adrenal hemorrhage, and other factors available early in this disturbance . PATIENTS AND METHODS: Prospective observational study of 24 patients (14 boys, 10 girls), aged 2.9.24 years, admitted to the pediatric intensive care unit with sepsis and septic shock with petechiae during a 1.5-year period . The control group included 26 healthy children (13 boys, 13 girls), aged 8.8.6.4.2 years . Plasma cortisol and adrenocorticotropic hormone (ACTH) were measured by radioimmunoassay and adrenal ultrasonography was performed . RESULTS: Plasma cortisol and ACTH levels were 243.7 ng/ml and 135.0 pg/ml in the patient group and 145.4 ng/ml and 21.1 pg/ml in the control group (p<0.01 in both) . Adrenal insufficiency was found in four patients . Children with insufficiency more frequently required noradrenaline than did those with normal adrenal function (4/4 vs 2/20) . Necrotic purpura (2/4 vs 2/20), massive adrenal hemorrhage (2/3 vs 1/20), lower platelet count (69.500 vs 212.895/l), lower prothrombin activity (19.0 vs 49.2%), lower fibrinogenemia (51.2 vs 304,4 mg/dl), higher pediatric risk of mortality III (PRISM III) scores (11.7 vs 2.7) and higher mortality rate (3/4 vs 1/20) were found in children with adrenal insufficiency than in those with normal adrenal function . CONCLUSIONS: Plasma cortisol and ACTH levels were increased in children with sepsis and septic shock . Adrenal insufficiency was uncommon . Adrenal insufficiency was associated with severe hemodynamic failure, necrotic purpura, disseminated intravascular coagulopathy, massive bilateral adrenal hemorrhage and high mortality rate.

Pediatr Infect Dis J, 2001 Apr, 20(4), 439 - 42
Congenital tuberculosis presenting as sepsis syndrome: case report and review of the literature; Mazade MA et al.; We report an infant with congenital tuberculosis who presented with fulminant septic shock, disseminated intravascular coagulation and respiratory failure . Aggressive resuscitation and supportive care and prompt initiation of antituberculosis medications led to resolution of the shock state . We reviewed six other cases with a similar presentation . Congenital tuberculosis should be in the differential of the infant presenting acutely with sepsis syndrome.

Curr Opin Crit Care, 2000 Aug, 6(4), 253 - 266
Nutritional support in sepsis: still skeptical?
Nitenberg G.
The immediate metabolic response to a septic challenge is probably adaptive, meaning that nutritional interference, mainly via the parenteral route, during this early phase of instability can do more harm than good . During the later phases, a gradual increase in enteral nutrition, at the expense of parenteral nutrition, combined with the administration of nutraceuticals such as glutamine and omega-3 fatty acids, can counteract wasting and modulate the complex inflammatory response and immunosuppression associated with sepsis . In these times of scarce resources, there is an urgent need to clearly document the efficacy of immuno/pharmaconutrients, individually and in combination, enterally or parenterally, before proposing them for routine management of septic patients in the intensive care unit.

Curr Opin Crit Care, 2000 Aug, 6(4), 247 - 252
How to feed patients with sepsis; Hawker FH; Sepsis is associated with profound catabolism and hypermetabolism that complicate provision of nutritional support . These metabolic changes are caused by inflammatory mediators involved in the septic process and cannot be reversed by nutritional means . High protein isocaloric nutritional regimens are recommended if possible, in association with aggressive measures to control the sepsis . However, nutritional therapy and its complications may also affect the incidence and course of sepsis . Hyperglycemia and conventional intravenous fat emulsions have been shown to increase susceptibility to infection . Enteral nutrition is associated with fewer infectious complications than parenteral nutrition, at least in severely injured patients . Recently nutritional formulations have been introduced that contain novel substrates that enhance various aspects of immunity . Several studies have suggested that this immunonutrition reduces infection risk in the critically ill, and preliminary findings suggest it may even have an effect on survival in sepsis.

Vet Rec, 2001 Mar 24, 148(12), 376 - 80
Treatment of sepsis in the small tarsal joints of 11 horses with gentamicin-impregnated polymethylmethacrylate beads; Booth TM et al.; Gentamicin-impregnated polymethylmethacrylate beads were used to treat infective arthritis in the small tarsal joints of 11 severely lame horses . Under general anaesthesia, between five and 10 beads were placed into a 7 to 8 mm tract drilled across the affected joint and, in all except one horse, they were left in place for 14 days . Two of the horses were euthanased for reasons other than persistent tarsal joint sepsis, but the other nine survived and seven of them returned to their previous level of athletic performance.

Intensive Care Med, 2001, 27 Suppl 1, S116 - 27
Other supportive therapies in sepsis; Perez J et al.; Patients who survive the circulatory and organ deficits in sepsis may still fall victim to complications such as pulmonary embolism and stress ulcer bleeding . Although there is no clearcut evidence to quantitate the impact of such complications on mortality, the anticipated impact is grave when considering the compromised physiological reserve of these patients . For this reason it is important to institute effective prophylaxis to minimize the impact . In addition, catabolism associated with sepsis likely influences the recovery of patients with sepsis and moreover can compromise the response of the immune system against an infectious insult . Early and adequate nutritional support therefore appears important . There is much controversy and lack of prospective research regarding effect of supportive therapies on outcome in patients with severe sepsis . This research is needed.

Chemotherapy, 2001 May-Jun, 47(3), 194 - 202
Circulating tumor necrosis factor-alpha production during the progression of rat endotoxic sepsis; Xuan D et al.; The endotoxin-mediated tumor necrosis factor-alpha (TNF-alpha) induction was investigated in a rat endotoxin septic shock model . Rats were challenged intravenously with lethal doses of endotoxin . Circulating endotoxin and TNF-alpha concentrations were measured over various times following endotoxin administration . A derivative of human immunoglobulin G, 5S-IgG, was administered at various times relative to endotoxin dosing to test its anti-endotoxin activity . Results showed that endotoxin challenge initiated substantial amounts of TNF-alpha release into the rat circulatory system leading to death . A temporal pattern of TNF-alpha increases following endotoxin administration was observed; the rat plasma TNF-alpha level rapidly increased 60 min after endotoxin injection, peaked around 120 min and returned to low levels by 240 min . A rapid clearance pattern of endotoxin was also observed in rats . 5S-IgG exhibited its moderate anti-endotoxin activity by partially suppressing the endotoxin-mediated TNF-alpha release and decreasing the overall mortality only when given before triggering of TNF-alpha induction . However, this inhibitory effect of 5S-IgG on endotoxin-mediated TNF-alpha release and the resultant protective effect against endotoxin lethality rapidly diminished when 5S-IgG was administered after the occurrence of TNF-alpha induction . Collectively, these results suggest that the timing of the anti-endotoxin treatment is critical in achieving its effectiveness and imply that the endotoxin levels after the onset of the cytokine cascade is of questionable significance .

Ned Tijdschr Geneeskd, 2001 Mar 31, 145(13), 613 - 6
{Activated protein C, coagulation, inflammation, and treatment of severe sepsis}; van Deventer SJ et al.; During the past 20 years several treatments designed to reduce inflammatory responses to sepsis have been unsuccessful . Sepsis results from a generalised inflammatory and procoagulant response to an infection . Activated protein C, a component of the anticoagulant system, is an anti-thrombotic serine protease with anti-inflammatory properties . A recently published study reported the results of a large clinical trial in which recombinant human activated protein C significantly reduced mortality in patients with severe sepsis . Treatment with activated protein C also reduced circulating D-dimer and IL-6 levels, which are markers of coagulation activation and inflammation . There are several reasons why activated protein C could be effective in sepsis . Firstly, reduced levels of protein C are found during sepsis and are associated with an increased risk of death . Secondly, activated protein C can directly inhibit factors Va and VIIIa, resulting in decreased thrombin formation . Finally, activated protein C can reduce plasminogen activator inhibitor I, thereby stimulating fibrinolysis . In addition to these effects on thrombin formation, activated protein C directly reduces pro-inflammatory responses by as yet unknown mechanisms.

Ann Surg, 2001 Apr, 233(4), 581 - 7
Energy metabolism of infants and children with systemic inflammatory response syndrome and sepsis; Turi RA et al.; OBJECTIVE: To evaluate whether critically ill children with systemic inflammatory response syndrome (SIRS) or sepsis have altered resting energy expenditure (REE) and substrate utilization . SUMMARY BACKGROUND DATA: Studies in adults with sepsis have shown increased energy expenditure and mobilization of endogenous fat . In infants and children, energy metabolism and substrate utilization during sepsis have not been characterized . METHODS: Metabolic studies were performed in 21 critically ill children with SIRS or sepsis . Twenty-one stable control children, matched for weight, were also studied . Seven patients required inotropic support and 17 received mechanical ventilation . Fifteen patients with SIRS had evidence of bacterial, fungal, or viral infection and were considered septic . Respiratory gas exchange was measured by computerized indirect calorimetry for 1 to 2 hours continuously . RESULTS: The REE of patients with SIRS or sepsis was not different from that of controls . Similarly, there were no differences in carbon dioxide production and oxygen consumption . Resting energy metabolism was not different between patients with SIRS and patients with sepsis . In addition, the presence of low platelet count or inotropic support did not affect resting energy metabolism . The median respiratory quotient of patients with SIRS or sepsis was 0.88 (range 0.75-1.12), indicating mixed utilization of fat and carbohydrate; this was not significantly different from that of controls . The Pediatric Risk of Mortality Score was not significantly correlated with REE or respiratory quotient . CONCLUSIONS: The energy requirements of children with SIRS or sepsis are not increased . Their resting metabolism is based on both carbohydrate and fat utilization . The authors speculate that these children divert the energy for growth into recovery processes.

Tidsskr Nor Laegeforen, 2001 Mar 10, 121(7), 799 - 801
{Neuromuscular complications of sepsis}; Karlsen B et al.; BACKGROUND: Neuromuscular complications are common in patients treated for sepsis and multiple organ dysfunction in critical care units . Failure to wean from the ventilator, due to involvement of the respiratory system, and severe muscular weakness are typical symptoms . Electrophysiological examination demonstrates fibrillation potentials and reduction of compound muscular action potential amplitudes . MATERIAL AND METHODS: We report three patients with severe muscular weakness during treatment of critical illness . RESULTS: Critical illness polyneuropathy was the main cause of weakness in two patients, with a presumed superimposed myopathy in one . A third patient had critical illness myopathy . INTERPRETATION: Critical illness polyneuropathy and myopathy--either as separate or combined entities--are common causes of muscular weakness during treatment of critical illness . These disorders are often difficult to distinguish from each other, as the clinical and electrophysiological findings may overlap . Sepsis and multiple organ dysfunction are the main aetiological factors, but certain drugs may contribute in the pathogenesis . No specific treatment exists . In the most severe cases long-lasting physiotherapy and rehabilitation is needed.

Crit Care, 2001, 5 Suppl 2(2), S1 - 5 Epub 2001 Mar 08.
Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology; Vincent JL; Severe sepsis, defined as sepsis associated with acute organ dysfunction, results from a generalized inflammatory and procoagulant host response to infection . Coagulopathy in severe sepsis is commonly associated with multiple organ dysfunction, and often results in death . The molecule that is central to these effects is thrombin, although it may also have anticoagulant and antithrombotic effects through the activation of Protein C and induction of prostacyclin . In recent years, it has been recognized that chemicals produced by endothelial cells play a key role in the pathogenesis of sepsis . Thrombomodulin on endothelial cells coverts Protein C to Activated Protein C, which has important antithrombotic, profibrinolytic and anti-inflammatory properties . A number of studies have shown that Protein C levels are reduced in patients with severe infection, or even in inflammatory states without infection . Because coagulopathy is associated with high mortality rates, and animal studies have indicated that therapeutic intervention may result in improved outcomes, it was rational to initiate clinical studies.

Cytokine, 2001 Apr 7, 14(1), 37 - 48
IL-10 mediation of activation-induced TH1 cell apoptosis and lymphoid dysfunction in polymicrobial sepsis; Ayala A et al.; Recent studies suggest that increased activation-induced lymphocyte apoptosis (AICD) is detected in mouse splenocytes during polymicrobial sepsis which may contribute to lymphocyte immune dysfunction {i.e., decreased interleukin (IL-)2 and interferon-gamma (IFN-gamma) production} leading to the associated morbidity seen in those animals . Thus, we wanted to examine the hypothesis that immune suppressive agents, such as IL-4, IL-10 or prostaglandin E2(PGE2), known to be elevated in septic animals, also contribute to this increase in AICD . Here we demonstrate that the inclusion of monoclonal antibody (mAb) to IL-10, but not anti-IL-4 or ibuprofen (IBU), blunted this sepsis induced increase in splenocyte AICD . Additionally, septic mice deficient in the IL-10 gene product (-/-) showed neither an increase in AICD nor a loss of IL-2/IFN-gamma release capacity . Interestingly, mAb to IL-10 did not altered the extent of AICD in a Th2-cell line, but exogenous IL-10 did potentiate Th1-like cell line AICD . This was consistent with the finding that the increased AICD seen in septic mouse splenocytes was restricted largely to the CD4+ cells producing IL-2 (Th1-cells) and that mAb to IL-10 treatment suppressed this change . Furthermore, IL-10 appears to mediate its AICD effect by upregulation of the Fas receptor and Fas receptor signaling protein components, but not by altered expression of Bcl/Bax/Bad family members, in septic mouse splenocytes . To the extent that these processes contribute in a pathological fashion to the animal's capacity to survive sepsis we have previously observed that in vivo post-treatment of mice with mAb IL-10 markedly attenuated septic mortality . Collectively, these data indicate that in the septic mouse the Th2 cytokine IL-10 not only serves to actively induce Th1 lymphocyte immune dysfunction but also plays a role in their apoptotic depletion . These processes in turn appear to contribute to the animal's inability to ward off lethal septic challenge .

J Hepatobiliary Pancreat Surg, 2001, 8(1), 20 - 6
Sepsis and cholestasis: basic findings in the sinusoid and bile canaliculus; Hirata K et al.; It is well known that the liver plays a major role in the clearance of systemic toxemia and is postulated as a regulational organ in the host-defense system . The well-controlled interaction between hepatic parenchymal cells and sinusoidal lining cells including macrophages and Kupffer cells can systematically regulate even critical infections . However, when patients are under the overload condition caused by severe infection, rejection of a transplanted liver and other hapatic dysfunction often are experienced following surgery . Among various signs and symptoms of hepatic dysfunction, progressive cholestasis is recognized as a polarized representation of the irreversible changes in hepatic constitutional cellular functions, especially in hepatic parenchymal cells . Bile canaliculi, the smallest components of the biliary tree, lie between the apical surfaces of adjacent hepatocytes . Septic cholestasis might be a result of disturbance of the total bile canalicular system, i.e., bile secretion, canalicular contraction, and so on . Recently, the molecular biology of the hepatocellular transport system has become better understood, and the pathophysiological condition of cholestasis can be explained as a representation of the intracellular molecular transcriptional system . Cellular changes in surgical cholestasis and molecular findings concerning the bile canaliculus are introduced in this article.

FASEB J, 2001 Apr, 15(6), 879 - 92
Apoptosis in sepsis: a new target for therapeutic exploration; Oberholzer C et al.; The treatment of sepsis and septic shock remains a clinical conundrum, and recent prospective trials with biological response modifiers aimed at the inflammatory response have shown only modest clinical benefit . Recently, interest has shifted toward therapies aimed at reversing the accompanying periods of immune suppression . Studies in experimental animals and critically ill patients have demonstrated that increased apoptosis of lymphoid organs and some parenchymal tissues contributes to this immune suppression, anergy, and organ system dysfunction . During sepsis syndromes, lymphocyte apoptosis can be triggered by the absence of IL-2 or by the release of glucocorticoids, granzymes, or the so-called 'death' cytokines: tumor necrosis factor alpha or Fas ligand . Apoptosis proceeds via auto-activation of cytosolic and/or mitochondrial caspases, which can be influenced by the pro- and anti-apoptotic members of the Bcl-2 family . In experimental animals, not only can treatment with inhibitors of apoptosis prevent lymphoid cell apoptosis; it may also improve outcome . Although clinical trials with anti-apoptotic agents remain distant due in large part to technical difficulties associated with their administration and tissue targeting, inhibition of lymphocyte apoptosis represents an attractive therapeutic target for the septic patient.

Am J Physiol Gastrointest Liver Physiol, 2001 May, 280(5), G968 - 73
Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats; Weiss YG et al.; Sepsis is the leading cause of death in surgical intensive care units . Although both mild sepsis secondary to cecal ligation and single puncture (CLP) and fulminant, double puncture CLP (2CLP) may provoke hepatocyte death, we hypothesize that regeneration compensates for cell death after CLP but not 2CLP . In male Sprague-Dawley rats, hepatic necrosis, as determined by serum alpha-glutathione S-transferase (alpha-GST) levels, was significantly but equally elevated over time after both CLP and 2CLP . Apoptosis, evaluated using both terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and morphological examination, was minimal after both CLP and 2CLP . Regeneration, assayed by staining tissue for incorporation of exogenously administered bromodeoxyuridine, was present after CLP but not after 2CLP . To further substantiate impaired regeneration, steady-state levels of mRNAs encoding JunB, LRF-1, and cyclin D1 were determined . After 2CLP, the absence of JunB, LRF-1, and cyclin D1 mRNAs confirmed failed activation of the mitogen-activated protein kinase-linked proliferative pathway and progression through the cell cycle . Therefore, failed hepatocyte regeneration may be a manifestation of hepatic dysfunction in fulminant sepsis.

Am J Physiol Gastrointest Liver Physiol, 2001 May, 280(5), G812 - 8
Increased apoptosis in lamina propria B cells during polymicrobial sepsis is FasL but not endotoxin mediated; Chung CS et al.; Recent studies from our laboratory demonstrated that mucosal lymphoid tissue such as Peyer's patch cells and lamina propria (LP) B lymphocytes from mice shows evidence of increased apoptosis after sepsis that is associated with localized inflammation/activation . The mechanism for this is poorly understood . Endotoxin as well as Fas/Fas ligand (FasL) have been shown to augment lymphocyte apoptosis; however, their contribution to the increase of apoptosis in LP B-cells during sepsis is not known . To study this, sepsis was induced by cecal ligation and puncture (CLP) in endotoxin-tolerant C3H/HeJ or FasL-deficient C3H/HeJ-FasL(gld) (FasL(-)) mice and LP lymphocytes were isolated 24 h later . Phenotypic, apoptotic, and functional indexes were assessed . The number of LP B cells decreased markedly in C3H/HeJ mice but not in FasL-deficient animals at 24 h after CLP . This was associated with comparable alteration in apoptosis and Fas antigen expression in the B cells of these mice . Septic LP lymphocytes also showed increased IgA production, which was absent in the FasL-deficient CLP mice . Furthermore, Fas ligand deficiency appeared to improve survival of septic challenge . These data suggest that the increase in B cell apoptosis in septic animals is partially due to a Fas/FasL-mediated process but not endotoxin.

Clin Liver Dis, 1999 Aug, 3(3), 465 - 75
Sepsis and cholestasis; Moseley RH; Sepsis-associated cholestasis should always be considered as part of the differential diagnosis of jaundice in the hospitalized or critically ill patient . The development of a disproportionate elevation of serum bilirubin in comparison with serum alkaline phosphatase and serum aminotransferases should be considered an early warning sign of an underlying infection, even in the absence of fever, leukocytosis, or other signs or symptoms . Prompt recognition and appropriate medical and surgical intervention may reduce morbidity and mortality.

Lancet, 2001 Mar 24, 357(9260), 911 - 6
Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study; Schortgen F et al.; BACKGROUND: Hydroxyethylstarch used for volume restoration in brain-dead kidney donors has been associated with impaired kidney function in the transplant recipients . We undertook a multicentre randomised study to assess the frequency of acute renal failure (ARF) in patients with severe sepsis or septic shock treated with hydroxyethylstarch or gelatin . METHODS: Adults with severe sepsis or septic shock were enrolled prospectively in three intensive-care units in France . They were randomly assigned 6% hydroxyethylstarch (200 kDa, 0.60-0.66 substitution) or 3% fluid-modified gelatin . The primary endpoint was ARF (a two-fold increase in serum creatinine from baseline or need for renal replacement therapy) . Analyses were by intention to treat . FINDINGS: 129 patients were enrolled over 18 months . Severity of illness and serum creatinine (median 143 {IQR 88-203} vs 114 {91-175} micromol/L) were similar at baseline in the hydroxyethylstarch and gelatin groups . The frequencies of ARF (27/65 {42%} vs 15/64 {23%}, p=0.028) and oliguria (35/62 {56%} vs 23/63 {37%}, p=0.025) and the peak serum creatinine concentration (225 {130-339} vs 169 {106-273} micromol/L, p=0.04) were significantly higher in the hydroxyethylstarch group than in the gelatin group . In a multivariate analysis, risk factors for acute renal failure included mechanical ventilation (odds ratio 4.02 {95% CI 1.37-11.8}, p=0.013) and use of hydroxyethylstarch (2.57 {1.13-5.83}, p=0.026) . INTERPRETATIONS: The use of this preparation of hydroxyethylstarch as a plasma-volume expander is an independent risk factor for ARF in patients with severe sepsis or septic shock.

Clin Microbiol Infect, 2000 Dec, 6(12), 657 - 60
Changes in lymphocyte subpopulations and CD3+/DR+ expression in sepsis; Holub M et al.; OBJECTIVE: To detect lymphocyte subpopulations and CD3+/DR + expression in sepsis . METHODS: In a prospective clinical study we evaluated subpopulations of lymphocytes and percentage of CD3+/HLA-DR+ lymphocytes using two-color flow cytometry in 40 patients with sepsis and compared them with 34 healthy adults . RESULTS: Septic patients, when compared with healthy controls, have significantly lower percentage and absolute numbers of total T lymphocytes and CD4 T lymphocytes (P < 0.01) . Absolute numbers of CD8 T lymphocytes, NK cells, CD3+/DR + lymphocytes and CD4/CD8 ratio were also decreased (P < 0.01) . The percentage of B lymphocytes was increased (P < 0.01) . CONCLUSION: Our results are in agreement with previous findings in patients with sepsis after major surgery or trauma . The decreases in the percentage and absolute numbers of circulating lymphocyte subsets in non-surgical sepsis could represent a general reaction to stress . Increased percentage of B lymphocytes is most probably related to the bacterial etiology of the disease.

South Med J, 2001 Mar, 94(3), 350 - 2
Newly diagnosed human immunodeficiency virus after sepsis-like reaction of trimethoprim-sulfamethoxazole; Moran KA et al.; A rare sepsis-like hypersensitivity reaction has been observed in persons with human immunodeficiency virus (HIV) after exposure to trimethoprim-sulfamethoxazole . This reaction most commonly occurs on rechallenge with the drug and is manifested by a syndrome resembling bacterial sepsis . The mechanism of this unusual reaction remains unclear . We describe the first case in which this severe hypersensitivity reaction was the initial manifestation of HIV.

