Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed a conscious septic dog model suitable for in vivo tracer studies. Dogs weighing 10 to 20 kg underwent general anesthesia followed by the insertion of long-term arterial, venous, and portal cannulas and the formation of a long-term tracheostomy. After 7 to 10 days of convalescence, the animals were fed in the morning and 4 hours later 10(10) live Escherichia coli organisms were infused intra-arterially over approximately 30 minutes. One hour later a second dose of 5 X 10(9) bacteria was given, again over 30 minutes. Resuscitation was provided by infusion of 1000 ml of lactated Ringer solution over 3 hours. Twenty-four hours after the induction of sepsis the animals were hemodynamically stable and suitable for study. Cardiac output was increased from the control value of 185 +/- 35 ml/kg X min to 308 +/- 44 ml/kg X min in the septic animals. Heart rate was increased from 98 +/- 10 to 125 +/- 5 beats/min, and arterial pressure was not significantly altered. We employed indirect calorimetry and primed constant infusions of both radioactive and stable isotopes to assess a variety of metabolic parameters. The metabolic rate was increased approximately 25%, and the energy for this increase was primarily provided by the increased oxidation of both free fatty acids and triglyceride. The release of free fatty acids was approximately three times greater than the control value, and triglyceride synthesis increased 500%. The oxidation rate of free fatty acids and the fatty acids contained in very low density lipoproteins-triglyceride increased 40% and 900%, respectively. Glucose production was maintained at approximately the control value, and the rate of glucose oxidation (as measured with 14C-glucose) was also not significantly altered. The plasma insulin concentration was moderately elevated, and plasma glucagon concentration was five to six times greater than the control value. Plasma catecholamine levels were increased significantly. This model is suitable for the performance of metabolic studies in sepsis. The induction of a hyperdynamic septic state in less than 24 hours avoids the complications of starvation and dehydration frequently seen in the various peritonitis and abscess models. Most importantly, the model is predictable in its time course and reproducibly creates a situation that hormonally, hemodynamically, and metabolically resembles what is commonly seen in humans with sepsis.
 ...
PMID:A conscious septic dog model with hemodynamic and metabolic responses similar to responses of humans. 636 96

Glucose turnover is increased during shock and in acute sepsis, but relatively little information is available concerning the regulation of carbohydrate metabolism during the hypermetabolic phase of sepsis. In these studies peritoneal sepsis was induced in rats, following chronic vascular catheterization, by intraperitoneal administration of a pooled fecal inoculum. The resultant peritonitis has been shown to produce a sustained hypermetabolic state during the first three days of infection. Glucose and lactate kinetics were studied using a constant infusion of radiolabeled tracers during the peak of the hypermetabolic phase (day 2). The septic animals exhibited a 42% increase in glucose turnover and a 63% increase in the metabolic clearance rate of glucose, as compared to time-matched control rats. Hepatic glycogenolysis could only contribute 1% to 2% to the increased rate of glucose appearance. A major portion of the elevated glucose turnover was accounted for by a 93% increase in glucose recycling, indicating an enhancement of gluconeogenesis from glucose-derived gluconeogenic precursors. The increased importance of lactate as a precursor for gluconeogenesis in sepsis was indicated by the elevated lactate turnover (34%) and the increased percentage of 14C-glucose derived from 14C-lactate. The insulin to glucagon ratio was decreased in the septic animals as a result of a reduction in the plasma insulin concentration (56%) and an increased glucagon concentration (67%). We conclude that during the hypermetabolic phase of sepsis, the increased peripheral glucose uptake generated more gluconeogenic precursors but did not appear to have a major direct contribution to the increased aerobic metabolism.
 ...
PMID:Carbohydrate dynamics in the hypermetabolic septic rat. 638 22

Canine pancreata obtained at total pancreatectomy were cannulated via the ducts and perfused with collagenase to prepare a tissue suspension that was isografted into the spleen (preparation congruent to 2 h, mean graft vol = 10 +/- 1 ml containing 24% of the B-cell mass/pancreas). In 13 dogs the tissue was implanted by reflux into terminal splenic veins: two died postoperatively, and in two the intrasplenic vein wall was inadvertently punctured during cannulation. In the remaining nine, mean fasting blood glucose (BG) was less than or equal to 150 mg/dl initially; one was killed at 2 wk (distemper) and one at 6 wk (sepsis, diabetes), and one died at 9 wk (intestinal obstruction). Mean BG was 94 +/- 4 mg/dl at 1 mo and remained in this range until the dogs were killed at 5 mo (91 +/- 13 mg/dl). During glucose-tolerance testing 1 wk preimplantation and 1 mo and 2-3 mo postimplant, mean values were: K (decline in glucose concentration, %/min), 3.4 +/- 0.2, 1.4 +/- 0.1, and 1.5 +/- 0.1; peak insulin (microU/ml), 50 +/- 5, 12 +/- 1, and 11 +/- 2; fasting serum glucagon (pg/ml), 33 +/- 3, 59 +/- 12, and 53 +/- 9, with no change in the glucagon response. Histologically, the spleens contained prominent islets. In five other dogs, the tissue was injected into the splenic pulp: mean BG rose to greater than or equal to 250 mg/dl at 2 wk (compared with initial series, P less than 0.001) and remained elevated until death at 6 wk, when histologic examination of the spleens showed severe fibrosis and no islets. Apancreatic controls (N = 4) survived 10 +/- 3 days; BG was 343 +/- 11 mg/dl terminally. We conclude that this modified method for collagenase perfusion of a single large-mammal pancreas via the ducts provides sufficient viable islets to induce prolonged normoglycemia (5 mo) and preserve the response to glucose challenge. Reflux of pancreatic fragments into splenic veins appears more efficient than intrapulp implantation.
 ...
PMID:Normoglycemia after reflux of islet-containing pancreatic fragments into the splenic vascular bed in dogs. 640 80

