Cardiovasc Res, 2002 Nov, 56(2), 225 - 34 Sepsis causes presynaptic histamine H3 and alpha2-adrenergic dysfunction in canine myocardium; Cheng ZQ et al.; OBJECTIVE: Histamine H3 receptors and alpha2-adrenoceptors are presynaptic receptors that modulate norepinephrine (NE) release from sympathetic nerves innervating the cardiovascular system . We previously showed that cardiac H3 receptors are activated in sepsis, and that this activation leads to a decrease in the adrenergic response (AR) {J . Appl . Physiol . 85 (1998) 1693-1701} H3-receptors and alpha2-receptors appear to be coupled to GTP binding regulatory proteins (G) that modulate transmitter release by reducing calcium current into the nerve terminals through neuronal calcium channels . There may also be interaction between H3-receptors and alpha2-receptors on AR that may occur either at the receptor or a more downstream level . METHODS: In the present study, we examined the effect of septic plasma on AR in a canine ventricular preparation in which field stimulation was used to produce AR . We determined whether there was interaction between H(3)-receptors and alpha2-adrenoceptors and tested whether H3 activation would attenuate the alpha2-agonist and alpha2-antagonist effects of clonidine and yohimbine, respectively . We also determined whether the mechanism by which septic plasma decreases the adrenergic response involves inactivation of an inhibitory G protein and used pertussis toxin (PTX) to assess this effect . RESULTS: We found that septic plasma attenuated AR produced by field stimulation, and that this decrease was mediated by a PTX sensitive inhibitory G protein . H3 activation also attenuated the alpha2-agonist and alpha2-antagonist effects on adrenergic activation as compared with nonseptic plasma . CONCLUSION: We conclude that presynaptic sympathetic dysfunction may contribute to cardiovascular collapse in sepsis. Shock, 2002 Oct, 18(4), 380 - 6 NF-kappaB activation has tissue-specific effects on immune cell apoptosis during polymicrobial sepsis; Joshi AR et al.; Studies indicate that critically ill patients who succumb to sequela of sepsis/multiorgan failure, as well as septic animals, exhibit an apparently pathological increase in apoptosis (Ao) in the immune system . However, the mechanisms regulating these changes are unclear . Studies also indicate that, dependent on the cell population and the nature and/or duration of the stimuli, activation of the nuclear factor (NF)-kappaB can either suppress or enhance Ao . Thus, the aim of this study was to determine the contribution of NF-kappaB activation to the onset of Ao seen in divergent immune cell populations during sepsis, as produced by cecal ligation and puncture (CLP) . To assess this, C3H/HeN mice were pretreated (for 1 h) subcutaneously with either 100 mg/kg body weight of pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor, or with saline vehicle, prior to subjecting them to CLP or Sham-CLP (Sham) . Thymocytes, phagocytes, and Peyers Patch cells were harvested 24 h later, and the extent of Ao was determined by flow cytometry . The results indicate that PDTC pretreatment had no marked effect on the increase in thymocyte or phagocyte Ao seen following CLP, but there was a significant decline in the extent of Ao observed in septic mouse Peyer's patch B cells . To the extent that this was a result of NF-kappaB inhibition, we demonstrate by Western analysis, electrophoretic mobility shift assay (EMSA) and transfactor assay that the translocation of c-Rel to septic mouse Peyer's patch B cell nuclei is attenuated by PDTC . PDTC pretreatment also markedly reduced the number of Peyer's patch B cells that were producing IgA as well as attenuated the increase of proinflammatory cytokines in the blood . Interestingly, PDTC pretreatment did not restore peritoneal macrophage function or improve animal survival . Taken together, the inability of PDTC pretreatment to alter the Ao response of thymocytes or phagocytes, while inhibiting the increase in Peyer's patch B cell Ao in septic mice, implies not only that the activation of NF-kappaB has highly tissue/cell-specific effects that must be discerned when trying to clarify the pathophysiological role of NF-kappaB in sepsis, but that the activation of NF-kappaB may contribute to the early adaptive responses required by the host to fend off septic challenge. Shock, 2002 Oct, 18(4), 301 - 5 Differential regulation of systemic IL-18 and IL-12 release during postoperative sepsis: high serum IL-18 as an early predictive indicator of lethal outcome; Emmanuilidis K et al.; Systemic levels of the key immune regulatory cytokines IL-12 and IL-18 were measured over time in 66 patients with postoperative sepsis (38 survivors and 28 nonsurvivors) . Sepsis mortality was not significantly associated with any of the clinical parameters examined, including age, gender, underlying disease, and surgical procedure . Analysis of cytokine levels showed that during the entire observation period, IL-12 was significantly reduced in sepsis patients compared with control surgical patients without sepsis . IL-12 serum levels did not significantly differ between sepsis survivors and nonsurvivors . In contrast to IL-12, IL-18 serum levels were significantly higher in both surviving and nonsurviving sepsis patients than in controls . Importantly, we also observed that IL-18 levels were significantly increased in patients with lethal sepsis compared with sepsis survivors at all time points studied, including day 1 after sepsis diagnosis . IL-18 levels were significantly increased during the course of lethal sepsis, but remained at a comparable level in sepsis survivors . Logistic regression analysis of IL-18 values measured on days 1 or 2 of sepsis revealed that high serum IL-18 represents an early predictive factor for the lethal outcome of postoperative sepsis . Consistent with previous work in mouse models, our results suggest that IL-12 may contribute to protective immune reactions against a septic challenge, whereas IL-18 may preferentially promote organ injury and lethal shock. Clin Pharmacol Ther, 2002 Oct, 72(4), 391 - 402 Pharmacokinetic-pharmacodynamic analysis of drotrecogin alfa (activated) in patients with severe sepsis; Macias WL et al.; OBJECTIVE: We aimed to characterize the pharmacokinetics and pharmacodynamics of drotrecogin alfa (activated) (recombinant human activated protein C) in patients with severe sepsis . METHODS: Patients (N = 1690) in a randomized, double-blind, placebo-controlled phase 3 trial received a 96-hour infusion of placebo (n = 840) or drotrecogin alfa (activated) (n = 850), 24 microg x kg(-1) x h(-1) . Plasma samples from 680 patients were collected for pharmacokinetic assessment . Pharmacodynamic effects on activated partial thromboplastin time, D-dimer, protein C, and interleukin 6 were analyzed by drotrecogin alfa (activated) steady-state plasma concentration (C(ss)) quartile . RESULTS: Transient endogenous activated protein C concentrations above 10 ng/mL were observed in 11 placebo-treated patients (3.3%) . In drotrecogin alfa (activated)-treated patients, the median C(ss) was 44.9 ng/mL and the median plasma clearance (CL(p)) was 40.1 L/h . C(ss) was reached within 2 hours after the infusion was started . Plasma concentrations were below the assay quantitation limit of 10 ng/mL within 2 hours after the infusion was stopped in 92% of patients . CL(p) increased with increasing body weight, so infusion rates should be based on predose body weight . Mean CL(p) associated with age, sex, or baseline hepatic or renal function differed by less than 30% from the mean CL(p) in all patients and resided within the interquartile range of CL(p) in all patients . Dose adjustment is not required on the basis of these factors alone or in combination . No correlation was detected between C(ss) quartile and bleeding risk or the magnitudes of effect on biomarkers of coagulopathy (D-dimers and protein C) and inflammation (interleukin 6) . CONCLUSIONS: Plasma concentrations of drotrecogin alfa (activated) attain steady state rapidly after the infusion is started and decline rapidly after the infusion is stopped . The infusion rate should be based on predose body weight and not on any other demographic or baseline clinical covariate. Prof Nurse, 2002 Oct, 18(2), 68 - 9 Sepsis: early detection and care; Odell M; Nurses need to be aware of the signs and symptoms of sepsis . Staff education to encourage the early identification of this life-threatening condition will be aided by a new resource kit. Eur J Intern Med . 2002 Oct;13(7):434. Association between hypophosphatemia and cardiac arrhythmias in the early stages of sepsis; Schwartz A et al.; BACKGROUND: The purpose of this study was to evaluate a possible association between serum phosphate levels and the incidence of cardiac arrhythmias in the early stages of sepsis . METHODS: We conducted a prospective, controlled study in the General Intensive Care Unit (GICU) of a university hospital . Sixteen patients with sepsis, but without any previous cardiac disease, were studied during their first 24 h in the GICU . Patients were connected to a continuous ECG recording device . Blood samples for serum phosphate level determinations were drawn during the first 6 h after admission to the unit . RESULTS: Ten of 16 patients had 21 episodes of atrial and ventricular arrhythmias . These patients had higher mean Apache II scores (20.2+/-6.2) than the six patients without arrhythmias (13.2+/-1.7; P<0.05) and significantly lower mean phosphate levels (0.73+/-0.16 vs . 1.02+/-0.32 mmol/l; P<0.03) . No association was found between serum phosphate levels and mortality among patients with arrhythmias, or when all survivors (with and without arrhythmia) were compared to all non-survivors . CONCLUSIONS: The results indicate that patients with sepsis and low serum phosphate levels are at a greater risk of developing cardiac arrhythmias . We suggest that phosphate supplementation in the early stages of sepsis may prevent cardiac arrhythmias. Infection, 2002 Oct, 30(5), 267 - 71 Efficacy and safety of G-CSF mobilized granulocyte transfusions in four neutropenic children with sepsis and invasive fungal infection; Grigull L et al.; BACKGROUND: Bacterial and fungal infections are serious complications of cancer therapy . Especially during longstanding neutropenia, patients are at risk for life-threatening infections . The aim of this study was to assess the effect and safety of G-CSF mobilized granulocyte transfusions (GTX) in four neutropenic pediatric patients with sepsis . PATIENTS AND METHODS: The patients were between 4.6-17.5 years old and their diagnoses included very severe aplastic anemia, non-Hodgkin's lymphoma (NHL) and acute myeloid leukemia . Before GTX, all patients had fever despite antibiotic and antimycotic therapy, neutropenia (absolute neutrophil count ANC < 500/microl), increasing C-reactive protein (CRP) values, hypotension requiring dopamine infusion and three patients needed supplemental oxygen . The granulocyte donors received G-CSF (Neupogen, 5 microg/kg body weight) 12 h prior to granulocyte apheresis . RESULTS: In total, 40 GTX were performed (range 2-28 per patient) . The mean increase of the granulocyte count 1 h after GTX was 1,310/microl (range 200-2,950/microl) . Within the period of GTX the CRP values decreased in all patients . During or 24 h after the last GTX, the hypotension resolved and supplemental oxygen was stopped . One GTX was discontinued because of oxygen desaturation . CONCLUSION: GTX were a safe therapeutic measure with beneficial effects on serious infections in neutropenic children. Int J Biochem Cell Biol, 2002 Dec, 34(12), 1527 - 33 Sepsis: current concepts in intracellular signaling; Strassheim D et al.; Sepsis is the systematic response to infection . In septic patients who develop severe disease, excessive inflammation damages the lungs, liver, kidneys, and cardiovascular system, leading to multiple organ failure and an associated high mortality rate . Sepsis is the leading cause of death in the intensive care unit . The damage to critical organs is primarily due to excessive acute inflammatory response rather than inadequate combat of the infection per se . Impairment of critical organs is closely associated with infiltration of activated neutrophils into those tissues as well as increased activation of endothelial, epithelial, and macrophage populations within the organs to produce a deregulated, overly aggressive inflammatory response . New pharmacological advances hold promise in improving survival from this multi-systemic disorder . Increasing understanding of the signal transduction pathways of inflammatory cells involved in the disease suggests that targeting specific kinases and transcriptional regulatory mechanisms may prove improve outcome from sepsis. Am J Physiol Endocrinol Metab, 2002 Nov, 283(5), E1032 - 9 Phosphorylation of eukaryotic initiation factor eIF2Bepsilon in skeletal muscle during sepsis; Vary TC et al.; We reported that the inhibition of protein synthesis in skeletal muscle during sepsis correlated with reduced eukaryotic initiation factor eIF2B activity . The present studies define changes in eIF2Bepsilon phosphorylation in gastrocnemius of septic animals . eIF2B kinase activity was significantly elevated 175% by sepsis compared with sterile inflammation, whereas eIF2B phosphatase activity was unaffected . Phosphorylation of eIF2Bepsilon-Ser(535) was significantly augmented over 2-fold and 2.5-fold after 3 and 5 days and returned to control values after 10 days of sepsis . Phosphorylation of glycogen synthase kinase-3 (GSK-3), a potential upstream kinase responsible for the elevated phosphorylation of eIF2Bepsilon, was significantly reduced over 36 and 41% after 3 and 5 days and returned to control values after 10 days of sepsis . The phosphorylation of PKB, a kinase thought to directly phosphorylate and inactivate GSK-3, was significantly reduced approximately 50% on day 3, but not on days 5 or 10, postinfection compared with controls . Treatment of septic rats with TNF-binding protein prevented the sepsis-induced changes in eIF2Bepsilon and GSK-3 phosphorylation, implicating TNF in mediating the effects of sepsis . Thus increased phosphorylation of eIF2Bepsilon via activation of GSK-3 is an important mechanism to account for the inhibition of skeletal muscle protein synthesis during sepsis . Furthermore, the study presents the first demonstration of changes in eIF2Bepsilon phosphorylation in vivo. Intensive Care Med, 2002 Oct, 28(10), 1434 - 9 Epub 2002 Jul 23. Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial; Busund R et al.; OBJECTIVE: To determine the therapeutic efficacy and safety of plasmapheresis in the treatment of patients with severe sepsis and septic shock . DESIGN: Prospective, randomised, clinical trial with a planned, midstudy, interim analysis . SETTING: Intensive care unit in a university hospital in Archangels, Russia . PATIENTS: Consecutive patients with severe sepsis or septic shock . INTERVENTIONS: One hundred and six patients were randomised to receive either standard therapy or an add-on treatment with plasmapheresis . MEASUREMENTS AND RESULTS: The primary endpoint was 28-day survival . Septic shock was diagnosed in 57% of the plasmapheresis-treated patients and 54% of the control patients . Mean APACHE III score at entry was 56.4 in the plasmapheresis group and 53.5 in the control group . The 28-day, all-cause mortality rate was 33.3% (18/54) in the plasmapheresis group and 53.8% (28/52) in the control group . This represents a relative risk for fatal outcome in the plasmapheresis group of 0.61, an absolute risk reduction of 20.5% and a number of patients needed to treat of 4.9 . Apart from six transient episodes of hypotension and one allergic reaction to fresh frozen plasma, no adverse reactions were attributable to the plasmapheresis treatment in this study . CONCLUSIONS: Plasmapheresis may be an important adjuvant to conventional treatment to reduce mortality in patients with severe sepsis or septic shock . Plasmapheresis is a safe procedure in the treatment of septic patients . A prospective randomised multicentre trial is warranted to confirm our results and to determine which subgroups of septic patients will benefit most from this treatment modality. Pathophysiol Haemost Thromb, 2002 May-Jun, 32(3), 143 - 50 Quantification of antithrombin isoform proportions in plasma samples of healthy subjects, sepsis patients, and in antithrombin concentrates; Romisch J et al.; Antithrombin (AT) circulates in plasma in two isoforms, AT-alpha (90-95%) and AT-beta (5-10%) . AT isoform proportions were measured in plasma samples of 17 healthy subjects and 26 posttraumatic or postoperative septic patients, as well as in 4 commercially available AT concentrates . Total AT was immune-purified from plasma and concentrates . Micellar electrokinetic chromatography was used to analytically separate and quantify the isoforms . Compared with plasma samples of healthy donors, septic plasmas revealed significantly reduced AT activity (p < 0.001) and beta-isoform content (p < 0.05) . AT-beta correlated inversely with urea and creatinine serum concentrations (p < 0.01), indicating a relationship between better renal function and higher beta-isoform content . beta-Isoform neither correlated with age, gender, and 28-day mortality, nor with plasma concentrations of various inflammatory and organ function parameters . The commercial AT concentrate, which is equivalent to the current WHO standard, had an AT-beta content close to that found in plasma of healthy subjects . The availability of this novel quantitative AT isoform assay allows, for the first time, a closer look at the role of AT isoforms in hemostasis and sepsis pathophysiology . Kidney Int, 2002 Nov, 62(5), 1806 - 18 Impact of different modalities of continuous venovenous hemofiltration on sepsis-induced alterations in experimental pancreatitis; Yekebas EF et al.; BACKGROUND: Continuous venovenous hemofiltration (CVVH) is assumed to attenuate systemic complications in septic diseases . The impact of different treatment intensities of CVVH on immunologic and systemic alterations in experimental pancreatitis was evaluated . METHODS: Eighty-four minipigs were allocated either to an untreated control group (group 1) or to one of six treatment groups (groups 2 to 7) that underwent CVVH in different modalities: (1): "late" CVVH, started after a decline of total peripheral resistance of 30% versus "prophylactic" CVVH started immediately after the induction of pancreatitis; (2) no change of hemofilters versus a periodic change of filters every 12 hours; (3) low-volume CVVH with a filtrate turnover of 20 mL/kg body weight (BW)/h versus high-volume CVVH (100 mL/kg/h) . Pancreatitis was induced by intraductal injection of sodium-taurocholate (3%, 1 mL/kg BW) and enterokinase (2 U/kg BW) . We focused on the occurrence of sepsis, serum cytokines, down-regulation of major histocompatibility complex II (MHC II) and the endotoxin receptor CD14 expression, bacterial translocation/endotoxemia, and pulmonary and renal histologic alterations . RESULTS: CVVH delayed or definitively prevented the occurrence of sepsis . Pancreatitis was associated with a tremendous initial tumor necrosis factor-alpha (TNF-alpha) response prior to a return to near baseline levels in the late course of sepsis . Endotoxin hyporesponsiveness, suggested by the dissociation of decreasing TNF-alpha levels and increasing endotoxemia in end-stage sepsis, was favorably influenced by CVVH . Down-regulation of MHC II and CD14 expression was prevented in non-septic animals . CVVH-related sepsis-protection led to a significant attenuation of histological injury in lungs and kidneys . "Prophylactic" CVVH prevented histological changes more effectively than "late" CVVH . CONCLUSIONS: CVVH offers a therapeutic option for supportive treatment in severe pancreatitis . The efficiency of CVVH is associated with the duration of filter use and cumulative plasma turnover . Since CVVH may lead to sepsis-protection and long-term survival, further evaluation in controlled, clinical trials is warranted. EDTNA ERCA J, 2002, Suppl 2, 13 - 8 Importance of increased ultrafiltration volume and impact on mortality: sepsis and cytokine story and the role for CVVH; Ronco C et al.; There is growing interest in extracorporeal blood purification therapies (EBPT) as adjuvants in the complex therapy of sepsis and multiple organ dysfunction syndrome (MODS) . Nowadays the only routinely used purification technique is 'renal replacement therapy' (RRT) during acute renal failure (ARF), one of the almost inevitable and deadly components of MODS . RRT has been the first and still is the most utilised and effective type of EBPT . Evidence is growing about its ability to maintain homeostatic balance in critically ill patients, and specifically in septic patients with MODS . Clinical trials have been recently designed to modify or improve these therapies . In detail, the following issues have been currently addressed: effects on blood purification provided by different therapies, adequacy of prescription and delivery of therapy, toxins and solutes to be removed with these techniques . Based on these speculations we will briefly review the current understanding of these issues and the rationale for application of RRT in the intensive care unit (ICU) . In particular, we will focus on the importance of increased ultrafiltration volume and its impact on mortality in the general ICU population and in septic patients. Pancreas, 2002 Oct, 25(3), 245 - 50 Human leukocyte antigen-DR expression on peripheral monocytes as a predictive marker of sepsis during acute pancreatitis; Satoh A et al.; INTRODUCTION: The mortality associated with severe acute pancreatitis is still high, and death in the later stage of the disease is chiefly due to bacterial infection and sepsis . However, objective parameters for the risk of sepsis in acute pancreatitis have not been established . AIM: To investigate the value of human leukocyte antigen-DR (HLA-DR) on peripheral monocytes for predicting the development of sepsis during acute pancreatitis . METHODOLOGY: The expression of HLA-DR on peripheral monocytes was measured in 64 patients by flow cytometry at admission and 7 and 14 days after the onset of acute pancreatitis . Twenty-eight patients with severe acute pancreatitis and 36 with mild acute pancreatitis, as determined by the Atlanta classification, were enrolled . RESULTS: Six patients had sepsis, and two of them died during the hospital stay . At admission, the percentage of HLA-DR-expressing cells in the monocyte population was significantly lower in the patients who had sepsis in the later course than in the patients who did not have sepsis . A percentage lower than 80% at admission was observed in 17 patients, and the patients who had persistently low percentages of HLA-DR-expressing monocytes throughout the observation period had sepsis in the later clinical course, whereas the patients in whom expression recovered to the normal range were spared the development of sepsis . CONCLUSION: In acute pancreatitis, the low percentage of HLA-DR-expressing cells in the monocyte population is a reliable predictor of the development of sepsis . Monitoring of monocyte HLA-DR expression may be a useful marker for identifying the patients who are at high risk of sepsis in acute pancreatitis. Antibiot Khimioter, 2002, 47(5), 3 - 7 {Leukinferon in the treatment of patients with sepsis and multiple organ dysfunction syndrome}; Kuznetsov VP et al.; Dynamics of clinical signs, blood formula and some cytokins in serum samples of the patients with sepsis complicated by multiorgan disfunction syndrome (as a rule kidney and liver were involved) were investigated . Etiotropic therapy was combined with immunocorrecting treatment with leukinferone Combined regime provided positive results in clinical symptoms, in lymphocytes number normalization (abs . and per cent), stimulated T lymphocytes differentiation and facilitated intoxication finishing according to LII) . Immunocorrection practically had no effect on TNF-alpha, IL-1 alpha, IL-6, and stimulated IL-8 secretion more effectively than etiotropic therapy . IF-gamma level enhanced along with stopped IL-10 production . As a result ratio of IF-gamma/IL-10 enhanced from 0.56 to 1.0, in the case of etiotropic therapy this ratio diminished from 0.48 to 0.3 . It is concluded that immunocorrecting therapy provided positive dynamics in the ration IF-gamma/IL-10, recurring cell immune reactions . The recurrence period was shortened and lethality level was substantially lower (2.5 times). Curr Opin Crit Care, 2002 Oct, 8(5), 376 - 88 Myocardial dysfunction in the patient with sepsis; Krishnagopalan S et al.; The nature of myocardial dysfunction during sepsis and septic shock has been investigated for more than half a century . This review traces the evolution of scientific thought regarding this phenomenon during this period with particular emphasis on the current understanding of both the clinical manifestations and the molecular/cellular basis of septic myocardial dysfunction in critically ill patients . Current data suggest, contrary to older literature, that patients with septic shock develop a hyperdynamic circulatory state after fluid resuscitation and maintain this hyperdynamic circulatory state until death or recovery . Overt myocardial depression, as manifested by decreased cardiac output, is decidedly uncommon, even in the preterminal phase . Nonetheless, myocardial depression, as evidenced by biventricular dilation and depression of the ejection fraction, can be demonstrated in most patients with septic shock by using either radionuclide cineangiography or echocardiography . Depression is reversible over the course of 7 to 10 days in survivors . Available evidence suggests that myocardial hypoperfusion is not responsible for septic myocardial depression, because examination of humans with septic shock demonstrates increased myocardial perfusion, and animal models of septic shock appear to maintain myocardial high-energy phosphates . A circulating factor or factors, including the cytokines tumor necrosis factor alpha and interleukin-1beta, appear to have a significant role in the phenomenon . In addition, septic myocardial depression appears to be mediated in part through combinations of nitric oxide-dependent and -independent alterations of basal and