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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disturbances in normal glucose metabolism and homeostasis which manifest as hyperglycemia and glucose intolerance are often observed during clinical sepsis. Skeletal and myocardial muscle as well as whole body insulin resistance have been demonstrated in this laboratory and others during experimental and clinical sepsis. The existence of hepatic insulin resistance in sepsis has yet to be fully elucidated. This study was undertaken to assess hepatic insulin resistance during chronic hyperdynamic sepsis. Animals were randomly assigned to a septic (n = 7), sham (n = 7), or control (n = 7) group. Sepsis was induced in anesthetized dogs via a midline laparotomy whereby a fecal-soaked gauze sponge was placed amid the intestines. Sham animals underwent a laparotomy with mechanical manipulation of the intestines but no fecal implant. Control animals had no previous surgery. Sham and control dogs were pair-fed with the septic dogs. On postoperative day 7, after an overnight fast, animals were anesthetized, intubated, and ventilated. Via a left subcostal laparotomy, electromagnetic flow probes were placed to measure hepatic arterial and portal venous blood flows. Cannulae were placed in femoral, portal, and hepatic veins and femoral artery and used to calculate hepatic outputs of glucose, lactate, and oxygen during a basal period and hyperinsulinemic-euglycemic clamps which used intravenous insulin infusions which ranged from 0.4 to 4,000 mU/min. Mean arterial blood pressure decreased with increasing insulin concentrations in septic animals while no change was seen in control or sham animals. In control and sham animals, net hepatic glucose output (NHGO) decreased in response to increasing insulin levels. Septic animals showed no such inverse relationship and, moreover, showed no change in glucose output response to any insulin infusion, i.e., hepatic insulin unresponsiveness during sepsis. Net hepatic lactate output during basal pre-insulin period during sepsis was negative. This was in contrast to the positive outputs in control and sham animals. Glucose infusion rates (GIR) increased during insulin infusion but were not different between groups at any insulin infusion rate. These data demonstrated a hepatic insulin resistance (unresponsiveness) during chronic hyperdynamic, hypermetabolic sepsis.
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PMID:Hepatic insulin resistance during chronic hyperdynamic sepsis. 142 10

The ideal energy substrate for critically ill patients receiving total parenteral nutrition (TPN) remains controversial. While glucose has been proved to have nitrogen sparing properties in postoperative patients, critically ill patients tolerate glucose loads poorly and fat appears to be an obligatory fuel in sepsis. Furthermore, it is not yet certain whether the changes in whole body protein metabolism induced by critical illness are influenced by the nature of the TPN provided. This study was conducted on patients admitted to a surgical intensive care unit (SICU) who fulfilled the criteria of requiring TPN and mechanical ventilation for at least four days. Patients were randomized to receive either glucose (G) or equicaloric proportions of glucose and lipid (GF) as an intravenous energy source. TPN was commenced early, within 24-48 hr of trauma or surgery and admission to the ICU. Nonprotein calorie intake was 125% of calculated basal energy expenditure. Nitrogen balance was calculated from 24-hr urinary urea excretion. Protein synthesis, turnover, and catabolism were measured on Day 4 of the study using an established radiolabeled C14-leucine technique. Degree of sepsis and illness were calculated using published scores. Fifty patients entered the trial but 32 were excluded by Day 4. Of the 18 patients completing an initial four day study, eight went on to complete a second study on the alternative regimen--a total of 26 studies (14 G, 12 GF). Net protein synthesis was achieved in 18 studies (12 G, 6 FG) and positive nitrogen balance by Day 4 in 22 studies. Four patients on the G regimen were withdrawn due to glucose intolerance while none of the patients on GF developed glucose intolerance or hyperlipidaemia. Both whole body protein synthesis and catabolism correlated significantly with degree of sepsis. The type of TPN fuel used, G and GF, did not appear to influence whole body protein dynamics, both regimens achieving greatly improved whole body protein kinetics.
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PMID:The effect of fuel source on amino acid metabolism in critically ill patients. 174 Sep 40

