Society of Cardiovascular Anesthesiologists

Increased mortality associated with growth hormone treatment in critically ill adults

Authors: Takala J, Ruokonen E, Webster N R, Nielsen M S, Zandstra D F, Vundelinckx G, Hinds C J.

Reference: N Engl J Med 1999; 341:785-92.

Reviewer:
Rose Christopherson, M.D., Ph.D.
Oregon Health Sciences University
Anesthesiology Service
Portland V.A. Medical Center
Portland, OR

Background:

Although growth hormone can attenuate the catabolic response to injury, surgery, and sepsis, the effect of high doses of growth hormone on critically ill adults in ICU's was not known.

Methods:

Two prospective randomized double-blind multicenter trials were performed. One involved 247 Finnish patients, the other, 285 patients in other European countries. Criteria for enrollment were having been in an ICU for 5-7 days, and being expected to require at least another 10 days of ICU care. Study patients had had cardiac surgery, abdominal surgery, multiple trauma, or acute respiratory failure. Patients were randomized to receive either growth hormone, "0.10 +/- 0.02 mg/kg" or placebo until ICU discharge or up to 21 days.

Results:

In both studies, in-hospital mortality was higher in patients who received growth hormone (P <0.001, each study). In the Finnish study the mortality rate was 39% in the growth hormone group and 20% in the placebo group; in the multinational study, the rates were 44% and 18% respectively. Relative risks of dying in the growth hormone group were 1.9 (95% C.I. 1.3-2.9) in the Finnish study and 2.4 (95% C.I. 1.6-3.5) in the international study. Among survivors, length of stay in the ICU, length of hospital stay, and duration of mechanical ventilation were all prolonged among patients randomized to the growth hormone group compared to those who received placebo.

Conclusions:

Patients suffering from severe prolonged illness requiring ICU care had increased mortality rates and increased morbidity when given high dose growth hormone compared to those who received placebo.

Comment:

Studies have shown benefit associated with growth hormone in growth hormone deficient adults, patients with severe burns, trauma patients receiving parenteral nutrition, surgery patients, and children who have been burned. However, these studies reported surrogate outcomes such as improved nitrogen balance, grip strength, or ventilator weaning rather than survival. Furthermore, they were small studies on patients who were less ill, in which mortality rates would be low and would be unlikely to be significantly different between groups.

The authors felt that the adverse effect of growth hormone in their two studies may have been due to an effect of the growth hormone on immune function, since the causes of death in the growth hormone groups included a preponderance of multiple-organ failure, septic shock, and / or uncontrolled infection. Growth hormone also induces resistance to insulin, and patients in these studies who received growth hormone had higher blood glucose levels and insulin requirements than placebo-treated patients. The authors speculated that the growth hormone might have caused glucose deprivation on an intracellular level. Growth hormone also affects thyroid and adrenocortical function. It prevents mobilization of glutamine from muscle, which may result in less glutamine for rapidly dividing cells such as leukocytes and enteric epithelium. They suggested that the causes of the increased mortality associated with administration of growth hormone might have been diverse and complex, given all these effects of the hormone.

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