catecholamine-stimulated cardiac myocyte contractility. Indian J Pediatr, 2002 Aug, 69(8), 663 - 5 Serum cortisol and thyroid hormone levels in neonates with sepsis; Das BK et al.; OBJECTIVE: To evaluate the thyroid hormone and cortisol levels in neonates with sepsis in relation to the final outcome . It was hypothesized that the hormonal level could act as some prognostic guideline . METHODS: Forty nine neonates, aged 8- 28 days, diagnosed as neonatal sepsis were selected for the study . Neonates below 8 days of age, 35 weeks of gestation and 2000 g of birth weight were excluded from the study . Twenty FT-AGA neonates beyond day 7 of life served as control for the study . The hormones were estimated by radioimmunoassay . RESULTS: The neonates with sepsis had significantly higher mean serum cortisol and lower mean serum total T4 at admission as compared to healthy neonates . The mean serum total T3 level was also lower, but the difference was not statistically significant . The mean serum TSH levels were comparable in both groups . The levels normalised following recovery . Sixteen neonates succumbed to the disease process . The non-survivors had significantly lower mean total T3 and total T4 levels as compared to the survivors . CONCLUSION: The endocrinal abnormalities are of transient nature as a response to sepsis . Low total T3 and total T4 are the predictors of adverse outcome in neonates with sepsis. J Paediatr Child Health, 2002 Oct, 38(5), 459 - 64 Utility of haematological parameters and C-reactive protein in the detection of neonatal sepsis; Manucha V et al.; OBJECTIVE: To evaluate various haematological parameters, individually and in combination, to formulate a haematological scoring system (HSS, defined by Rodwell et al.), which can then be used to screen for sepsis in neonates who are clinically suspected of infection.1 METHODS: The study cohort consisted of 150 neonates (from birth to 3 days old) with clinically suspected infection . Blood was collected by peripheral venepuncture in all neonates . A complete blood count, differential leucocyte count, total leucocyte count (TLC), total neutrophil count (TNC), immature neutrophil count, band form count and platelet count were performed . Immature total neutrophil count (I/T) and immature/mature neutrophil count (I/M) ratios were then obtained . C-reactive protein (CRP) was measured semiquantitatively and blood culture and antibiotic sensitivity were performed in each case . The haematological parameters were compared individually and in combination (by HSS) with CRP . RESULTS: Twenty-one (14%) neonates had blood culture proven sepsis . On evaluation of various haematological parameters, TLC < 10 x 109/L, TNC < 8 x 109/L, I/M > 0.25, I/T > 0.14, band count > 15% and platelet count < 150 x 109 were found to have optimal sensitivities and negative predictive values (NPV) . Using these values, an HSS was formulated . A haematological score > or = 3 had a sensitivity of 86% and NPV of 96% . C-reactive protein as a single test had a sensitivity of 76% and NPV of 96% . A combination of CRP with haematological parameters decreased the sensitivity and NPV of the HSS . CONCLUSIONS: A haematological score can be obtained by a complete blood count and examination of peripheral blood smear, thus permitting an objective assessment of haematological changes that occur in a neonate suspected of sepsis . C-reactive protein does not have any advantage over HSS, either as a single test or in combination. Shock, 2002 Sep, 18(3), 285 - 8 Sepsis-induced depressed contractile function of isolated ventricular myocytes is due to altered calcium transient properties; Ren J et al.; Chronic peritoneal sepsis in a rodent model produces myocardial dysfunction characterized by decreased rates of ventricular contraction and relaxation in the isolated heart preparation . However, it remains controversial whether the ventricular contractility is altered during sepsis . In the present study, we determined the effect of chronic peritoneal sepsis on the mechanical properties and intracellular Ca2+ handling of cardiac myocytes isolated from septic rats at 24 or 48 h . Mechanical properties were evaluated by use of an IonOptix MyoCam system . Myocytes were electrically stimulated at 0.5 Hz . The contractile properties analyzed included peak shortening (PS), time-to-peak shortening (TPS), time-to-90% relengthening (TR90), and maximal velocities of shortening and relengthening (+/-dL/dt) . Intracellular Ca2+ handling was evaluated with fura-2 fluorescent dye . Myocytes obtained from 24-h postseptic animals exhibited a depressed PS (85% of control), normal TPS, prolonged TR90 (147% of control), and reduced +/-dL/dt (both 79% of control) . Myocytes from 48-h postseptic animals also exhibited a reduced peak of intracellular Ca2+ sequestration (55% of control), but resting intracellular Ca2+ and Ca2+-transient decay were comparable with the values seen in myocytes from untreated rats . Myocytes from septic and control animals were equally responsive over a range of stimulation frequencies (0.1-5 Hz) . Myocytes from septic animals were unresponsive (5% of control) to increase of extracellular Ca2+ (0.5-3 mM) . These results demonstrate that sepsis produces substantial deficits in cardiac myocytes function that can be attributed to altered calcium transient properties. Shock, 2002 Sep, 18(3), 265 - 71 Influence of starvation, surgery, and sepsis on cardiac protein synthesis in rats: effects of parenteral nutrition, glutamine, and growth hormone; O'Leary MJ et al.; The effect of sepsis on the rate of protein synthesis in the heart is poorly described . We have investigated changes in protein synthesis in the ventricles of the heart over time after cecal ligation and puncture (CLP) in rats in comparison with sham-operated and unoperated animals (ad libitum) . All operated animals were starved from the time of surgery to the time of sacrifice . When operated animals were compared with ad libitum animals, ventricular weight and ventricular protein, and DNA and RNA contents were unchanged at 24 h, but were invariably reduced at 72 and 96 h . Fractional rate of protein synthesis (FSR), RNA activity, and cellular efficiency were reduced at 24 h and further reduced at 72 and 96 h . There were no differences, however, between septic and sham-operated animals . Eighteen hours after CLP, additional groups of rats were infused intravenously with 0.9% sodium chloride, parenteral nutrition (PN), or PN with glutamine, and were given a single dose of 400 microg recombinant human growth hormone (rhGH) or an equal volume of 0.9% sodium chloride . FSR was higher in animals given PN when compared with those given 0.9% sodium chloride only, and did not differ from FSR measured in unoperated animals . There was no additional benefit from the acute administration of either glutamine-enriched PN or rhGH . These results indicate that ventricular protein synthesis is markedly reduced by surgery and starvation, but that superimposed sepsis does not further influence these changes . PN can prevent the fall in cardiac protein synthesis associated with starvation, surgery, and sepsis, but neither glutamine nor rhGH produced any additional benefit. Crit Care Med, 2002 Sep, 30(9), 2083 - 90 A novel animal model of sepsis after acute lung injury in sheep; Murakami K et al.; OBJECTIVE: Patients with acute lung injury after smoke inhalation often develop pneumonia subsequently complicated by sepsis . This often is a fatal complication . The aim of this study was to develop a standardized and reproducible model of hyperdynamic sepsis after smoke inhalation in sheep . DESIGN: Prospective, experimental study in sheep . SETTINGS: Experimental laboratory in a university hospital . SUBJECTS: Twenty-one female Merino ewes . INTERVENTION: Animals were anesthetized and surgically prepared for this chronic study . After a week of recovery, baseline data were collected . After tracheostomy was performed, sheep were connected to a volume-controlled ventilator . Acute lung injury was produced by insufflating the lungs with 48 breaths of cotton smoke . During halothane anesthesia, live bacteria suspended in a 30-mL saline solution containing 2-5 x 10(11) colony-forming units were instilled through a bronchoscope into the right lower and middle lung lobes (10 mL each) and left lower lung lobe (10 mL; n = 10) . Eleven sheep were given smoke but not bacteria . After injury and the bacterial challenge, the animals were ventilated mechanically with 100% oxygen . The animals were monitored for 48 hrs . was detected in blood cultures after 14-48 hrs . MEASUREMENTS AND MAIN RESULTS: The sheep developed a hyperkinetic cardiovascular response concomitant with a decrease in Pao similar to severe sepsis in human patients who meet the criteria for acute respiratory distress syndrome (PaO2 /FIO2 <200) . These changes were more severe than in animals exposed to smoke inhalation alone . Mean arterial pressures at 48 hrs in the smoke-alone and the smoke + sepsis group were 85.5 +/- 5.2 and 68.1 +/- 7.6 mm Hg, respectively (mean +/- se, p<.05) . CONCLUSION: This animal model closely resembles hyperdynamic sepsis in humans and may be of great value for studies of sepsis with smoke inhalation. J Obstet Gynaecol India, 1979 Apr, 29(2), 264 - 8 A comparative study of sepsis as a complication of M.T.P . and induced abortion; Kapoor K et al.; PIP: In the 12 month period from April 1976 to April 1977, the number of septic abortions admitted at Bhagalpur Medical College Hospital was 60 . This figure represented 12.6% of all abortion cases (476) and 2.06% of all obstetrical admissions . 6 died (10%), and all were admitted moribund . Medical termination was carried out in 4 cases only, 2 at the College Hospital . The majority of septic abortions occurred in women between 30 and 40 years of age having 3 or more children . Many of the women reported previous spontaneous or induced abortions . All were treated conservatively with antibiotics and antisera, except those in whom hemorrhage or drainage of pus indicated surgical management . N Engl J Med, 2002 Sep 26, 347(13), 993 - 1000 An economic evaluation of activated protein C treatment for severe sepsis; Manns BJ et al.; BACKGROUND: Recombinant human activated protein C was shown in the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study to reduce mortality among patients with severe sepsis . A post hoc reanalysis by the Food and Drug Administration (FDA) of data from this study suggested that the reduction in mortality was restricted to patients with Acute Physiology and Chronic Health Evaluation (APACHE II) scores of 25 or more . METHODS: We estimated the cost effectiveness of activated protein C as compared with conventional care for patients with severe sepsis . We performed an economic analysis involving all patients, as well as analyses of subgroups defined according to age and severity of illness . The probabilities of transition between clinical states and the estimates of resource use were derived from a population-based cohort of patients with severe sepsis . We used data on the effectiveness of activated protein C from the PROWESS study and analyses by the FDA . RESULTS: The cost per life-year gained by treating all patients with activated protein C was $27,936 . It was more cost effective to treat patients with an APACHE II score of 25 or more ($24,484 per life-year gained) than those with a lower APACHE II score ($35,632 per life-year gained) . The cost effectiveness of treating patients with an APACHE II score of 24 or less increased to $575,054 per life-year gained when the FDA's estimates of effectiveness were considered . For patients with an APACHE II score of 25 or more, the cost per life-year gained increased with age ($16,309 for patients less than 40 years of age; $28,100 for those 80 years of age or older) . CONCLUSIONS: Activated protein C is relatively cost effective when targeted to patients with severe sepsis, greater severity of illness (an APACHE II score of 25 or more), and a reasonable life expectancy if they survive the episode of sepsis . Further research is needed to determine the cost effectiveness of activated protein C for patients with sepsis and less severe illness . Rev Biol Trop, 2002 Jun, 50(2), 485 - 505 The function of female resistance behavior: intromission by male coercion vs . female cooperation in sepsis flies (Diptera: Sepsidae); Eberhard WG; Female resistance behavior that occurs prior to intromission does not by itself imply forced copulation . Such behavior may function instead as a test of the male in order to favor some males over others, or to induce the male to desist . Thus, male persistence and forcefullness may sometimes be better described as persuasion rather than coercion . Under the persuasion hypothesis, the male only gains intromission due to an active response of the female . Under the coercion hypothesis, male and female are opposed in a physical battle which the female loses if copulation occurs . In species in which males are morphologically incapable of forcing intromission without active female cooperation (I argue here that this is probably a very common situation), data on the behavioral and ecological context in which resistance