Bone Marrow Transplant, 2001 Jan, 27(2), 217 - 8
Fatal sepsis due to mycobacterium tuberculosis after allogeneic bone marrow transplantation; Kindler T et al.; Mycobacterium tuberculosis is a serious, but rare infectious complication after allogeneic bone marrow transplantation . We describe a case of fatal sepsis due to Mycobacterium tuberculosis after allogeneic bone marrow transplantation for Philadelphia chromosome-positive ALL . The diagnosis was made after BAL . Although broad-spectrum antituberculous therapy was started immediately after diagnosis, blood cultures became positive for Mycobacterium tuberculosis . The patient developed severe pyrexias and finally died of multi-organ failure . Rapid progression of mycobacterial infection should be considered in patients post BMT with unexplained fever, particularly in patients from endemic areas.

Intensive Care Med, 2001 Jan, 27(1), 211 - 5
Comparison of procalcitonin with C-reactive protein and serum amyloid for the early diagnosis of bacterial sepsis in critically ill neonates and children; Enguix A et al.; OBJECTIVES: To evaluate procalcitonin (PCT) as a diagnostic marker of bacterial sepsis in critically ill neonates and children and to compare the results of PCT with those of C-reactive protein (CRP) and serum amyloid (SAA) . DESIGN AND SETTING: Prospective, observational study in neonatal and pediatric intensive care units . PATIENTS: A total of 116 divided into four groups according to age and diagnosis: neonates (aged 3-30 days) with sepsis (n = 20), neonates without sepsis (n = 26), children (aged 2-12 years) with sepsis (n = 32), and children without sepsis (n = 38) . INTERVENTIONS: Serum PCT, CRP, and SAA were measured on admission or when a bacterial sepsis was suspected . Area under the receiver operating characteristic (ROC) curve, optimum predictive values, and optimum diagnostic cut off values were evaluated . RESULTS: Admission PCT was significantly higher in neonates and children with sepsis than in the other groups . In the neonates the area under the ROC curve was 0.99 for PCT, 0.95 for CRP, and 0.98 for SAA; in the children it was 1 for PCT, 0.93 for CRP, and 0.96 for SAA . Cutoff concentrations for optimum prediction of sepsis in the neonates were PCT > 6.1 ng/ml (diagnostic efficiency: 93.8%), CRP > 23.0 mg/l (89.7%), and SAA > 41.3 mg/l (95.3%); in the children they were PCT > 8.1 ng/ml (100%), CRP > 22.1 mg/l (89.8%), and SAA > 67.2 mg/l (94.4%) . CONCLUSION: In critically ill children PCT concentration is a better diagnostic marker of sepsis than CRP and SAA . In critically ill neonates, however, PCT, CRP, and SAA are similar diagnostic markers of sepsis . A PCT concentration higher than 8.1 ng/ml identified all children with bacterial sepsis.

Anesth Analg, 2001 Apr, 92(4), 959 - 66
ONO1714, a new inducible nitric oxide synthase inhibitor, attenuates sepsis-induced diaphragmatic dysfunction in hamsters; Nishina K et al.; Sepsis causes impairment of diaphragmatic contractility and endurance capacity . Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in the pathogenesis . Peroxynitrite, a NO-derived powerful oxidant, may be responsible for infection-induced diaphragmatic muscle failure . Therefore, we examined whether ONO1714, a new selective iNOS inhibitor, prevents sepsis-induced diaphragmatic dysfunction . Fifty male Golden-Syrian hamsters were randomly divided into five groups: hamsters that underwent sham laparotomy alone and received saline injection (Group Sham), those that underwent cecal ligation with puncture (CLP) and received saline injection (Group Sepsis), those that underwent sham laparotomy and received injection of ONO1714 0.3 mg/kg (Group Sham-ONO1714high), those that underwent CLP and received ONO1714 0.1 mg/kg (Group Sepsis-ONO1714low), and those that underwent CLP and received ONO1714 0.3 mg/kg (Group Sepsis-ONO1714high) . ONO1714 or saline was intraperitoneally injected 10 min before surgery . Diaphragmatic contractility was assessed in vitro using diaphragm muscle strips excised 24 h after operation . Diaphragm fatigability was assessed by time until tension decreased to 50% of the initial value (T50%) during fatigue trials . Twitch, tetanic tensions, and T50% during fatigue trials were reduced in Group Sepsis . Pretreatment with ONO1714 dose-dependently attenuated sepsis-induced diaphragmatic contractile profiles and endurance capacity . CLP increased plasma nitrite/nitrate (NOx; stable NO metabolites), and diaphragm malondialdehyde (MDA; a product of lipid peroxidation), positive immunostaining for nitrotyrosine (peroxynitrite footprint), and iNOS activity . ONO1714 attenuated the increase . This beneficial effect of ONO1714 may be attributable, in part, to inhibition of peroxynitrite-induced lipid peroxidation in the diaphragm . IMPLICATIONS: Sepsis impairs diaphragmatic contractility and endurance capacity, which may be involved in acute respiratory failure . Pretreatment with ONO1714, a new selective inducible nitric oxide synthase inhibitor, attenuated sepsis-induced diaphragmatic dysfunction in hamsters.

Intensive Care Med, 2000 Dec, 26(12), 1786 - 93
Comparison of Sepsis-related Organ Failure Assessment (SOFA) score and CIS (cellular injury score) for scoring of severity for patients with multiple organ dysfunction syndrome (MODS); Oda S et al.; OBJECTIVE: To evaluate the usefulness of cellular injury score (CIS) and Sepsis-related Organ Failure Assessment (SOFA) score for determination of the severity of multiple organ dysfunction syndrome (MODS) . DESIGN: A prospective observational study . SETTING: A medical and surgical intensive care unit (ICU) of a teaching hospital . Patients: Forty-seven consecutive MODS patients . MEASUREMENTS AND RESULTS: SOFA score and CIS were measured every day for 12 months for 47 MODS patients . Comparison was made of the SOFA score and CIS for usefulness in the scoring of severity of MODS in 26 survivors and 21 non-survivors . In addition, receiver operating characteristics (ROC) analysis was used to determine the usefulness of these two indexes as predictors of prognosis . No significant differences were found on admission between the survivors and non-survivors, but significant differences between the two subgroups (p < 0.001) were found in maximum value within 1 week after admission and maximum value during the course of treatment for both indexes . Analysis of changes after admission indicated that significant differences between survivors and non-survivors began to appear on day 3 of admission for both indexes; at that time SOFA score began to deteriorate in the non-survivors while CIS began to improve in the survivors . ROC analysis demonstrated that the area under the ROC curve was 0.769 for SOFA scores and 0.760 for CIS . CONCLUSIONS: Both SOFA score and CIS sequentially reflected the severity of MODS . Furthermore, they were comparable in diagnostic value as predictors of prognosis . These findings may indicate the possibility that MODS is a summation of effects of cellular injury . In addition, sequential evaluation of both SOFA score and CIS would provide a more accurate prediction of prognosis than conventional methods.

Am Surg, 2001 Mar, 67(3), 253 - 5; discussion 255-6
The effects of triiodothyronine augmentation on antithrombin III levels in sepsis; Chapital AD et al.; Sepsis and multisystem organ failure are often associated with disseminated intravascular coagulation and consumption of coagulation inhibitors such as antithrombin III (ATIII) . The "sick euthyroid syndrome" is also seen in association with significant illnesses and consists of decreased levels of circulating triiodothyronine (T3) . We evaluated whether T3 supplementation would affect ATIII levels in septic rats . Thirty Sprague-Dawley rats were divided into three groups: sham laparotomy (S) plus saline, cecal ligation and puncture (CLP) plus saline, and CLP plus T3 (3 ng/hour) via an osmotic minipump . Twenty-four hours after laparotomy blood was drawn, and T3 and ATIII levels were then compared with baseline values . T3 supplementation partially negated the sepsis-induced decrease in circulating T3 levels . The levels are expressed as percentage change from the levels before surgery (S, -12.9 +/- 3.1; CLP, -60.0 +/- 5.3; CLP + T3, -34.9 +/- 4.3; mean +/- standard error; P < 0.05) . T3 supplementation also statistically changed the percentage difference in ATIII levels toward the control (S, 9.6 +/- 2.8; CLP, -37.9 +/- 5.4; CLP + T3, -16.0 +/- 4.5; mean +/- standard error; P < 0.01) . T3 supplementation reduced the sepsis-induced decrease in ATIII levels . Whether this was accomplished by decreased consumption or increased production of ATIII via the direct anabolic effect of T3 on acute-phase protein synthesis in the liver is unknown and warrants further investigation.

J Trauma, 2001 Mar, 50(3), 510 - 5
Objective estimates of the incidence and consequences of multiple organ dysfunction and sepsis after burn trauma; Cumming J et al.; BACKGROUND: Organ dysfunction and sepsis are frequent after major burn trauma, represent quantifiable consequences of the systemic response to injury, and may be important end points by which to measure treatment effectiveness . However, standard and widely applied methods for their measurement have not been applied to burn trauma victims . Therefore, the purpose of this study was to quantify these complications after burn trauma . METHODS: Patients with > or = 20% total body surface area burns admitted to a single center were prospectively enrolled . Standard sepsis criteria and multiple organ dysfunction (MOD) scores for the pulmonary, renal, cardiovascular, hepatic, and hematologic systems were determined . The incidence and risk factors for severe MOD (cumulative MOD score > or = 6) and severe sepsis were determined . The relationships between these complications and mortality and resource utilization were examined by univariate and multivariate analyses . RESULTS: A total of 85 patients were enrolled over 1 year . Severe MOD developed in 24 (28%) and severe sepsis or septic shock developed in 12 (14%) . Both were associated with increasing age and burn size and were more likely to occur in men . Most patients who developed severe MOD or severe sepsis survived (71% and 67%, respectively), and both were associated with longer intensive care unit stays and duration of mechanical ventilation . CONCLUSION: According to simple and objective scoring systems, severe MOD and severe sepsis/septic shock are both related to burn size, age, and male sex . Both are related to intensive care unit length of stay and duration of mechanical ventilation.

Zhonghua Zheng Xing Shao Shang Wai Ke Za Zhi, 1999 Jan, 15(1), 49 - 52
{Experimental study on the mechanisms of enhancement of aerobic glycolysis of muscles in burns and sepsis--the verification of the existence and the enhancement of the aerobic glycolysis of muscles in early postburn period and sepsis}; Chai J et al.; OBJECTIVE: To verify if aerobic glycolysis exists in the muscle cells in normal rats and to analyze the changes in aerobic glycolysis in the muscle cells in the early postburn period and in septic states . METHOD: Using septic model of rats, we established the in vitro muscle incubation system with sufficient oxygen supply as well as the NADH fluoremetric method for the detection of trace amount of lactate in the samples . Extensor digitorium longus (EDL) and soleus muscles which represent two types of muscle fiber were studied . RESULTS: In the early postburn period as well as in septic states, the lactate production of muscle cells was significantly elevated as compared to the normal controls even though the muscles were incubated in a fully oxygenated media . The levels of aerobic glyoclysis, as well as its changes in postburn period and in septic states, vary depending on the difference in the fiber composition of the muscles . CONCLUSION: Muscle cells might develop a kind of metabolic enhancement which is referred to as aerobic glycolysis rather than the metabolic defect which results from tissue hypoperfusion and hypoxia in the early postburn period as well as in septic states . This provides us a special insight to elucidate the mechanisms of the metabolic derangement in the early postburn period and in sepsis.

Anaesth Intensive Care, 2001 Feb, 29(1), 54 - 7
Acute haemorrhagic leucoencephalitis complicating sepsis; Tanser SJ et al.; A case of acute haemorrhagic leucoencephalitis presenting as fatal septic encephalopathy is reported . The clinical features of this condition are reviewed and the potential for earlier diagnosis is considered.

Clin Pediatr (Phila), 2001 Feb, 40(2), 71 - 7
An examination of the unintended consequences of the rule-out sepsis evaluation: a parental perspective; Paxton RD et al.; In order to document unintended consequences of the "rule-out" sepsis (ROS) evaluation, a survey of parents of infants who had undergone such an evaluation at Primary Children's Medical Center in 1997 was conducted . Sixty parents were interviewed . Parental perceptions of the sepsis evaluation and its impact on their families were recorded . Specific data evaluated included parental anxiety, impact on breastfeeding, perceived complications, financial stress, and parental preferences . The majority of parents found the ROS evaluation very stressful . Parental perception of illness increased significantly after being told the infant would require an ROS evaluation, with nearly 30% of parents, after speaking with a physician, believing their infant might die . Breastfeeding problems were reported by 36% of the mothers . Iatrogenic complications were reported by 33% . Although all infants were covered by some form of insurance, 43% of parents reported financial stress . Forty-two percent of parents would have preferred to be treated at home and all parents would prefer an evaluation that could be accomplished in 24 hours . We conclude that unintended consequences of the ROS evaluation included excessive parental anxiety, cessation of breastfeeding, iatrogenic complications, and financial stress . Suggestions to decrease these adverse consequences are given.

Nat Immunol, 2000 Jul, 1(1), 42 - 6
Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2; Nagase T et al.; Adult respiratory distress syndrome (ARDS) is characterized by acute lung injury with a high mortality rate and yet its mechanism is poorly understood . Sepsis syndrome and acid aspiration are the most frequent causes of ARDS, leading to increased lung permeability, enhanced polymorphonuclear neutrophil (PMN) sequestration and respiratory failure . Using a murine model of acute lung injury induced by septic syndrome or acid aspiration, we investigated the role of cytosolic phospholipase A2 (cPLA2) in ARDS . We found that disruption of the gene encoding cPLA2 significantly reduced pulmonary edema, PMN sequestration and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration . Acute lung injury induced by acid aspiration was similarly reduced in mice with a disrupted cpla2 gene . Our observations suggest that cPLA2 is a mediator of acute lung injury induced by sepsis syndrome or acid aspiration . Thus, the inhibition of cPLA2-initiated pathways may provide a therapeutic approach to acute lung injury, for which no pharmaceutical agents are currently effective.

FASEB J, 2001 Mar, 15(3), 568 - 70 Epub 2001 Jan 19.
Protective effects of anti-C5a peptide antibodies in experimental sepsis; Huber-Lang MS et al.; We evaluated antibodies to different peptide regions of rat C5a in the sepsis model of cecal ligation and puncture (CLP) for their protective effects in rats . Rabbit polyclonal antibodies were developed to the following peptide regions of rat C5a: amino-terminal region (A), residues 1-16; middle region (M), residues 17-36; and the carboxyl-terminal region (C), residues 58-77 . With rat neutrophils, the chemotactic activity of rat C5a was significantly inhibited by antibodies with the following rank order: anti-C > anti-M >> anti-A . In vivo, antibodies to the M and C (but not A) regions of C5a were protective in experimental sepsis, as determined by survival over a 10-day period, in a dose-dependent manner . The relative protective efficacies of anti-C5a preparations (in descending order of efficacy) were anti-C > anti-M >> anti-A . In CLP rats, a delay in infusion of antibodies, which were injected at 6 or 12 h after CLP, still resulted in significant improvement in survival rates . These in vivo and in vitro data suggest that there are optimal targets on C5a for blockade during sepsis and that delayed infusion of anti-C5a antibody until after onset of clinical evidence of sepsis still provides protective effects.

J Exp Med, 2001 Mar 19, 193(6), 679 - 88
Pivotal role of signal transducer and activator of transcription (Stat)4 and Stat6 in the innate immune response during sepsis; Matsukawa A et al.; Signal transducer and activator of transcription (Stat)4 and Stat6 are transcription factors that provide type 1 and type 2 response, respectively . Here, we explored the role of Stat4 and Stat6 in innate immunity during septic peritonitis . Stat4-/- and Stat6-/- mice were resistant to the lethality compared with wild-type (WT) mice . At the mechanistic level, bacterial levels in Stat6-/- mice were much lower than in WT mice, which was associated with increased peritoneal levels of interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, macrophage-derived chemokine (MDC), and C10, known to enhance bacterial clearance . In Stat4-/- mice, hepatic inflammation and injury during sepsis were significantly ameliorated without affecting local responses . This event was associated with increased hepatic levels of IL-10 and IL-13, while decreasing those of macrophage inflammatory protein (MIP)-2 and KC . Sepsis-induced renal injury was also abrogated in Stat4-/- mice, which was accompanied by decreased renal levels of MIP-2 and KC without altering IL-10 and IL-13 levels . Thus, Stat6-/- and Stat4-/- mice appeared to be resistant to septic peritonitis by enhancing local bacterial clearance and modulating systemic organ damage, respectively, via balancing cytokine responses . These results clearly highlight an important role of local type 1 and systemic type 2 cytokine response in protective immunity during sepsis, which can be regulated by Stat proteins.

J Am Soc Nephrol, 2001 Feb, 12 Suppl 17, S60 - 4
Effects of genomic polymorphisms on the course of sepsis: is there a concept for gene therapy?
Stuber F.
Sepsis and its sequelae are still a major cause of morbidity and mortality on today's intensive care units . The evidence that endogenous mediators actually mediate the individual's response to infection has led to various approaches to assess the individual's contribution to the course of the disease . The role of an individual's genetic background and predisposition for the extent of inflammatory responses is determined by variabilities of genes encoding endogenous mediators that constitute the pathways of inflammation . Primary responses in inflammation are mediated by proinflammatory cytokines such as tumor necrosis factor and interleukin 1 . Conversely, anti-inflammatory mediators are released and may induce a state of immunosuppression in sepsis . Pro- and anti-inflammatory responses contribute to the outcome of patients with systemic inflammation and sepsis . Therefore, all genes encoding proteins involved in the transduction of inflammatory processes are candidate genes to determine the human genetic background that is responsible for interindividual differences in systemic inflammatory responses to injury . The genetically determined capacity of cytokine production and release, heat shock protein expression, nitric oxide synthase activity, gene polymorphisms of coagulation factors or factors of the innate immune system-like defensins, and other genes involved in inflammation may contribute to a wide range of clinical manifestations of an inflammatory disease . Genomic information may be used to identify groups of patients with a high risk of developing severe sepsis and multiple organ dysfunction, and determining which patients will benefit from antimediator strategies because of their genetic determination to high cytokine release in the inflammatory response will be the subject of future trials.

J Am Soc Nephrol, 2001 Feb, 12 Suppl 17, S53 - 9
Monitoring of organ dysfunction in sepsis/systemic inflammatory response syndrome: novel strategies; Koch T et al.; Sepsis and systemic inflammatory response syndrome-induced severe disruption of microcirculation and consecutive tissue hypoxia is considered a key factor in the development of organ dysfunction and multiple organ failure . The conventionally measured global variables such as lactate or macrohemodynamic parameters using a pulmonary artery catheter do not adequately mirror microcirculatory disturbances . Evaluation of the severity of microcirculatory distress and the effectiveness of resuscitation strategies requires new clinical technologies aimed at the microcirculation . It is anticipated that novel techniques such as optical spectroscopy and intelligent biosensors will play a major role in the development of new monitoring systems . In general, the current monitoring of organ dysfunction is characterized by a trend from invasive to noninvasive and "safe" techniques, which provide bedside or even on-line monitoring and allow a more precise and earlier detection of organ dysfunction . Techniques for the assessment of regional perfusion and microcirculatory bioenergetics to direct therapeutic procedures are expected to refine and optimize clinical treatment of critically ill patients in the future . This article addresses the question of which variables should be monitored, what is feasible, and what is valid for therapeutic consequences . Recent developments in monitoring of macro- and microcirculation and organ-specific dysfunction, e.g., lung, kidney, are described with respect to their advantages and limitations, and future directions are outlined.

Clin Infect Dis, 2001 Mar 15, 32(6), E107 - 10 Epub 2001 Mar 09.
Successful treatment of an infant with Chromobacterium violaceum sepsis; Moore CC et al.; Chromobacterium violaceum sepsis, a rarely reported phenomenon, has a high mortality rate . We report a unique case of C . violaceum sepsis in an infant . A 4-month-old girl presented to our institution with fever, pustular skin lesions, and distended abdomen, as well as diminished activity and mental status . Radiological investigation revealed brain, lung, and hepatic abscesses . The infant was successfully treated with trimethoprim-sulfamethoxazole and ciprofloxacin.

Crit Care Med, 2001 Feb, 29(2), 380 - 4
Dehydroepiandrosterone decreases mortality rate and improves cellular immune function during polymicrobial sepsis; Oberbeck R et al.; OBJECTIVE: Sepsis is associated with a marked depression of cellular immune function . The steroid hormone dehydroepiandrosterone (DHEA) is proposed to have immunoenhancing activities . We, therefore, investigated the effect of DHEA on the mortality rate and cellular immune functions in an experimental model of sepsis . DESIGN: Randomized animal study . SETTING: Level I trauma center, university research laboratory . SUBJECTS: Male NMRI mice . INTERVENTIONS: Mice were subjected to laparotomy (sham) or cecal ligation and puncture (CLP) . Mice were treated with (sham/DHEA; CLP/DHEA) or without (sham; CLP) the steroid hormone DHEA (30 mg/kg sc) . Animals were killed 48 hrs after the onset of sepsis . MEASUREMENTS AND MAIN RESULTS: The survival rate of septic mice was determined 24 and 48 hrs after onset of sepsis . Forty-eight hours after the septic challenge, a white blood cell count was performed and serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta concentrations were monitored using ELISA . Furthermore, the delayed type of hypersensitivity (DTH) reaction was evaluated on the basis of ear pinna swelling after dinitrofluorobenzene (DNFB) administration, and clinical variables (body weight, temperature, heart rate, fluid input/output, food intake) were monitored using metabolic cages . DHEA administration improved the survival rate (87% vs . 53% after 48 hrs; p <.001) . This was accompanied by a restoration of the depressed DTH reaction and a reduction in TNF-alpha serum concentrations (20.7 +/- 1.4 pg/mL vs . 32.4 +/- 6.6 pg/mL) . CONCLUSIONS: These results demonstrate that DHEA administration leads to an increased survival following a septic challenge . The immunoenhancing effect of DHEA is accompanied by a reduction of TNF-alpha release and an improved activity of T-cellular immunity . DHEA administration may, therefore, be beneficial in systemic inflammation.

