The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans.

The in vivo alterations in organ-specific substrate processing and endogenous mediator production induced by endotoxin were investigated in healthy volunteers. An endotoxin bolus (20 U/kg) produced increased energy expenditure, hyperglycemia, hypoaminoacidemia, and an increase in circulating free fatty acids. These changes included increased peripheral lactate and free fatty acid output, along with increased peripheral uptake of glucose. Coordinately, there were increased splanchnic uptake of oxygen, lactate, amino acids, and free fatty acids, and increased splanchnic glucose output. There were no changes in circulating glucagon, or insulin and transient changes in epinephrine and cortisol were insufficient to explain the metabolic changes. Plasma cachectin levels peaked 90 min after the endotoxin infusion, and hepatic venous (HV) cachectin levels (peak 250 +/- 50 pg/ml) were consistently higher than arterial levels (peak 130 +/- 30 pg/ml, P less than 0.05 vs. HV). No interleukin 1 alpha or 1 beta was detected in the circulation. Circulating interleukin 6, measured by B.9 hybridoma proliferation, peaked 2 h after the endotoxin challenge (arterial, 16 +/- 2 U/ml; HV, 21 +/- 3 U/ml). The net cachectin efflux (approximately 7 micrograms) from the splanchnic organs demonstrates that these tissues are a major site for production of this cytokine. Hence, splanchnic tissues are likely influenced in a paracrine fashion by regional cachectin production and may also serve as a significant source for systemic appearance of this cytokine.

Intravenous refeeding blocks growth hormone (GH)-provoked rises in serum free fatty acids and blunting of somatotroph response to GH-releasing hormone in normal men.

We measured the serum GH responses to GHRH (1 micrograms/kg) in six normal men who had been rendered hyperinsulinemic and hypolipidemic by 10 days of total parenteral nutrition (TPN subjects) with a 25% dextrose-amino acid solution. The men underwent GHRH testing after 3 h of infusion of NaCl or Met-human (h) GH (2 micrograms/kg.h). The results of these tests were compared with those of five men tested in the post-absorptive state (PA subjects). The serum GH response to GHRH during NaCl infusion was significantly lower in the TPN subjects than in the PA subjects. During the Met-hGH infusion, the serum GH response to GHRH in the PA subjects was significantly lower than that after the NaCl infusion, whereas in the TPN subjects the response was similar to that during the NaCl infusion. The mean integrated areas under the GH response-time curve after GHRH treatment were 3963 +/- 2086 min/micrograms.L following NaCl infusion and 413 +/- 64 min/micrograms.L following Met-hGH infusion in PA subjects; they were 1127 +/- 500 min/micrograms.L following NaCl infusion and 1456 +/- 682 min/micrograms.L during Met-hGH infusion in the TPN subjects. The Met-hGH infusions resulted in a significant increase in serum FFA concentrations in the PA, but not the TPN, subjects. These results suggest that hyperalimentation induces a metabolic background which inhibits GH secretion, as manifested by a diminished serum GH response to GHRH administered after NaCl infusion. The absent FFA response to Met-hGH infusion in the TPN subjects may explain why the Met-hGH infusion in them did not result in a reduced serum GH response to GHRH as occurred in the PA subjects. Hence, FFA may play an important role in the effects of short term Met-hGH infusion on GH secretion.

Clinical predictors of morbidity and mortality in patients with myocardial infarction or revascularization who underwent cardiac rehabilitation, and importance of diabetes mellitus and exercise capacity.