Free fatty acid (FFA) metabolism was studied in 18 traumatized and/or septic patients. Each patient was studied while receiving 5% dextrose (D5W) and after 4 to 7 days of total parenteral nutrition (TPN). Nonprotein energy during TPN was given either entirely as glucose (Glucose System) or as equal portions of intravenous fat and glucose (Lipid System). Plasma FFA concentrations were in the normal range on D5W and decreased markedly with TPN. FFA turnover was higher than normal on D5W and did not decrease significantly with TPN. The poor correlation between these two variables emphasizes the need to perform kinetic studies to characterize FFA metabolism in trauma and sepsis. Plasma FFA oxidation and net whole body fat oxidation measured by indirect calorimetry were in the normal range on D5W, 35 and 82%, respectively, of resting energy expenditure (REE). With a glucose intake averaging 108% of REE, plasma FFA oxidation and net fat oxidation decreased to 17 and 13%, respectively, of REE. Nonprotein RQ increased only to 0.94 despite administration of glucose in excess of REE, indicating an abnormal persistence of fat oxidation. During D5W administration, plasma FFA accounted for less than one half of total fat oxidation, indicating that unlabeled fat, such as tissue or plasma triglycerides not in rapid equilibrium with plasma FFA, accounted for the bulk of fat oxidation. Glucagon concentrations which were high on D5W did not decrease significantly with TPN. Insulin concentrations were normal on D5W and increased in response to TPN. The abnormal hormonal milieu may account for much of the abnormal fat metabolism. Administration of large amounts of glucose decreased FFA oxidation much more than FFA mobilization. Thus, the infused glucose acts to increase the rate of "futile cycling" of FFA in these acutely ill patients.
 ...
PMID:Free fatty acid mobilization and oxidation during total parenteral nutrition in trauma and infection. 641 94

This is a brief review of the observed hormonal alterations following trauma and sepsis. The major changes noted in the metabolic status of the stressed patient have been characterized by deranged carbohydrate metabolism, altered metabolic rate as measured by oxygen consumption and increased ureagenesis. Each of these phenomena are regulated to a large extent by the specific hormonal profile of the patient. Failure of insulin and growth hormone production have been associated with glucose intolerance, excessive urinary nitrogen loss and a fatal outcome. Glucagon, cortisol and catecholamines exhibit sustained elevation and have been associated with increased metabolic rate and excessive ureagenesis. These changes are usually self limited following trauma but will persist if the patient enters a septic phase. The use of specific nutritional support, namely hypertonic glucose versus a balanced fat emulsion system in the face of sepsis is considered.
 ...
PMID:Hormonal changes and their influence on metabolism and nutrition in the critically ill. 675 38

Glucose intolerance and its hormonal influence was examined in patients with sepsis. Eighteen patients were included in the protocol, which studied the response to a standard intravenous glucose tolerance test (GTT) in the postoperative stressed, septic, and septic protein malnourished (depressed albumin level) states. Four groups could be defined: stress (1), sepsis with depressed albumin level and normal glucose tolerance (2), sepsis with mild glucose intolerance and normal albumin levels (3), and sepsis with severe glucose intolerance and depressed albumin (4). Serial hormone levels were measured during the GTT, including insulin, glucagon, epinephrine, and human growth hormone values. Each group demonstrated a characteristic hormone profile. In a comparison with controls, group 2 was associated with mild suppression of insulin; group 3 exhibited mild glucose intolerance, hyperglucagonemia, and increased insulin; and group 4 demonstrated severe glucose intolerance, hyperglucagonemia, and marked suppression of growth hormone production.
 ...
PMID:Sepsis, glucose intolerance, and protein malnutrition: a metabolic paradox. 677 57

