Skeletal muscle insulin unresponsiveness during chronic hyperdynamic sepsis in the dog

Recent reports from our laboratory and others have documented changes in insulin unresponsiveness and electrolyte and hormonal changes characteristic of hypodynamic shock states in anesthetized animals. Since most acute shock protocols do not adequately mimic the clinical profile of sepsis, the present study was undertaken to document the hemodynamic and metabolic changes associated with chronic hyperdynamic peritonitis in dogs. Mongrel dogs of either sex weighing 20 +/- 2 kg were surgically instrumented with an electromagnetic aortic flow probe for monitoring cardiac output determinations, and aortic and central venous catheters for withdrawing blood for blood pressure and chemical analyses. Following a recovery period (7-10 days) control hemodynamic and metabolic measurements were made. Sepsis was induced (peritoneal abscess) by implanting a 4" X 4" gauze sponge, previously inoculated with human fecal bacteria, amid the intestines. Experimental (N = 18) and pair-fed control (N = 6) animals were monitored daily for 21 days or until death. During the septic protocol, cardiac index increased from a control value of 3.4 L/min/m2 to 5.5 L/min/m2 by the end of the experimental period. Mean arterial blood pressure, total peripheral resistance index, body weight, and plasma Ca++ fell below control values during the experimental period. Body temperature, plasma glucose, insulin, glucagon, and Mg++ were all elevated with sepsis. At the end of the chronic experimental period, skeletal muscle insulin responsiveness was assessed in the isolated, innervated, constantly perfused gracilis muscle preparation. Pair-fed control animals responded to various concentrations of local insulin infusion by increasing glucose uptake by the gracilis muscle. However, septic animals had a blunted response to local insulin infusion resulting in a decrease in the maximum dose response effect. These data demonstrate that: chronic, hyperdynamic peritonitis in the dog more closely mimics the human clinical profile of sepsis; and hyperdynamic sepsis is associated with a state of skeletal muscle insulin unresponsiveness which results from a post-receptor defect.