Douglas W. Wilmore

Development and analysis of a small animal model simulating the human postburn hypermetabolic response

Growing guinea pigs and mature rats are good models of the human metabolic response to thermal injury demonstrating a dose-response relationship between burn size and metabolic rate, an elevation in metabolic rate related to the stage of convalescence and hypermetabolism that may be altered but not abated by external heating. A 50% total body surface burn must be produced before reliable elevations in metabolic rate are observed. The mature rat is the best of the three animal models and is suitable for evaluation of the mediators and modulators of the hypermetabolic response to thermal injury.

Hormonal Responses and Their Effect on Metabolism

The author reviews the endocrine response to major stress and relates these hormonal changes to the alterations in physiology and biochemistry of critically ill surgical patients.

Glucose-dependent hepatic membrane transport in nonbacteremic and bacteremic thermally injured patients☆

Hepatic clearance of indocyanine green was measured in 106 studies in 25 thermally injured patients with an average total body surface burn of 59% and a mean age of 35 years. Seventeen patients subsequently developed positive blood cultures and were restudied. Fourteen serial measurements of dye concentration taken over a 70-min period were computer fitted to describe each disappearance curve, and the two rate constants, k1 and k2 were determined (all r2 > 0.94). n nICG plasma disappearance was unimpaired in nonbacteremic patients when glucose or glucose plus amino acids were part of the parenteral regimen (−k1 = 0.241 ± 0.023 and 0.255 ± 0.009 min−1) but significantly decreased when near isocaloric amounts of glucose-free amino acid solutions were administered (−k1 = 0.150 ± 0.016 min−1, P < 0.001). Bacteremic patients had markedly impaired ICG hepatic clearance irrespective of the hypocaloric dietary regimen. Both exclusion of glucose from the nutrient infusates in nonbacteremic patients and bacteremia result in a marked reduction in the maximal velocity of the ICG dye transport reaction. n nSeptic patients infused with glucose and insulin improved their clearance of the dye (from k1 = 0.169 ± 0.029 to 0.183 ± 0.028 min−1, P < 0.01). These alterations could not be related to changes in circulation or perfusion. Urea production varied inversely and endogenous insulin levels directly with the k1 suggesting that membrane transport is related to the ornithine cycle and/or is influenced by insulin. n nOptimal metabolic integrity of the hepatocyte is substrate specific and dependent upon the provision of exogenous energy. Hepatic transport function is limited in bacteremic patients as well as burn patients who are deprived of glucose. Restoration of hepatic transport processes may be achieved by providing sufficient energy in the form of glucose.

The effect of central nervous system narcosis on the sympathetic response to stress.

Heat production at the end of three hours of cold exposure (14°C) in normal men was significantly lower during He-O2 inhalation when compared with room air (43.8 ± 3.2 kcal/m2hr vs 58.8 ± 5.5, P < 0.05) as was core temperature (36.5 ± 0.1 vs 36.7 ± 0.1, P < 0.02). No effects on metabolism were noted in eight thermal neutral nonstressed studies (metabolic rate 37.8 ± 1.5 vs 35.2 ± 3.0, air vs He-O2). In six studies in normals, metabolism was unchanged following epinephrine infusion while breathing He-O2 (47.2 ± 2.0 vs 48.3 ± 0.9), suggesting helium dampens CNS sympathetic outflow but does not act as a peripheral blocking agent. n nFour burn patients (mean burn size 47% total body surface) were studied while breathing He-O2 for two hours, two (mean burn size 38%) while breathing argon-O2, and five (mean burn size 74%) following intravenous morphine administration. Hypermetabolism did not decrease with inhalation of the inert gases in the burn patient. However, morphine administration (0.38 mg/kg/hr) signficantly decreased oxygen consumption (77.4 ± 5.9 vs 55.0 ± 3.7), pulse rate (115 ± 4 beats/min vs 104 ± 5), core temperature (38.2 ± 0.1°C vs 37.3 ± 0.1), and minute ventilation (21.5 ± 2.5 liter/min. vs. 12.0 ± 1.0) while blood pressure and blood gases remained unchanged. n nThe CNS response to injury or cold exposure may be dampened by central narcosis. The effect produced varies with the extent of stress, and some agents that modify mild stress in normal men exert no detectable effects on the hypermetabolic response to injury.