Thirty dogs underwent hemorrhage over a 60-min period to a predetermined O2 debt of 60-120 mL O2/kg, monitored with a Beckman metabolic cart, and then were resuscitated with 120% of the shed volume. Twenty survived and were followed over the next 7 days. On day 4, hepatic insufficiency was suggested by an elevation in [total amino acids] and [lactate] and a decrease in [urea] and [branched-chain amino acids]/[aromatic amino acids]. Net whole body catabolism on day 4 is suggested by a decrease in [glutamine] and an increase in plasma [3-methylhistidine], [phenylalanine], and [tyrosine]. These changes were significantly related to cardiac index, mean blood pressure, [lactate], O2 debt, and shed volume during the hemorrhage 4 days earlier. On day 7 there was a significant increase in the cardiac index and the VO2. These data suggest that hemorrhage induces sequelae similar to major injury or sepsis: hepatic insufficiency, net catabolism, hypermetabolism, and a hyperdynamic circulation. The hyperdynamic circulation may be necessary to meet increased tissue delivery requirements for O2 and amino acids.
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PMID:Hepatic insufficiency and increased proteolysis, cardiac output, and oxygen consumption following hemorrhage. 177 49

Septic surgical patients often require fluid administration to maintain cardiovascular stability due, in part, to the sepsis-induced increase in vascular permeability and associated plasma volume depletion. Plasma fibronectin deficiency exists in such septic patients. We determined if maintenance of fibronectin levels by administration of fibronectin-rich human plasma cryoprecipitate would lower the resuscitative fluid volume needed for support of arterial pressure in septic postoperative sheep which were experimentally depleted of plasma fibronectin. Following a 2-hr postoperative baseline period, denatured collagen (gelatin, 8.7 mg/kg), which has a high affinity for fibronectin, was infused into both control and experimental sheep in order to acutely deplete plasma fibronectin. Sheep were then challenged both intraperitoneally and intravenously with live Pseudomonas (5 x 10(10) bacteria IP; 5 x 10(9) bacteria IV). Experimentals were given fresh plasma cryoprecipitate intravenously at a dose of 4 units bolus, followed by 3 units/hr for 5 hr. Controls received plasma cryoprecipitate selectively depleted of fibronectin by affinity chromatography. Bacterial challenge rapidly resulted in severe systemic hypotension. Ringer's lactate was infused intravenously into both groups at a rate sufficient to maintain a systemic arterial pressure of approximately 50 mm Hg with a maximum pulmonary artery wedge pressure of 15-18 mm Hg. Its rate of infusion was periodically adjusted to maintain this hemodynamic status. Comparison was made of the volume of Ringer's lactate required to maintain an arterial pressure of 50 mm Hg in both groups. Net fluid requirement was significantly (p less than 0.05) less in postoperative septic sheep (47.4 +/- 6.2 mg/kg/hr) treated with fibronectin-rich cryoprecipitate compared to the fluid requirement (71.7 +/- 4.7 mg/kg/hr) for postoperative septic sheep receiving fibronectin-deficient cryoprecipitate. Thus elevation of plasma fibronectin concentration lowers the fluid requirements needed for hemodynamic support in postoperative Gram-negative sepsis.
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PMID:Effect of fibronectin-rich human cryoprecipitate on fluid volume requirements in sheep during postoperative sepsis. 313 Apr 90

Chronic sepsis is always associated with profound wasting leading to increased release of amino acids from skeletal muscle. Net protein catabolism may be due to decreased rate of synthesis, increased rate of degradation, or both. To determine whether protein synthesis is altered in chronic sepsis, the rate of protein synthesis in vivo was estimated by measuring the incorporation of [3H]-phenylalanine in skeletal muscle protein in a chronic (5-day) septic rat model induced by creation of a stable intra-abdominal abscess using an E. coli + B. fragilis-infected sterile fecal-agar pellet as foreign body nidus. Septic rats failed to gain weight at rates similar to control animals, therefore control animals were weight matched to the septic animals. The skeletal muscle protein content in septic animals was significantly reduced relative to control animals (0.18 +/- 0.01 vs. 0.21 +/- 0.01 mg protein/gm wet wt; p less than 0.02). The rate of incorporation of [3H]-phenylalanine into skeletal muscle protein from control animals was 39 +/- 4 nmole/gm wet wt/hr or a fractional synthetic rate of 5.2 +/- 0.5%/day. In contrast to control animals, the fractional synthetic rate in septic animals (2.6 +/- 0.2%/day) was reduced by 50% compared to control animals (p less than 0.005). The decreased rate of protein synthesis in sepsis was not due to an energy deficit, as high-energy phosphates and ATP/ADP ratio were not altered. This decrease in protein synthesis occurred even though septic animals consumed as much food as control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of skeletal muscle protein synthesis in septic intra-abdominal abscess. 339 97

