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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pathologic oxygen supply dependency (PO2SD) may be etiologic in multisystem organ failure (MSOF) and has been related to mortality in sepsis. Although elevated lactate levels are generally assumed to be a marker of anaerobiosis in these patients, endotoxin may increase serum lactate by inactivation of pyruvate dehydrogenase (PDH), unrelated to tissue PO2. We hypothesized that regional lactate flux may correlate poorly with local oxygen delivery in sepsis. This study examined both the whole-body (WB) and regional (isolated hind limb L and gut G) responses to endotoxin infusion in terms of oxygen delivery, oxygen uptake, and lactate flux in 12 pentobarbital-anesthetized dogs. To separate hypoxia-induced lactate production from that related to inactivation of PDH by endotoxin, half the dogs received dichloroacetate (DCA), a PDH activator. After endotoxin and volume resuscitation, each animal had low systemic vascular resistance with normal to high cardiac output. Despite adequate oxygen delivery to WB, L, and G, arterial lactate levels rose significantly. A 30-min hypoxic challenge (12% FIO2) did not increase lactate levels but did increase WB O2 uptake. DCA normalized lactate levels without influencing oxygen delivery and uptake relations. These data show that lactate levels in endotoxic states may be a poor marker of tissue hypoxia and may be more related to PDH activity.
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PMID:Regional and systemic oxygen delivery/uptake relations and lactate flux in hyperdynamic, endotoxin-treated dogs. 129 May 54

We have investigated the responsiveness of protein kinetics to insulin and the role of glucose oxidation rate as a mediator of the protein catabolic response to burn injury and sepsis by assessing the response of leucine and urea kinetics to a 5-h hyperinsulinemic euglycemic clamp with and without the simultaneous administration of dichloroacetate (DCA) (to further increase glucose oxidation via stimulation of pyruvate dehydrogenase activity) in eight severely burned and eight septic patients. Leucine and urea kinetics were measured by the primed-constant infusions of [1(-13)C]leucine and [15N2]urea. Compared with controls, basal leucine kinetics (flux and oxidation) were significantly elevated (P less than 0.01) in both groups of patients. Hyperinsulinemia elicited significant (P less than 0.05) decreases in leucine kinetics in both groups of patients. Consistent with this observation, hyperinsulinemia caused urea production to decrease significantly (P less than 0.05) in both patient groups. The administration of DCA to patients during hyperinsulinemia elicited a significant increase in glucose oxidation rate compared with the clamp rate (P less than 0.05), and the percent of glucose uptake oxidized increased from 45.5 +/- 5.5 to 53.5 +/- 4.8%; yet the response of leucine and urea kinetics to the clamp plus DCA was not different from the response to the clamp alone. These results suggest that the maximal effectiveness of insulin to suppress protein breakdown is not impaired and that a deficit in glucose oxidation or energy supply is probably not playing a major role in mediating the protein catabolic response to severe burn injury and sepsis.
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PMID:Role of insulin and glucose oxidation in mediating the protein catabolism of burns and sepsis. 267 28

A study of the combined effects of intravenous infusion of the recombinant cytokines beta-interleukin 1 (IL-1) and alpha-tumor necrosis factor (TNF) on energy substrate metabolism in awake, conditioned, adult rabbits was performed. After a 2-h basal or control period, 48-h fasted rabbits were administered TNF and IL-1 as a bolus (5 micrograms/kg) followed by a continuous intravenous infusion (25 ng.kg-1.min-1) for 3 h. Significant increases in plasma lactate (P less than 0.01), glucose (P less than 0.01), and triglycerides (P less than 0.05) occurred during the combined infusion of IL-1 and TNF, whereas neither cytokine alone had no effect. There was a 33% increase in the rate of glucose appearance (P less than 0.05), but glucose clearance was not altered compared with the control period. Glucose oxidation increased during the combined cytokine infusion period and glucose recycling increased by 600% (P less than 0.002). Lactic acidosis and decreased oxygen consumption, as a result of the cytokine infusions, indicated development of anaerobic glycolytic metabolism. A reduction in the activity state of hepatic mitochondrial pyruvate dehydrogenase (65 vs. 82% in control animals, P less than 0.05) was consistent with the observed increase in anaerobic glycolysis. Thus the combined infusion of IL-1 and TNF in rabbits produces metabolic manifestations seen in severe injury and sepsis in human patients and, as such, may account for the profound alterations of energy metabolism seen in these conditions.
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PMID:Role of interleukin 1 and tumor necrosis factor on energy metabolism in rabbits. 314 80

