Sepsis

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 gene expression of TPP II in extensor digitorum longus muscles . This result was blunted by the glucocorticoid receptor antagonist RU 38486, indicating that glucocorticoids participate in the upregulation of TPP II in skeletal muscle during sepsis . The results suggest that proteolytic mechanisms downstream of the proteasome may be important for the complete degradation of muscle proteins during sepsis.

Klin Khir, 2002 Apr, (4), 24 - 6
{Sepsis . The fundamentals of the therapeutic program development}; Shapoval SD et al.; The more than ten-year experience of treatment of 287 patients with sepsis, caused by severe surgical disease of the soft tissues, was summarized . Algorithm of therapeutic program was proposed . Necessity of specialized hospitals organization was substantiated . Was paid attention on importance of early diagnosis of sepsis, full value treatment of primary focus of infection and conduction of therapy, based on principles of evidence-based medicine.

Auton Neurosci, 2002 Jun 28, 98(1-2), 33 - 6
Involvement of COX and NOS induction in the sympatho-activation during sepsis; Vayssettes-Courchay C et al.; The role of NOS and/or COX induction on sympathetic nerve activation induced by sepsis was investigated in pentobarbital anesthetized rats . Sepsis was induced by i.v . administration of lipopolysaccharide (LPS) in control experiments and during treatment with anti-inflammatory drugs or inhibitors of NOS and COX (five to six rats per group) . Mean arterial blood pressure (MBP), rectal temperature (RT) and renal sympathetic nerve activity (RSNA) were recorded for up to 6 h after LPS infusion . LPS administration induced profound increases in RSNA and decreases in MBP . The corticosteroid anti-inflammatory drug dexamethasone had a potent protector effect on blood pressure and survival of the LPS-treated animals and inhibited the RSNA increase . The nonsteroid anti-inflammatory compound indomethacin inhibited the sympathetic activation but did not alter the hypotensive action of LPS . The nonselective NOS inhibitor nitroarginine methyl ester (L-NAME) accelerated the fall in MBP and death of the animals while the inducible NOS inhibitor L-NIL delayed the fall in MBP and reduced the sympatho-activation without affecting survival time in LPS rats . The neuronal NOS inhibitor 7-nitroindazole (7-NINA) did not improve the hypotensive effect and survival of the LPS animals but potentiated the RSNA increase . The COX-1 inhibitor SC560 accelerated hypotension and death of the LPS animals without affecting the RSNA increase . The COX-2 inhibitor NS398 did not modify the effect of LPS on blood pressure but reduced its sympatho-excitatory effect; NS398 also abolished the LPS-induced increase in RT . The results indicate that different mechanisms are involved in the effects of sepsis on MBP, sympathetic activation and fever . Sympathetic nerve activation during sepsis appears to depend on the induction of NOS and COX; the COX pathway is involved in the elevation of temperature and in the activation of sympathetic nerve activity but not in the hypotension . The potent effect of dexamethasone suggests that a NOS- and COX-independent arachidonic acid pathway also plays a role.

Crit Care, 2002 Jun, 6(3), 271 - 4 Epub 2002 May 01.
What are the challenges of translating positive trial results in severe sepsis into clinical practice? A media roundtable debate, 18 March 2002, Brussels, Belgium; Ball J; The clinical syndrome of sepsis is common, increasing in incidence and responsible for as many deaths annually as ischaemic heart disease . Two recent interventional trials have demonstrated that early recognition and intervention can result in dramatic reductions in acute (28-day) mortality . This roundtable discussion was convened to identify ways in which these recent advances could be translated into clinical practice . The first obstacle surrounds the woolly and confusing terminology surrounding 'sepsis' with the systemic inflammatory response syndrome (SIRS) model largely discredited . Overcoming this should facilitate wider recognition, not only among health care providers (in particular those working in acute specialties outside intensive care units {ICUs}) but also politicians and the general public . Such education is vital if early recognition and intervention are to be successfully implemented.

Crit Care, 2002 Jun, 6(3), 251 - 9 Epub 2002 Apr 19.
Physiological-dose steroid therapy in sepsis {ISRCTN36253388}; Yildiz O et al.; INTRODUCTION: The aim of the study was to assess the prognostic importance of basal cortisol concentrations and cortisol response to corticotropin, and to determine the effects of physiological dose steroid therapy on mortality in patients with sepsis . METHODS: Basal cortisol level and corticotropin stimulation test were performed within 24 hours in all patients . One group (20 patients) received standard therapy for sepsis and physiological-dose steroid therapy for 10 days; the other group (20 patients) received only standard therapy for sepsis . Basal cortisol level was measured on the 14th day in patients who recovered . The outcome of sepsis was compared . RESULTS: Only Sequential Organ Failure Assessment (SOFA) score was found related to mortality, independent from other factors in multivariate analysis . No significant difference was found between the changes in the percentage of SOFA scores of the steroid therapy group and the standard therapy group in survivors, nor between the groups in basal and peak cortisol levels, cortisol response to corticotropin test and mortality . The mortality rates among patients with occult adrenal insufficiencies were 40% in the steroid therapy group and 55.6% in the standard therapy group . DISCUSSION: There was a trend towards a decrease in the mortality rates of the patients with sepsis who received physiological-dose steroid therapy . In the advancing process from sepsis to septic shock, adrenal insufficiency was not frequent as supposed . There was a trend (that did not reach significance) towards a decrease in the mortality rates of the patients with sepsis who received physiological-dose steroid therapy.

Crit Care, 2002 Jun, 6(3), 190 - 1 Epub 2002 May 09.
Cortisol replacement for severe sepsis and septic shock: what should I do?
Annane D.
Based on several recently completed randomized controlled trials, cortisol replacement is likely to become a standard of care for vasopressor dependent septic shock . Further studies are needed in order to accomplish whether this treatment should be limited to patients with a blunted cortisol response to corticotrophin . Similarly, in patients with severe sepsis who do not need vasopressors, the benefit/risk ratio of cortisol replacement remains to be assessed.

Zhonghua Yi Xue Za Zhi, 2002 Jul, 82(13), 903 - 6
{Association of tumor necrosis factor microsatellites TNF with the susceptibility to and outcome of postoperative severe sepsis}; Shu Q et al.; OBJECTIVE: To investigate whether tumor necrosis factor microsatellites TNFa and TNFb were associated with the susceptibility to and outcome of post operative severe sepsis . METHODS: 122 postoperative patients suffering from severe sepsis and 138 ethnically matched healthy individuals (controls) were included in this study . The genotypes of microsatellites TNFa and TNFb were analyzed using modified nested-PCR followed by polyacrylamide gel electrophoresis with silver staining . RESULTS: Microsatellites TNFa and TNFb consisted of 14 alleles (TNFa1-14) and 5 alleles (TNFb1, 3-5, 7) respectively . The frequency of TNFa6 microsatellite allele was significantly higher in patients with severe sepsis than in controls (20.1% versus 10.5%, P < 0.05) . The frequency of TNFa2 microsatellite allele was significantly lower in patients with severe sepsis than in controls (21.3% versus 31.5%, P < 0.05) . Furthermore, among patients with severe sepsis, the frequency of TNFa10 microsatellite allele was significantly higher in non-survivors than in survivors (19.5% versus 9.5%, P < 0.05) . Whereas, there was no significant difference in the distribution of TNFb microsatellite alleles between patients and controls, and non-survivors and survivors (both P > 0.05) . CONCLUSION: Microsatellite TNFa is significantly associated with both the susceptibility to and outcome of severe sepsis . In contrast, microsatellite TNFb is neither associated with the susceptibility to severe sepsis nor with the outcome of severe sepsis.

Semin Hematol, 2002 Jul, 39(3), 197 - 205
Activated protein C: potential therapy for severe sepsis, thrombosis, and stroke; Griffin JH et al.; Activated protein C (APC) reduced all-cause 28-day mortality by 19% in patients with severe sepsis (sepsis associated with acute organ dysfunction) in the Protein C Evaluation in Severe Sepsis (PROWESS) trial, leading to recent approval of recombinant APC for treatment of this condition in adults . This review summarizes current knowledge derived from studies of a variety of animal models in which infused human APC demonstrated beneficial activities . Based on in vivo and also in vitro data, APC manifests antithrombotic, profibrinolytic, anti-inflammatory, and antiapoptotic activities . APC is a normal circulating component of plasma, derived from the protein C zymogen, and is thus a natural endogenous protective homeostatic factor . Because of its multiple activities, APC has a potential role in the treatment of complex and challenging medical disorders, including thrombosis and stroke .

Intensive Care Med, 2002 Jul, 28(7), 981 - 4 Epub 2002 May 28.
Low plasma granulocyte-macrophage colony stimulating factor is an indicator of poor prognosis in sepsis; Perry SE et al.; OBJECTIVE: Monocyte dysfunction has been shown to be associated with adverse consequences in septic patients . The cytokine growth factor granulocyte-macrophage colony stimulating factor (GM-CSF) may be required for optimal monocyte function in these patients . The current study investigates whether plasma GM-CSF levels were significantly different in septic patients and whether there was an association with prognosis . DESIGN: Plasma samples were collected from all septic patients from day 1 of the diagnosis of sepsis for 3 days . Healthy volunteer plasma served as control samples . A novel enzyme-linked immuno-adsorbent assay was developed with suitable sensitivity for detection of GM-CSF in patient and normal plasma . APACHE II score, age, sex and outcome were determined for all patients . SETTING: A single centre study at the Royal Liverpool University Hospital in a medico-surgical 13 bed intensive care unit . PATIENTS: All septic patients (n = 53) fulfilling the criteria of the APCC for the diagnosis of sepsis, were recruited for the study with informed consent from day 1 of the diagnosis of sepsis and plasma GM-CSF measured on three consecutive days . Patients were excluded from the study if on immunosuppressive therapy . Normal healthy volunteers (n = 33) were included in the study to serve as controls . RESULTS: Plasma GM-CSF levels were statistically significantly depressed in patients who died compared with those who survived, who had levels comparable with healthy controls . CONCLUSIONS: The results indicate that low plasma GM-CSF is associated with adverse consequences for septic patients . The measurement of GM-CSF in the plasma of septic patients merits further study for use as a prognostic marker and also to identify the type of immunotherapy the patient may benefit from.

Mult Scler, 2002 May, 8(3), 229 - 36
Cortisol is increased in postmortem cerebrospinal fluid of multiple sclerosis patients: relationship with cytokines and sepsis; Erkut ZA et al.; Hypothalmo-pituitary-adrenal (HPA) axis activity is altered in patients with multiple sclerosis (MS), resulting in elevated basal levels and enhanced response of cortisol in stimulation tests . HPA axis hyperactivation in MS is thought to be the result of complex interactions of genetic, immunologic, and neuroendocrinological mechanisms . In order to investigate whether cytokine levels in the central nervous system are associated with the activation of the HPA axis in MS, we measured cortisol, interleukin (IL)-6, IL-10 and TNF-alpha levels in postmortem cerebrospinal fluid (CSF) of 18 patients with severe MS and 50 controls . We also investigated the cortisol and cytokine levels in the CSF of a group of MS patients and controls who died with sepsis, in order to see whether acute infectious situations affect the association between cortisol and cytokines . The cortisol levels in MS patients were increased by 80% in comparison to controls (p=0.008) . There was no difference in IL-6 levels between the groups, while IL-10 and TNF-alpha levels of the majority of subjects were below detection limits . There was a positive correlation between cortisol and IL-6 only in control patients with sepsis (r=0.89, p=0.019), but not within the MS patents with sepsis or MS and control groups without sepsis . Cortisol levels in postmortem serum and CSF were highly correlated (r>0.78, p<0.001) . We concluded that the basal level of cortisol is significantly increased in the CSF of MS patients and that IL-6 is not responsible for this rise . The relationship between cortisol and IL-6 in sepsis is discussed.

Am J Respir Crit Care Med, 2002 Jul 15, 166(2), 138 - 43
A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction; Presneill JJ et al.; Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates hemopoiesis and effector functions of granulocytes and macrophages and is involved in pulmonary surfactant homeostasis . We investigated whether GM-CSF therapy improved clinically diagnosed severe sepsis and respiratory dysfunction in critically ill patients . This randomized, double-blind, placebo-controlled phase II study added low-dose (3 mcg/kg) intravenous recombinant human GM-CSF daily for 5 days to conventional therapy in 10 patients, with a further eight patients receiving placebo . GM-CSF-treated patients showed improvement in Pa(O(2))/FI(O(2)) over 5 days (p = 0.02) and increased peripheral blood neutrophils (p = 0.08), whereas alveolar neutrophils decreased (p = 0.02) . GM-CSF therapy was not associated with decreased 30-day survival or with increased acute respiratory distress syndrome or extrapulmonary organ dysfunction . GM-CSF therapy was associated with increased blood granulocyte superoxide production and restoration or preservation of blood and alveolar leukocyte phagocytic function . We conclude that low-dose GM-CSF was associated with improved gas exchange without pulmonary neutrophil infiltration, despite functional activation of both circulating neutrophils and pulmonary phagocytes . In addition, GM-CSF therapy was not associated with worsened acute respiratory distress syndrome or the multiple organ dysfunction syndrome, suggesting a homeostatic role for GM-CSF in sepsis-related pulmonary dysfunction.

Magn Reson Imaging, 2002 Apr, 20(3), 271 - 6
In vivo fate of superparamagnetic iron oxides during sepsis; Fujii H et al.; The enzymatic generation of nitric oxide (NO) in vivo has been reported to be modulated by ions, such as copper and iron . Superparamagnetic iron oxide (SPIO) or ferumoxides is a liver-specific magnetic resonance contrast agent that is taken up by the Kupffer cells, where NO is generated by inducible nitric oxide synthase (iNOS) . Thus, it is important to evaluate SPIO in vivo under conditions, such as infectious disease, where significant amounts of NO are generated by iNOS . In this study, we monitored the pharmacokinetics of SPIO in the liver of septic-shock mice and rats . A significant decrease in the ferric iron EPR signal was observed during NO generation in septic-shock mice compared with control mice doped with only SPIO . These results were also confirmed in a model reaction system consisting of SPIO and the NO donor, S-nitroso-N-acetyl DL penicillamine (SNAP) . We compared NO generation quantitatively in the liver of the septic-shock rats, either in the presence or absence of SPIO, and found that the presence of SPIO did not affect the NO-generating activity of NOS expressed in the liver . T2-weighted MR images of an agarose gel phantom containing different SPIO to NO donor (SNAP) ratios clearly demonstrated that the contrast enhancement by SPIO decreased with increasing NO at constant SPIO levels . The reduced contrast is most probably due to the reduction of ferric to ferrous irons, resulting in a decrease in paramagnetic relaxation of water protons . These results show that SPIO can be a versatile NO-sensitive indicator, especially employing MRI as a powerful tool to 'visualize' sites of NO generation.

Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai), 1999, 31(4), 373 - 378
Group II Phospholipase A(2) Activity and Its Molecular Regulation in Rat Heart during Sepsis; Jiang ZS et al.; Changes of activity and content of myocardial group II phospholipase A(2) and its mRNA transcription and stability during rat sepsis were investigated . Results showed that, compared with control group,myocardial group II phospholipase A(2) activity in early and late sepsis decreased by 25.0%(P<0.05) and increased by 47.6%(P<0.01),respectively group II phospholipase A(2) protein concentration reduced by 27.0% and augmented by 48.0%(P<0.01),respectively . Myocardial group II phospholipase A(2) mRNA transcription rate and content showed similar two-phases changes . The mRNA transcription rate during early and late sepsis decreased by 45.0% and increased by 70.0%(P<0.01),respectively . The mRNA content decreased by 34.1% in early sepsis and increased by 157.0% in late sepsis(P<0.01), respectively . The half-life of group II phospholipase A(2) mRNA remained unchanged notably during early and late stage of sepsis . These data suggest that myocardial group II phospholipase A(2) activity decreased in early stage of sepsis and increased in its late stage, and these changes were regulated transcriptionally.

Am J Physiol Lung Cell Mol Physiol, 2002 Aug, 283(2), L476 - 84
Role of heme oxygenases in sepsis-induced diaphragmatic contractile dysfunction and oxidative stress; Barreiro E et al.; Heme oxygenases (HOs), essential enzymes for heme metabolism, play an important role in the defense against oxidative stress . In this study, we evaluated the expression and functional significance of HO-1 and HO-2 in the ventilatory muscles of normal rats and rats injected with bacterial lipopolysaccharide (LPS) . Both HO-1 and HO-2 proteins were detected inside ventilatory and limb muscle fibers of normal rats . Diaphragmatic HO-1 and HO-2 expressions rose significantly within 1 and 12 h of LPS injection, respectively . Inhibition of the activity of inducible nitric oxide synthase (iNOS) in rats and absence of this isoform in iNOS(-/-) mice did alter sepsis-induced regulation of muscle HOs . Systemic inhibition of HO activity with chromium mesoporphyrin IX enhanced muscle protein oxidation and hydroxynonenal formation in both normal and septic rats . Moreover, in vitro diaphragmatic force generation declined substantially in response to HO inhibition both in normal and septic rats . We conclude that both HO-1 and HO-2 proteins play an important role in the regulation of muscle contractility and in the defense against sepsis-induced oxidative stress.

Eur J Surg, 2002, 168(2), 119 - 23
Proteolysis in severe sepsis is related to oxidation of plasma protein; Abu-Zidan FM et al.; OBJECTIVE: To test the hypothesis that the oxidation of proteins is part of the mechanism of proteolysis in catabolic states . DESIGN: Prospective, observational study . SETTING: Critical care unit at a university teaching hospital, New Zealand . PATIENTS: 13 patients (6 male, 7 female; median age 61, range 26-76 years) who were admitted to the Department of Critical Care Medicine at Auckland Hospital with a diagnosis of severe sepsis . The median APACHE II score during the first 24 hours after admission was 22 (range 15-34) . Control values of protein carbonyl in plasma were established in 15 healthy volunteers . INTERVENTIONS: We made serial measurements of total body protein (by neutron activation analysis) and plasma protein carbonyl (by ELISA) concentrations over a period of 10 days . MAIN OUTCOME MEASURE: Plasma protein carbonyl concentration and total body protein . RESULTS: The total amount of body protein decreased significantly over the 10 days (p < 0.001) . Plasma protein carbonyl concentrations were significantly higher in the septic patients than in the control group throughout the study period (p < 0.0001) . There was a significant reduction in plasma protein carbonyl concentration over the study period (p < 0.008) . The early increase in the concentration of protein carbonyl formation was followed by an ongoing loss of body protein . There was a significant positive correlation between total body protein and plasma protein carbonyl (p < 0.03) . CONCLUSIONS: Severe sepsis results in oxidation of plasma proteins and this precedes and is related to the loss of body protein.

Ther Apher, 2002 Jun, 6(3), 234 - 40
Continuous hemodiafiltration with polymyxin-B immobilized fiber is effective in patients with sepsis syndrome and acute renal failure; Suzuki H et al.; The aim of this study was first, to evaluate the effects of continuous hemodiafiltration (CHDF) alone or combined with CHDF and polymyxin-B immobilized fiber (PMX) on survival rates of patients with sepsis and acute renal failure, and second, to evaluate the changes in plasma levels of inflammatory cytokines before and after treatment with CHDF and PMX and CHDF alone in these patients . Forty-eight patients with septic shock and acute renal failure were enrolled in this study . The survival rate of all patients at 28 days was 25% for those with CHDF and 75% for those with PMX and CHDF treatment . Combination treatment produced a significant reduction of plasma levels of endotoxin and interleukin-6 compared to the basal values and to the treatment with CHDF alone . From these data, it is suggested that the combined therapy with PMX and CHDF is effective in improvement of survival rate of patients with septic shock and acute renal failure.

Intensive Care Med, 2002 Jun, 28(6), 793 - 6 Epub 2002 Apr 10.
Increased endogenous carbon monoxide production in severe sepsis; Zegdi R et al.; OBJECTIVE: A comparison was made between the endogenous carbon monoxide (CO) production in mechanically ventilated critically ill adult patients with, and those without, severe sepsis . DESIGN: Prospective comparative study . SETTING: Medical ICU in a community hospital . PATIENTS: Twenty-four patients with severe sepsis of various etiologies and five control patients with varying diagnoses . INTERVENTION: CO concentration was determined with an infrared CO analyzer on exhaled breath collected at the outlet of the ventilator . Endogenous CO production was estimated by the lung CO excretion rate measured at steady state . MEASUREMENTS AND MAIN RESULTS:: Endogenous CO production was higher in the sepsis group during the first 3 days of treatment in comparison to the control group (10.9+/-5 (SD) microl/kg per h on day 1, 7.8+/-4.9 microl/kg per h on day 2 and 6.9+/-4.7 microl/kg per h on day 3 versus 2.1+/-0.5 microl/kg per h; p<0.01 for each comparison) . Survivors of sepsis had a significantly higher endogenous CO production on day 1 compared to non-survivors (14.7+/-5.3 versus 8.5+/-3.3 microl/kg per h; p=0.02) . CONCLUSION: Endogenous CO production was significantly higher in mechanically ventilated patients suffering from severe sepsis . Further studies are required in order to determine the mechanism(s) and the functional significance of this increase.

J Microbiol Immunol Infect, 2002 Jun, 35(2), 71 - 7
Apoptosis contributes to the decrement in numbers of alveolar macrophages from rats with polymicrobial sepsis; Lu MC et al.; To investigate the effects of sepsis-related acute lung injury on the events of alveolar macrophages apoptosis and phagocytosis, cecal-ligated-and-punctured male Sprague-Dawley rats were employed as sepsis model . At the early (9 h) and late (20 h) stages of sepsis, cecal-ligated-and-punctured and sham-operated animals were sacrificed and their lungs were removed . Alveolar macrophages were isolated by bronchoalveolar lavage and counted . The results showed that the purity of alveolar macrophages from both groups was over 98% as stained by Giemsa . The number of alveolar macrophages in late-stage septic rats significantly decreased . Alveolar macrophages apoptosis was then evaluated by labeling with fluorescein-conjugated annexin-V and exclusion of propidium iodide . There were minimal levels of baseline apoptosis in sham-operated rats . Compared with that of sham-operated rats, cecalligated-and-puncture operation resulted in 2.5- and 3.2-fold time-dependent increases in the amount of apoptotic alveolar macrophages in early- and late-stage septic animals, respectively . Among cecal-ligated-and-punctured and sham-operated rats of 9 and 20 h, the ability of alveolar macrophages to phagocytize opsonized fluorescence particles did not change significantly . However, the total alveolar macrophages phagocytic capacity of septic animals reduced due to the decrease in the number of alveolar macrophages . We conclude that apoptosis contributes to the decrement in the number of alveolar macrophages in cecal-ligated-and-punctured rats . Considering that alveolar macrophages have important roles in the defense and immunoregulation of the lungs, these results suggest that the defensive ability of septic lungs may be reduced, and could explain, at least in part, the increased susceptibility of septic lungs to superimposed infections.

J Microbiol Immunol Infect, 2002 Jun, 35(2), 125 - 8
Infected cephalohematoma associated with sepsis and scalp cellulitis: a case report; Fan HC et al.; Infected cephalohematoma is rarely complicated by sepsis . We report a case of an infected cephalohematoma caused by Escherichia coli sepsis in an otherwise healthy neonate . Skull X-ray revealed soft tissue swelling over parieto-temporal region but no osteolytic lesion . 99mTc bone scan showed scalp cellulitis . Blood culture and scalp wound culture identified E . coli . Treatment with surgical incision and drainage and administration of antibiotics resulted in prompt improvement . The relationship of scalp cellulitis, infected cephalohematoma, and sepsis are discussed.

Shock, 2002 Jul, 18(1), 24 - 8
Early interleukin-10 treatment improves survival and enhances immune function only in males after hemorrhage and subsequent sepsis; Kahlke V et al.; Recent studies have demonstrated gender differences in the immune response following hemorrhagic shock with an enhanced immune function and lower mortality following subsequent sepsis in females . Early interleukin-10 (IL-10) treatment has been shown to have beneficial effects on the depressed immune function in males, but not in females following shock . However, it remains unclear if the observed gender-related effect of IL-10 treatment results in an advantage following subsequent polymicrobial sepsis . To study this, male and female CBA/J mice (age 2-3 months) were subjected to hemorrhage (35 +/- 5 mmHg for 90 min and fluid resuscitation) . At resuscitation, each received either 10 microg of recombinant murine IL-10 or placebo i.p. . At 48 h after resuscitation, either peritoneal macrophages (pMphi) and plasma were harvested, or polymicrobial sepsis was induced by cecal ligation and puncture (CLP) . Following CLP, either survival over 10 days was measured, or pMphi and plasma were harvested 4 h after CLP to assess TNF-alpha, IL-6, IL-10, and prostaglandin E2 (PGE2) release of pMphi and plasma levels of IL-10, free testosteron, and 17-beta estradiol . Early IL-10 treatment restored depressed proinflammatory immune response in males (TNF-alpha and PGE2), which was associated with an enhanced survival (P < 0.05) following subsequent sepsis as compared with placebo-treated mice (8/20 and 1/20, respectively) . In contrast, the immune response and survival in females receiving IL-10 was not significantly changed, although females treated with IL-10 had a trend towards higher mortality (7/15 and 2/15, respectively; P = 0.08) . Thus, early IL-10 anti-inflammatory treatment following hemorrhage has potential beneficial effects only in males associated with enhanced survival following subsequent sepsis.

J Clin Invest, 2002 Jul, 110(1), 101 - 8
Increased C5a receptor expression in sepsis; Riedemann NC et al.; Excessive production of the complement activation product C5a appears to be harmful during the development of sepsis in rodents . Little is known about the role of the C5a receptor (C5aR) and its presence in different organs during sepsis . Using the cecal ligation/puncture (CLP) model in mice, we show here that C5aR immunoreactivity was strikingly increased in lung, liver, kidney, and heart early in sepsis in both control and neutrophil-depleted mice . C5aR mRNA expression in these organs was also significantly increased during sepsis . Immunohistochemical analysis revealed patterns of increased C5aR expression in parenchymal cells in all four organs following CLP . Mice injected at the start of CLP with a blocking IgG to C5aR (alphaC5aR) showed dramatically improved survival when compared with animals receiving nonspecific IgG, as did mice injected with alphaC5a . In alphaC5aR-treated mice, serum levels of IL-6 and TNF-alpha and bacterial counts in various organs were significantly reduced during CLP when compared with control CLP animals . These studies demonstrate for the first time that C5aR is upregulated in lung, liver, kidney, and heart during the early phases of sepsis and that blockade of C5aR is highly protective from the lethal outcome of sepsis.

Acad Emerg Med, 2002 Jul, 9(7), 661 - 70
Heart rate variability in emergency department patients with sepsis; Barnaby D et al.; OBJECTIVE: To test the hypothesis that heart rate variability (HRV) can provide an early indication of illness severity among patients presenting to the emergency department (ED) with sepsis . METHODS: The authors enrolled a convenience sample of 15 ED patients meeting the American College of Chest Physicians/Society of Critical Care Medicine criteria for sepsis . Each patient had continuous Holter monitoring performed in the ED . Acute Physiology and Chronic Health II (APACHE II) and Sequential Organ Failure (SOFA) scores were calculated for the day of presentation . Holter tapes obtained in the ED were analyzed off-line to calculate HRV variables for the 5-minute segment with the least artifact and non-sinus beats . These variables were correlated with APACHE II and SOFA scores . RESULTS: LFnu (normalized low-frequency power), an assessment of the relative sympathetic contribution to overall HRV, was correlated with increased illness severity as calculated using APACHE II (r = -0.67, r(2) = 0.43) and SOFA (r = -0.80, r(2) = 0.64) scores . LF/HF ratio (low-frequency/high-frequency ratio), a measure of sympathovagal balance, was correlated with the SOFA score {r = -0.54 (95% CI = -0.83 to -0.01), r(2) = 0.29} . All five patients who required critical care monitoring or ventilatory support or who died during the first 5 days of their hospitalization had LFnu values below 0.5 and LF/HF ratios less than 1.0 . None of the patients with measurements greater than these threshold values died or required these interventions during the five days following admission . CONCLUSIONS: A single variable, LFnu, which reflects sympathetic modulation of heart rate, accounted for 40-60% of the variance in illness severity scores among patients presenting to the ED with sepsis . HRV, as reflected in LFnu and the LF/HF ratio and measured with a single brief (5-minute) period of monitoring while in the ED, may provide the emergency physician with a readily available, noninvasive, early marker of illness severity . The threshold effect of LFnu and LF/HF in the prediction of early clinical deterioration was an unexpected finding and should be regarded as hypothesis-generating, pending further study.

Sb Lek, 2001, 102(3), 411 - 8
{Chorioamnionitis and early-onset neonatal sepsis do not significantly affect levels of interleukin-6 in very low birth weight neonates}; Janota J et al.; OBJECTIVE: To determine the influence of maternal chorioamnionitis and neonatal sepsis on interleukin-6 (IL-6) levels in cord blood and in blood obtained from very low birth weight (VLBW) infants within the first two hours of life . DESIGN: Prospective clinical study . SETTING: Institute for the Care of Mother and Child, Prague . METHODS: We measured the serum levels of IL-6 in 30 consecutive VLBW infants born in our institute . IL-6 levels were evaluated in cord blood and in neonatal blood within 2 hours after delivery . Maternal chorioamnionitis and neonatal sepsis within the first 72 hours of life were monitored . RESULTS: Maternal chorioamnionitis was detected in 7 of 30 patients (23.3%) . There was no significant increase in IL-6 level in cord blood of newborns with maternal chorioamnionitis (p = 0.42) . Serum level of IL-6 in this group did not differ from the level in newborns of mothers without signs of intraamniotic infection (p = 0.39) . Neonatal early-onset sepsis was diagnosed in 7 of 30 patients (23.3%) . There was no influence of neonatal sepsis on IL-6 level in cord blood (p = 0.98) and IL-6 level in neonatal blood (p = 0.19) . We did not find any correlation between the group "chorioamnionitis positive" and "sepsis positive" (p = 0.31) . CONCLUSION: IL-6 in cord blood or in neonatal blood within 2 hours of life was not enough sensitive and specific marker of maternal chorioamnionitis as well as for early-onset neonatal sepsis in the group of very low birth weight infants.

Am J Respir Crit Care Med, 2002 Jul 1, 166(1), 98 - 104
Microvascular blood flow is altered in patients with sepsis; De Backer D et al.; Microvascular blood flow alterations are frequent in animal models of sepsis and may impair tissue oxygenation . We hypothesized that alterations of the microcirculation are present in patients with sepsis . We used an orthogonal polarization spectral imaging technique to investigate the sublingual microcirculation in 10 healthy volunteers, 16 patients before cardiac surgery, 10 acutely ill patients without sepsis (intensive care unit control subjects), and 50 patients with severe sepsis . The effects of topical application of acetylcholine (10(-2) M) were tested in 11 patients with sepsis . In each subject, five to seven sublingual areas were recorded and analyzed semiquantitatively . Data were analyzed with nonparametric tests and are presented as medians (25th-75th percentiles) . No significant difference in microvascular blood flow was observed between healthy volunteers and patients before cardiac surgery or intensive care unit control subjects . The density of all vessels was significantly reduced in patients with severe sepsis (4.5 {4.2-5.2} versus 5.4 {5.4-6.3}/mm in volunteers, p < 0.01) . The proportion of perfused small (< 20 microm) vessels was reduced in patients with sepsis (48 {33-61} versus 90 {89-92}% in volunteers, p < 0.001) . These alterations were more severe in nonsurvivors . The topical application of acetylcholine totally reversed these alterations . In conclusion, microvascular blood flow alterations are frequent in patients with sepsis and are more severe in patients with a worse outcome.

