Endocrinology in intensive care medicine: new insights and therapeutic consequences

Abstract

Sepsis, excessive inflammation, multiple organ failure and weakness prolong the need for intensive care in critically ill patients. Furthermore, the risk of death is high in the prolonged critically ill patient (20% after two weeks and 30% after 3 weeks). In prolonged critical illness, protein hypercatabolism and relative preservation of adipose tissue with fatty infiltration of vital organ systems is present. In view of the crucial role of the hypothalamus-pituitary axis for metabolic homeostasis, we have studied this endocrine organ in the context of critical illness. The initial "adaptive" neuroendocrine response to critical illness illness consists primarily of activated anterior pituitary function. In the chronic phase of critical illness, a uniformly reduced pulsatile secretion of anterior pituitary hormones has been observed, whereby impaired function of target organs. A reduced availability of thyrotropin (TSH)-releasing hormone (TRH), gonadotropin (LH)-releasing hormone (GnRH), the endogenous ligand of the growth hormone (GH)-releasing peptide (GHRP) receptor (ghrelin) and, in very long-stay critically ill men also of GH-releasing hormone (GHRH), inferrentially appears involved. Pulsatile secretion of GH, TSH and LH can be re-amplified by relevant combinations of releasing factors which also substantially increases circulating levels of insulin-like growth factor (IGF)-I, GH-dependent IGF-binding proteins, thyroxine (T4), triiodothyronine (T3) and testosterone. Anabolism is only evoked when GH-secretagogues, TRH and GnRH are administered together whereas the effect of single hormone treatment is minor and accompanied by side effects. A remarkable observation was that a high serum concentration of IGF-binding protein 1 predicts death in the ICU. This observation challenged the classical dogma of adaptive hyperglycemia during critical illness. In a large prospective randomized clinical study (1548 patients), we showed that ICU mortality was reduced by 42% with strict normalization of glycemia using exogenous insulin infusion (N Engl J Med 2001). This was due to prevention of typical ICU complications such as sepsis, multiple organ failure and need for prolonged invasive organ support and intensive care. We conclude that the new concept of reduced stimulation of pituitary function in prolonged critically ill patients opens new therapeutic perspectives to reverse the paradoxical 'wasting syndrome' but that maintenance of strict normoglycemia with insulin is crucial to also increase the chances of survival of these patients.