There seems little doubt that there are signals for the increased mobilization of fat in shock, trauma, and sepsis. Whether those signals are reflected by an actual increase in mobilization is dependent on many variables including cardiovascular status. A hypothetical scheme based on our own experiments in the hyperdynamics phases of response to burn injury and to sepsis is presented in Figure 8. According to this scheme, catecholamines stimulate lipolysis in the adipose tissue, resulting in the release of glycerol and FFA into the plasma at increased rates. The glycerol is cleared by the liver and converted into glucose--a process stimulated by, among other things, glucagon. Some of the increased flux of FFA is also cleared by the liver, whereupon the fatty acids are incorporated into VLDL and released again into the plasma. The increased FFA levels also exert a dampening effect on the factors stimulating hepatic glucose production. At the periphery, plasma FFA as well as VLDL fatty acids are taken up at an increased rate. The tissues are attuned to the oxidation of fat, and as a consequence most of the energy production is derived from fat oxidation. The increased fatty acids exert an inhibitory effect on the complete oxidation of glucose, so although glucose may be taken up at an accelerated rate, the relative contribution of glucose oxidation to total energy production may fall. Rather than being completely oxidized, pyruvate is reduced to lactate and released into the plasma at an accelerated rate. The lactate then contributes to the production of glucose in the liver, completing a cyclical process called the Cori Cycle. Although all aspects of this scheme are supported by data highlighted in this paper, it certainly must be an oversimplification of the overall response of substrate metabolism to trauma and sepsis. It is presented for the purpose of highlighting the potential role of fat as a controller of the metabolic response, and to suggest that the enhanced mobilization and oxidation of fat is one of the fundamental responses to stress.
 ...
PMID:Energy metabolism in trauma and sepsis: the role of fat. 686 23

Major alterations in the glucose-mediated regulation of growth hormone are associated with sepsis; however, these alterations are not related to the rate of change in plasma glucose or changes in glucagon, epinephrine levels, or circulating levels of arginine. Alterations in the growth hormone regulatory mechanism occurred among septic patients who manifested severe glucose intolerance which was associated with suppression of insulin production. Inhibition of growth hormone release in these patients may have an adverse effect on amino acid movement, which lends further support to the concept that sustained hyperglycemia in the septic patient is undesirable.
 ...
PMID:Glucose-dependent changes in growth hormone regulation associated with sepsis. 702 2

After trauma or sepsis, the liver undergoes a reprioritization of export protein synthesis with elevated production of some acute-phase reactants and reduced production of others. We have examined the effects of combinations of insulin and the counterregulatory hormones (dexamethasone, glucagon, and epinephrine), in the presence or absence of interleukin (IL)-6, on the production by isolated hepatocytes of the positive acute-phase proteins C-reactive protein, alpha 1-antichymotrypsin, alpha 1-acid glycoprotein, and haptoglobin, and the negative acute-phase proteins prealbumin and transferrin. The effect of IL-6 on the production of the above proteins was influenced significantly by insulin and all of the counterregulatory hormones. Significant three-way interactions as well as higher order interactions between the stress hormones and insulin were seen in the case of C-reactive protein. The results indicate that both positive and negative acute-phase proteins respond differently to insulin and the counterregulatory hormones and that the potential exists for the regulation of synthesis of individual acute-phase reactants by interaction between the cytokine network and the classical endocrine hormones.
 ...
PMID:Insulin and counterregulatory hormones influence acute-phase protein production in human hepatocytes. 754 33

Sepsis is associated with alterations in hepatic gluconeogenesis. We have previously demonstrated that this change is associated with reduced expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene, despite an endogenous hormonal milieu that should favor increased expression of the gene. To further elucidate the mechanisms involved, we induced sepsis in fasted Sprague-Dawley rats via cecal ligation and single puncture, with sham-operated animals serving as controls, and we performed two sets of experiments. First, liver tissue was obtained from septic and sham-operated animals at 2, 6, 16, and 24 h after the induction of sepsis. Northern blot hybridization analysis revealed a progressive, sepsis-induced decrease in expression of PEPCK and an increase in the expression of beta-fibrinogen, an acute-phase reactant. In the second set of experiments, we tested whether this reduced expression resulted from an attenuated response to 1) glucagon and 2) 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP). Twenty-four hours after the induction of sepsis, the liver was isolated and perfused with either Krebs buffer with substrate only (unstimulated controls), Krebs buffer + substrate + 10(-8) M glucagon, or Krebs buffer + substrate + 10(-5) M 8-BrcAMP. In sham-operated animals, perfusion with glucagon increased PEPCK mRNA levels and activity, whereas perfusion with buffer alone did not change mRNA levels and decreased activity. Glucagon perfusion of septic livers did not change either PEPCK mRNA levels or activity. Perfusion of sham-operated animals with 8-BrcAMP increased PEPCK mRNA levels and activity, whereas perfusion with buffer alone resulted in a decrease in mRNA levels and activity.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Sepsis-induced attenuation of glucagon and 8-BrcAMP modulation of the phosphoenolpyruvate carboxykinase gene. 757 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>