Am J Respir Crit Care Med, 2002 Jul 1, 166(1), 16 - 20
Adenosine deaminase inhibition attenuates microvascular dysfunction and improves survival in sepsis; Cohen ES et al.; The ability of increased endogenous adenosine to mitigate microvascular derangements in sepsis was studied . Pentostatin (2'-deoxycoformycin), an inhibitor of adenosine deaminase, was administered to mice immediately after induction of sepsis by cecal ligation and puncture . Intravital video microscopy of cremasteric postcapillary venules was performed . Leukocyte rolling and adhesion were significantly increased in septic mice compared with control mice . Treatment of septic mice with pentostatin significantly decreased leukocyte rolling and adhesion (6.02 +/- 0.09 versus 1.72 +/- 0.12 rolling cells/min, 2.07 +/- 0.04 versus 0.62 +/- 0.05 adherent cells/100 microm per minute; p < 0.001) . Albumin leakage (ratio) was significantly attenuated in septic animals treated with pentostatin (0.42 +/- 0.05 versus 0.21 +/- 0.04; p < 0.01) . Circulating levels of interleukin-6, tumor necrosis factor-alpha, and soluble tumor necrosis factor type II receptor were decreased in septic mice treated with pentostatin . Survival was significantly improved at 48 hours in mice treated with pentostatin . These results suggest an important role for adenosine in modulating both leukocyte-dependent and -independent mechanisms of endothelial injury in sepsis . Exploiting the advantageous action of endogenous adenosine represents a potentially useful and novel therapeutic approach for the treatment of sepsis.

Res Commun Mol Pathol Pharmacol, 2001 Jul-Aug, 110(1-2), 107 - 16
Liposomal atp or NAD+ protects human endothelial cells from energy failure in a cell culture model of sepsis; Han YY et al.; Sepsis depletes intracellular stores of ATP and NAD+, leading to cellular energy failure . Liposome encapsulation improves intracellular delivery of bulky, charged molecules and substrates susceptible to extracellular enzyme degradation . We hypothesized that treatments with liposome encapsulated ATP or NAD+ would protect human endothelial cells exposed to endotoxin (LPS) and interferon-gamma (IFN-gamma) from energy failure . Liposomal ATP and NAD+ were prepared by a modification of the thin film method . Human endothelial cells were exposed to LPS 50 microg/ml and IFN-gamma 50 ng/ml for 72 hours, and liposomal ATP and NAD+ treatments were dosed at 0 and 24 hours . Energy state was determined by rate of mitochondrial respiration as measured by WST-1 assay . Mitochondrial respiration significantly decreased to 57% +/- 3 of control in LPS/IFN-gamma exposed cells after 72 hours . Liposomal ATP (200 microM) and NAD+ (100 microM) completely reversed this respiratory depression while empty liposomes, free ATP (200 microM) . and free NAD+ (100 microM) did not . These results support the hypothesis that treatments with liposome encapsulated ATP or NAD+ protect human endothelial cells from energy failure in a cell culture model of sepsis and potentially may provide a novel therapy for use in clinical sepsis.

Rev Med Chir Soc Med Nat Iasi, 2000 Apr-Jun, 104(2), 97 - 102
{Evaluation of sepsis prognosis using Saps II}; Grigore L et al.; The simplified acute physiological score (SAPS II), the only valid score in sepsis according Pilly (1997) includes 17 variables: 12 physiological variables, age, type of admission and 3 variables that reffer to the background diseases: AIDS, neoplasm and haematologic malignant diseases . SAPS II was used in 30 patients with sepsis . The evaluation for each variable were between 0-26 points . Our data suggest that values over 0.552 coincided with death in 12 patients and values below 0.552 coincided with a favourable course in 18 patients.

S Afr J Surg, 2002 Feb, 40(1), 11 - 4
Abdominal wound sepsis associated with gynaecological surgery at King Edward VIII Hospital, Durban; Jjuuko G et al.; OBJECTIVE: To establish the prevalence of postoperative wound infection in major gynaecological surgery . SETTING: King Edward VIII Hospital (KEH), a large urban referral hospital for the province of KwaZulu-Natal, serving an underprivileged population . METHOD: A prospective study of postoperative wound sepsis in 270 patients who had had emergency and elective laparotomies . Data for each patient were obtained pre-operatively and during the postoperative period . RESULTS: The prevalence of surgical wound sepsis was 11.9% . The wound sepsis rate in emergency, elective and semi-elective cases was 14.6%, 6.5% and 4% respectively . Twenty-three per cent of the patients were HIV-infected, and this group had a wound sepsis rate of 28.6% compared with 6.8% in HIV-negative cases (P = 0.03) . CONCLUSION: Surgical wound sepsis in major gynaecological surgery is common at KEH . HIV infection is associated with a high rate of wound sepsis.

Best Pract Res Clin Gastroenterol, 2002 Jun, 16(3), 379 - 90
Pancreatic sepsis: prevention and therapy; Gloor B et al.; Except for a minority of early fatalities, most deaths in acute pancreatitis occur after the first 7 to 10 days due to infective complications, particularly infected necrosis . Hence, preventing this risk factor seems to represent a major step forward in the clinical management of severe pancreatitis . Consequently, antibiotics emerged as a cornerstone of the treatment of severe acute pancreatitis . The duration of such treatment, the route of administration and the substance(s) of choice need to be carefully selected . Surgical debridement is the treatment of choice of infected necrosis, while percutaneous drainage is successful in some patients .

J Pediatr Surg, 2002 Jul, 37(7), 1042 - 7; discussion 1042-7
Altered neutrophil function in the neonate protects against sepsis-induced lung injury; Calkins CM et al.; BACKGROUND/PURPOSE: Neutrophils (PMNs) are well known effectors of lung injury after sepsis . The accumulation of PMNs into the lung is dependent on a complex cascade of events that includes the local production of chemokines . Interestingly, neonates are protected from lung injury after zymosan-induced sepsis . The authors hypothesized that this protection was caused by either altered PMN function or diminished lung chemokine production compared with the adult . METHODS: Sepsis was induced in neonatal and adult rats by an intraperitoneal injection of zymosan . Animals were killed 24 hours later and lungs examined for PMN accumulation and function, chemokine production, and lung injury . RESULTS: Septic neonates (SN) were protected from pulmonary edema when compared with septic adults (SA) . Lung PMN number and chemokine (MIP-2) production increased in both septic neonates and adults when compared with vehicle (V) treated animals . Conversely, PMN function was decreased significantly in neonates when compared with adults . CONCLUSIONS: Despite equivalent lung PMN accumulation and chemotactic protein production, PMN function and lung injury in septic neonates was diminished when compared with that of adults . These findings suggest that neonates may be relatively protected from sepsis-induced lung injury caused by immature PMN function .

J Immunol, 2002 Jul 1, 169(1), 384 - 92
Anti-IL-10 therapeutic strategy using the immunomodulator AS101 in protecting mice from sepsis-induced death: dependence on timing of immunomodulating intervention; Kalechman Y et al.; The role of IL-10 in experimental sepsis is controversial . The nontoxic immunomodulator, ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) has been previously shown to inhibit IL-10 expression at the transcriptional level . In this study, we show that in mice subjected to cecal ligation and puncture (CLP), treatment with AS101 12 h after, but not before, CLP significantly increased survival of septic mice . This was associated with a significant decrease in serum IL-10 and in IL-10 secretion by peritoneal macrophages 24-48 h after CLP . At that time, the ability of these cells to secrete TNF-alpha and IL-1beta was restored in AS101-treated mice . The increased survival of AS101-treated mice was due to the inhibition of IL-10, since cotreatment with murine rIL-10 abolished the protective activity of AS101 . AS101 increased class II Ag expression on peritoneal macrophages, severely depressed in control mice, while it did not affect the expression of class I Ags . This was accompanied by a significant elevation in the level of IFN-gamma secreted by splenocytes . Moreover, AS101 ameliorated bacterial clearance in the peritoneum and blood and decreased severe multiple organ damage, as indicated by clinical chemistry . Furthermore, myeloperoxidase levels in the liver and lung of AS101-treated mice, an indirect means of determining the recruitment of neutrophils, were significantly decreased . We suggest that nontoxic agents such as AS101, with the capacity to inhibit IL-10 and stimulate macrophage functions, may have clinical potential in the treatment of sepsis, provided they are administered during the phase of sepsis characterized by immune suppression.

J Immunol, 2002 Jul 1, 169(1), 307 - 14
Altered neutrophil trafficking during sepsis; Guo RF et al.; In sepsis, dysregulation of the inflammatory system is well known, as reflected in excessive inflammatory mediator production, complement activation, and appearance of defects in phagocytic cells . In the current study sepsis was induced in rats by cecal ligation/puncture . Early in sepsis the beta(1) and beta(2) integrin content on blood neutrophils increased in a nontranscriptional manner, and the increase in beta(2), but not beta(1), integrin content was C5a dependent . Similar changes could be induced in vitro on blood neutrophils following contact with phorbol ester or C5a . Direct injury of lungs of normal rats induced by deposition of IgG immune complexes (IgG-IC) caused 5-fold increases in the myeloperoxidase content that was beta(2), but not beta(1), dependent . In contrast, in cecal ligation/puncture lungs myeloperoxidase increased 10-fold after IgG immune complex deposition and was both beta(1) and beta(2) integrin dependent . These data suggest that sepsis causes enhanced neutrophil trafficking into the lung via mechanisms that are not engaged in the nonseptic state.

Pediatr Infect Dis J, 2002 Apr, 21(4), 356 - 7
Peripheral thromboembolism associated with Malassezia furfur sepsis; Kessler AT et al.; Malassezia furfur fungemia can cause sepsis in low birth weight neonates receiving parenteral lipids through central intravenous catheters . Its presentation has varied from nonspecific signs and symptoms to pulmonary vasculitis and endocarditis . We report the case of a premature infant who developed peripheral thromboembolic phenomena without evidence of endocarditis associated with M . furfur fungemia, an association not previously described.

Dis Colon Rectum, 2002 Jun, 45(6), 826 - 8
Retroperitoneal sepsis complicating stapled hemorrhoidectomy: report of a case and review of the literature; Maw A et al.; Stapled hemorrhoidectomy (mucosectomy) is a new technique that has recently been introduced for the treatment of third-degree and fourth-degree hemorrhoids and rectal mucosal prolapse . We present a case of severe retroperitoneal sepsis complicating stapled hemorrhoidectomy that was successfully treated by conservative means, further surgery therefore being avoided . The literature on the more serious complications associated with stapled hemorrhoidectomy is reviewed.

Am J Respir Crit Care Med, 2002 Jun 15, 165(12), 1634 - 9
Role of inducible nitric oxide synthase in pulmonary microvascular protein leak in murine sepsis; Wang le F et al.; The effects of nitric oxide (NO) from calcium-independent NO synthase (iNOS) on microvascular protein leak in acute lung injury (ALI) are uncertain, possibly because of disparate effects of iNOS-derived NO from different cells . We assessed the contribution of iNOS from inflammatory versus parenchymal cells to pulmonary protein leak in murine cecal ligation and perforation-induced ALI . We studied iNOS+/+, iNOS-/-, and two reciprocally bone marrow-transplanted iNOS chimeric mice groups: + to - (iNOS+/+ donor bone marrow-transplanted into iNOS-/- recipient mice) and - to + . Sepsis-induced ALI was characterized by pulmonary leukocyte infiltration, increased pulmonary iNOS activity, and increased pulmonary microvascular protein leak, as assessed by Evans blue (EB) dye . Despite equal neutrophil infiltration, sepsis-induced EB-protein leak was eliminated in iNOS-/- mice and in - to + iNOS chimeras (parenchymal cell-localized iNOS) but was preserved in + to - chimeric mice (inflammatory cell-localized iNOS) . EB-protein leak was also prevented by pretreatment with allopurinol and superoxide dismutase . Microvascular protein leak in sepsis-induced ALI is uniquely dependent on iNOS in inflammatory cells with no obvious contribution of iNOS in pulmonary parenchymal cells . Pulmonary protein leak is also dependent on superoxide, suggesting an effect of peroxynitrite rather than NO itself.

Shock, 2002 Jun, 17(6), 463 - 7
Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days; Remick DG et al.; Virtually of the all recent therapeutic interventions for treating sepsis have failed to improve survival . One potential explanation is that the heterogeneity of the immune response to the septic challenge is such that only a portion of the patients die as a result of excessive inflammation . The clinical trials lacked power because traditional measurements do not accurately identify these patients . Previous work has shown that higher levels of interleukin (IL)-6 are found in those mice that die from septic peritonitis; therefore, we sought to determine whether IL-6 measured 6 h after surgery could predict outcome . Adult, female BALB/c mice (n = 79) were subjected to cecal ligation and puncture with a 21-gauge needle and treated with imipenem in D5W every 12 h for 5 days, resulting in a homogenous population at the outset . Six hours after surgery, 20 microL of blood was obtained from the tail vein to measure IL-6 . Mortality was followed for 21 days . Overall 3-day survival was 77%, and 21-day mortality was 56% . Plasma IL-6 levels >2,000 pg/mL were determined to predict mortality within the first 3 days with a sensitivity of 58% and specificity of 97% . To further refine the mortality prediction, body weight and a complete blood count were performed 24 hours after cecal ligation and puncture . Discriminate analysis indicated that a weighted formula combining body mass, lymphocyte, and platelet count would predict death with sensitivity of 83% and a specificity of 79% . We tested the value of the IL-6 prediction by surgically resecting the cecum in those animals with IL-6 > 2000 pg/mL, which resulted in a significant improvement in survival . These data demonstrate that IL-6 measured 6 h after injury accurately predicts mortality resulting from experimental sepsis . This measurement may be determined quickly so that therapy may be targeted only to those individuals at significant risk of dying and initiated within sufficient time to be effective.

J Arthroplasty, 2002 Jun, 17(4 Suppl 1), 36 - 40
Staged exchange arthroplasty for shoulder sepsis; Seitz WH Jr et al.; Eight patients with shoulder sepsis were treated with staged exchange arthroplasty using antibiotic-impregnated polymethyl methacrylate spacers shaped and fitted to the patient's anatomy after extensive joint debridement . Intravenous antibiotic therapy followed for a minimum of 3 months . At the end of 6 months, the patients were evaluated for any clinical or laboratory signs of infection; none were encountered . Exchange prosthetic reconstructions were performed using standard implants fixed with antibiotic-impregnated polymethyl methacrylate cement . Three patients underwent a revision to total shoulder arthroplasty, whereas 5 underwent hemiarthroplasty of the humerus with local capsular flap covering of the glenoid . All patients experienced substantial pain relief and improvement in function despite limited total overhead motion, showing this technique to be a satisfactory salvage procedure for managing sepsis of the glenohumeral joint primarily and after total shoulder arthroplasty .

Clin Exp Immunol, 2002 Jun, 128(3), 411 - 5
Modification of bacteraemia by specific antibodies and relation with mortality in a pneumococcal mouse sepsis model; Yuste J et al.; The relationship between mortality and the bacteraemic profile was investigated in a pneumococcal (serotype 6B) sepsis BALB/c mouse model where animals received protection by specific hyperimmune serum . A single intraperitoneal dose of hyperimmune serum obtained from mice immunized with the heat-inactivated strain was administered (non-diluted or diluted to 1/4 or to 1/16) to 5-mice study groups 1 h prior to intraperitoneal inoculation with the infective inoculum (3.57 x 108 cfu/ml) . Blood cultures were performed daily over 15 days, with 8 microl of blood being collected from the tail vein; the samples were resuspended in Todd-Hewitt broth containing 10% trisodium citrate and plated onto blood agar for colony counting . Animals included in the control group received placebo (PBS) . Mortality was 100% in control animals within the first 48 h . Hyperimmune serum decreased and delayed mortality in a dose-related trend, producing 100%, 80%, 60% and 40% survival rates at 72, 96, 144 and 360 h, with non-diluted serum . Bacteraemic profiles with maximum colony counts > or =5 x 107 cfu/ml in blood during the follow-up period were related to > or =65% probability of death, regardless of the serum dilution administered.

J Neurochem, 2002 Apr, 81(1), 185 - 93
Sepsis inhibits reduction of dehydroascorbic acid and accumulation of ascorbate in astroglial cultures: intracellular ascorbate depletion increases nitric oxide synthase induction and glutamate uptake inhibition; Korcok J et al.; Sepsis is associated with oxidative stress and impaired glutamatergic transmission in brain . We investigated whether sepsis impairs accumulation of the antioxidant, ascorbate, and uptake of glutamate by astrocytes . Bacterial endotoxin (Escherichia coli lipopolysaccharide, LPS) and the inflammatory cytokine, interferon-gamma (IFNgamma), were applied to primary astrocyte cultures to model sepsis . In the absence of ascorbate, the combination of LPS and IFNgamma (LPS + IFNgammay) up-regulated inducible nitric oxide synthase (iNOS) and decreased the initial rate of glutamate uptake by 50% within 24 h . Cell viability and facilitated glucose transport activity were not affected at 24 h . Pre-treatment with ascorbate-2-O-phosphate increased intracellular ascorbate concentration and attenuated the induction of iNOS and inhibition of glutamate uptake caused by LPS + IFNgamma . Subsequent experiments examined the mechanisms by which cells accumulate ascorbate . LPS + IFNy decreased slightly the initial rate of uptake of ascorbate and inhibited markedly the rate with which intracellular dehydroascorbic acid (DHAA) was reduced to ascorbate . We conclude that septic insult impairs astrocytic clearance of DHAA from the extracellular fluid and decreases intracellular ascorbate concentration . Furthermore, sepsis induces iNOS and inhibits glutamate uptake by astrocytes through mechanisms that can be modulated by intracellular ascorbate . These results indicate treatments that increase intracellular ascorbate concentration may be beneficial for patients at risk for neurologic complication in sepsis.

Infect Immun, 2002 Jul, 70(7), 3602 - 10
Inhibition of leukocyte rolling by nitric oxide during sepsis leads to reduced migration of active microbicidal neutrophils; Benjamim CF et al.; We developed two models of sepsis with different degrees of severity, sublethal and lethal sepsis, induced by cecal ligation and puncture . Lethal sepsis induced by cecal ligation and puncture (L-CLP) resulted in failure of neutrophil migration to the infection site and high mortality . Treatment of septic animals with aminoguanidine (AG), a nitric oxide (NO) synthase inhibitor, precluded the failure of neutrophil migration and protected the animals from death . However, cytokine-induced NO synthase (iNOS)-deficient (iNOS(-/-)) mice subjected to L-CLP did not present neutrophil migration failure, but 100% lethality occurred . iNOS(-/-) mice subjected to sublethal sepsis induced by cecal ligation and puncture (SL-CLP) also suffered high mortality despite the occurrence of neutrophil migration . This apparent paradox could be explained by the lack of microbicidal activity in neutrophils of iNOS(-/-) mice present at the infection site due to their inability to produce NO . Notably, SL- and L-CLP iNOS(-/-) mice showed high bacterial numbers in exudates . The inhibition of neutrophil migration by NO is due to inhibition of a neutrophil/endothelium adhesion mechanism, since a reduction in leukocyte rolling, adhesion, and emigration was observed in L-CLP wild-type mice . These responses were prevented by AG treatment and were not observed in the iNOS(-/-) L-CLP group . There was no significant change in L-selectin expression in neutrophils from L-CLP mice . Thus, it seems that the decrease in leukocyte rolling is due to a defect in the expression of adhesion molecules on endothelial surfaces mediated by iNOS-derived NO . In conclusion, the results indicate that despite the importance of NO in neutrophil microbicidal activity, its generation in severe sepsis reduces neutrophil migration by inhibiting leukocyte rolling and their firm adhesion to the endothelium, in effect impairing the migration of leukocytes and consequently their fundamental role in host cell defense mechanisms.

Cytokine, 2002 Mar 21, 17(6), 294 - 300
Differential effects between marimastat, a TNF-alpha converting enzyme inhibitor, and anti-TNF-alpha antibody on murine models for sepsis and arthritis; Tsuji F et al.; We investigated the effects of marimastat, an inhibitor of TNF-alpha converting enzyme and matrix metalloproteinases, and anti-TNF-alpha antibodies on a murine model for sepsis, and on arthritis in human TNF-alpha transgenic mice . Marimastat (25-200 mg/kg) inhibited lipopolysaccharide (LPS)-induced soluble TNF-alpha production in mice in a dose-dependent manner . At an oral dose of 200 mg/kg, marimastat almost completely inhibited LPS-induced soluble TNF-alpha production, but only slightly delayed LPS lethality . On the other hand, anti-TNF-alpha antibodies completely abolished LPS-induced morbidity . In addition, anti-TNF-alpha antibodies, but not marimastat (200 mg/kg/day), inhibited the development of arthritis in human TNF-alpha transgenic mice . These results suggest that cell surface TNF-alpha may be important in the pathogenesis of murine models for sepsis and arthritis .

Clin Infect Dis, 2002 Jul 1, 35(1), 62 - 8 Epub 2002 Jun 07.
Intra-abdominal Sepsis in Elderly Persons; Podnos YD et al.; Elderly patients represent a greater percentage of the population now than ever before, with 12.4% of North Americans being >65 years of age . Intra-abdominal illnesses in this population often have different etiologies than those seen in younger populations . Because of a variety of physiologic changes that occur as people age, elderly persons have different sites of infection, may present with vague symptoms and longer histories, are more gravely ill, and, overall, have worse prognoses . The major causes of intra-abdominal sepsis in elderly persons are reviewed, explanations for the differences in presentation and prognosis are offered, and the treatments of each cause are reviewed.

J Crit Care, 2002 Mar, 17(1), 39 - 49
Patient characteristics and costs of severe sepsis and septic shock in Quebec; Letarte J et al.; BACKGROUND: We investigated the cost of health care resources for the treatment of severe sepsis and/or septic shock patients . MATERIALS AND METHODS: One hundred retrospective chart abstractions from patients with severe sepsis or septic shock were included . The average cost, per episode, through day 28, as well as an analysis of a patient subset through 1 year was calculated . Mean values for all abstracted patient's costs and outcomes, as well as analyses of the survivor and nonsurvivor populations, were undertaken . Data from the Canadian Institute for Health Information and recent published literature were used to estimate the number of severe sepsis cases, and the resulting burden of illness for Quebec . RESULTS: The mean cost for all patients abstracted was $11,474 per episode of care ($1,064/day) . The survivors had a mean cost for their treatment of $16,228 per episode of care ($877/day) . The total cost per episode was $7,584 per nonsurvivor ($1,724/day) . An average cost of $27,481 for survivors after day 28 through 1 year was calculated . The burden of severe sepsis was estimated to be $36.4 to $72.9 million per year, but higher if costs beyond day 28 are included . CONCLUSIONS: The cost of severe sepsis is a significant burden to the Quebec health care system .

FASEB J, 2002 Jun, 16(8), 887 - 8 Epub 2002 Apr 23.
C5a receptor and thymocyte apoptosis in sepsis; Riedemann NC et al.; In sepsis, apoptosis occurs in many different organs . The mediators responsible for induction of apoptosis are not clearly known, although there are some suggestions that C5a and the C5a receptor (C5aR) might be directly linked to apoptosis . In the cecal ligation/puncture (CLP) model of sepsis in rats, apoptosis occurs early in a variety of organs, especially in the thymus . We demonstrate that thymocytes from normal rats show specific, saturable, and high affinity binding of 125I-labeled recombinant rat C5a . C5a binding to thymocytes was significantly increased 3 h after CLP and also when thymocytes from normal rats were first incubated in vitro with lipopolysaccharide (LPS) or IL-6 . The expression of C5aR mRNA in thymocytes was markedly increased 3, 6, and 12 h after CLP and increased similarly when normal thymocytes were first exposed to LPS or IL-6 in vitro . Thymocytes obtained 2 or 3 h after CLP and exposed in vitro to C5a, but not normal thymocytes, underwent increased apoptosis, as demonstrated by annexin-V binding, coinciding with increased activation of caspases 3, 6, and 8 . These data provide the first direct evidence that in the early onset of sepsis, increased expression of C5aR occurs in thymocytes, which increases their susceptibility to C5a-induced apoptosis.

Pathophysiology, 2002 Jun, 8(3), 141 - 148
Microvascular responses to sepsis: clinical significance; Bauer PR; Sepsis can be defined as a phenomenon related to the host's response to infection . Sepsis is considered an uncontrolled, unregulated, and self-sustaining intravascular inflammation, resulting from an imbalance between systemic proinflammatory reaction and excessive anti-inflammatory response . Microcirculatory dysfunction lies at the center of sepsis pathogenesis and involves all three elements of the microcirculation: arterioles, capillaries, and venules . Endothelium plays a pivotal role in the pathogenesis of sepsis, not only because it modulates the inflammatory response but also because endothelial cells activated with excessive amounts of inflammatory mediators become dysfunctional . In response to various stimuli, the endothelium exhibits a wide range of responses that may lead to local as well as systemic changes, giving rise to the phenotypic heterogeneity seen in sepsis . Therapeutic approaches, such as targeting the coagulation system, nitric oxide synthesis or intracellular signal transduction, have been considered . The administration of activated protein C has been associated with a dramatic reduction in mortality and ongoing studies with tissue factor pathway inhibitor seem promising . Glucocorticoids also seem promising for use in sepsis as a result of their anti-inflammatory effects.

Chin J Traumatol, 2002 Jun, 5(3), 146 - 50
Gene expression of adhesion molecules in pulmonary and hepatic microvascular endothelial cells during sepsis; Wu R et al.; OBJECTIVE: To study the gene expression of adhesion molecules in pulmonary and hepatic microvascular endothelial cells during sepsis in mice . METHODS: Male mice were subjected to cecal ligation and puncture (CLP) and microvascular endothelial cells in pulmonary and hepatic tissues were harvested at 3 hours (early sepsis) and 12 hours (late sepsis) after CLP, respectively . Gene expression of the adhesion molecules was assessed by reverse transcription polymerase chain reaction (RT-PCR) . Simultaneously, the alterations of myeloperoxidase (MPO) activity in pulmonary and hepatic tissues were also examined . RESULTS: E-selectin mRNA levels markedly increased at 3 hours after CLP in both pulmonary and hepatic microvascular endothelial cells, then they returned to the normal level at 12 hours after CLP . Increases in intercellular adhesion molecule-1 (ICAM-1) mRNA levels were found at 3 hours after CLP in both pulmonary and hepatic microvascular endothelial cells, and these levels became higher at 12 hours after CLP . Adhesion molecule-1 (VCAM-1) mRNA expression of vascular cells also increased significantly at 3 hours and 12 hours after CLP in both pulmonary and hepatic microvascular endothelial cells . The level of VCAM-1 mRNA in hepatic microvascular endothelial cells was higher at 3 hours than that at 12 hours after CLP, while the level of VCAM-1 mRNA in pulmonary microvascular endothelial cells was higher at 12 hours than that at 3 hours after CLP . The MPO activity in pulmonary and hepatic tissues increased at 3 hours after CLP, compared with that of the sham group . They both declined significantly at 12 hours after CLP, but they were still higher than that of the sham group . CONCLUSIONS: The up-regulation of the gene expression of adhesion molecules in pulmonary and hepatic microvascular endothelial cells is an important step for the migration and accumulation of leukocytes at the site of inflammation, which plays a critical role in organ damage during sepsis . And the contribution of the heterogeneity of endothelial cells in organs' vulnerability during sepsis is worth a further investigation.

Clin Chim Acta, 2002 Jul, 321(1-2), 123 - 6
Decrease of serum dipeptidylpeptidase activity in severe sepsis patients: relationship to procalcitonin; Bergmann A et al.; A significant decrease of DPP IV activity has been found in patients with severe sepsis in relationship to the increase of procalcitonin . These findings might be explained by the high concentration of other substrates for DPP IV present in these patients . It can be hypothesized that this enzymatic decrease is bound to some changes in immunomodulation . Further studies will be necessary to elucidate the clinical importance of these findings.

J Am Pharm Assoc (Wash), 2002 May-Jun, 42(3), 520 - 2
Drotrecogin alfa (activated) approved for treatment of severe sepsis; Poe K; Drotrecogin alfa (activated) is a recombinant form of human activated protein C that has been shown to reduce mortality in severely septic patients with a high risk of death . Given the complexity of the inclusion and exclusion criteria, the stability and unique duration of infusion, and the cost of treatment, therapy with this agent should be carefully considered to ensure its appropriate use.

Intensive Care Med, 2002 May, 28(5), 594 - 8 Epub 2002 Mar 15.
Daily organ-system failure for diagnosis of persistent intra-abdominal sepsis after postoperative peritonitis; Paugam-Burtz C et al.; OBJECTIVE: To evaluate the time-course of two organ failure scores (SOFA and Goris) after surgery for postoperative peritonitis in critically ill patients according to the persistence/nonpersistence of intraabdominal sepsis (IAS) . DESIGN: Retrospective study . PATIENTS: Sixty-two consecutive patients (SAPSII = 38+/-14) admitted in the surgical ICU . METHODS: Patients were classified according to the persistence of IAS (IAS+, n=36) confirmed by a second laparotomy or the lack of IAS (IAS-, n=26) assessed by a favorable 30-day evolution without reintervention . Scores were calculated daily from day 0 preoperatively to postoperative day 5 . RESULTS: In both groups, SOFA scores were higher on day 1 when compared to day 0 (8.3+/-3.1 vs 6.1+/-3.7 in the IAS+ group and 5.2+/-3.4 vs 2.7+/-2.7 in the IAS- group) . In the IAS- patients, the SOFA score displayed a decrease starting on day 2 when compared to day 1 (4.4+/-3.6 vs 5.2+/-3.4, P=0.03) . In contrast, in the IAS+ patients, the SOFA score remained unchanged until day 5 . The time course of the Goris score was strictly similar to the SOFA scores . CONCLUSION: In critically ill patients with postoperative peritonitis, the postoperative time course of the SOFA and the Goris organ failure scores was different between patients with or without intra-abdominal persistent sepsis . The lack of improvement of one of these scores on postoperative day 2 may suggest persistent intraabdominal sepsis and supports the need for a new surgical exploration.

Minerva Anestesiol, 2002 May, 68(5), 445 - 8
Antithrombin III in Sepsis . New evidences and open questions; Ostermann H; Antithrombin III (ATIII) has been found to be a marker for DIC and to be of prognostic significance in septic patients . Several studies have shown that administration of ATIII in patients with sepsis related DIC is effective in shortening the duration of DIC . Despite a meta-analysis of randomized controlled trials have shown a significant reduction in 28-day mortality, a prospective randomized double-blind placebo-controlled trial failed to show a significant improvement in overall survival . However the concomitant use of heparin, which does not seem to have an additional beneficial effect, may have obscured the efficacy of ATIII . More studies are needed to understand mechanism of action of ATIII and better define patient population that may benefit from ATIII.

Scand J Immunol, 2002 Jun, 55(6), 629 - 38
CD14+CD16+ monocytes in the course of sepsis in neonates and small children: monitoring and functional studies; Skrzeczynska J et al.; The phenotype and function of peripheral blood monocytes change after trauma and during sepsis . The aim of the study was to evaluate monocyte expression of human leucocyte antigen (HLA)-DR and Fc receptor III (FcR III) (CD16) in neonates and small children with high risk of sepsis (hospitalized at the intensive care unit) . The reduced proportion of CD14+HLA-DR+ monocytes was observed in all patients at the intensive care unit, while the increase of CD16 expression on monocytes was observed in the course of sepsis . The measurement of CD16 expression on monocytes also proved to be more useful for monitoring patient . The proportion of both CD14dimCD16+ and CD14highCD16+ monocytes increased during sepsis; however, monocytes showed reduced ability to phagocytose Escherichia coli, compromised ability to cooperate with T cells and reduced CD86 expression in parallel to HLA-DR depression . The reduced interleukin (IL)-1 but rather increased IL-10 production was associated with sepsis . The differences between CD14+CD16+ monocytes of healthy donors and patients with sepsis are discussed.

Minerva Anestesiol, 2002 Apr, 68(4), 127 - 31
Resurrection of steroids for sepsis resuscitation; Annane D; Corticosteroids were proposed to treat patients with severe sepsis as early as 1940 . A summary of all available randomized controlled trials performed between 1966 and 1993 was provided in two systematic review that recommended to abandon the use of high dose coricosteroids to treat patients with severe infection . Nonetheless, a doubt still persist regarding the efficacy of a strategy of replacement therapy in cathecolamines-dependent shock . This strategy relies mainly on the concept that septic shock may be complicated by 1) an occult adrenal insufficiency, 2) a glucocorticoid peripheral resistance syndrome . Some studies demonstrated the effect of replacement therapy with hydrocortisone on the sistemic inflammatory response and on the cardiovascular function during sepsis . The effect of this therapy on survival to septic shock is controversial both in recent and old studies . Finally a recently completed multicenter, placebo controlled, randomized, double-blind study has evaluated the efficacy and tolerance of a replacement therapy with a combination of hydrocortisone (50 mg intravenous bolus four times per day) and fludrocortisone (50 g orally once a day) given for 7 days . This study included 300 catecholamines- and ventilator-dependent septic shock . The authors found a significant reduction in 28-day mortality in patient with occult renal insufficiency . In sum, short course with high doses of corticosteroids should not be given in severe sepsis, except for specific entitles like severe typhoid fever, pneumocystis carinii pneumonia in AIDS or bacterial meningitis in children . The rational for a replacement therapy with hydrocortisone in catecholamines-dependent septic shock grows stronger.