Decreased pyruvate dehydrogenase (PDH) activity in skeletal muscle has been observed during sepsis and may contribute to the altered glucose kinetics seen in this condition. The purpose of the present study was to determine if dichloroacetate (DCA), a known stimulator of PDH activity, could reverse the sepsis-induced increase in glucose metabolism. Hypermetabolic sepsis was produced in chronically catheterized rats by repeated subcutaneous injections of live Escherichia coli. Whole body glucose kinetics, assessed by a constant iv infusion of [6-3H and U-14C]-glucose, were determined in fasted septic and nonseptic rats before and for 4 hr after an injection of DCA (30 mg/100 g BW, iv). Sepsis produced hyperthermia (+1.6 degrees C) and increased the rates of glucose appearance (Ra; 95%), recycling (318%), metabolic clearance (MCR; 114%), and elevated plasma lactate levels (295%) compared to nonseptic controls. After injection of DCA into septic rats, glucose levels gradually fell, and the sepsis-induced hyperlactacidemia was completely reversed. Treatment of septic rats with DCA reversed the elevated glucose Ra; recycling, although reduced, was still elevated by 50% compared to control animals. DCA did not alter the hyperglucagonemia seen in septic animals, but it did reduce the plasma insulin levels by 60%. Hepatic and muscle PDH activities were not different in saline-treated septic and nonseptic animals. DCA elevated PDH activity in muscle from septic rats, but the increase was smaller than that seen in control animals. This may explain the smaller decline in glucose recycling and plasma lactate in septic animals. These results are consistent with DCA reducing the elevated glucose Ra in sepsis by partial activation of PDH, which reduces the elevated precursor (lactate) supply for gluconeogenesis. However, alterations in PDH activity did not appear to contribute to the underlying increase in glucose Ra and recycling observed in sepsis.
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PMID:Glucose kinetics and pyruvate dehydrogenase activity in septic rats treated with dichloroacetate. 331 89

The metabolic effects of dichloroacetate on carbohydrate metabolism were investigated in normal fed, sterile inflammatory, and chronic septic animals. Chronic sepsis, but not sterile inflammation, was associated with elevated plasma, liver, and skeletal muscle lactate concentrations. Sodium dichloroacetate significantly reduced both plasma and intracellular pyruvate and lactate concentrations in all conditions examined, while plasma glucose concentrations remained unchanged. Decreased tissue metabolite concentrations were associated with a significantly increased active pyruvate dehydrogenase complex in liver and skeletal muscle in each of the conditions examined. In liver, dichloroacetate fully activated (greater than 85%) the pyruvate dehydrogenase complex under all conditions. In skeletal muscle from chronic septic animals, the dichloroacetate-induced increases in active pyruvate dehydrogenase were significantly less than those observed in non-septic animals. The data suggest that although dichloroacetate can partially reverse the sepsis-induced effects on skeletal muscle pyruvate dehydrogenase activity, there may be additional regulatory factors in skeletal muscle from septic animals. The dichloroacetate stimulation of the pyruvate dehydrogenase activity may provide a pharmacological method for reducing the elevated lactate concentrations observed in chronic severe sepsis.
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PMID:Metabolic effects of partial reversal of pyruvate dehydrogenase activity by dichloroacetate in sepsis. 334 93