Crit Care Med, 2001 Feb, 29(2), 310 - 6
The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone; Schroeder S et al.; OBJECTIVE: To investigate the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with severe sepsis by stimulating with corticotropin-releasing hormone (CRH) . DESIGN: Prospective observational study in consecutive intensive care unit patients with severe sepsis . SETTING: Surgical intensive care unit and outpatient department of endocrinology in a university hospital . PATIENTS: The study included 20 patients with the diagnosis of severe sepsis; six critically ill, nonseptic patients after major surgery; ten patients with primary adrenal insufficiency; ten patients with anterior pituitary insufficiency; and ten individuals without clinical signs of HPA axis disturbance . INTERVENTIONS: CRH tests were performed with an intravenous bolus injection of 100 microg of human CRH . MEASUREMENTS AND MAIN RESULTS: We studied the functional integrity of the HPA axis in patients with severe sepsis by performing the CRH test . In addition, during the period of severe sepsis, we repeatedly measured basal plasma concentrations of adrenocorticotropin hormone (ACTH) and cortisol . The mean basal plasma cortisol concentration was decreased significantly in nonsurvivors with severe sepsis (288.8 +/- 29.1 {sem} nmol/L) compared with survivors (468.1+/- 18.6 nmol/L; p <.01) . By calculating the ACTH/cortisol indices, we found no evidence for adrenal insufficiency in patients with severe sepsis . The mean ACTH/cortisol indices of nonsurvivors with severe sepsis (0.02 +/- 0.008) and survivors (0.01 +/- 0.002) were significantly lower compared with the index of patients with primary adrenal insufficiency (6.8 +/- 1.0; p <.001) . In contrast, in nonsurvivors with severe sepsis, the plasma cortisol response to CRH stimulation was impaired compared with survivors: The mean basal cortisol concentration within the CRH test was 269.4 +/- 39.8 nmol/L in nonsurvivors compared with 470.8 +/- 48.4 nmol/L in survivors and increased to a peak value of 421.6 +/- 72.6 nmol/L in nonsurvivors and 680.7 +/- 43.8 nmol/L in survivors (p <.02) . However, the change in plasma cortisol, expressed as mean +/- sem and calculated by subtracting the basal cortisol from the peak cortisol after CRH stimulation, was not significantly different in survivors with severe sepsis (243.5 +/- 36.1, range 111.0-524.0 nmol/L, n = 15) compared with nonsurvivors (161.0 +/- 38.9, range 42.0-245.0 nmol/L, n = 5; p >.05) . CONCLUSIONS: We found lower basal plasma cortisol concentrations in nonsurvivors compared with survivors of severe sepsis . In addition, the plasma cortisol response to a single CRH stimulation was impaired in nonsurvivors compared with survivors . Reduced responses to CRH stimulation may reflect a state of endocrinologic organ dysfunction in severe sepsis.

Crit Care Med, 2001 Feb, 29(2), 256 - 61
The hepatosplanchnic area is not a common source of lactate in patients with severe sepsis; De Backer D et al.; OBJECTIVE: To investigate the role of the splanchnic region in the hyperlactatemia of septic patients . DESIGN: Prospective, observational study . SETTING: Thirty-one-bed mixed medicosurgical intensive care unit . PATIENTS: Ninety invasively monitored and mechanically ventilated patients with severe sepsis . MEASUREMENTS AND MAIN RESULTS: Splanchnic lactate balance was measured in all patients . Splanchnic blood flow was determined by using the primed continuous indocyanine green infusion technique in 69 patients . In 71 patients, gastric mucosal Pco2 and the Pco2 gap (the difference between gastric and arterial Pco2) also were determined by using gas tonometry with an automated gas analyzer . In each patient, arterial, mixed-venous, and hepatic venous blood samples were obtained to determine hemoglobin oxygen saturations and lactate concentrations . Arterial and hepatic venous lactate concentrations were determined in triplicate and were averaged, and the arterial hepatic venous difference in lactate and lactate consumption were calculated . The splanchnic region produced lactate in only six of the 90 patients . Mean arterial pressure, cardiac index, arterial lactate, hepatic venous oxygen saturation, and catecholamine use were similar in the six patients with splanchnic lactate production and in the 84 others . The arterial hepatic venous differences in lactate and splanchnic lactate consumption were related directly to arterial lactate concentrations (y = 0.073x + 0.209, r(2) =.06, p <.05, and y = 0.06x + 0.183, r(2) =.08, p <.05, respectively) but were not related to Pco2 gap, to the gradient between mixed-venous and hepatic venous oxygen saturations, or to bilirubin concentrations . CONCLUSIONS: Splanchnic lactate release is uncommon in septic patients, even when hyperlactatemia is severe.

Biochem Biophys Res Commun, 2001 Mar, 281(5), 1331 - 6
The transcription factors NF-kappab and AP-1 are differentially regulated in skeletal muscle during sepsis; Penner CG et al.; Sepsis is associated with increased muscle proteolysis and upregulated transcription of several genes in the ubiquitin-proteasome proteolytic pathway . Glucocorticoids are the most important mediator of sepsis-induced muscle cachexia . Here, we examined the influence of sepsis in rats on the transcription factors NF-kappaB and AP-1 in skeletal muscle and the potential role of glucocorticoids in the regulation of these transcription factors . Sepsis was induced by cecal ligation and puncture (CLP) . Control rats were sham-operated . NF-kappaB and AP-1 DNA binding activity was determined by electrophoretic mobility shift assay (EMSA) in extensor digitorum longus muscles at different time points up to 16 h after sham-operation or CLP . Sepsis resulted in an early (4 h) upregulation of NF-kappaB activity followed by inhibited NF-kappaB activity at 16 h . AP-1 binding activity was increased at all time points studied during the septic course . When rats were treated with the glucocorticoid receptor antagonist RU38486, NF-kappaB activity increased, whereas AP-1 activity was not influenced by RU38486 . The results suggest that NF-kappaB and AP-1 are differentially regulated in skeletal muscle during sepsis and that glucocorticoids may regulate some but not all transcription factors in septic muscle .

Nutrition, 2001 Feb, 17(2), 112 - 6
Parenteral supplementation with a fish-oil emulsion prolongs survival and improves rat lymphocyte function during sepsis; Lanza-Jacoby S et al.; Nutritional intervention with omega-3 fatty acids during trauma and infection has been shown to improve the clinical outcome of patients and the survival rate in laboratory animals . This study evaluated the effects of parenteral administration of lipid emulsions containing fish oil (FO) or soybean oil (SBO) on survival and T-lymphocyte response during sepsis . Male Sprague-Dawley rats (250-275 g) were prepared for parenteral feeding 4 d before inducing sepsis by cecal ligation and puncture (CLP) . Standard resuscitation was provided with normal saline . Thirty minutes after completing CLP, sham control or CLP rats were infused continuously with saline or a parenteral diet containing SBO or a 1:1 FO:SBO emulsion . The survival rate was significantly improved in rats receiving the FO-supplemented diet, with 50% alive by 120 h in comparison with the saline-infused, chow-fed rats (0% alive by 120 h) or the SBO-fed rats (12% alive at 120 h) . The T-lymphocyte response was evaluated at 24 h after CLP . Sepsis led to a decline in lymphocyte proliferation in rats infused with saline or the SBO emulsion, which was associated with a greater release of splenocyte interleukin-10, transforming growth factor-beta and prostaglandin E2 . Administering the 1:1 FO:SBO parenteral diet during sepsis improved the survival rate and prevented the sepsis-induced suppression of lymphocyte proliferation and interleukin-2 release . The FO effect on lymphocyte function was associated with decreased splenocyte release of transforming growth factor-beta and prostaglandin E2.

Arthroscopy, 2001 Mar, 17(3), 311 - 315
Inhibiting the inflammatory response in joint sepsis; Hogan CJ et al.; PURPOSE: We created a rabbit model of infectious arthritis to test the effects of WRC-0470 (2-cyclohexylmethylidenehydarazinoadenosine), an adenosine analogue, and rolipram, a type IV phosphodiesterase inhibitor, on intra-articular white blood cell recruitment . Type of Study: Randomized trial involving mature rabbits . METHODS: Intra-articular injections ranging from 0 to 2,000 ng of Escherichia coli lipopolysaccharide (LPS) were tested as the infectious stimulus . The optimal LPS amount was determined based on synovial fluid analysis for white blood cell counts . A separate cohort of rabbits then received various intravenous concentrations of either rolipram, WRC-0470, or a combination of the 2 medications . Synovial fluid aspirations after a 6-hour incubation were analyzed for white blood cell counts . RESULTS: Intra-articular injections of 200 ng of LPS reproducibly generated an inflammatory response of 4,000 cells/mL of synovial fluid, establishing the use of this dose of LPS for our septic arthritis model . Following infusions of 10 microg/kg/min, the average white blood cell count dropped to 800 cells/mL for WRC-0470 (P <.01) and 1,225 cells/mL for rolipram (P <.05) . A synergistic effect was seen with the combination of both medications at just 1.0 microg/kg/min, with a mean white blood cell count of 1,090 cells/mL (P <.01) . CONCLUSIONS: Septic arthritis is a common clinical entity that frequently results in major long-term morbidity . Although bacteria can directly damage the articular surface, the cytokine-mediated immune response to the infection can exacerbate the insult by promoting the release of proteolytic enzymes by white blood cells . Currently, no established intervention exists that will decrease the inflammatory response to infectious challenges . Our study shows that WRC-0470 and rolipram effectively reduce the intra-articular recruitment of white blood cells in a septic arthritis model . Future investigations of these drugs will determine their ultimate degree of efficacy at limiting the joint destruction associated with septic arthritis.

Hosp Med, 2001 Feb, 62(2), 101 - 3
Empirical treatment of sepsis in neutropenic patients; Klastersky J; Mortality associated with febrile neutropenia has dramatically decreased over the last three decades; a pivotal role has been played by the concept of hospital-based empirical therapy with broad-spectrum combinations of antibiotics . Nevertheless, there is evidence that a subgroup of patients with febrile neutropenia might benefit from less aggressive treatments.

Klin Med (Mosk), 2000, 78(11), 32 - 5
{Clinical variants and treatment of urological sepsis}; Mustafin DG et al.; The paper describes current clinical features of urological sepsis, factors provoking sepsis in urological patients, leading laboratory and clinical characteristics of the disease, principles of treatment and its results.

Foot Ankle Clin, 2000 Dec, 5(4), 913 - 28, vii-viii
Sepsis and osteomyelitis about the ankle joint; Thordarson DB et al.; Sepsis and osteomyelitis about the ankle joint present a challenging clinical problem . Osteomyelitis usually follows open fracture of the distal tibia, often with a pilon fracture component . This article outlines the prevention of osteomyelitis in these difficult fractures . Treatment of subsequent osteomyelitis and sepsis, including the authors' experiences, is discussed . Septic ankle arthritis can occur hematogenously . In some patients, the optimal treatment for concomitant osteomyelitis and sepsis is a below knee amputation.

Shock, 2001 Feb, 15(2), 130 - 4
The decrease of PKCalpha is associated with hepatic apoptosis at early and late phases of polymicrobial sepsis; Jao HC et al.; The present study investigates the relationship between the PKC-alpha and hepatic apoptosis during sepsis . Cecal ligation and puncture- (CLP) induced animal model of polymicrobial sepsis was used, with early and late sepsis referring to those animals sacrificed at 9 and 18 h, respectively, after CLP . The expressions of PKCalpha and Bcl-2 family proteins as well as poly(ADP-ribose) polymerase (PARP) cleavage were quantified to evaluate the possible factors involved in the hepatic cell death during sepsis . The apoptosis of hepatocytes under septic condition or hepatocytes treated with PKCalpha antisense was evaluated by gel electrophoresis and/or flow cytometry after Annexin-V-Fluos and propidium iodide staining . The results indicated that (1) the protein expression of membrane-associated PKCalpha was decreased at early (P < 0.05) and late (P < 0.01) sepsis; (2) the protein expressions of Bcl-2 and Bcl-xL were decreased, whereas Bax expression was increased at late sepsis; (3) the percentage of PARP cleavage was increased at early (P < 0.05) and late (P < 0.01) sepsis; (4) severe DNA fragmentation was observed at late sepsis; (5) the apoptotic cell population was increased at early and late sepsis; and (6) the percentage of apoptotic cell population in PKCalpha antisense-treated cells was significantly higher than that in untreated cells . These results suggest that inactivation of PKCalpha may play an important role in modulating hepatic apoptosis during sepsis and the apoptosis is closely associated with the alterations of Bcl-2 family proteins.

Paediatr Drugs, 2001, 3(1), 9 - 27
Management of sepsis and septic shock in infants and children; von Rosenstiel N et al.; Sepsis and septic shock constitute an important cause of morbidity and mortality in critically ill children . Thus, the systemic response to infection and its management remains a major challenge in clinical medicine . Apart from antibiotic administration, the majority of available therapies are limited to supportive strategies, although considerable efforts are being undertaken to devise innovative approaches that modulate host inflammatory responses . In suspected sepsis, 2 or 3 days' empiric antibiotic therapy should begin immediately after cultures have been obtained without awaiting results . Antibiotics should be re-evaluated when the results of the cultures and susceptibility tests are available . The initial antibiotic (combination) is determined by the likely causative agent, susceptibility patterns within a specific institution, CNS penetration, toxicity, and the patient's hepatic and renal function . The likely offending micro-organism in turn depends primarily on the patient's age, coexistence of any premorbid condition leading to impaired immune response, and the presenting signs and symptoms . Close attention to cardiovascular, respiratory, fluid and electrolyte, haematological, renal and metabolic/nutritional support is essential to optimise outcome . Fluid resuscitation is of utmost importance to overcome hypovolaemia on the basis of a diffuse capillary leak . Monitoring and normalisation of the heart rate is essential . In case of nonresponse to fluid resuscitation, inotropic and vasoactive agents are commonly used to increase cardiac output, maintain adequate blood pressure and enhance oxygen delivery to the tissue . Because respiratory distress syndrome is seen in about 40% of critically ill children with septic shock, increased inspired oxygen is essential . To provide optimal relief from respiratory muscle fatigue and facilitate the provision of positive airway pressure, early intubation and mechanical ventilation should be considered . Renal support is essential to avoid prolonged renal shutdown in hypoperfusion states . Haematological support comprises replacement therapy of clotting factors to overcome disseminated intravascular coagulation . Metabolic support may include glucose support, extraction of ammonia from the body and recognition of liver dysfunction . Nutritional support may modify the inflammatory host response, and early enteral feeding can improve outcome in critical illness . To date, glucocorticoid and non-glucocorticoid anti-inflammatory agents have not shown significant benefit in septic patients.

Crit Care Clin, 2001 Jan, 17(1), 219 - 37
Cytopathic hypoxia . Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis; Fink MP; Several lines of evidence support the notion that cellular energetics are deranged in sepsis, not on the basis of inadequate tissue perfusion, but rather on the basis of impaired mitochondrial respiration and/or coupling; that is, organ dysfunction in sepsis may occur on the basis of cytopathic hypoxia . If this concept is correct, then the therapeutic implications are enormous . Efforts to improve outcome in patients with sepsis by monitoring and manipulating cardiac output, systemic Do2, and regional blood flow are doomed to failure . Instead, the focus should be on developing pharmacologic strategies to restore normal mitochondrial function and cellular energetics.

Clin Hemorheol Microcirc, 2000, 23(1), 43 - 9
Importance of measurement temperature in detecting the alterations of red blood cell aggregation and deformability studied by ektacytometry: a study on experimental sepsis in rats; Baskurt OK et al.; It is well known that RBC rheological parameters are affected by temperature . Usually, the measurement temperature of these parameters is kept constant throughout a given study, however it can be seen that different temperatures are used by different groups, during the measurement of a given parameter . It is assumed that the data should not be qualitatively different when measured at different temperatures, although significant quantitative differences exist . This study revealed that the selected temperature for RBC elongation index measurements by ektacytometry is important in detecting a given impairment in RBC deformability induced by experimental sepsis . RBC elongation indexes were found to be significantly different in septic and normal rats, only if measured at 37 degrees C . The differences in RBC aggregation parameters for septic and normal rats were also affected by the measurement temperature, however statistically significant differences were present in a wider range of temperatures between 25-37 degrees C . Therefore, it is strongly recommended that the measurement of RBC deformability and aggregation be performed using a controlled-temperature device, set to 37 degrees C.

Mediators Inflamm, 2000, 9(6), 285 - 7
Sera from patients with sepsis induce nitric oxide production in vascular smooth muscle cells; Fujita H et al.; BACKGROUND: Nitric oxide (NO) is an important physiological mediator of vascular tone and is involved in pathophysiology of septic shock . Although plasma nitrite is a stable end product of NO oxidation derived from endogenous NO, the plasma nitrite level is also easily affected by the intake of various foods, bacterial products and renal functional status . AIMS: We propose an excellent alternative assay technique for measuring endogenous NO production . METHODS: We measured the nitrite level in cultured vascular smooth muscle cells (SMC) treated with serum obtained from patients with sepsis (4 patients), by means of a chemiluminescence detector . RESULTS: The nitrite concentrations in such cells were significantly higher as compared to those in the cells treated with normal serum . Moreover, the increased nitrite levels in the SMC treated with the sera obtained from patients with sepsis were completely inhibited by L-nitroarginine (1 mmol/L), a nitric oxide synthase inhibitor . CONCLUSION: These data suggest that this assay method enable us to know the ability of endogenous NO production in each patient.

Minerva Anestesiol, 2000 Nov, 66(11 Suppl 1), 3 - 23
{Antithrombin III concentrates in the treatmetn of sepsis and septic shock: indictions, limits and future prospects} ; Baudo F et al.; Sepsis and septic shock are the most frequent cause of mortality in non cardiologic intensive care units . Mortality of the severe form is still elevated in spite of the progress in the antibiotic therapy and in the hemodynamic and respiratory support . The most frequent cause of death is the Multi Organ Dysfunction Syndrome (MODS) . The excessive inflammatory reaction and the damage of the microvascular bed secondary to the inflammation and to the disseminated intravascular coagulation (DIC) are important pathogenetic factors . In the sepsis a complex system of cellular activation initiates the release and the interaction of activators and inhibitors of the inflammation (cytokines), the activation of the enzymatic cascade systems (coagulation, fibrinolytic and complement systems) and the synthesis of proteases and anti proteases . The activation of the coagulation system, uncontrolled by the fibrinolytic system with formation of fibrin in the micro vascular bed, has an important role in the MODS . Experimental data and clinical observations suggest a possible therapeutic role of antithrombin III (AT) in sepsis; its plasma concentration is constantly decreased in patients with sepsis or septic shock and the entity of the decrease is correlated with the severity of the clinical picture and the outcome . At has a double function: regulation of the coagulation system and anti inflammatory properties . The anti inflammatory properties depend in part on the binding to the glycosaminoglycans of the endothelial cells and the consequent release of prostacyclin (PGI2) . The anti inflammatory effect is independent from the anticoagulant one . The preliminary studies on the clinical use of AT were carried out in small groups of patients with DIC associated with pathologies of different etiology and often in very critical conditions . In general the evaluation criteria were the improvement or the normalization of the laboratory data . The interpretation of the therapeutic effect of AT is difficult because the dysomogeneity of these studies . The effect on mortality is controversial . Recently three prospective, randomized, double blind studies have been published in patients with severe sepsis and septic shock . The results of the single studies are inconclusive but the limited number of patients included in each study may explain the results . A meta-analysis of the data referring to the patients with severe sepsis and septic shock evidenced an odd ratio (OR) of 0.43 with 95% confidential interval of 0.20-0.92 (p = 0.029) . The preliminary analysis of the results of a phase III study is unconclusive . Time, dosage and duration of treatment are still open to question . In perspective AT may be used in other clinical conditions associated with activation of the hemostatic system (cardiac surgery, stem cell transplantation, burns) even though the preliminary results must be confirmed by prospective studies . All these data suggest severe sepsis and septic shock as main criteria for treatment.

Khirurgiia (Mosk), 2001, (1), 71 - 3
{Extracorporeal detoxication in combined treatment of surgical sepsis}; Reshetnikov EA et al.; The methods of extracorporeal detoxication acquire special importance in combined treatment of sepsis . The sessions of plasmapheresis, hemodialysis and isolated ultrafiltration were performed in 61 of 83 patients with sepsis . Indications to these methods are determined, their efficacy is evaluated . It is established that administration of antibiotics and immunoglobulins after sessions of plasmapheresis and hemodialysis to achieves therapeutic drug concentration in blood . It is difficult to select the dose of antibiotics and immunodrugs in permanent round-the-clock ultrafiltration since the part of them are eliminated through the filters . Overall lethality was 20.4% (17 of 83 patients died), in the group of patients with severe polyorganic insufficiency and septic shock who needed extracorporeal detoxication--27%.

Afr J Med Med Sci, 1999 Sep-Dec, 28(3-4), 151 - 3
Efficacy of pefloxacin in the treatment of postoperative sepsis in gynaecology; Arowojolu AO et al.; Twenty four women with postoperative sepsis following gynaecological surgery were recruited into a study designed to determine the efficacy of Pefloxacin . With the standard oral dose of Pefloxacin, clinical cure or improvement occurred in 98% of the patients . In-vitro, 90% of bacterial isolates were sensitive to Pefloxacin . No adverse effect was encountered in any of the patients . We concluded that Pefloxacin is effective in the treatment of postoperative bacterial infections following gynaecological surgery.

Shock, 2001 Jan, 15(1), 49 - 55
Calcium uptake by sarcoplasmic reticulum is impaired during the hypodynamic phase of sepsis in the rat heart; Wu LL et al.; Alterations of the ATP-dependent Ca2+ uptake in the cardiac sarcoplasmic reticulum (SR) during the 2 hemodynamically distinct phases of sepsis were investigated . Sepsis was induced by cecal ligation and puncture (CLP) . Control rats were sham-operated . The SR vesicles were isolated by sucrose gradient centrifugation . The results show that the rates of ATP-dependent Ca2+ uptake in the cardiac SR were unaffected during the early hyperdynamic phase, whereas they were decreased by 41-46% (P < 0.01) during the late hypodynamic phase of sepsis . Analysis of the kinetics of Ca2+ transport indicates that during the late phase of sepsis, the Vmax values of Ca2+ pump for ATP and Ca2+ were decreased, whereas the affinities of Ca2+ pump for ATP and Ca2+ were unaffected . Magnesium stimulated, whereas vanadate inhibited the ATP-dependent Ca2+ uptake, but the Mg2+-stimulated and the vanadate-inhibited Ca2+ uptake activities were significantly lower during the late sepsis . Phosphorylation of SR by the cAMP-dependent and the calmodulin-dependent protein kinases stimulated the ATP-dependent Ca2+ uptake in the control and the early septic experiments, whereas it failed to stimulate Ca2+ uptake in the late sepsis . The extent of the phosphorylation-stimulated Ca2+ uptake activities was reduced by 65-69% (P < 0.01) during the early sepsis, and they were completely abolished during the late sepsis . These data indicate that the ATP-dependent Ca2+ uptake in cardiac SR was impaired during the late hypodynamic phase of sepsis . The impaired Ca2+ uptake during late sepsis was associated with a defective phosphorylation of SR proteins . Because the ATP-dependent Ca2+ uptake by cardiac SR plays an important role in the regulation of contraction-relaxation coupling, our findings may contribute to the understanding of the pathogenesis of altered cardiac function during the progression of sepsis.

