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Endocrine and Metabolic Effects of Growth Hormone (GH) Compared with GH-Releasing Peptide, Thyrotropin-Releasing Hormone, and Insulin Infusion in a Rabbit Model of Prolonged Critical Illness

Department of Intensive Care Medicine, Burn Unit and Center for Experimental Surgery and Anesthesiology (F.W., M.M., G.V.d.B.), Laboratory for Experimental Medicine and Endocrinology (E.V.H., W.C.), and Laboratory for Comparative Endocrinology (V.M.D.), Catholic University of Leuven, Leuven, Belgium; and Department of Medicine, Mayo Graduate and Medical Schools (J.D.V.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Frank Weekers, M.D., Department Intensive Care Medicine, University of Leuven, B-3000 Leuven, Belgium. E-mail: frank.weekers{at}uz.kuleuven.ac.be.

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 µg/kg·h GHRP-2 and 60 µg/kg·h TRH, iv (n = 9); or 3.5 mg/kg rhGH, sc (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.

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