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Treatment with recombinant human GH (rhGH) increases the mortality of critical illness. We postulated that combined GH-releasing peptide-2 (GHRP-2), TRH, and insulin infusion is a less toxic anabolic strategy through a putative inability to overstimulate the GH axis and a capacity to normalize thyroid hormone concentrations while foregoing excessive hyperglycemia. Burn-injured, parenterally fed, New Zealand White rabbits were randomized to receive 4-d treatment with saline (n=8); 60 microg/kg.h GHRP-2 and 60 microg/kg.h TRH, i.v. (n=9); or 3.5 mg/kg rhGH, s.c. (n=7). In the GHRP-2+TRH group, insulin was adjusted to maintain blood glucose below 180 mg/dl. Endocrine function and biochemical organ system function markers were studied. Animals were killed for assay of deiodinase activity in snap-frozen liver. Mortality, organ system function, hyperglycemia, and insulin requirement were equal in the three groups. GHRP-2+TRH increased pulsatile rabbit GH (rGH) and TSH release on d 1. After 4 d, rGH secretion and T4 and T3 concentrations were elevated, with a significant increase in hepatic activity of type 1 deiodinase and a decrease in type 3 deiodinase. Exogenous rhGH suppressed endogenous rGH secretion and increased IGF-I more than GHRP-2+TRH without altering thyroid hormone levels. Unlike GHRP-2+TRH, rhGH down-regulated liver type 3 deiodinase and did not affect type 1 deiodinase. We conclude that in experimentally induced critical illness, GHRP-2+TRH reactivated the GH and TSH axes and altered liver deiodinase activity, driving T4 to T3 conversion. In contrast to the human model, high dose rhGH was not rapidly lethal in this rabbit model. Whether this is explained by lack of rhGH-induced insulin resistance and hyperglycemia remains unclear.

High doses of GH, used to induce anabolism in prolonged critically ill patients, unexpectedly increased mortality. To further explore underlying mechanisms, a valid animal model is needed. Such a model is presented in this study. Seven days after arterial and venous cannulae placement, male New Zealand White rabbits were randomly allocated to a control or a critically ill group. To induce prolonged critical illness, a template controlled 15% deep dermal burn injury was imposed under combined general and regional (paravertebral) anesthesia. Subsequently, critically ill rabbits received supplemental analgesia and were parenterally fed with glucose, insulin, amino acids, and lipids. On d 1 and d 8 after randomization, acute and chronic spontaneous hormonal profiles of GH, TSH, and PRL secretion were obtained by sampling blood every 15 min for 7 h. Furthermore, GH, TSH, and PRL responses to an iv bolus of GH-releasing peptide 2 (GHRP-2) + TRH were documented on d 0, 1, and 8. Hemodynamic status and biochemical parameters were evaluated on d 0, 1, 3, 5, and 8, after which animals were killed and relative wet weight and water content of organs was determined. Compared with controls, critically ill animals exhibited transient metabolic acidosis on d 1 and weight loss, organ wasting, systolic hypertension, and pronounced anemia on d 8. On d 1, pulsatile GH secretion doubled in the critically ill animals compared with controls, and decreased again on d 8 in the presence of low plasma IGF-I concentrations from d 1 to d 8. GH responses to GHRP-2 + TRH were elevated on d 1 and increased further on d 8 in the critically ill animals. Mean TSH concentrations were identical in both groups on d 1 and 8, in the face of dramatically suppressed plasma T(4) and T(3) concentrations in the critically ill animals. PRL secretion was impaired in the critically ill animals exclusively on d 8. TSH and PRL responses to GHRP-2 and TRH were increased only on d 1. In conclusion, this rabbit model of acute and prolonged critical illness reveals several of the clinical, biochemical, and endocrine manifestations of the human counterpart.

The etiology of the prompt decline in serum T3 in patients with nonthyroidal illness syndrome has not been adequately explained. It has been attributed to various parameters, including test artifacts, inhibitors of T4 and T3 binding to proteins, decreased 5′-deiodinase activity, and circulating cytokines. Currently, much attention is centered on the role of IL-6 and TNFα in developing the nonthyroidal illness syndrome through an effect on the hypothalamus, pituitary, and possibly 5′-deiodinase activity. We therefore studied the relation of the endogenous serum IL-6 and TNFα rise early in the course of nonthyroidal illness syndrome to the early decline in serum T3 in 19 apparently healthy individuals, aged 43 ± 16 yr, who underwent elective abdominal surgery for cholelithiasis or gastroplasty. Serum T3, free T3, T4, free T4, rT3, TSH, IL-6, and TNFα were measured before and at various time intervals up to 42 h after skin incision. We observed a prompt decline in serum T3 30 min before skin incision, which continued to decline throughout the observational period. The magnitude of the decline reached 20% from the baseline value at 2 h. The early decline of T3 was attenuated and lasted from the 2–8 h, probably due to the sharp increase in serum TSH that started immediately after the entrance to the operating room and lasted for 2 h. In contrast, serum T4 and free T4 concentrations were increased soon after skin incision and remained elevated during the first postoperative day. Serum rT3 increased approximately 6 h after the initiation of surgery and remained elevated thereafter. Serum IL-6 remained essentially undetectable for 2 h after skin incision, whereas serum T3 was low. Two hours after skin incision, serum IL-6 increased sharply and remained elevated throughout the observational period. Serum TNFα remained essentially undetectable throughout the postoperative period. Serum cortisol increased rapidly upon entrance to the operating room and remained elevated throughout the postoperative period. We conclude that the decline in serum T3 early in the course of nonthyroidal illness syndrome is not due to increased serum IL-6 or TNFα levels. The brisk TSH secretion soon after the onset of the syndrome attenuates the decline in serum T3 due to T3 secretion from the thyroid. The early and brisk cortisol response to surgery may at least in part explain the early decrease in serum T3 in nonthyroidal illness syndrome.