Shock, 2001 Jan, 15(1), 42 - 8
Evolution of an immune suppressive macrophage phenotype as a product of P38 MAPK activation in polymicrobial sepsis; Song GY et al.; Studies indicate that polymicrobial sepsis in humans and animals is characterized by a biphasic response, which is dominated early by proinflammation, but over time develops into a state of generalized anti-inflammation (depressed Th1 cell response and decreased macrophage (M0) capacity to release proinflammatory cytokines) . However, with respect to the macrophage, it remains unknown what mechanism(s) controls this change . In this regard it is well documented that the p38 mitogen activated protein kinase pathway (MAPK) plays a central role in the regulation of Mphi functions . However, the contribution of p38 MAPK activation to the loss of these Mphi functions in polymicrobial septic animals remains unknown . To determine this we induced polymicrobial sepsis in C3H/HeN male mice using cecal ligation and puncture (CLP) . Twenty-four hours post-CLP, during the late, immune-suppressed stage of sepsis, splenic and peritoneal Mphi were harvested, stimulated with lipopolysaccharide (LPS), and the activation of p38 MAPK assessed . In Mphi from CLP mice, p38 MAPK activity was markedly increased . To determine the extent that these changes in p38 MAPK had an impact on Mphi immune function, cells were pretreated with 10 microM of the p38 MAPK inhibitor, SB203580, or with DMSO vehicle, and subsequently stimulated with LPS . IL-10, IL-6, IL-12, and nitric oxide release was determined . Our results indicate that with LPS stimulation alone, there was a marked increase in the release of the anti-inflammatory mediator, IL-10 after CLP . Alternatively, proinflammatory IL-12 and IL-6 release was suppressed . Treatment with SB203580 suppressed the increase in IL-10 release seen after CLP, while partially restoring IL-12 secretion . IL-6 release was partially restored only in splenic macrophages treated with SB203580 . To the extent that these in vitro findings could be translated to an in vivo setting, we assessed the in vivo effects of p38 MAPK inhibition on survival . Mice were given 100 mg of SB203580/kg body weight or saline vehicle (intraperitoneal) either immediately post-CLP or 12 h post-CLP . Delayed administration of SB203580 significantly improved survival, while also preventing the increased NO and IL-10 release and improving IL-12 release by macrophages . These results suggest that p38 MAPK pathway plays a critical role in the induction of an immune-suppressive macrophage phenotype, and that inhibition of p38 MAPK markedly improves survival following polymicrobial sepsis.

Intensive Care Med, 2000 Nov, 26(11), 1701 - 6
Coagulation inhibitors in sepsis and disseminated intravascular coagulation; Lee WL et al.; Sepsis is a syndrome that is increasing in frequency and continues to be associated with an unacceptably high mortality . DIC is an important and common sequel of sepsis, is implicated in the development of multiple organ failure, and has been shown repeatedly to connote a poor prognosis . Increasing understanding of the pathogenesis of DIC has suggested several novel therapies designed to correct deficiencies in inhibitors of coagulation . To date, small randomized, controlled studies of antithrombin III concentrates in sepsis and DIC have shown a trend to increased survival, but have not achieved statistical significance . Currently, a large randomized controlled trial of antithrombin III in sepsis is being conducted . Until more data are available, important questions remain as to its proper place in the treatment of sepsis, septic shock, and DIC . Similarly, therapy with protein C and tissue factor-pathway inhibitor has been beneficial in animal models of sepsis and DIC . The results of controlled clinical trials in humans are eagerly awaited.

Akush Ginekol (Sofiia), 2000, 39(3), 3 - 6
{Cesarean section in modern obstetrics and methods of prophylaxis of postoperative sepsis}; Kozovski I; The author discusses the problem Caesarean section in present day obstetrics and points out that the percentage of Caesarean births has been unnecessarily increased . This justifies the term "Caesarean epidemy" . In spite of discussions and recommendations it turns out impossible to cope with this problem, i.e . reducing the rate to 15% in these countries where it is higher . Methods of infections morbidity prophylaxis are discussed too, especially the peri- and intraoperative antibiotic application (PAP, IAL) as well as the inaugurated by the author in 1987 postoperative intermittent intrauterine antibiotic lavage (PIAL) . PIAL should be applied in very high risk cases, e.g . severe chorionamnionitis or vulvovaginitis combined with PAP and IAL . The use of these methods renders hysterectomy as ultra ratio prophylactic measure unnecessary . It is explicitly stressed that there is no prophylactic method to compensate defective surgical skills or flaws in aseptics and antiseptics.

Nihon Rinsho Meneki Gakkai Kaishi, 1999 Feb, 22(1), 37 - 42
{Successful treatment for disseminated intra-vascular coagulation due to sepsis and brain abscess with low molecular weight heparin in a patient with antiphospholipid syndrome}; Hiroishi K et al.; The management of disseminated intravascular coagulation (DIC) in a 22-year-old female patient with antiphospholipid syndrome is reported . Gabexate mesilate was given by continuous drip infusion at 1.5 g/day . No effect was seen, therefore Dalteparin sodium (DS) was administered by continuous drip infusion at 70 U/kg/day . The DIC score improved gradually during the first 4 days to normalization by 10 days . However, convulsive seizure was developed . Computed tomographic scan of brain demonstrated brain abscess at lt-basal ganglia . Continuous drainage was performed while administered continuous drip infusion of DS . Follow-up CT after operation showed reduction of low density area which means brain abscess . Finding in this case suggest that DS may play a role in the management of DIC accompanying intracranial infection.

Am J Respir Crit Care Med, 2001 Jan, 163(1), 218 - 25
Caspase inhibition prevents cardiac dysfunction and heart apoptosis in a rat model of sepsis; Neviere R et al.; Despite intensive therapy, severe septic shock is commonly associated with myocardial dysfunction and death in humans . No new therapies have proven efficiency against cardiovascular alterations in sepsis . Here, we addressed the question of a beneficial effect of pharmacological inhibition of caspases on myocardial dysfunction following endotoxin treatment . Hearts from rats treated with endotoxin (10 mg/kg, intravenously) were isolated 4 h posttreatment for analysis . Assessment of myocardial contractility ex vivo and detection of apoptosis were performed . Hearts from endotoxin-treated rats displayed multiple caspase activities and also typical apoptosis pattern as detected by TUNEL, DNA fragmentation assays, and cytochrome c release as compared with control rats . z-VAD.fmk (3 mg/kg, intravenously), a broad spectrum caspase inhibitor (but not the irrelevant peptide z-FA.fmk), in coinjection with endotoxin, not only reduced caspase activities and nuclear apoptosis but also completely prevented endotoxin-induced myocardial dysfunction evaluated 4 h and even 14 h after endotoxin challenge . These data indicate that caspase activation plays an important role in myocardial cell dysfunction . Moreover, these results suggest that inhibitors of caspases may have important therapeutic applications in sepsis.

Am J Physiol Regul Integr Comp Physiol, 2001 Feb, 280(2), R382 - 8
The small intestine plays an important role in upregulating CGRP during sepsis; Zhou M et al.; Although studies have indicated that calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide, is upregulated after endotoxic shock, it remains controversial whether this peptide increases during sepsis and, if so, whether the gut is a significant source of CGRP under such conditions . To study this, polymicrobial sepsis was induced by cecal ligation and puncture (CLP) followed by fluid resuscitation . Plasma levels of CGRP were measured at 2, 5, and 10 h after CLP (i.e., early, hyperdynamic sepsis) and at 20 h after CLP (late, hypodynamic sepsis) . The results indicate that plasma CGRP did not increase at 2--5 h but increased by 177% at 10 h after CLP (P < 0.05) . At 20 h after the onset of sepsis, however, the elevated plasma CGRP returned to the sham level . To determine the source of the increased plasma CGRP, the liver, spleen, small intestine, lungs, and heart were harvested, and tissue CGRP was assayed at 10 h after CLP in additional animals . Only the small intestine showed a significant increase in tissue levels of CGRP (by 129%, P < 0.05) . Determination of portal vs . systemic levels of CGRP indicates that portal CGRP was 65.7 +/- 22.7% higher than the systemic level at 10 h after CLP, whereas portal CGRP in sham-operated rats was only 4.9 +/- 2.1% higher . Immunohistochemistry examination revealed that CGRP-positive stainings increased in the intestinal tissue but not in the liver at 10 h after the onset of sepsis . The distribution of CGRP stainings was associated with intestinal nerve fibers . These results, taken together, demonstrate that upregulation of CGRP occurs transiently during the progression of sepsis (at the late phase of the hyperdynamic sepsis), and the gut appears to be a major source of such an increase in circulating levels of this peptide.

Am J Physiol Gastrointest Liver Physiol, 2001 Feb, 280(2), G291 - 7
Endothelial E- and P-selectin expression in iNOS- deficient mice exposed to polymicrobial sepsis; Lush CW et al.; In vitro, nitric oxide (NO) decreases leukocyte adhesion to endothelium by attenuating endothelial adhesion molecule expression . In vivo, lipopolysaccharide-induced leukocyte rolling and adhesion was greater in inducible NO synthase (iNOS)-/- mice than in wild-type mice . The objective of this study was to assess E- and P-selectin expression in the microvasculature of iNOS-/- and wild-type mice subjected to acute peritonitis by cecal ligation and perforation (CLP) . E- and P-selectin expression were increased in various organs within the peritoneum of wild-type animals after CLP . This CLP-induced upregulation of E- and P-selectin was substantially reduced in iNOS-/- mice . Tissue myeloperoxidase (MPO) activity was increased to a greater extent in the gut of wild-type than in iNOS-/- mice subjected to CLP . In the lung, the reduced expression of E-selectin in iNOS-/- mice was not associated with a decrease in MPO . Our findings indicate that NO derived from iNOS plays an important role in sepsis-induced increase in selectin expression in the systemic and pulmonary circulation . However, in iNOS-/- mice, sepsis-induced leukocyte accumulation is affected in the gut but not in the lungs.

Crit Care Med, 2001 Jan, 29(1), 117 - 22
Soluble L-selectin at levels present in septic patients diminishes leukocyte-endothelial cell interactions in mice in vivo: a mechanism for decreased leukocyte delivery to remote sites in sepsis; Ferri LE et al.; OBJECTIVE: Recent in vivo studies of both septic humans and animals demonstrate that leukocyte delivery is attenuated to sites remote from the primary infection . The mechanisms for this are not entirely clear . L-selectin is integral to rolling, the first step in leukocyte recruitment to an inflammatory site . L-selectin is shed from leukocytes in sepsis, resulting in increased levels of soluble L-selectin in plasma (2.33 microg/mL) . This study investigates the effects of soluble L-selectin at levels found in sepsis on leukocyte trafficking in vivo . DESIGN: Prospective, controlled trial . SETTING: Surgical research laboratory in a university hospital . SUBJECTS: Swiss white male mice of 25-35 g . INTERVENTIONS: Mice were randomized to one of three study groups: soluble L-selectin 2.33, soluble L-selectin 8.0, or albumin . Intravital microscopy was performed on postcapillary venules of 20-40 microm in diameter in the cremaster muscle of mice . Leukocyte-endothelial cell interactions (rolling, adherence, and rolling velocity) were measured pre- and post- (1, 15, 30, and 45 mins) intravenous infusion of human recombinant soluble L-selectin (2.33 and 8.0 microg/mL) or human albumin (8.0 microg/mL) . MEASUREMENTS AND MAIN RESULTS: The intravenous administration of soluble L-selectin to a systemic concentration of 2.33 microg/mL diminished rolling significantly . Soluble L-selectin at 8.0 microg/mL decreased rolling and increased rolling velocity to a greater degree . Injection of albumin did not alter leukocyte-endothelial cell interactions at any time point . No difference between groups in blood pressure, shear rate, or leukocyte counts was detected . CONCLUSIONS: Soluble L-selectin diminishes leukocyte rolling at levels present in sepsis (2.33 microg/mL) . This effect is dose dependent, and could not be explained by differences in blood pressure, shear rate, or leukocyte counts . These findings identify increased soluble L-selectin levels as one of the mechanisms for decreased leukocyte delivery and exudation to remote sites in septic patients.

Ann Surg, 2001 Feb, 233(2), 266 - 75
Norepinephrine modulates myelopoiesis after experimental thermal injury with sepsis; Tang Y et al.; OBJECTIVE: To determine whether thermal injury and sepsis cause an increase in bone marrow norepinephrine release and whether such a release influences bone marrow monocytopoiesis . SUMMARY BACKGROUND DATA: The authors previously demonstrated enhanced bone marrow monocytopoiesis after burn with sepsis . They also showed that physiologic stress and bacterial challenge without injury could lead to a dynamic release of norepinephrine from the bone marrow compartment . In this study, they sought to determine the potential cause-and-effect relationship of bone marrow norepinephrine release on increased monocytopoiesis after burn sepsis . METHODS: Norepinephrine release from bone marrow was determined by traditional pulse-chase methods . Tissue and bone marrow norepinephrine content was ablated by chemical sympathectomy with 6-hydroxydopamine treatment . Clonogenic potential in response to colony-stimulating factors was determined in total nucleated bone marrow cells . Dual color flow cytometry was used to document the distribution pattern of monocyte progenitors . RESULTS: Burn sepsis induced increased norepinephrine release in bone marrow, spleen, and heart . Colony-forming assays demonstrated an increase in responsive colonies, which was significantly attenuated when norepinephrine content was reduced in animals before burn sepsis . Flow cytometric analysis of early and late monocyte progenitors showed a significantly altered distribution profile of monocyte progenitors in norepinephrine-depleted mice compared with norepinephrine-intact mice . Abrogation of bone marrow norepinephrine content resulted in a 62% survival rate in burn septic mice compared with no survivors in norepinephrine-intact mice . CONCLUSIONS: These data suggest that enhanced bone marrow norepinephrine release after burn sepsis may play a role in bone marrow monocytopoiesis, thus contributing to the sustenance of inflammation.

J Pediatr Surg, 2001 Feb, 36(2), 282 - 6
Glutamine and glutathione counteract the inhibitory effects of mediators of sepsis in neonatal hepatocytes; Babu R et al.; BACKGROUND/PURPOSE: Surgical neonates are at risk of sepsis-associated liver dysfunction . Hydrogen peroxide (H(2)O(2)) and nitric oxide (NO) are important mediators of sepsis, which impair neonatal hepatic metabolism . Glutamine has been shown to have beneficial effects on hepatocyte metabolism during neonatal sepsis . However, the molecular basis of these effects are unknown . The aim of this study was to test the hypotheses that (1) glutamine and its dipeptides counteract the inhibitory effect of septic mediators on neonatal hepatocyte oxygen consumption and (2) the effects of glutamine are specific and not shared by other amino acids . In addition, we wished to determine the metabolic pathways and mediators involved in the action of glutamine . METHODS: Hepatocytes were isolated from suckling rats, and O(2) consumption measured polarographically . Study A: the ability of 10 mmol/L glutamine to reverse the inhibitory effects of 1.5 mmol/L H(2)O(2) and 300 micromol/L S-Nitroso-N-acetylpenicillamine (SNAP; a nitric oxide donor) on O(2) consumption was examined . Study B: the ability of other amino acids and dipeptides of glutamine to reverse the effects of H(2)O(2) was examined . Study C: various concentrations of glutamine were tested for their ability to reverse the H(2)O(2) inhibition of O(2) consumption . Study D: the mechanism of action of glutamine was examined by incubating hepatocytes with either an inhibitor of entry into the Krebs cycle or an inhibitor of glutathione synthesis . Study E: the ability of glutathione to reverse the inhibitory effects of H(2)O(2) was examined . RESULTS: Study A: glutamine reversed the inhibition of hepatocyte O(2) consumption exerted by either H(2)O(2) or NO . Study B: glutamine dipeptides reversed the inhibition of hepatocyte O(2) consumption by H(2)O(2), but other amino acids did not . Study C: the counteracting effect of glutamine was proportional to the dose administered . Study D: blocking entry of glutamine into the Krebs cycle did not abolish the effects of glutamine, but blocking glutathione synthesis completely abolished the effect of glutamine . Study E: exogenous glutathione reversed the inhibitory effect of H(2)O(2) on hepatocyte O(2) consumption . CONCLUSIONS: This study found that glutamine and its dipeptides are unique in reversing the effects of septic mediators on neonatal rat liver oxidative metabolism . The effectiveness of glutamine appears to be mediated via glutathione synthesis . Addition of glutamine, glutamine dipeptides, or glutathione to total parenteral nutrition (TPN) may be beneficial in preventing liver damage in neonatal sepsis.

Chest, 2001 Feb, 119(2), 523 - 9
Filgrastim in patients with pneumonia and severe sepsis or septic shock; Wunderink R et al.; STUDY OBJECTIVES: Evaluate the safety of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) administration, combined with standard therapy, in patients with pneumonia and either septic shock or severe sepsis who were receiving mechanical ventilation . DESIGN: Multicenter, double-blind, randomized, placebo-controlled study . SETTING: ICU, multicenter . PATIENTS: Eighteen patients with pneumonia and hypotension, or in the absence of shock, two or more end-organ dysfunctions, were enrolled and treated . Baseline acute physiology and chronic health evaluation II scores and median age for the filgrastim (n = 12) and placebo (n = 6) groups were 25.0 and 49.5 years and 31.5 and 56.5 years, respectively . INTERVENTION: Filgrastim (300 microg) or placebo was administered IV daily for up to 5 days . Measurements and results: Study end points included safety; biological response, including endogenous cytokine levels, endotoxin levels, and neutrophil counts; and mortality . Cytokine and endotoxin levels were highly variable in both groups . By day 29, 3 of 12 filgrastim-treated patients and 4 of 6 placebo-treated patients had died . There were no differences in types and occurrences of adverse events, including ARDS, or in outcome between the two groups . Three of four placebo-treated patients had persistent bacterial growth on bronchoscopy repeated after 48 h compared with 2 of 10 filgrastim-treated patients . CONCLUSION: Filgrastim appeared to be well tolerated in this population of patients with pneumonia and severe sepsis or septic shock . Larger studies to determine the benefit of filgrastim in patients with pneumonia and sepsis or organ dysfunction are warranted.

Clin Sci (Lond), 2001 Feb, 100(2), 169 - 82
Iron signalling regulated directly and through oxygen: implications for sepsis and the acute respiratory distress syndrome; Quinlan GJ et al.; Reactive oxygen species produced at toxic levels are damaging species . When produced at sub-toxic levels, however, they are involved as second messengers in numerous signal transduction pathways . In addition to these findings, we can add the concept that iron (often viewed as the "villain" in free radical biology) can also be considered as a signalling species . Iron is intimately involved in the regulation of its own storage, compartmentalization and turnover . During adult respiratory distress syndrome (ARDS) and sepsis, such regulation may be aberrant or altered in some predisposed way . Such changes may have profound implications for tissue damage, and for the modulation of the inflammatory response in these patients . The search for a genetic predisposition in patients that leads to the development of ARDS associated with abnormalities in iron turnover and signalling would seem to be an important and logical progression for studies into the disease . These may lead eventually to the design of effective treatment regimens that involve the control of iron.

ANZ J Surg, 2001 Jan, 71(1), 15 - 20
iNOS expression by activated neutrophils from patients with sepsis; Tsukahara Y et al.; BACKGROUND: Enhanced production of nitric oxide (NO) is associated with various inflammatory diseases such as sepsis . Although activated neutrophils are presumably involved in septic organ injury, the expression of inducible nitric oxide synthase (iNOS) by these cells has not been elucidated . The authors investigated whether activated neutrophils in sepsis could induce mRNA for iNOS and produce NO . METHODS: Peripheral blood neutrophils were obtained from healthy volunteers, and septic patients underwent a surgical operation . The neutrophils of the healthy volunteers were stimulated with lipopolysaccharide (LPS) and/or tumour necrosis factor-alpha (TNF-alpha) . The iNOS expression and NO production were examined by the reverse transcription-polymerase chain reaction and Griess method, respectively . RESULTS: Circulating neutrophils obtained from patients with sepsis expressed higher levels of iNOS mRNA than those from patients with systemic inflammatory response syndrome (SIRS) . Resting neutrophils from normal controls did not express iNOS mRNA and thus did not produce NO . After in vitro stimulation with LPS and TNF-alpha, the neutrophils did express iNOS mRNA and thus produce NO . CONCLUSION: Activated neutrophils may be one source of NO production in sepsis.

Injury, 2001 Jan, 32(1), 5 - 12
Early risk factors for sepsis in patients with severe blunt trauma; Flores JM et al.; We studied 43 patients with blunt trauma (injury severity score, > or =25), age >14 years and length of the intensive care unit (ICU) stay >48 h in order to estimate the frequency of sepsis and to identify early risk factors related to its development . Clinical data were collected during the first 24 h and several inflammatory mediators were determined from serum samples of the first 2 days after injury.Twenty-one patients (48.8%) met sepsis criteria during their ICU stay, 9 (20.9%) fulfilled only criteria for sepsis; 6 (13.9%) fulfilled criteria for severe sepsis and another 6 (13.9%) criteria for septic shock.An APACHE II score > or =14, the presence of hypovolemic shock, the need for three or more units of blood to be transfused and the administration of a total volume of fluids > or =10 l were all factors associated significantly with the development of sepsis . In the multivariant analysis, the need for a total volume of fluids > or =10 l was the only independent risk factor (adjusted odds ratio=10.49, 95% CI, 2.34-47.02; P=0.002) . No significant differences were documented in relation to the behaviour of the serum markers.

J Surg Res, 2001 Feb, 95(2), 207 - 18
The role of adrenomedullin in producing differential hemodynamic responses during sepsis; Koo DJ et al.; Although the hemodynamic response to polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase, the factors responsible for producing the transition from the hyperdynamic to the hypodynamic stage are not fully understood . The failure to recognize or prevent this transition may lead to progressive deteriorations in cell and organ functions and ultimately result in multiple organ failure . Despite the fact that several vasoactive mediators (i.e., nitric oxide, prostacyclin, calcitonin gene-related peptide) have been implicated in producing cardiovascular alterations during sepsis, recent studies have indicated that adrenomedullin (AM), a novel vasodilatory peptide, plays an important role in initiating the hyperdynamic response during the early stage of polymicrobial sepsis . In addition, the reduced vascular responsiveness appears to be responsible for producing the transition from the early, hyperdynamic phase to the late, hypodynamic phase of sepsis . Moreover, modulation of AM vascular responsiveness reduces sepsis-induced mortality . In this review the physiological effects of AM, mechanisms of its action, and regulation of its production under various pathophysiological conditions will be discussed . Furthermore, the role of AM in producing the biphasic hemodynamic responses observed during polymicrobial sepsis and approaches for pharmacologically modulating vascular responsiveness and hemodynamic stability under such conditions will be described .