Shock, 2002 May, 17(5), 423 - 6
Nitric oxide scavenging, alone or with nitric oxide synthesis inhibition, modulates vascular hyporeactivity in rats with intraperitoneal sepsis; Kim HW et al.; Elevated levels of nitric oxide (NO) may be a primary cause of the vascular hyporeactivity (vasoplesia) and refractory hypotension in sepsis . This study was initiated to determine the efficacy of NO scavenging with acellular hemoglobin (Hb) solution in modulating sepsis-mediated vasoplesia . Male Sprague Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP) . Twenty-four hours post-CLP, the animals were randomly assigned to one of four groups (n = 5-6 each) and given an intravenous injection of 0.5 mL bovine serum albumin (BSA; 5 g/dL), 0.5 mL human Hb (7g/dL), 50 microL Nomega-nitro L-arginine methyl ester (NAME; 1 M), or both Hb and NAME . Blood pressure (BP), cardiac output, systemic vascular resistance, and vascular reactivity (VR) to norepinephrine (NE; 40 ng/Kg) were assessed before and after an experimental treatment . In some animals, inducible NO synthase (iNOS) mRNA expression was assessed in selected tissue samples harvested at the conclusion of experiment using a reverse transcription-polymerase chain reaction (RT-PCR) method . Treatment with Hb, NAME, or NAME + Hb elicited a significant improvement in mean BP and VR compared with the control (BSA) group (P < 0.05, analysis of variance and Neuman-Keuls tests) . Tissue samples from 24-h CLP rats clearly exhibited iNOS gene expression; higher iNOS gene expression in the intestine compared with aorta suggests that the intestine may be a major source of the elevated NO level in this model . In conclusion, NO scavenging with Hb, alone, or in combination with NO synthesis inhibition, appears to be effective in modulating sepsis-mediated vascular hyporeactivity and may reduce complications associated with global NO synthesis inhibition.

Shock, 2002 May, 17(5), 389 - 93
Altered phospholamban-calcium ATPase interaction in cardiac sarcoplasmic reticulum during the progression of sepsis; Wu LL et al.; The purpose of this study was to investigate alterations of phospholamban phosphorylation and its interaction with Ca2+ transport(Ca2+-ATPase activity and Ca2+ uptake) in sarcoplasmic reticulum (SR) during the progression of sepsis . Sepsis was induced by cecal ligation and puncture (CLP) . Phospholamban phosphorylation was studied by the labeling of the myocardial ATP pool by perfusing isolated rat hearts with {32P}H3PO4 followed by identification of the phosphorylated phospholamban . Results show that phospholamban phosphorylation was increased by 153% during the early hyperdynamic phase (9 h after CLP), while it was decreased by 51% during the late hypodynamic phase (18 h after CLP) of sepsis . The increase in phospholamban phosphorylation during early sepsis was associated with increases in +dP/dt(max) and tissue cAMP content, while Ca2+ transport, left ventricular developed pressure (LVDP), and -dP/dt(max) remained unchanged . The decrease in phospholamban phosphorylation during late sepsis was accompanied by decreases in Ca2+ transport, LVDP, +/-dP/dt(max), and tissue cAMP content . When isoproterenol was present in the perfusion medium, all parameters measured were stimulated in all three experimental groups (control, early sepsis, and late sepsis) except that Ca2+-ATPase activity and SR Ca2+ uptake were unresponsive in the early and the late septic groups . These findings demonstrate that during the late hypodynamic phase of sepsis, the observed decrease in myocardial contractility was due to the decrease in phospholamban phosphorylation, which resulted in decreased Ca2+ transport across the SR . In contrast, during the early hyperdynamic phase of sepsis, the increase in phospholamban phosphorylation did not correlate with increases in Ca2+ uptake and Ca2+-ATPase activity . Thus, the interaction between phospholamban phosphorylation and Ca2+ transport across the SR was disrupted during the early phase of sepsis.

Am J Respir Crit Care Med, 2002 May 15, 165(10), 1426 - 32
Functional inhibition of constitutive nitric oxide synthase in a rat model of sepsis; Scott JA et al.; Induction of inducible nitric oxide synthase (iNOS) expression is likely important in the pathogenesis of sepsis . However, the sepsis-mediated induction of iNOS is associated with a decrease in constitutive NO synthase (cNOS) activity (which is reversible following acute but not chronic sepsis) . Whether this decreased cNOS activity is due to functional inhibition of cNOS by the high concentrations of NO produced by iNOS or to downregulation of cNOS expression is not clear . Thus, we tested the hypothesis that sepsis produces a reversible iNOS/NO-mediated inhibition of cNOS activity . Using a rat cecal ligation and perforation (CLP) model of sepsis, we examined the time course of the changes in iNOS and cNOS activities in lung and thoracic aortae . Reversibility of the sepsis-induced decrease in cNOS activity was assessed in vitro by enzyme activity determination following selective inhibition of iNOS . iNOS and endothelial cNOS protein concentrations were determined by Western blotting . In all septic tissues, cNOS activity was depressed at 6, 12, 24, and 48 hours post-CLP . Inhibition of the increased iNOS activity with aminoguanidine, in vitro, partially restored cNOS activity following acute (6-12 hours) but not chronic sepsis (24-48 hours post-CLP) . Consistent with the irreversible depression of cNOS activities in tissues following chronic sepsis, endothelial NOS protein concentrations declined progressively during the time course of sepsis . We have demonstrated the restoration of cNOS activity following in vitro inhibition of iNOS, early, and the downregulation of endothelial NOS, later, in a rat CLP model of sepsis . This suggests that further study is required before iNOS-selective inhibition can be considered in human sepsis.

Crit Care Med, 2002 May, 30(5), 1015 - 23
Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: Longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients; Tschaikowsky K et al.; OBJECTIVE: To determine the time course of histocompatibility leukocyte antigen (HLA)-DR expression in peripheral blood mononuclear cells and their relationship to markers of inflammation, organ function, and outcome during severe sepsis . DESIGN: Prospective, longitudinal study . SETTING: University hospital intensive care unit . PATIENTS: Twenty-three postoperative patients with severe sepsis and 26 patients with uneventful postoperative course as well as 24 healthy, age-matched subjects . INTERVENTIONS: Serum procalcitonin was determined by using an immunochemiluminescence assay, and C-reactive protein and leukocyte antigens were determined by using flow cytometry over 14 days in parallel with clinical data collection . MEASUREMENTS AND MAIN RESULTS: Despite a relative lymphopenia, absolute lymphocyte counts and CD4+/CD8+ T-cell ratio in septic patients were significantly elevated above normal . Particularly, CD4+ and CD8+ T-cell counts in nonsurvivors of sepsis were approximately twice as high as those of survivors . Significantly decreased monocytic HLA-DR expression was observed in both survivors and nonsurvivors at the onset of severe sepsis . Percentages of HLA-DR+ lymphocytes, however, were significantly increased during sepsis, especially in nonsurvivors . Whereas survivors of sepsis showed a continuous recovery of monocytic HLA-DR expression to >or=70% within 10 days, nonsurvivors were characterized by a second decrease in monocytic HLA-DR expression after day 7 or a permanent suppression (<40%) . Peak of systemic inflammatory reaction, documented by maximum serum concentrations of procalcitonin and C-reactive protein, coincided with the nadir of monocytic HLA-DR expression . Moreover, procalcitonin and C-reactive protein as well as scores on the Acute Physiology and Chronic Health Evaluation II and Sepsis Organ Failure Assessment were inversely correlated with the monocytic HLA-DR expression . CONCLUSIONS: Decreases in monocytic HLA-DR expression occurred simultaneously with signs of hyperinflammation as early as the onset of severe sepsis and usually developed in opposite directions than inflammatory markers and sepsis severity scores.

Life Sci, 2002 Mar 8, 70(16), 1875 - 88
Role of skeletal muscle Na+-K+ ATPase activity in increased lactate production in sub-acute sepsis; McCarter FD et al.; Bacterial sepsis is frequently accompanied by increased blood concentration of lactic acid, which traditionally is attributed to poor tissue perfusion, hypoxia and anaerobic glycolysis . Therapy aimed at improving oxygen delivery to tissues often does not correct the hyperlactatemia, suggesting that high blood lactate in sepsis is not due to hypoxia . Various tissues, including skeletal muscle, demonstrate increased lactate production under well-oxygenated conditions when the activity of the Na+-K+ ATPase is stimulated . Although both muscle Na+-K+ ATPase activity and muscle plasma membrane content of Na+, K+-ATPase subunits are increased in sepsis, no studies in vivo have demonstrated correlation between lactate production and changes in intracellular Na+ and K+ resulting from increased Na+-K+ pump activity in sepsis . Plasma concentrations of lactate and epinephrine, a known stimulator of the Na+-K+ pump, were increased in rats made septic by E . coli injection . Muscle lactate content was significantly increased in septic rats, although muscle ATP and phosphocreatine remained normal, suggesting oxygen delivery remained adequate for mitochondrial energy metabolism . In septic rats, muscle intracellular ratio of Na+:K+ was significantly reduced, indicating increased Na+-K+ pump activity . These data thus demonstrate that increased muscle lactate during sepsis correlates with evidence of elevated muscle Na+-K+ ATPase activity, but not with evidence of impaired oxidative metabolism . This study also further supports a role for epinephrine in this process.

Crit Care Med, 2002 May, 30(5 Suppl), S341 - 8
The era of genomics: impact on sepsis clinical trial design; Cariou A et al.; OBJECTIVE: This article aims to address the predictable impact of genetics on the design of clinical trials in the field of critical care medicine, with emphasis on the pathophysiology of sepsis and its treatment . DATA SOURCES: Published articles reporting studies on sepsis and septic shock or assessing the influence of genetics and pharmacogenomics in the treatment of critical illnesses . DATA ANALYSIS: Because most common diseases including sepsis have been shown to be influenced by inherited differences in our genes, completion of the Human Genome Project and the concomitant publication of the human single nucleotide polymorphism map both contribute to change our approach to medicine . Advances in genotyping techniques and bioinformatics enabling detection of single nucleotide polymorphisms have caused an explosion in pharmacogenomics-the research dealing with the interactions of an individual's genotype and the outcome of a drug therapy . Pharmacogenomics will undoubtedly be used to improve future health care and clinical research in different ways . Whereas treatment allocation has been based mainly on phenotype, genetic characterization will help researchers to identify suitable subjects for clinical trials, to facilitate interpretation of the results of clinical trials, and to identify novel targets for future drugs or new markets for current products . As interindividual variability in drug response is a substantial clinical problem, the second major objective of pharmacogenomic research is to decrease adverse responses to therapy through determination of adequate therapeutic targets and genetic polymorphisms that alter drug specificity and toxicity . Ultimately, genetic information will be used to select the most effective therapeutic agent and the optimal dosage to elicit the expected drug response for a given individual . Implementation of genetic criteria for stratification of patient populations and individual assessment of treatment risks and benefits emerges as a major challenge to the pharmaceutical industry . CONCLUSIONS: In the future, technologies such as gene chip array will enhance genetic medicine and provide novel insights into a patient's susceptibility to disease, enabling a better assessment of prognostic risk factors, quicker diagnosis, and accurate prediction of individual responsiveness to drugs . The predictable consequences of such an approach on the prevention and treatment of diseases could revolutionize medicine.

Crit Care Med, 2002 May, 30(5 Suppl), S313 - 7
Platelet function in sepsis; Vincent JL et al.; OBJECTIVE: To evaluate platelet function in sepsis . DATA SOURCES: The MEDLINE database and bibliographies of selected articles . DATA SYNTHESIS: The common occurrence of thrombocytopenia in critically ill patients has been recognized for many years and is known to be associated with an increased mortality rate . Platelet function can be divided into four areas: activation, adhesion, aggregation, and secretion . Studies have found that activated platelets secrete key components of the coagulation and inflammatory cascades and are involved in the regulation of vascular tone . However, studies on platelet function in sepsis have been scarce, and their data are often conflicting . In sepsis, aggregation of circulating platelets seems to be reduced, yet platelet receptors are present in normal amounts . CONCLUSIONS: Platelets play a complex role in sepsis; they are able to modulate not only their own function but also that of cells around them . Further study is needed to better define the precise mechanisms and effects of platelet activation in sepsis and to determine the benefits and risks of inhibiting platelet function.

Crit Care Med, 2002 May, 30(5 Suppl), S302 - 12
Markers of endothelial damage in organ dysfunction and sepsis; Reinhart K et al.; OBJECTIVES: To review the literature on direct and indirect markers of endothelial activation and damage in patients with sepsis and systemic inflammation and to assess their clinical usefulness for diagnosis and outcome . Various markers derived from or activated by endothelial cells are described, such as adhesion molecules, thrombomodulin, von Willebrand factor, parameters of the coagulation system, and interleukin-6 . Furthermore, the association of these markers with the severity of sepsis, systemic inflammation, and outcome is evaluated . DATA EXTRACTION AND SYNTHESIS: Published research and review articles related to these parameters, with special emphasis on clinical studies . CONCLUSIONS: Endothelial activation and damage occur early during sepsis and play a major role in the pathophysiology of systemic inflammation . Various markers of endothelial activation are increased during sepsis and systemic inflammation, and in most studies, the level of markers such as soluble intercellular adhesion molecule, vascular cell adhesion molecule, and E selectin correlate well with the severity of inflammation and the course of the disease . However, to date, it remains unclear whether adhesion molecules and coagulation parameters are superior in this respect to interleukin-6 and procalcitonin, as direct comparisons are lacking . In addition, it is evident that markers of endothelial activation and coagulation parameters lack specificity for infection-induced endothelial damage and organ dysfunction.

Crit Care Med, 2002 May, 30(5 Suppl), S263 - 7
Migration inhibitory factor in the cerebral and systemic endothelium in sepsis and malaria; Clark I et al.; OBJECTIVE: We have included migration inhibitory factor (MIF) in an ongoing immunohistochemical study comparing the site and intensity of the generation of inflammatory mediators in falciparum malaria, sepsis, and other causes of pediatric death in Africa . We wanted to determine whether it could account for our observation that inducible nitric oxide synthase is less strongly induced in the cerebral, compared with the systemic, vasculature . DATA SOURCES: Comparisons of tissue samples taken from blood vessel walls from the brain and the axillary space in a series of sepsis and falciparum malaria autopsies of African children . DATA SUMMARY: Intense staining for MIF has been detected in endothelial cells of axillary region vessels of all sepsis cases and most of the malaria cases examined . This parallels our findings with inducible nitric oxide synthase staining . African and Western control tissues from noninfectious causes of death stained lightly or not at all . In contrast, MIF could not be detected in vascular endothelial cells within the brain, where inducible nitric oxide synthase staining was much less intense . Detection of both MIF and inducible nitric oxide synthase in ependymal and glial cells in the same brains served as an internal positive staining control . CONCLUSION: These outcomes add weight to the proposal that endothelial cells are a site of intense inflammatory mediator activity in sepsis and malaria . They also suggest that suppression of anti-inflammatory glucocorticoids by MIF may be lower in the brain than elsewhere in the body . The lack of MIF in cerebral vasculature endothelial cells may be linked to the absence of thrombomodulin in these cells . The systemic cellular distribution and intensity of MIF in human systemic inflammatory states has not been described.

Crit Care Med, 2002 May, 30(5 Suppl), S225 - 8
Endothelial cell apoptosis in sepsis; Hotchkiss RS et al.; OBJECTIVE: To discuss a potential role for endothelial cell apoptosis in the pathogenesis of sepsis . DATA SOURCES: Studies published in biomedical journals and studies from the authors' laboratory . STUDY SELECTION: In vitro and in vivo studies of endothelial cell apoptosis in endotoxin and sepsis models . DATA EXTRACTION AND SYNTHESIS: Relevant studies that investigate the role of apoptosis in endotoxemia and sepsis are presented . The divergent results of the different studies and the potential reasons for the discrepant findings are presented . The importance of apoptosis in sepsis and the potential impact on endothelial cells and organ function are highlighted . CONCLUSIONS: Apoptosis is an important mechanism of lymphocyte and gastrointestinal epithelial cell death in sepsis . Although abundant in vitro studies indicate that endothelial cell apoptosis can occur in response to certain pathogenic organisms (e.g., Rickettsia rickettsii), data documenting endothelial cell apoptosis in in vivo models of sepsis are lacking . Because endothelial cells that undergo apoptosis detach from the vessel basement membrane, enter the circulation, and are rapidly cleared, it may be difficult to detect endothelial cell apoptosis in in vivo models of sepsis . The impact of endothelial cell apoptosis in sepsis may either be detrimental or beneficial to host survival, depending on the particular pathogen.

Am J Pathol, 2002 May, 160(5), 1867 - 75
Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis; Laudes IJ et al.; Sepsis and trauma are the two most common causes of disseminated intravascular coagulation and multiple organ dysfunction syndrome . Both disseminated intravascular coagulation and the systemic inflammatory response syndrome often lead to multiple organ dysfunction syndrome . The current studies have evaluated the relationship between the anaphylatoxin, C5a, and changes in the coagulation/fibrinolytic systems during the cecal ligation and puncture (CLP) model of sepsis in rats . CLP animals treated with anti-C5a had a much improved number of survivors (63%) compared to rats treated with pre-immune IgG (31%) . In CLP rats treated with pre-immune IgG there was clearly increased procoagulant activity with prolongation of the activated partial thromboplastin time and prothrombin time, reduced platelet counts, and increased levels of plasma fibrinogen . Evidence for thrombin formation was indicated by early consumption of factor VII:C, subsequent consumption of factors XI:C and IX:C and anti-thrombin and increased levels of the thrombin-anti-thrombin complex and D-dimer . Limited activation of fibrinolysis was indicated by reduced plasma levels of plasminogen and increased levels of tissue plasminogen activator and plasminogen activator inhibitor . Most of these parameters were reversed in CLP rats that had been treated with anti-C5a . Production of C5a during sepsis may directly or indirectly cause hemostatic defects that can be reduced by blockade of C5a.

Biochim Biophys Acta, 2002 Apr 24, 1586(3), 299 - 306
Saturation of adrenomedullin receptors plays an important role in reducing pulmonary clearance of adrenomedullin during the late stage of sepsis; Ornan DA et al.; Adrenomedullin (AM) is a potent vasodilator that plays a major role in the cardiovascular response during the progression of sepsis . Although pulmonary clearance of AM (i.e., the primary site of AM clearance) is reduced during the late, hypodynamic stage of sepsis, the role of AM receptors under such conditions remains unclear . This study was carried out to test the hypothesis that saturation of AM receptors is responsible for the decreased clearance of AM in the lungs during sepsis . Polymicrobial sepsis was induced in male adult rats by cecal ligation and puncture (CLP) . At 20 h after CLP (i.e., the late phase), 125I-labeled rat AM was administered through the jugular vein, both with (+) and without (-) pre-injection of the human AM fragment AM(22-52) (an AM receptor antagonist) . Pulmonary tissue samples were harvested after 30 min and the radioactivity was determined . In addition, lung levels of AM were determined at 5 and 20 h after CLP by radioimmunoassay . Alterations in gene expression of the recently identified AM receptor subunits calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein-2 and -3 (RAMP-2 and -3) were assessed in the lungs by reverse transcription-polymerase chain reaction (RT-PCR) at 5 and 20 h after CLP . The results indicate that there was a significant decrease in pulmonary {125I}AM clearance at 20 h in -AM(22-52) CLP animals . Lung clearance in +AM(22-52) sham animals was significantly lower than in -AM(22-52) sham animals and was not statistically different from the -AM(22-52) CLP group . There was no statistical difference between +AM(22-52) and -AM(22-52) CLP groups . However, there was a significant increase in lung AM levels at 20 but not 5 h after CLP . In addition, RAMP-3 expression was significantly upregulated at 5 but not 20 h after CLP . There were no alterations in the expression of CRLR or RAMP-2 at either time point . These results suggest that pulmonary AM receptors become saturated as more AM enters the bloodstream, thereby reducing the ability of the lungs to clear this peptide during late sepsis . Early upregulation of RAMP-3 may be a compensatory mechanism to help clear the upregulated AM from the bloodstream . The lack of upregulation of RAMP-3 during late sepsis could also contribute to the decreased clearance observed during this phase.

Hepatogastroenterology, 2002 Mar-Apr, 49(44), 585 - 8
Sepsis delays gastric emptying following pylorus-preserving pancreaticoduodenectomy; Kimura F et al.; BACKGROUND/AIMS: The mechanism of delayed gastric emptying following pylorus-preserving pancreaticoduodenectomy is not completely understood . METHODOLOGY: The records of 25 patients who underwent pylorus-preserving pancreaticoduodenectomy were reviewed . Correlations of postoperative delayed gastric emptying defined as the need for postoperative nasogastric decompression for > 10 days, with perioperative parameters and clinical outcome were analyzed . RESULTS: Delayed gastric emptying occurred in 13 patients . Age, gender, presence of pancreatic carcinoma, operating time, estimated blood loss, and preservation of right gastric artery did not affect the incidence of delayed gastric emptying . Patients with pancreatic fibrosis (n = 13) had a significantly lower incidence of delayed gastric emptying than in those without fibrosis (n = 12) (23% vs . 83%, P = 0.0048) . Ten patients developed postoperative septic complications, including anastomotic leakage (n = 7), pneumonia (n = 2), and severe wound infection (n = 1) . The incidence of postoperative delayed gastric emptying was significantly higher in patients with septic complications than in those without septic complications (100% vs . 20%, P = 0.0001) . Also, patients with intraabdominal sepsis had a significantly higher incidence of delayed gastric emptying (P = 0.0052) . CONCLUSIONS: Delayed gastric emptying following pylorus-preserving pancreaticoduodenectomy is related to the presence of non-fibrotic pancreas and postoperative septic complications.

Am J Emerg Med, 2002 May, 20(3), 202 - 6
Diagnostic value of procalcitonin levels as an early indicator of sepsis; Guven H et al.; Researchers and clinicians have been investigating and implementing various methods of early diagnosis for sepsis before documentation of infection . The aim of this study was to outline the efficiency of procalcitonin (PCT), C-reactive protein (CRP), and white blood cell count (WBC) in determining the early diagnosis of sepsis in the emergency department . Between January 1999 and September 2000, 34 patients with signs of systemic inflammatory response syndrome (SIRS) were enrolled in the study . The patients were divided into 2 groups according to non-suspected sepsis and suspected sepsis clinically . Admission PCT was significantly higher in suspected sepsis group (median 68.7 microg/L; lower {L} = 15.24 microg/L, upper {U} = 120.54 microg/L) compared with the unsuspected sepsis group (.23 microg/L; L =.10 microg/L, U =.44 microg/L) . PCT values were compared with WBC and CRP levels . Predictive accuracy for sepsis expressed as area under the receiver operating characteristic (ROC) curve was.88 for PCT,.44 for WBC, and.34 for CRP . PCT can probably be used as a predictive marker in bacterial infections in emergency departments .

Crit Care Med, 2002 Mar, 30(3), 684 - 91
Complement activation alters myocellular sodium homeostasis during polymicrobial sepsis; Wang W et al.; OBJECTIVE: To determine whether complement activation alters sodium homeostasis in fast-twitch skeletal muscles during sepsis, and if protein kinase-C is involved in this process . DESIGN: Prospective, randomized, controlled animal study . SETTING: Research laboratory . SUBJECTS: Male Sprague-Dawley rats weighing 60-75 g . INTERVENTIONS: Rats underwent cecal ligation and puncture (CLP) or sham-operation with or without soluble complement receptor-1 treatment . Soluble complement receptor-1 (20 mg/kg) was administered intraperitoneally 5 mins before operation . Twenty-four hours after operation, fast-twitch extensor digitorum longus muscles were isolated and incubated in normal Krebs-Henseleit buffer (pH 7.4) . In addition, extensor digitorum longus muscles isolated from normal rats were incubated for 1 hr in the Krebs-Henseleit buffer media containing normal rat sera, zymosan-activated (4 or 10 mg/mL) rat sera, or heat-inactivated rat sera . Ten percent diluted rat sera were used as a complement source in all groups . Last, extensor digitorum longus muscles isolated from normal rats were incubated for 1 hr in the Krebs-Henseleit buffer media containing zymosan-activated or heat-inactivated rat sera in the presence of protein kinase-C inhibitors (i.e., 4 microM GF109203X or 5 microM rottlerin) . Soluble C5b-9 complex concentrations in zymosan-activated human sera were determined by enzyme-linked immunosorbent assay to evaluate the degree of complement activation induced by zymosan . MEASUREMENTS AND MAIN RESULTS: Incubated extensor digitorum longus muscles from CLP, sham-operated, or normal rats were used to measure intracellular Na+ and K+ contents ({Na+}i or {K+}i) . Polymicrobial sepsis, as produced by CLP, markedly increased {Na+}i and {Na+}i/{K+}i ratios in fast-twitch extensor digitorum longus muscles 24 hrs after CLP compared with sham operation . Administration of soluble recombinant complement receptor 1 before operation significantly decreased myocellular {Na+}i and {Na+}i/{K+}i ratios . Zymosan profoundly elevated soluble C5b-9 concentrations in human sera in vitro . Sublytic zymosan-activated rat sera significantly increased myocellular {Na+}i and {Na+}i/{K+}i ratios relative to heat-inactivated rat sera . No difference in myocellular {Na+}i and {Na+}i/{K+}i ratios was observed when we used 4 mg/mL compared with 10 mg/mL of zymosan for activation . Last, incubation of extensor digitorum longus muscles with GF109203X or rottlerin significantly attenuated increases in myocellular {Na+}i and {Na+}i/{K+}i ratios induced by sublytic zymosan-activated rat sera . CONCLUSIONS: Polymicrobial sepsis alters sodium homeostasis in fast-twitch skeletal muscles, which is significantly attenuated by administration of soluble complement receptor 1 . Protein kinase-C inhibition completely blocks changes in myocellular {Na+}i and {Na+}i/{K+}i ratios induced by sublytic zymosan-activated rat sera . Collectively, these results suggest that an inappropriate activation of complement is, at least in part, responsible for changes in skeletal muscle sodium homeostasis during sepsis, and activation of PKC is one of the intracellular signaling pathways by which complement activation alters myocellular sodium homeostasis.

Crit Care Med, 2002 Mar, 30(3), 617 - 22
Administration of human inter-alpha-inhibitors maintains hemodynamic stability and improves survival during sepsis; Yang S et al.; OBJECTIVES: The major forms of human inter-alpha-inhibitor proteins circulating in the plasma are inter-alpha-inhibitor (IalphaI, containing one light peptide chain called bikunin and two heavy chains) and pre-alpha-inhibitor (PalphaI, containing one light and one heavy chain) . Although it has been reported that a decrease in IalphaI/PalphaI is correlated with an increased mortality rate in septic patients, it remains unknown whether administration of IalphaI/PalphaI early after the onset of sepsis has any beneficial effects on the cardiovascular response and outcome of the septic animal . The aim of this study, therefore, was to determine whether IalphaI and PalphaI have any salutary effects on the depressed cardiovascular function, liver damage, and mortality rate after polymicrobial sepsis . DESIGN: Prospective, controlled, randomized animal study . SETTING: A university research laboratory . SUBJECTS: Male adult rats were subjected to polymicrobial sepsis by cecal ligation and puncture or sham operation followed by the administration of normal saline (i.e., resuscitation) . MEASUREMENTS AND MAIN RESULTS: At 1 hr after cecal ligation and puncture, human IalphaI/PalphaI at a dose of 30 mg/kg body weight or vehicle (normal saline, 1 mL/rat) were infused intravenously over a period of 30 mins . At 20 hrs after cecal ligation and puncture (i.e., the late, hypodynamic stage of sepsis), cardiac output was measured by using a dye dilution technique, and blood samples were collected for assessing oxygen content . Oxygen delivery, consumption, and extraction ratio were determined . Plasma concentrations of liver enzymes alanine aminotransferase and aspartate aminotransferase as well as lactate and tumor necrosis factor-alpha also were measured . In additional animals, the necrotic cecum was excised at 20 hrs after cecal ligation and puncture with or without IalphaI/PalphaI treatment, and survival was monitored for 10 days thereafter . The results indicate that administration of human IalphaI/PalphaI early after the onset of sepsis maintained cardiac output and systemic oxygen delivery, whereas it increased oxygen consumption and extraction at 20 hrs after cecal ligation and puncture . The elevated concentrations of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-alpha, and lactate were attenuated by IalphaI/PalphaI treatment . In addition, administration of human IalphaI/PalphaI improved the survival rate from 30% to 89% in septic animals at day 10 after cecal ligation and puncture and cecal excision . CONCLUSION: Human IalphaI/PalphaI appears to be a useful agent for maintaining hemodynamic stability and improving survival during the progression of polymicrobial sepsis.

Inflammation, 2002 Apr, 26(2), 97 - 101
Muscle proteolysis and weight loss in a neonatal rat model of sepsis syndrome; Premer DM et al.; Our hypothesis is that nitrogen loss in septic neonates is caused by increased muscle proteolysis . Sprague-Dawley rat pups (P7) were injected intraperitoneally with NaCl or 4 mg/kg/BW lipopolysaccharide (LPS) and then sacrificed at 2, 4, 24, and 48 hr . Sepsis syndrome was confirmed by elevated serum tumor necrosis factor (24.6 ng/mL +/- 18.4 {LPS} and < 1.0 ng/mL {controls}; p < .05) . Proteolysis in gastrocnemius/soleus muscle was analyzed by quantitation of tissue tyrosine loss . The neonatal rats injected with LPS had significant media tyrosine release at 24 hr compared to the controls (0.39 +/- 0.14 versus 0.25 +/- 0.11 micromol tyrosine/g muscle; p < .05) . At 48 hr, LPS-induced muscle tyrosine release ceased (0.24 +/- 0.04 {control} versus 0.23 +/- 0.03 micromol tyrosine/g muscle {LPS}) . After 48 hr, gastrocnemius/soleus weight was less in the LPS-injected rats (50.5 +/- 4.8 to 31.2 +/- 4.0 g; p < .0001) . Similar changes were not seen in the extensor digitorum longus, suggesting that some muscles were relatively preserved . Also, LPS resulted in significant weight loss . We conclude that selective muscle proteolysis contributes to nitrogen loss in neonatal sepsis . Although proteolysis abates by 48 hr, short-term injury results in significant muscle-mass deficit.

Lakartidningen, 2002 Mar 27, 99(13), 1456 - 7, 1460
{Antithrombin therapy of no value in sepsis according to a large clinical trial}; Gardlund B; Antithrombin has been used for over two decades as adjuvant therapy in severe sepsis, especially when associated with coagulopathy . A positive effect has been demonstrated in several experimental sepsis models and a number of small clinical trials have suggested a beneficial effect . A large confirmatory randomized clinical trial with 2,314 evaluable patients with severe sepsis was recently completed {1} . No treatment effect of antithrombin was demonstrated (28 day overall mortality was 38.9% and 38.7% in the treatment and placebo groups, respectively) . Among various secondary effect and subgroup analyses, it is noteworthy that no trend indicating a beneficial effect of antithrombin substitution was found even in the subgroup of patients with plasma levels of antithrombin < 60% on randomization (n = 1,117) . In summary, there is presently no support for the general use of antithrombin as adjuvant therapy in severe sepsis/septic shock.

An Med Interna, 2002 Jan, 19(1), 35 - 43
{Sepsis and septic shock: a turmoil of inflammatory mediators with difficult therapeutic management}; Duran Gimenez-Rico HJ et al.; Sepsis and septic shock continue being a topic of enormous interest for their high frequency, and for not existing a decrease in the figures of mortality in spite of the new acquired knowledges relation with their physiopathology and the advances arisen in the diverse applied treatments . The purpose of the present study is to update the present notions in the specialized literature, trying to summarize the complex existent interaction among different mediators of double character: exogenous and endogenous, and to enunciate the possible causes for those that the novel treatments applied in the sepsis continue not to be very promising.