occurs can distinguish between the two possibilities . Partially congruent functions of resistance, seen from the female point of view, are female resistance to screen (male persuasion), and female resistance to avoid males non-selectively (male coercion) . Sepsis flies illustrate these ideas . Females often struggle energetically in apparent attempts to dislodge mounted males and to prevent intromission, and males grasp females with powerful species-specific structures on their front legs and genitalia . This suggests the possibility of coerced intromission . But behavioral and morphological evidence demonstrate that active female cooperation occurs at the moment of intromission, and that males are probably dependent on this cooperation because they are not morphologically equipped to force their genitalia into those of an uncooperative female . Despite the impression from previous publications, male insects in general may seldom be able to achieve intromission by genitalic force . The species-specific forms of the grasping genitalia of male sepsis are probably not the result of an evolutionary arms race between coercive males and unselectively resistant females. Scand J Infect Dis, 2002, 34(8), 620 - 2 Comparison of procalcitonin with CRP and differential white blood cell count for diagnosis of culture-proven neonatal sepsis; Blommendahl J et al.; We analysed the utility of procalcitonin (PCT) assay, either alone or in combination with 2 simple blood assays, for the diagnosis of culture-proven neonatal septicaemia . Tests for serum PCT concentration, serum CRP concentration and blood immature to total neutrophil leucocyte ratio all had reasonable (58-77%) sensitivity, reasonable (62-84%) specificity, good (94-97%) negative predictive value and poor (16-24%) positive predictive value for the diagnosis of sepsis . Algorithms combining various tests produced slight improvements in sensitivity or specificity . Although the PCT test appeared to be useful for the diagnosis of neonatal sepsis in this small study, it did not offer any significant advantages over traditional tests for the diagnosis of infection. Respiration, 2002, 69(5), 464 - 7 Weaning from mechanical ventilation by long-term nasal positive pressure ventilation in two patients with acute respiratory distress syndrome associated with pneumococcal sepsis; Windisch W et al.; Only few data concerning weaning by nasal positive pressure ventilation (NPPV) are available, and successful weaning by using NPPV in patients with acute respiratory distress syndrome (ARDS) and severe complications has not yet been described . Two cases with ARDS and both preexisting thoracopulmonary disease (infundibulum abnormality and suspected COPD) and associated complications (recurrent sepsis, acute renal failure, need for lobectomy, severe malnutrition) could not be weaned by invasive ventilatory techniques . Both patients presented with rapid shallow breathing and PaCO(2) values >60 mm Hg during intermittent trials of spontaneous breathing, although the primary pathology and associated complications had been resolved . Patients were successfully adapted on NPPV in a stepwise approach after 93 days and 67 days of invasive ventilation . In one patient withdrawal from NPPV was possible after 2 months . In the other patient the duration of daily ventilation could be significantly reduced from 18 to 6 h/day after 9 months on NPPV . Therefore, patients with ARDS who cannot be weaned by invasive ventilatory strategies might be removed successfully from invasive mechanical ventilation by using NPPV even when there are preexisting thoracopulmonary disease and major complications during invasive ventilation . Am J Physiol Lung Cell Mol Physiol, 2002 Oct, 283(4), L799 - 805 Alveolar macrophage activation after trauma-hemorrhage and sepsis is dependent on NF-kappaB and MAPK/ERK mechanisms; Jarrar D et al.; The acute respiratory distress syndrome (ARDS) is a major cause of morbidity after injury . We hypothesized that alveolar macrophage (AMPhi) chemokine and cytokine release after hemorrhage and sepsis is regulated by NF-kappaB and MAPK . Adult male rats underwent soft tissue trauma and hemorrhagic shock (~90 min) followed by crystalloid resuscitation . Sepsis was induced by cecal ligation and puncture (CLP) 20 h after resuscitation . AMPhi were harvested, and TNF-alpha, IL-6, and macrophage inflammatory protein (MIP)-2 release and serum IL-6 and TNF-alpha levels were measured at 5 h after HCLP . Lung tissues were analyzed for activation of NF-kappaB, myeloperoxidase activity, and wet/dry weight ratio . In control animals, AMPhi were stimulated with LPS with or without inhibitors of NF-kappaB and MAPK . Serum TNF-alpha and IL-6 levels and spontaneous AMPhi TNF-alpha and MIP-2 release were elevated (P < 0.05) after HCLP, concomitantly with the development of lung edema and leukocyte activation . Activation of NF-kappaB increased in lungs from the hemorrhage and CLP group compared with shams . Inhibition of NF-kappaB or the upstream MAPK significantly decreased LPS-stimulated AMPhi activation . Because enhanced release of inflammatory mediators by AMPhi may contribute to ARDS after severe trauma, inhibition of intracellular signaling pathways represents a target to attenuate organ injury under those conditions. Eur J Intern Med . 2002 Sep;13(6):389. Successful treatment of fulminant pneumococcal sepsis with recombinant tissue plasminogen activator; Akol H et al.; This case report describes a patient with a rapidly progressive pneumococcal septic shock and purpura fulminans . Despite maximal conventional treatment, the patient developed progressive multiple organ failure with imminent necrosis of the extremities . This extremely rare, but often fatal, disease responded dramatically to the infusion of recombinant tissue plasminogen activator. Crit Care, 2002 Aug, 6(4), 363 - 70 Epub 2002 Jun 13. Expression of the C5a receptor (CD88) on granulocytes and monocytes in patients with severe sepsis; Furebring M et al.; INTRODUCTION: Treatment of patients with severe sepsis with agents antagonising the effects of C5a has been proposed based on beneficial effects in animal experiments and in vitro studies demonstrating upregulation of the C5a receptor (CD88) on granulocytes by endotoxin . MATERIALS AND METHODS: CD88 expression on leukocytes from 12 patients with severe sepsis or septic shock was analysed by flow cytometer, and serum complement factors C3a and C5b-9 were measured by enzyme immunoassay techniques . RESULTS: The granulocyte CD88 expression on day 1 was lowered (36; range, 2-59) in comparison with controls (63; range, 25-88) (P < 0.001), despite complement activation, while the monocyte CD88 expression was unchanged . The receptor reduction correlated significantly to the APACHE II score (r2 = 0.35, P < 0.05) . The recovery of CD88 expression was slow . DISCUSSION: In contrast to the findings in animals, it is concluded that granulocyte CD88 expression is reduced at the time when the diagnosis of severe sepsis or septic shock can clinically be made . The reason for this needs further investigation but it may be due to a previous complement activation or to cytokine effects. Crit Care, 2002 Aug, 6(4), 357 - 62 Epub 2002 May 14. The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis {ISRCTN28863830}; Tugrul S et al.; INTRODUCTION: In this prospective, randomized controlled study, we aimed to evaluate the effect of IgM-enriched immunoglobulin treatment on progression of organ failure and septic shock in patients with severe sepsis . MATERIALS AND METHODS: Forty-two patients with severe sepsis were enrolled in the study . Patients in the study group (n = 21) received an intravenous immunoglobulin preparation (Pentaglobin in addition to standard therapy . Pentaglobin therapy was commenced on the day of diagnosis of severe sepsis: 5 ml/kg per day Pentaglobin (38 g/l IgG, 6 g/l IgM, and 6 g/l IgA) was infused over 6 hours and repeated for 3 consecutive days . Patients in the control group (n = 18) received standard sepsis therapy, but no immunoglobulin administration . Blood samples for procalcitonin (PCT) measurements were taken daily for 8 days . Severity of critical illness and development of organ failure were assessed by obtaining daily acute physiological and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores . RESULTS AND DISCUSSION: Procalcitonin levels showed a statistically significant decrease in the Pentaglobin group (P < 0.001); however, an improvement in SOFA scores could not be demonstrated . Procalcitonin levels and SOFA scores did not change significantly in the control group . Septic shock incidence (38% versus 57%) and 28-day mortality rate (23.8% versus 33.3%) were found to be similar between the Pentaglobin and control groups . The evaluation of serial APACHE II scores did not demonstrate a difference between Pentaglobin and control groups either . CONCLUSION: Present data could not demonstrate any beneficial effects of polyclonal immunoglobulin preparation Pentaglobin on organ morbidity, septic shock incidence and mortality rate in patients with severe sepsis. Crit Care, 2002 Aug, 6(4), 349 - 56 Epub 2002 Jun 24. Quality of life effects of antithrombin III in sepsis survivors: results from the KyberSept trial {ISRCTN22931023}; Rublee D et al.; INTRODUCTION: Treatment of sepsis is aimed at increasing both the duration and quality of survival . A long-term focus on quality of life (QoL) in clinical trial evaluations of sepsis care should be a priority . METHOD: QoL data were used to evaluate the effects of intravenous antithrombin III treatment for severe sepsis measured for up to 90 days during the follow-up phase of the KyberSept phase III clinical trial . A visual analog scale and a Karnofsky scale were used to measure physical, psychologic, and social QoL at regular intervals . Changes from baseline between placebo and antithrombin III groups were assessed using Wilcoxon statistical tests, with additional analyses by severity of illness and admitting diagnosis . RESULTS: Among all sepsis survivors in the trial, there was a significant advantage on some attributes of QoL in the antithrombin III subgroup of patients who did not receive heparin as compared with the corresponding placebo group . DISCUSSION: The present study represents the first attempt to evaluate patient QoL over a relatively long period in a large, randomized, placebo-controlled sepsis trial . Over a 90-day period, survivors of severe sepsis receiving antithrombin III experienced significant improvements as compared with placebo on several attributes of QoL . In conclusion, the present study demonstrated that clinical improvements over an extended time period with antithrombin III were complemented by improvements in QoL, particularly in social and psychologic functioning, in many patients. Pharmacotherapy, 2002 Sep, 22(9), 1140 - 56 Stress-dose corticosteroid therapy for sepsis and acute lung injury or acute respiratory distress syndrome in critically ill adults; MacLaren R et al.; Sepsis and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) are associated with high mortality rates despite recent therapeutic advances . Both disease states involve uncontrolled host defense responses that lead to inflammation, endothelial damage, enhanced coagulation, diminished fibrinolysis and fibroproliferation to produce microthrombi, and relative adrenal insufficiency . Corticosteroids inhibit the host defense response and may offer an inexpensive therapeutic option . Results of several randomized, double-blind studies demonstrated no survival benefit and higher secondary infection rates when supraphysiologic doses of corticosteroids were administered for less than 24 hours . Recently, the emphasis of research for corticosteroid therapy has involved adrenocortical replacement dosage regimens administered for several days to weeks, with doses corresponding to the stress level of the disease . Stress-dose therapy with hydrocortisone in patients with septic shock who require vasopressor support, especially if adrenal insufficiency is present, accelerates hemodynamic stability and reduces mortality . The frequency of gastrointestinal hemorrhage was higher with corticosteroid therapy than with placebo, but the occurrence of secondary infections was similar to that of placebo . The only randomized, double-blind study that evaluated stress-dose methylprednisolone therapy for ARDS was terminated early after only 24 patients were enrolled because therapy with methylprednisolone was associated with enhanced survival despite higher secondary infection rates . A multicenter study investigating stress-dose methylprednisolone for ARDS is under way and should provide valuable information . Sufficient data support stress-dose hydrocortisone therapy for vasopressor-dependent septic shock . Stress-dose methylprednisolone therapy for ALI-ARDS requires further study but may be warranted in cases of refractory infection-induced ARDS when impending mortality is likely. Pharmacotherapy, 2002 Sep, 22(9), 1084 - 90 The effect of sepsis during parenteral nutrition on hepatic microsomal function in rats; Dickerson RN et al.; STUDY OBJECTIVE: To investigate the effect of sepsis during parenteral nutrition on hepatic