J Immunol, 2001 Feb 1, 166(3), 2025 - 32
Expression of the complement anaphylatoxin C3a and C5a receptors on bronchial epithelial and smooth muscle cells in models of sepsis and asthma; Drouin SM et al.; The presence of the complement-derived anaphylatoxin peptides, C3a and C5a, in the lung can induce respiratory distress characterized by contraction of the smooth muscle walls in bronchioles and pulmonary arteries and aggregation of platelets and leukocytes in pulmonary vessels . C3a and C5a mediate these effects by binding to their specific receptors, C3aR and C5aR, respectively . The cells that express these receptors in the lung have not been thoroughly investigated, nor has their expression been examined during inflammation . Accordingly, C3aR and C5aR expression in normal human and murine lung was determined in this study by immunohistochemistry and in situ hybridization . In addition, the expression of these receptors was delineated in mice subjected to LPS- and OVA-induced models of inflammation . Under noninflamed conditions, C3aR and C5aR protein and mRNA were expressed by bronchial epithelial and smooth muscle cells of both human and mouse lung . C3aR expression increased significantly on both bronchial epithelial and smooth muscle cells in mice treated with LPS; however, in the OVA-challenged animals only the bronchial smooth muscle cells showed increased C3aR expression . C5aR expression also increased significantly on bronchial epithelial cells in mice treated with LPS, but was not elevated in either cell type in the OVA-challenged mice . These results demonstrate the expression of C3aR and C5aR by cells endogenous to the lung, and, given the participation of bronchial epithelial and smooth muscle cells in the pathology of diseases such as sepsis and asthma, the data suggest a role for these receptors during lung inflammation.

Anesth Analg, 2001 Feb, 92(2), 437 - 41
Propofol depressed neutrophil hydrogen peroxide production more than midazolam, whereas adhesion molecule expression was minimally affected by both anesthetics in rats with abdominal sepsis; Inada T et al.; The treatment of sepsis may require mechanical ventilation of the lungs and sedation . Because neutrophils are the most important effector cells for protecting against sepsis, and propofol and midazolam are the most widely used anesthetics for sedation, we studied the effects of these two anesthetics on the neutrophil function during sepsis . Sepsis was induced in rats by cecal ligation and puncture . At either 4 h or 24 h after cecal ligation and puncture, blood and peritoneal neutrophils were obtained, incubated with the test anesthetics, and the hydrogen peroxide (H(2)O(2)) production and CD11b/c expression were determined by flow cytometry . In both early (at 4 h) and late (at 24 h) sepsis, propofol and midazolam depressed H(2)O(2) production by blood and peritoneal neutrophils at clinical concentrations . Propofol caused more depression than midazolam (P < 0.005) . In both early and late sepsis, the effect of the anesthetics on the up-regulation of the stimulation-induced CD11b/c expression on blood neutrophils was minimal at clinical concentrations . If these results ultimately become clinically relevant, midazolam may be preferable to propofol for sedation during sepsis.

Am J Respir Cell Mol Biol, 2001 Feb, 24(2), 210 - 7
Free radical-induced contractile protein dysfunction in endotoxin-induced sepsis; Callahan LA et al.; Recent studies have indicated that sepsis is associated with enhanced generation of several free-radical species (nitric oxide {NO}, superoxide, hydrogen peroxide) in skeletal muscle . It is also known that this enhanced free-radical generation results in reductions in skeletal muscle force-generating capacity, but the precise mechanism(s) by which free radicals exert this effect in sepsis has not been determined . We postulated that free radicals might react directly with the contractile proteins in this condition, altering contractile protein force-generating capacity . To test this theory, we compared the force generation of single Triton-skinned diaphragmatic fibers (Triton skinning exposes the contractile apparatus, permitting direct assessment of contractile protein function) from the following groups of rats: (1) control animals; (2) endotoxin-treated animal; (3) animals given endotoxin plus polyethylene glycol- superoxide dismutase (PEG-SOD), a superoxide scavenger; (4) animals given endotoxin plus N(omega)-nitro-L-arginine methylester (L-NAME), a NO synthase inhibitor; (5 ) animals given only PEG-SOD or L-NAME; and (6 ) animals given endotoxin plus denatured PEG-SOD . We found that endotoxin administration produced both a reduction in the maximum force-generating capacity (Fmax) (i.e., a decrease in Fmax) of muscle fibers and a reduction in fiber calcium sensitivity (i.e., an increase in the Ca2+ concentration required to produce half-maximal activation {Ca50}) . L-NAME and PEG-SOD administration preserved Fmax and Ca50 in endotoxin-treated animals; neither drug affected these parameters in non-endotoxin treated animals . Denatured PEG-SOD failed to inhibit endotoxin-related alterations in contractile protein function . Sodium dodecyl sulfate polyacrylamide gel electrophoresis of skinned fibers from endotoxin-treated animals revealed a selective depletion of several proteins; administration of L-NAME or PEG-SOD to endotoxin-treated animals prevented this protein depletion, paralleling the effect of these two agents to prevent a reduction in contractile protein force-generating capacity . These data indicate that free radicals (superoxide, NO, or daughter species of these radicals) play a central role in altering skeletal muscle contractile protein force-generating capacity in endotoxin-induced sepsis.

Surg Today, 2000, 30(3), 223 - 7
The incidence and outcome of pelvic sepsis following handsewn and stapled ileal pouch anal anastomoses; Fukushima T et al.; The incidence and outcome of pelvic sepsis was analyzed in 210 patients who underwent restorative proctocolectomy for ulcerative colitis (UC) in 197 patients, and for familial adenomatous polyposis (FAP) in 13 patients . Pelvic sepsis developed in 18 patients (8.6%) and a significantly higher incidence was seen in men than in women, at 13.6% vs 3.7%, respectively (P < 0.05) . The incidence of pelvic sepsis in patients with UC complicated by toxic megacolon and/or fulminant colitis was significantly higher that in those without any preoperative complications, at 36.4% vs 7.4% (P < 0.05) . The incidence of pelvic sepsis following handsewn anastomosis was significantly higher than that following stapled anastomosis, at 15.6% vs 5.5% (P < 0.05) . The outcome of pelvic sepsis in patients with a stapled anastomosis was better than that in those with a handsewn anastomosis . The prognosis of women who developed pelvic sepsis was better than that of men who developed pelvic sepsis . The risk factors predisposing to pelvic sepsis were UC, especially when complicated by toxic megacolon and/or fulminant colitis, and male sex, while a handsewn anastomosis was more vulnerable than a stapled anastomosis.

Arch Surg, 2001 Jan, 136(1), 95 - 100
Sepsis increases the plasma membrane content of alpha1 and alpha2 isoforms of Na+-K+ adenosine triphosphatase in rat skeletal muscle; Shimoda N et al.; HYPOTHESIS: Increased Na(+)-K(+) adenosine triphosphatase (ATPase) activity in skeletal muscle during sepsis is caused by transient increases in enzyme content within the plasma membrane . DESIGN: Randomized controlled study . SETTING: University laboratory . INTERVENTION: Eighty-eight adult male Wistar rats were randomly assigned to undergo cecal ligation and puncture (CLP) or sham operation . MAIN OUTCOME MEASURES: Gastrocnemius muscles were harvested 6, 12, 24, and 48 hours after operation and Na(+)-K(+) ATPase activities were measured spectrofluorimetrically . Messenger RNA (mRNA) levels for the alpha1 and alpha2 isoforms of Na(+)-K(+) ATPase were determined by Northern blot analysis . Crude membranes, internal membranes, and purified plasma membranes were isolated from gastrocnemius muscles and protein levels of alpha1 and alpha2 isoforms were determined by Western blot analysis . RESULTS: Na(+)-K(+) ATPase activity in the CLP group was significantly higher compared with the sham group 24 hours after operation (P<.05) . However, there were no differences between the sham and CLP groups 6, 12, or 48 hours after operation . No significant differences between the CLP and sham groups were noted in mRNA levels for Na(+)-K(+) ATPase alpha1 and alpha2 isoforms . Western blot analysis revealed that the plasma membrane (but not internal membrane or crude membrane) content of alpha2 and alpha1 isoforms from the CLP group was significantly increased compared with the sham group 24 hours after operation (P<.05) . CONCLUSIONS: Na(+)-K(+) ATPase activity increases 24 hours after CLP in gastrocnemius muscle and then declines . This increase is caused by increased Na(+)-K(+) ATPase protein levels in the plasma membrane.

J Immunol, 2001 Jan 15, 166(2), 1193 - 9
Role of C5a in multiorgan failure during sepsis; Huber-Lang M et al.; In humans with sepsis, the onset of multiorgan failure (MOF), especially involving liver, lungs, and kidneys, is a well known complication that is associated with a high mortality rate . Our previous studies with the cecal ligation/puncture (CLP) model of sepsis in rats have revealed a C5a-induced defect in the respiratory burst of neutrophils . In the current CLP studies, MOF occurred during the first 48 h with development of liver dysfunction and pulmonary dysfunction (falling arterial partial pressure of O(2), rising partial pressure of CO(2)) . In this model an early respiratory alkalosis developed, followed by a metabolic acidosis with increased levels of blood lactate . During these events, blood neutrophils lost their chemotactic responsiveness both to C5a and to the bacterial chemotaxin, fMLP . Neutrophil dysfunction was associated with virtually complete loss in binding of C5a, but binding of fMLP remained normal . If CLP animals were treated with anti-C5a, indicators of MOF and lactate acidosis were greatly attenuated . Under the same conditions, C5a binding to blood neutrophils remained intact; in tandem, in vitro chemotactic responses to C5a and fMLP were retained . These data suggest that, in the CLP model of sepsis, treatment with anti-C5a prevents development of MOF and the accompanying onset of blood neutrophil dysfunction . This may explain the protective effects of anti-C5a in the CLP model of sepsis.

Ann Pharmacother, 2000 Dec, 34(12), 1389 - 94
Bayesian approach to control of amikacin serum concentrations in critically ill patients with sepsis; Lugo-Goytia G et al.; OBJECTIVE: To compare the predictive performance of a Bayesian program incorporating a population model with and without severity of illness covariates in intensive care unit (ICU) patients with sepsis . DESIGN: The clinical, physiologic, and pharmacokinetic data of 62 patients with sepsis admitted to a tertiary-care center were analyzed retrospectively . The patients were randomly assigned to a active group and a validation group . The model was developed using a three-step approach involving Bayesian estimation of pharmacokinetic parameters, selection of covariates by principal component analysis, and final selection of covariates by stepwise multiple linear regression . The predictive performance of this model was tested in patients from the validation group and compared with that of a general population model without covariates . RESULTS: Regression analysis revealed that the Acute Physiologic and Chronic Health Evaluation (APACHE II) score was the most important determinant for amikacin volume of distribution (1.5 L/kg, APACHE II; r2 = 0.77) . For amikacin clearance (CIamik), creatinine clearance (CIcr), positive end-expiratory pressure (PEEP), and use of catecholamines (CAT) were the most important predictors (CIamik = 44.5 + 0.67 CIcr - 1.29 PEEP - 8.34 CAT; r2 = 0.72) . The relative mean error (deltaME) and root mean-square error (deltaRMSE) (95% CI) were -0.62 (-1.2 to 0.01) and 3.78 (2.3 to 4.8) mg/L, respectively . Since the 95% CI for deltaRMSE did not include zero, it appears that the model with covariates is significantly improved in terms of precision . CONCLUSIONS: Our results show that, in ICU patients treated with amikacin, it is relevant to consider covariates related to pathophysiologic status and therapeutic measures . Application of a Bayesian program allows improved control of the pharmacokinetic parameters in patients who exhibit rapidly changing physiologic conditions.

Eur J Emerg Med, 2000 Sep, 7(3), 169 - 75
Invasive and noninvasive haemodynamic monitoring of acutely ill sepsis and septic shock patients in the emergency department; Shoemaker WC et al.; The objective of this study was to describe early circulatory events of patients presenting to the emergency department (ED) with severe sepsis or septic shock . Invasive and noninvasive monitoring were used to evaluate sequential patterns of both central haemodynamics and peripheral tissue perfusion/oxygenation and to test the hypothesis that increased cardiac output is an early compensation to increased body metabolism . This is a prospective observational study of 45 patients who entered the ED with severe sepsis or septic shock in an urban academic ED . Invasive clinical monitoring was performed using a radial artery catheter and a thermodilution pulmonary artery catheter . Noninvasive monitoring consisted of an improved thoracic electrical bioimpedance device to estimate cardiac output; pulse oximetry for arterial saturation to reflect changes in pulmonary function, and transcutaneous oxygen (PtcO2) and carbon dioxide tensions (PtcCO2) as a reflection of tissue perfusion . Survivors had higher cardiac index, mean arterial pressure (MAP), and better tissue perfusion as measured by PtcO2, oxygen delivery, and oxygen consumption . Oxygen extraction ratio was higher in the nonsurvivors (p < 0.05) and there were episodes of high PtcCO2 values in the nonsurvivors . No significant differences were found in the heart rate, PAOP (wedge pressure) and SaO2 by pulse oximetry between the two groups . It is concluded that ED monitoring septic patients provides a unique opportunity to document early physiologic interactions between cardiac, pulmonary, and tissue perfusion functions in surviving and nonsurviving patients with septic shock . The data is consistent with the concept that increased cardiac output is an early compensatory response to increased body metabolism . Real time haemodynamic monitoring of patients in the ED provides early warning of outcome and may be used to guide therapy.

Ann Surg, 2001 Jan, 233(1), 97 - 106
Myeloid commitment shifts toward monocytopoiesis after thermal injury and sepsis; Santangelo S et al.; OBJECTIVE: To demonstrate enhanced bone marrow monocytopoiesis in response to thermal injury and sepsis and to provide a mechanism for this observation . SUMMARY BACKGROUND DATA: Although monocyte activation and the resultant dysregulated cytokine production are now the accepted hallmarks of systemic inflammatory response syndrome, no information is available on the status of bone marrow monocyte production under injury conditions; neither has the balance between the two arms of myelopoiesis (monocytopoiesis and granulocytopoiesis) been delineated . METHODS: Peripheral blood absolute neutrophil and monocyte counts were determined 72 hours after the initial injury in sham, burn, and burn sepsis mice . Colony-forming potential in response to colony-stimulating factors (granulocyte, macrophage, and granulocyte/macrophage) was determined in both total nucleated and monocyte progenitor enriched bone marrow cells . Dual color flow cytometry was used to document the distribution pattern of monocyte progenitors . Macrophage colony-stimulating factor receptor density in monocyte progenitors was assessed by 125I macrophage colony-stimulating factor binding assay . RESULTS: Burn sepsis induced circulating monocytosis and granulocytopenia . Colony-forming assays demonstrated an increase in the growth potential of monocyte progenitors and a significant decrease in granulocyte progenitors after burn and burn sepsis . Flow cytometric analysis of early (ER-MP12) and late (ER-MP20) monocyte progenitors showed an increase in monocyte lineage growth in burn sepsis . Radioligand binding assay demonstrated an increase in macrophage colony-stimulating factor receptor expression in monocyte progenitors in burn sepsis . CONCLUSIONS: The data validate the premise that enhanced monocytopoiesis in thermal injury and sepsis results from an imbalance in myelopoiesis that is driven by the increased expression of macrophage colony-stimulating factor receptor.

Free Radic Biol Med, 2001 Jan 1, 30(1), 129 - 38
Free radicals alter maximal diaphragmatic mitochondrial oxygen consumption in endotoxin-induced sepsis; Callahan LA et al.; Recent studies indicate that sepsis is associated with enhanced generation of several free radical species (nitric oxide, superoxide, hydrogen peroxide) in skeletal muscle . While studies suggest that free radical generation causes uncoupling of oxidative phosphorylation in sepsis, no previous report has examined the role of free radicals in modulating skeletal muscle oxygen consumption during State 3 respiration or inhibiting the electron transport chain in sepsis . The purpose of the present study was to examine the effects of endotoxin-induced sepsis on State 3 diaphragm mitochondrial oxygen utilization and to determine if inhibitors/scavengers of various free radical species would protect against these effects . We also examined mitochondrial protein electrophoretic patterns to determine if observed endotoxin-related physiological derangements were accompanied by overt alterations in protein composition . Studies were performed on: (a) control animals, (b) endotoxin-treated animals, (c) animals given endotoxin plus PEG-SOD, a superoxide scavenger, (d) animals given endotoxin plus L-NAME, a nitric oxide synthase inhibitor, (e) animals given only PEG-SOD or L-NAME, (f) animals given endotoxin plus D-NAME, and (g) animals given endotoxin plus denatured PEG-SOD . We found: (a) no alteration in maximal State 3 mitochondrial oxygen consumption rate at 24 h after endotoxin administration, but (b) a significant reduction in oxygen consumption rate at 48 h after endotoxin, (c) no effect of endotoxin to induce uncoupling of oxidative phosphorylation, (d) either PEG-SOD or L-NAME (but neither denatured PEG-SOD nor D-NAME) prevented endotoxin-mediated reductions in State 3 respiration rates, (e) some mitochondrial proteins underwent tyrosine nitrosylation at 24 h after endotoxin administration, and (f) SDS-page electrophoresis of mitochondria from endotoxin-treated animals revealed a selective depletion of several proteins at 48 h after endotoxin administration (but not at 24 h); (g) administration of L-NAME or PEG-SOD prevented this protein depletion . These data provide the first evidence that endotoxin-induced reductions in State 3 mitochondrial oxygen consumption are free radical-mediated.

Pediatrics, 2001 Jan, 107(1), 97 - 104
Toward the early diagnosis of neonatal sepsis and sepsis-like illness using novel heart rate analysis; Griffin MP et al.; BACKGROUND AND OBJECTIVE: Abrupt clinical deterioration because of sepsis is a major cause of morbidity and mortality in neonates, and earlier diagnosis should improve therapy of this potentially catastrophic illness . In practice, clinical signs and laboratory data have not been perceived as sensitive or specific for early stages of sepsis . Because heart rate characteristics (HRC) are abnormal during fetal distress and neonatal illness, we hypothesized that abnormal HRC might precede the clinical diagnosis of neonatal sepsis, adding independent information to standard clinical parameters . METHODS: In the neonatal intensive care unit at the University of Virginia, we prospectively studied infants admitted from August 1995 to April 1999 who were at risk for developing sepsis . Infants in the sepsis (culture-positive) and sepsis-like illness (culture-negative) groups had an abrupt clinical deterioration that raised clinical suspicion of infection and prompted physicians to obtain blood cultures and start antibiotic therapy . Infants without sepsis raised no clinical suspicion of illness and had no cultures obtained . We measured novel characteristics-moments and percentiles-of normalized heart rate (HR) time series for 5 days before and 3 days after sepsis, sepsis-like illness, or a random time in controls . We also calculated the Score for Neonatal Acute Physiology (SNAP) and the Neonatal Therapeutic Intervention Scoring System (NTISS) as clinical scores of the severity of illness . RESULTS: There were 46 episodes of culture-positive sepsis in 40 patients and 27 episodes of culture-negative sepsis-like illness in 23 patients . We analyzed 29 control periods in 26 patients . Infants with sepsis and sepsis-like illness had lower birth weights and gestational ages and higher SNAP and NTISS scores than did infants without sepsis . The most important new finding was that the infants in the sepsis and sepsis-like illness groups had increasingly abnormal HRC for up to 24 hours preceding their abrupt clinical deterioration . The abnormal HRC were reduced baseline variability and short-lived decelerations in HR . These abnormalities led to significant changes in HRC measures, for example, the third moment (skewness:.59 +/-.10 for sepsis and.51 +/- . 12 for sepsis-like illness, compared with -.10 +/-.13 for control over the 6 hours before abrupt deterioration) . Culture-positive and culture-negative patients had similar HRC and clinical scores, including a significant rise in SNAP in the 24 hours before the event . Multivariable logistic regression analysis showed that HRC and clinical scores independently added information in distinguishing infants with sepsis and sepsis-like illness from control patients in the 24 hours before abrupt deterioration . CONCLUSIONS: Newborn infants who had abrupt clinical deterioration as a result of sepsis and sepsis-like illness had abnormal HRC and SNAP that worsened over 24 hours before the clinical suspicion of sepsis . A strategy for monitoring these parameters in infants at risk for sepsis and sepsis-like illness might lead to earlier diagnosis and more effective therapy.heart rate variability, neonatal sepsis, Score for Neonatal Acute Physiology, Neonatal Therapeutic Intervention Scoring System, newborn.

Pediatrics, 2001 Jan, 107(1), 36 - 41
A randomized trial of granulocyte-macrophage colony-stimulating factor in neonates with sepsis and neutropenia; Bilgin K et al.; OBJECTIVES: To determine whether adjunctive therapy with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) could reverse sepsis-associated neonatal neutropenia and improve neonatal survival and to assess its safety compared with conventional therapy in a control group . STUDY DESIGN: This prospective, randomized, controlled trial was performed in 60 infants with neutropenia and clinical signs of sepsis . A subcutaneous injection of rhGM-CSF (5 microgram/kg/day) was administered to 30 of the patients for 7 consecutive days . Hematologic parameters (absolute neutrophil, eosinophil, monocyte, lymphocyte counts, and platelet number) and outcome were compared with 30 conventionally treated (control) patients . RESULTS: Twenty-five patients from the GM-CSF-treated group and 24 from the conventionally treated group had early-onset sepsis (</=3 days' postnatal age), and the other 11 patients had late-onset sepsis (>3 days' postnatal age) . There was no difference between groups in terms of birth weight; gestational age; gender; maturity; maternal age; and incidence of prolonged rupture of membranes, maternal hypertension, or severity of sepsis . All neonates tolerated GM-CSF well with no adverse reactions . The absolute neutrophil count on day 7 was significantly increased in the GM-CSF-treated group compared with the conventionally treated group: 8088 +/- 2822/mm(3) versus 2757 +/- 823/mm(3) . The mean platelet count was significantly higher on days 14 in the GM-CSF-treated group compared with conventionally treated group: 266 867 +/- 55 102/mm(3) versus 229 200 +/- 52 317/mm(3) . Hematologic parameters were otherwise similar between groups before treatment and on day 28 . Twenty-seven neonates in the rh-GMCSF group and 21 in the control group survived to hospital discharge . The mortality rate in the rhGM-CSF group (10%) was significantly lower than in the conventionally treated group (30%) . CONCLUSION . Treatment with rhGM-CSF is associated with an increase in absolute neutrophil, eosinophil, monocyte, lymphocyte, and platelet counts and decreased mortality in critically ill septic neutropenic neonates . These results suggest that rhGM-CSF may be effective in the treatment of neonatal sepsis with neutropenia, and further randomized trials are needed to confirm its beneficial effects.