Different routes of endotoxin administration have been used to mimic inflammatory and metabolic responses observed during sepsis. Because the origin of endotoxemia may affect the reactions to endotoxin, we compared the induction of tumor necrosis factor (TNF), interleukin-6 (IL-6), hormones, and glucose production after endotoxin (1.0 microg/kg Escherichia coli 0111:B4) administration into a peripheral (n = 8) versus the portal (n = 8) vein in anesthetized dogs. Prior to endotoxin, a laparotomy was performed for cannulation of hepatic vessels. To evaluate the effects of surgery and anesthesia, we also studied the effects of peripheral endotoxin administration in six awake dogs. The rate of appearance of glucose was measured by primed continuous infusion of [6,6-2H2]glucose. In anesthetized dogs, arterial concentrations of TNF and IL-6 increased after endotoxin administration (P < 0.01 vs basal; NS between groups). Net hepatic TNF production was increased after endotoxin administration (peripheral vs portal endotoxin administration: 533 +/- 177 vs 2135 +/- 1127 ng/min, both P < 0.05 vs basal; NS between groups). Net hepatic IL-6 production was stimulated only after portal endotoxin delivery (from 86 +/- 129 to 4740 +/- 1899 ng/min, P < 0.05; NS between groups). Although there were no differences in neuroendocrine activation, portal endotoxin administration resulted in decreased glucose production compared with peripheral administration (13.6 +/- 0.9 vs 16.8 +/- 1.2 micromol/kg.min, P < 0. 05). In contrast to anesthetized dogs, endotoxin increased glucose production considerably in awake dogs from 13.8 +/- 1.2 to 24.2 +/- 3.2 micromol/kg.min (P < 0.05; P < 0.05 vs anesthetized dogs). The contribution of anesthesia and surgery increased the endotoxin-induced IL-6 response by approximately 350% compared with the effect of endotoxin in awake dogs (P < 0.01). In conclusion, there are no major differences in the responses to endotoxin between peripherally treated and portally treated dogs, except for differences in glucose production. Portal delivery compared with systemic delivery of endotoxin alters hepatic metabolism through nonendocrine mechanisms, reflected in decreased glucose production. The inflammatory, endocrine, and metabolic effects of endotoxin are altered by the combination of surgery and anesthesia.
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PMID:Origin of endotoxemia influences the metabolic response to endotoxin in dogs. 944 92

Because experimental studies have shown that intact alveolar epithelial fluid transport function is critical for resolution of pulmonary edema and acute lung injury, we measured net alveolar fluid clearance in 79 patients with acute lung injury or the acute respiratory distress syndrome. Pulmonary edema fluid and plasma were sampled serially in the first 4 hours after intubation. Net alveolar fluid clearance was calculated from sequential edema fluid protein measurements. Mean alveolar fluid clearance was 6%/h. Of the patients, 56% had impaired alveolar fluid clearance (< 3%/h), 32% had submaximal clearance (> or = 3%/h, < 14%/h), and 13% had maximal clearance (> or = 14%/h). These findings are contrasted to our recent report of 65 patients with hydrostatic pulmonary edema, in whom mean alveolar fluid clearance was 13%/h; only 25% had impaired clearance whereas 75% had submaximal or maximal clearance (J Appl Physiol 1999;87:1301-1312). Acute lung injury with maximal alveolar fluid clearance were more likely to be female (p = 0.03), and less likely to have sepsis (p = 0.01). Endogenous and exogenous catecholamines did not correlate with alveolar fluid clearance. Patients with maximal alveolar fluid clearance had significantly lower mortality and a shorter duration of mechanical ventilation. In summary, in contrast to hydrostatic pulmonary edema, alveolar fluid clearance in patients with acute lung injury and the acute respiratory distress syndrome is impaired in the majority of patients, and maximal alveolar fluid clearance is associated with better clinical outcomes.
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PMID:Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. 1137 84