J Trauma, 2002 May, 52(5), 951 - 61
Does endotoxin-activated complement alter myocellular sodium homeostasis during sepsis?
Wang W, Okamoto K, Jacobs DO.
BACKGROUND: Inappropriate complement activation is closely related to tissue injury and organ dysfunction during systemic infection . It is not clear, however, if endotoxin-induced complement activation is responsible for changes in myocellular sodium homeostasis during sepsis . METHODS: Rats underwent cecal ligation and puncture (CLP) or sham operation . Twenty-four hours after operation, fast-twitch extensor digitorum longus (EDL) muscles were isolated, incubated at 30 degrees C for 1 hour in Krebs-Henseleit buffer (KHB) (pH 7.4), and used to measure intracellular Na+ and K+ contents . Blood samples were collected to measure serum hemolytic complement activity and endotoxin levels . In addition, EDL muscles isolated from normal animals were incubated at 30 degrees C for 1 hour with zymosan-activated (10 mg/mL at 37 degrees C for 1 hour) rat sera, with lipopolysaccharide (LPS)-activated (LPS from Escherichia coli 055:B5, 10 or 200 microg/mL at 37 degrees C for 30 minutes) rat sera, with heat-inactivated (56 degrees C for 30 minutes) rat sera, with LPS (1 or 20 microg/mL), or in KHB . EDL muscles isolated from normal animals were also incubated with septic sera collected 6 or 24 hours after CLP with or without administration of soluble complement receptor type 1 (20 mg/kg, intraperitoneally) . Myocellular Na+ and K+ contents ({Na+}i and {K+}i) were assayed using "washout" technique . Soluble C5b-9 complex levels in zymosan-activated or LPS-activated human sera were determined by enzyme-linked immunosorbent assay to evaluate the degree of complement activation induced by zymosan or LPS . RESULTS: Myocellular {Na+}i and {Na+}i/{K+}i ratios increased significantly 24 hours after CLP as compared with sham operation and were associated with decreased serum hemolytic complement activity and increased serum endotoxin levels . Zymosan-activated rat sera at sublytic concentrations markedly increased {Na+}i and {Na+}i/{K+}i ratios in isolated EDL muscles relative to heat-inactivated rat sera . LPS-activated rat sera, however, did not alter these two indices . In addition, myocellular {Na+}i and {Na+}i/{K+}i ratios were equivalent among normal EDL muscles incubated with septic sera, soluble complement receptor type 1-treated septic sera, or KHB . CONCLUSION: These results collectively suggest that polymicrobial sepsis, as produced by CLP, alters sodium homeostasis in fast-twitch skeletal muscles in association with changes in systemic complement activation and circulating endotoxin levels . Although endotoxin can activate the complement cascade, endotoxin-induced complement activation does not appear to be responsible for changes in myocellular sodium homeostasis observed during sepsis in rats.

J Trauma, 2002 May, 52(5), 817 - 25; discussion 825-6
The G-->A single nucleotide polymorphism at the -308 position in the tumor necrosis factor-alpha promoter increases the risk for severe sepsis after trauma; O'Keefe GE et al.; BACKGROUND: Clinical factors do not adequately explain why some patients develop severe sepsis after trauma and why others do not . We sought to determine whether genetic factors contribute to this risk . METHODS: Patients admitted to a single Level I trauma center were enrolled and DNA was isolated from leukocytes . The risk for severe sepsis and for death associated with polymorphism in the tumor necrosis factor-alpha promoter was determined by multivariate analysis . RESULTS: One hundred fifty-two patients had a 24% incidence of severe sepsis and a 13% case fatality rate . The A-allele was most common at the -308 position (n = 35) . A-allele carriage at this location was associated with an adjusted odds ratio of 4.6 (95% confidence interval, 1.9-10.9) for severe sepsis and of 2.1 (95% confidence interval, 0.6-7.3) for death . CONCLUSION: The A-allele at the -308 position in the tumor necrosis factor-alpha promoter increases the risk for severe sepsis and possibly for death after trauma.

Issues Emerg Health Technol, 2002 Mar, (30), 1 - 4
Activated protein C for severe sepsis; Garces K; Severe sepsis is a systemic inflammatory response to infection involving organ dysfunction . Severe sepsis is a common cause of death and is associated with a 20% to 56% mortality rate . Drotrecogin alpha (activated) is a recombinant human activated protein C(rhAPC) approved in the U.S . for the reduction of mortality in adult patients with severe sepsis who have a high risk of death . Drotrecogin alpha (activated), when administered to adult patients with clinically defined severe sepsis, demonstrated a 6.1% absolute reduction (p=0.005) in 28-day all-cause mortality in one published, randomized, double-blind study of 1,690 patients (PROWESS) . Drotrecogin alpha (activated) is used as an adjunct to standard therapy and is therefore and "add-on" cost . Close attention must be paid to proper patient selection for treatment with drotrecogin alpha (activated) . Certain individuals, such as those at a greater risk of bleeding, could be harmed from therapy . The benefit or harm in individuals not meeting the trial selection criteria is uncertain.

Przegl Epidemiol, 2001, 55 Suppl 3, 38 - 40
{Sepsis in HIV-positive patients--own observation}; Lemanska M et al.; In the period of 1988-2001 (June) 24 HIV-positive patients with symptoms of sepsis were observed . Most of them (17 persons) were intravenous drug addicts, six patients were infected HIV trough sexual contact and one person-via blood transfusion . There were 26 cases analyzed (one of the patients went trough three episodes of sepsis) . Bacterial sepsis dominated (22 cases) . In three patients fungoid etiology was diagnosed, and one case was of mixed character . The highest risk factors of sepsis were: intravenous drug addiction and advanced stage of HIV infection.

Ther Apher, 2002 Apr, 6(2), 109 - 15
Endotoxin and cytokine removal in sepsis; Tetta C et al.; Sepsis, the leading cause of mortality in intensive care units, is a complex series of interrelated effects caused by the overproduction of multiple mediators and their unrestrained biological activity . Both proinflammatory and antiinflammatory mediators participate in the high complexity of sepsis and explain the failure of specific therapies to improve survival . Continuous extracorporeal therapies have been proposed as therapeutic options and as tools for blood purification in sepsis . Along these lines and in order to achieve higher clearances and mass removal rates, we studied the effects of plasmafiltration coupled with adsorption and provided in vitro and in vivo evidence that adsoprtion of multiple cytokines, activated complement components, and lipid mediators such as the platelet-activating factor occurs . We also showed that such treatment may lead to improved survival in a rabbit model of sepsis and to improved hemodynamics, reduced norepinephrine dose, and restoration of near-to-normal responsiveness of blood leukocytes to endotoxin in humans . It is anticipated that treatment of plasma, as a modular device to conventional hemofiltration, may pave the way to innovative approaches in the extracorporeal treatment of septic patients.

Am J Surg, 2002 Apr, 183(4), 372 - 83
Mucosal and enterocyte IL-6 production during sepsis and endotoxemia--role of transcription factors and regulation by the stress response; Pritts T et al.; BACKGROUND: Sepsis and endotoxemia are associated with increased production of interleukin-6 (IL-6) in gut mucosa . Mucosal IL-6 may regulate enterocyte acute phase protein synthesis and intestinal IgA production . In addition, increased IL-6 has been proposed to be a mechanism of loss of mucosal integrity in critical illness . The purpose of this review is to describe current knowledge of the regulation of IL-6 production in the enterocyte/mucosa during inflammation caused by sepsis and endotoxemia . DATA SOURCES: Recent publications describing the influence of sepsis, endotoxemia, and proinflammatory cytokines on mucosal/enterocyte IL-6 production . CONCLUSIONS: IL-6 production is increased in gut mucosa during sepsis and endotoxemia and in cultured enterocytes after treatment with endotoxin or proinflammatory cytokines . The IL-6 gene is regulated by multiple transcription factors, including NF-kappaB, AP-1, and C/EBP . Because of the multiple important biological roles of IL-6, understanding the cellular and molecular mechanisms of mucosal/enterocyte IL-6 production as well as methods to modulate IL-6 production is of clinical importance in the setting of sepsis and other critical illness.

Ned Tijdschr Geneeskd, 2002 Apr 6, 146(14), 649 - 52
{Gluteal abscess complicated by sepsis as the expression of Crohn's disease}; Bosscha K et al.; Two young women, aged 19 and 25 years, suffered from persistent perianal sepsis after local drainage of unusual gluteal abscesses . Preoperative CT scanning showed unrecognised and inadequately treated abscesses and signs of inflammatory bowel disease . Both patients underwent a reoperation: affected bowel segments were removed, stomas were created and abscesses were drained . In the case of unusual perianal abscesses the diagnosis 'Crohn's disease' must be considered . Preoperative examinations should include CT or MRI scans of the abdomen and pelvis . Intraoperative colonoscopy can often be helpful in assessing the extent of the affected bowel segment.

Intensive Care Med, 2002 Apr, 28(4), 493 - 500 Epub 2002 Mar 12.
Ciprofloxacin pharmacokinetic profiles in paediatric sepsis: how much ciprofloxacin is enough?
Lipman J, Gous AG, Mathivha LR, Tshukutsoane S, Scribante J, Hon H, Pinder M, Riera-Fanego JF, Verhoef L, Stass H.
OBJECTIVE: To determine the pharmacokinetic profile of ciprofloxacin 20 mg/kg per day (10 mg/kg administered intravenously 12 hourly) in paediatric patients with severe sepsis . DESIGN: Open and prospective . SETTING: Tertiary referral multi-disciplinary ICU . PATIENTS: Twenty patients (two groups - group A: 3 months-1 year; group B 1-5 years) . INTERVENTIONS: Timed blood samples were taken for pharmacokinetics after the first dose (D(0)), as well as day 2 (D(2)) and then between days 6-8 . MEASUREMENTS AND RESULTS: Ciprofloxacin serum levels were measured by high performance liquid chromatography . Demographic and clinical data and all adverse events were noted . Standard pharmacokinetic variables were calculated by non-compartmental methods . Peak concentrations (C(max)) for group A were D(0) 6.1+/-1.2 mg/l, D(2) 9.0+/-1.8 mg/l and D(7) 5.8+/-1.3 mg/l and, for group B, 7.4+/-1.3 mg/l, 7.8+/-1.6 mg/l and 6.4+/-1.3 mg/l, respectively, for the study periods . Concentration 12 h after the start of infusion (C(min)) for all periods were 0.2 mg/l or less . Areas under the curve (AUC, 12 h) were group A: 15.6+/-1.3, 19.2+/-1.63 and 14.1+/-1.4 mg/h per l, and group B: 15.9+/-1.3, 18.0+/-1.7 and 13.2+/-1.26 mg/h per l . One patient presenting with seizures, initially controlled, had another convulsion and a further patient developed seizures whilst on ciprofloxacin . C(max) in these patients were higher than the average C(max) . The convulsions of both patients were easily controlled . No other drug-related serious adverse events occurred . No arthropathy was noted . Three patients died of their underlying disease . CONCLUSIONS: There was no accumulation of drug even after 7 days of administration . Our C(max) and AUC were lower than that achieved in a similar adult pharmacokinetic study . To achieve end points of area under the inhibitory curve (AUIC) of 100-150 mg/h per l, 10 mg/kg ciprofloxacin eight hourly would be required for some resistant ICU organisms.

Virchows Arch, 2002 Feb, 440(2), 181 - 6
Lectin binding patterns of alveolar epithelium and subepithelial seromucous glands of the bronchi in sepsis and controls--an approach to characterize the non-specific immunological response of the human lung to sepsis; Tsokos M et al.; A delayed or deficient immunological protection as well as an overstimulation of the mucosal immune system may act as possible additional promoters of sepsis-induced lung injury in patients suffering from a severe septic condition . Lectin-binding patterns in pulmonary tissue samples obtained at autopsy from septic patients and control individuals were studied using 11 carbohydrate-specific lectins (Con A, UEA, GSA I, GSA II, MPA, PNA, Jac, WGA, MAA, LPA, and SNA) . There were no differences in the secretory product of serous parts of bronchial glands detectable in the two study groups, whereas lectin binding patterns of alveolar epithelium and mucous parts of subepithelial seromucous glands were different in sepsis cases when compared to controls . Apart from differences in binding sites for alpha-mannose, N-acetyl-neuraminic acid and alpha-(2-6)-galactose (as detected by different expression for Con A, MAA and SNA) in the two study groups, the main finding was that no binding sites for alpha-N-acetyl-galactosamine (as investigated by MPA immunoreactivity) could be detected on alveolar epithelial cells and mucous parts of subepithelial seromucous glands in sepsis cases in contrast to the presence of such binding sites in the control cases . We hypothesize that the finding of an altered secretory product of alveolar epithelial cells and bronchial glands in sepsis may be a result of specific carbohydrate deprivation or consumption, respectively, possibly due to direct bacterial effects or pathogenetic events in response to bacterial toxins during the complex cascade of the host's systemic inflammatory response in sepsis . The altered type of mucus glycoprotein physiologically secreted by alveolar epithelium and mucous parts of subepithelial seromucous glands of the bronchi with subsequent loss of a considerable proportion of protection of the mucosal barrier in sepsis may play an important additional role in the development of sepsis-induced lung injury.

J Pediatr Orthop, 2002 May-Jun, 22(3), 329 - 32
Deep vein thrombosis associated with pediatric musculoskeletal sepsis; Walsh S et al.; Deep vein thrombosis (DVT) is uncommon in children but can occur given certain circumstances . The authors describe four children in whom DVT developed in association with musculoskeletal sepsis . One child died . Prothrombotic screens were performed on the three surviving children, showing normal hematologic parameters . The severity of DVT complicating musculoskeletal sepsis is emphasized, particularly the potential for septic embolic complications . Deep vein thrombosis should be considered in any child with musculoskeletal sepsis, particularly when a limb is severely swollen or when there are pulmonary septic emboli.

Am J Physiol Regul Integr Comp Physiol, 2002 May, 282(5), R1324 - 32
Inhibiting adenosine deaminase modulates the systemic inflammatory response syndrome in endotoxemia and sepsis; Adanin S et al.; By pharmacological manipulation of endogenous adenosine, using chemically distinct methods, we tested the hypothesis that endogenous adenosine tempers proinflammatory cytokine responses and oxyradical-mediated tissue damage during endotoxemia and sepsis . Rats were pretreated with varying doses of pentostatin (PNT; adenosine deaminase inhibitor) or 8-sulfophenyltheophylline (8-SPT; adenosine receptor antagonist) and then received either E . coli endotoxin (lipopolysaccharide; 0.01 or 2.0 mg/kg) or a slurry of cecal matter in 5% dextrose in water (200 mg/kg) . Resultant levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 were measured in serum and in liver and spleen . Untreated, 2 mg/kg lipopolysaccharide elevated serum TNF-alpha, IL-1beta, and IL-10 . PNT dose dependently attenuated, without ablating, the elevation in serum TNF-alpha and IL-1beta and raised liver and spleen IL-10 . PNT also attenuated elevation of TNF-alpha in serum, liver, and spleen at 4 and 24 h after sepsis induction, and 8-SPT resulted in higher proinflammatory cytokines . Modulating endogenous adenosine was also effective in exacerbated (8-SPT) or diminished (PNT) tissue peroxidation . Survival from sepsis was also improved when PNT was used as a posttreatment . These data indicate that endogenous adenosine is an important modulatory component of systemic inflammatory response syndromes . These data also indicate that inhibition of adenosine deaminase may be a novel and viable therapeutic approach to managing the systemic inflammatory response syndrome without ablating important physiological functions.

Int J Mol Med, 2002 May, 9(5), 443 - 9
The cardiovascular response in sepsis: proposed mechanisms of the beneficial effect of adrenomedullin and its binding protein (review); Fowler DE et al.; Sepsis and its complications are leading causes of morbidity and mortality . A better understanding of the mechanisms responsible for the shift from the early, hyperdynamic phase of sepsis to the late hypodynamic phase could lead to novel therapies that might improve the outcome of the septic patient . Adrenomedullin is a vasodilatory peptide which shows sustained elevation starting early in sepsis and is important in initiating the hyperdynamic response . As sepsis progresses, however, the vascular response to adrenomedullin is blunted and this decreased sensitivity is important in producing the shift to the late, hypodynamic phase . The decline in the vascular response to adrenomedullin is related to a sepsis-induced decrease in the binding protein for adrenomedullin (i.e., adrenomedullin binding protein-1) rather than a change in gene expression of the components of adrenomedullin receptors . Treatment of septic animals with the combination of adrenomedullin and its binding protein prevents the transition to the late phase of sepsis, maintains cardiovascular stability, and reduces sepsis-induced mortality . We propose that the mechanisms responsible for the beneficial effect of adrenomedullin and adrenomedullin binding protein-1 in sepsis are associated with downregulation of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), maintainence of endothelial constitutive nitric oxide synthase, and reduction of vascular endothelial cell apoptosis.

Acta Anaesthesiol Scand, 2002 Apr, 46(4), 405 - 10
Influence of surgery and endotoxin-induced sepsis combined on natural killer cell activity, oxidative burst of granulocytes and antigen presentation capability of monocytes; Toft P et al.; BACKGROUND: Cell mediated immunity is affected in the course of sepsis and following surgical stress . The natural killer (NK) cells, the granulocytes and the monocytes constitute the immediate unspecific cell mediated immunity . We therefore investigated the effect of surgery- and endotoxin-induced sepsis on NK cells, granulocytes and monocytes in a two-hit model . METHODS: Three groups of 40 mice . Each group was divided into four groups of 10 mice . All the animals were anesthetized and subjected to either: laparotomy; treatment with Escherichia coli endotoxin i.p.; laparotomy followed 20 min later by endotoxin i.p.; or left untreated as a control group . In the first 40 mice the NK cell activity in the spleen and number of NK cells in the liver were measured, in the second the oxidative burst of granulocytes, and in the third the antigen presentation capacity of monocytes . RESULTS: Endotoxin stimulated the NK cell activity and up-regulated the antigen presentation capability on monocytes . In contrast, surgical stress reduced the NK cell activity, the number of NK cells and down-regulated the antigen presentation capability on monocytes . After surgery, followed by administration of endotoxin, the oxidative burst of granulocytes was stimulated while antigen presentation capability on monocytes was down-regulated . Endotoxin prevented or reverted the postoperative suppression of NK cell activity . CONCLUSION: Our two-hit model shows that some cell types of the unspecific immune system exhibit an excessive inflammatory response (NK cells, granulocytes) while specific functions of other cell types (monocytes) are simultaneously diminished . This diversity makes a potential therapeutic immunomodulation very complex as some cell types would need to be down-regulated while others need to be stimulated.

Eur J Obstet Gynecol Reprod Biol, 2002 May 10, 102(2), 131 - 6
Influence of maternal preeclampsia on recombinant human granulocyte colony-stimulating factor effect in neutropenic neonates with suspected sepsis; Zuppa AA et al.; AIM: To evaluate the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in preterm neonates with suspected sepsis and severe neutropenia (<1500 mm(3)), and to define the influence of maternal preeclampsia on rhG-CSF activity . METHODS: Twenty neonates of normotensive mothers (NNMs) (GA 29.2+/-0.5 weeks and BW 1.024+/-81 g) and 20 born to preeclamptic mothers (NPMs) (GA 29+/-0.4 weeks and BW 946+/-55 g) were treated with rhG-CSF, 10 microg/kg per day for 3 days . Complete blood counts were obtained at day 0 (before rhG-CSF administration) and 1-4, 6, 9, 20 and 30 days later . RESULTS: Absolute neutrophil count (ANC) increased rapidly (three-fold within 24h), and significantly (maximum approximately 20-25 times starting values) and remained within normal range in both groups . However, in NNMs a two-phase increase occurred with an early peak on day 2 and a further peak on day 6 giving significantly higher ANC (P<0.001) than for NPMs at days 2-4 and 6 . NPMs showed a gradual ANC increase with a single late peak occurring 3 days later than NNMs (day 9) . The highest peak values for ANC were similar (15,900+/-1395 mm(-3) for NNMs and 13,880+/-1097 mm(-3) for NPMs) . Neutropenia was completely resolved within 2 days in NNMs and within 4 days in NPMs . CONCLUSION: Preeclampsia seemed to influence the course of the ANC in spite of rhG-CSF administration, and a higher daily-dose for NPMs with neutropenic sepsis may more rapidly resolve neutropenia by overcoming the preeclampsia-associated inhibitor of rhG-CSF through a dose-dependent mechanism.

Acta Anaesthesiol Scand, 2002 Feb, 46(2), 145 - 51
Adrenocortical function and multiple organ failure in severe sepsis; Loisa P et al.; BACKGROUND: Some patients with severe sepsis may have relative adrenocortical insufficiency, although not all studies confirm this finding . Corticosteroids play an important role in controlling excessive immune response, and they may reduce the severity of organ dysfunction in critical illness . In this prospective study, we investigated the incidence of adrenal insufficiency in severe sepsis and its relation to the development of multiple organ failure . METHODS: Forty-one patients meeting the criteria for severe sepsis were studied . A short ACTH stimulation test was carried out within 24 h of the diagnosis of sepsis . Peak serum cortisol level < 680 nmol/L and a rise of less than 260 nmol/L were used as the criteria for relative adrenocortical insufficiency . RESULTS: Relative adrenocortical insufficiency was detected in six patients . Duration of the ICU stay (P = 0.002) and mechanical ventilation (P = 0.024) were significantly longer in patients with impaired adrenal function . In the survivors, SOFA scores were significantly higher in patients with impaired adrenal function . The plasma ACTH levels were normal in most of the patients with relative adrenal insufficiency, whereas most patients with normal adrenal function had extremely low plasma ACTH levels . CONCLUSION: The ICU stay was longer and multiple organ failure more severe in patients with impaired adrenocortical function . There was a clear dissociation between ACTH and cortisol levels in AAR patients . This finding suggests that the integrity of the hypothalamic-pituitary-adrenal axis may be impaired in severe sepsis.

Acta Anaesthesiol Scand, 2002 Feb, 46(2), 138 - 44
Effect of hemodiafiltration and sepsis on chemotaxis of granulocytes and the release of IL-8 and IL-10; Toft P et al.; BACKGROUND: Extracorporeal circulation, such as cardiopulmonary bypass and hemodialysis, has been associated with an activation of the immune system . Continuous veno venous hemodiafiltration (CVVHD) is used in critically ill septic patients . During CVVHD, cytokines are excreted in ultrafiltrate . When the membranes, used in CVVHD, are incubated with leukocytes in vitro a slight production of cytokines is observed . Due to the underlying disease it is difficult to investigate the effect of CVVHD in septic patients . We therefore studied the separate effect of CVVHD on the chemotaxis of granulocytes, the proliferation of lymphocytes and the release of IL-8 and IL-10 in healthy pigs compared to an endotoxin and a control group . METHODS: Thirty-one pigs were anesthetized and mechanically ventilated . CVVHD was performed in 10 pigs . Eleven pigs received an infusion of Escherichia coli endotoxin 30 microg/kg, and 10 pigs served as a control group . The chemotaxis of granulocytes was measured in an assay chamber, and the cytokines IL-8 and IL-10 with an enzyme-linked immunosorbent assay . The adhesion molecules CD18 and CD62 on lymphocytes were measured using monoclonal antibodies, and the lymphocyte proliferation was measured without stimulation and in response to mitogens . RESULTS: CVVHD was accompanied by lymphocytopenia and increased spontaneous lymphoproliferative response, but no change in adhesion molecules on lymphocytes or cytokine levels in plasma, and no decrease in the chemotaxis of granulocytes . Following endotoxin we observed a pronounced lymphocytopenia and an increased secretion of IL-8 and IL-10, a decrease in the expression of CD18 on lymphocytes and in the stimulated lymphocyte proliferation and in the chemotaxis of granulocytes . CONCLUSION: CVVHD does not, in contrast to endotoxin-induced sepsis, influence chemotaxis of granulocytes, the production of IL-8 and IL-10 or the proliferation of lymphocytes.

Crit Care Med, 2002 Apr, 30(4), 894 - 9
Modification of alpha1 -adrenoceptors by peroxynitrite as a possible mechanism of systemic hypotension in sepsis; Takakura K et al.; OBJECTIVE: It is well known that nitric oxide synthase is induced by endotoxin or inflammatory cytokines, and consequently large amounts of nitric oxide cause vascular hyporeactivity to vasoconstrictor agents and myocardial dysfunction, hence hypotension . However, there is considerable controversy as to whether these pathologic cardiovascular features are mediated directly by nitric oxide or also through the formation of secondary reaction products such as peroxynitrite (ONOO-1) . Our objective was to investigate inhibitory effects of ONOO-1 on alpha1-adrenoceptors . DESIGN: Prospective, controlled, in vitro, laboratory study . SETTING: Laboratory of a health sciences university . SUBJECTS: Chinese hamster ovary cells that expressed the human recombinant alpha1a-, alpha1b-, or alpha1d-adrenoceptors, rat aorta strips . INTERVENTIONS: Binding experiments of {3H}prazosin were done in the Chinese hamster ovary cell membranes pretreated with 100 microM to 3 mM ONOO-1 . Displacement experiments with noradrenaline or 3-nitro-l-tyrosine also were conducted . Mobilization of intracellular Ca2+ evoked by 1 nM to 10 microM noradrenaline was monitored in a fluorescence spectrophotometer with dual excitation at 340 nm/380 nm and emission at 500 nm in fura-2/AM-loaded Chinese hamster ovary cells . Contractile force produced by noradrenaline was monitored in rat aorta strips that have alpha1a- and alpha1d-adrenoceptors, pretreated with 1 mM ONOO-1 . Either 0.3 N NaOH or the decomposed ONOO-1 was used as the control . MEASUREMENTS AND MAIN RESULTS: The specific binding of {3H}prazosin to alpha1a- and alpha1d-adrenoceptor was inhibited by ONOO-1 in a concentration-dependent manner . We found that 3 mM ONOO-1 decreased maximum binding sites by 40% to 50% in alpha1a- and alpha1d-adrenoceptors . Binding affinities for prazosin and noradrenaline were not affected by 1 mM ONOO-1 in all subtypes . We found that 3-nitro-l-tyrosine did not affect the prazosin binding to three adrenoceptor subtypes . Noradrenaline increased intracellular Ca2+ concentration ({Ca2+}i) concentration-dependently, which was inhibited by ONOO-1 in alpha1a- and alpha1d-adrenoceptors . ONOO-1 had no effect on alpha1b-adrenoceptor . Contractile force produced by noradrenaline decreased significantly in aorta strips pretreated with ONOO-1 . CONCLUSION: ONOO-1 reduces the binding capacity of alpha1a- and alpha1d- but not alpha1b-adrenoceptors without changing the affinities . Treatment with ONOO-1 attenuates noradrenaline-stimulated increase in {Ca2+}i in alpha1a- and alpha1d-adrenoceptors but not in alpha1b-adrenoceptor . ONOO-1 also weakens noradrenaline-induced contractions in rat aorta that has alpha1a- and alpha1d-adrenoceptors . Cardiovascular hyporeactivity to catecholamines in septic shock may be caused in part by the inactivation of alpha-adrenoceptors by ONOO-1.

Crit Care Med, 2002 Apr, 30(4), 868 - 73
Effects of inhaled nitric oxide in a mouse model of sepsis-induced acute lung injury; Razavi HM et al.; OBJECTIVE: Although inhaled nitric oxide transiently improves oxygenation in patients with acute lung injury, it has not affected clinical outcomes . As well, the effects of inhaled nitric oxide on the pathophysiologic features of acute lung injury have not been well defined . Therefore, we assessed the effects of inhaled nitric oxide on the degree of pulmonary inflammation and injury in a mouse model of sepsis-induced acute lung injury . DESIGN: Randomized, controlled animal study . SETTING: Research laboratory of an academic institution . SUBJECTS: Male C57Bl/6 mice . INTERVENTIONS: Sepsis was induced by cecal ligation and perforation . At the time of surgery, septic and naive mice were randomized to exposure to either 40 ppm inhaled nitric oxide or room air for 24 hrs before they were killed . MEASUREMENTS AND MAIN RESULTS: Sepsis-induced acute lung injury was characterized by increased pulmonary myeloperoxidase (68 +/- 13 vs . 13 +/- 3 mU/mg protein in naive mice, p <.01), pulmonary 8-isoprostane content (627 +/- 51 vs . 88 +/- 20 pg/mg protein in naive mice, p <.01), and protein in bronchoalveolar lavage fluid (p <.05) . Inhaled nitric oxide exposure in septic mice completely abrogated the septic increases in myeloperoxidase activity (p <.05) and pulmonary 8-isoprostane content (p <.05) but had no effect on bronchoalveolar lavage protein . The induction of sepsis also was associated with an increase in pulmonary inducible NO synthase activity (2.8 +/- 0.5 vs . 0.4 +/- 0.1 pmol small middle dotmin-1 small middle dotmg-1 protein in naive mice, p <.05), and inhaled nitric oxide attenuated this increase in pulmonary inducible NO synthase activity (p <.05) . CONCLUSIONS: Exposure to inhaled nitric oxide early in the course of sepsis-induced acute lung injury is associated with reduced pulmonary leukocyte infiltration and less oxidative injury . Decreased lung inflammation and injury with inhaled nitric oxide is associated with decreased pulmonary inducible NO synthase activity . Therefore, inhaled NO may have greater clinical benefit if administered earlier in the natural history of acute lung injury in patients.

Zentralbl Chir, 2002 Mar, 127(3), 174 - 9
{New treatment approaches in sepsis}; Bloos F et al.; The treatment of sepsis consists of focus control as well as supportive and adjuvant therapy . Especially the last option has been investigated during the last years . Different approaches showed promising results in animal experiments and phase-I trials but did not prove to be successful in large multicenter studies . The application of TNF-receptors or interleukin-1 receptor antagonists did not lead to an improvement of outcome in patients with sepsis . Most studies with TNF-antibodies also presented negative results . However, a recent large study with a monoclonal antibody against TNFalpha demonstrated a significant survival benefit . The recently published PROWESS study is the first investigation demonstrating the decrease of mortality in patients with sepsis after administration of protein C . Additionally, current data support the low-dose hydrocortisone therapy in patients with vasopressor dependent septic shock.

Am J Physiol Endocrinol Metab, 2002 May, 282(5), E1046 - 54
Cr supplementation decreases tyrosine phosphorylation of the CreaT in skeletal muscle during sepsis; Wang W et al.; Myocellular creatine (Cr) uptake is predominantly governed by a sodium-dependent Cr transporter (CreaT) and plays a pivotal role in skeletal muscle energy metabolism . The CreaT belongs to a neurotransmitter transporter family that can be functionally regulated by protein tyrosine kinase-induced tyrosine phosphorylation . The association between myocellular Cr and c-Src-related tyrosine phosphorylation of the CreaT and the influence of oral Cr supplementation on this association were investigated during sepsis . Animals were randomized to receive standard rat chow or standard rat chow with oral Cr supplementation for 4 days followed by cecal ligation and puncture (CLP) or sham operation . Fast-twitch gastrocnemius muscles were harvested 24 h after operation . Myocellular free Cr levels were 70% higher after CLP . Western blotting of the immunoprecipitated CreaT with an anti-phosphotyrosine or anti-phospho-c-Src (Y-416) antibody revealed that tyrosine phosphorylation of the CreaT and tyrosine-phosphorylated c-Src (Tyr(416)) expression in the CreaT-c-Src complex were significantly increased after CLP compared with sham operation . These changes were observed in homogenates and plasma membrane fractions of gastrocnemius muscles . Although oral Cr supplementation increased myocellular free Cr levels equivalently in CLP and sham-operated animals, c-Src-related tyrosine phosphorylation of the CreaT in homogenates and plasma membrane fractions of gastrocnemius muscles was, however, downregulated in Cr-supplemented CLP animals compared with Cr-supplemented sham-operated rats . During sepsis, increased myocellular free Cr levels are associated with enhanced tyrosine phosphorylation of the CreaT, which is likely induced by active c-Src . Oral Cr supplementation downregulates c-Src-related tyrosine phosphorylation of the CreaT . The data suggest that myocellular Cr homeostasis and CreaT activity are tightly regulated and closely related during sepsis.

