Although this discussion concentrates on the potential value of treating patients with NTIS with replacement thyroid hormone, several important recent studies expand the concept to other areas, including treatment of the associated hyperglycemia, relative adrenal insufficiency, and possible use of GHRH and testosterone. Van den Berghe and co-workers have suggested that the acute and prolonged critical illness responses are entirely different neuroendocrine conditions. In protracted severe illness, patients are kept alive with conditions that previously caused death. However, this process has unmasked a variety of nonspecific wasting syndromes including protein loss, accumulation of fat stores, hyperglycemia and insulin resistance, hypoproteinemia, hypercalcemia, potassium depletion, and hypertriglyceridemia. In prolonged illness, cortisol values are elevated, although ACTH levels are low, indicating that other mechanisms are driving the steroid response. Growth hormone secretory pulses are reduced, and the mean concentration is low in prolonged critical illness. FSH and LH are reduced, and testosterone levels are reduced. These authors maintain that the reduced neuroendocrine drive, present in the chronic phase of illness in an intensive care setting, is unlikely to be an evolutionary preserved beneficial process. They suggest that the administration of hypothalamic physiotropic releasing peptides may be a safer strategy than the administration of peripherally active hormones (86).    Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Van den Berghe et al carried out a prospective randomized study on ICU patients on mechanical ventilation, maintaining blood glucose at a level between 80 and 110 mg/dl, versus allowing glucose to range between a level of 180 – 200 mg/dl Intensive insulin therapy reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care (87).In isolated brain injury patients, intensive insulin therapy reduced mean and maximal intracranial pressure while identical cerebral perfusion pressures were obtained with eightfold less vasopressors. Seizures and diabetes insipidus occurred less frequently. At 12 months follow-up, more brain-injured survivors in the intensive insulin group were able to care for most of their own needs. Preventing even moderate hyperglycemia with insulin during intensive care protected the central and peripheral nervous systems, with clinical consequences such as shortening of intensive care dependency and possibly better long-term rehabilitation (87a). Prevention of catabolism, acidosis, excessive inflammation, and impaired innate immune function may explain previously documented beneficial effects of intensive insulin therapy on outcome of critical illness.(87b

    Severe burns are known to be associated with a hypermetabolic state and a strong sympathetic response. Beta blockade given as propranolol to reduce the resting heart rate by 20% decreased resting energy expenditure and increased net muscle protein balance  significantly in a group of burn patients. It is logical that this would be a significant benefit (140). Severe sepsis, which is of course associated with NTIS, is frequently associated with relative adrenal insufficiency, and possibly systemic inflammation-induced glucocorticoid receptor resistance. In a prospective randomized study, Annane et al studied a seven day treatment of patients with septic shock, by giving hydrocortisone, 50 mg q6h, and 9-alpha-fludrocortisone, 50 mg once daily. The risk of death in this treated group was significantly reduced without increasing any adverse effects. . The treatment was clearly most beneficial, in individuals who responded poorly to a 250 mg ACTH test, which was conducted prior to the therapy Non-response was defined as a response of 9 mg/dl or less, between the lowest, and highest concentration taken after the ACTH injection. Samples were taken in this study at 30 and 60 minutes (141). The severity of the illness was suggested by the statistics that 63% died in the placebo group, and 53% in the corticosteroid treatment group. The authors recommend that all patients with catecholamine dependent septic shock should be given a combination of hydrocortisone and fludrocortisone as soon as a short corticotropin stimulation test is performed, and the treatment should be continued for seven days in non-responders. Hamrahian et al advise caution in using total serum cortisol measurements in patients with serum albumin levels below 21.5gm/dl. They observed that these patients may have low total cortisol because of low CBG, but have normal or elevated free cortisol levels (142)    Pulsatile GNRH treatment, in patients with prolonged severe illness and the NTIS, only partially overcomes the associated hypogonadotropic hypogonadism. This indicates that there is both a hypothalamic and an end organ defect in this condition. However, the administration of androgen in this situation has not so far been shown to be beneficial (143). In contrast to the generally beneficial effects of hormonal therapy described above, high levels of growth hormone given to critically ill patients were found by Takala et al to augment mortality. The dosage used was 0.1 mg/kg bw, for up to 21 days. Mortality rate was nearly double. These authors suggest that GH may have an adverse effect upon immunity, cause fluid retention, and cause hyperglycemia (144).Treatment With Hypothalamic Releasing Hormones

Van Den Berghe and collaborators have pioneered studies on the effects of hypothalamic releasing hormones in patients with severe NTIS. The logic supporting this approach is that it corrects a major cause of the low hormonal state, and may allow normal feed-back control and peripheral regulation of hormones, thus being more physiological than replacing the peripheral hormone deficit directly. Extensive studies document restoration of T4 and T3 levels following administration of TRH and GH secretagaugue (79). In a rabbit model of NTIS treatment with GHRP-2 and TRH reactivated the GH and TSH axes and altered liver deiodinase activity, driving T4 to T3 conversion (145).

In NTIS there are suppressed pulsatile GH, TSH, LH secretion in the face of low serum concentrations of IGF-I, IGFBP-3 and the acid-labile subunit (ALS), thyroid hormones, and total and estimated free testosterone levels, whereas free oestradiol (E2) estimates are normal. Ureagenesis and breakdown of bone tissue are increased. Baseline serum TNF-alpha, IL-6 and C-reactive protein level and white blood cell (WBC) count are elevated; serum lactate is normal. Coadministration of GHRP-2, TRH and GnRH reactivated the GH, TSH and LH axes in prolonged critically ill men and evoked beneficial metabolic effects which were absent with GHRP-2 infusion alone and only partially present with GHRP-2 + TRH. These data underline the importance of correcting the multiple hormonal deficits in patients with prolonged critical illness to counteract the hypercatabolic state(145a

Contrary to expectation, intensive insulin therapy suppressed serum IGF-I, IGFBP-3, and acid-labile subunit concentrations. This effect was independent of survival of the critically ill patient. Concomitantly, serum GH levels were increased by intensive insulin therapy. The data suggest that intensive insulin therapy surprisingly suppressed the somatotropic axis despite its beneficial effects on patient outcome. GH resistance accompanied this suppression of the IGF-I axis. To what extent and through which mechanisms the changes in the GH-IGF-IGFBP axis contributed to the survival benefit under intensive insulin therapy remain elusive (145b) While outcome studies using this approach are not available, it is quite possible that treatment of NTIS by us of hypothalamic releasing hormones may be a preferred approach.