This investigation was a prospective, follow-up study to assess whether baseline clinical and investigational parameters were predictors of cardiovascular morbidity and mortality in patients enrolled into the cardiac rehabilitation program. A cohort of 418 patients (70% were men) with coronary heart disease was followed up 3.2 +/- 1.1 years. Two hundred twenty-seven of them (54%) had a recent myocardial infarction (MI), with a thrombolytic rate of 54%. Percutaneous transluminal coronary angioplasty (PTCA) was performed in 45% of patients. The covariates assessed include age, gender, smoking habit, body mass index, the presence of hypertension or diabetes mellitus, exercise habit, site and severity of MI, status of thrombolytic therapy, peak creatine phosphokinase, plasma lipid profiles, ejection fraction, PTCA performed, number of diseased coronary arteries, and exercise capacity. Low-density lipoprotein cholesterol decreased significantly (3.2 +/- 1.0 vs 2.7 +/- 0.7 mmol/L, p < 0.001). The cumulative mortality was 13%. In a univariate model, the parameters that significantly predict mortality included older age, diabetes, low exercise capacity (< or = 4 metabolic equivalents) 3-vessel disease, those without PTCA performed, and a low ejection fraction. In the Cox proportional-hazards model analysis, the independent factors were coexisting diabetes (chi-square 6.1, p = 0.01) and a low metabolic equivalent (chi-square 6.5, p = 0.01). One hundred six patients were rehospitalized for nonfatal cardiovascular events that included unstable angina (48%), heart failure (21%), acute MI (6%), symptomatic arrhythmia (6%), and severe hypertension (1%). Factors that independently predicted rehospitalization were low exercise capacity (p = 0.02) and the presence of diabetes (chi-square 4.8, p = 0.03). Diabetes was also associated with more episodes of hospital admission (2.3 +/- 2.1 vs 1.6 +/- 1.4, p = 0.04) and a longer cumulative hospital stay (25.5 +/- 34.6 vs 11.4 +/- 19.6 days, p = 0.02). Thus, in patients with MI or after PTCA receiving conventional medical therapy, the cardiac rehabilitation program should focus on aggressive diabetic control and enhancement of exercise capacity.

Influence of enterectomy on peripheral tissue glutamine efflux in critically ill patients.

Glutamine and alanine are dominant nitrogen carriers from skeletal muscle stores to splanchnic organs. In addition, these amino acids may also serve as a primary energy source for the gastrointestinal tract during injury. To investigate these contributions, we studied extremity amino acid efflux during hypocaloric dextrose feedings and during total parenteral nutrition in a population of normal volunteers (NL VOL) (n = 9), a group of patients with sepsis who had undergone laparotomy without bowel resection and were in the intensive care unit (ICU) (n = 7), and patients with sepsis after laparotomy (PT) (n = 2) who had recently undergone greater than 80% bowel resection. Circulating alanine and glutamine levels were significantly lower in the patients compared with NL VOL under both feeding conditions. The peripheral output of alanine was higher in the ICU group than in the NL VOL during hypocaloric feedings. Glutamine efflux, however, was independent of either the counterregulatory hormone or substrate background. By contrast, enterectomy was associated with a marked decrease of extremity glutamine efflux compared with NL VOL or the ICU patients who did not undergo enterectomy (-62 +/- 9 nmol/min/dl tissue in the PT vs -265 +/- 32 nmol/min/dl tissue in the NL VOL and -311 +/- 58 nmol/min/dl tissue in the ICU group) during the dextrose feedings; this difference persisted during subsequent total parenteral nutrition (+12 +/- 13 nmol/min/dl tissue in PT vs -178 +/- 56 nmol/min/dl tissue in the NL VOL and -287 +/- 81 nmol/min/dl tissue in the ICU group). These data suggest that distinct mechanisms regulate peripheral alanine and glutamine balance and that the gastrointestinal tract provides a feedback signal to peripheral tissues to maintain glutamine mobilization under both nonstressed and stressed conditions.

Tumor necrosis factor-enhanced leukotriene B4 generation and chemotaxis in human neutrophils.