Nutrition, 2002 Apr, 18(4), 298 - 300
Fatty acid oxidation in neonatal hepatocytes: effects of sepsis and glutamine; Kim SC et al.; OBJECTIVE: Little is known about fat use during sepsis during the neonatal period . Intramitochondrial O(2) consumption is inhibited in isolated hepatocytes from suckling septic rats and this impairment is reversed by glutamine . We investigated the effect of neonatal sepsis on fat oxidation and whether glutamine can directly affect fatty acid oxidation . METHODS: Suckling Wistar rats (11 d) received an intraperitoneal injection of 300 microg/kg of lipopolysaccharide (Escherichia coli 055:B5); controls received normal saline . At 2 h, hepatocytes were isolated . Hepatocytes were incubated at 37 degrees C with 0.5 mM {1-(14)C}palmitate or 0.5 mM {1-(14)C}palmitate plus 10 mM glutamine . After 1 h, the perchloric acid-soluble (14)C-radioactivity (representing mainly ketone bodies) and (14)CO(2) were measured . Hepatocyte O(2) consumption from 0.5 mM palmitate was measured with and without 2.5 ng/mL myxothiazol to estimate intramitochondrial O(2) consumption . RESULTS: There were no significant differences in fatty acid oxidation between control and endotoxemic hepatocytes measured as acid-soluble radioactivity (which represents mainly ketogenesis, plus Krebs cycle intermediates), as (14)CO(2) production, or as the sum of acid-soluble radioactivity plus (14)CO(2) generation . Glutamine significantly increased fatty acid oxidation (acid-soluble radioactivity plus (14)CO(2)) in hepatocytes from control and endotoxic animals . CONCLUSIONS: The finding of no significant difference in fatty acid oxidation between hepatocytes from control and endotoxemic rats is surprising given that intramitochondrial O(2) consumption from palmitate is decreased . This may reflect altered use of acetyl-coenzyme A to ketone bodies and Krebs cycle intermediates . Glutamine enhanced fatty acid oxidation from control and endotoxemic hepatocytes, suggesting that it may promote substrate oxidation during endotoxemia.

Hosp Med, 2002 Mar, 63(3), 166 - 9
Anorectal sepsis; Hughes F et al.; Anorectal sepsis is a common cause of hospital admission, presenting with abscess or fistula formation . This article discusses the aetiology of acute anorectal sepsis and its management.

J Infect Dis, 2002 Apr 15, 185(8), 1115 - 20 Epub 2002 Apr 01.
Glutathione protects mice from lethal sepsis by limiting inflammation and potentiating host defense; Villa P et al.; Neutrophils have a dual role in sepsis-defending against infection and mediating organ failure . Because glutathione (GSH) is lower in sepsis, the hypothesis that GSH depletion might impair the migratory response of neutrophils to infection was tested . In a mouse model of polymicrobial sepsis induced by cecal ligation and puncture, GSH depletion inhibited peritoneal neutrophil infiltration, increased bacterial colonies, augmented pulmonary neutrophil infiltrate, and worsened survival . The reduced peritoneal influx of neutrophils was explained by a reduced in vivo neutrophil migration in response to locally administered chemokines and by reduced chemotactic activity and chemokine levels in peritoneal lavage fluid . Conversely, the GSH precursor N-acetyl-l-cysteine augmented neutrophil infiltration in the peritoneum but not in the lung, decreased bacterial colonies, and improved survival . Thus, migration of neutrophils to a site of infection and to a distant site is differently regulated, and optimal GSH levels are important for an efficient response to sepsis.

Ann Clin Biochem, 2002 Mar, 39(Pt 2), 130 - 5
Biochemical markers of neonatal sepsis: value of procalcitonin in the emergency setting; Guibourdenche J et al.; BACKGROUND: We evaluated procalcitonin (PCT) assay in the emergency diagnosis of neonatal bacterial infection, especially in preterm infants, relative to C-reactive protein (CRP) and fibrinogen . METHODS: One hundred and twenty neonates (32 preterm), of whom 21 were infected, were tested . RESULTS: Concentrations of PCT, CRP and fibrinogen in uninfected infants were not affected by gestational age at birth . Concentrations of CRP and PCT increased rapidly during the first 24 h of life, while fibrinogen concentrations increased gradually from birth . All marker concentrations were significantly greater in neonates with bacterial infection . Receiver-operating characterstic analysis showed that optimum cut-off values for fibrinogen, CRP and PCT were 3.0 g/L, 7.5 mg/L and 2.5 microg/L respectively, for the diagnosis of sepsis at birth . CONCLUSIONS: Determination of PCT is of value in excluding bacterial infection in neonates since it has a negative predictive value of 93%.

Ann Surg, 2002 Apr, 235(4), 560 - 7
Impaired monocyte IL-12 production before surgery as a predictive factor for the lethal outcome of postoperative sepsis; Weighardt H et al.; OBJECTIVE: To investigate whether monocyte paralysis resistant to interferon-gamma (IFN-gamma) costimulation may exist before surgery and postoperative infection and may correlate with the outcome of postoperative sepsis . SUMMARY BACKGROUND DATA: Several studies have correlated monocyte paralysis during the course of sepsis with lethal outcome . Although the authors' previous work indicated that preoperative defects in monocyte interleukin (IL)-12 production are associated with the development of severe postoperative sepsis, the functional state of monocytes before surgery and infection and its significance for sepsis requires further analysis . METHODS: In a prospective study, monocyte functions of 1,113 consecutive patients were examined before major visceral surgery . Monocytes were isolated from peripheral blood and were stimulated in vitro with IFN-gamma and lipopolysaccharide . The secretion of IL-12 p70, IL-12 p40, IL-10, and tumor necrosis factor was measured . RESULTS: Preoperative monocyte secretion of IL-12 p70 and IL-12 p40 was significantly reduced in patients who developed lethal postoperative sepsis compared with sepsis survivors and patients with uneventful postoperative recovery . Moreover, preoperative monocyte IL-12 production was an independent predictive factor for the lethal outcome of postoperative sepsis by multivariate analysis . Preoperative monocyte IL-10 production was impaired in the sepsis group but did not correlate with death from sepsis . Preoperative monocyte tumor necrosis factor secretion was comparable between patients with uneventful recovery, sepsis survivors, and nonsurvivors . Thus, impaired preoperative monocyte IL-12 secretion in patients developing lethal postoperative sepsis did not result from an overproduction of IL-10 or from a generalized monocyte paralysis . The association between impaired preoperative monocyte IL-12 production and death from sepsis was also not explained by gender differences, underlying malignant disease, tumor type, neoadjuvant therapy, or age . CONCLUSIONS: These results identify a selective preoperative defect in monocyte IL-12 production as a predictive factor for the lethal outcome of postoperative sepsis . These data suggest that a partial preoperative monocyte paralysis severely impairs the host defense against postoperative infection, resulting in an increased risk of lethal sepsis.

Hematol J, 2000, 1(5), 357 - 9
Prevention of postsplenectomy sepsis: how much do patients know?
Hegarty PK, Tan B, O'Sullivan R, Cronin CC, Brady MP.
INTRODUCTION: Asplenia causes a deficiency in immunity with a long-term risk of fulminant infection, associated with significant mortality . Patient compliance requires an understanding of risks of infection and its prevention . The impact of patient education has been little studied . MATERIALS AND METHODS: To ascertain the degree of knowledge held by patients who have undergone splenectomy, a comprehensive survey was designed . This also aimed to determine which group of health professionals was most successful in conveying information to patients . Patients who had undergone total splenectomy were interviewed by telephone, using a standardised list of questions to assess their understanding of the post-operation risks . RESULTS: Of 40 consecutive patients, 32.5% had a good knowledge of the risks of asplenia and their prevention, 52.5% had a fair knowledge and 15% a poor knowledge . Haematologists were most successful in initially conveying information to patients, and general practitioners also played a critical role in patient education . In this survey, it appears that surgeons were not effective at educating patients . CONCLUSION: Patient education postsplenectomy is poor . Measures to prevent infection in the asplenic patient are not being adequately implemented.

Ann Pharmacother, 2002 Apr, 36(4), 648 - 54
New and emerging therapies for sepsis; Healy DP; OBJECTIVE: To review the recent advances related to the pathophysiology of sepsis and the rationale for recombinant human-activated protein C (drotrecogin alfa) and other antisepsis agents currently in Phase III trials . DATA SOURCES: A MEDLINE (1990-December 2001) search was performed to identify pertinent literature on the pathophysiology of sepsis and treatment strategies . The search was supplemented with AdisInsight (Adis International) using the search terms sepsis, severe sepsis, or septic shock combined with agents in Phase II or higher clinical development . Abstracts presented at infectious diseases and critical care meetings were also reviewed . STUDY SELECTION AND DATA EXTRACTION: Clinical efficacy studies were selected for drotrecogin alfa and other Phase III investigational agents . DATA SYNTHESIS: Our current understanding of the pathophysiology of sepsis underscores the contribution of increased coagulation and diminished fibrinolytic activity working in conjunction with an excessive and dysregulated inflammatory response . The loss of homeostatic balance among these systems results in a systemic inflammatory response with generalized coagulopathy, microvascular thrombosis, and, ultimately, acute organ failure and death . As a result of these advances, several compounds are now in various phases of development . A recombinant human form of endogenous activated protein C (drotrecogin alfa) was recently approved by the Food and Drug Administration for severe sepsis in adults who have a high risk of death . It possesses anticoagulant, profibrinolytic, and antiinflammatory properties . Other compounds currently in Phase III trials include tissue-factor pathway inhibitor, tumor-necrosis factor antibody fragment, platelet-activating factor acetylhydrolase, antithrombin III, and pyridoxylated hemoglobin polyoxyethylene . CONCLUSIONS: With the recent approval of drotrecogin alfa, there is renewed optimism that we can effectively reduce sepsis-associated mortality.

Clin Infect Dis, 2002 Apr 15, 34(8), 1084 - 93 Epub 2002 Mar 12.
Clinical trials of immunomodulatory therapies in severe sepsis and septic shock; Vincent JL et al.; Sepsis remains one of the leading causes of mortality in critically ill patients . Increased insight into the complexities of this disease process has resulted in the targeting of various aspects of the inflammatory response as offering potential therapeutic benefits . There have been encouraging results in the past few years . Some of the tested agents have been shown to improve mortality rates in large randomized controlled trials involving patients with severe sepsis . In this article, we discuss the positive and negative results of trials in this field; some of the possible reasons for the negative results are examined, and directions for the future are suggested.

Crit Care Clin, 2002 Jan, 18(1), 165 - 75
Cytopathic hypoxia . Is oxygen use impaired in sepsis as a result of an acquired intrinsic derangement in cellular respiration?
Fink MP.
Several lines of evidence indicate that cellular energetics are deranged in sepsis, not by inadequate tissue perfusion but rather by impaired mitochondrial respiration; that is, organ dysfunction in sepsis may result from cytopathic hypoxia . If this concept is correct, the therapeutic implications are enormous . Efforts to improve outcome in septic patients by monitoring and manipulating cardiac output, systemic oxygen (DO2), and regional blood flow are doomed to failure . Instead, the focus should be on developing pharmacologic strategies (e.g., isoform-selective iNOS or PARP inhibitors) to restore normal mitochondrial function and cellular energetics.

Intensive Care Med, 2002 Feb, 28(2), 122 - 9 Epub 2002 Jan 17.
Impact of sepsis, lung injury, and the role of lipid infusion on circulating prostacyclin and thromboxane A(2); Suchner U et al.; OBJECTIVE: To investigate whether plasma levels of prostacyclin (PGI2) and thromboxane A(2) (TxA2) are a function of the infusion rate of soybean-based fat emulsions, severity of systemic inflammation, and pulmonary organ failure . DESIGN: Prospective, randomized, crossover study . SETTING: Intensive care unit of a university hospital . PATIENTS: Eighteen critically ill patients, ten presenting with severe sepsis, eight with SIRS or sepsis complicated with ARDS . INTERVENTIONS: Patients were randomly assigned to receive rapid fat infusion over 6 h (rFI) or slow fat infusion over 24 h (sFI) along with parenteral nutrition . MEASUREMENTS AND RESULTS: The stable prostanoids 6-keto-PGF1alpha and TxB2 were measured in arterial and mixed venous blood samples, and at 6-h periods trans-pulmonary balances (TPB) were calculated . Free linoleic acid fraction was determined in arterial blood . rFI induced greater increase of linoleic acid than sFI in both groups . Enhanced prostanoid levels and correlations with linoleic acid availabilities were found, however, in ARDS patients only, revealing the highest sepsis- and lung injury scores . Averaged TPB per 24 h was positive in the sepsis group and negative in the ARDS group as rFI induced lowest TPB values for TxB2 at 6 h . CONCLUSION: The quantity of prostanoids formed and their subsequent utilization are dependent on the availability of precursor linoleic acid and are probably affected by the severity of SIRS or sepsis and the existence of pulmonary organ failure, respectively . Because TxA2 might be extracted by the injured lung, rapid infusion of soybean-based fat emulsions should be avoided in patients suffering from severe pulmonary organ failure.

J Immunol, 2002 Apr 1, 168(7), 3412 - 8
Increased survival in sepsis by in vivo adenovirus-induced expression of IL-10 in dendritic cells; Oberholzer A et al.; The dendritic cell (DC) is the most potent APC of the immune system, capable of stimulating naive T cells to proliferate and differentiate into effector T cells . Recombinant adenovirus (Adv) readily transduces DCs in vitro allowing directed delivery of transgenes that modify DC function and immune responses . In this study we demonstrate that footpad injection of a recombinant Adv readily targets transduction of myeloid and lymphoid DCs in the draining popliteal lymph node, but not in other lymphoid organs . Popliteal DCs transduced with an empty recombinant Adv undergo maturation, as determined by high MHC class II and CD86 expression . However, transduction with vectors expressing human IL-10 limit DC maturation and associated T cell activation in the draining lymph node . The extent of IL-10 expression is dose dependent; transduction with low particle numbers (10(5)) yields only local expression, while transduction with higher particle numbers (10(7) and 10(10)) leads additionally to IL-10 appearance in the circulation . Furthermore, local DC expression of human IL-10 following in vivo transduction with low particle numbers (10(5)) significantly improves survival following cecal ligation and puncture, suggesting that compartmental modulation of DC function profoundly alters the sepsis-induced immune response.

Nippon Rinsho, 2002 Mar, 60(3), 578 - 84
{Monoclonal antibodies against inflammatory mediators for the treatment of patients with sepsis}; Matsubara T; Sepsis is a common cause of morbidity and mortality, particularly in immunocompromised and critically ill patients . Recently, a new designation, systemic inflammatory response syndrome(SIRS), has been studied . When an abnormal generalized inflammatory reaction is due to an infection, the terms sepsis and SIRS are synonymous . The systemic response to infection is mediated via the macrophage-derived cytokines that target end organ receptors in response to injury or infection . One strategy used to perturb the septic cascade is to block a particular inflammatory molecule . Results have been published on clinical trials in sepsis patients treated with several monoclonal antibodies, such as antiendotoxin antibodies, anti-tumor necrosis factor antibodies, and anti CD14 antibodies . In this chapter, the results of clinical trials in patients and in vivo data from animal models of sepsis are summarized.

Intensive Care Med, 2002 Mar, 28(3), 265 - 71 Epub 2002 Feb 08.
Dobutamine and gastric-to-arterial carbon dioxide gap in severe sepsis without shock; Lebuffe G et al.; OBJECTIVES: To evaluate the effect of an early dobutamine infusion on gastrointestinal perfusion in patients with severe sepsis . DESIGN: Prospective, randomized, controlled, multicenter clinical study . SETTING: Six medical and/or surgical intensive care units (ICU) of teaching hospitals . PATIENTS: Forty-two patients with severe sepsis . INTERVENTIONS: Patients were divided into two groups according to gastric-to-arterial CO2 gap (DeltaCO2) {normal DeltaCO2 group ( n=17): DeltaCO2 < or = 8 mmHg; increased DeltaCO2 group ( n=25): DeltaCO2 > 8 mmHg} . Patients within each group were then randomized to receive either dobutamine (5 microg/kg per min) or saline for 72 h . MEASUREMENTS AND MAIN RESULTS: SAPS II was similar in both groups {group 1: 44.0 (33.0-56.5); group 2: 48.5 (40.5-59.0), p=0.27} . At ICU admission, mean arterial pressure was lower in the high DeltaCO2 group {73.0 (67.0-79.5) mmHg, p=0.03} than in the normal DeltaCO2 group {84.0 (73.7-104.0) mmHg} while blood lactate {normal DeltaCO2 group: 1.6 (0.8-2.3); high DeltaCO2 group: 1.6 (1.1-1.9) mmol/l} was similar for the two groups . DeltaCO2 was significantly lower in the normal DeltaCO2 group {5.0 (2.0-6.0) mmHg)} than in the high DeltaCO2 group {11.0 (10.0-19.0) mmHg} . Dobutamine infusion did not significantly change hemodynamics, blood lactate concentration or tonometric parameters in any group within the first 72 h and had no particular beneficial effect in this population . CONCLUSIONS: An early infusion of dobutamine at a fixed dose of 5 microg/kg per min during the first 72 h of severe sepsis does not influence gastric DeltaCO2.

Crit Care Med, 2002 Jan, 30(1), 32 - 7
Effect of the interleukin-6 promoter polymorphism (-174 G/C) on the incidence and outcome of sepsis; Schluter B et al.; OBJECTIVE: A biallelic polymorphism within the human interleukin (IL)-6 gene promoter region (-174 G/C) has been shown to affect IL-6 transcription in vitro and IL-6 plasma levels in healthy adults . Because IL-6 is excessively released into the circulation during sepsis and closely correlates with the clinical course, we studied whether this promoter polymorphism has an effect on the incidence and/or outcome of sepsis . DESIGN: Population-based association study in critically ill patients and healthy controls . SETTING: Surgical intensive care unit (ICU) in a German university hospital . PATIENTS: Surgical patients (n = 326) of German Caucasian origin with an ICU stay of at least 3 days admitted between 1997 and 1999 were prospectively enrolled . In a subset of 50 patients, sepsis was diagnosed according to consensus criteria (American College of Chest Physicians 1992) . Healthy sex-matched adults of the same ethnic and geographic background served as controls . INTERVENTIONS: Blood sampling . MEASUREMENTS AND MAIN RESULTS: The (-174 G/C) polymorphism was genotyped by an allele-specific polymerase chain reaction . IL-6 plasma levels were determined by enzyme-linked immunosorbent assay . Genotype distribution and allele frequencies did not differ significantly between patients with or without sepsis and healthy controls . In patients who finally succumbed to sepsis, significantly less GG homozygotes were observed compared with survivors (p = .008) . Median systemic IL-6 levels in septic patients closely correlated with outcome (p < .0001) but were not associated with the IL-6 promoter genotype . CONCLUSIONS: The IL-6 promoter polymorphism (-174 G/C) does not affect the incidence of sepsis . However, the GG homozygous genotype is significantly associated with an improved survival in sepsis . Because this association is independent from the systemic IL-6 response, we suggest that other genetically linked polymorphisms may be the primary cause.

Crit Care Med, 2002 Jan, 30(1), 100 - 6
A phase II randomized, controlled trial of continuous hemofiltration in sepsis; Cole L et al.; OBJECTIVE: To study the effect of early and continuous venovenous hemofiltration (CVVH) on the plasma concentrations of several humoral mediators of inflammation and subsequent organ dysfunction in septic patients . DESIGN: Randomized, controlled trial . SETTING: Intensive care unit of a tertiary hospital . PATIENTS: Twenty-four patients with early septic shock or septic organ dysfunction . INTERVENTIONS: Random allocation to receive 48 hrs of isovolemic CVVH at 2 L/hr of fluid exchange or no hemofiltration . MEASUREMENTS AND MAIN RESULTS: We measured the plasma concentrations of complement fractions C3a and C5a, interleukins 6, 8, and 10, and tumor necrosis factor alpha at baseline and 2, 24, 26, 48, and 72 hrs . A multiple organ dysfunction score (MODS) was calculated daily for each patient until death or discharge from the intensive care unit . The concentrations of most mediators decreased between baseline and 72 hrs . Some significant falls in concentration could be identified between specific time points, but CVVH was not associated with an overall reduction in any plasma cytokine concentrations . There was also no difference between the mean cumulative MODS for control survivors (43.3 +/- 19.7) and CVVH survivors (33.2 +/- 19.0; p = .30), and no difference between the average MODS calculated for all controls (4.1 +/- 1.9) and all CVVH subjects (3.3 +/- 1.7; p = .26) . CVVH did not improve oxygenation, lower the platelet count, or reduce the duration of vasopressor support and mechanical ventilation . CONCLUSIONS: Early use of CVVH at 2 L/hr did not reduce the circulating concentrations of several cytokines and anaphylatoxins associated with septic shock, or the organ dysfunction that followed severe sepsis . CVVH using current technology cannot be recommended as an adjunct to the treatment of septic shock unless severe acute renal failure is present.

J Trauma, 2002 Mar, 52(3), 443 - 8
Activated polymorphonuclear leukocytes enhance production of leukocyte microparticles with increased adhesion molecules in patients with sepsis; Fujimi S et al.; BACKGROUND: Leukocyte microparticles (MPs) derived from polymorphonuclear leukocytes (PMNLs) have been recently found to be activators of vascular endothelium in vitro . The precise role of leukocyte MPs has not been clarified in patients suffering severe insult . The objective of this study was to evaluate production of leukocyte MPs and expression of adhesion molecules on the MP surface in patients with sepsis . METHODS: Twenty-one patients with severe infection (fulfilling the criteria of sepsis with serum C-reactive protein > 10 mg/dL) and 21 healthy volunteers were included as study subjects . Production of leukocyte MPs, expression of CD11b on the MPs, and oxidative activity of PMNLs were measured by flow cytometry in the presence and absence of formyl-methionyl-leucyl-phenylalanine . CD11b expression was evaluated according to the MP size (more than, equal to, or less than 1.0 microm) . Soluble E-selectin, thrombomodulin, and PMNL elastase were also measured in blood . RESULTS: Production of leukocyte MPs and superoxide production in PMNLs with and without formyl-methionyl-leucyl-phenylalanine increased significantly in patients with sepsis in comparison with production in normal volunteers . In patients with sepsis, expression of CD11b was also markedly enhanced on MPs less than 1.0 microm in diameter in comparison with expression in control subjects . Levels of soluble E-selectin, thrombomodulin, and PMNL elastase in blood were significantly increased in patients with sepsis . We succeeded in detecting leukocyte MPs visually by fluorescence microscopy . CONCLUSION: Activated PMNLs enhance production of leukocyte MPs with increased adhesion molecules in patients with sepsis . Activated leukocyte MPs may play a role in the pathogenesis of endothelial activation and leukocyte-endothelium interaction in the presence of sepsis.

Shock, 2002 Mar, 17(3), 193 - 8
Induction of peritoneal sepsis increases the susceptibility of isolated hearts to a calcium paradox-mediated injury; Omachi A et al.; The present study was designed to test the hypothesis that induction of chronic peritoneal sepsis in rats would produce a more severe calcium paradox-mediated myocardial injury in isolated heart preparation than is seen in normal hearts, and that this would be inhibited by sucrose as in normal hearts . Male Sprague-Dawley rats were made septic using 200 mg of cecal material (obtained from a donor rat) suspended in 5 mL of 5% dextrose in sterile water D5 W/kg . In septic animals, the cecal material was injected in the peritoneum, while sham-septic animals received only D5 W/kg (5 mL/kg) . A third group consisting of normal rats (no surgery) group was also included . Hearts were harvested from all three groups and were subjected to a calcium paradox-mediated injury in an isolated heart preparation . Hearts were perfused with Krebs-Henseleit (KH) medium and were allowed to stabilize, followed by a perfusion with Ca2+-free KH for 10 min . After this 10-min Ca2+-free KH perfusion, rats were reperfused with KH medium for 60 min . Ca2+-free KH medium was used in control experiments, while sucrose experiments were conducted with the same medium except that 150 mM sucrose replaced 75 mM NaCl . A marked decrease in ATP and phosphocreatine occurred during Ca2+ reperfusion in all hearts in absence of sucrose . In the presence of the disaccharide, no change in high-energy phosphate (HEP) levels was observed in normal hearts, while lower ATP concentrations were seen in sham and septic hearts . Thus, sucrose did not inhibit cellular injury in sham and septic hearts as it did in normal hearts, and this might be due to a smaller HEP availability . Control studies with normal, sham, and septic hearts exhibited cessation of contractions in the absence of Ca2+, and appearance of large amounts of cytosolic protein in the effluent perfusate during Ca2+ reperfusion . With normal hearts, perfusion with sucrose caused a 96% inhibition of the total creatine kinase (CK) release observed in control experiments . With sham hearts, 32% of CK release was inhibited by sucrose, while 68% of the CK release was attributed to stress associated with surgery performed in the sham-septic group . In septic hearts, only 8% of the CK release was inhibited by sucrose, suggesting that more severe myocardial injury occurs when septic hearts are subjected to a calcium paradox as compared to other groups . It is evident that sucrose can inhibit a small fraction of the CK release from septic hearts during the calcium paradox as compared to the large CK loss associated with sham sepsis . We have concluded that induction of sepsis made the heart more susceptible to a calcium paradox-mediated myocardial injury.

Br J Nutr, 2002 Jan, 87 Suppl 1, S69 - 75
Parenteral nutrition with n-3 lipids in sepsis; Mayer K et al.; Dietary supplements of n-3 fatty acids have long been used to influence chronic inflammatory disorders . Recent studies with an immune-enhancing diet partly based on n-3 fatty acids report beneficial effects in patients with acute hyper-inflammatory diseases, such as the sepsis syndrome or adult respiratory distress syndrome (ARDS) . The possible suppression of exaggerated leucocyte activity, the improvement of microcirculatory events, as well as the opportunity to administer intravenous lipids enriched in n-3 fatty acids signal the possibility of a combination of parenteral caloric support and pharmacological intervention . Using parenteral administration of fish oil-based lipids, a new rapid and highly effective anti-inflammatory agent may allow the option to alter the immune status in hyper-inflammatory diseases such as sepsis and ARDS.

Early Hum Dev, 2002 Apr, 67(1-2), 1 - 9
Monocyte phagocytosis as a reliable parameter for predicting early-onset sepsis in very low birthweight infants; Hallwirth U et al.; BACKGROUND: Septic complications lead to a high mortality rate in very low birthweight infants (VLBWI) . Therefore, prognostic markers for the development of sepsis attach importance to start an efficient therapy as early as possible . AIMS: Functional and phenotypical variables of blood monocytes in the cord and peripheral blood were investigated to evaluate the parameters for predicting early-onset and late-onset sepsis (nosocomial infections) . STUDY DESIGN: In a prospective study, 25 VLBWI were investigated . METHODS: In the cord blood taken immediately after birth, the capacity of the monocytes to phagocytose non-opsonized E . coli bacteria by flow cytometry and the ex-vivo production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6 (enzyme-linked immunoassay (ELISA)) after lipopolysaccharide (LPS) stimulation were measured . At the third day, the HLA-DR expression on the monocytes (flow cytometry) and the LPS-induced cytokine production were measured from the peripheral blood . RESULTS: Five VLBWI already developed early septic complications after 24-72 h, while the other three infants had late-onset sepsis 10-18 days after birth . The prognostic significance for early-onset sepsis was highest for the decreased monocyte phagocytic capacity (sensitivity and specificity: 100%) and for the LPS-induced formation of TNF-alpha and IL-1 beta in cord blood . Moreover, in septic VLBWI, the HLA-DR expression on the monocytes was lowered on day 3 after birth . The prognostic significance for late-onset sepsis was highest for TNF-alpha and IL-1 beta levels in the peripheral blood on the third day after birth . CONCLUSIONS: The determination of phagocytosis in the cord blood seems to be a reliable parameter for predicting early-onset sepsis and offers the possibility for a forward start of an antibiotic therapy.

Ann R Coll Surg Engl, 2002 Jan, 84(1), 26 - 8
Cyclic neutropenia and pyomyositis: a rare cause of overwhelming sepsis; Waites MD et al.; Primary pyomyositis is a pyogenic infection of skeletal muscle with abscess formation, which traditionally lacks an identifiable cause . We present a case of pyomyositis for which a cause was established . This was largely due to the fact that the patient was young and fit, enabling him to survive such overwhelming sepsis long enough for cycling of his neutrophil count to become apparent . Having had multiple abscesses drained, he was successfully treated with granulocyte colony stimulating factor and has remained well since.

Crit Care Med, 2002 Feb, 30(2), 461 - 72
Randomized, controlled clinical trials in sepsis: has methodological quality improved over time?
Graf J, Doig GS, Cook DJ, Vincent JL, Sibbald WJ.
OBJECTIVE: To systematically evaluate the methodological quality of randomized clinical trials and to determine whether randomized clinical trials of sepsis improved in methodological quality over time . DATA SOURCES: Computerized MEDLINE search of articles published in any language from 1966 to 1998 combined with a manual search of bibliographies of published articles and communication with known experts in the field . STUDY SELECTION: All randomized clinical trials of sepsis, severe sepsis, and septic shock performed in adults and published as full articles . DATA EXTRACTION: Abstracts of all retrieved records were reviewed and the inclusion criteria were applied . All selected articles were classified into (a) trials designed to detect differences in mortality as the primary end point, or (b) trials focusing on surrogate outcome measures (i.e., physiological or biochemical parameters) . All retrieved trials were then graded for methodological quality using an objective grading scheme developed specifically for this study . The data selection and extraction process was carried out independently by two of the authors; any disagreement was resolved by discussion . DATA SYNTHESIS: Seventy-four randomized clinical trials involving septic patients qualified for inclusion in this study (40 reporting mortality outcomes, 34 reporting other surrogate outcomes) . Trials reporting mortality as the primary outcome had significantly higher quality scores compared with trials reporting surrogate outcome measures (29.6 +/- 1.0 vs . 24.3 +/- 0.8, p =.0006) . From 1976 to 1998, trial methodology improved significantly over time (an average of 0.36 points per year, p =.021) . Mortality outcome trials improved an average of 0.58 points per year (p =.0011) whereas surrogate outcome trials did not demonstrate an improvement in methodological quality over time (p =.249) . CONCLUSION: The methodological limitations identified in this article can help to target further improvement in trial design to enhance the validity of findings from future randomized clinical trials of sepsis.

Crit Care Med, 2002 Feb, 30(2), 300 - 5
Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: improved short-term survival and acid-base balance with Hextend compared with saline; Kellum JA; OBJECTIVE: To compare resuscitation with 0.9% saline with Hextend, a synthetic colloid in a balanced electrolyte solution, in terms of acid-base status and survival time in an experimental model of septic shock in the rat . DESIGN: Randomized, open-label, controlled experiment . SETTING: University research laboratory . SUBJECTS: Sixty adult, male Sprague-Dawley rats . INTERVENTION: Animals were studied for 12 hrs after intravenous infusion of Escherichia coli endotoxin (20 mg/kg) . Animals were volume resuscitated to maintain a mean arterial pressure >60 mm Hg using either 0.9% saline (n = 25), Hextend (n = 25), or lactated Ringer's (n = 10) . MEASUREMENTS: Arterial blood gases and electrolytes were measured before and after resuscitation (0, 180, 360, and 540 mins after endotoxin infusion) . Survival time was measured, up to 12 hrs . RESULTS: Mean survival time among animals treated with saline or Ringer's was 45% less compared with Hextend-treated animals: 391 +/- 151 mins and 362 +/- 94 mins vs . 567 +/- 140 mins, respectively, p <.0001 . Overall survival (at 12 hrs) was 0% with saline or Ringer's vs . 20% with Hextend, p =.05 . After resuscitation with saline, arterial standard base excess and plasma apparent strong ion difference were both significantly lower (-19.3 +/- 5.2 vs . -12.1 +/- 5.7, p <.001, and 23.0 +/- 6.2 vs . 30.3 +/- 2.9, p <.0001, respectively) and plasma Cl(-) was significantly higher (123 +/- 7 vs . 115 +/- 3 mmol/L, p <.0001) compared with Hextend . Resuscitation with Ringer's solution resulted in a standard base excess, and Cl(-) between that of saline and Hextend (-15.4 +/- 3.1, and 117 +/- 3, respectively) . CONCLUSION: Compared with 0.9% saline, volume resuscitation with Hextend was associated with less metabolic acidosis and longer survival in this experimental animal model of septic shock.