cytochrome P450 (CYP) activity in rats . DESIGN: Prospective, randomized, controlled study . SETTING: University-based animal research laboratory . ANIMALS: Twenty adult male Sprague-Dawley rats . INTERVENTION: The animals were cannulated intravenously and randomized to receive parenteral nutrition (PN), intravenous live Escherichia coli 4 x 10(8) colony-forming units/100 g body weight for 2 consecutive days with PN (PNEC), or chow (CH) . MEASUREMENTS AND MAIN RESULTS: Both PN alone and PNEC resulted in a progressive decline in hepatic CYP concentration compared with CH (0.53 +/- 0.10, 0.41 +/- 0.17, and 0.35 +/- 0.14 nmol/mg microsomal protein, respectively, p < 0.05) . Parenteral nutrition alone was associated with a 57% decrease in isoenzyme ethoxycoumarin-O-deethylase activity (ECOD) compared with CH, but sepsis did not further decrease ECOD activity any more than PN alone (0.103 +/- 0.049, 0.044 +/- 0.018, and 0.050 +/- 0.020 nmol/mg microsomal protein/min, respectively, p < 0.05) . CONCLUSION: Hepatic CYP concentration declines with PN and is further decreased when compounded by sepsis . The disproportional decrease in ECOD activity relative to CYP concentration with PN is unchanged by sepsis, indicating a selective alteration in hepatic isoenzymes by PN. Surgery, 2002 Aug, 132(2), 334 - 40 Complement regulatory protein CD59 involves c-SRC related tyrosine phosphorylation of the creatine transporter in skeletal muscle during sepsis; Wang W et al.; BACKGROUND: Myocellular creatine (Cr) uptake is predominantly governed by the creatine transporter (CreaT) and plays a pivotal role in skeletal muscle energy metabolism . The CreaT belongs to a neurotransmitter transporter family that is functionally regulated by protein tyrosine kinase induced tyrosine phosphorylation . Recently, complement regulatory protein CD59 has been found not only to protect host tissue from C5b-9 complex attack that occurs in sepsis but also to initiate the activation of Src family kinase and tyrosine phosphorylation of its downstream proteins . The purpose of this study was to determine the association between myocellular free Cr, c-Src related tyrosine phosphorylation of the CreaT, and CD59 during sepsis . METHODS: Male Sprague-Dawley rats (250 to 300 g) were randomized to undergo cecal ligation and puncture (CLP) or sham operation . Fast-twitch gastrocnemius muscles were harvested 24 hours after operation . Myocellular free Cr levels were measured by high-performance liquid chromatography . Combination of protein immunoprecipitation with Western blotting was used to assess tyrosine phosphorylation status of the CreaT and the association between CD59, c-Src, and CreaT . RESULTS: Myocellular free Cr levels were 70% greater after CLP . Tyrosine phosphorylation of the CreaT was significantly increased after CLP as compared to sham operation . Tyrosine phosphorylated c-Src (Tyr-416) in the CreaT-c-Src immune complex was 24% higher after CLP . Sepsis also increased protein expression of tyrosine phosphorylated c-Src (Tyr-416) or CreaT in the CD59-c-Src or CD59-CreaT complex by 20% or 30%, respectively . CONCLUSIONS: During sepsis, an increase in myocellular free Cr levels is associated with enhanced tyrosine phosphorylation of the CreaT, which is likely induced by active c-Src . CD59 is physically associated with both c-Src and CreaT, which suggests that CD59 may participate in the regulation of myocellular Cr metabolism via the CreaT during sepsis. Surgery, 2002 Aug, 132(2), 289 - 92 Interferon-gamma gene polymorphisms and the development of sepsis in patients with trauma; Stassen NA et al.; BACKGROUND: The outcome of patients with trauma does not always correlate with injury severity or premorbid health status . This study evaluates the relationship between polymorphisms in the first intron of the interferon-gamma gene and the development of sepsis after trauma . METHODS: DNA was extracted from peripheral leukocytes of patients with trauma and an injury severity score of 16 or greater . Data collected included demographics, injury mechanism, injuries sustained, development of sepsis, and outcome . A previously identified cytosine/adenine repeated polymorphism was amplified, alleles/genotypes identified, and the results correlated with patient outcome . RESULTS: Sixty-one patients were evaluated . Thirty patients (49%) became septic . The injury severity score, race, age, and gender distribution was similar for both the septic and nonseptic groups . Six alleles and 10 genotypes were identified . Alleles C (34%) and D (52%) were the most common . Patients who were septic had a 62% chance of having a D allele (P =.06), whereas they had only a 29% chance of having a C allele . Homozygotes for allele D (DD) were the most likely to become septic (65%) . CONCLUSIONS: Homozygotes for the D allele (DD) of the interferon-gamma gene have an increased chance of developing sepsis after traumatic injury compared with other allelic combinations . This supports the hypothesis that genetic composition plays a role in patient outcome. J Immunol, 2002 Sep 15, 169(6), 3223 - 31 Complement-induced impairment of innate immunity during sepsis; Huber-Lang MS et al.; This study defines the molecular basis for defects in innate immunity involving neutrophils during cecal ligation/puncture (CLP)-induced sepsis in rats . Blood neutrophils from CLP rats demonstrated defective phagocytosis and defective assembly of NADPH oxidase, the latter being due to the inability of p47(phox) to translocate from the cytosol to the cell membrane of neutrophils after cell stimulation by phorbol ester (PMA) . The appearance of these defects was prevented by in vivo blockade of C5a in CLP rats . In vitro exposure of neutrophils to C5a led to reduced surface expression of C5aR and defective assembly of NADPH oxidase, as defined by failure in phosphorylation of p47(phox) and its translocation to the cell membrane, together with failure in phosphorylation of p42/p44 mitogen-activated protein kinases . These data identify a molecular basis for defective innate immunity involving neutrophils during sepsis. Arch Surg, 2002 Sep, 137(9), 1037 - 43; discussion 1043 Decreased cytokine expression in peripheral blood leukocytes of patients with severe sepsis; Cabioglu N et al.; BACKGROUND: High levels of tumor necrosis factor (TNF) alpha messenger RNAs and interleukin (IL) 8 have been reported in leukocytes of patients with sepsis . HYPOTHESIS: Assessment of leukocyte intracytoplasmic levels of proinflammatory and anti-inflammatory cytokines might be clinically more relevant to determine prognosis in patients with severe sepsis . DESIGN: Cohort study . SETTING: Surgical intensive care units of a university hospital . PATIENTS AND INTERVENTIONS: Leukocyte suspensions obtained from 16 patients, 6 during early sepsis or septic shock and 10 during late sepsis or septic shock, were incubated with anti-CD14 and anti-CD2 or anti-CD3 monoclonal antibodies and then with intracytoplasmic anticytokine antibodies staining for interferon-gamma, TNF-alpha, IL-2, IL-6, IL-8, IL-10, and IL-12 and analyzed with a flow cytometer . MAIN OUTCOME MEASURES: Mann-Whitney test and Spearman correlation test were used in statistical evaluations according to the 28-day all-cause mortality rates and multiple organ dysfunction and sepsis-related organ failure assessment scores . RESULTS: Higher serum IL-6, IL-8, C-reactive protein, and procalcitonin levels were found in patients with high multiple organ dysfunction and sepsis-related organ failure assessment scores (greater than or equal to the median values {8 and 11, respectively}), in contrast to decreased T-lymphocyte-associated IL-6 and TNF-alpha and monocyte-associated IL-10 and IL-12 proportions . Furthermore, in 28-day all-cause mortality analysis, there were higher levels of C-reactive protein and procalcitonin in nonsurvivors (n = 9) than in survivors (n = 7), while T-lymphocyte-associated IL-2, IL-6, IL-10, and TNF-alpha and monocyte-associated IL-10 and TNF-alpha proportions decreased in the nonsurvivors . CONCLUSION: These results suggest that diminished lymphocyte- and monocyte-associated proinflammatory and anti-inflammatory cytokine levels are associated with worse prognosis in patients with severe sepsis. Intensive Care Med, 2002 Sep, 28(9), 1351 - 6 Epub 2002 Aug 07. Procalcitonin: a marker to clearly differentiate systemic inflammatory response syndrome and sepsis in the critically ill patient? Giamarellos-Bourboulis EJ, Mega A, Grecka P, Scarpa N, Koratzanis G, Thomopoulos G, Giamarellou H. OBJECTIVES: To define the role of procalcitonin in the differential diagnosis, prognosis and follow-up of critically ill patients . DESIGN: Prospective study during the 2-year period from January 1998-2000 . PATIENTS: One hundred nineteen critically ill patients: 29 with systemic inflammatory response syndrome (SIRS) without any signs of infection, 11 with sepsis, 17 with severe sepsis, 10 with septic shock and 52 controls . Daily measurements of procalcitonin were performed by an immunocheminoluminometric assay, and values were correlated to the clinical characteristics of the patients . RESULTS: Mean concentrations of procalcitonin were 5.45 (95% CI: 2.11, 8.81), 7.29 (95% CI: -1.92,14.59), 6.26 (95% CI: -1.32, 13.85) and 38.76 ng/ml (95% CI: 0.15, 77.38) on the 1st day in patients with SIRS, sepsis, severe sepsis and septic shock, respectively, and were statistically superior to those of control patients . Procalcitonin was gradually diminished over time with the resolution of the syndrome, while it was sustained in the same or more augmented levels upon worsening . Mean concentrations of procalcitonin on the 1st day for patients finally progressing to ARDS, to ARDS and acute renal failure, to ARDS, acute renal failure and DIC and to ARDS, acute renal failure, DIC and hepatic failure were 10.48, 8.08, 32.72 and 43.35 ng/ml, respectively . ROC curves of the sensitivity and specificity of procalcitonin for the evaluation of SIRS and sepsis were similar . CONCLUSIONS: The definite differential diagnosis between SIRS and sepsis may not rely on a single application of procalcitonin but on the complete clinical and laboratory evaluation of the patient with procalcitonin playing a considerable role . Procalcitonin is an early prognostic marker of the advent of MODS; therefore, daily determinations might help in the follow-up of the critically ill patient. Intensive Care Med, 2002 Sep, 28(9), 1220 - 5 Epub 2002 Jul 19. Predictive value of procalcitonin and interleukin 6 in critically ill patients with suspected sepsis; Pettila V et al.; OBJECTIVE: To evaluate the performance of procalcitonin (PCT), interleukin-6 (IL-6), C-reactive protein, leukocyte count, D-dimer, and antithrombin III at onset of septic episode and 24 h later in prediction of hospital mortality in critically ill patients with suspected sepsis . DESIGN AND SETTING: Prospective, cohort study in two university hospital intensive care units . PATIENTS: 61 critically ill patients with suspected sepsis . MEASUREMENTS AND RESULTS: The outcome measure was hospital mortality . Hospital survivors ( n=41) and nonsurvivors ( n=20) differed statistically significantly on day 1 (admission) in PCT, IL-6, SOFA score, and APACHE II score, and 24 h later in PCT, IL-6, and D-dimer values . AT III, CRP, and leukocyte count did not differ . The areas under receiver operating curves showed reasonable discriminative power (>0.75) in predicting hospital mortality only for day 2 IL-6 (0.799) and day 2 PCT (0.777) values which were comparable to that of APACHE II (0.786), and which remained the only independent predictor of mortality . CONCLUSIONS: Admission and day 2 IL-6, and day 2 PCT, and day 2 D-dimer values differed significantly between hospital survivors and nonsurvivors among critically ill patients with suspected sepsis . However, in prediction of hospital mortality, only the discriminative power of day 2 PCT and IL-6 values, and APACHE II was reasonable as judged by AUC analysis (>0.75). Intensive Care Med, 2002 Sep, 28(9), 1208 - 17 Epub 2002 Jul 27. Opening the microcirculation: can vasodilators be useful in sepsis? Buwalda M, Ince C. OBJECTIVE: A prominent feature of sepsis is dysfunction of the microcirculation, with impaired perfusion and regional tissue oxygenation causing a deficit in oxygen extraction . If shunting of oxygen transport past closed hypoxic microcirculatory beds is responsible for this, vasodilator therapy, which raises the driving pressure of the microcirculation and thereby promotes flow, could recruit such shunted microcirculatory units and improve tissue oxygenation . DESIGN: A literature search was conducted in Medline for evidence of this expected benefit of vasodilators in sepsis . METHODS: Studies were searched using the keyword for vasodilating drugs in combination with "sepsis," "septic," "multiple organ failure," or "critically ill patients." The search included animal and clinical investigations but only where the effects of vasodilator therapy were demonstrated by regional measures of oxygen transport variables (e.g., oxygen extraction variables, regional ischemia, microcirculatory flow or tissue oxygenation measurements) . The vasodilating drugs investigated included prostacyclin, pentoxifylline, N-acetyl-cysteine, and nitric oxide donors used in animal and human sepsis . RESULTS: Prostacyclin and nitric oxide donors are the best studied vasodilating agents in experimental sepsis and have shown improved tissue perfusion and oxygen extraction . In several clinical studies prostacyclin has also been shown to have such beneficial effects . Recent studies using orthogonal polarization spectral imaging have shown microcirculatory recruitment by nitric oxide donors in hemodynamically resuscitated septic patients . Whether such therapeutic modalities aimed at recruitment of the microcirculation improve outcome, however, still has to be determined. Proc Natl Acad Sci U S A, 2002 Sep 17, 99(19), 12351 - 6 Epub 2002 Sep 03. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation; Ulloa L et al.; Sepsis, a potentially fatal clinical syndrome, is mediated by an early (e.g., tumor necrosis factor and IL-1) and late {e.g., high mobility group B-1 (HMGB1)} proinflammatory cytokine response to infection . Specifically targeting early mediators has not been effective clinically, in part because peak mediator activity often has passed before therapy can be initiated . Late-acting downstream effectors, such as HMGB1, that mediate sepsis lethality may be more relevant therapeutic targets . Ethyl pyruvate (EP) recently was identified as an experimental therapeutic that significantly protects against lethal hemorrhagic shock . Here, we report that EP attenuates lethal systemic inflammation caused by either endotoxemia or sepsis even if treatment begins after the early tumor necrosis factor response . Treatment with EP initiated 24 h after cecal puncture significantly increased survival (vehicle survival = 30% vs . EP survival = 88%, P < 0.005) . EP treatment significantly reduced circulating levels of HMGB1 in animals with established endotoxemia or sepsis . In macrophage cultures, EP specifically inhibited activation of p38 mitogen-activated protein kinase and NF-kappaB, two signaling pathways that are critical for cytokine release . This report describes a new strategy to pharmacologically inhibit HMGB1 release with a small molecule that is effective at clinically achievable concentrations . EP now warrants further evaluation as an experimental "rescue" therapeutic for sepsis and other potentially fatal systemic inflammatory disorders. Alcohol Clin Exp Res, 2002 Aug, 26(8), 1245 - 51 Glutathione replacement preserves the functional surfactant phospholipid pool size and decreases sepsis-mediated lung dysfunction in ethanol-fed rats; Velasquez A et al.; BACKGROUND: Alcohol abuse increases the incidence of acute respiratory distress syndrome (ARDS) . Previous evidence from our laboratory links ethanol-mediated glutathione depletion to impaired surfactant production by alveolar epithelial cells in vitro and to endotoxin-mediated edematous injury in isolated lungs ex vivo . ARDS patients have an imbalance between the inactive small aggregate (SA) and the bioactive large aggregate (LA) forms of surfactant phospholipid (as reflected by increased SA/LA ratios) . Therefore, we hypothesized that ethanol ingestion, via glutathione depletion, could alter surfactant phospholipid distribution between LA and SA forms and thereby exacerbate sepsis-mediated lung dysfunction in vivo . METHODS: Rats fed an isocaloric diet with or without ethanol (36% total calories) for 6 weeks were made septic via cecal ligation and perforation . Some ethanol-fed rats had their diets supplemented with the glutathione precursor procysteine (>L-2-oxothiaxolidine-4-carboxylate) . Sepsis physiology was assessed by determining respiratory rates, arterial blood pressures, and plasma lactate levels, and lung dysfunction was assessed by determining lung lavage fluid protein levels (index of alveolar endothelial/epithelial barrier disruption), arterial hypoxemia (index of impaired gas exchange) and surfactant phospholipid SA and LA fractions (index of the alveolar epithelium's ability to maintain a functional surfactant pool during sepsis) . RESULTS: Ethanol ingestion decreased (p< 0.05) lung lavage fluid glutathione levels, and this defect was prevented by procysteine . Although ethanol ingestion had no effect (p< 0.05) on any of the indices of sepsis, it increased (p< 0.05) lung lavage fluid protein levels, worsened hypoxemia, and decreased the functional (LA) surfactant phospholipid pool after sepsis, all of which was prevented by procysteine . CONCLUSIONS: Ethanol ingestion, via glutathione depletion, increased sepsis-mediated lung dysfunction, and these effects could contribute to the increased risk of ARDS seen in alcoholic patients. Ann Pharmacother, 2002 Sep, 36(9), 1424 - 9 Recombinant human activated protein C for use in severe sepsis; Bearden DT et al.; OBJECTIVE: To review the efficacy and safety of drotrecogin alfa (recombinant human activated protein C) in the treatment of sepsis . DATA SOURCES: Literature was identified through a MEDLINE search (1966-January 2002), the product manufacturer, and the Food and Drug Administration . STUDY SELECTION/DATA EXTRACTION: All relevant information identified from the data sources was evaluated . DATA SYNTHESIS: Drotrecogin alfa reduces coagulation and inflammation in septic patients . A large placebo-controlled clinical trial (n = 1690) of drotrecogin alfa in severely septic patients demonstrated a reduction in mortality (24.7% vs . 30.8%; p = 0.005), with increased bleeding risks (24.9% vs . 17.7%; p <0.001) . Patients with more severe sepsis appeared to gain the most benefit . The complete clinical and economic impact of this agent requires further analysis . CONCLUSIONS: Drotrecogin alfa offers a significant advance in the treatment of severe sepsis . Judicious use in appropriate patients is necessary to control cost and maximize clinical benefits. Eur Radiol, 2002 Sep, 12(9), 2172 - 9 Epub 2002 Jul 06. Non-traumatic abdominal emergencies: imaging and intervention in sepsis; Lee MJ; Cross-sectional imaging, in particular CT, has become the main method of detecting abdominal collections . Indium-labelled white-cell scintigraphy and gallium scintigraphy are reserved for patients in whom there is a high clinical suspicion of abdominal sepsis but CT has not revealed a source of sepsis . Scintigraphy is also used in patients with suspected vascular graft infections or suspected infected hip prostheses . Percutaneous abscess drainage (PAD) has revolutionised the treatment of abdominal abscesses over the past 20 years, with repeat laparotomy for postoperative abscesses becoming a rare event . Ultrasound or CT can be used to guide PAD . Choosing an access route that does not cross intervening organs is of crucial importance to the safe performance of PAD . The Trocar or Seldinger techniques can be used with equal success . The cavity should be aspirated until dry and irrigated with saline . Repeat imaging after drainage is helpful to detect any undrained locules . PAD endpoints include patient defervescence, reduction in white blood cell count and catheter drainage of less than 10 ml per day . Details regarding PAD in specific abdominal regions are discussed . Success rates for PAD are high (close to 90%) in most abdominal organs . Slightly lower success rates are seen with PAD of pancreatic abscesses and abscesses associated with fistulas (60-85% success rates) . Complication rates lie between 0% and 10% . Complications can be minimised by ensuring that the patient has broad spectrum antibiotic coverage before drainage, by carefully planning the access route and by ensuring diligent post-procedure care by radiology staff. Am J Physiol Regul Integr Comp Physiol, 2002 Sep, 283(3), R553 - 60 Adrenomedullin binding protein-1 modulates vascular responsiveness to adrenomedullin in late sepsis; Zhou M et al.; Adrenomedullin (AM), a potent vasodilatory peptide, plays an important role in initiating the hyperdynamic response during the early stage of sepsis . Moreover, the reduced vascular responsiveness to AM appears to be responsible for the transition from the early, hyperdynamic to the late, hypodynamic phase of sepsis . Although the novel specific AM binding protein-1 (AMBP-1) enhances AM-mediated action in a cultured cell line, it remains to be determined whether AMBP-1 plays any role in modulating vascular responsiveness to AM during sepsis . To study this, adult male rats were subjected to sepsis by cecal ligation and puncture (CLP) . The thoracic aorta was harvested for determination of AM-induced vascular relaxation . Aortic levels of AMBP-1 were determined by Western blot analysis, and AM receptor gene expression in the aortic tissue was assessed by RT-PCR . The results indicate that AMBP-1 significantly enhanced AM-induced vascular relaxation in aortic rings from sham-operated animals . Although vascular responsiveness to AM decreased at 20 h after CLP (i.e., the late, hypodynamic stage of sepsis), addition of AMBP-1 in vitro restored the vascular relaxation induced by AM . Moreover, the aortic level of AMBP-1 decreased significantly at 20 h after CLP . In contrast, AM receptor gene expression was not altered under such conditions . These results, taken together, suggest that AMBP-1 plays an important role in modulating vascular responsiveness to AM, and the reduced AMBP-1 appears to be responsible for the vascular AM hyporesponsiveness observed during the hypodynamic phase of sepsis. Inflammation, 2002 Aug, 26(4), 167 - 74 Calcitonin gene-related peptide partially reverses decreased production of chemokines KC and MIP-2 following murine sepsis; Wang X et al.; The secretion of calcitonin gene-related peptide (CGRP) and the chemokines KC and MIP-2 are increased in the animal models of endotoxemic and septic shock . We tested whether CGRP could modulate KC and MIP-2 secretion from different sources of macrophages after murine sepsis induced by cecal ligation and puncture (CLP) . Macrophages were obtained from the peritoneal exudate and lung of female BALB/c mice 16 h after CLP and plated in culture with CGRP and/or LPS for 12 h . The results showed that peritoneal macrophage production of the chemokines (KC, MIP-2) and cytokines (TNF-alpha, IL-6) was markedly decreased in CLP mice . Alveolar macrophages did not display decreased cytokine/chemokines production after CLP . CGRP (0.1 nM-10 nM) partially reversed this decreased production of LPS-induced KC and MIP-2 from peritoneal macrophages . These results suggest that CGRP might be intimately involved in recruitment of neutrophils by promoting local production of the chemokines KC and MIP-2 in murine sepsis. Surg Today, 2002, 32(8), 695 - 700 Gut glutamine metabolism at different stages of sepsis in rats; Nose K et al.; PURPOSE: To investigate gut glutamine metabolism and determine the effects of glutamine supplementation in different stages of sepsis in a rat model.METHODS: Sepsis was induced by cecal ligation and puncture (CLP), and control rats underwent a sham operation . In the first experiment, a continuous infusion of normal saline was started at the end of the operation . Intestinal blood flow, glutamine concentrations of the abdominal aorta and superior mesenteric vein (SMV) were measured, and gut glutamine extraction and flux were calculated 5 h after the sham operation, and 5 and 20 h after CLP, being groups Ia ( n = 9), Ib ( n = 8), and Ic ( n = 8), respectively . In the second experiment, animals received a continuous infusion of alanyl-glutamine instead of normal saline and were divided into groups IIa ( n = 8), IIb ( n = 8), and IIc ( n = 6) . The same parameters were measured in each group and compared with those of the corresponding group in the first experiment.RESULTS: In the first experiment, no significant difference in SMV blood flow was seen among the groups . The arterial glutamine concentration was increased in group Ic ( P < 0.05) compared with that in groups Ia and Ib . Gut glutamine extraction was significantly increased in group Ib ( P < 0.01) and significantly decreased in group Ic ( P < 0.05) compared with that in group Ia . In the second experiment, gut glutamine flux was significantly increased in group Ilb ( P < 0.01) compared with that in group Ib, but the increase did not reach statistical significance between groups Ia and IIa or between groups Ic and IIc.CONCLUSION: These results indicate that intestinal glutamine uptake is increased and glutamine utilization is enhanced by glutamine supplementation in early sepsis. Curr Opin Hematol, 2002 Sep, 9(5), 416 - 21 Coagulation inhibition for sepsis; Key NS et al.; Following on the heels of multiple failed clinical trials of adjunctive therapeutic agents in sepsis, the positive outcome of a recent phase III study using activated protein C (APC) has led to a renewed optimism in targeted biotherapies for this syndrome . A growing body of data (both preclinical and clinical) suggests that the protection against death afforded by APC cannot be solely explained by its antithrombotic activity but rather is likely explained by its associated anti-inflammatory and profibrinolytic effects . Although a recent phase III study failed to demonstrate any protective effect of another important antithrombotic molecule, antithrombin, it is premature to conclude that the benefit