Pediatrics, 2001 Jan, 107(1), 30 - 5
A randomized, double-masked, placebo-controlled trial of recombinant granulocyte colony-stimulating factor administration to preterm infants with the clinical diagnosis of early-onset sepsis; Miura E et al.; OBJECTIVE: We performed a randomized, double-masked, parallel-groups, placebo-controlled trial of recombinant granulocyte colony-stimulating factor (rG-CSF) administration to 44 preterm neonates who had blood cultures obtained and antibiotics begun because of the clinical diagnosis of early-onset sepsis . Two primary outcome variables were tested 1) mortality and 2) development of nosocomial infections over the 2-week period after dosing . DESIGN AND METHODS: The treatment group (n = 22) received 10 microgram/kg/day of intravenous rG-CSF once daily for 3 days and the placebo group (n = 22) received the same volume of a visually indistinguishable vehicle . Mortality and culture-proven nosocomial infections were recorded . Immediately before the first, second, and third doses, and again 10 days after the first dose, serum concentrations were determined for tumor necrosis factor-alpha, interleukin 6, granulocyte-macrophage colony stimulating factor, and G-CSF, and blood leukocyte counts, absolute neutrophil counts, immature/total neutrophil ratios, platelet counts, and hemoglobin concentrations were measured . RESULTS: The treatment and placebo groups were of similar gestational age (29 +/- 3 vs 31 +/- 3 weeks) and birth weight (1376 +/- 491 vs 1404 +/- 508 g), and had similar Apgar scores and 24-hour Score for Neonatal Acute Physiology scores . The mortality rate was not different between treatment and placebo groups . However, the occurrence of a subsequent nosocomial infection was lower in the rG-CSF recipients (relative risk:.19; 95% confidence interval:.05-.78) . rG-CSF treatment did not alter the serum concentrations of the cytokines measured (except for G-CSF) . Serum G-CSF levels and blood neutrophil counts were higher in the treatment than in the placebo group 24 hours and 48 hours after dosing . CONCLUSIONS: Administration of 3 daily doses of rG-CSF (10 microgram/kg/day) to premature neonates with the clinical diagnosis of early-onset sepsis did not improve mortality but was associated with acquiring fewer nosocomial infections over the subsequent 2 weeks.

Mediators Inflamm, 2000, 9(3-4), 197 - 200
Platelet-activating factor acetylhydrolase and haemophagocytosis in the sepsis syndrome; Trimoreau F et al.; Sepsis syndrome (SS) is associated with depressed PAF acetylhydrolase, the enzyme responsible for the degradation of platelet activating factor . PAF acetylhydrolase is in a large part produced by macrophages, whose inadequate activation with haemophagocytosis is frequent in patients with SS . The aim of this study was to test the hypothesis that PAF acetylhydrolase levels could be affected in these critically ill patients, because of the large amounts produced by activated macrophages in vitro and in vivo in animal models . The levels of serum PAF acetylhydrolase were assessed in 90 SS patients, who were divided into three groups: patients with (n = 34) or without haemophagocytosis (n = 31), and patients without thrombocytopenia (n = 25) who were used as a control group . The number of organ dysfunctions was matched between patients with haemophagocytosis and controls . Normal reference values were obtained in 59 randomly selected blood donors . Circulating levels of PAF acetylhydrolase were significantly (p = 0.0001) decreased in patients with SS (57+/-3 nmol/ml/min, n = 90) when compared with healthy subjects (69+/-3 nmol/ml/min, n = 59) . PAF acetylhydrolase levels were greater in the presence of a haemophagocytosis but without statistical significance (64.2+/-6.5 vs . 50.1+/-2.8:p = 0.25) . Despite the fact that macrophagic activation stimulates the in vitro release of PAF acetylhydrolase, no difference was found between patients with or without haemophagocytosis . The mechanism and the role of the PAF acetylhydrolase reduction in SS patients remain to be determined.

J Hepatol, 2000 Dec, 33(6), 933 - 40
Sepsis decreases the spontaneous and agonist-induced contractile activities in the rat portal vein; Mastrangelo D et al.; BACKGROUND/AIMS: The portal vein has spontaneous and agonist-induced contractile activities and whether sepsis alters these two types of contractile activities is unknown . METHODS: To study the effect of sepsis on the spontaneous contractile activity and the contractile responses to norepinephrine (NE), angiotensin II (AT(II)), and neurokinin B (NKB) in the rat portal vein (RPV), we performed a cecal ligature and puncture (CLP) 24 h before RPV isolation . RESULTS: CLP decreased the spontaneous activity and induced hyporesponsiveness to AT(II) and NKB . The vascular failure was correlated to the severity of sepsis . In contrast, the reactivity to NE was not altered . Although inducible NO synthase was detected in RPV isolated from CLP rats, NO synthase inhibitors did not restore either the responsiveness to AT(II) and NKB or the spontaneous activity . Additionally, hyporesponsiveness to AT(II) and NKB was not modified by indomethacin . CONCLUSIONS: CLP decreases the spontaneous activity of the RPV as well as the contractile responses to AT(II) and NKB . The vascular failure is correlated to the severity of sepsis . The reactivity to NE is not altered in this model . Neither NO nor prostaglandins are responsible for the vascular abnormalities observed during CLP.

Inflammation, 2000 Dec, 24(6), 547 - 57
Lung compartmentalization of inflammatory cells in sepsis; Yin K et al.; Lung injury commonly occurs in the setting of systemic inflammatory response syndrome occurring during bacterial sepsis . There has been little work quantifying different leukocytes within the different compartments of the lung and their association with overt lung injury in sepsis . We examined the pathogenesis of lung injury after cecal ligation and puncture (CLP), a clinically relevant model of sepsis . To assess the sequestration and migration of leukocytes, leukocyte differentials were obtained for the lung vascular compartment and the bronchoalveolar airspace . At 24 h post CLP, there were signs of edema in the lung, while at 48 h after CLP, there were clear indications of alveolar wall thickening with increased cellularity and diffuse alveolar hemorrhage . The number of lymphocytes in the pulmonary vascular compartment dropped by 50% and doubled in the (bronchoalveolar lavage) BAL, 24 h after CLP compared to sham controls suggesting that there was transendothelial migration of lymphocytes . At 48 h after CLP, lymphocyte numbers in the vasculature was similar to controls but BAL lymphocyte numbers were still raised . The number of pulmonary intravascular neutrophils were similar to controls at 24 h post CLP but were greatly elevated 48 h after CLP . The increase in neutrophils was partly due to a substantial increase in the percentage of immature band cells, indicating recruitment of neutrophils from the bone marrow . There were very few neutrophils in the BAL of sham controls and CLP rats . Perfusate monocyte/macrophages were significantly increased 48 h after CLP and a similar increase in macrophages was observed in the BAL . These results strongly suggest a role for lymphocytes and macrophages in the development of overt lung injury as the migration of these cells corresponds to that of the appearance of lung injury 48 h after CLP . Importantly our data also demonstrates the compartmentalization and migration of different inflammatory cell-types during the development of sepsis.

Intensive Care Med, 2000 Oct, 26(10), 1547 - 52
In rats with sepsis, the acute fall in IGF-I is associated with an increase in circulating growth hormone-binding protein levels; O'Leary MJ et al.; OBJECTIVE: Growth hormone (GH) given to reverse muscle catabolism in critical illness increased mortality, illustrating the need for better understanding of the pathophysiology of the GH axis . We describe the relationship between changes in plasma insulin-like growth factor-I (IGF-I) and growth hormone-binding protein (GHBP) levels and hepatic growth hormone-binding in rats with sepsis . Design: Randomised, controlled study . SETTING: University research laboratory . SUBJECTS: One hundred and eleven male Wistar rats . INTERVENTION: Three groups of rats underwent caecal ligation and puncture (CLP) and three groups laparotomy only (LAP) . Survivors were killed at 24, 72, and 96 h . All animals were starved during the study . Twelve rats were killed at the start of the experiment (baseline) and twelve (allowed food) at 96 h . MEASUREMENTS AND RESULTS: Plasma levels of IGF-I and GHBP and binding of 125I-labelled human GH in liver homogenates were measured . IGF-I fell significantly following both CLP and LAP; at 24 h, IGF-I levels were lower after CLP than LAP (950 +/- 74 vs 1,522 +/- 60 microg/l, P = < 0.001) . GHBP increased at 24 h following both CLP and LAP (45.6 +/- 1.87 and 47.7 +/- 3.01 vs 38.7 +/- 1.98 ng/ml at baseline, P = < 0.05) . In LAP animals GHBP fell to below baseline by 72 h, and significantly so by 96 h (33.5 +/- 1.43, P = < 0.05), whereas GHBP remained elevated 72 h following CLP, returning to baseline by 96 h . The density of GH-binding sites in liver tended to increase, following both CLP and LAP at both 24 and 96 h, but these changes failed to achieve statistical significance . CONCLUSION: Reduced IGF-I levels in sepsis in the rat are associated with elevations in GHBP and a trend to increased hepatic GH binding . This suggests that in sepsis 'GH resistance' is not associated with reduced GH receptor numbers.

Artif Organs, 2000 Nov, 24(11), 902 - 8
Combination of inhaled nitric oxide therapy and inverse ratio ventilation in patients with sepsis-associated acute respiratory distress syndrome; Okamoto K et al.; Inverse ratio ventilation (IRV) is a ventilatory technique that uses an inspiratory to expiratory ratio (I:E) greater than 1:1 . We studied the effects of mechanical ventilation with an I:E of 1:3, 1:1, and 2:1 on arterial oxygenation in 10 patients with sepsis-associated acute respiratory distress syndrome (ARDS) . At each I:E, patients received 0 and 4 ppm of inhaled nitric oxide (INO) in random order for 30 min . Respiratory and cardiovascular parameters were measured . Of the 10 patients studied, 7 responded to IRV and 3 did not . An increase in the I:E and the addition of INO significantly improved arterial oxygenation in the responders (p < 0 . 0001 and p < 0.006, respectively) . The combination of an increase in the I:E and INO had an additive effect on arterial oxygenation . The combined use of IRV and INO is a more effective method of avoiding hypoxemia than either INO or IRV alone.

Arch Surg, 2000 Dec, 135(12), 1432 - 42
Signaling mechanisms of altered cellular responses in trauma, burn, and sepsis: role of Ca2+; Sayeed MM; Alterations in cellular responses in various organ systems contribute to trauma-, burn-, and sepsis-related multiple organ dysfunction syndrome . Such alterations in muscle contractile, hepatic metabolic, and neutrophil and T-cell inflammatory-immune responses have been shown to result from cell-signaling modulations and/or impairments in the respective cell types . Altered Ca(2+) signaling would seem to play an important role in the myocardial and vascular smooth muscle contractile dysfunction in the injury conditions; Ca(2+)-linked signaling derangement also plays a crucial role in sepsis-induced altered skeletal muscle protein catabolism and resistance to insulin-mediated glucose use . The injury-related increased hepatic gluconeogenesis and acute-phase protein response could also be caused by a pathophysiologic up-regulation of hepatocyte Ca(2+)-signal generation . The increased oxidant production by neutrophil, a potentially detrimental inflammatory response in early stages after burn or septic injuries, seems to result from an up-regulation of both the Ca(2+)-dependent as well as Ca(2+)-independent signaling pathways . The injury conditions would seem to cause an inappropriate up-regulation of Ca(2+)-signal generation in the skeletal myocyte, hepatocyte, and neutrophil, while they lead to a down-regulation of Ca(2+) signaling in T cells . The crucial signaling derangement that causes T-cell proliferation suppression seems to be a decrease in the activation of protein tyrosine kinases, which subsequently down-regulates Ca(2+) signaling . The delineation of cell-signaling derangements in trauma, burn, or sepsis conditions can lead to development of therapeutic interventions against the disturbed cellular responses in the vital organ systems.

Clin Infect Dis, 2000 Oct, 31 Suppl 5, S234 - 41
Antipyretic therapy in patients with sepsis; Hasday JD et al.; Sepsis is a clinical syndrome characterized by a systemic inflammatory response to infection . Mortality rates in sepsis have remained high, despite recent advances in our understanding of the immunological mechanisms that cause sepsis . Fever, a nonspecific acute-phase response, has been associated with improved survival and shortened disease duration in some infections . This article reviews the biological effects of fever and the influence of antipyretic therapy on the outcome in sepsis in experimental models and in humans and offers clinical recommendations for antipyretic therapy in early and late stages of the disorder.

Lipids, 2000 Oct, 35(10), 1079 - 85
Escherichia coli sepsis increases hepatic apolipoprotein B secretion by inhibiting degradation; Phetteplace HW et al.; Sepsis leads to hypertriglyceridemia in both humans and animals . Previously, we reported that plasma very low density lipoprotein apolipoprotein (apo) B and hepatic production of apoB increased during Escherichia coli sepsis . The present experiments were undertaken to determine whether the altered hepatic secretion of apoB was associated with an increase in synthesis or a decrease in degradation rate . Sepsis was induced in male, Lewis rats (225-275 g) by intravenous injection of 3.8 x 10(8) live E . coli colonies/100 g body . Twenty-four hours later rats were sacrificed, and primary hepatocytes were prepared and incubated overnight with 35S-methionine . Hepatocytes from E . coli-treated rats secreted twice as much apoB-48 and total apoB than the hepatocytes from control rats . Escherichia coil sepsis increased cellular triglyceride mass by 86%, which was due to a stimulation in triglyceride synthesis from newly synthesized fatty acids, measured by 3H2O incorporation into triglycerides . The apoB synthesis rate, apoB mRNA levels, and apoB mRNA editing were not altered during E . coil sepsis . The pulse-chase experiments showed that the rate of apoB degradation decreased in E . coli-treated rats . These findings demonstrate that the secretion of apoB is regulated posttranslationally during E . coli sepsis by decreasing the degradation of newly synthesized apoB, which contributes to the development of hypertriglyceridemia.

Int J Legal Med, 2000, 113(6), 338 - 42
Immunohistochemical expression of E-selectin in sepsis-induced lung injury; Tsokos M et al.; The vascular endothelium controls leukocyte extravasation into tissue by the induction and modulation of endothelial cell adhesion molecules, such as E-selectin (CD62E) . E-selectin is not expressed by non-stimulated endothelium, but is activated by cytokines and initiates neutrophil recruitment in sepsis-induced lung injury . The aim of the present study was to assess the value of the immunohistochemical expression of endothelial E-selectin for the post-mortem differentiation between death due to sepsis and death due to other causes . The immunohistochemical expression of E-selectin was investigated in lung specimens obtained at autopsy from sepsis-associated fatalities (n = 6), possible sepsis-associated fatalities (n = 7), non-sepsis group I (death due to unnatural causes, e.g . trauma, electrocution, drowning, hanging n = 17) and non-sepsis group II fatalities (death due to natural causes, e.g . myocardial infarction, intracerebral bleeding n = 7) . E-selectin was detected in paraffin sections using the ABC technique and the expression was scored semiquantitatively by evaluating the intensity and incidence of positively stained endothelium of the interstitial pulmonary microvasculature . E-selectin was strongly expressed in all cases of the definite sepsis group, in 29% of the possible sepsis-associated fatalities and in only 4% of the cases in the non-sepsis groups I and II . In comparison to all other study groups, E-selectin expression in the definite sepsis group differed significantly (p < 0.05) . Cases with inflammatory and mechanical lung tissue alterations from the control groups showed no positive immunohistochemical reaction for E-selectin; therefore, false positive results should not be expected in non-sepsis cases . Our findings suggest that the immunohistochemical detection of an intense expression of E-selectin in lung tissue may prove to be a valuable diagnostic tool in the forensic post-mortem elucidation of death due to sepsis.

Crit Care Med, 2000 Nov, 28(11), 3659 - 63
Procalcitonin release patterns in a baboon model of trauma and sepsis: relationship to cytokines and neopterin; Redl H et al.; OBJECTIVES: Procalcitonin (PCT) has been described as an early, discriminating marker of bacteria-associated sepsis in patients . However, little is known of its source and actions, in part because no appropriate animal models have been available . We tested the hypothesis that plasma PCT increases during various pathophysiological conditions, such as hemorrhagic shock and sepsis, which differ with regard to the degree of associated endotoxemia . We further hypothesized that in sepsis, PCT would be significantly different in survivors vs . nonsurvivors . DESIGN: Prospective, blinded analysis of previously collected plasma of experimental animals . SETTING: Independent nonprofit research laboratory in a trauma hospital and a contract research institute . SUBJECTS: A total of 22 male baboons (17.5-31 kg) . INTERVENTIONS: Hemorrhagic-traumatic shock was induced by hemorrhage for up to 3 hrs, reperfusion with shed blood and infusion of cobra venom factor (n = 7) . By using a similar experimental setup, severe hyperdynamic sepsis was induced (n = 15) by intravenous infusion of live Escherichia coli (2 x 10(9) colony-forming units/kg) over 2 hrs, followed by antibiotic therapy (gentamicin 4 mg/kg twice a day) . MEASUREMENTS AND MAIN RESULTS: Plasma PCT at baseline was barely detectable, but levels increased significantly (p < .05) to 2+/-1.8 pg/mL 2 hrs after the start of reperfusion in the shock group, and to 987+/-230 pg/mL at 4 hrs after E . coli in the sepsis group . Levels were maximal between 6 and 32 hrs and had returned nearly to baseline levels at 72 hrs . Interleukin-6 levels paralleled the course of PCT measurements, whereas a significant increase in neopterin was seen at 24 hrs . PCT levels were approximately three times higher in the sepsis group than in the shock group, corresponding to endotoxin levels (at the end of hemorrhage, 286+/-144 pg/mL vs . 3576+/-979 pg/mL at the end of E . coli infusion; p = .003) . PCT levels were significantly different at 24 hrs between survivors (2360+/-620 pg/mL) and nonsurvivors (4776+/-563 pg/mL) in the sepsis group (p = .032), as were interleukin-6 (1562+/-267 vs . 4903+/-608 pg/mL; p = .01) and neopterin/creatinine ratio (0.400+/-0.038 vs . 0.508+/-0.037; p = .032) . CONCLUSIONS: PCT is detectable in the baboon as in humans, both in hemorrhagic shock and sepsis . PCT levels are significantly higher in sepsis than in hemorrhage, a finding that is probably related to the differences in endotoxin . The baboon can be used for the study of PCT kinetics in both models; PCT kinetics are clearly different from other markers of sepsis, either IL-6 or neopterin, in both models . There are significant differences between survivors and nonsurvivors in the sepsis model.

Crit Care Med, 2000 Nov, 28(11), 3599 - 605
Long-term health-related quality of life in survivors of sepsis . Short Form 36: a valid and reliable measure of health-related quality of life; Heyland DK et al.; OBJECTIVE: To describe the long-term health-related quality of life (HRQL) of survivors of sepsis and to evaluate the reliability and validity of the medical outcomes study Short Form-36 (SF-36) in this population . STUDY DESIGN: Cross-sectional survey . SETTING: University intensive care unit . PATIENTS: Surviving patients over the age of 17 yrs who met the criteria for the Society of Critical Care Medicine/American College of Chest Physicians definition of sepsis identified through a review of patients admitted to the intensive care unit from 1994 to 1998 . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Baseline demographics and clinical characteristics were abstracted from the medical chart . After hospital discharge, the SF-36 and Patrick's Perceived Quality of Life scale were administered by telephone . The SF-36 was readministered 2 wks later . We screened the charts of 109 patients; 78 had a diagnosis of sepsis . Of these, 31 had died, 3 had severe communication problems, 9 refused to participate, and 5 patients could not be located . A total of 30 patients completed the first interview; 26 completed the second . Compared with established norms for the U.S . general population, survivors of sepsis scored significantly lower on the physical functioning, role physical, general health, vitality, and social functioning domains, as well as on the Physical Health Summary Scale . Mean scores on the Mental Health Summary Scale were very similar between the survivors of sepsis and U.S . norms . The SF-36 demonstrated high internal consistency (Cronbach's alpha ranged from 0.65 to 0.94) and excellent test-retest stability (intraclass correlation coefficient ranged from 0.75 to 0.97) . Both the Physical Health Summary Scale and the Mental Health Summary Scale correlated well with overall Perceived Quality of Life scores (Pearson correlation coefficients 0.45 and 0.56, respectively) . CONCLUSIONS: The long-term HRQL of survivors of sepsis is significantly lower than that of the general U.S . population . The SF-36 demonstrated good reliability and validity when used to measure HRQL in survivors of sepsis.

Clin Infect Dis, 2000 Dec, 31(6), 1338 - 42 Epub 2000 Nov 22.
Relationship between interleukin-6 plasma concentration in patients with sepsis, monocyte phenotype, monocyte phagocytic properties, and cytokine production; Spittler A et al.; Monocyte phenotype, their phagocytic capacity as well as the cytokine production from 10 patients with sepsis with low interleukin-6 (IL-6) serum concentrations (<1000 pg/mL) and 8 patients with sepsis with high IL-6 (> or = 1000 pg/mL) plasma concentrations were investigated within 24 hours of fulfilling the criteria for sepsis . Monocytes from patients with high IL-6 levels had higher levels of human leukocyte antigen (HLA)-DR, HLA-ABC, CD64, and CD71, and the production of tumor necrosis factor-alpha (TNF-alpha) and IL-8, as well as the capacity of monocytes to phagocytose, was significantly elevated . Of 8 patients with high levels of plasma IL-6, 4 patients died . In contrast, all 10 patients with low plasma IL-6 concentrations survived until day 28 . Patients who died had constant high IL-6 concentrations during the first 3 days, whereas IL-6 levels in patients who survived decreased by 88% . Our data indicate that IL-6 levels are a better prognostic parameter in the early phase of sepsis than the monocyte HLA-DR expression.

J Clin Endocrinol Metab, 2000 Nov, 85(11), 3996 - 9
A characteristic serpin cleavage product of thyroxine-binding globulin appears in sepsis sera; Jirasakuldech B et al.; T4-binding globulin (TBG), the principal thyroid hormone-binding protein of serum, is a member of the serine protease inhibitor (serpin) superfamily . We report a characteristic serpin cleavage product of TBG in sepsis sera . At 49-50 kDa, the TBG remnant is 4-5 kDa smaller than the intact protein and is the same molecular mass as a TBG cleavage product produced by incubation with polymorphonuclear elastase . Incubation with polymorphonuclear leukocytes also produces the 49- to 50-kDa remnant, and this proteolysis is stimulated by zymosan activation . Polymorphonuclear cell cleavage of TBG increases the ratio of free/bound T4 . As previously described, in vitro cleavage of TBG by elastase also increases free/bound T4 . These findings are consistent with the hypothesis that serine proteases present at inflammatory sites cleave TBG, releasing its hormonal ligands.

Crit Care, 2000, 4(2), 69 - 71 Epub 2000 Feb 16.
Hemofiltration in sepsis: where do we go from here?
Kellum JA, Bellomo R.
Hemofiltration as an adjunct to therapy for sepsis is now 10 years old . Despite early successes and significant theoretical advantages, the treatment remains experimental . Although feasibility has been established, efficacy has proved to be much more difficult . Clinical as well as technical difficulties remain important considerations to future studies . These issues are discussed and the brief history of hemofiltration in sepsis is reviewed.

Am J Physiol Gastrointest Liver Physiol, 2000 Dec, 279(6), G1274 - 81
Gut-derived norepinephrine plays a critical role in producing hepatocellular dysfunction during early sepsis; Yang S et al.; Although plasma norepinephrine (NE) increases and hepatocellular function is depressed during early sepsis, it is unknown whether gut is a significant source of NE and, if so, whether gut-derived NE helps produce hepatocellular dysfunction . We subjected rats to sepsis by cecal ligation and puncture (CLP), and 2 h later (i.e., early sepsis) portal and systemic blood samples were collected and plasma levels of NE were assayed . Other rats were enterectomized before CLP . Hepatocellular function was assessed with an in vivo indocyanine green (ICG) clearance technique, systemic levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were determined, and the effect of NE on hepatic ICG clearance capacity was assessed in an isolated, perfused liver preparation . Portal levels of NE were significantly higher than systemic levels at 2 h after CLP . Prior enterectomy reduced NE levels in septic animals . Thus gut appears to be the major source of NE release during sepsis . Enterectomy before sepsis also attenuated hepatocellular dysfunction and downregulated TNF-alpha, IL-1beta, and IL-6 . Perfusion of the isolated livers with 20 nM NE (similar to that observed in sepsis) significantly reduced ICG clearance capacity . These results suggest that gut-derived NE plays a significant role in hepatocellular dysfunction and upregulating inflammatory cytokines . Modulation of NE release and/or hepatic responsiveness to NE should provide a novel approach for maintaining hepatocellular function in sepsis.