Crit Care Med, 2002 Feb, 30(2), 271 - 5
Predictive value of antithrombin III and serum C-reactive protein concentration in critically ill patients with suspected sepsis; Pettila V et al.; OBJECTIVE: To evaluate at admission the performance of serum antithrombin III, serum C-reactive protein, white blood cell and platelet counts, and thromboplastin time values in prediction of hospital mortality rates in critically ill patients with suspected sepsis . DESIGN: Prospective, cohort study . SETTING: University hospital medical-surgical intensive care unit . PATIENTS: One hundred eight consecutive critically ill patients with suspected sepsis . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: The outcome measure was hospital mortality rate . Hospital survivors (n = 66) and nonsurvivors (n = 42) differed statistically significantly in admission antithrombin III activity (percentage of normal): survivors' median 66% (interquartile range, 48% to 82%) vs . nonsurvivors' median 46% (37% to 65%, p =.0002 by Mann-Whitney test) . Analysis revealed similarly statistically significant differences between survivors and nonsurvivors in admission platelet count, admission thromboplastin time, day 1 Logistic Organ Dysfunction score, and Acute Physiology and Chronic Health Evaluation III score, but not in serum C-reactive protein concentrations or in white blood cells . However, the areas under the receiver operating curves (AUC) showed significantly worse discriminative power for admission antithrombin III concentration (AUC, 0.71; SE, 0.05), platelet count (AUC, 0.67; SE, 0.05), thromboplastin time (AUC, 0.65; SE, 0.05), C-reactive protein concentration (AUC, 0.60; SE, 0.05), and white blood cell count (AUC, 0.53; SE, 0.06) than did the day 1 Logistic Organ Dysfunction score (AUC, 0.82; SE, 0.04) and the Acute Physiology and Chronic Health Evaluation III score (AUC, 0.84; SE, 0.04) . Multivariate logistic regression analysis revealed that only the Acute Physiology and Chronic Health Evaluation III score was independently associated with hospital mortality rate . CONCLUSIONS: Admission antithrombin III concentrations, but not C-reactive protein concentrations, differ significantly between hospital survivors and nonsurvivors among critically ill patients with septic infection . However, in prediction of hospital mortality rate, the discriminative power of admission antithrombin III concentration is poor, as judged by analysis of areas under the receiver operating curves, and is not independently associated with hospital mortality rate.

Indian J Med Sci, 2001 Sep, 55(9), 495 - 500
Early diagnosis of neonatal sepsis using a hematological scoring system; Ghosh S et al.; OBJECTIVE: To assess the utility of the hematologic scoring system (HSS) of Rodwell et al for the early detection of neonatal sepsis . DESIGN: Analysis of the peripheral smear findings according to the HSS by a pathologist blinded to the infection status of the neonate . SUBJECTS: One hundred and three high risk neonates having predisposing perinatal factors or clinical suspicion of sepsis . RESULTS: Analysis of the hematologic profiles in the light of the HSS found that an abnormal immature to total neutrophil (1:T) ratio followed by an abnormal immature to mature neutrophil (1:M) ratio were the most sensitive indicators in identifying infants with sepsis . These two criteria along with thrombocytopenia (< 1,50,000/cm3) had a high negative predictive value over 94% . The study also found that the higher the score the greater the certainty of sepsis being present . CONCLUSION: The HSS is simple, quick, cost effective and readily available tool in the early-diagnosis of neonatal sepsis and could provide a guideline to decisions regarding antibiotic therapy.

Am J Health Syst Pharm, 2002 Feb 15, 59 Suppl 1, S3 - 8
Pathophysiology of sepsis; Jacobi J; The roles of inflammation and coagulation in the pathophysiology of sepsis are described . Sepsis results when an infectious insult triggers a localized inflammatory reaction that then spills over to cause systemic symptoms of fever or hypothermia, tachycardia, tachypnea, and either leukocytosis or leukopenia . These clinical symptoms are called the systemic inflammatory response syndrome . Severe sepsis is defined by dysfunction of one of the major organ systems or unexplained metabolic acidosis . The inflammatory reaction is mediated by the release of cytokines, including tumor necrosis factor-alpha, interleukins, and prostaglandins, from neutrophils and macrophages . The cytokines activate the extrinsic coagulation cascade and inhibit fibrinolysis . These overlapping processes result in microvascular thrombosis; thrombosis is one potential factor producing organ dysfunction . Activation of the coagulation system leads to consumption of endogenous anticoagulants (e.g., protein C and antithrombin); this may be an important factor in the development of microvascular coagulation . Antiinflammatory mediators as well as inflammatory mediators have a role in sepsis, and an excess of either can result in poor patient outcomes . Sepsis is a complex syndrome involving activation of a variety of systems.

Am J Health Syst Pharm, 2002 Feb 15, 59 Suppl 1, S19 - 23
Recombinant human activated protein C in severe sepsis; Mann HJ; The role of activated protein C (APC) in coagulation, inflammation, and fibrinolysis and the pharmacology, pharmacokinetics, and trials of recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated), in sepsis are described . Protein C, a naturally occurring vitamin K-dependent serine protease in the blood, remains inactive until exposed to the thrombin-thrombomodulin complex . This change between the inactive and active forms occurs constantly in humans and serves to balance the coagulation cascade . APC functions in concert with protein S as an anticoagulant, a fibrinolytic agent, and an antiinflammatory agent . In response to serious infection, a procoagulant process is activated leading to thrombin and fibrin deposition in small vessels that results in decreased blood flow, decreased oxygen delivery, and organ failure . The body's natural defense during severe sepsis is to activate protein C through the thrombin-thrombomodulin complex in an attempt to restore the imbalance of the hemostatic systems . However, APC has a short half-life, and the pool of circulating protein C is rapidly depleted in severe sepsis . Low protein C levels have been correlated with poor outcome in patients with severe sepsis and in animal models . These observations led to a Phase III safety and efficacy trial of drotrecogin alfa (activated) that demonstrated a significant improvement in mortality compared with placebo (24.7% versus 30.8%) . This 6.1% absolute difference in mortality translates to a 19.4% reduction in relative risk of death in the treated patients . The proper use of drotrecogin alfa (activated) will require careful consideration of appropriate patients to treat and further studies in patient populations that were excluded from the Phase III trial, as well as possible modification of dosing schemes on the basis of patient response.

Zhonghua Shao Shang Za Zhi, 2001 Apr, 17(2), 96 - 8
{The effects of extensive excision of massive invasive infected burn wound on the REE of burn patients with sepsis}; Chai J et al.; OBJECTIVE: To explore the effects of extensive excision of massive invasive infected burn wound on the REE of burn patients with sepsis . METHODS: REEs and plasma levels of IL -- 6, IL -- 8, TNFalpha and LPS were determined before and after surgical interventions and when patients', condition improved in 8 burned cases with sepsis . RESULTS: All the 8 patients survived after treatment . The REE level in patients after operation was significantly lower than those before the operation (P < 0.01) . REE in patients whose condition improved decreased obviously when compared to that after operation (P < 0.01) . The plasma levels of IL -- 6, IL -- 8, TNFalpha and LPS decreased markedly after the operation when compared to those before operation (P < 0.05) . and there were lower levels of these factors when the patients', condition improved (P < 0.001) . Furthermore, there were closely positive correlations between REE and plasma IL -- 6, IL -- 8, TNFalpha and LPS (P < 0.01) . CONCLUSION: Over -- releasing of some inflammatory mediators could be corrected by means of extensive excision of massive invasively infected burn wound . This might be beneficial to the control or the amelioration of the hypermetabolism in burn patients with sepsis.

Zhonghua Shao Shang Za Zhi, 2000 Apr, 16(2), 78 - 81
{The experience of the management of burn sepsis with different strategies in our department during the past 29 years}; Chai J et al.; OBJECTIVE: To retrospectively sum up the experiences in the prevention and treatment of sepsis after thermal injury . METHODS: From January 1970 through October 1998, altogether 5 330 burn patients were admitted to our burn center, and among them 451 patients developed sepsis . To analyze the efficacy of different treatment strategies developed during these 29 years, three periods were divided, namely 1970 to 1979, 1980 to 1992, and 1993 to 1998 . The incidence and mortality of sepsis were compared, thereupon the efficacy of different treatment strategies were analyzed . RESULTS: The overall incidence and mortality of sepsis in all patients and those in patients with burn extent exceeding 30% TBSA were significantly lower in the latter period compared with the former two periods (P < 0.05 similar 0.01) . In addition, in the last period, blood levels of LPS, TNFalpha, IL -- 6, and IL -- 8 were obviously higher throughout the course of MODS, especially before death, in the patients who finally died of sepsis, complicated by MODS, compared with those in the survivors (P < 0.05 similar 0.01) . CONCLUSION: Summing up our experiences, it is our belief that the treatment strategies for prevention of postburn sepsis in extensively burned patients should include rapid, adequate fluid resuscitation for burn shock, effective control of infection, early excision of deep burnwounds followed by good skin coverage, and reinforcement of organ support . Once burn wound sepsis occurs, prompt removal of infected necrotic tissue is the key procedure to ensure a successful result.

Clin Exp Immunol, 2002 Feb, 127(2), 331 - 6
Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis; Arnalich F et al.; This study aims to determine the influence of the polymorphism within the intron 2 of the interleukin-1 receptor antagonist gene (IL-1RN*) on the outcome of severe sepsis, and to assess its functional significance by correlating this polymorphism with the total production of interleukin-1 receptor antagonist (IL-1Ra) protein determined in stimulated peripheral blood mononuclear cells (PBMC) . A group of 78 patients with severe sepsis (51 survivors and 27 nonsurvivors) was compared with a healthy control group of 130 blood donors, and 56 patients with uncomplicated pneumonia . We found a significant association between IL-1RN* polymorphism and survival . Thus, after adjusting for age and APACHE II score, multiple logistic regression analysis showed that patients homozygotes for the allele *2 had a 6.47-fold increased risk of death (95% CI 1.01--41.47, P = 0.04) . Besides, compared with patients homozygous or heterozygous for the allele *1, IL-1RN*2 homozygotes produced significantly lower levels of IL-1Ra from their PBMC . Our results suggest that insufficient production of this cytokine might contribute, among other factors, to the higher mortality rate found in severe sepsis patients with the IL-1RN*2 homozygous genotype.

Clin Diagn Lab Immunol, 2002 Mar, 9(2), 440 - 5
Elevated levels of lipopolysaccharide-binding protein and soluble CD14 in plasma in neonatal early-onset sepsis; Berner R et al.; No data on lipopolysaccharide-binding protein (LBP) in newborns with sepsis have been available up to now . We therefore determined levels of LBP and soluble CD14 (sCD14) in plasma of healthy and septic neonates in order to evaluate their potential diagnostic role . The study included prospectively collected patient samples of two recently published studies on cytokine expression in neonatal sepsis . Twenty-nine septic patients were enrolled in the present analysis . Samples--either cord blood or peripheral blood--from patients admitted within the first 24 h of life for suspicion of sepsis and cord blood samples of a control group of 40 healthy mature infants delivered spontaneously were analyzed . For seven patients of the septic group, a second sample collected between 24 and 48 h of life was available . Levels of sCD14 and LBP in plasma were determined by an enzyme immunoassay using recombinant CD14 and LBP as standards . LBP and sCD14 were correlated to cytokine plasma levels . In septic neonates, LBP (median, 36.6 versus 7.8 microg/ml; P < 0.001) and sCD14 (median, 0.42 versus 0.28 microg/ml; P < 0.001) levels were highly elevated when compared to those of healthy neonates and strongly correlated to granulocyte colony-stimulating factor (G-CSF), interleukin-1beta (IL-1beta), IL-6, and IL-8 levels . LBP levels in septic neonates analyzed between 24 and 48 h of life even increased when compared to samples obtained at or shortly after delivery (median, 36.6 versus 60 microg/ml; P = 0.038) . In summary, levels of LBP in plasma of neonates with early-onset sepsis are significantly elevated; the elevated plasma levels seem to persist for more than 24 h, which could provide the clinician with a prolonged time period to identify the newborn with bacterial sepsis.

Lancet Infect Dis, 2001 Oct, 1(3), 165 - 74
Immunotherapy of sepsis; van der Poll T; Sepsis is a clinical syndrome that results from a systemic host response to an infection . The outcome of sepsis is poor, and mortality rates are as high as 30-40% . Sepsis is associated with the activation of multiple inflammatory pathways, including the cytokine network and the coagulation system . Sepsis can also result in an immunodepressed state that could leave patients more susceptible to secondary nosocomial infections . Modulation of the host response to infection has been studied as an adjunctive therapeutic approach in many preclinical investigations and clinical trials in the past 20 years . As a result of these studies our knowledge of the pathogenesis of sepsis has increased considerably . This review focuses on immunomodulatory strategies that have reached the phase of clinical evaluation in patients with sepsis.

Intensive Crit Care Nurs, 2001 Aug, 17(4), 242 - 4
Steroids in sepsis--more effective than activated protein C?
Bradley C.
Early studies using high doses of steroids in septic shock resulted in increased mortality . More recently, work by Annane et al . using lower doses closer to those that might constitute a stress dose of hydrocortisone have shown encouraging results with a 30% decrease in mortality in septic shock . Although this result is more impressive than the reduction in mortality resulting from the use of activated protein C in septic shock, the numbers of patients involved in the steroid study are low and the results remain unpublished in a peer-reviewed journal.

Intensive Crit Care Nurs, 2001 Jun, 17(3), 177 - 8
Activated protein C in severe sepsis; Bradley C; A recent large trial has shown that recombinant activated protein C reduced mortality in severe sepsis . This is the first real advance in the pharmacotherapy of sepsis since the introduction of antibiotics in the last century.

J Trop Pediatr, 2002 Feb, 48(1), 10 - 4
Procalcitonin: a marker of neonatal sepsis; Athhan F et al.; This study was designed to assess the value of procalcitonin in establishing the diagnosis and evaluating the prognosis of neonatal sepsis . Thirty-four infants with neonatal sepsis were included in the study . Procalcitonin values of the cases with sepsis were (2.21 +/- 2.48 ng/ml) significantly higher than the values in the control group (0.71 +/- 0.5 ng/ml; p = 0.01) . On the 7th day of therapy neonates who had achieved clinical recovery had a significant decrease of procalcitonin levels (0.55 +/- 0.27 ng/ml) compared to the initial values (p = 0.001) . Initial mean procalcitonin levels of the cases resulting in death were 4.31 +/- 3.66 g/ml . This was significantly higher than the initial values of the patients who had clinical recovery (1.18 +/- 1.24 ng/ml;p = 0.02) . Procalcitonin is a valuable marker for diagnosis, for evaluating prognosis and response to therapy in neonatal sepsis.

J Pediatr, 2002 Feb, 140(2), 171 - 6
Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants; Van Marter LJ et al.; OBJECTIVE: This case-control study of chronic lung disease (CLD) evaluated the hypothesis that chorioamnionitis promotes CLD and interacts with other risk factors for CLD, including mechanical ventilation and postnatal infection . STUDY DESIGN: We identified a population of 193 infants who met our case criteria for CLD whose birth weights were <or=1500 g . These infants were matched 1:1 with control infants for gestational age and hospital of birth . RESULTS: Univariable analyses revealed decreased CLD risk associated with histologic chorioamnionitis and increased risk associated with mechanical ventilation >7 days and culture-documented sepsis . In multivariable analyses, infants were at greatest risk for CLD when they had exposure to both chorioamnionitis and either mechanical ventilation >7 days (odds ratio, 3.2; 95% confidence interval, 0.9-11) or postnatal infection (odds ratio, 2.9; 95% confidence interval, 1.1-7.4) . CONCLUSIONS: We conclude that prolonged mechanical ventilation or postnatal infection increases the risk of CLD among surviving preterm infants and that these 2 factors interact with antenatal infection to further increase the risk of CLD.

J Clin Pathol, 2002 Feb, 55(2), 152 - 3
Localisation of C reactive protein in infarcted tissue sites of multiple organs during sepsis; Baidoshvili A et al.; This report hypothesises an active role for the acute phase protein, C reactive protein (CRP), in local inflammatory reactions . This was studied in infarction sites from liver and kidney in a patient who died as a result of multiple complications after cholecystectomy . In this patient, a general acute phase protein reaction was induced, with an increase in plasma CRP . In infarction sites of kidney and liver, colocalisation of CRP and activated complement were found, whereas non-infarct sites were negative for CRP and complement . These results suggest that CRP directly participates in local inflammatory processes, possibly via complement activation, after binding of a suitable ligand.

J Immunol, 2002 Mar 1, 168(5), 2493 - 500
Depletion of dendritic cells, but not macrophages, in patients with sepsis; Hotchkiss RS et al.; Dendritic cells (DCs) are a group of APCs that have an extraordinary capacity to interact with T and B cells and modulate their responses to invading pathogens . Although a number of defects in the immune system have been identified in sepsis, few studies have examined the effect of sepsis on DCs, which is the purpose of this study . In addition, this study investigated the effect of sepsis on macrophages, which are reported to undergo apoptosis, and MHC II expression, which has been noted to be decreased in sepsis . Spleens from 26 septic patients and 20 trauma patients were evaluated by immunohistochemical staining . Although sepsis did not decrease the number of macrophages, sepsis did cause a dramatic reduction in the percentage area of spleen occupied by FDCs, i.e., 2.9 +/- 0.4 vs 0.7 +/- 0.2% in trauma and septic patients, respectively . The number of MHC II-expressing cells, including interdigitating DCs, was decreased in septic, compared with trauma, patients . However, sepsis did not appear to induce a loss of MHC II expression in those B cells, macrophages, or DCs that were still present . The dramatic loss of DCs in sepsis may significantly impair B and T cell function and contribute to the immune suppression that is a hallmark of the disorder.

Thromb Haemost, 2002 Feb, 87(2), 218 - 23
The tissue factor and plasminogen activator inhibitor type-1 response in pediatric sepsis-induced multiple organ failure; Green J et al.; STUDY OBJECTIVE: Cytokines increase endothelial tissue factor (TF) and tissue plasminogen activator inhibitor type-1 (PAI-1) expression in vitro . Tissue factor interacts with factor VII to facilitate thrombosis and PAI-1 inhibits fibrinolysis by endogenous plasminogen activators . Because cytokine release is increased in children with sepsis-induced multiple organ failure (MOF), we hypothesized a cytokine associated increase in circulating TF and PAI-1 antigen release, and systemic activity in these patients . STUDY DESIGN: One hundred and seven consecutive children, who met the criteria for sepsis, and 10 critically ill children without sepsis, were enrolled in the study . Plasma TF and PAI-1 antigen and activity levels, Interleukin-6 antigen levels (IL-6), nitrite + nitrate levels (marker of nitric oxide production) and number of organs failing were measured on days 1-3 of sepsis . RESULTS: Increased TF and PAI-1 antigen, and PAI-1 activity levels were associated with increasing IL-6 and nitrite + nitrate levels (p <0.05), the development of MOF (p <0.05), and mortality (p <0.05) . Increased systemic PAI-1 activity was associated with cardiovascular, renal . and hepatic failure (p <0.05) . Increased systemic TF activity was associated with the development of coagulopathy (p <0.05) and tended to be associated with mortality (p = 0.06, power .77) CONCLUSIONS: A shift to an anti-fibrinolytic endothelium phenotype characterizes children who develop sepsis-induced MOF and mortality . Children with coagulopathy have a shift to a pro-coagulant phenotype . These findings support potential therapeutic roles for PAI-1 and TF pathway inhibitors in reversal of this devastating pathophysiologic process.

Curr Opin Clin Nutr Metab Care, 2002 Mar, 5(2), 167 - 74
Reactive oxygen species as mediators of organ dysfunction caused by sepsis, acute respiratory distress syndrome, or hemorrhagic shock: potential benefits of resuscitation with Ringer's ethyl pyruvate solution; Fink MP; Reactive oxygen species are reactive, partly reduced derivatives of molecular oxygen . Important reactive oxygen species in biological systems include superoxide radical anion, hydrogen peroxide, and hydroxyl radical . Peroxynitrite, is another important species in biological systems . A variety of enzymatic and non-enzymatic processes can generate reactive oxygen species in mammalian cells . An extensive body of experimental evidence from studies using animal models supports the view that reactive oxygen species are important in the pathogenesis of ischemia-reperfusion syndromes, sepsis, acute respiratory distress syndrome, and multiple organ dysfunction syndrome . This view is further supported by data from clinical studies that correlate biochemical evidence of reactive oxygen species-mediated stress with the development of acute respiratory distress syndrome or sepsis in patients . Ethyl pyruvate, a simple derivative of pyruvic acid, has been shown to be efficacious in several animal models of critical illness, and warrants further evaluation in this regard.

Biol Neonate, 2002, 81(2), 86 - 90
Race, Candida sepsis, and retinopathy of prematurity; Tadesse M et al.; The objective of this observational cohort study at Georgetown University Hospital from January 1, 1994 through December 31, 1997 was to investigate race, Candida sepsis, and duration of oxygen exposure in infants with retinopathy of prematurity (ROP) with birth weight < or = 1,000 g . The incidence of ROP was 70.8% (114/161) . The incidence of stage III or greater ROP in the Caucasian infants was significantly higher at 46.7% (14/30) than in the African-American infants at 23.8% (20/84) with p < 0.02 . In addition, the incidence of threshold disease was higher in Caucasian infants 33.3% (10/30) when compared to African-American infants 9.5% (8/84) with p < 0.002 . Using multiple logistic regression, African-American race was found to be an independent protective factor against developing severe ROP {adjusted odds ratio 0.39; 95% confidence interval (UCI) 0.16-0.97} . Extremely-low-birth-weight African-American infants with comparable severity of illness (including birth weight, gestational age, duration of supplemental oxygen exposure, and Candida sepsis) are less likely to develop severe ROP than Caucasian infants .

J Infus Nurs, 2002 Jan-Feb, 25(1), 45 - 53
Metabolic response and parenteral nutrition in trauma, sepsis, and burns; Orr PA et al.; Trauma, sepsis, and burns cause abnormal manifestations in the body . These manifestations can cause alterations in body metabolism, which complicates nutritional management . Goals of nutrition support with assessment modifications for a constantly changing population are reviewed . Patients in such stress states as burns, trauma, and sepsis many times need altered nutrition . This article outlines guidelines for total parenteral formula modification and monitoring, and discusses other complications such as drug interactions with parenteral formulas.

Zhonghua Wai Ke Za Zhi, 2000 Sep, 38(9), 686 - 9
{Anisodamine in prevention and treatment of sepsis of severely burned patients}; Chai J et al.; OBJECTIVE: To observe the preventive effect of anisodamine on possible sepsis of patients with major burns and the effect of anisodamine on patients with sepsis . METHODS: Forty-two patients with extensive burn admitted to our burn institute from April 1998 to November 1999 were divided randomly into two groups: treatment group (T group) and control group (C group) . In the T group, all 20 patients received fluid resuscitation regimen with anisodamine, and in the C group, 22 patients received the regimen with no anisodamine . A tonometery catheter was positioned in the stomach, connecting with the automatic gas analysis machine (Datex-Engtrom Corporation, Dutch) for determining gastric intramucosal pH (pHi) . The plasma concentrations of diamine oxidase (DAO) and endotoxin were measured . Correlation analysis between pHi, DAO and endotoxin were made respectively during early stage of postburn . All the parameters in 7 patients with sepsis before and after administration of anisodamine were compared with those in 6 patients with sepsis without use of anisodamine . RESULTS: The incidence of sepsis in the T group was lower (20.0%) than that in C group (40.9%) . The gastric pHi value in the early period of postburn was significantly higher in the T group than in the C group (P < 0.05) . Concurrently, the plasma concentrations of DAO and endotoxin were significantly lower in the T group than in the C group (P < 0.05 or 0.01) . A significant negative correlation was seen between the gastric pHi and respective values of DAO, endotoxin (P < 0.05 or 0.01) . There were a decrease in gastric pHi, and an increase in plasma DAO and endotoxin level in patients with septic episode; however all the parameters after administration of anisodamine were improved compared with those in septic patients without use of anisodamine . CONCLUSIONS: Intestinal ischemic injury plays an important role in provoking sepsis during early postburn period . Anisodamine is effective in restoring intestinal circulation both in the shock phase and after the development of sepsis.

Zhonghua Wai Ke Za Zhi, 2000 Jun, 38(6), 405 - 8
Effect of extensive excision of burn wound with invasive infection on hypermetabolism in burn patients with sepsis; Chai J et al.; OBJECTIVE: To evaluate the effect of extensive excision of invasive burn wound infection on hypermetabolic response in burn patients with sepsis . METHODS: Eight patients with major burn, complicated by invasive burn wound infection and sepsis, were consecutively admitted to our hospital from September 1997 to October 1998 . Resting energy expenditures (REEs) were monitored by means of cardiorespiratory diagnostic system (Medical Graphics Corporation, USA) at patients' bedside . Plasma concentration of IL-6, IL-8, TNF-alpha, and LPS were assayed before and after surgical intervention and at the time when the patients' vital signs became stable . Correlation analysis between REEs and IL-6, IL-8, TNF-alpha, and LPS were made, respectively . RESULTS: A total of 8 treated patients survived . Values of REE before surgical intervention were significantly higher than those after surgical intervention (P < 0.01), and when patients' vital signs became stable the values were significantly lower than those after surgical intervention (P < 0.01) . The plasma concentrations of IL-6, IL-8, TNF-alpha, and LPS after excision of invasive burn wound infection were significantly lower than those before surgical intervention (P < 0.05) . The lowest levels of these inflammatory mediators were observed when the conditions of patients became stable, and the values were significantly lower than those before surgical intervention (P < 0.001) . There was a significant positive correlation between REE level and respective values of plasma IL-6, IL-8, TNF-alpha, and LPS (P < 0.01) . CONCLUSIONS: It seemed that the extensive excision of invasively infected burn wound in patients with major burn should be performed as early as possible to reduce an increased release of inflammatory mediators and to control the hypermetabolic response during sepsis.

Zhonghua Wai Ke Za Zhi, 2000 May, 38(5), 385 - 7
{Apoptosis of endothelial cells in alteration of microvascular permeability in lung during sepsis}; Wu R et al.; OBJECTIVE: To investigate the apoptosis of endothelial cells in the alteration of microvascular permeability in lung during sepsis . METHODS: Twenty-four male NIH mice were subjected to cecal ligation and puncture (CLP) or sham operation (SO) . The microvascular endothelial cells of the lungs were harvested at 3 hours and 12 hours after operation . The apoptosis of endothelial cells (VIII factor related antigen positive cells) in the lungs was determined by 2-color flow cytometry (FITC-labeled VIII factor related antigen and PI) and Apop Tag) in situ apoptosis detection kit in situ . The apoptosis related gene (bcl-2) was detected by RT-PCR . The microvascular permeability in lung tissue was also examined . RESULTS: The apoptosis of microvascular endothelial cells was increased significantly at 12 hours after CLP (5.03 +/- 0.92 vs . 3.48 +/- 1.21, P < 0.05) . The increased apoptosis was paralleled with the decrease in bcl-2 gene expression . The microvascular permeability in lung tissue was slightly increased at 3 hours after CLP, but significantly increased at 12 hours after CLP (0.106 +/- 0.008 vs 0.047 +/- 0.003, P < 0.01) . CONCLUSIONS: Apoptosis in microvascular endothelial cells seems to be an important reason for the alteration of microvascular permeability.

Zhonghua Wai Ke Za Zhi, 1998 Nov, 36(11), 643 - 5
{Effect of recombinant human growth hormone with total parenteral nutrition on albumin synthesis in patients with peritoneal sepsis}; Li W et al.; OBJECTIVE: To investigate the effect of recombinant human growth hormone (rhGH) in combination with total parenteral nutrition (TPN) on albumin synthesis in patients with peritoneal sepsis . METHOD: 17 patients with peritoneal sepsis were divided randomly into two groups . The control group received TPN only for 7 days, and the GH group received both rhGH (12 U/d) and TPN for 7 days . The TPN scheme and other treatment were the same in the two groups . RESULT: Serum albumin, prealbumin, and transferrin concentration were increased in patients in the GH group (P < 0.01), but no apparent effect was observed in the control group (P > 0.05) . CONCLUSION: In condition of serious peritoneal sepsis, TPN can not increase albumin, prealbumin, and transferrin synthesis alone, whereas rhGH in combination with TPN significantly increase the synthesis of visceral proteins.

Kongressbd Dtsch Ges Chir Kongr, 2001, 118, 265 - 7
{Supportive sepsis therapy: what is still valid today?}; Angele MK et al.; Following several disappointing approaches to decrease the mortality of septic patients using various adjuncts, protein C is the first substance leading to a significant reduction of the mortality rate (PROWESS) . The increased risk for bleeding complications in patients receiving protein C, however, limits its use in septic surgical patients . Administration of AT III in septic patients (KYBERSEPT) reduced the mortality rate solely in patients which were not treated with heparin . Although hydrocortisone reduced the amount of vasoactive katecholamines the effect of hydrocortisone administration on the survival rate remains unknown . In summary, early intervention to eliminate the septic focus and the use of antibiotics according to an antibiogramm still remains the most efficient basis for the treatment of septic patients.

Arch Surg, 2002 Jan, 137(1), 74 - 9
Estradiol administration improves splanchnic perfusion following trauma-hemorrhage and sepsis; Kuebler JF et al.; HYPOTHESIS: The female sex steroid 17beta-estradiol improves immune functions following trauma-hemorrhage in rodent models . Therefore, we hypothesized that 17beta-estradiol administration following trauma-hemorrhage would also improve cardiac output, splanchnic perfusion, and oxygen utilization, even after the induction of subsequent sepsis . SETTING: A university laboratory . INTERVENTION: Male rats underwent midline laparotomy (ie, soft tissue injury) . They were bled to a mean arterial pressure of 35 to 40 mm Hg for 90 minutes and resuscitated over 60 minutes with lactated Ringer solution . At the beginning of resuscitation, 17beta-estradiol (l mg/kg) or a vehicle was administered . At 20 hours after resuscitation, polymicrobial sepsis was induced by cecal ligation and puncture (CLP) . MAIN OUTCOME MEASURES: At 5 hours after CLP, cardiac performance (via a left ventricular catheter), cardiac output, and organ blood flow were determined using strontium 85 microspheres . Blood samples were collected from the femoral artery and jugular, portal, and renal veins to determine systemic and regional oxygen delivery and consumption . Moreover, circulating levels of 17beta-estradiol, its adrenal precursor dehydroepiandrosterone (DHEA), and corticosterone were assessed by enzyme-linked immunosorbent assay . RESULTS: Hemorrhage and subsequent sepsis significantly depressed cardiac performance, cardiac output, organ perfusion, and oxygen consumption . Estrogen did not restore cardiac output or systemic oxygen consumption; nonetheless, it restored the depressed intestinal perfusion . Rats treated with estrogen had significantly elevated levels of plasma 17beta-estradiol, but the levels of DHEA or corticosterone were not affected . CONCLUSIONS: The increase in gut perfusion could represent a potential mechanism for the salutary effects of 17beta-estradiol following trauma-hemorrhage . Because 17beta-estradiol improves systemic and intestinal perfusion after trauma-hemorrhage and induction of subsequent sepsis, this agent appears to be a promising adjunct for the treatment of trauma victims.

Cleve Clin J Med, 2002 Jan, 69(1), 65 - 73
Sepsis: menu of new approaches replaces one therapy for all; Larosa SP; Effective therapies for sepsis are being devised, after many failures . However, instead of a "one therapy for all" approach, management of sepsis will involve a menu of treatments, depending on the presence of inflammatory markers, the severity of disease, and other factors . This article looks at promising new therapies, including recombinant human activated protein C (rhAPC; drotrecogin alfa, Xigris), recently approved by the US Food and Drug Administration.

J Infect Chemother, 1999 Mar, 5(1), 21 - 31
Clinical trial of in-situ hybridization method for the rapid diagnosis of sepsis; Shimada J et al.; We evaluated the utility of in-situ hybridization (ISH) for the rapid diagnosis of sepsis . We applied this approach to polymorphonuclear neutrophil (PMN)-rich smears from patients with suspected bacterial infection . Positive results by ISH were obtained in the smears of 123 of 292 patients (42%), while only 32 of the 292 (11%) were positive by blood culture . These findings indicate that ISH is almost four times more sensitive than the culture method for the detection of sepsis . ISH results are obtained within 1 day, while 1 day to 2 weeks is required for the results of blood culture . Blood culture and ISH methods detected the same bacteria in two patients . ISH also successfully identified the same bacteria in blood and PMN-rich body fluid (bronchoalveolar lavage samples) in 6 patients . In 19 patients, ISH of blood detected the same bacteria as those found in subcultures from other sources (e.g., stool, sputum, nasal cavity) . We discuss these results in comparison with blood culture results in terms of evaluating a rapid approach to the management of patients with sepsis.