observed with APC is unique among inhibitors of the coagulation system . The result of a third phase III study examining the effect of tissue factor pathway inhibitor (TFPI) in sepsis is currently awaited, and the possibility that other antithrombotic agents--and combinations thereof--have a place in the therapeutic armamentarium will undoubtedly be the topic of future studies . Expert Opin Biol Ther, 2002 Aug, 2(6), 659 - 64 Drotrecogin alfa: a new approach in the treatment of severe sepsis; Vincent JL; Severe sepsis is a common and frequently fatal condition . Evidence showing a link between the coagulation system and the inflammatory response to sepsis led to the development of drotrecogin alfa (activated) as an agent in the treatment of sepsis . This recombinant form of the natural protein, activated protein C (Xigris, Eli Lilly Co.), has been shown to significantly reduce mortality in a large randomised, controlled Phase III study involving 1690 patients . The exact mode of action of drotrecogin alfa (activated) remains uncertain, although it clearly combines anticoagulant and anti-inflammatory properties . Although associated with an increased risk of bleeding, this is usually procedure-related rather than spontaneous . Although costly, this is a drug that effectively reduces mortality rates in patients with severe sepsis. J Trauma, 2002 Aug, 53(2), 276 - 82; discussion 282-3 Mechanism of immune dysfunction in sepsis: inducible nitric oxide-meditated alterations in p38 MAPK activation; Song GY et al.; BACKGROUND: After the onset of sepsis, there is a marked dysfunction in cell-mediated immunity that contributes to the morbidity and mortality seen in this condition . Although both nitric oxide (NO) from inducible NO synthase (iNOS) and the activation of p38 mitogen-activated protein kinase (p38 MAPK) appear to contribute to this immune dysfunction, the extent to which NO regulates p38 MAPK activity in sepsis remains unknown . METHODS: To examine this, we induced sepsis by cecal ligation and puncture (CLP) in iNOS knockout (iNOS -/-) or C57BL/6 control mice . Twenty-four hours after CLP or sham operation, splenic T cells and macrophages were isolated and then stimulated with monoclonal antibody against the T-cell marker CD3 (anti-CD3) or lipopolysaccharide . At 4 or 24 hours after stimulation, cytokine release was determined by enzyme-linked immunosorbent assay, and p38 MAPK phosphorylation (activation) was determined by immunoblotting with antibody specific to phosphorylated p38 MAPK . RESULTS: Splenic T-cell p38 MAPK activation and interleukin (IL)-10 release was increased by CLP, whereas Th1 cytokine (IL-2, interferon-gamma) release was depressed . iNOS gene deficiency inhibited p38 MAPK activation in splenic T cells taken from septic mice, and also suppressed IL-10 release in both sham and septic mice . Interestingly, although deficiency of iNOS restored IL-2 release after CLP, both sham and CLP T cells remained depressed in their ability to release interferon-gamma . Septic insult markedly suppressed C57BL/6 splenic macrophage release of proinflammatory agents tumor necrosis factor, IL-12, and IL-1, while augmenting the release of IL-10 . However, although deficiency of iNOS concomitantly restored the ability to produce tumor necrosis factor while suppressing the rise in IL-10 release and p38 MAPK activation, it only partially restored IL-1 release and had no effect on IL-12 production seen after CLP . CONCLUSION: These data suggest that NO release from iNOS regulates aspects of sepsis-induced immune dysfunction by the activation of p38 MAPK. Am J Physiol Endocrinol Metab, 2002 Sep, 283(3), E472 - 81 Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis; Yumet G et al.; During sepsis, growth hormone (GH) resistance contributes to the catabolism of muscle protein . To determine the role of tumor necrosis factor (TNF) as a mediator of GH resistance, we examined the effects of a TNF antagonist {TNF-binding protein (TNFbp)} on the GH/insulin-like growth factor (IGF) I system during abdominal sepsis . To investigate potential mechanisms, the effects of TNF on the IGF-I response to GH and GH signaling were examined in cultured rat hepatocytes (CWSV-1) . Three groups of rats were studied: Control, Sepsis, and Sepsis + TNFbp . Liver, gastrocnemius, and plasma were collected on day 5 . In gastrocnemius, neither sepsis nor TNFbp altered the abundance of IGF-I mRNA . However, septic rats demonstrated an increase in circulating GH and a reduction in plasma IGF-I concentrations that was ameliorated by pretreatment with TNFbp . Liver from septic rats demonstrated a 50% reduction in GH receptor (GHR) and IGF-I mRNA on day 5 that was attenuated by TNFbp . However, the abundance of GHR protein was not different in liver from Control, Sepsis, or Sepsis + TNFbp rats . Consequently, a decreased amount of hepatic GHR does not explain the GH-resistant septic state . In CWSV-1 hepatocytes, TNF-alpha had no effect on GHR protein level but inhibited the induction of IGF-I mRNA by GH . Nuclear protein from TNF-treated hepatocytes demonstrated similar levels of phosphorylated signal transducer and activator of transcription-5 (STAT5) and DNA binding relative to controls 5 min after GH treatment . However, both of these parameters were decreased (vs . control) in TNF-treated cells 60 min after GH treatment . Collectively, these results suggest that TNF mediates hepatic GH resistance during sepsis by inhibiting the duration of signaling via the janus kinase-2/STAT5 pathway. Acta Med Austriaca, 2002, 29(3), 80 - 8 Plasminogen activators in inflammation and sepsis; Pechlaner Ch; Mortality of severe sepsis remains at 40% to 50% . Intensive efforts over the past two decades have only marginally improved outcome . Improving outcome in sepsis depends on understanding its pathophysiology, which involves triggers, responses of the organism, and dysfunction . Stress, injury, or infection trigger host responses, including local and systemic orchestrated mechanisms . Dysfunction and outcome depend on both trigger and response . Blood coagulation, inflammation, immunity, and fibrinolysis are critical components of the organism's responses . Understanding their role in sepsis pathophysiology is the key to effective treatment . Relevant studies were identified by a systematic literature search, complemented by manual search of individual citations . Using PubMed, 'sepsis' yields more than 62,000 references, 'plasminogen activators' more than 21,000 . The selection of citations was guided by preference for reviews that expand important threads of argumentation . Single original studies were included when relevant to critical points . This analytical review describes the essential elements of pathophysiology and the current status of sepsis treatment . Based on this context, an emerging therapeutic option will be discussed: plasminogen activators. Eur J Pharmacol, 2002 Aug 9, 449(3), 279 - 85 Nitric oxide supports atrial function in sepsis: relevance to side effects of inhibitors in shock; Price S et al.; The mechanisms underlying myocardial dysfunction in sepsis remain poorly understood . The theoretical benefits of nitric oxide synthase (NOS) inhibition in reversing the haemodynamic changes that characterise septic shock have not been supported by clinical trials, some of which have demonstrated detrimental myocardial effects . We have therefore assessed the effects of endotoxaemia on NOS enzyme expression as well as a number of functional responses of myocardial tissue from rats . Atrial tissue expressed high levels of mRNA for inducible (i) NOS and released increased levels of nitrite after animals were treated with endotoxin . In parallel, the inotropic response stimulated by isoprenaline was reduced in atria from endotoxin-treated animals, an effect that was reversed when endogenous release of NO was maximised . Our results suggest that myocardial contractility is maintained by NO production and that inhibitors may compromise cardiac output; this may explain the deleterious effects of NOS inhibition on cardiac function in clinical trials. Shock, 2002 Aug, 18(2), 111 - 5 Pathophysiologic and clinical correlates of hypophosphatemia and the relationship with sepsis and outcome in postoperative patients after hepatectomy; Giovannini I et al.; Hypophosphatemia in critically ill and postoperative (p.o.) patients is a multifactorial event, and is also related to severity of illness . This study was conducted to assess pathophysiologic correlates of hypophosphatemia and the simultaneous relationship with clinical events after hepatectomy . A total of 333 measurements were obtained in 59 patients: these were performed preoperatively and at p.o . days 1, 3, and 7 in all patients, and subsequently, until recovery or death, only in those with complications . Measurements included plasma phosphate together with a large number of additional blood chemistries, taking into account primary and associated diseases, events associated with the operation, doses of parenteral substrates, occurrence of sepsis or other p.o . complications, outcome, and a consistent set of complementary variables . Plasma phosphate decreased at p.o . days 1 and 3 (P < 0.001) and retumed to a level close to baseline at p.o . day 7 . Regression analysis showed that phosphate was related simultaneously to patient age (inversely), levels of creatinine and potassium (directly), and dose of parenteral amino acids (inversely; P < 0.001 for all) . Independently of covariation with these variables, there was a decrement in phosphate at p.o . days 1 and 3 that was related specifically to p.o . condition; this decrement had a general component common to all patients, an additional component related to duration of previous hepatic ischemia at surgery, and a further component predictive of the subsequent development of complications (in most cases, sepsis) . Plasma phosphate at p.o . day 1 was related inversely to APACHE II score (r2 = 0.4, P < 0.001), and levels lower than 1.5 mg/dL were associated with an almost 4-fold increase in the rate of complications compared with cases with higher phosphate (P < 0.001) . The best single variable bridging early evidence of hypophosphatemia to subsequent development of complications was plasma cholesterol, which fell significantly from p.o . day 3 onward in patients with complications compared with those recovering normally (P < 0.01), and in nonsurvivors compared with survivors (P < 0.01) . Hypophosphatemia may anticipate clinical evidence of complications by reflecting an early stronger acute-phase response, with shift of phosphate from intra- to extravascular space, or true phosphorus deficiency, which may favor development of complications by impairing high-energy substrate availability for host defense and other cell functions. Eur Respir J, 2002 Jul, 20(1), 177 - 82 Sepsis and hyperoxia effects on the pulmonary surfactant system in wild-type and iNOS knockout mice; Bailey TC et al.; Alterations of pulmonary surfactant and increases in inducible nitric oxide synthase (iNOS) have been implicated in the pathophysiology of acute lung injury . It was hypothesised that these two observations are related and that alterations of the endogenous surfactant, due to either sepsis or hyperoxia, would be reduced in mice lacking the iNOS gene compared to wild-type mice . Wild-type and iNOS (-/-) mice were randomised into sham or sepsis, and in a separate experiment animals were randomised to normoxia or hyperoxia exposure for 48 h . Lungs were lavaged and analysed for total surfactant levels and surfactant subfractions (large (LA) and small (SA) aggregates) . Both sepsis groups had decreased SA compared to sham groups with no significant difference between the two genotypes . Mice exposed to hyperoxia had a decreased amount of total surfactant when compared to normoxia controls and there was no significant difference between the two genotypes . It is concluded that inducible nitric oxide synthase does not influence the amount of pulmonary surfactant or surfactant subfractions recovered in lavage after 18 h of sepsis or 48 h of hyperoxia. J Immunol, 2002 Aug 15, 169(4), 2093 - 101 Nitric oxide stimulates macrophage inflammatory protein-2 expression in sepsis; Skidgel RA et al.; NO is a crucial mediator of the inflammatory response, but its in vivo role as a determinant of lung inflammation remains unclear . We addressed the in vivo role of NO in regulating the activation of NF-kappaB and expression of inflammatory proteins using an in vivo mouse model of sepsis induced by i.p . injection of Escherichia coli . We observed time-dependent degradation of IkappaB and activation of NF-kappaB accompanied by increases in inducible NOS, macrophage inflammatory protein-2 (MIP-2), and ICAM-1 expression after E . coli challenge, which paralleled the ability of lung tissue to produce high-output NO . To determine the role of NO in this process, mice were pretreated with the NO synthase (NOS) inhibitor NG-methyl-L-arginine . Despite having relatively modest effects on NF-kappaB activation and ICAM-1 or inducible NOS expression, the NOS inhibitor almost completely inhibited expression of MIP-2 in response to E . coli challenge . These responses were associated with