Am J Physiol Endocrinol Metab, 2000 Dec, 279(6), E1391 - 7
Methionine transsulfuration is increased during sepsis in rats; Malmezat T et al.; Methionine transsulfuration in plasma and liver, and plasma methionine and cysteine kinetics were investigated in vivo during the acute phase of sepsis in rats . Rats were infected with an intravenous injection of live Escherichia coli, and control pair-fed rats were injected with saline . Two days after injection, the rats were infused for 6 h with {(35)S}methionine and {(15)N}cysteine . Transsulfuration was measured from the transfer rate of (35)S from methionine to cysteine . Liver cystathionase activity was also measured . Infection significantly increased (P < 0.05) the contribution of transsulfuration to cysteine flux in both plasma and liver (by 80%) and the contribution of transsulfuration to plasma methionine flux (by 133%) . Transsulfuration measured in plasma was significantly (P < 0.05) higher in infected rats than in pair-fed rats (0.68 and 0.25 micromol . h(-1) . 100 g(-1), respectively) . However, liver cystathionase specific activity was decreased by 17% by infection (P < 0.05) . Infection increased methionine flux (16%, P < 0.05) less than cysteine flux (38%, P < 0.05) . Therefore, the plasma cysteine flux was higher than that predicted from estimates of protein turnover based on methionine data, probably because of enhanced glutathione turnover . Taken together, these results suggest an increased cysteine requirement in infection.

Curr Infect Dis Rep, 1999 Aug, 1(3), 245 - 252
Therapeutic Approach to Candida Sepsis; Pappas PG et al.; Serious infections due to Candida species are an emerging nosocomial problem . Therapy for culture-proven candidemia in nonneutropenic patients has been studied extensively, and these studies suggest that fluconazole and conventional amphotericin B are equivalent treatments under most circumstances . Empiric antifungal therapy for the seriously ill, febrile, nonneutropenic intensive care unit patient has been less well studied, but an understanding of the important risk factors for invasive candidiasis can help guide rational therapeutic choices . The important role of empiric antifungal therapy in the persistently febrile neutropenic host has been well established . The role of the lipid formulations of amphotericin B in the treatment of candidiasis remains unclear, but these compounds should be considered in any patient requiring amphotericin B with significant renal dysfunction . The trend towards nonalbicans Candida species as a cause of invasive candidiasis, together with an improved understanding of antifungal susceptibility data, should help clinicians and investigators devise new and better approaches to the treatment of this important nosocomial infection.

Curr Infect Dis Rep, 1999 Aug, 1(3), 224 - 229
Adjunctive Therapies for Sepsis and Septic Shock; Breen G et al.; The inflammatory cascade that ensues after an infectious insult is protean in its manifestations, resulting in mild self-limited illness in some patients, while progressing to fulminant sepsis and multisystem organ failure in others . Research into the pathophysiology of this cascade has been intense, but advances in the treatment of sepsis have been few and far between . Although mortality rates have been impacted slightly in patients with sepsis--with improved survival in certain patient subgroups--overall survival still reaches only 55% to 60% . In this paper we will review some of the most recent advances in the therapy of the sepsis syndrome, specifically the roles of cytokine modifiers, supranormal delivery of oxygen, granulocyte colony-stimulating factor administration in leukopenic patients, and parenteral nutrition . Hopefully, these modalities represent additional steps in the path towards a meaningful improvement in survival from this catastrophic condition.

Shock, 2000 Nov, 14(5), 544 - 9
Effect of tyrosine kinase inhibition on sepsis-induced vascular hyporesponsiveness, inos mrna expression and NF-kappaB nuclear translocation in rats; Klein SM et al.; The dependence of the critical steps in the sepsis cascade on the transcription factor NF-kappaB andation to nitric oxide (NO) production are controversial . Tyrosine kinase (TK) is involved in several of the steps, and TK inhibitors (TKI) inhibit lipopolysaccharide (LPS)-induced vascular hyporesponsiveness in septic animals . We studied the relationship of TK inhibition, hemodynamics, vascular contraction, iNOS mRNA expression and NF-kappaB translocation in anesthetized endotoxic rats . The TKI AG556 (2.5 mg/kg i.p.), given 1 h before i.v . endotoxin (LPS) resulted in attenuation of early (<60 min) and late (60-120 min) hypotension, improved contraction of mesenteric arteries to norepinephrine 4 h after LPS, and attenuated tissue iNOS mRNA expression . LPS-induced NF-kappaB translocation was unaffected . The observed dissociation between NF-kappaB translocation and the salutary effect of TKI in vivo and ex vivo and its effect on iNOS mRNA expression suggest that although NF-kappaB may be involved in the sepsis cascade, it may not be essential for some of the molecular and vascular consequences of septic shock.

Schweiz Med Wochenschr, 2000 Oct 21, 130(42), 1572 - 5
The immature-to-total neutrophil ratio (IT ratio) is a sensitive indicator of sepsis after paediatric cardiopulmonary bypass; Frey B et al.; Cardiopulmonary bypass (CPB) causes a systemic inflammatory response syndrome (SIRS) with activation of neutrophils (increased immature-to-total neutrophil ratio, IT ratio) . Does an additional inflammatory response induced by sepsis further increase the IT ratio, so that it can still be used as an indicator of sepsis? In 160 children we analysed retrospectively the IT ratios from the day before CPB to the 10th day after the operation (controls) . The 95% confidence limits of the controls were plotted against postoperative day and compared with the IT ratio courses in all children of a 4-year period who developed sepsis during the first 10 days after CPB . All septic children (n = 9) had IT ratios above the upper 95% confidence limits of the controls on the day of positive culture or on the following day . The IT ratio remains a sensitive indicator of sepsis even after CPB.

Intensive Care Med, 2000 Sep, 26(9), 1360 - 3
Early signs of critical illness polyneuropathy in ICU patients with systemic inflammatory response syndrome or sepsis; Tennila A et al.; OBJECTIVE: To evaluate with electromyography the incidence and the time of appearance of neuromuscular abnormality in patients with systemic inflammatory response syndrome (SIRS) and/or sepsis . DESIGN: Follow-up study . SETTING: Intensive care unit of Helsinki University Hospital, Finland . PATIENTS: Nine mechanically ventilated patients with SIRS and/or sepsis . INTERVENTIONS: Electromyography and conduction velocity measurements on the 2nd-5th day after admission to the intensive care unit . MEASUREMENTS AND RESULTS: In all nine patients electromyography revealed signs of neuromuscular abnormality . The means of compound muscle action potential amplitudes of the median and ulnar nerves were decreased . Fibrillation was observed in four patients out of nine . CONCLUSION: Because neuromuscular abnormalities seem to develop earlier than previously reported, electroneuromyography should be used more frequently as a diagnostic test.

Intensive Care Med, 2000 Sep, 26(9), 1259 - 67
Effect of sepsis and cardiac surgery with cardiopulmonary bypass on plasma level of nitric oxide metabolites, neopterin, and procalcitonin: correlation with mortality and postoperative complications; Adamik B et al.; OBJECTIVES: To examine the hypothesis that nitrite/nitrate, neopterin, and procalcitonin (PCT) levels can be useful predictors of sepsis-associated mortality and predictors of the postoperative complications after cardiopulmonary bypass (CPB) . DESIGN: Prospective clinical study . SETTING: Intensive care unit of the Medical University Hospital . PATIENTS: 41 patients with sepsis, 42 patients subjected to open heart surgery with CPB, and 30 healthy volunteers . MEASUREMENTS AND RESULTS: Nitrite/nitrate, neopterin, and PCT levels were measured in septic patients as soon as sepsis was recognized and then on the 2nd, 3rd, and 5th days of treatment . Statistically significant differences between survivors and nonsurvivors were found for neopterin and PCT . The area under receiver operating characteristic curve (AUC) for both parameters as predictors of mortality was above 0.8 . The nitrite/nitrate level was also higher in nonsurvivors, but the AUC remained below 0.8, which indicates poor predictive power . The same parameters were measured in patients undergoing cardiac surgery before, during and after CPB establishment . The development of post-operative complications was correlated with increased postoperative neopterin and PCT levels . Additionally, neopterin was found as an early marker for the prognosis of postoperative complications, since patients who developed organ dysfunction had had elevated concentration of this parameter even before surgery (AUC 0.83) . Measurement of NO metabolite levels was less specific and less sensitive . CONCLUSIONS: Our results confirm the value of PCT and neopterin measurement as diagnostic tools in monitoring the clinical course of patients in intensive care units.

Dis Colon Rectum, 2000 Nov, 43(11), 1589 - 91
Tuberculous anal sepsis: report of clinical features in 20 cases; Kraemer M et al.; INTRODUCTION: Tuberculosis is a neglected cause of anal sepsis, often is not recognized, and therefore is not treated properly . METHOD: All patients were reviewed who had tuberculous anal sepsis diagnosed by histology reports of fistulectomy specimens or abscess scrapings from January 1990 to April 1999 . RESULTS: Twenty patients (median age, 53 years; 18 males) with anal tuberculous sepsis were identified . They presented with abscesses (n = 2), abscesses and fistulas (n = 6), or fistulas (n = 12) . All patients had a long history of anal complaints (3 months to 20 years), for which 15 patients were operated on previously . Nearly all fistulas (17/18) were complex, and secondary tracks or additional complicating features were common, even at first presentation . Eight patients had active concurrent pulmonary tuberculosis, and six showed evidence of previous pulmonary tuberculosis . Six patients had no signs of concurrent or previous tuberculosis elsewhere . Recurrence was observed only in cases where tuberculosis was initially not recognized, and antitubercular treatment therefore was not started . CONCLUSION: Contrary to views held previously, anal tubercular sepsis seems to have characteristic clinical features . It should be considered in cases of known pulmonary or extrapulmonary tuberculosis or if anal sepsis is persistent, recurrent, or complex in nature.

Gan To Kagaku Ryoho, 2000 Oct, 27(12), 1989 - 92
{A complication with hepatic arterial infusion chemotherapy--a case of sepsis related to catheter tip dislocation to the duodenal bulb}; Kuwabara H et al.; Extra-arterial dislocation of a catheter is one of the complications with hepatic arterial infusion chemotherapy . The authors report a case of sepsis related to catheter tip dislocation to the duodenal bulb . A 69-year-old man underwent sigmoidectomy for sigmoid colon cancer and partial hepatectomy for synchronous metastasis to the liver . We performed hepatic arterial catheterization via the femoral artery, and the patient underwent prophylactic hepatic arterial infusion chemotherapy with 5-FU . Thirty months later, computed tomography during arteriography (CTA) using a port system revealed the dislocation of catheter tip to the duodenal bulb . He showed no symptoms, so we kept him under observation . Sepsis occurred because of the dislocated catheter 39 months later . After removal of the catheter, the symptoms of sepsis disappeared.

J Clin Invest, 2000 Nov, 106(10), 1271 - 80
Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis; Guo RF et al.; Multiorgan apoptosis occurs during sepsis . Following cecal ligation and puncture (CLP) in rats, thymocytes underwent apoptosis in a time-dependent manner . C5a blockade dramatically reduced thymocyte apoptosis as measured by thymic weight, binding of annexin V to thymocytes, and laddering of thymocyte DNA . When C5a was generated in vivo by infusion of purified cobra venom factor (CVF), thymocyte apoptosis was significantly increased . Similar results were found when CVF was injected in vivo during the early stages of CLP . In animals 12 hours after induction of CLP, there was an increase in the activities of caspase-3, -6, and -9, but not caspase-1 and -8 . Cytosolic cytochrome c levels increased by twofold, whereas mitochondrial levels showed a 50% decrease . Western blot analysis revealed that the content of Bcl-X(L) (but not of Bcl-2, BAX, Bad, and Bim) significantly decreased in thymocytes after CLP . C5a blockade in the sepsis model almost completely inhibited caspase-3, -6, and -9 activation, significantly preserved cytochrome c in the mitochondrial fraction, and restored Bcl-X(L) expression . These data suggest that systemic activation of complement induces C5a-dependent apoptosis of thymocytes and that the blockade of C5a during sepsis rescues thymocytes from apoptosis.

Infect Control Hosp Epidemiol, 2000 Oct, 21(10), 633 - 8
Applicability of two surgical-site infection risk indices to risk of sepsis in surgical patients; Farinas-Alvarez C et al.; OBJECTIVE: To compare the ability of the Study of the Efficacy of Nosocomial Infection Control (SENIC) and the National Nosocomial Infection Surveillance (NNIS) indices to predict the development of nosocomial sepsis in subjects undergoing surgery . DESIGN: 1-year prospective case-control study . SETTING: A tertiary-care center in Spain . PATIENTS: Cases were surgical patients with nosocomial sepsis defined using the criteria of the Consensus Conference on Sepsis, identified by daily prospective surveillance . METHODS: Controls were randomly selected from the daily list of surgical inpatients . Data were prospectively collected . To determine whether either index added explanatory information to the other, two methods were used . The first method involved computing a set of residuals for both variables . Residuals and primary variables were introduced in logistic regression models . The second method evaluated both indices with the Goodman-Kruskal (G) nonparametric coefficient . RESULTS: 99 cases and 97 controls were included . After controlling for confounders, both the SENIC index (P<.001) and the NNIS index (P=.04) showed a significant trend . Residuals of the SENIC index added discriminating ability to the NNIS index, whereas residuals of the NNIS index did not improve the prediction ability of the SENIC index . Similar results were yielded by the G statistic: the SENIC index showed higher predictive power than the NNIS index (G=0.56 vs G=0.41) . CONCLUSIONS: Both indices performed about equally well for discriminating risk of nosocomial sepsis . The SENIC index had a somewhat better ability than the NNIS index only when the number of discharge diagnoses (not truly a predictive factor) were involved in the calculation of the SENIC index.

J Trop Pediatr, 2000 Oct, 46(5), 267 - 71
Serial interleukin 6 measurements in the early diagnosis of neonatal sepsis; Magudumana MO et al.; The objective of the present study was to evaluate serial interleukin 6 (IL6) levels in the early diagnosis of neonatal sepsis . Subjects included 255 neonates from the Neonatal Unit of Johannesburg Hospital evaluated for suspected sepsis between February and May 1998 . All infants had IL6, full blood count (FBC), C reactive protein (CRP) and blood cultures done at presentation . CRP and IL6 were repeated after 24 h . Infants were categorized into groups according to the likelihood of infection on the basis of clinical presentation, CRP, FBC and culture results, i.e., group 1 (no infection) to group 4 (definite infection) . IL6 was compared between the groups by the U-test of Mann-Whitney; stepwise logistic regression was done to establish the best predictors of infection, sensitivity, specificity, positive and negative predictive values were determined . The initial IL6 level was significantly raised in those infants with possible infection {880.67 pg/ml (2966.04), p value 0.0104}, probable infection {422.62pg/ml (4077.7), p value 0.0021} and definite infection {11164.39pg/ml (24139.77), p value 0.0000} as compared to those infants without infection {58.65 (182.4)} . The best predictors of infection were the combination of the initial IL6 value and CRP value after 24 h (goodness of fit 97.7 per cent) . An initial IL6 value below 20 pg/ml gave a negative predictive value of 90.18 per cent . It is concluded that an IL6 value done at the time of presentation of signs and symptoms suggestive of infection is useful in the early diagnosis of neonatal sepsis . In particular, an initial IL6 value below 20 pg/ml may allow antibiotics to be withheld in a number of infants evaluated for sepsis . There is no benefit in serial determination of IL6 in the diagnosis of neonatal sepsis.

J Perinat Neonatal Nurs, 2000 Mar, 13(4), 50 - 66
Neoteric physiologic and immunologic methods for assessing early-onset neonatal sepsis; Horns KM; Septicemia is a growing problem among low birth weight infants . Early identification and treatment of sepsis in these infants would help to reduce the high mortality and morbidity seen with this disorder . Newer techniques may make earlier diagnosis a reality . In the following review article, early-onset sepsis in the premature infant is described, specifically focusing on the neonatal inflammatory response, neutropenia, and its somewhat inconsistent and delayed role as a marker for sepsis risk factors . Physiological signs, laboratory indicators, skin temperature, peripheral perfusion, and the interaction of macro-environmental factors are also discussed . Newer (neoteric) immunologic and cytokine markers of sepsis are reviewed . Finally, thermography, a noninvasive bioinstrument measuring vasoactive peripheral perfusion, which has potential for early recognition of neonatal septicemia, is described.

Clin Chim Acta, 2000 Dec, 302(1-2), 11 - 22
Potential protective effect of NF-kappaB activity on the polymicrobial sepsis of rats preconditioning heat shock treatment; Yang RC et al.; The present study was designed to investigate the role of NF-kappaB in influencing the outcome of sepsis modulated by previous heat shock treatment . Sepsis was induced in rats by cecum ligation and puncture (CLP) method, which manifests two distinct clinical phases: an initial hyperdynamic phase (9 h after CLP, early sepsis) followed by a hypodynamic phase (18 h after CLP, late sepsis) . Rats of heated group were treated by whole body hyperthermia 24 h prior to the CLP operation . Lymphocytes were collected during the early and late sepsis phases . The expressions of Hsp72, p65 and I-kappa B were evaluated by Western blot and immunochemical analysis . NF-kappaB activity was detected by EMSA . The results showed that NF-kappaB activation was initiated during early sepsis and apparently suppressed during late stage of sepsis . Previously treated by heat shock, late-sepsis rats emerged with high preservation of p65 expression and NF-kappaB activity, while Hsp72 was over-expressed . In conclusion, down-regulation of NF-kappaB activity during late sepsis could be attenuated by pretreatment of heat shock through the preservation of p65 expression . The results may provide a mechanistic explanation for the improved outcome to polymicrobial sepsis of rats that are preconditioned with heat shock, as well as a novel highlight for therapeutic intervention of severe infection.

Am J Respir Crit Care Med, 2000 Nov, 162(5), 1877 - 83
NF-kappaB expression in mononuclear cells of patients with sepsis resembles that observed in lipopolysaccharide tolerance; Adib-Conquy M et al.; The expression of NF-kappaB was studied in freshly isolated peripheral blood mononuclear cells (PBMC) of patients with severe sepsis and major trauma . The expression of p65p50 heterodimer, the active form of NF-kappaB, was significantly reduced for all patients as compared with control subjects . The p50p50 homodimer, an inhibitory form of NF-kappaB, was reduced in the survivors of sepsis and in patients with trauma . Subsequent in vitro stimulation of PBMC with lipopolysaccharide (LPS) did not induce further NF-kappaB nuclear translocation: the survivors of sepsis and trauma patients showed low expression of both p65p50 and p50p50, whereas nonsurvivors of sepsis showed a predominance of the inactive homodimer and a low p65p50/p50p50 ratio when compared with control subjects . In the later group of patients there was a reverse correlation between plasma IL-10 levels and the p65p50/p50p50 ratio after in vitro LPS stimulation (r = -0.8, p = 0.04) . The reduced expression of nuclear NF-kappaB was not due to its inhibition by IkappaBalpha, as very low expression of IkappaBalpha, as well as low levels of p65 and p50 were found in the cytoplasm of PBMC from patients with sepsis and trauma when compared with control subjects . These results demonstrate that upon LPS activation, PBMC of patients with systemic inflammatory response syndrome show patterns of NF-kappaB expression that resemble those reported during LPS tolerance: global down-regulation of NF-kappaB in survivors of sepsis and trauma patients and the presence of large amounts of the inactive homodimer in the nonsurvivors of sepsis.

Clin Orthop, 2000 Nov, (380), 9 - 16
Articulating versus static spacers in revision total knee arthroplasty for sepsis . The Ranawat Award; Fehring TK et al.; Antibiotic laden spacer blocks frequently are used to treat an infected total knee arthroplasty . Static spacer blocks make exposure at reimplantation difficult secondary to quadriceps shortening . Unexpected bone loss attributable to migration of the spacer block also has been reported . To avoid these problems, a temporary articulating molded implant made of antibiotic cement was used in a consecutive series . The authors sought to determine whether its use would affect the reinfection rate, improve functional results, or prevent bone loss compared with static spacers . Twenty-five patients were treated with static nonarticulating spacers . Since 1996, 30 patients have been treated with tobramycin-laden articulating spacers . The knee arthroplasties in three patients treated with a static spacer became reinfected (12%) . The knee arthroplasty in one patient with an articulating spacer became reinfected (7%) . Fifteen of the 25 patients with static spacers had unexpected bone loss between stages . No appreciable bone loss could be measured in the patients who received articulating spacers . The average Hospital for Special Surgery score was 83 points in the patients with static spacers and 84 points for the patients with articulating spacers . Range of motion at final followup averaged 98 degrees in the patients who received static spacers and 105 degrees in the patients who received articulating spacers . Articulating spacers seem to facilitate reimplantation of infected total knee arthroplasty without additional risk of infection . Unexpected bone loss is no longer a concern with this two-stage technique . Articulating spacers offered no functional advantage over static spacers in this study group.

Expert Opin Investig Drugs, 2000 Jul, 9(7), 1651 - 63
Anti-inflammatory therapies in sepsis and septic shock; Freeman BD et al.; Despite advances in supportive care, the morbidity and mortality rate resulting from sepsis and septic shock remain high (30 - 50%) . A central hypothesis driving sepsis research in recent years is that this syndrome is the result of excessive inflammation . Therapies designed to inhibit the inflammatory response were first shown to be markedly beneficial in animal models of sepsis and then tested in numerous clinical trials involving thousands of patients . Three broad anti-inflammatory strategies have been investigated . First, glucocorticoids in high doses administered at the onset of sepsis were studied . This approach proved unsuccessful . More recently, however, glucocorticoids in lower doses have been found to have a beneficial effect in patients with septic shock . Whether the mechanism of this treatment benefit is through inhibition of inflammation, or by counteracting a relative steroid refractoriness occurring during sepsis, remains unknown . The next focus of research were agents active against the endotoxin molecule . However, as with the experience with glucocorticoids, this approach lacked a consistent pattern of efficacy . It is unclear if this lack of efficacy is the result of endotoxin being a poor therapeutic target, or from testing agents which lacked the appropriate biological activity . Most recently, clinical trials in sepsis have focused on inhibiting specific host pro-inflammatory mediators (e.g., TNF, interleukins) . While individual trials of inhibitors of these pro-inflammatory mediators failed to show a convincing benefit, pooling the results of these trials suggest that this approach has a marginal effect, supporting a role for excessive inflammation in sepsis . An unanswered question is reconcilling the very favourable effects obtained with anti-inflammatory treatments in animal models with the marginal results in humans . Further clinical and laboratory research is needed and may provide insight into more effective ways to use the anti-inflammatory agents already tested, or to investigate other potentially more effective anti-inflammatory agents in this syndrome.