Intensive Care Med, 2001 Nov, 27(11), 1807 - 13 Epub 2001 Sep 11.
Jejunal luminal nitric oxide during severe hypovolemia and sepsis in anesthetized pigs; Snygg J et al.; OBJECTIVE: Lowered gut blood perfusion and the associated intestinal mucosal barrier dysfunction is considered important in the pathophysiology leading to critical illness . Intestinal mucosal nitric oxide formation has been attributed a key role in the regulation of epithelial permeability and other properties of the intestinal mucosal barrier . This study was performed to delineate intestinal mucosal NO formation during hypovolemia or sepsis, both of which are associated with intestinal hypoperfusion . MATERIALS AND METHODS: Seventeen pigs were subjected to 2 h of severe hypovolemia (bleeding induced) or sepsis (systemic infusion of live Escherichia coli) or no treatment (controls) . Jejunal mucosal NO production was monitored by a tonometer . Mesenteric blood flow was measured as portal venous blood flow by an ultrasonic transit time flowmeter probe, and oxygen delivery and consumption were calculated from regional blood samples . RESULTS: Intestinal perfusion and oxygen delivery were reduced by the same order of magnitude in both groups . Jejunal mucosal NO production and oxygen consumption decreased markedly in the hypovolemia group but remained stable in the group subjected to septic shock . CONCLUSIONS: These data suggest that blood loss inhibits jejunal mucosal NO production as part of a general downregulation of nonvital organs . Sepsis represents a more complex stress condition with activation/maintenance of host defense mechanisms as reflected by maintained jejunal mucosal NO production despite reduced gut blood perfusion.

Shock, 2002 Jan, 17(1), 55 - 60
Differential alterations in cardiovascular responses during the progression of polymicrobial sepsis in the mouse; Yang S et al.; Although the mouse has been extensively used to study immune consequences of sepsis and other genetic anomalies, the changes in various cardiovascular parameters such as cardiac output, organ perfusion, as well as oxygen utilization have not been characterized in this species during sepsis . To determine this, polymicrobial sepsis was induced in male adult C3H/NeN mice by cecal ligation and puncture (CLP, two punctures with a 22-gauge needle) . The animals were then resuscitated with normal saline subcutaneously . At 5 or 24 h after CLP (time points previously shown to be within the hyperdynamic and hypodynamic stage of sepsis, respectively, in the rat), cardiac output and blood flow in major organs were determined using a well-established radioactive microsphere method, and stroke volume and total peripheral resistance were calculated . In addition, oxygen delivery and consumption were determined . The results indicate that cardiac output, stroke volume, oxygen delivery and consumption, and blood flow in the liver, small intestine, spleen, and kidneys increased significantly at 5 h after CLP . This was associated with significantly decreased total peripheral resistance . In contrast, total peripheral resistance increased and the other above-mentioned parameters, as well as mean arterial pressure, decreased significantly at 24 h after the onset of sepsis . Thus, the cardiovascular response to polymicrobial sepsis in the mouse is characterized by an early hyperdynamic phase (i.e., 5 h after CLP) followed by a late hypodynamic phase (24 h post-CLP) . Since the radioactive microsphere technique provides a reliable method for determining various hemodynamic parameters in the mouse, the correlation between the cardiovascular response and immune or potentially genetic alterations can be examined in this species during the progression of sepsis.

Shock, 2002 Jan, 17(1), 1 - 8
Sepsis research in the next millennium: concentrate on the software rather than the hardware; Tjardes T et al.; Today the basic principles of septic conditions are understood . Nevertheless, sepsis research has reached a critical point . To integrate our knowledge towards a consistent theory of the disease process and to derive effective therapies, new perspectives for future research that fit the complexity of the problem have to be found . We conducted a review of the literature concerning systemic inflammatory response syndrome (SIRS) and sepsis with particular reference to liver pathophysiology . And compared our findings with characteristic features of complex systems . The complexity of sepsis is broadly recognized . A review of the different aspects of liver inflammation during SIRS and sepsis, i.e . endotoxin challenge, cytokine induced dysfunction, the mechanisms of leukocyte transmigration, and hormonal and neuroendocrine regulatory mechanisms is given . Key aspects of complex systems, including parallelism, locality, emergence, and cross-scale interactions are introduced . We conclude that sepsis research needs new perspectives that allow us to handle the complex interactions occurring during the disease process . We propose to focus research on the interactions between the constituents of the system rather than only describing isolated aspects of the disease process . We also conclude that the ideas and techniques of non-linear systems theory are suitable tools for the analysis of complex and dynamic diseases like SIRS and sepsis.

Curr Opin Crit Care, 2001 Oct, 7(5), 367 - 70
Recent developments in clinical management of surgical sepsis; Danielson D et al.; The current clinical management of surgical patients with sepsis is governed by two principles: control of the source of infection and supportive management of the patient until recovery . Recently, there has been renewed interest in the concept of source control-in particular, its importance for evaluating and comparing clinical trials . This brief review highlights some of the developments in the surgical literature . Important recent publications center on source control, the management of systemic inflammatory response syndrome, necrotizing pancreatitis, acute diverticulitis, gastrointestinal fistulas, and the role of laparoscopy in surgical infections . Novel interventions in supportive care are being developed, and their clinical applicability and effectiveness will be improved with increased understanding of the pathophysiology of systemic inflammation.

Curr Opin Crit Care, 2001 Oct, 7(5), 347 - 53
Clinical impact of novel anticoagulation strategies in sepsis; Opal SM; Derangements in coagulation and fibrinolysis are frequent complications of systemic infection, and septic shock is the most common recognized cause of disseminated intravascular coagulation . Anticoagulant therapy has been used as a treatment strategy for severe sepsis for several decades without compelling evidence of efficacy until the 2001 publication of the phase III trial with recombinant human activated protein C . Major phase III international trials with antithrombin and tissue factor pathway inhibitor also have been completed recently . The molecular mechanisms by which the clotting system interacts with the innate immune response have greatly facilitated the understanding of coagulation and the pathophysiology of septic shock . Anticoagulants such as recombinant human activated protein C and related agents may become the mainstay of adjuvant therapies for severe sepsis in the near future.

Zhonghua Yi Xue Za Zhi, 2001 Jan 25, 81(2), 78 - 81
{Prediction of prognosis of patients with multiple organ dysfunction syndrome by sepsis-related organ failure assessment}; Du B et al.; OBJECTIVE: To describe the clinical properties of multiple organ dysfunction syndromB (MODS) with sepsis-related organ failure assessment (SOFA) . METHODS: A total of 366 MODS patients admitted to the 5 participating ICUs from 1990 to 1996 were included in this study . SOFA score and demographic data were retrospectively evaluated . RESULTS: Total maximum SOFA score, delta SOFA and admission total SOFA score exhibited a good correlation with hospital mortality rate, with the area under the ROC curve of 0.819, 0.750 and 0.616, respectively . The SOFA score for patients without organ failure was 3.7 +/- 1.2, with a mortality rate of 21.7%, and the SOFA score for patients with failure of all 6 organs was 20.2 +/- 1.4, with a mortality rate of 77.8% . A maximum score was firstly reached for respiratory system (1.41 days after admission), and last for cardiovascular system (4.89 days) . Logistic regression model revealed that the central nervous system was associated with the highest relative contribution (odds ratio 1.75) to hospital outcome, followed by renal (OR 1.42), cardiovascular (OR 1.38), coagulation (OR 1.34) and respiratory (OR 1.17) systems . No independent contribution was found for the hepatic score (OR 0.99) . CONCLUSION: Total maximum SOFA score and delta SOFA can be used to quantify the progress of MODS during ICU stay.

Zhonghua Yi Xue Za Zhi, 2000 Mar, 80(3), 193 - 5
{Association of tumor necrosis factor microsatellite polymorphism with incidence and outcome of severe postoperative sepsis}; Shu Q et al.; OBJECTIVE: To investigate whether tumor necrosis factor (TNF) microsatellite polymorphism within the TNF locus is associated with the incidence and outcome of severe postoperative sepsis . METHODS: 122 patients with severe postoperative sepsis were included in this study; 138 local ethnically matched healthy individuals served as controls . Microsatellite TNFc polymorphism within the TNF locus was typed using polymerase chain reaction (PCR) followed by polyacrylamide gel electrophoresis with silver staining . RESULTS: Microsatellite TNFc polymorphism had two alleles (TNFc1 and TNFc2) and three kinds of genotype (homozygotes TNFc1c1 and TNFc2c2, and heterozygote TNFc1c2) . The genotype distribution fit Hardy-Weinberg equilibrium . The frequency of TNFc1 microsatellite allele was significantly higher in patients with severe sepsis (79%) than in healthy individuals (71%) (P < 0.05) . The frequency of heterozygote TNFc1c2 was significantly higher in non-surviving patients (46%) with severe sepsis than in survivors (27%) (P < 0.05) . CONCLUSIONS: TNFc microsatellite polymorphism is significantly associated with the incidence and outcome of severe postoperative sepsis.

Arch Immunol Ther Exp (Warsz), 2001, 49(5), 399 - 404
Proinflammatory cytokines (IL-6, IL-8), cytokine inhibitors (IL-6sR, sTNFRII) and anti-inflammatory cytokines (IL-10, IL-13) in the pathogenesis of sepsis in newborns and infants; Sikora JP et al.; The levels of the proinflammatory cytokines interleukin 6 (IL-6) and IL-8, and the anti-inflammatory cytokines IL-10 and IL-13 were studied in child patients with sepsis . The changes of the cytokine inhibitors soluble IL-6 receptor and soluble p75 TNF-alpha receptor were also investigated in the patients' sera . An increase of pro- and anti-inflammatory cytokine levels was demonstrated at the time of diagnosis . Pharmacotherapy was accompanied by a decrease of the elevated concentrations of both cytokines and their inhibitors . The time pattern of changes in cytokine and cytokine inhibitor serum concentrations along with the time course of acute phase indices, including procalcitonin and C-reactive protein, allows for an evaluation of the system inflammatory response and may support diagnostic and prognosis methods.

Intensive Care Med, 2001 Dec, 27(12), 1835 - 41 Epub 2001 Oct 25.
Protective functions of intracellular heat-shock protein (HSP) 70-expression in patients with severe sepsis; Bruemmer-Smith S et al.; Intracellular expression of heat-shock-protein 70 (HSP70) arose early in evolutionary development as a tool to protect cellular homeostasis . HSP70 detects proteins that are incorrectly folded or denatured . They form a complex with such proteins which can lead to correct folding, compartmentalization in organelles, or to proteolytic degradation . HSP70 also appears to protect proteins from degeneration . Intracellular HSP70-expression is induced by a wide variety of stimuli including heat, fever, hypoxia, oxygen radicals, endotoxins, cytokines, and heavy metal ions . Pre-emptive induction of HSP70-expression reduces organ dysfunction and mortality in animal models of sepsis.

N Engl J Med, 2001 Nov 8, 345(19), 1368 - 77
Early goal-directed therapy in the treatment of severe sepsis and septic shock; Rivers E et al.; BACKGROUND: Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit . This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand . The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit . METHODS: We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit . Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment . In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups . RESULTS: Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics . In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P = 0.009) . During the interval from 7 to 72 hours, the patients assigned to early goal-directed therapy had a significantly higher mean (+/-SD) central venous oxygen saturation (70.4+/-10.7 percent vs . 65.3+/-11.4 percent), a lower lactate concentration (3.0+/-4.4 vs . 3.9+/-4.4 mmol per liter), a lower base deficit (2.0+/-6.6 vs . 5.1+/-6.7 mmol per liter), and a higher pH (7.40+/-0.12 vs . 7.36+/-0.12) than the patients assigned to standard therapy (P < or = 0.02 for all comparisons) . During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0+/-6.3 vs . 15.9+/-6.4, P < 0.001) . CONCLUSIONS: Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.

Ann Pharmacother, 2001 Dec, 35(12), 1570 - 4
Candida lusitaniae catheter-related sepsis; Pietrucha-Dilanchian P et al.; OBJECTIVE: To present a case describing Candida lusitaniae candidemia in an immunocompetent patient successfully treated with fluconazole antifungal therapy . Time-kill studies of the C . lusitaniae isolate using amphotericin B, and an extensive review of the literature are also presented . CASE SUMMARY: A 52-year-old immunocompetent Latin-American woman was admitted to the special care unit with severe sepsis . Her recent medical history included an exploratory laparotomy for gallstone pancreatitis, requiring cholecystectomy, segmental sigmoid colectomy, drainage of peritoneal abscesses, and a colostomy . In addition, the patient required a central venous catheter (CVC) placement for prolonged broad-spectrum antibiotic therapy and total parenteral nutrition therapy . Yeast was isolated from the abdominal abscess and blood cultures obtained on day 1, and from the catheter tip on day 5 . The woman received initial empiric antifungal therapy with fluconazole, which was later changed to amphotericin B . After the yeast was identified as C . lusitaniae on day 8, this was changed to fluconazole for the duration of therapy . C . lusitaniae was not present in blood cultures taken two weeks after the CVC was removed, and the cultures remained negative thereafter . After a prolonged hospitalization, the patient was discharged home . DISCUSSION: Disseminated infections with C . lusitaniae usually occur in immunocompromised patients, although isolated reports of C . lusitaniae infections in immunocompetent patients have been described . Therapeutic challenges of C . lusitaniae treatment include its primary resistance to amphotericin B and species misidentification . Isolates recovered from our patient were submitted for fungus time--kill studies that suggested unique susceptibility patterns to amphotericin B, indicating a trend toward resistance . CONCLUSIONS: Based on variable susceptibility patterns of C . lusitaniae to amphotercin B and flucytosine, fluconazole is an appropriate choice as first-line therapy for C . lusitaniae candidemia.

Am J Respir Crit Care Med, 2002 Jan 15, 165(2), 221 - 8
Mechanical ventilation protects against diaphragm injury in sepsis: interaction of oxidative and mechanical stresses; Ebihara S et al.; Overproduction of nitric oxide (NO) with attendant oxidative and nitrosative stress has been implicated in sepsis-induced diaphragm dysfunction . Here we determined the impact of controlled mechanical ventilation (MV) on rat diaphragm sarcolemmal injury, inducible NO synthase (iNOS) expression, and oxidative stress during endotoxemia . At 4 h after injection of endotoxin, impaired sarcolemmal integrity and decreased force production by the diaphragm were observed in spontaneously breathing rats . The use of MV during endotoxemia largely eliminated sarcolemmal damage and significantly improved diaphragm force production . These benefits were not associated with alterations in either iNOS expression or protein carbonyls (marker of oxidation), which remained abnormally elevated in septic diaphragms despite MV . Therefore, we hypothesized that the protection afforded by MV was due to its ability to decrease the level of mechanical stress placed on the sarcolemma, because the latter could be hyperfragile in the setting of increased oxidative stress . Using an in vitro system to independently modulate oxidative and mechanical stresses, we confirmed that these two factors act together in a synergistic fashion to favor sarcolemmal injury . Accordingly, our data suggest that MV protects the diaphragm during sepsis by abrogating an injurious interaction between oxidative and biomechanical stresses imposed on the sarcolemma.

Transfus Med Rev, 2002 Jan, 16(1), 11 - 24
Myeloid hematopoietic growth factors and their role in prevention and/or treatment of neonatal sepsis; Parravicini E et al.; Sepsis continues to be an important cause of morbidity and mortality among both full-term and preterm infants, secondary to an immaturity in neonatal host defense . The incidence of neonatal sepsis ranges from 30% in very low birth weight infants to 0.4% in preterm neonates and 0.1% in term neonates . The dysregulation of the expression and production of hematopoietic cytokines in the neonate contributes to quantitative and qualitative deficiencies in neonatal myeloid progenitor activity and decreased availability and function of mature effector neutrophils . These abnormalities contribute in large part to the increased incidence and mortality associated with neonatal sepsis . In this review, we have summarized and analyzed the studies investigating the dysregulation, expression and production of myelopoietic growth factors in neonates, the preclinical in vivo effects of myelopoietic growth factors in neonatal animals, the preclinical in vivo effects of myelopoietic growth factors during experimental sepsis in neonatal animals, the in vitro effects of growth factors on human neonatal phagocytic immunity, and clinical results of myelopoietic growth factors in human neonates . Future studies should be focused on investigating other abnormalities of neonatal host defense and multiple and simultaneous approaches to circumvent identified defects to attempt to reduce both the incidence and severity of neonatal host defense .

Plast Reconstr Surg, 2002 Jan, 109(1), 108 - 13; discussion 114-5
The effectiveness of muscle flaps for the treatment of prosthetic graft sepsis; Graham RG et al.; The objective of this study was to assess the efficacy and reliability of muscle flaps in the treatment of prosthetic graft sepsis . A retrospective analysis was performed to assess the outcome of all patients with prosthetic graft sepsis who were treated with a muscle flap at Groote Schuur Hospital between January of 1991 and July of 2000 . The specific end points studied were flap survival, limb salvage rate, and mortality . A total of 27 muscle flaps were raised to cover 24 sites of graft sepsis in 21 patients . Twenty-five flaps were performed primarily and two secondarily . The mortality rate was zero . Limb salvage was achieved in 15 of 21 patients (71 percent), with no recurrent sepsis after an average follow-up period of 36 months . The groin was the most common site of infection, with an 86 percent incidence . Eighteen sartorius flaps were raised in the groin . Seventeen of the 18 sartorius flaps survived (94 percent), and a 71 percent limb salvage was achieved with no recurrent sepsis after 36 months of follow-up . This series supports the use of muscle flaps for the treatment of prosthetic graft sepsis . The sartorius flap has been shown to be reliable as a flap in the groin, with successful limb salvage in the majority of patients.

Peptides, 2001 Dec, 22(12), 2099 - 103
Isolation and characterization of serum procalcitonin from patients with sepsis; Weglohner W et al.; Procalcitonin (PCT) is one of the precursors in the synthesis of calcitonin in thyroidal C-cells and other neuroendocrine cells . PCT and other calcitonin precursors are elevated in the serum of many conditions leading to systemic inflammatory response syndrome . The measurement of PCT in patients suffering from severe bacterial infections is a useful tool for the diagnosis of sepsis . Furthermore, therapeutic decisions are often based on the increase or decline of serum PCT levels . PCT was reported to have 116 amino acids . The aim of our study was the determination of the primary structure of serum PCT from septic patients . Sera containing high PCT-concentrations (>100 ng/ml) were collected from 22 patients with severe sepsis and were pooled for further purification (12.7 microg total concentration of PCT) . Pooled PCT was purified on a CT 21-immunoaffinity column, further purified by reversed phase HPLC, and the resulting pure PCT was digested with endoproteinase Asp-N . N-terminal Edman sequencing showed that the first two amino acids (Ala-Pro) of the proposed pro-peptide were missing . Further analyses by MALDI-TOF mass spectroscopy resulted in a distinct mass signal of 12640 Da +/- 0.1%, which is in concordance with the theoretical molecular weight of the N-terminal truncated form (12628 Da) . As opposed to previous suggestions, we could not detect any chemical modifications of PCT . In summary, we could demonstrate that PCT in the serum of septic patients is a peptide of only 114 amino acids, instead of the predicted 116 amino acids, lacking the N-terminal dipeptide Ala-Pro . This information on the primary structure of PCT might help in further studies on the physiological role of PCT during sepsis.

Braz J Infect Dis, 2001 Oct, 5(5), 277 - 9
Leptospirosis mimicking sepsis after orthopedic surgery: a case report; Abboud CS et al.; We report a case of leptospirosis that occurred after elective surgery involving tendon transfer and shoulder arthroscopy . The disease mimicked hospital infection after orthopedic surgery and was at first misdiagnosed as post-operative sepsis . The patient was 60 year old female that developed sepsis with hypotension, shock, bleeding, jaundice and renal insufficiency 4 hours after surgery . Shock treatment procedures were performed and broad spectrum antibiotic therapy was used with coverage for bacteria acquired in hospitals . A careful investigation was carried out by the Hospital Infection Control Service in search of the possible source of the infection . After clinical evaluation by a specialist in infectious diseases, the hypothesis of leptospirosis was put forward based on clinical and epidemiological data . The hypothesis was later confirmed by the positive result of serological tests with the microagglutination method that yielded 1:800 and then 1:12,600 7 days later . This is the first reported case of leptospirosis manifest directly following surgery, mimicking postoperative sepsis.

Chin Med J (Engl), 2000 Jan, 113(1), 18 - 21
Alternation of Na(+)-Ca2+ exchange in rat cardiac sarcolemmal membranes during different phases of sepsis; Wang X et al.; OBJECTIVE: To study the alteration of Na(+)-Ca2+ exchange in rat cardiac sarcolemmal membrane during phases of septic shock . METHODS: Sepsis was induced by cecal ligation and puncture (CLP) . Na(+)-Ca2+ exchange was assayed by radioactive analysis . RESULTS: Na(+)-dependent 45Ca2+ uptake was decreased by 62%-69% in late phase of sepsis, whereas it was not affected in early phase of sepsis . Na(+)-Ca2+ exchange stimulated by 5' guanylyl imidodiphosphate {Gpp (NH) p} was decreased by 65.7% in late phase of sepsis but unaltered in early phase of sepsis . Two agonists (angiotensin II and phenylephrine) coupled to Gq and a protein kinase C activator, phorbol 12-myristate 13-acetate (PMA) all inhibited Na(+)-Ca2+ exchange in late phase of sepsis . Na(+)-Ca2+ exchange activities induced by phosphorylation of Na(+)-Ca2+ exchange were decreased in late phase of sepsis, whereas inhibition of Na(+)-Ca2+ exchange by dephosphorylation was increased both in early and late phases of sepsis . CONCLUSION: The alteration of Na(+)-Ca2+ exchange during different phases of sepsis might be related to the activities of Gq, protein kinase C, and phosphorylation/dephosphorylation.

Expert Opin Investig Drugs, 2002 Jan, 11(1), 69 - 74
Coagulation inhibitors in the treatment of sepsis; Freeman BD et al.; Despite advances in supportive care, sepsis and septic shock continue to be major causes of morbidity and mortality in critically ill patients . The lack of efficacy of anti-inflammatory drugs in patients with sepsis has shifted interest toward developing alternative treatments . The observation that clotting system activation may in part underlie the physiological derangements of sepsis has resulted in efforts to target the clotting cascade as a therapeutic strategy . Anticoagulants have been shown to ameliorate physiological derangements and improve survival in animal sepsis models . Three agents have undergone extensive study in humans: recombinant human activated protein C (rhAPC, drotrecogin-alpha), antithrombin III (ATIII) and tissue factor pathway inhibitor (TFPI) . While a recent Phase III study of rhAPC suggests a survival benefit in patients with sepsis, major concerns about this trial include the manner in which the study was conducted, the potential toxicity of rhAPC and the questionable efficacy of this agent in patients with low mortality risk . Further clinical testing of rhAPC appears to be necessary to better define the target population most appropriate for its use . In contrast, a large Phase III study of high dose ATIII in patients with sepsis failed to show a treatment benefit with this agent . Finally, while TFPI has undergone extensive preclinical and Phase II testing, the results of Phase III studies have not been published . In summary, while coagulation inhibitors may ultimately have a therapeutic role in selected subgroups of patients with sepsis, the efficacy and safety of this class of agents remain to be proven.

Shock, 2001 Dec, 16(6), 479 - 83
Cyclooxygenase-2-mediated regulation of Kupffer cell interleukin-6 production following trauma-hemorrhage and subsequent sepsis; Knoferl MW et al.; Studies indicate that trauma-hemorrhage results in activation of Kupffer cells to release inflammatory mediators and it leads to immunosuppression and increased susceptibility to subsequent sepsis . The cyclooxygenase (COX) product prostaglandin (PG) E2 appears to be central to this process, however, non-selective inhibition of COX activity with non-steroidal anti-inflammatory agents that block both the constitutive (COX-1) and inducible (COX-2) isoforms of cyclooxygenase has not yielded promising results in trauma patients . Nonetheless, it remains unknown whether selective inhibition of COX-2 activity has any salutary effect following trauma-hemorrhage and subsequent induction of sepsis . To study this, male C3H/HeN mice were subjected to laparotomy (i.e., soft-tissue trauma) and hemorrhagic shock (35 +/- 5 mmHg for 90 min, then resuscitated) or to sham operation . Twenty-four hours later, the mice were subjected to sepsis by cecal ligation and puncture (CLP) or to sham CLP . The mice were treated with the COX-2 inhibitor NS-398 (10 mg/kg body weight, intraperitoneally) or vehicle immediately after trauma-hemorrhage or sham operation, 12 h thereafter, and following CLP or sham CLP . At 5 h after CLP, plasma PGE2, Interleukin-(IL) 6, and TNF-alpha levels were determined along with Kupffer cell IL-6 and TNF-alpha production in vitro . NS-398 treatment markedly suppressed the elevation in plasma PGE2 levels following CLP . The increase in plasma IL-6 levels after CLP were also significantly attenuated by NS-398 treatment . In vitro Kupffer cell IL-6 production after CLP was significantly reduced by in vivo NS-398 treatment . However, NS-398 had no effect on TNF-alpha levels, in vivo and in vitro . These findings indicate that activation of COX-2 following trauma-hemorrhage and subsequent sepsis up-regulates Kupffer cell IL-6 production . Thus, selective inhibition of COX-2 activity may reduce the deleterious consequences of sepsis under such conditions.

Shock, 2001 Dec, 16(6), 425 - 9
Role of IFN-gamma in bacterial containment in a model of intra-abdominal sepsis; Qiu G et al.; Interferon-gamma (IFN-gamma) is a specific activator of macrophage function and plays a critical role in the host immune defense to bacterial infection . In this study we examined the role of IFN-gamma in the regulation of bacterial load in the cecal ligation and puncture (CLP) model of intra-abdominal sepsis in the rat . In initial studies, levels of IL-12, MCP-1, and IFN-gamma were measured in the peritoneal lavage fluid 24 and 48 h after CLP . IL-12 and MCP-1 levels were both significantly increased at 24 h after CLP compared to sham controls and this difference was maintained at 48 h after CLP . Interestingly, IFN-gamma levels were not significantly increased 24 h after CLP, but were increased at 48 h after CLP . These results clearly suggest that although an inflammatory response had occurred 24 h post-surgery, with increases in the proinflammatory cytokine IL-12 and the potent chemotactic agent MCP-1, levels of IFN-gamma in CLP rats were similar to sham controls . To further investigate the role of IFN-gamma on the development of sepsis we examined the effect(s) of administering anti-IFN-gamma antibody on bacterial load after CLP . We show that use of anti-IFN-gamma antibody can significantly decrease bacterial load in the peritoneum . The mechanism of the effect(s) of anti-IFN-gamma is probably by increasing intestinal adhesions to seal the cecum and reduce bacterial movement into the peritoneum.

Zhonghua Wai Ke Za Zhi, 2001 Sep, 39(9), 721 - 3
{Effect of sepsis on the expression of ubiquitin and ubiquitinated protein in rat skeletal muscle}; Chai J et al.; OBJECTIVE: To study the regularity of ubiquitin and ubiquitinated protein expression in rat skeletal muscle during sepsis, and the molecular mechanism of enhancement in skeletal muscle protein catabolism . METHODS: Wistar rats with sepsis were administered endotoxin peritoneally . The rats were randomly divided into 4 groups rats: 2, 6, 12 and 24 h after administration of endotoxin; each group (16) included normal controls . In vitro muscle incubation system with sufficient oxygen supply was used with amino acid automatic analyzer for detecting the proteolytic rate of the extensor digitorium longus(EDL) and soleus(SOL) muscle in the sample . The expression of ubiquitin and ubiquitinated protein in rat EDL muscle was determined by western blot . RESULTS: Total proteolytic rate in the EDL muscle increased slightly at 2 and 6 h after administering endotoxin into the peritoneal cavity, and no significant difference at 12 and 24 h was observed . There was a progressive increase of 155% and 220% in myofibrillar proteolytic rate at 2 and 6 h, and 40% at 12 h, respectively, as compared with that of the normal controls . The expression of ubiquitin and ubiquitinated protein in the EDL muscle rose by 46% and 2.4 fold at 2 h and 6 h after administering endotoxin, while the ubiquitinated protein of high molecular weight was determined . No significant changes were noted in the expression of ubiquitin and ubiquitinated protein at 12 and 24 h . CONCLUSION: The results indicate that activation of ubiquitin-proteasome pathway occurs in rat skeletal muscle during sepsis, and high expression of ubiquitin and ubiquitinated protein means that the substrate flowing into ubiquitin-proteasome pathway increases markedly, and then leads to muscle wasting.

Eur J Surg, 2001 Sep, 167(9), 675 - 8
Emergency oesophagectomy and proximal deviating oesophagostomy for fulminent mediastinal sepsis; Lundell L et al.; OBJECTIVE: To evaluate an aggressive surgical strategy in patients with mediastinal sepsis as a result of oesophageal leakage . DESIGN: A prospective clinical study . SETTING: University hospital, Sweden . SUBJECTS: 11 consecutive patients who presented with mediastinal sepsis as a result of a damaged oesophagus caused by instrumental perforation in 4 cases and spontaneous rupture in 6 cases during a 6-year period . INTERVENTIONS: Ten patients were treated with oesophagectomy with a diverting proximal oesophagostomy and in one case a primary cervical oesophagogastrostomy was done after emergency resection . MAIN OUTCOME MEASURES: Mortality and morbidity . RESULTS: The median delay from onset of symptoms to admission to the unit was 3 days (range 0-6) . All patients required artificial ventilation postoperatively and the stay in the ICU amounted to 12.5 days but only 1 patient died during the postoperative course . All patients have subsequently undergone substernal oesophageal replacement with either a gastric tube or a colonic graft . CONCLUSION: Emergency oesophagectomy and proximal deviating oesophagostomy is a salvage procedure for patients with severe fulminant mediastinal sepsis, and it can be done in selected cases with good results.

Zhonghua Wai Ke Za Zhi, 2001 Aug, 39(8), 638 - 42
{Changes in plasma free amino acid concentrations in rats during sepsis}; Wu Y et al.; OBJECTIVE: To explore the relationship between plasma free amino acid concentrations and skeletal muscle proteolysis in rats during sepsis . METHODS: An animal model of sepsis in rats was established by administering endotoxin into the peritoneal cavity . The plasma concentrations of free amino acid, ALT, AST, cortisol, TNF-alpha and IL-6 were determined . The rats were randomly divided into normal control, 2, 6, 12 and 24 h groups after administration of endotoxin(8 rats for each group) . RESULTS: The total plasma free amino acids concentrations fluctuate within normal range within 24 h after administration of endotoxin . A marked decrease in BCAA (branch-chainamino acid) was observed at 2, 6 and 12 h after administration of endotoxin, but aromatic amino acids (AAA) increased in varying degrees . BCAA/AAA was lower at 2 h and 6 h as compared with that of the normal control, while Phe/Tyr increased obviously at every time point . Lys, Sar, Cys and P-Ser showed no significant changes within 24 h after the administration of endotoxin . Thr, Glu, Orn, His, 3-MH and Ala increased during sepsis, and other amino acids more or less decreased . Plasma concentrations of ALT, AST, cortisol, TNF-alpha and IL-6 obviously increased within 24 h after the administration of endotoxin(P < 0.01) . Cortisol peaked at 6 h and IL-6 peaked at 12 h, while TNF-alpha at 2 h . CONCLUSION: The results suggested that metabolic disorder of plasma free amino acids during sepsis is due to enhancement of skeletal muscle proteolysis and liver overloading.

J Neurol, 2001 Nov, 248(11), 929 - 34
Neurological complications of sepsis: critical illness polyneuropathy and myopathy; Hund E; Sepsis may cause not only failure of parenchymal organs but can also cause damage to peripheral nerves and skeletal muscles . It is now recognized that sepsis-mediated disorders of the peripheral nerves and the muscle, called critical illness polyneuropathy (CIP) and critical illness myopathy, are responsible for weakness and muscle atrophy occurring de novo in intensively treated patients . CIP represents an acute axonal neuropathy that develops during treatment of severely ill patients and remits spontaneously, once the critical condition is under control . The course is monophasic and self-limiting . Among the critical illness myopathies, three main types have been identified: a non-necrotizing "cachectic" myopathy (critical illness myopathy in the strict sense), a myopathy with selective loss of myosin filaments ("thick filament myopathy") and an acute necrotizing myopathy of intensive care . Clinical manifestations of both critical illness myopathies and CIP include delayed weaning from the respirator, muscle weakness, and prolonging of the mobilization phase . The pathogenesis of these neuromuscular complications of sepsis is not understood in detail but most authors assume that the inflammatory factors that mediate systemic inflammatory response and multiple organ failure are closely involved . In thick filament myopathy and acute necrotizing myopathy, administration of steroids and neuromuscular blocking agents may act as triggers . Specific therapies have not been discovered . Stabilization of the underlying critical condition and elimination of sepsis appear to be of major importance . Steroids and muscle relaxants should be avoided or administered at the lowest dose possible.

