Correspondence

Increased Mortality Associated with Growth Hormone Treatment in Critically Ill Adults

N Engl J Med 2000; 342:134-136January 13, 2000

Article

To the Editor:

Takala et al. (Sept. 9 issue)1 report that high-dose growth hormone therapy increased the mortality rate in a group of critically ill patients. Although the causes of death in the patients who died while receiving intensive care were given, the causes of later deaths, which accounted for approximately 20 percent of all deaths, were not. Furthermore, although the mean daily dose of growth hormone was similar in the patients who died and in those who survived, neither the duration of treatment nor the number of patients still receiving treatment at the time of death was given. Thus, the authors' speculation that modulation of immune function or insulin resistance was responsible for the higher death rate in the growth hormone group may be based on an incomplete analysis of the causes of death.

The authors state that growth hormone resistance may have resulted in decreased production of insulin-like growth factor I (IGF-I), but they do not examine this possibility further. Taking the hypothesis of reduced sensitivity to growth hormone and the administration of high doses of growth hormone into consideration, we propose another explanation for the increased mortality rate in the group of patients treated with growth hormone. Several studies have shown that IGF-I inhibits apoptosis in various cell lines.2 In patients with acromegaly and high serum growth hormone and IGF-I concentrations, myocyte apoptosis is increased.3 We suggest that growth signals to damaged cells may trigger cell death in some tissues. Thus, the effects of growth hormone appear to be organ-specific and dependent on local growth hormone and IGF-I concentrations. High doses of growth hormone lead to increases in the production of IGF-I, depending on the number and sensitivity of growth hormone receptors. Simultaneous stimulation of the growth hormone and IGF-I receptor pathways could trigger apoptotic signals in compromised cells, a fact that would explain organ failure in critically ill patients.

Karl Josef Osterziel, M.D.
Rainer Dietz, M.D.
Humboldt-Universität, D-13125 Berlin, Germany

Michael B. Ranke, M.D.
Eberhardt-Karls-Universität, D-72076 Tübingen, Germany

3 References

1. 1

   Takala J, Ruokonen E, Webster NR, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999;341:785-792
   Full Text | Web of Science | Medline

2. 2

   O'Connor R. Survival factors and apoptosis. Adv Biochem Eng Biotechnol 1998;62:137-166
   Medline

3. 3

   Frustaci A, Chimenti C, Setoguchi M, et al. Cell death in acromegalic cardiomyopathy. Circulation 1999;99:1426-1434
   Web of Science | Medline

To the Editor:

The patients studied by Takala et al. were assumed to have resistance to growth hormone on the basis of their low serum IGF-I and IGF-binding protein 3 concentrations and on the basis of the high serum growth hormone concentrations reported in patients after trauma and elective surgery; the resistance is due in part to the reduced expression of growth hormone receptors.1 Very high doses of growth hormone were administered to overcome this resistance.

There is reason to believe that the high growth hormone dose selected for these studies was based on inappropriate assumptions. Patients who have long stays in the intensive care unit, such as those in the studies reported by Takala et al., do not have overt resistance to growth hormone, if they have resistance at all.2,3 Indeed, they have decreased pulsatile growth hormone secretion and low serum IGF-I concentrations, suggesting a relative deficiency of growth hormone. The relative growth hormone deficiency has a hypothalamic origin, because growth hormone secretion and serum concentrations of IGF-I and growth hormone–dependent binding proteins increase in response to infusions of growth hormone secretagogues, with preserved pulsatility and intact feedback inhibition preventing overtreatment. Treatment of patients in the chronic phase of critical illness may raise serum IGF-I concentrations into the range associated with acromegaly and can cause excessive fluid retention (up to 20 percent of body weight), pronounced insulin resistance, and hypercalcemia.4 Thus, the high growth hormone doses administered by Takala et al. to sick but growth hormone–responsive patients may have had serious side effects, which were nonspecific and could easily have been mistaken for spontaneous deterioration associated with the underlying disease.

In addition, generalized hypothalamic–pituitary suppression occurs in patients with protracted critical illness, resulting in hypothyroidism, hypogonadism, and sometimes hypoadrenalism, as well as growth hormone deficiency.2 These concomitant endocrine deficiencies may have amplified the side effects of growth hormone: hypothyroidism, for example, impairs free water clearance, and hypoadrenalism may mimic septic shock in patients in the intensive care unit.

Greet Van den Berghe, M.D., Ph.D.
Catholic University of Leuven, B-3000 Leuven, Belgium

4 References

1. 1

   Hermansson M, Wickelgren RB, Hammarqvist F, et al. Measurement of human growth hormone receptor messenger ribonucleic acid by a quantitative polymerase chain reaction-based assay: demonstration of reduced expression after elective surgery. J Clin Endocrinol Metab 1997;82:421-428
   CrossRef | Web of Science | Medline

2. 2

   Van den Berghe G, de Zegher F, Bouillon R. Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83:1827-1834
   CrossRef | Web of Science | Medline

3. 3

   Van den Berghe G, Wouters P, Weekers F, et al. Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. J Clin Endocrinol Metab 1999;84:1311-1323
   CrossRef | Web of Science | Medline

4. 4

   Van den Berghe G, de Zegher F, Vanhaecke J, Verleden G, Lauwers P. Growth hormone as a rescue treatment after heart-lung or double lung transplantation. Endocrinol Metab 1994;1:187-190
   

