Increased mortality associated with growth hormone treatment in critically ill adults.

A BSTRACT Background The administration of growth hormone can attenuate the catabolic response to injury, surgery, and sepsis. However, the effect of high doses of growth hormone on the length of stay in intensive care and in the hospital, the duration of mechanical ventilation, and the outcome in critically ill adults who are hospitalized for long periods is not known. Methods We carried out two prospective, multicenter, double-blind, randomized, placebo-controlled trials in parallel involving 247 Finnish patients and 285 patients in other European countries who had been in an intensive care unit for 5 to 7 days and who were expected to require intensive care for at least 10 days. The patients had had cardiac surgery, abdominal surgery, multiple trauma, or acute respiratory failure. The patients received either growth hormone (mean [±SD] daily dose, 0.10±0.02 mg per kilogram of body weight) or placebo until discharge from intensive care or for a maximum of 21 days. Results The in-hospital mortality rate was higher in the patients who received growth hormone than in those who did not (P<0.001 for both studies). In the Finnish study, the mortality rate was 39 percent in the growth hormone group, as compared with 20 percent in the placebo group. The respective rates in the multinational study were 44 percent and 18 percent. The relative risk of death for patients receiving growth hormone was 1.9 (95 percent confidence interval, 1.3 to 2.9) in the Finnish study and 2.4 (95 percent confidence interval, 1.6 to 3.5) in the multinational study. Among the survivors, the length of stay in intensive care and in the hospital and the duration of mechanical ventilation were prolonged in the growth hormone group. Conclusions In patients with prolonged critical illness, high doses of growth hormone are associated with increased morbidity and mortality. (N Engl J Med 1999;341:785-92.)

[1]  P. Cole,et al.  Growth hormone is a human macrophage activating factor. Priming of human monocytes for enhanced release of H2O2. , 1995, Journal of immunology.

[2]  D. Wilmore,et al.  Growth Hormone Stimulates Protein Synthesis during Hypocaloric Parenteral Nutrition: Role of Hormonal‐Substrate Environment , 1988, Annals of surgery.

[3]  M. Rennie,et al.  Muscle protein turnover and the wasting due to injury and disease. , 1985, British medical bulletin.

[4]  J. L. Gall,et al.  APACHE II--a severity of disease classification system. , 1986, Critical care medicine.

[5]  D. Wilmore,et al.  Use of growth hormone for postoperative respiratory failure. , 1996, American journal of surgery.

[6]  G. Van den Berghe,et al.  The somatotropic axis in critical illness: effect of continuous growth hormone (GH)-releasing hormone and GH-releasing peptide-2 infusion. , 1997, The Journal of clinical endocrinology and metabolism.

[7]  J. H. Shaw,et al.  Anabolic and cardiovascular effects of recombinant human growth hormone in surgical patients with sepsis , 1996, The British journal of surgery.

[8]  D. Löhlein,et al.  Improved cumulated nitrogen balance after administration of recombinant human growth hormone in patients undergoing gastrointestinal surgery. , 1994, Infusionstherapie und Transfusionsmedizin.

[9]  B. Angelin,et al.  Growth hormone potentiates the in vivo biological activities of endotoxin in the rat , 1996, European journal of clinical investigation.

[10]  D. Wilmore,et al.  Low‐Dose Growth Hormone and Hypocaloric Nutrition Attenuate the Protein‐Catabolic Response After Major Operation , 1989, Annals of surgery.

[11]  K. Noonan,et al.  The effect of growth hormone replacement therapy on cortisol–cortisone interconversion in hypopituitary adults: evidence for growth hormone modulation of extrarenal 11β‐hydroxysteroid dehydrogenase activity , 1998, Clinical endocrinology.

[12]  S. Lowry,et al.  Recombinant human growth hormone enhances the metabolic efficacy of parenteral nutrition: a double-blind, randomized controlled study. , 1992, The Journal of clinical endocrinology and metabolism.

[13]  A. Benzer,et al.  Improvement of septic syndrome after administration of recombinant human growth hormone (rhGH)? , 1991, The Journal of trauma.

[14]  R. S. V. STRACK VAN SCHIJNDEL,et al.  Effects of Recombinant Human Growth Hormone in Patients With Severe Sepsis , 1992, Annals of surgery.