Peptides, 2001 Nov, 22(11), 1835 - 40
Andrenomedullin and cardiovascular responses in sepsis; Wang P; The typical cardiovascular response to polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase . Although the factors and/or mediators responsible for producing the transition from the hyperdynamic to the hypodynamic stage are not fully understood, recent studies have suggested that adrenomedullin (AM), a potent vasodilatory peptide, appears to play an important role in initiating the hyperdynamic response following the onset of sepsis . In addition, the reduced vascular responsiveness to AM may result in the transition from the early, hyperdynamic phase to the late, hypodynamic phase of sepsis . It is possible that changes in newly reported AM receptors calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein-2 or -3 (RAMP2, RAMP3) as well as AM binding protein-1 (AMBP-1) may also play distinct roles in the biphasic cardiovascular response observed during sepsis . Although it remains unknown whether AM gene delivery or a chronic increase in vascular AM production in transgenic animals attenuates the development of hypodynamic sepsis and septic shock, it has been shown that modulation of AM vascular responsiveness with pharmacologic agents reduces sepsis-induced mortality . It has been recently demonstrated that AMBP-1 enhances AM's physiologic effects and plasma levels of AMBP-1 decrease following infections . We therefore propose that downregulation of AMBP-1 and the reduced AM receptor responsiveness are crucial factors responsible for the transition from the hyperdynamic phase to the hypodynamic phase of sepsis.

Am J Surg, 2001 Nov, 182(5), 491 - 7
Severe sepsis induces deficient interferon-gamma and interleukin-12 production, but interleukin-12 therapy improves survival in peritonitis; Ono S et al.; BACKGROUND: After severe sepsis, there is an increase of Th2 cytokine and a decrease in Th1 cytokine that may account for impaired cellular immunity . The aim of this study is to evaluate the Th1, Th2 cytokine balance in the serum, peritoneal lavage fluid (PLF) and liver mononuclear cells (MNC) of experimental peritonitis mice, and determine the effect of interleukin-12 (IL-12), a cytokine stimulating Th1 cytokine production, when administered to septic mice . METHODS: Experimental bacterial peritonitis mice was induced by cecal ligation and puncture (21-gauge needle, mild peritonitis) or cut (5 mm, severe peritonitis) . Serum and PLF levels and liver MNC production of interferon (IFN)-gamma, IL-10, and IL-12 were measured after the procedure . Mild and severe peritonitis mice were treated intraperitoneally with recombinant IL-12 (r-IL-12) either 6 hours before or 6 and 24 hours after the procedure . The survival rates were then compared with nontreated mice . RESULTS: Serum and PLF IFN-gamma, IL-12 levels in severe peritonitis mice were significantly lower than those in mild peritonitis mice at 6 and 12 hours after the procedure . On the other hand, serum and PLF IL-10 levels in severe peritonitis mice were significantly higher than those in mild peritonitis mice at 6 hours after the procedure . Furthermore, liver MNC IFN-gamma production in severe peritonitis mice was significantly higher than that in mild peritonitis mice at 6 hours after the procedure, but liver MNC IL-12 production in severe peritonitis mice was significantly lower than that in mild peritonitis mice at 12 hours after the procedure . Severe peritonitis mice treated with r-IL-12 at 6 hours before the procedure improved survival rate, and mild peritonitis mice treated with r-IL-12 at 24 hours after the procedure showed significantly improved survival rates . CONCLUSIONS: Change in the Th1, Th2 cytokine balance in peritonitis mice might induce a shift toward a Th2 dominant phenotype according to the severity of peritonitis, and the capacity to produce IFN-gamma and IL-12 by liver MNC is reduced . Therapies designed to augment the production of Th1 cytokines, such as IL-12, may thus prove to be beneficial in the treatment of severe sepsis after peritonitis.

Ann Surg, 2002 Jan, 235(1), 105 - 12
Female sex hormones regulate macrophage function after trauma-hemorrhage and prevent increased death rate from subsequent sepsis; Knoferl MW et al.; OBJECTIVE: To determine whether reduction of circulating female sex hormones by ovariectomy causes suppression of macrophage (Mphi) function after trauma-hemorrhage and increases susceptibility to subsequent sepsis . SUMMARY BACKGROUND DATA: Studies indicate that immune functions are markedly depressed in males but not in proestrus females after trauma-hemorrhage . Although male sex steroids are immunosuppressive, it remains unknown whether female sex hormones are immunoprotective after trauma-hemorrhage . METHODS: Circulating female sex hormones were reduced by ovariectomy of 8-week-old female CBA/J mice . Two weeks afterward, ovariectomy and proestrus sham-ovariectomy mice were subjected to laparotomy (i.e., soft tissue trauma) and hemorrhagic shock (35 +/- 5 mm Hg for 90 minutes, then resuscitated) or sham operation . Two hours afterward, splenic and peritoneal Mphi and Kupffer cells were isolated and cytokine production was assessed . In a second series of experiments, animals were subjected to sepsis by cecal ligation and puncture at 24 hours after trauma-hemorrhage or sham operation, and survival was assessed . RESULTS: Release of interleukin-1 and interleukin-6 by splenic and peritoneal Mphi from proestrus mice was maintained after trauma-hemorrhage, whereas release of interleukin-1 and interleukin-6 by Mphi from ovariectomized mice was depressed by approximately 50% . In contrast, trauma-hemorrhage resulted in a fourfold increase of Kupffer cell release of tumor necrosis factor-alpha in ovariectomized females and a fivefold increase in plasma concentrations of tumor necrosis factor-alpha . Release of tumor necrosis factor-alpha and plasma concentrations were unchanged in proestrus mice under such conditions . When proestrus and ovariectomized animals were subjected to sepsis by cecal ligation and puncture at 24 hours after trauma-hemorrhage or sham operation, ovariectomized mice had a significantly higher death rate than proestrus mice . CONCLUSIONS: These findings suggest that female sex hormones play a critical role in maintaining immune responses after trauma-hemorrhage by suppressing the elaboration of tumor necrosis factor-alpha and prevent the increased lethality from subsequent sepsis . Thus, female sex hormones may be a useful adjunct in preventing trauma-induced immunodepression and increased susceptibility to subsequent sepsis.

J Clin Epidemiol, 2001 Dec, 54(12), 1251 - 7
Early diagnostic markers for neonatal sepsis: comparing C-reactive protein, interleukin-6, soluble tumour necrosis factor receptors and soluble adhesion molecules; Dollner H et al.; We compared six inflammatory mediators (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumour necrosis factor receptors (p55 and p75) and soluble adhesion molecules (ICAM-1, E-selectin)) as early diagnostic tests for neonatal sepsis, and studied the possible benefit of combining parameters . Blood samples were obtained from 166 consecutively admitted neonates, who were suspected to suffer from infection within the first week of life . Neonates were retrospectively classified as infected (sepsis, clinical sepsis or pneumonia), possibly infected, or non-infected . Twenty-four infected neonates had higher serum levels of all six mediators (all P < 0.05), and 18 possibly infected neonates had higher levels of CRP, IL-6, ICAM-1 and E-selectin (all P < 0.05), than neonates without infection (n = 124) . Receiver operator characteristic plots showed that CRP was the single best diagnostic test . Multiple logistic regression modelling, including various combinations of two to six mediators, consistently showed that IL-6, in addition to CRP, predicted sepsis . With infected and possibly infected neonates as the reference standard, a combined test of CRP > or = 10 mg/l and/or IL-6 > or = 20 pg/ml had a sensitivity of 85%, specificity of 62%, and negative likelihood ratio of 0.24 . Using infected neonates as reference standard alone, and including possibly infected as controls, sensitivity increased to 96%, whereas specificity decreased to 58%; a negative test result (CRP < 10 mg/l and IL-6 < 20 pg/ml) ruled out sepsis with high certainty (likelihood ratio = 0.07) . CRP performed best as a diagnostic test for neonatal sepsis . Diagnostic accuracy was further improved by combining CRP and IL-6, whereas the other parameters (p55, p75, ICAM-1 and E-selectin) added no further diagnostic information.

Am J Physiol Heart Circ Physiol, 2002 Jan, 282(1), H156 - 64
Effect of a maldistribution of microvascular blood flow on capillary O(2) extraction in sepsis; Ellis CG et al.; Inherent in the remote organ injury caused by sepsis is a profound maldistribution of microvascular blood flow . Using a 24-h rat cecal ligation and perforation model of sepsis, we studied O(2) transport in individual capillaries of the extensor digitorum longus (EDL) skeletal muscle . We hypothesized that erythrocyte O(2) saturation (SO(2)) levels within normally flowing capillaries would provide evidence of either a mitochondrial failure (increased SO(2)) or an O(2) transport derangement (decreased SO(2)) . Using a spectrophotometric functional imaging system, we found that sepsis caused 1) an increase in stopped flow capillaries (from 10 to 38%, P < 0.05), 2) an increase in the proportion of fast-flow to normal-flow capillaries (P < 0.05), and 3) a decrease in capillary venular-end SO(2) levels from 58.4 +/- 20.0 to 38.5 +/- 21.2%, whereas capillary arteriolar-end SO(2) levels remained unchanged compared with the sham group . Capillary O(2) extraction increased threefold (P < 0.05) and was directly related to the degree of stopped flow in the EDL . Thus impaired O(2) transport in early stage sepsis is likely the result of a microcirculatory dysfunction.

Semin Thromb Hemost, 2001 Dec, 27(6), 577 - 83
Disseminated intravascular coagulation in sepsis; Hardaway RM et al.; Disseminated intravascular coagulation (DIC) has been considered a rather rare syndrome characterized by severe bleeding . In fact, both of these beliefs are wrong . Bleeding is fairly rare in DIC . The clotting parameters are usually normal unless the DIC is fulminating . It is usually thought that fibrinogen may be low or absent in DIC . However, afibrinogenemia is rare . Fibrinogen is usually high in DIC because of the high rate of fibrinogen manufacture by the liver in response to stress . DIC is very common and most cases are never diagnosed . This is because it has been hard to find fibrin thrombi in autopsy cases and because acute severe bleeding is uncommon . The reason fibrin thrombi are rare may be because they have been lysed by endogenous fibrinolytic enzymes before the autopsy . The appearance of endogenous fibrinolytic response could be a defense mechanism to lyse the microclots of DIC . In fact, this response is often successful . This defense can be aided by the administration of plasminogen activators that will lyse the clots . Heparin has been used for the treatment of DIC but has proved useless and is, in fact, dangerous . This is because heparin will not dissolve clots and may actually promote platelet agglutination . Administration of plasminogen activators will actually prevent bleeding diathesis.

J Trauma, 2001 Dec, 51(6), 1104 - 9
Enhanced expression of heat shock proteins in activated polymorphonuclear leukocytes in patients with sepsis; Hashiguchi N et al.; BACKGROUND: Heat shock proteins (HSPs) in cells, as molecular chaperons, have been reported to regulate cell functions . The objective of this study was to investigate the HSP expression in polymorphonuclear leukocytes (PMNLs) from severe septic patients and the relation between the expression of HSPs and PMNL function . METHODS: In blood samples from 21 patients with sepsis and serum C-reactive protein levels more than 10 mg/dL, we used flow cytometry to measure expressions of HSP27, HSP60, HSP70, and HSP90; oxidative activity; and levels of apoptosis in PMNLs during sepsis . In in vitro studies, we used cells from 14 healthy volunteers to examine the relation between the expression of HSP70 and PMNL function . Quercetin (30 microM), a suppressor of HSP, and sodium arsenite (100 microM), an inducer of HSP, were used to regulate the expression of HSP70 in PMNLs, and oxidative activity and apoptosis in these cells were measured . RESULTS: In patients with sepsis, the expressions of HSP27, HSP60, HSP70, and HSP90 and oxidative activity in PMNLs were significantly increased . Apoptosis of these PMNLs was markedly inhibited . In the in vitro studies, administration of sodium arsenite enhanced the expression of HSP70, significantly increased oxidative activity, and inhibited apoptosis . Administration of quercetin before sodium arsenite prevented the expression of HSP70, the increase in oxidative activity, and the inhibition of apoptosis . CONCLUSION: Sepsis causes the enhanced expression of HSPs in activated PMNLs . In PMNLs with enhanced expression of HSP70, oxidative activity is increased and apoptosis is inhibited . The enhanced expression of HSPs may play a role in regulating PMNL function in patients with sepsis.

Blood, 2001 Dec 15, 98(13), 3800 - 8
High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes; Zweigner J et al.; Lipopolysaccharide-binding protein (LBP), an acute-phase protein recognizing lipopolysaccharide (LPS), catalyzes in low concentrations its transfer to the cellular LPS receptor consisting of CD14 and Toll-like receptor-4 . It has recently been shown that high concentrations of recombinant LBP can protect mice in a peritonitis model from the lethal effects of LPS . To determine whether in humans the acute-phase rise of LBP concentrations can inhibit LPS binding to monocytes and induction of proinflammatory cytokines, LBP concentrations were analyzed in 63 patients meeting the American College of Chest Physicians/Society of Critical Care Medicine criteria of severe sepsis or septic shock and the ability of these sera to modulate LPS effects in vitro was assessed employing different assays . Transfer of fluorescein isothiocyanate-labeled LPS to human monocytes was assessed by a fluorescence-activated cell sorter-based method, and activation of monocytes was investigated by measuring LPS-induced tumor necrosis factor-alpha secretion in the presence of the sera . Anti-LBP antibodies and recombinant human LBP were instrumental for depletion and reconstitution of acute-phase sera and subsequent assessment of their modulating effects on LPS activity . Sera of patients with severe sepsis/septic shock exhibited a diminished LPS transfer activity and LPS-induced tumor necrosis factor-alpha secretion as compared with sera from healthy controls . LBP depletion of sepsis sera and addition of rhLBP resulting in concentrations found in severe sepsis confirmed that LBP was the major serum component responsible for the observed effects . In summary, the inhibition of LPS effects by high concentrations of LBP in acute-phase serum, as described here, may represent a novel defense mechanism of the host in severe sepsis and during bacterial infections.

Eur J Clin Invest, 2001 Nov, 31(11), 978 - 83
Postnatal increase of procalcitonin in premature newborns is enhanced by chorioamnionitis and neonatal sepsis; Janota J et al.; BACKGROUND: To determine the influence of chorioamnionitis and neonatal sepsis on procalcitonin (PCT) levels in very-low-birth-weight (VLBW) infants within the first week of life . DESIGN: PCT serum levels were measured in cord blood 1 h after delivery and on day 3 and day 7 of life . Chorioamnionitis and neonatal sepsis within the first week were monitored . RESULTS: Chorioamnionitis was present in eight of 37 patients (21.6%) . PCT on day 3 was increased in both the "No chorioamnionitis" (2.54 ng mL(-1), SEM 0.51) and "Chorioamnionitis" (6.96 ng mL(-1), SEM 2.93) groups of VLBW infants compared with the 1st hour values (0.45 and 0.58 ng mL(-1) SEM 0.07 and 0.11, respectively, P < 0.001) of the same patients . The postnatal gain was higher in the "Chorioamnionitis" group (P < 0.01) . Neonatal sepsis was diagnosed (after exclusion) in 12 of 32 patients (37.5%) . Mean values of maximum PCT in patients with and without sepsis were 8.41 ng mL(-1) (SEM 1.87) and 3.02 ng mL(-1) (SEM 1.38), respectively (P < 0.05) . Sensitivity to sepsis of PCT, ratio of immature to total neutrophils (I : T), and C-reactive protein (CRP) were 75%, 50% and 25%, respectively . CONCLUSIONS: In the group of VLBW infants the PCT level within 72 h of delivery was markedly increased in patients with chorioamnionitis . Compared with I : T and CRP, PCT appears to be a more sensitive marker of neonatal sepsis.

Br J Surg, 2001 Dec, 88(12), 1583 - 9
Role of the neutrophil in the development of systemic inflammatory response syndrome and sepsis following abdominal aortic surgery; Spark JI et al.; INTRODUCTION: There is evidence to suggest that the polymorphonuclear neutrophil (PMN) plays a critical early step in the development of the ischaemia-reperfusion syndrome, the systemic inflammatory response syndrome (SIRS) and sepsis . The PMN receptor CD16 plays an important role in phagocytosis, cell-mediated cytotoxicity and the release of free radicals and proteolytic enzymes . The aim of this study was to determine whether there is any relationship between PMN CD16 expression, phagocytosis and the development of sepsis . METHODS: Fifty patients who underwent elective infrarenal abdominal aortic aneurysm repair were studied . Venous blood was taken before operation, throughout surgery and for 7 days after operation . CD16 expression was measured, unstimulated and following further stimulation, by means of flow cytometry . Phagocytosis was determined using flow cytometry . RESULTS: Some 36 patients had an uncomplicated recovery; 14 developed SIRS or sepsis . There was no difference between the two groups with respect to nutritional, co-morbid or technical factors . In the group that developed septic complications after operation, the level of PMN CD16 expression was significantly higher before surgery (mean channel fluorescence (MCF) 30.2 versus 10.4; P < 0.05, Mann-Whitney U test) and throughout the postoperative period . Surgery produced no change in CD16 expression . After operation, stimulation of PMNs in the septic group resulted in a fall in CD16 expression (40.8 versus 20.4 MCF; P < 0.05, Mann-Whitney U test); surgery produced no change in the level of expression in the uncomplicated group . CONCLUSION: This study provides evidence of phenotypic and functional differences in neutrophil behaviour in patients who develop sepsis following aneurysm surgery.

J Surg Res, 2001 Dec, 101(2), 202 - 9
Heat shock pretreatment influences the expression of PKC isoforms during sepsis; Chen HW et al.; Protein Kinase C (PKC) plays a central role in signal transduction and participates in diverse biological and biochemical functions . PKC dysfunction leads to general immunosuppression that, in turn, increases host susceptibility to infection and sepsis . In our previous study, we demonstrated that the mortality of sepsis is significantly decreased in rats treated with heat shock . It was considered that the modulation of PKC content by previous heat shock might contribute to the resistance to a severe infection . In this study, we attempted to understand the change of various PKC isoforms in the lymphocytes during sepsis and to investigate the role of previous heat shock in influencing PKC expression . Cecal ligation and puncture (CLP) was used as the experimental sepsis model for its biphasic clinical manifestation . Heat shock protein and PKC isoforms were detected by immunochemical study . Ten PKC isoforms (alpha, beta, gamma, delta, epsilon, zeta, theta, iota, lambda, and mu) were detected from peripheral lymphocytes . Results showed that all the PKC isoforms have a declination tendency along with the progression of CLP-induced sepsis, and previous heat shock treatment could prevent the declination of PKC content, particularly the isoforms beta, gamma, and epsilon, during sepsis . We suggest that heat shock response may participate in maintenance of PKC expression and contribute to decrease the severity of systemic infection.

Am J Respir Crit Care Med, 2001 Nov 15, 164(10 Pt 1), 1988 - 96
Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons; Welty-Wolf KE et al.; Sepsis-induced tissue factor (TF) expression activates coagulation in the lung and leads to a procoagulant environment, which results in fibrin deposition and potentiates inflammation . We hypothesized that preventing initiation of coagulation at TF-Factor VIIa (FVIIa) complex would block fibrin deposition and control inflammation in sepsis, thereby limiting acute lung injury (ALI) and other organ damage in baboons . A model of ALI was used in which adult baboons were primed with killed Escherichia coli (1 x 10(9) CFU/kg), and bacteremic sepsis was induced 12 h later by infusion of live E . coli at 1 x 10(10) CFU/kg . Animals in the treatment group were given a competitive inhibitor of TF, site-inactivated FVIIa (FVIIai), intravenously at the time of the infusion of live bacteria and monitored physiologically for another 36 h . FVIIai dramatically protected gas exchange and lung compliance, prevented lung edema and pulmonary hypertension, and preserved renal function relative to vehicle (all p < 0.05) . Treatment attenuated sepsis-induced fibrinogen depletion (p < 0.01) and decreased systemic proinflammatory cytokine responses, for example, interleukin 6 (p < 0.01) . The protective effects of TF blockade in sepsis-induced ALI were confirmed by using tissue factor pathway inhibitor . The results show that TF-FVIIa complex contributes to organ injury in septic primates in part through selective stimulation of proinflammatory cytokine release and fibrin deposition.

Eur J Radiol, 2001 Dec, 40(3), 244 - 7
Sepsis from dropped clips at laparoscopic cholecystectomy; Hussain S; We report seven patients in whom five dropped surgical clips and two gallstones were visualized in the peritoneal cavity, on radiological studies . In two, subphrenic abscesses and empyemas developed as a result of dropped clips into the peritoneal cavity during or following laparoscopic cholecystectomy . In one of these two, a clip was removed surgically from the site of an abscess . In two other patients dropped gallstones, and in three, dropped clips led to no complications . These were seen incidentally on studies done for other indications . Abdominal abscess secondary to dropped gallstones is a well-recognized complication of laparoscopic cholecystectomy (LC) . We conclude that even though dropped surgical clips usually do not cause problems, they should be considered as a risk additional to other well-known causes of post-LC abdominal sepsis.

Vet Clin North Am Small Anim Pract, 2001 Nov, 31(6), 1147 - 62, v-vi
Systemic inflammatory response syndrome, sepsis, and multiple organ dysfunction; Brady CA et al.; Companion animals with sepsis and multiple organ dysfunction can be the most challenging of all patients to treat . Current research in humans and laboratory models offers some exciting insights into the pathophysiology behind some of our most frustrating clinical challenges . This article applies several current concepts to a clinical case of pancreatitis and secondary sepsis to illustrate some of the cardiovascular, immune, and coagulation abnormalities commonly seen.

J Reprod Med, 2001 Oct, 46(10), 913 - 5
Sepsis after Bartholin's duct abscess marsupialization in a gravida; Miller NR et al.; BACKGROUND: Little information exists regarding sepsis following marsupialization of a Bartholin's duct abscess . We report a gravida who became septic after marsupialization . CASE: A 30-year-old primigravida at 32 weeks' gestation underwent marsupialization of a Bartholin's gland abscess . Postoperatively, she developed fever with maternal and fetal tachycardia . She was admitted to the hospital and started on broad-spectrum antibiotics . Her temperature increased to 39 degrees C, and she became hypotensive . Blood work demonstrated evidence of disseminated intravascular coagulopathy . The patient was stabilized with aggressive fluid resuscitation, antibiotics, transfusion of blood products and oxygen therapy . Within 24 hours, the fever and coagulopathy resolved . She was discharged on postoperative day 5 and gave birth without complications at 38 weeks' gestation . CONCLUSION: Pregnant women undergoing marsupialization of a Bartholin's gland abscess should be considered at high risk and managed accordingly.

Br J Pharmacol, 2001 Dec, 134(7), 1367 - 74
Effects of sepsis on mast cells in rat dura mater: influence of L-NAME and VIP; Tore F et al.; 1 . The influence of lipopolysaccharide (LPS)-induced sepsis on the various mast cell phenotypes of rat dura mater were examined both by immunohistochemical and biochemical methods . 2 . Three different populations of mast cells were identified in control rats: connective tissue type mast cells (CTMC) which contain rat mast cell protease1 (RMCP1), histamine, serotonin and heparin, mucosal type mast cells (MMC) which contain RMCP2, histamine and serotonin, and intermediate type which contains both RMCP1 and RMCP2 and probably various proportions of amines and heparin . 3 . LPS (25 mg kg(-1) i.p.) caused changes in the proportions of the various types of mast cells . The number of MMC and intermediate type mast cells significantly increased and the number of mast cells immunopositive for both heparin and serotonin significantly decreased . Biochemical analysis showed that the histamine concentration of dura increased while its serotonin concentration decreased . 4 . While vasoactive intestinal peptide (VIP) (25 ng kg(-1) i.p.) appears to potentiate LPS effects on dura mater mast cells, non-selective inhibition of nitric oxide (NO) synthase by N(g)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(-1) i.p.) did not influence sepsis-induced mast cell changes . 5 . These findings suggest that mast cells of dura mater may play a role in brain protection during sepsis.

Curr Infect Dis Rep, 2001 Dec, 3(6), 496 - 506
The Role of Intravascular Devices in Sepsis; Crnich CJ et al.; Intravascular devices (IVDs) are widely used in modern day health care . Unfortunately, their use is associated with substantial risk of bloodstream infection (BSI) and sepsis, with increased hospitalization and hospital mortality . IVDs are the most common cause of nosocomial BSI . The wider use of new methodologies for diagnosis of IVD-related infection should allow earlier and more focused therapy and, especially, improve the accuracy of surveillance . Of all nosocomial infections, IVD-related BSIs are most amendable to prevention.

Am J Obstet Gynecol, 2001 Nov, 185(5), 1081 - 5
Does the combined antenatal use of corticosteroids and antibiotics increase late-onset neonatal sepsis in the very low birth weight infant?
How HY, Sutler D, Khoury JC, Donovan EF, Siddiqi TA, Spinnato JA.
OBJECTIVE: The purpose of this study was to determine whether the combined use of maternal antenatal corticosteroids and antibiotic therapy is associated with an increased risk of late-onset neonatal sepsis among very low birth weight infants . STUDY DESIGN: The outcomes of infants admitted to the 3 Cincinnati neonatal intensive care units between May 1991 and May 2000 were retrospectively evaluated . Late-onset neonatal sepsis was defined either as the occurrence of a positive blood culture obtained after 72 hours of life with clinical signs of sepsis or as the need for >5 consecutive days of antibiotic therapy for presumed sepsis that initiated after 72 hours of life . Wilcoxon rank sum, chi-square test, and multiple logistic regression were used for analysis . RESULTS: Among the parturients delivering the study infants, 434 women (24%) received corticosteroids only, 175 women (9%) received antibiotics only, 819 women (46%) received both corticosteroids and antibiotics, and 370 women (20%) received neither corticosteroids nor antibiotics . Among 1978 study infants, there were 732 infants (41%) with late-onset neonatal sepsis . By univariate analysis, the odds ratio for late-onset neonatal sepsis caused by combined corticosteroid and antibiotic use was 0.96 (95% CI, 0.89%, 1.04%) . Multiple logistic regression analysis was used to evaluate the risk of combined corticosteroids and antibiotic use after controlling for potential covariates and confounders . After controlling for outborn birth (odds ratio, 1.3; 95% CI, 1.0%-1.8%), increasing gestational age at delivery (odds ratio, 0.63; 95% CI, 0.60%-0.66%), interaction between white race and male gender (P =.01) and interaction between antibiotics and prolonged rupture of membranes (P =.02), the use of corticosteroids and antibiotics was not associated with an increased risk of late-onset neonatal sepsis (P =.9) . CONCLUSION: The combined use of maternal corticosteroids and antibiotic therapy is not associated with an increased risk for late-onset neonatal sepsis.

Zhonghua Yi Xue Za Zhi, 1999 Jul, 79(7), 546 - 8
{Impact of intracellular Na+ concentration alteration on intracellular aerobic glycolysis in skeletal muscles in sepsis}; Chai J et al.; OBJECTIVE: To evaluate the impact of the changes of the intracellular Na+ concentration on the cellular lactate production of different skeletal muscles in septic rats as compared to that of the normal ones . METHODS: Using septic model of rats, we established the in vitro muscle incubation system with sufficient oxygen supply as well as the NADH fluoremetric method for the detection of trace amount of lactate in the samples . By using the specific Na+ ionorphor--monensin, the distribution of transmembrane Na+ was under control and the lactate production of the muscle cells were measured . RESULTS: The intracellular glycolysis was activated by increasing of intracellular Na+ probably because of the mechanism of Na+ pump activation . The sensitivity of muscles to monensin varied according to different muscle fiber composition . The mechanism of the aerobic glycolysis activation in sepsis was identical to the roles of monensin in the cells . CONCLUSION: The increase of the permeability of Na+ in skeletal muscle cells as well as the increment of the intracellular concentration of Na+ can directly lead to the enhancement of muscular aerobic glycolysis and its mechanism plays a significant role in the enhancement of muscular glycolysis in septic states.

Pharmacotherapy, 2001 Nov, 21(11), 1389 - 402
Recombinant human activated protein C, drotrecogin alfa (activated): a novel therapy for severe sepsis; Kanji S et al.; Sepsis remains a major cause of death in hospitalized patients . Despite a massive research effort over the past 2 decades to identify innovative therapies for sepsis, current treatment strategies consist primarily of antiinfective agents and a variety of supportive measures . Activated protein C, an endogenous protein that inhibits thrombosis and inflammation while promoting fibrinolysis, plays an important role in the pathogenesis of sepsis . Recombinant human activated protein C, drotrecogin alfa (activated), when compared with placebo in a randomized, double-blind study of 1690 patients with severe sepsis (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis {PROWESS} trial), decreased the relative risk of death at 28 days by 19.4% (95% confidence interval 6.6-30.5%, p=0.005), although there was a trend for more serious bleeding (3.5% vs 2.0%, p=0.06) with its use . Drotrecogin alfa is the first antisepsis drug found to have a mortality benefit . It should be administered only to patients with severe sepsis who meet the PROWESS study inclusion criteria and should be avoided when risk factors for bleeding are present . Ongoing research will help determine the cost-effectiveness of drotrecogin alfa, as well as its role in critically ill populations not studied in the PROWESS trial.

Curr Opin Nephrol Hypertens, 2001 Nov, 10(6), 755 - 61
Importance of increased ultrafiltration volume and impact on mortality: sepsis and cytokine story and the role of continuous veno-venous haemofiltration; Ronco C et al.; While in end-stage renal disease dialysis dose correlates with morbidity and mortality, this correlation is less evident in acute renal failure . In spite of a poor literature in the field, a few recent papers seem to suggest that an increase in treatment dose may result in an improved outcome of critically ill patients affected by acute renal failure . This improvement appears to plateau at a certain level of dialysis dose in the general population while, in septic patients, the correlation between treatment dose and outcome continues linearly . These results suggest that, while the 'renal dose' of renal replacement therapy has a threshold beyond which further improvements cannot be expected, the 'septic dose' of renal replacement therapy is probably higher and may provide benefits beyond simple blood purification from uremic toxins . This approach is in agreement with the recently proposed 'peak concentration hypothesis', which suggests that sepsis may derive from a complete derangement of the immunological response, featuring simultaneous peaks of pro- and anti-inflammatory mediators . This would explain the systemic inflammatory syndrome and the cell hyporesponsiveness of the septic patient and, at the same time, would explain the beneficial effects of new therapies such as high volume hemofiltration, coupled plasmafiltration adsorption and dialysis with hyperpermeable membranes . These therapies could be able to reduce the peaks of the pro- and anti-inflammatory substances circulating during the syndrome, leading to a less severe degree of inflammation and immunodepression.

Ulus Travma Derg, 2001 Oct, 7(4), 219 - 23
{The effect of pentaglobin therapy on prognosis in patients with severe sepsis}; Tugrul S et al.; This study was designed to assess the effects of polyclonal immunoglobulin administration on septic shock incidence and prognosis in patients with severe sepsis . Patients with severe sepsis were randomly allocated into two groups . One group (n = 21) received 5 ml/kg/day IgM enriched immunoglobulin preparation (Pentaglobin) for 3 days . Other group did not receive immunoglobulins (n = 18) . Simplified Organ Failure Assessment (SOFA) scores, leucocyte count, duration of mechanical ventilation, ICU stay, duration of severe sepsis did not show significant differences between the groups, as regards to septic shock incidence and mortality . However, a significant decrease in procalcitonin levels were detected only in patients who received pentaglobin (p = 0.001) . Mortality rate was 5/21 (23.8%) in pentaglobin group and 5/18 (27.7%) in the control group . Although pentaglobin therapy could not achieve a statistically significant improvement in septic shock occurrence and mortality, the constant reduction in procalcitonin levels indicated the beneficial effects of immunotherapy on the severity of inflammatory response to infection in severe sepsisPublication Types:

	Clinical Trial
	Randomized Controlled Trial

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