Sepsis has been shown to decrease skeletal muscle glucose oxidation by inhibiting the pyruvate dehydrogenase activity (PDHa) and to increase proteolysis and use of branched-chain amino acids (BCAA). The effects of dichloroacetate (DCA), which reverses PDHa inhibition, were studied in skeletal muscle from a septic (S) rat model of intra-abdominal abscess (E. coli + B. fragilis) and compared to control (C) and sterile inflammatory abscess (I) animals. In one set of S, I, and C animals, DCA (1 mmol/kg) was injected intraperitoneally at 0, 30, and 60 min. Septic, but not I, rats had a twofold increase in skeletal muscle lactate concentrations over C, but no changes in pyruvate. After DCA, both lactate and pyruvate were reduced (p less than 0.001) to same level in S, I, and C. Skeletal muscle alanine was increased in S compared to I or C, but after DCA was reduced threefold in C, S, and I (p less than 0.001) suggesting that alanine synthesis may be impaired due to decreased pyruvate availability. Like alanine, skeletal muscle BCAA were increased in S compared to C, but not altered in I. Following DCA, BCAA levels in muscle from S were reduced (p less than 0.001) to values seen in C or I. Muscle phenylalanine content was significantly elevated in S (p less than 0.05) compared to C or I, but was reduced (p less than 0.05) after DCA in S but not in C or I. Decreased muscle phenylalanine associated with lowered BCAA suggests DCA may decrease septic muscle protein catabolism and/or enhance protein synthesis. Coupled with an increased PDHa and reduced lactate levels, this suggests that DCA may reverse the excess muscle catabolism and BCAA dependence of sepsis by increasing glucose and lactate oxidation and may be a useful therapeutic modality.
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PMID:Pharmacological reversal of abnormal glucose regulation, BCAA utilization, and muscle catabolism in sepsis by dichloroacetate. 341 55

Regulation of the pyruvate dehydrogenase (PDH) complex has been demonstrated to be a key mechanism in the control of carbohydrate oxidation and conservation of glucose carbon. The effect of sterile inflammation and chronic sepsis (small and large abscess) on the activity of the PDH complex was examined in liver and skeletal muscle. Sepsis altered the proportion of PDH in the active, dephosphorylated form. In hepatic tissue, sterile inflammation leads to a 2.5-fold increase in the proportion of active PDH complex compared to fed control. The same increase in the proportion of active PDH complex was observed in rats with a small septic abscess. However, when the severity of septic episode was increased, the proportion of active PDH complex decreased relative to sterile inflammation or small septic abscess animals. A different pattern in the response to sterile inflammation and sepsis on the proportion of active PDH complex was observed in skeletal muscle compared to liver. In contrast to liver, sterile inflammation did not alter the proportion of active PDH in skeletal muscle. In addition, sepsis (either small or large septic abscess) resulted in a 3-fold decrease in the proportion of active PDH relative to fed control or sterile inflammatory animals. The decrease in the proportion of active PDH complex in sepsis was associated with a corresponding increase in the skeletal muscle acetyl-CoA/CoA ratio. The mechanism responsible for lowered PDH complex activity may have been due to increased PDH kinase activity, secondary to increased skeletal muscle acetyl-CoA/CoA ratios.
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PMID:Regulation of glucose metabolism by altered pyruvate dehydrogenase activity. I. Potential site of insulin resistance in sepsis. 352 46