Muscle blood flow following thermal injury

Peripheral circulation is markedly increased during the hyperdynamic-hypermetabolic phase of thermal injury and appears to be directed primarily to the burn wound. To determine whether any portion of this extra blood flow reaches another major peripheral vascular bed, blood flow in the tibialis anterior muscle of the lower leg was measured by 133Xe clearance in ten hemodynamically stable, nonseptic burn patients (mean burn size = 42.5% total body surface) and five control subjects. Muscle blood flow was 3.52 +/- 0.26 ml/100 g.min (mean +/- S.E.M.) in these patients and 3.29 +/- 0.24 in controls, indicating that resting muscle perfusion was unaffected by the extent of total body surface injury, size of leg burn, or elevated rectal temperature (38.2 +/- 0.2 degrees C) of the patients. These results confirm the interpretations of previous studies suggesting that most of the increased peripheral blood flow following thermal injury is directed to the surface wound. Local and systemic factors responsible for the maintenance of muscle perfusion in the face of alterations in muscle metabolism following thermal injury are discussed. Language: en

Control of blood flow in a large surface wound

To study the factors which control the increased blood flow to a large granulating wound, Doppler flow probes were implanted around the external iliac arteries bilaterally in 20–40 kg goats. Following operative recovery and basal measurements, skin was excised from one hind limb. Blood flow in the injured leg of five awake, resting goats rose above that of the uninjured leg by the fourth postoperative day and plateaued at 70–90% above uninjured leg flows for the next two weeks. The increase in injured leg blood flow was associated in time with the formation of a highly vascularized wound. This increased blood flow to the injured leg persisted in 11 anesthetized goats studied 9–12 days postinjury (186 + 27 ml/minute versus 107 + 19, p < 0.01, mean ± SEM). Substrate turnover revealed that elevated blood flow to the injured leg was not the result of increased oxygen consumption, but was associated with increased glucose uptake (7.8 ±1.1 mg/minute versus 2.7 ± 0.6, p < 0.001) and lactate release (3.6 ± 1.3 mg/minute versus 1.1 ± 0.7, p < 0.05). Limitations in oxygen delivery failed to explain the increased blood flow to the injured leg, since raising arterial Po2 or exposing the leg to a high oxygen environment had no effect on limb perfusion. Although lactate and potassium, both potential vasodilators, were elevated in the femoral vein blood from the injured leg, a series of cross perfusion studies failed to reduce vascular resistance in another leg on the same or a second uninjured animal. Additional studies revealed that changes in leg vascular resistance were markedly diminished in the injured leg following hemorrhage, spinal anesthesia, or intravenous infusion of epinephrine or norepinephrine. These studies of large granulating wounds reveal: 1) elevated injured leg flow is not the result of local hypoxia; 2) any wound vasodilators have no impact on systemic circulation; 3) the wound vasculature appears relatively insensitive to circulating and neurogenic vasomotor drives.

Erythrocyte sodium transport and membrane adenosine triphosphatase in patients with thermal injury

Various aspects of erythrocyte sodium movement have been measured in 48 patients with extensive thermal injury. Intracellular sodium and potassium concentrations were determined and found to be identical to those observed in a group of healthy individuals of comparable age. Flux studies, using 22Na, revealed no differences between burn patients and controls in the ouabain-sensitive transport of sodium from the cell; only a slight decrease in the ouabain-insensitive exit was noted among burn patients. Furthermore, there was no statistically significant difference in sodium influx for the two groups. Consistent with these results were essentially normal values for red cell membrane adenosine triphosphatase activities, including Km and Vmax. Burn patients, however, did demonstrate nearly a 2-fold increase in red cell hexokinase activity, and the implications of this finding are discussed with respect to red cell glucose utilization and membrane cation permeability.

Hypermetabolism in Trauma

Body injury, whether it be the result of a carefully planned surgical procedure or due to some accidental means, alters the normal homeostatic balance of the organism and initiates a well-integrated, total body response. The metabolic components of this response were first documented in the early 1900s when it was reported that haemorrhage and operation increased urinary nitrogen excretion (Hawk and Gies, 1904; Haskins, 1907). Evolution of this field of investigation has recently been described by Sir David Cuthbertson (1976), a man who over the last fifty years, has been its single major contributor.