In an in vivo study of five normal volunteers infused with endotoxin (20 U/kg of US reference endotoxin lot EC-5), increased neutrophil (PMN) generation of leukotriene B4 and chemotaxis to leukotriene B4 were found concomitantly with elevated plasma tumor necrosis factor (TNF) levels. To clarify the role of TNF in PMN activation, neutrophil responsiveness after in vitro treatment with TNF was examined. Neutrophils from seven normal subjects were incubated with TNF for 30 minutes and tested for chemotaxis to leukotriene B4, formyl-methionyl-leucyl-phenylalanine and zymosan-activated serum, or the calcium ionophore A23187 to assess leukotriene B4 generation. A range of 10(-13) to 10(-9) mol/L of TNF was used for these assays. When 10(-9) mol/L of TNF was used, the amount of leukotriene B4 that was produced was significantly greater than in control cells. The effect of TNF on PMN chemotaxis was uniformly inhibitory for the three stimuli at 10(-10) mol/L compared with untreated cells. At a picomolar range, PMN migration to leukotriene B4, but not to zymosan-activated serum or formyl-methionyl-leucyl-phenylalanine, was significantly increased over that of PMNs not exposed to TNF. This suggests that TNF has a specific facilitatory effect on PMN responsiveness for both leukotriene B4 production and chemotaxis to leukotriene B4 and may be the same signal for this phenomenon in endotoxemic patients.

Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans.

Intestinal mucosal atrophy, as induced by total parenteral nutrition (TPN) and/or prolonged bowel rest, is hypothesized to enhance bowel endotoxin (LPS) translocation and may alter host responses to infection. To examine the effect of TPN-induced bowel atrophy on the response to LPS, 12 healthy volunteers were randomized to receive either enteral feedings (ENT, n = 6) or seven days of TPN without oral intake (TPN, n = 6). Enteral or TPN feedings were terminated 12 hours before the study period when a constant dextrose infusion (50 mg/kg/hour) was initiated and continued throughout the subsequent study period. After placement of arterial, hepatic vein, and femoral vein catheters, metabolic parameters were determined before and for six hours after an intravenous E. coli LPS challenge (20 U/kg). Subsequent peak levels of arterial glucagon (ENT, 189 +/- 39 pg/mL; TPN, 428 +/- 48; p less than 0.01), arterial epinephrine (ENT, 236 +/- 52 pg/mL; TPN, 379 +/- 49; p less than 0.05) and hepatic venous cachectin/tumor necrosis factor (cachectin/TNF) (ENT, 250 +/- 56 pg/mL; TPN, 479 +/- 136; p less than 0.05) were significantly higher in the TPN group than in the ENT group. The extremity efflux of lactate (ENT, -16 +/- 4 micrograms/min-100cc tissue; TPN, -52 +/- 13; t = 2 hours; p less than 0.05) and of amino acids (ENT, -334 +/- 77 nmol/min-100cc tissue; TPN, -884 +/- 58; t = 4 hours; p less than 0.05) were higher in the TPN subjects after the endotoxin challenge. Circulating C-reactive Protein (CRP) levels measured 24 hours postendotoxin were also significantly higher in the TPN subjects (ENT, 1.7 +/- 0.2 mg/dL; TPN, 3.2 +/- 0.3; p less than 0.01). Hence the counter-regulatory hormone and splanchnic cytokine responses to LPS were enhanced after TPN and bowel rest. This is associated with a magnified acute-phase response, peripheral amino acid mobilization, and peripheral lactate production. Thus antecedent TPN may influence the metabolic alterations seen in infection and sepsis via both an exaggerated counter-regulatory hormone response as well as an enhanced systemic and splanchnic production of cytokines.

Interleukin 1 receptor blockade attenuates the host inflammatory response.

Cytokines, including interleukin 1 (IL-1), tumor necrosis factor alpha, and interleukin 6, are often produced in response to tissue injury and contribute to several host responses such as weight loss, anorexia, and acute-phase protein synthesis. However, the role of IL-1 in specific tissue responses is unclear. To test our hypothesis that specific in vivo blockade of IL-1's action might inhibit the catabolic host changes associated with inflammation, mice were passively immunized with a monoclonal antibody directed against the murine IL-1 receptor prior to initiation of a turpentine-induced sterile abscess. This antibody prevents IL-1-mediated proliferation of murine thymocytes in vitro by inhibiting IL-1 alpha and IL-1 beta by way of competition for a common receptor. Weight loss following turpentine challenge was prevented by daily injections of anti-IL-1 receptor monoclonal IgG. Body composition analysis confirmed that lean tissue and fat were preserved by passive immunization. Furthermore, pretreatment with an anti-IL-1 receptor monoclonal antibody significantly attenuated the plasma amyloid P and interleukin 6 responses but did not affect the decline in plasma albumin or the increase in circulating corticosterone. Passive immunization of similar mice with polyclonal antisera against another cytokine, tumor necrosis factor alpha, failed to prevent either the weight loss or hepatic acute-phase protein changes observed in this inflammatory model. These findings suggest that IL-1 orchestrates weight loss and body compositional changes during inflammation and contributes to the induction of interleukin 6 and acute-phase protein synthesis.