J Pediatr, 2000 Nov, 137(5), 623 - 8
Preterm infants with low immunoglobulin G levels have increased risk of neonatal sepsis but do not benefit from prophylactic immunoglobulin G; Sandberg K et al.; OBJECTIVE: In a prospective, randomized, placebo-controlled, multicenter study, we evaluated the prevention of neonatal infections with intravenous immunoglobulin G (IVIgG) prophylaxis for preterm infants (gestational age <33 weeks) with umbilical cord blood IgG levels < or =4 g/L . STUDY DESIGN: Intravenous IgG or placebo (albumin), 1 g/kg body weight, was given on days 0, 3, 7, 14, and 21 to 81 infants with umbilical cord blood IgG levels < or =4 g/L: (1) IVIgG group, n = 40, mean (SD) gestational age 27.5 (2.2) weeks and birth weight 1.06 (0.39) kg; (2) placebo group, n = 41, mean (SD) gestational age 27.7 (2.5) weeks and birth weight 1.13 (0.38) kg . Infants with umbilical cord blood IgG levels >4 g/L (n = 238) served as a separate comparison group . Neonatal infections according to European Society of Pediatric Infectious Disease criteria were monitored until 28 days of life . RESULTS: Infants with IgG levels < or =4 g/L at birth who received IVIgG had no significant reduction in infectious episodes or mortality rate when compared with those given placebo . However, infants with a serum concentration of IgG >4 g/L at birth had significantly fewer infectious episodes (culture-proven sepsis) than infants with low serum concentrations of IgG (< or =4 g/L) when compared at the same gestational ages (26 to 29 weeks, P <.003) . CONCLUSIONS: Prophylactic immunotherapy with IVIgG did not improve the immune competence in preterm infants with low serum IgG concentrations at birth . We speculate that a spontaneously high serum IgG concentration at birth reflects placenta function and is an indicator of a more mature immune system capable of protecting the preterm infant against severe neonatal infections.

Crit Care Med, 2000 Oct, 28(10), 3405 - 11
Changing pattern of organ dysfunction in early human sepsis is related to mortality; Russell JA et al.; OBJECTIVE: We examined the pattern of organ system dysfunction, the evolution of this pattern over time, and the relationship of these features to mortality in patients who had sepsis syndrome . DESIGN: Prospective, multicenter, observational study . SETTING: Intensive care units in tertiary referral teaching hospitals . PATIENTS: A total of 287 patients who had sepsis syndrome were prospectively identified in intensive care units . MATERIALS AND MEASUREMENTS: Cardiovascular, pulmonary, neurologic, coagulation, renal, and hepatic dysfunction were assessed at onset and on day 3 of sepsis syndrome . Organ dysfunction was classified as normal, mild, moderate, severe, and extreme dysfunction . We calculated the occurrence rate and associated 30-day mortality rate of organ dysfunction at the onset of sepsis syndrome . We then measured the change in organ dysfunction from onset to day 3 of sepsis syndrome and determined, for individual organ systems, the associated 30-day mortality rate . RESULTS: At the onset of sepsis syndrome, clinically significant pulmonary dysfunction was the most common organ failure, but was not related to 30-day mortality . Clinically significant cardiovascular, neurologic, coagulation, renal, and hepatic dysfunction were less common at the onset of sepsis syndrome but were significantly associated with the 30-day mortality rate . Worsening neurologic, coagulation, and renal dysfunction from onset to day 3 of sepsis syndrome were associated with significantly higher 30-day mortality than with improvement or no change in organ dysfunction . CONCLUSIONS: Increased mortality rate in sepsis syndrome is associated with a pattern characterized by failure of nonpulmonary organ systems and, in particular, worsening neurologic, coagulation, and renal dysfunction over the first 3 days . Although initial pulmonary dysfunction is common in patients with sepsis syndrome, it is not associated with an increased mortality rate.

Eur J Clin Microbiol Infect Dis, 2000 Sep, 19(9), 655 - 62
Clinical trial evaluating a new hub device designed to prevent catheter-related sepsis; Luna J et al.; A new commercial hub device designed to minimise catheter-related infections was evaluated in a prospective, randomised trial in the intensive care and surgical units of the Hospital de Tortosa Verge de la Cinta in patients in whom the central venous catheters were expected to remain indwelling for at least 7 days . The assessments conducted at catheter withdrawal included cultures of the skin at the catheter site and cultures of the catheter tip and the catheter hubs; moreover, in cases of suspected catheter-related sepsis, samples of peripheral blood and infusion solutions were also cultured . Of the 130 catheters evaluated, 26 (20%) were withdrawn because of suspected catheter-related sepsis; 10 (15%) were in the control group and 16 (24%) in the new product group . Catheter-related sepsis was diagnosed in nine patients, six of whom were in the new product group and three in the control group; all infections in the former group and only one in the latter group were caused by the catheter connection . The rates of catheter hub colonisation (10 cfu) and catheter colonisation (15 cfu in semiquantitative culture and/or >1,000 cfu in quantitative culture) of hub origin were not significantly different between the groups (15 cases in the control group vs . 20 cases in the new product group, and 5 cases in the control group vs . 11 cases in the new product group, respectively) . The data indicate that the use of the new catheter hub device is no more effective in preventing catheter-related infection than standard good clinical procedures.

Crit Care, 2000, 4(1), 45 - 9 Epub 2000 Jan 24.
Heat stress is associated with decreased lactic acidemia in rat sepsis; Deshpande GG et al.; BACKGROUND: Elevated plasma lactate has been shown to correlate with mortality in patients with septic shock . Heat stress prior to sepsis has resulted in reduction in acute lung injury and mortality . We investigated whether heat stress resulted in decreased plasma lactate concentration and protected the lung by decreasing the inflammatory response to sepsis . RESULTS: Plasma lactate concentration was elevated in septic rats without prior heat stress . Lactic acid levels were significantly lower in heat-treated septic rats (P < 0.05) and were not significantly different when compared with control rats . Septic rats with or without heat pretreatment had significantly higher myeloperoxidase activity in the lung than did control groups . Heat pretreatment did not prevent neutrophil infiltration or inflammatory mediator production in the lung . CONCLUSION: Prior heat stress ameliorates lactic acidemia in rat sepsis . Heat stress did not attenuate the pulmonary inflammatory process . The mechanism of heat-induced protection from lactic acidemia in sepsis needs to be further explored.

Crit Care, 1999, 3(1), 45 - 50
Comparison of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations at different SOFA scores during the course of sepsis and MODS; Meisner M et al.; OBJECTIVES: The relation of procalcitonin (PCT) plasma concentrations compared with C-reactive protein (CRP) was analyzed in patients with different severity of multiple organ dysfunction syndrome (MODS) and systemic inflammation . PATIENTS AND METHODS: PCT, CRP, the sepsis-related organ failure assessment (SOFA) score, the Acute Physiology, Age, Chronic Health Evaluation (APACHE) II score and survival were evaluated in 40 patients with systemic inflammation and consecutive MODS over a period of 15 days . RESULTS: Higher SOFA score levels were associated with significantly higher PCT plasma concentrations (SOFA 7-12: PCT 2.62 ng/ml, SOFA 19-24: PCT 15.22 ng/ml) (median), whereas CRP was elevated irrespective of the scores observed (SOFT 7-12: CRP 131 mg/l, SOFT 19-24: CRP 135 mg/l) . PCT of non-surviving patients was initially not different from that of survivors but significantly increased after the fourth day following onset of the disease, whereas CRP was not different between both groups throughout the whole observation period . CONCLUSIONS: Measurement of PCT concentrations during multiple organ dysfunction syndrome provides more information about the severity and the course of the disease than that of CRP . Regarding the strong association of PCT and the respective score systems in future studies we recommend evaluation also of the severity of inflammation and MODS when PCT concentrations were compared between different types of disease.

Crit Care, 1999, 3(1), 11 - 16
Elevated calcitonin precursor levels are related to mortality in an animal model of sepsis; Steinwald PM et al.; BACKGROUND: Increased serum levels of procalcitonin (ProCT) and its component peptides have been reported in humans with sepsis . Using a hamster model of bacterial peritonitis, we investigated whether serum ProCT levels are elevated and correlate with mortality and hypocalcemia . RESULTS: Incremental increases in doses of bacteria resulted in proportional increases in 72h mortality rates (0, 20, 70, and 100%) as well as increases in serum total immunoreactive calcitonin (iCT) levels at 12 h (250, 380, 1960, and 4020 pg/ml, respectively, vs control levels of 21 pg/ml) . Gel filtration studies revealed that ProCT was the predominant (> 90%) molecular form of serum iCT secreted . In the metabolic experiments, total iCT peaked at 12 h concurrent with the maximal decrease in serum calcium . CONCLUSIONS: In this animal model, hyper-procalcitoninemia was an early systemic marker of sepsis which correlated closely with mortality and had an inverse correlation with serum calcium levels.

Crit Care, 1998, 2(2), 61 - 66
Sepsis-related organ failure assessment and withholding or withdrawing life support from critically ill patients; Miguel N et al.; BACKGROUND: We studied the incidence of withholding or withdrawing therapeutic measures in intensive care unit (ICU) patients, as well as the possible implications of sepsis-related organ failure assessment (SOFA) in the decision-making process and the ethical conflicts emerging from these measures . METHODS: The patients (n = 372) were placed in different groups: those surviving 1 year after ICU admission (S; n = 301), deaths at home (DH; n = 2), deaths in the hospital after ICU discharge (DIH; n = 13) and deaths in the ICU (DI; n = 56) . The last group was divided into the following subgroups: two cardiovascular deaths (CVD), 20 brain deaths (BD), 25 deaths after withholding of life support (DWH) and nine deaths after withdrawal of life support (DWD) . RESULTS: APACHE III, daily therapeutic intervention scoring system (TISS) and daily SOFA scores were good mortality predictors . The length of ICU stay in DIH (20 days) and in DWH (14 days) was significantly greater than in BD (5 days) or in S (7 days) . The number of days with a maximum SOFA score was greater in DWD (5 days) than in S, BD or DWH (2 days) . CONCLUSIONS: Daily SOFA is a useful parameter when the decision to withhold or withdraw treatment has to be considered, especially if the established measures do not improve the clinical condition of the patient . Although making decisions based on the use of severity parameters may cause ethical problems, it may reduce the anxiety level . Additionally, it may help when considering the need for extraordinary measures or new investigative protocols for better management of resources.

Am J Physiol Endocrinol Metab, 2000 Nov, 279(5), E1178 - 84
Effect of sepsis on eIE4E availability in skeletal muscle; Vary TC et al.; Chronic septic abscess formation causes an inhibition of protein synthesis in gastrocnemius that is not observed in rats with a sterile abscess . The inhibition is associated with an impaired translation initiation . The present study was designed to investigate the effects of sepsis on phosphorylation and availability of eukaryotic initiation factor (eIF)4E in gastrocnemius 5 days after induction of a sterile or septic abscess . Neither sepsis nor sterile inflammation altered the extent of eIF4E phosphorylation . Moreover, no changes in the amount of the binding protein 4E-BP1 associated with eIF4E or in the phosphorylation of 4E-BP1 were observed during sepsis or sterile inflammation . In contrast, sepsis and sterile inflammation caused a reduction in the relative amount of eIF4G bound to eIF4E compared with controls . The diminished amount of eIF4G bound to eIF4E was not the result of a reduced abundance of eIF4E . Sepsis, but not sterile inflammation, caused an increase in the cellular abundance of eIF4E . The results provide evidence that alterations in the eIF4E system are probably not rate controlling for the synthesis of total, mixed proteins in gastrocnemius during sepsis . Instead, on the basis of our previous studies, changes in eIF2B appear to be responsible for limiting protein synthesis in skeletal muscle during sepsis.

Am J Physiol Endocrinol Metab, 2000 Nov, 279(5), E1145 - 58
IGF-I/IGFBP-3 binary complex modulates sepsis-induced inhibition of protein synthesis in skeletal muscle; Svanberg E et al.; The present study evaluated the ability of insulin-like growth factor I (IGF-I) complexed with IGF binding protein-3 (IGFBP-3) to modulate the sepsis-induced inhibition of protein synthesis in gastrocnemius . Beginning 16 h after the induction of sepsis, either the binary complex or saline was injected twice daily via a tail vein, with measurements made 3 and 5 days later . By day 3, sepsis had reduced plasma IGF-I concentrations approximately 50% in saline-treated rats . Administration of the binary complex provided exogenous IGF-I to compensate for the sepsis-induced diminished plasma IGF-I . Sepsis decreased rates of protein synthesis in gastrocnemius relative to controls by limiting translational efficiency . Treatment of septic rats with the binary complex for 5 days attenuated the sepsis-induced inhibition of protein synthesis and restored translational efficiency to control values . Assessment of potential mechanisms regulating translational efficiency showed that neither the sepsis-induced change in gastrocnemius content of eukaryotic initiation factor 2B (eIF2B), the amount of eIF4E associated with 4E binding protein-1 (4E-BP1), nor the phosphorylation state of 4E-BP1 or eIF4E were altered by the binary complex . Overall, the results are consistent with the hypothesis that decreases in plasma IGF-I are partially responsible for enhanced muscle catabolism during sepsis.

Dis Colon Rectum, 2000 Oct, 43(10 Suppl), S54 - 8
Effect of early postoperative feeding on the healing of colonic anastomoses in the presence of intra-abdominal sepsis in rats; Kiyama T et al.; PURPOSE: Intra-abdominal infection is generally considered a major risk factor for dehiscence of primary colon anastomosis . To elucidate the indications for nutritional support during intra-abdominal sepsis, we investigated the healing of anastomoses in an animal model . METHODS: Twenty male Sprague-Dawley rats (280-320 g) underwent cecal ligation and single puncture . After 24 hours the perforated cecum was removed, and the left colon was transected and anastomosed in a single-layer inverted fashion . Animals were randomly assigned to receive both chow and water (early-fed group; n = 10) or water alone for the first 72 hours and chow thereafter (late-fed group; n = 10) . Colon-bursting pressure was measured five days after the anastomosis, at which time the anastomosis was excised . RESULTS: The survival rate after cecal ligation and single puncture was 100 percent, and blood cultures were positive in 20 percent of animals five days after surgery . All data are expressed as means +/- standard error of the mean . Body weight increased more in the early-fed group than in the late-fed group (15.6+/-3 vs . -6.3+/-2.8 g; P < 0.001) . Early feeding resulted in increased anastomotic bursting pressure (200+/-11 vs . 161+/-12 mmHg; P < 0.05) and total collagen concentration at the site of anastomosis (2.36+/-0.09 vs . 2.01+/-0.07 microg/mg wet tissue; P < 0.01) compared with the late-fed group . CONCLUSION: Early feeding has a positive effect on anastomotic healing in the presence of intraabdominal sepsis . The mechanism by which early feeding enhances the colonic anastomotic healing is unclear, although preservation of colonic collagen seems to play a significant role.

Rev Med Liege, 2000 Aug, 55(8), 798 - 802
{How I explore .. . value of isotopic techniques in the detection of sepsis in valvular prostheses}; Karsera D et al.; Vascular graft infection is a rare but serious complication of vascular surgery . The diagnosis is frequently difficult . White blood cell imaging (111In or 99mTc-HMPAO) is an adequate technique for detecting vascular graft infection . This is a sensitive and specific method and has some advantages in the detection of perioperative or low grade infection in comparison to conventional imaging . The usefulness of other techniques like the 18FDG-PET scan is studied, but not yet evaluated . We compare the different methods actually used by illustrating three case reports of vascular graft infection for whom the diagnosis was formally made by isotopic imaging.

Biol Neonate, 2000 Oct, 78(3), 230 - 2
Plasma carbon monoxide levels in term newborn infants with sepsis; Shi Y et al.; Carbon monoxide (CO) has been implicated as a new endogenously produced mediator similar to nitric oxide (NO) . CO was measured in plasma samples from 7 term newborn infants with sepsis and from 30 healthy neonates . Plasma CO levels were significantly higher in the group with sepsis at the time of admission to the neonatal intensive care unit than in the healthy controls (p < 0.05) . Moreover, the elevated plasma CO levels were significantly related to increased NO production, as indicated by plasma nitrite/nitrate levels (p < 0.05) . The present study suggests that, in addition to NO, CO might be another important mediator taking part in the pathogenesis of neonatal sepsis .

J Surg Res, 2000 Nov, 94(1), 61 - 7
Interdependence of adenosine and nitric oxide in hepato-splanchnic circulation during sepsis; Sam AD 2nd et al.; BACKGROUND: We tested the hypothesis that some of the maintenance of resting, regional hepato-splanchnic perfusion that is mediated by endogenous adenosine (ADO) during sepsis is interdependent with nitric oxide (NO) . MATERIALS AND METHODS: Twenty-four hours after sepsis/sham induction, rats were divided into two groups . Group 1 received a 10-min infusion of the ADO antagonist 8-sulfophenyltheophylline (8-SPT; 0.9 mg/kg x min), followed by 10 min of 8-SPT plus L-NAME (0.5 mg/kg x min) . Group 2 received L-NAME first followed by 8-SPT in the presence of L-NAME (all groups: n = 6-10) . Hemodynamic and regional hepato-splanchnic blood flow measurements were made prior to infusions, 10 min after initiation of each single agent infusion, and again after double agent infusion . RESULTS: Twenty-four hours after sepsis hepato-splanchnic blood flow was significantly elevated, compared to nonseptic rats . Both ADO receptor blockade alone and NOS inhibition alone decreased total hepato-splanchnic blood flow to nonseptic values . Decreases in small intestinal and cecal blood flow accounted for the majority of this decrease, but decreased hepatic arterial perfusion contributed as well . No further alterations were seen when 8-SPT was infused in the presence of L-NAME, nor when L-NAME was infused in the presence of 8-SPT . CONCLUSIONS: These data indicate that there is significant interdependence of endogenous NO and ADO in maintaining resting small bowel, cecal, and hepatic arterial perfusion during sepsis . The lack of responses in other regions of the hepato-splanchnic circulation demonstrate regional specificity of this ADO-NO interdependence .

Lakartidningen, 2000 Sep 13, 97(37), 3995 - 6, 3999-4001
{Increased procalcitonin level in bacteriogenic metabolic disturbances . A new possibility for diagnosis and treatment monitoring in sepsis}; Lindstedt G et al.; Earlier observations of increased plasma concentrations of immunoreactive calcitonin (32 amino acids) in sepsis and other non-tumorous conditions may be explained by increased secretion of procalcitonin, the 116-amino acid prohormone . At present, the site(s) of origin of procalcitonin in sepsis, the factors regulating its biosynthesis and release, the route(s) of its elimination from blood as well as its biological function(s) are unknown . The rapid increase in procalcitonin concentration in sepsis--in some patients earlier than that of C-reactive protein--and decrease upon successful chemotherapy makes procalcitonin a potentially important biomarker in monitoring patients with suspected or confirmed sepsis.

Klin Khir, 2000 Aug, (8), 13 - 6
{Prognostic value of oxygen metabolism indices in the diffuse purulent peritonitis complicated by sepsis}; Denisenko AI; There were the results of examination of 42 patients with diffuse purulent peritonitis, complicated by sepsis, analyzed . High risk of the oxygen debt, occurring due to limitation of the oxygen delivery to tissues, was noted . Normalization of delivery consumption ratio of oxygen and elimination of the oxygen debt in the early course of the disease are needed for the disease severity reduction and the mortality lowering.

J Immunol, 2000 Oct 15, 165(8), 4537 - 43
Increased resistance against acute polymicrobial sepsis in mice challenged with immunostimulatory CpG oligodeoxynucleotides is related to an enhanced innate effector cell response; Weighardt H et al.; Recent reports support the concept that the major defect in polymicrobial sepsis is an impaired immunologic response to infection . Oligodeoxynucleotides containing CpG sequence motifs (CpG-ODN) were previously shown to induce immune protection in models of chronic infection with intracellular bacteria, parasites, and viruses due to their ability to augment IFN-gamma-dependent Th1 responses . Here, we demonstrate that challenging mice with CpG-ODN substantially increases the resistance against acute polymicrobial sepsis . Systemic levels of IL-12, IL-18, and IL-10 were not altered in CpG-ODN-treated mice as compared with controls . In contrast, administration of CpG-ODN resulted in a strongly enhanced accumulation of neutrophils at the primary site of infection . Neutrophils of CpG-ODN-treated mice exhibited an up-regulation of phagocytic receptors, an increased phagocytic activity, and an elevated production of reactive oxygen metabolites . These results suggest that the protective effects of CpG-ODNs in acute polymicrobial sepsis are related to an enhanced effector cell response of innate immunity . CpG-ODN may therefore represent potent agents for the treatment of sepsis-associated immunoparalysis.

Clin Nutr, 2000 Oct, 19(5), 313 - 8
Effects of dietary fish oil on survival rate, plasma amino acid pattern, and inflammatory-related mediators in diabetic rats with sepsis; Chyi A et al.; This study was designed to investigate the effects of dietary fish oil on survival rates, plasma amino acid profiles, and inflammatory-related mediators in diabetic rats with sepsis . Diabetes mellitus (DM) was induced in rats by streptozotocin . The DM rats were maintained for 4 weeks on medium fat (10%, w/w) diets containing either fish oil or safflower oil . After that, sepsis was induced by cecal ligation and puncture (CLP) . There were 2 groups in this study: fish oil sepsis group (FOS) and safflower oil sepsis group (SOS) . The survival rate was observed after CLP . Also, changes of the amino acid pattern as well as interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, prostaglandin (PG) E(2)at 6, 12, and 24 h after CLP were investigated . The results demonstrated that survival rates were not significantly different between the 2 groups . Plasma arginine levels were significantly lower in sepsis groups than that in the DM-chow group, regardless of whether the diabetic rats were fed fish oil or safflower oil . No significant differences were observed in plasma valine, leucine, isoleucine, glutamine, or arginine concentrations between the FOS and SOS groups at different time points . Concentrations of IL-1 beta in peritoneal lavage fluid (PLF) at 6 h and TNF-alpha at 6 h as well as at 12 h after CLP in the FOS group were significantly higher than those in the SOS group . PGE(2)levels in PLF, by contrast, were lower in the FOS group at 6 and 12 h after CLP than in the SOS group . These results suggest that differences in IL-1 beta, TNF-alpha, and PGE(2)levels in PLF in the early period of sepsis did not influence the survival rates and plasma amino acid profiles of the FOS and SOS groups . Compared with safflower oil, feeding diabetic rats with fish oil had no beneficial effects on survival rates and muscle protein breakdown . The immunologic impact of dietary n-3 polyunsaturated fatty acids on diabetic rats with sepsis requires further investigation .

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