the inhibition of migration of neutrophils in lung tissue and increased permeability induced by E . coli . In mice pretreated with NG-methyl-L-arginine, coadministration of E . coli with the NO donor (Z)-1-{N-(2-aminoethyl)-N-(2-ammonioethyl)amino}diazen-1-ium-1,2-diolate substantially restored MIP-2 expression but decreased ICAM-1 expression . The results suggest that NO generated after administration of E . coli serves as an important proinflammatory signal to up-regulate MIP-2 expression in vivo . Thus, NO production in high quantities may be important in the mechanism of amplification of the lung inflammatory response associated with sepsis. J Assoc Physicians India, 2002 Apr, 50, 527 - 31 Efficacy and safety of phlogenzym--a protease formulation, in sepsis in children; Shahid SK et al.; BACKGROUND: Infections are a major cause of hospitalisation wherein the host mounts an inflammatory response against the infecting agent . Administration of proteolytic enzymes could regulate the host's immune system and help early recovery from sepsis . OBJECTIVE: To test the efficacy and safety of an oral enzyme formulation, Phlogenzym (Mucos Pharma GmbH, Geretsried, Germany; constituents of each enteric-coated tablet were bromelain 90 mg, trypsin 48 mg, rutin 100 mg) as adjuvant therapy in treatment of sepsis in children . SUBJECTS AND METHODS: Double-blind, randomised, controlled phase III study at a tertiary care centre wherein 60 eligible children aged one month to 12 years with sepsis were randomised to receive either phlogenzym (n=30; 17 boys) or placebo (n=30; 22 boys) tablets (1 tablet/10 kg body weight up to maximum six tablets a day in two or three divided doses for 14-21 days) along with appropriate antibiotics and supportive treatment . RESULTS: Median time taken for fever to subside was three days (range 1-12; 95% CI--1.14 to 7.14) in the phlogenzym group vs four days (range 1-18; 95% CI--3.52 to 11.52) in the placebo group (p < 0.05); haemodynamic support was needed for two days (range 1-3; 95% CI--0.84 to 3.16) in the phlogenzym group but three days (range 1-8; 95% CI--0.76 to 5.24) in the placebo group (p < 0.05) . The modified Glasgow coma scale score normalized in three days (range 1-14; 95% CI--4.62 to 9.62) in the phlogenzym group vs 5.5 days (range 1-18; 95% CI--2.52 to 13.52) in the placebo group (p > 0.05) . Oral feeds could be started in four days (range 1-15; 95% CI--1.74 to 9.74) in the phlogenzym group vs five days (range 1-11; 95% CI--1.26 to 11.26) in the placebo group (p > 0.05) . Two patients died in the placebo group . CONCLUSION: Phlogenzym is effective as an adjuvant with antibiotics and supportive treatment for early improvement of pediatric patients with sepsis. Crit Care Med, 2002 Aug, 30(8), 1842 - 7 Soluble L-selectin attenuates tumor necrosis factor-alpha-mediated leukocyte adherence and vascular permeability: a protective role for elevated soluble L-selectin in sepsis; Ferri LE et al.; OBJECTIVE: We have previously demonstrated that leukocyte delivery to remote sites is decreased in sepsis and that increased concentrations of soluble L-selectin are, in part, responsible for this finding . Given that leukocytes have been implicated in the pathogenesis of vascular leakage, we hypothesized that the elevated soluble L-selectin concentrations in sepsis may translate into decreased inflammation-mediated leukocyte-endothelial cell interactions and vascular leakage at these sites . DESIGN: Prospective, controlled animal study . SETTING: Surgical research laboratory in a university hospital . SUBJECTS: Swiss white male mice weighing 25-35 g . INTERVENTIONS: Mice were randomized to one of three study groups: intracremaster tumor necrosis factor-alpha with subsequent intravenous bicarbonate buffered solution; intracremaster tumor necrosis factor-alpha with intravenous soluble L-selectin (10 microg/mL); and intracremaster bicarbonate buffered solution with intravenous bicarbonate buffered solution . The cremaster muscle was prepared for both light and fluorescence intravital microscopy 2 hrs after intracremaster injection, and fluorescein isothiocyanate-labeled albumin was injected intravenously . Leukocyte-endothelial interactions (rolling flux, rolling velocity, and adherence) were counted off-line . Postcapillary venule leakage was determined by the permeability index (perivenular/intravenular fluorescence) after intravenous injection of fluorescent albumin . MEASUREMENTS AND MAIN RESULTS: Soluble L-selectin significantly attenuated tumor necrosis factor-alpha-mediated increases in leukocyte adherence and vascular leakage . Leukocyte rolling velocity was restored to baseline with soluble L-selectin; however, rolling flux was not altered . Blood pressure, shear rate, and leukocyte counts did not differ between groups . CONCLUSIONS: Soluble L-selectin decreases local inflammation-mediated leukocyte adherence and vascular leakage in vivo . The increased concentrations of soluble L-selectin in sepsis may represent a protective mechanism by which the host attempts to diminish the deleterious systemic effects of activated leukocytes during sepsis. Crit Care Med, 2002 Aug, 30(8), 1794 - 8 Systemic neuropeptide levels as predictive indicators for lethal outcome in patients with postoperative sepsis; Beer S et al.; OBJECTIVES: To document changes in serum levels of the vasoactive and immunoregulatory neuropeptides, calcitonin gene-related peptide (CGRP) and substance P, in human postoperative sepsis and to determine whether levels correlate with outcome . DESIGN: Prospective, descriptive cohort study with no interventions . SETTING: Surgical intensive care unit and clinical research center . PATIENTS: The study included 61 patients with sepsis after major visceral surgery (survivors, n = 37; nonsurvivors, n = 24) and 23 control patients without sepsis . MEASUREMENTS AND MAIN RESULTS: Serum levels of CGRP and substance P were measured by specific enzyme-linked immunoassays over the course of sepsis . Postoperative sepsis was associated with a significant increase in CGRP serum levels . Systemic CGRP levels were significantly higher in nonsurvivors than in survivors as early as day 1 of sepsis and remained significantly elevated in nonsurvivors throughout the entire course of sepsis . Substance P levels were also elevated in sepsis patients as compared with controls, but significant differences between survivors and nonsurvivors were only observed during the final phase of sepsis . CONCLUSIONS: High systemic CGRP levels were associated with lethal outcome already at the onset of sepsis, whereas high substance P levels were identified as late predictive indicators of lethal outcome . These results are consistent with the view that the neuropeptides, CGRP and substance P, may be involved in the pathogenesis of sepsis. Crit Care Med, 2002 Aug, 30(8), 1729 - 34 Tissue factor production not balanced by tissue factor pathway inhibitor in sepsis promotes poor prognosis; Gando S et al.; OBJECTIVE: To determine the precise relationship among tissue factor, tissue factor pathway inhibitor (TFPI), and neutrophil elastase in sepsis, as well as to test the hypothesis that low TFPI concentrations are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome and death . DESIGN: Prospective, cohort study . SETTING: General intensive care unit of tertiary care emergency department . PATIENTS: Thirty-one consecutive patients with sepsis, classified as 15 survivors and 16 nonsurvivors . Ten normal, healthy volunteers served as controls . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Tissue factor antigen concentration (tissue factor), TFPI, neutrophil elastase, and global variables of coagulation and fibrinolysis were measured on the day of diagnosis of sepsis, severe sepsis, and septic shock and days on 1-4 after diagnosis . The number of systemic inflammatory response syndrome criteria that patients met and the disseminated intravascular coagulation score were determined simultaneously . The results of these measurements were compared between the survivors and the nonsurvivors . In the nonsurvivors, significantly higher concentrations of tissue factor and neutrophil elastase were found compared with the survivors and control subjects . However, the TFPI values showed no difference between the two groups . No correlation was found between the peak concentrations of tissue factor and TFPI . Disseminated intravascular coagulation scores and numbers of the SIRS criteria met by the survivors significantly decreased from day 0 to day 4, but those of the nonsurvivors did not improve during the study period . The nonsurvivors showed thrombocytopenia and higher numbers of dysfunctioning organs than did the survivors . CONCLUSIONS: We systematically elucidated the relationship between tissue factor and TFPI in patients with sepsis, severe sepsis, and septic shock . Activation of tissue factor-dependent coagulation pathway not adequately balanced by TFPI has important roles in sustaining DIC and systemic inflammatory response syndrome, and it contributes to multiple organ dysfunction syndrome and death . High concentrations of neutrophil elastase released from activated neutrophils may explain, in part, the imbalance of tissue factor and TFPI in sepsis. Crit Care Med, 2002 Aug, 30(8), 1722 - 8 C1-inhibitor in patients with severe sepsis and septic shock: beneficial effect on renal dysfunction; Caliezi C et al.; OBJECTIVE: To investigate the efficacy and the safety of the parenteral administration of C1-inhibitor to patients with severe sepsis or septic shock . DESIGN: Double blind, randomized, and placebo-controlled trial . SETTING: Surgical and medical intensive care units of a tertiary care university hospital . PATIENTS: Forty consecutive patients (20 C1-inhibitor/20 placebo) who entered the intensive care unit with severe sepsis or septic shock . INTERVENTION: C1-inhibitor intravenously in a 1-hr infusion, starting with 6000 IU, followed by 3000 IU, 2000 IU, and 1000 IU at 12-hr intervals, compared with placebo . MEASUREMENTS AND MAIN RESULTS: C1-inhibitor administration significantly increased plasma C1-inhibitor antigen and activity levels during days 1-4 (p <.007) . Patients in the C1-inhibitor group had significantly lower serum creatinine concentrations on day 3 (p =.048) and 4 (p =.01) than placebo patients . Multiple organ dysfunction assessed by logistic organ dysfunction and sepsis-related organ failure assessment scores was less pronounced in patients treated with C1-inhibitor . Mortality rate was similar in both groups . There were no C1-inhibitor-related side effects . CONCLUSIONS: C1-inhibitor administration attenuated renal impairment in patients with severe sepsis or septic shock. Expert Opin Investig Drugs, 2002 Aug, 11(8), 1061 - 75 Cytokine modulation in sepsis and septic shock; Zanotti S et al.; Sepsis and septic shock are a major cause of morbidity and mortality in patients admitted to the intensive care unit . Since the introduction of antibiotic therapy, the mortality associated with sepsis has remained within the 30- 50% range . Sepsis constitutes the systemic response to infection . This response encompasses both pro-inflammatory and anti-inflammatory phases that are marked by the sequential generation of pro- and anti-inflammatory cytokines . Among the most important pro-inflammatory cytokines are TNF-alpha and IL-1beta . The pro-inflammatory effects of such cytokines are inhibited by soluble receptors/receptor antagonists and anti-inflammatory cytokines including IL-10 and transforming growth factor-beta . Modulation of the activity of both pro- and anti-inflammatory cytokines to improve outcome in patients with sepsis has been subject of multiple clinical studies . This review will examine clinical trials evaluating several strategies for blocking or attenuating TNF-alpha and IL-1beta activity . This review will also survey the current state of experimental therapies involving IL-10, transforming growth factor-beta, granulocyte colony-stimulating factor and IFN-phi . Finally, newer developments related to less known cytokines such as macrophage migration inhibitory factor and high mobility group 1 protein will be evaluated. Biochem Biophys Res Commun, 2002 Aug 9, 296(1), 41 - 7 Tripeptidyl-peptidase II expression and activity are increased in skeletal muscle during sepsis; Wray CJ et al.; Ubiquitin-proteasome-dependent protein degradation plays a central role in sepsis-induced muscle wasting . Because the proteasome degrades proteins into small peptides rather than free amino acids, it is likely that additional mechanisms downstream of the proteasome are involved in sepsis-induced muscle proteolysis . Recent studies suggest that the extralysosomal peptidase tripeptidyl-peptidase II (TPP II) degrades peptides generated by the proteasome . We hypothesized that TPP II expression and activity are increased in skeletal muscle during sepsis . Sepsis was induced in rats by cecal ligation and puncture . Control rats were sham-operated . TPP II activity was determined by using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin (AAF-AMC) . TPP II protein and gene expression were determined by Western blot and real-time PCR, respectively . Sepsis resulted in increased activity and protein and g