George H. A. Clowes

Differential tissue sensitivity to elevated endogenous insulin levels during experimental peritonitis in rats

Abstract Disturbances of glucose metabolism consequent to experimental peritonitis in rats were studied by measurement of insulin-related metabolism of isolated tissues in correlation with blood insulin and substrate levels. Blood insulin concentrations were threefold higher in infected fasting rats than in normal fasting controls, despite approximately equal blood glucose concentrations, suggesting resistance to the hypoglycemic action of insulin. The increased circulating insulin was associated with a threefold elevation of the insulin-sensitive adipose tissue pyruvate dehydrogenase enzyme complex, and a threefold increase in the rate of conversion of glucose to CO2 by fragments of epididymal fat pads. Fasting infected animals also had reduced circulating nonesterified fatty acids and relatively less depletion of epididymal adipose tissue, when compared to fasted controls presumably due to the potent action of insulin in opposing lipid mobilization. In contrast, diaphragm pyruvate dehydrogenase was not elevated, nor was diaphragm glucose conversion to CO2 stimulated in response to the elevated circulating insulin. It is proposed that reduced fat mobilization without concomitantly accelerated glucose oxidation by muscle may result in insufficient metabolic fuel for muscle and this may, in turn, promote amino acid combustion by muscle to meet cellular energy requirements. This suggested mechanism may provide a hypothetical biochemical explanation for the excessive protein catabolism associated with severe infection.

The Circulatory Abnormalities of Heat Stroke

Abstract Serial hemodynamic measurements in eight Marine recruits suffering from acute heat stroke (mean rectal temperature of 41.5°C) revealed a hyperdynamic circulation pattern in seven: mean car...

Septic lung and shock lung in man.

Two series of patients were studied by serial measurements of blood gas exchange and pulmonarmonary dysfunction and to evaluate the dangers of respiratory failure in post traumatic patients. There were 27 patients who had sustained profound hemorrhagic shock and massive blood replacement averaging 9.7 liters and 38 patients who suffered general peritonitis or other forms of fulminating nonthoracic sepsis. All were supported by endotrachael intubation and volume controlled ventilators. The overall mortality for the post shock patients without sepsis was 12% while in the septic patients it was 35%. The maximal pulmonary arteriovenous shunt encountered in the post hemorrhagic shock patients at 36 hours averaged 20 plus or minus 8% and was accompanied by high cardiac indices (average 5.1 plus or minus 1.3 L/M-2/min) but no significant rise of pulmonary arterial pressure or peak inspiratory pressure (PIP). Severe pulmonary dysfunction subsequently occurred only in those patients who later became septic. The studies on the septic patients were divided according to the magnitude of the cardiac indices (the high indices averaged 4.8 plus or minus 1.6L/M-2/min) and thelow indices averaged 1.9 plus or minus 1.0 L/M-2/min. In the former, the average maximal shunt of 30 plus or minus 6% was sustained for 4 or more days, accompanied by an elevation of PIP to 36 plus or minus 6 cm H2O and by Pa pressure of 28 plus or minus 5 mm Hg. The patients in low output septic shock usually had an associated bronchopneumonia and had an average venous admixture of 34 plus or minus 8% and PIP values of 41 plus or minus 8 cm H2O. The mean Pa pressure in this group was 29 plus or minus 6 mm Hg.

Survival from hepatic transplantation. Relationship of protein synthesis to histological abnormalities in patient selection and postoperative management

Forty-one patients, all in end stage hepatic failure, underwent 46 liver transplantations with a long-term survival rate of 63%. Six patients died of uncontrollable bleeding due to primary graft malfunction at or immediately after operation. Nine died early or late with overwhelming infection. In addition to clinical assessment, needle liver biopsy, central plasma clearance rate of amino acids (CPCR-AA), and routine “liver function tests” were employed to aid in selection of patients for transplantation and for guidance in postoperative management. Although liver biopsies usually afforded an exact diagnosis, neither they nor the routine liver function tests quantitated the extent to which hepatocyte function was impaired. CPCR-AA, which measures the rate of amino acid uptake by the liver and other central tissues for oxidation, gluconeogenesis, and protein synthesis was 91 ± 9 ml/M2/min in the preoperative transplant group. This compares with a value of 97 ± 16 in a previously studied series of cirrhotics who died following other forms of surgery and a CPCR-AA of 220 ± 26 ml/m2/min in those who survived. In addition, the preoperative CPCR-AA was found to correlate with the in vitro hepatic protein synthetic rate of slices from the resected recipient liver (r = 0.72, p < 0.02). After operation, serial hepatic needle biopsies were classified by histology into four grades of injury, ranging from normal liver transplant (Grade I) to mild hypoxic or rejection injury (Grade II), viral hepatitis (Grade III), and severe hypoxic or rejection injury (Grade IV). Significant relationships of the histological grades to ultimate mortality, CPCR-AA, and prothrombin times were found. CPCR-AA and pro-thrombin time correlate inversely (r = 0.57, p < 0.001), further demonstrating the relationship of CPCR-AA to protein synthesis of clotting factors. These patterns of posttransplant response were delineated by serial CPCR-AA values. “Early” responders had values over 290 ml/M2/min and all survived. Twelve patients with delayed response were characterized by values of 150 ± 12, rising to over 200 ml/M2/min after 2 weeks. Two who failed to increase CPCR-AA died. In six “poor” responders, CPCR-AA with Grade IV injury remained below 110 ml/M2/min. All died except for one whose CPCR-AA subsequently rose following retransplantation. It is concluded that percutaneous hepatic needle biopsies and CPCR-AA measurements in combination arc of proven value, not only in understanding the nature of injury and functional impairment of the liver, but are also important as guides to selection of patients and for their posttransplant management.

Myocardial performance in clinical septic shock: Effects of isoproterenol and glucose potassium insulin

Abstract Six patients with low-output septic shock were studied with Swan-Ganz pulmonary artery catheterization. The results indicate severe biventricular dysfunction. Inotropic therapy with isoproterenol produced improved ventricular performance but did not correct myocardial depression. Infusion of glucose/potassium/insulin dramatically improved myocardial performance and appeared to correct the myocardial abnormalities of low-output septic shock.

Relationship of hind limb energy fuel metabolism to the circulatory responses in severe sepsis

Abstract A comparison of basal fasting circulatory responses and peripheral substrate utilization to that of experimentally-induced peritonitis reveals: 1. 1. Two systemic and peripheral circulatory responses: 1.1. a. The high flow septic response—associated with survival, 1.2. b. The low flow septic response—associated with high mortality. 2. 2. Two patterns of substrate utilization during sepsis which parallel the circulatory response and clearly differ from the metabolic pattern of starvation: 2.1. a. The high flow septic pattern—characterized by hyperinsulinemia with peripheral glucose resistance and diminished fat utilization, resulting in protein catabolism to maintain peripheral energy production. 2.2. b. The low flow septic pattern—characterized by increased peripheral release and uptake of FFA, low insulin levels, and increased lactate production arising from increased catecholamine activity.