The pyruvate dehydrogenase (PDH) complex undergoes reversible phosphorylation catalyzed by a PDH kinase (inactivating) and a PDH phosphatase (activating). In skeletal muscle, a decreased proportion of PDH complex in the active, nonphosphorylated form (PDHa) limits glucose oxidation and promotes the conversion of pyruvate to lactate. Increased lactate formation with the accompanying hyperlactatemia is a frequent metabolic complication of sepsis. The time course for inactivation of the PDH complex in skeletal muscle during sepsis was contrasted with changes in PDHa during sterile inflammation 3,7, or 14 days following the implantation of the foreign body nidus. Total PDH complex activity was not altered in any of the conditions examined. Sepsis, but not sterile inflammation, caused a reduction in the muscle PDHa measured 3 or 7 days following induction of sepsis. The inhibition of the muscle PDHa during sepsis was associated with a sustained hyperlactatemia. PDH kinase activity measured in extracts of mitochondria was enhanced twofold during this period. Fourteen days after induction of sepsis, there were no differences in the PDHa or plasma lactate concentrations in septic rats compared with either control or sterile inflammation. Furthermore, the PDH kinase activity was decreased to values observed in control values. The results are consistent with the hypothesis that a reduced PDHa in skeletal muscle during sepsis is responsible, in part, for the hyperlactatemia characteristic of septic hypermetabolism. Furthermore, the results provide evidence that the decrease in PDHa results from a stable stimulation of PDH kinase activity.
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PMID:Sepsis-induced alterations in pyruvate dehydrogenase complex activity in rat skeletal muscle: effects on plasma lactate. 885 41

Energy substrate metabolism during stress is characterized by increased REE (resting energy expenditure), hyperglycemia, hyperlactatemia and protein catabolism. This stress-induced hypermetabolic responses are closely related to increased secretion of neurohormonal and cytokine mediators. The insulin resistance hyperglycemia has been called "stress diabetes" or "surgical diabetes". Glucose disposal has been thought to be impaired in this condition. However, glucose uptake in most tissue is non-insulin mediated. Recent studies showed glucose uptake elevated in sepsis or TNF infusion. Insulin-regulatable glucose transporter (GLUT4) is present only in muscle, heart and adipose tissues. It was demonstrated that insulin binding to membrane receptors in these tissues was intact. This hyperglycemia in stress diabetes results from a postreceptor mechanism. Stress hyperlactatemia is thought to be caused by decreased pyruvate dehydrogenase activity rather than tissue hypoperfusion. Hyperlactatemia may promote gluconeogenesis. Glucose is a essential energy substrate in some tissues such as brain, erythrocyte and leukocyte. Hyperglycemia may be viewed as a beneficial response during stress.
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PMID:[Energy substrate metabolism during stress]. 894 Jun 83

Cardiodepressant effects of tumor necrosis factor-alpha (TNF-alpha have been documented in numerous experimental settings in vivo and in vitro. In vivo administration of TNF-alpha mimicks the cardiovascular pattern of sepsis including septic cardiomyopathy. Serum levels of TNF-alpha were found to be elevated both in sepsis and in numerous non-septic heart disorders. Although an involvement of TNF-alpha in the pathogenesis of septic cardiomyopathy seems likely, presently no definite conclusion can be drawn with regard to the role of TNF-alpha in chronic heart failure. The origin and trigger mechanisms for the release of TNF-alpha in heart failure are a matter of debate, endotoxin (LPS) from intestinal translocation in venous congestion being one possible player. The negative inotropic impact of TNF-alpha is frequently ascribed to the induction of inducible nitric oxide (NO) synthase (iNOS). Results from in vitro studies rather suggest a complex interaction of TNF-alpha with the heart, with pleiotropic effects on cardiomyocyte performance, including an induction of iNOS at higher TNF-alpha concentrations, but NO-independent cardiodepression at low, pathophysiologically more relevant concentrations. TNF-alpha effects on the heart also vary with regard to the kinetics of the process: rapidly occuring cardiodepressant effects include a release of sphingosine and a suppression of the calcium transient, while chronic administration of TNF-alpha was shown to depress the synthesis of precursors for the phosphoinositide pathway and inhibit pyruvate dehydrogenase activity and mitochondrial function. Whether secondary cytokines induced by TNF-alpha in cardiomyocytes contribute to cardiodepression or whether apoptotic signals activated by TNF-alpha are involved in the cardiodepressive pathways is presently unknown.
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PMID:Cardiodepression by tumor necrosis factor-alpha. 988 17


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