The inducible isoform of nitric-oxide synthase (NOS2), a key enzyme catalyzing the dramatic increase in nitric oxide by lipopolysaccharide (LPS), plays an important role in the pathophysiology of endotoxemia and sepsis. Recent evidence suggests that Ets transcription factors may contribute to NOS2 induction by inflammatory stimuli. In this study, we investigated the role of Ets transcription factors in the regulation of NOS2 by LPS and transforming growth factor (TGF)-beta 1. Transient transfection assays in macrophages showed that Ets-2 produced an increase in NOS2 promoter activity, whereas the induction by Ets-1 was modest and NERF2 had no effect. Elk-3 (Net/Erp/Sap-2a) markedly repressed NOS2 promoter activity in a dose-dependent fashion, and overexpression of Elk-3 blunted the induction of endogenous NOS2 message. Mutation of the Net inhibitory domain of Elk-3, but not the C-terminal-binding protein interaction domain, partially alleviated this repressive effect. We also found that deletion of the Ets domain of Elk-3 completely abolished its repressive effect on the NOS2 promoter. LPS administration to macrophages led to a dose-dependent decrease in endogenous Elk-3 mRNA levels, and this decrease in Elk-3 preceded the induction of NOS2 mRNA. In a mouse model of endotoxemia, the expression of Elk-3 in kidney, lung, and heart was significantly down-regulated after systemic administration of LPS, and this down-regulation also preceded NOS2 induction. Moreover, TGF-beta 1 significantly increased endogenous Elk-3 mRNA levels that had been down-regulated by LPS in macrophages. This increase in Elk-3 correlated with a TGF-beta 1-induced down-regulation of NOS2. Taken together, our data suggest that Elk-3 is a strong repressor of NOS2 promoter activity and mRNA levels and that endogenous expression of Elk-3 inversely correlates with NOS2. Thus, Elk-3 may serve as an important mediator of NOS2 gene expression.
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PMID:Elk-3 is a transcriptional repressor of nitric-oxide synthase 2. 1289 68

The objective of this study is to estimate cost-effectiveness of pathogen inactivation for platelet transfusions in the Netherlands. We used decision tree analysis to evaluate the cost-effectiveness of the addition of pathogen inactivation of pooled platelets to standard procedures for platelet transfusion safety (such as, donor recruitment and screening). Data on transfusions were derived from the University Medical Centre Groningen (the Netherlands) for 1997. Characteristics of platelet recipients (patient group, age, gender and survival) and data/assumptions on viral and bacterial risks were linked to direct and indirect costs/benefits of pathogen inactivation. Post-transfusion survival was simulated with a Markov model. Standard methods for cost-effectiveness were used. Cost-effectiveness was expressed in net costs per life-year gained (LYG) and estimated in baseline- and sensitivity analysis. Sensitivity was analysed with respect to various assumptions including sepsis risk, reduction of the discard rate and discounting. Stochastic analysis to derive 90% simulation intervals (SIs) was performed on sepsis risk. Net costs per LYG for pathogen inactivation were estimated 554,000 euro in the baseline-weighted average over the three patient groups (90% SI: 354,000-1092,500 euro). Sensitivity analysis revealed that cost-effectiveness was insensitive to viral risks and indirect costing, but highly sensitive to the assumed excess transfusions required and discounting of LYG. Given relatively high net costs per LYG that are internationally accepted for blood transfusion safety interventions, our estimated cost-effectiveness figures for pathogen inactivation may reflect acceptable cost-effectiveness in this specific area. Two main assumptions of our model were that the pathogen inactivation was 100% effective in preventing transmission of the pathogens considered and was not associated with major and/or costly adverse reactions. Validation of several crucial parameters is required, in particular the Dutch risk for acquiring and dying of transfusion-related sepsis.
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PMID:Cost-effectiveness of pathogen inactivation for platelet transfusions in the Netherlands. 1620 52

A recent survey conducted by the publicly funded Competence Network Sepsis (Sep- Net) reveals that severe sepsis and/or septic shock occurs in 75,000 inhabitants (110 out of 100,000) and sepsis in 79,000 inhabitants (116 out of 100,000) in Germany annually. This illness is responsible for approx. 60,000 deaths and ranges as the third most frequent cause of death after acute myocardial infarction. Direct costs for the intensive care of patients with severe sepsis alone amount to approx. 1.77 billion euros, which means that about 30% of the budget in intensive care is used to treat severe sepsis. However, until now German guidelines for the diagnosis and therapy of severe sepsis did not exist. Therefore, the German Sepsis Society initiated the development of guidelines which are based on international recommendations by the International Sepsis Forum (ISF) and the Surviving Sepsis Campaign (SSC) and take into account the structure and organisation of the German health care system. Priority was given to the following guideline topics: a) diagnosis, b) prevention, c) causative therapy, d) supportive therapy, e) adjunctive therapy. The guidelines development process was carefully planned and strictly adhered to according to the requirements of the Working Group of Scientific Medical Societies (AWMF).
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PMID:[Diagnosis and therapy of sepsis]. 1686 90


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