[15]  R. Dantzer,et al.  Hypophysectomy Inhibits the Synthesis of Tumor Necrosis Factor α by Rat Macrophages: Partial Restoration by Exogenous Growth Hormone or Interferon γ , 1991 .

[16]  J. Mälstam,et al.  Therapeutic intervention scoring system (TISS) — a method for measuring workload and calculating costs in the ICU , 1992, Acta anaesthesiologica Scandinavica.

[17]  D. Clemmons,et al.  The effect of growth hormone on weight gain and pulmonary function in patients with chronic obstructive lung disease. , 1991, Chest.

[18]  M. Jeevanandam,et al.  Altered lipid kinetics in adjuvant recombinant human growth hormone-treated multiple-trauma patients. , 1994, The American journal of physiology.

[19]  J. Wernerman,et al.  Biosynthetic Human Growth Hormone Preserves Both Muscle Protein Synthesis and the Decrease in Muscle‐free Glutamine, and Improves Whole‐body Nitrogen Economy After Operation , 1992, Annals of surgery.

[20]  J. Nauta,et al.  Effects of human growth hormone in critically ill nonseptic patients: results from a prospective, randomized, placebo-controlled trial. , 1995, Critical care medicine.

[21]  T. Elsasser,et al.  Recombinant bovine somatotropin blunts plasma tumor necrosis factor-alpha, cortisol, and thromboxane-B2 responses to endotoxin in vivo. , 1994, Endocrinology.

[22]  K. Fukatsu,et al.  Growth hormone and insulinlike growth factor I enhance host defense in a murine sepsis model. , 1995, Archives of surgery.

[23]  D. Wilmore,et al.  Increased survival after major thermal injury: the effect of growth hormone therapy in adults. , 1995, The Journal of trauma.

[24]  C. Pichard,et al.  Lack of effects of recombinant growth hormone on muscle function in patients requiring prolonged mechanical ventilation: a prospective, randomized, controlled study. , 1996, Critical care medicine.

[25]  D. Halliday,et al.  POSTOPERATIVE POSITIVE NITROGEN BALANCE WITH INTRAVENOUS HYPONUTRITION AND GROWTH HORMONE , 1988, The Lancet.

[26]  M. Jeevanandam,et al.  Adjuvant recombinant human growth hormone normalizes plasma amino acids in parenterally fed trauma patients. , 1995, JPEN. Journal of parenteral and enteral nutrition.

[27]  L. Broemeling,et al.  Effects of recombinant human growth hormone on donor-site healing in severely burned children. , 1990, Annals of surgery.

[28]  G. Biolo,et al.  Effects of growth hormone administration on skeletal muscle glutamine metabolism in severely traumatized patients: preliminary report. , 1997, Clinical nutrition.

[29]  T Bendix,et al.  Fatigue and cardiorespiratory function following abdominal surgery , 1982, The British journal of surgery.

[30]  I. Macdonald,et al.  Increased whole body protein breakdown predominates over increased whole body protein synthesis in multiple organ failure. , 1993, Clinical science.

[31]  R. Wolfe,et al.  Effect of exogenous growth hormone on whole-body and isolated-limb protein kinetics in burned patients. , 1991, Archives of surgery.

[32]  B. Pedersen,et al.  In vitro effects of human growth hormone on the proliferative responses and cytokine production of blood mononuclear cells. , 1994, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[33]  A Kari,et al.  Septic shock and multiple organ failure , 1991, Critical care medicine.

[34]  J. Holly,et al.  Critical illness is associated with low circulating concentrations of insulin-like growth factors-I and -II, alterations in insulin-like growth factor binding proteins, and induction of an insulin-like growth factor binding protein 3 protease. , 1996, Critical care medicine.

[35]  D. Wilmore,et al.  Growth hormone attenuates the abnormal distribution of body water in critically ill surgical patients. , 1992, Surgery.

[36]  J. Miell,et al.  Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin–like growth factor‐I , 1991, Clinical endocrinology.

[37]  J. Nauta,et al.  Effects of human growth hormone on fuel utilization and mineral balance in critically ill patients on full intravenous nutritional support. , 1994, Journal of critical care.

[38]  V. Kvetan,et al.  Growth hormone and pulmonary disease. Metabolic effects in patients receiving parenteral nutrition. , 1990, Archives of internal medicine.