Role of the somatotrophic axis in the regulation of protein metabolism in the catabolic state

Abstract

The metabolic hallmark of severe sepsis is an enhanced rate of endogenous protein breakdown. When sepsis is prolonged, the continuing loss of protein in septic patients results in significant cardiopulmonary impairment and musculoskeletal weakness and is not corrected by the administration of total parenteral nutrition. The investigations described in this thesis utilize primed constant infusions of stable and radioisotopes and indirect calorimetry, and have sought to define the respective roles of the somatotrophic hormones (growth hormone, insulin like growth factor-I and insulin like growth factor-II) in the regulation of protein metabolism in the stressed and catabolic state. Specifically the aims of these investigations were: (i) To define the effects of adjuvant recombinant human growth hormone (rhGH) in addition to total parenteral nutrition on protein metabolism and clinical outcome in septic, catabolic surgical patients. (ii) To define the effects of pretreatment with growth hormone prior to the induction of a catabolic state, on protein metabolism, plasma insulin like growth factor-I concentration and the response to parenteral nutrition during a subsequent catabolic period. (iii) To clarify the endocrine role of endogenously produced insulin like growth factor-I in the regulation of protein metabolism in the catabolic state. (iv) To clarify the endocrine role of endogenously produced insulin like growth factor-II in the regulation of protein metabolism in the catabolic state. (v) To define the effect of adjuvant insulin like growth factor-I and parenteral nutrition on protein metabolism at a whole body and tissue level in the fasted, catabolic animal. (vi) To clarify the interrelationship between nutritional intake and circulating insulin like growth factor-I concentration in the regulation of protein metabolism in the catabolic state. The major findings of these investigations were as follows: (i) In the septic patient twice daily treatment with recombinant human growth hormone in addition to total parenteral nutrition (TPN) resulted in a significant decrease in the rate of endogenous protein catabolism in comparison to patients treated with placebo and TPN Treatment of those patients with an initial rate of net protein catabolism of ? 1.5 g/kg.day resulting in a decrease in the rate of protein loss of 125% and the induction of an anabolic state. In contrast treatment with growth hormone in those patients with an initial rate of net protein catabolism of > 1.5 g/kg.day was no more effective than treatment with placebo. Although treatment with growth hormone was well tolerated, rhGH treated patients required more insulin to maintain euglycaemia and no beneficial effect on daily sepsis score, Kehlet score, Karnovsky score, duration of parenteral feeding or total hospital stay was observed. However growth hormone treated patients were noted to have a significantly lower systolic, diastolic, and mean arterial pressure than the placebo treated patients on days 5 to 7 inclusive of treatment. During the same period pulse rate and pulse pressure remained unchanged suggesting a net change in cardiovascular efficiency. (ii) Following 48 hours of fasting, animals which had received, 7 days of prior treatment with growth hormone had a significantly decreased rate of net protein catabolism and an elevated circulating plasma insulin like growth factor-I concentration in comparison to those animals which did not receive prior growth hormone treatment. In addition the rate of net protein catabolism and whole body protein catabolism decreased significantly during a period of parenteral feeding following 48 hours of starvation in the treated animals. In contrast in untreated animals net protein catabolism and whole body protein catabolism continued to increase during the period of parenteral feeding. (iii) In catabolic animals, passive immunization against circulating insulin like growth factor-I using a specifc antibody, increased the rate of net protein catabolism significantly. This reached a Peak 30 minutes following antibody administration and returned to pretreatment levels within 60 minutes of antibody injection. (iv) In catabolic lambs the infusion of insulin like growth factor-I in non-parenterally fed animals increased the mean plasma insulin like growth factor-I concentration and decreased the rate of net protein loss by 17% in comparison to saline infused control animals. In addition the fractional synthetic rate of protein in cardiac and diaphragmatic muscle increased by 100% during the same Period. In contrast the concurrent infusion of insulin like growth factor-I and parenteral nutrition decreased the rate of net protein catabolism substantially and all catabolic animals were rendered anabolic within 60 minutes of commencing the combined infusion. Similarly the fractional synthetic rates of protein in cardiac muscle, diaphram, adductor muscle, psoas muscle and hepatic tissue were significantly increased in comparison to those animals which received only parenteral feeding or infusion of insulin like growth factor-I alone. (v) The infusion of insulin like growth factor-II concurrently with the insulin like growth factor-I resulted in a significant increase in the plasma insulin like growth factor-I and insulin like growth factor-II concentration. However in contrast to the infusion of insulin like growth factor-I alone, no decrease in the rate of net protein catabolism was observed during the combined infusion. In conclusion these investigations have demonstrated that: (i) 7 days of adjuvant rhGH at a dose of 0.3 IU /kg.day, in addition to adequate nutritional support, renders the moderately catabolic patient anabolic. However rhGH in this dose failed to improve protein kinetics in severely catabolic patients implying that these patients are growth hormone resistant. There were no definable improvements in severity of disease or physiological function attributable to improved protein metabolism or rhGH treatment. Further studies are required to address the optimal dose and duration of treatment in patients with varying degrees of catabolic illness and to define any effects on clinical course and outcome. (ii) Growth hormone in this dose was associated with minimal adverse effects in septic, catabolic patients although supplemental insulin may be required to achieve euglycaemia. Finally rhGH administration may improve myocardial and cardiovascular function in severely stressed patients and have a potential role in the hemodynamic management and rehabilitation of the critically ill. (iii) Pretreatment with growth hormone attenuates the catabolic response to subsequent metabolic stress and this suggests that growth hormone may have an important and currently unrecognised role in the preoperative management of the malnourished, high risk patient undergoing elective or urgent surgery. (iv) An acute decrease in circulating insulin like growth factor-I concentration is associated with a transient increase in protein catabolism. Correspondingly infusion of insulin like growth factor-I decreases net protein catabolism in catabolic animals by decreasing whole body protein catabolism. This suggests that insulin like growth factor-I plays an integrative role in the control of protein turnover. (v) Infusion of insulin like growth factor-II in conjunction with insulin like growth factor-I blocks the anabolic effects of insulin like growth factor-I and suggests that insulin like growth factor-II may play a physiological role as a circulating modulator of the anabolic effects of insulin like growth factor-I. (vi) When administered together insulin like growth factor-I and parenteral feeding act synergistically by decreasing whole body protein catabolism and enhancing whole body protein synthesis.