Author/Editor Response

The authors reply:

To the Editor: In response to Dr. Osterziel and colleagues, we did not include the causes of death for the patients who died after discharge from the intensive care unit because of incomplete records. Overall, 18 of the 108 deaths in the growth hormone–treated patients (17 percent) occurred after discharge from the intensive care unit. The median duration of growth hormone treatment in the patients who died was 14 days in the Finnish study and 7 days in the multinational study, and the median duration of treatment in the survivors was 15 days in the Finnish study and 17 days in the multinational study. Forty-two patients died during growth hormone treatment, and 43 patients died within one week after the last dose of growth hormone had been administered; 65 deaths in the intensive care unit (60 percent of all deaths) were due to multiple-organ failure and sepsis. Thus, we still believe that abnormal immune function is one of the more likely causes of increased mortality in the group of patients who received growth hormone. Among the many other possibilities, increased apoptosis is an interesting new suggestion. In both studies, however, serum IGF-I concentrations increased in response to growth hormone more frequently in the survivors than in the nonsurvivors, an observation that is inconsistent with the hypothesis of Dr. Osterziel and colleagues.

Dr. Van den Berghe's studies have indicated that patients who have long stays in the intensive care unit may not have resistance to growth hormone, and Dr. Van den Berghe suggests that the supraphysiologic doses of growth hormone used in our trials may have resulted in high serum IGF-I concentrations, excessive fluid retention, pronounced insulin resistance, and hypercalcemia, possibly worsened by generalized hypothalamic–pituitary suppression. However, the absence of resistance to growth hormone and the presence of generalized hypothalamic–pituitary suppression have so far been demonstrated only after several weeks of intensive care,1,2 whereas we studied patients who had been in the intensive care unit for only five to seven days. Nevertheless, we cannot exclude the possibility that alterations in responsiveness to growth hormone influenced our findings. However, most of the excess deaths in the multinational study and half the excess deaths in the Finnish study occurred within the first 10 days of growth hormone treatment, and neither hypercalcemia nor clinically evident excessive fluid retention was observed.

Jukka Takala, M.D., Ph.D.
Kuopio University Hospital, FIN-70210 Kuopio, Finland

Charles J. Hinds, M.D.
St. Bartholomew's Hospital, London EC1A 7BE, United Kingdom

2 References

1. 1

   Van den Berghe G, Wouters P, Weekers F, et al. Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. J Clin Endocrinol Metab 1999;84:1311-1323
   CrossRef | Web of Science | Medline

2. 2

   Van den Berghe G, de Zegher F, Baxter RC, et al. Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues. J Clin Endocrinol Metab 1998;83:309-319
   CrossRef | Web of Science | Medline

Citing Articles (9)

Citing Articles

1. 1

   Daniel Schmitz, Phillip Kobbe, Sven Lendemanns, Klaus Wilsenack, Michael Exton, Manfred Schedlowski, Reiner Oberbeck. (2008) Survival and cellular immune functions in septic mice treated with growth hormone (GH) and insulin-like growth factor-I (IGF-I). Growth Hormone & IGF Research 18:3, 245-252
   CrossRef

2. 2

   František Duška, Michal Fric, Petr Waldauf, Jaroslav Pažout, Michal Anděl, Pavel Mokrejš, Petr Tůma, Jan Pachl. (2008) Frequent intravenous pulses of growth hormone together with glutamine supplementation in prolonged critical illness after multiple trauma: Effects on nitrogen balance, insulin resistance, and substrate oxidation*. Critical Care Medicine 36:6, 1707-1713
   CrossRef

3. 3

   František Duška, Michal Fric, Jaroslav Pažout, Petr Waldauf, Petr Tůma, Jan Pachl. (2008) Frequent intravenous pulses of growth hormone together with alanylglutamine supplementation in prolonged critical illness after multiple trauma: Effects on glucose control, plasma IGF-I and glutamine. Growth Hormone & IGF Research 18:1, 82-87
   CrossRef

4. 4

   Yanqing Guo, Xiangjun Bai, Guanyu Lin, Zhaohui Tang. (2007) Altered nutrition state in the severe multiple trauma patients undergoing adjuvant recombinant human growth hormone nutritional support therapy. Journal of Huazhong University of Science and Technology 27:3, 299-302
   CrossRef

5. 5

   Linda Aoyama, Nancy Weintraub, David B. Reuben. (2006) Is Weight Loss in the Nursing Home a Reversible Problem?. Journal of the American Medical Directors Association 7:3, S66-S72
   CrossRef

6. 6

   Linda Aoyama, Nancy Weintraub, David B. Reuben. (2005) Is Weight Loss in the Nursing Home a Reversible Problem?. Journal of the American Medical Directors Association 6:4, 250-256
   CrossRef

7. 7

   Linda Aoyama, Nancy Weintraub, David B. Reuben. (2005) Is Weight Loss in the Nursing Home a Reversible Problem?. Journal of the American Medical Directors Association 6:4, 250???256
   CrossRef

8. 8

   J MECHANICK, E BRETT. (2002) Nutrition support of the chronically critically ill patient. Critical Care Clinics 18:3, 597-618
   CrossRef

9. 9

   Caroline MacIntosh, John E Morley, Ian M Chapman. (2000) The anorexia of aging. Nutrition 16:10, 983-995
   CrossRef