The influence of substrate background on the acute metabolic response to epinephrine and cortisol.

The acute metabolic effects of epinephrine and cortisol, as well as the influence of substrate background on the effects of these two hormones were investigated in normal subjects. While receiving a hypocaloric dextrose feeding (50 ng/kg/h) (DEX), the subjects received a 6-hour continuous intravenous infusion of epinephrine (30 ng/kg-min) (EPI), followed by a 6-hour infusion of a combination of epinephrine (30 mg/kg-min) and cortisol (3.0 microgram/kg-min) (EC). The hormone infusion was repeated 1 week after a continuous intravenous feeding regimen (TPN) was begun with a caloric content of 1.5 times the measured metabolic rate. Under both DEX and TPN, EPI produced increased energy expenditure, hyperglycemia, hyperlactic acidemia, and hypoaminoacidemia. Except for a further increase in circulating glucose levels during the DEX condition, these variables were not altered by the addition of cortisol. Epinephrine under both feeding conditions increased lactate efflux from the extremity without changes in peripheral oxygen or glucose uptake. The hypoaminoacidemic response to EPI in the DEX condition was associated with a decrease in extremity efflux of amino acids (-654 +/- 89 nmol/min/100 cm3 tissue at baseline vs -330 +/- 86 nmol/min/100 cm3 for EPI, p less than 0.05). No change in extremity amino acid flux was noted in response to EPI during total parenteral nutrition. Even with addition of cortisol no significant efflux of amino acids above baseline levels was noted in either feeding condition. We therefore conclude that (1) total parenteral nutrition cannot abolish the hypermetabolic or hyperglycemic response to epinephrine and cortisol; (2) increased extremity lactate efflux and lactic acidosis can occur in response to epinephrine without evidence of diminished oxygen delivery to the extremity; and (3) these two hormones are not primary mediators of acute extremity nitrogen loss.

Skeletal muscle amino acid and myofibrillar protein mRNA response to thermal injury and infection.

Skeletal muscle changes associated with severe injury were investigated in male Wistar rats subjected to 30% full thickness scald injury (burn) and thermal injury followed by immediate colonization with 10(8) colony-forming units of Pseudomonas aeruginosa (BI). Freely fed animals (FF) and animals pair fed to the BI animals (PF) served as controls. Thermal injury in conjunction with infection produced a rapid and sustained muscle cellular membrane depolarization (transmembrane potential difference at 12 h after injury: FF 92.1 +/- 0.3 and BI 85.2 +/- 2.3 mV; P less than 0.05). This was followed by body weight loss and skeletal muscle protein wasting (gastrocnemius protein at 7 days: FF 0.35 +/- 0.01 and BI 0.16 +/- 0.03 g; P less than 0.05) and intracellular high-energy phosphate depletion (ATP at 10 days: FF 6.6 +/- 0.4 and BI 4.5 +/- 0.4 mumol/g tissue; P less than 0.05). These body and cellular changes were not accounted for by the anorexia alone. Marked alterations in intracellular free amino acids were also noted in the BI group characterized by increases in levels of all amino acids (total intracellular free amino acids at 7 days: FF 51 +/- 7 and BI 91 +/- 12 mM; P less than 0.05) except intracellular glutamine (at 7 days: FF 6.0 +/- 0.2 and BI 2.4 +/- 0.6 mM; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)