- Email: [email protected]
Growth hormone treatment in critical illness — a critical appraisal
Growth Hormone & IGF Research 1999, 9, 8 3 - 8 4
Commentary
G r o w t h h o r m o n e t r e a t m e n t in c r i t i c a l illness- a critical appraisal O. G. P. Isaksson Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, Gbteborg, Sweden
Clinical trials in intensive care medicine are notoriously difficult to design and execute. 1 Control groups are usually poorly defined and there is some heterogeneity within the patient group. Furthermore, there are often confounding factors, such as repeated adjustments to the planned treatment due to alterations in the general condition of the patients during their stay in the intensive care unit (ICU). As a result, it is difficult to interpret results from studies involving critically ill patients. RATIONALE FOR GH TREATMENT CRITICALLY ILL PATIENTS
•
A general, but unproven, belief among many physicians is that catabolism following different forms of trauma is disadvantageous
•
Clear-cut beneficial results, in terms of mortality and morbidity, for nutritional over-supplementation of ICU patients are not available
•
Several recent published studies indicate that calorie restriction is beneficial for ICU patients in the early phase after surgical trauma
•
Could 'tissue catabolism' actually be beneficial to patient survival in the early stages of critical illness?
OF
The rationale for treating critically ill patients with recombinant human growth hormone (GH) is based on its protein-sparing effect. Several open pilot studies have revealed an improved nitrogen balance resulting from GH treatment of ICU patients, and it has been suggested that this may have beneficial effects on the clinical outcome of these patients (see also Hinds, page 71). Indeed, the ability of GH to reduce the breakdown of proteins in patients with severe burns has been documented. 2 Thus, the practice of treating critically ill patients with a negative nitrogen balance, regardless of origin, with GH appears to be logical. However, GH exerts many other effects that, it could tentatively be hypothesized, may counteract its potentially beneficial effects on protein metabolism in the ICU setting (see also Baxter, page 67). Furthermore, the question of whether the metabolic responses that occur in ICU patients should be regarded as advantageous or disadvantageous should also be taken into account. The current Correspondence to: O. G. P. Isaksson, Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, SE-41345 GSteborg, Sweden. Tel: +46 31 342383; Fax: +46 31 821524; Email: [email protected]
1096-6374/99/0A0083 + 02 $18.00/0
Table 1 Nutritional dogmas in ICU patients
nutritional dogmas for the treatment of ICU patients could be questioned as outlined in Table 1. A P P R A I S A L OF R E S U L T S OF G H T R E A T M E N T ICU PATIENTS
IN
Results from two recent, as yet unpublished, randomized, placebo-controlled, prospective studies demonstrated significantly increased mortality rates in critically ill patients treated with large doses of GH compared with controls. These well-designed and properly executed studies may serve as a good example for the design of future studies in ICU patients. A contributing factor to the negative outcome of these studies may have been the high doses of GH (16-24 IU/day; 5.3-8.0 rag/day) used in these patients. These doses are 10-20 times higher than normal GH replacement doses given to adults with GH deficiency (1-3 IU/day; 0.3-1.0 mg/day). One of the reasons for the high GH doses used in the ICU studies was that critically ill patients are thought to be GH resistant. However, while the term GH resistance might have some relevance for short GH-deficient children who receive GH replacement therapy, it is poorly defined in
© 1999 Churchill Livingstone
84
O.G.P. Isaksson
terms of the effects of GH on the metabolism of adult patients. In these patients, GH resistance may imply a decreased n u m b e r of GH receptors, impaired secretion of insulin-like growth factor I or a lower than expected increase in plasma insulin and glucose levels following the start of GH treatment. At present, the factors underlying the presumed GH resistance in critically ill patients have not been identified (see also Van den Berghe, page 77). With the benefit of hindsight, it is easy to criticise the rationale for treating critically ill patients with GH at such high doses. However, a n u m b e r of lessons can be learnt from these studies. Indeed, these results demonstrate that GH - a h o r m o n e that is usually considered to be 'gentle', with the primary effect of stimulating anabolism and b o d y growth in children can have serious deleterious effects in certain conditions. The o u t c o m e of the ICU studies do, however, demonstrate the importance of having an independent safety committee who have no vested interest in the study, but who have unblinded access to all the study data.
CONCLUSIONS
Although these studies have shown, without doubt, that treatment of critically ill patients with high doses of GH can have harmful effects, it would be premature to conclude that there is no beneficial role for GH in such patients. It may be that GH treatment is beneficial at a later stage in the patient's illness, when the patient has started to recover towards an 'anabolic' phase spontaneously. The negative outcome observed in these studies may have been due to the high GH doses used. Thus, a lower dose of GH with doses adjusted individually in order to achieve a defined degree of clinical/metabolic response may not cause the negative effects observed.
REFERENCES
1. Palazzo M, Soni N. Critical-care studies: redefining the rules. Lancet 1988; 352: 1306-1307. 2. Prudden JF, Pearson E, SoroffHS. Studies on growth hormone. II. The effect on the nitrogen metabolism of severely burned patients. Surg Gynecol Obstet 1956; 102: 695-700.
Commentary
G r o w t h h o r m o n e t r e a t m e n t in c r i t i c a l illness- a critical appraisal O. G. P. Isaksson Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, Gbteborg, Sweden
Clinical trials in intensive care medicine are notoriously difficult to design and execute. 1 Control groups are usually poorly defined and there is some heterogeneity within the patient group. Furthermore, there are often confounding factors, such as repeated adjustments to the planned treatment due to alterations in the general condition of the patients during their stay in the intensive care unit (ICU). As a result, it is difficult to interpret results from studies involving critically ill patients. RATIONALE FOR GH TREATMENT CRITICALLY ILL PATIENTS
•
A general, but unproven, belief among many physicians is that catabolism following different forms of trauma is disadvantageous
•
Clear-cut beneficial results, in terms of mortality and morbidity, for nutritional over-supplementation of ICU patients are not available
•
Several recent published studies indicate that calorie restriction is beneficial for ICU patients in the early phase after surgical trauma
•
Could 'tissue catabolism' actually be beneficial to patient survival in the early stages of critical illness?
OF
The rationale for treating critically ill patients with recombinant human growth hormone (GH) is based on its protein-sparing effect. Several open pilot studies have revealed an improved nitrogen balance resulting from GH treatment of ICU patients, and it has been suggested that this may have beneficial effects on the clinical outcome of these patients (see also Hinds, page 71). Indeed, the ability of GH to reduce the breakdown of proteins in patients with severe burns has been documented. 2 Thus, the practice of treating critically ill patients with a negative nitrogen balance, regardless of origin, with GH appears to be logical. However, GH exerts many other effects that, it could tentatively be hypothesized, may counteract its potentially beneficial effects on protein metabolism in the ICU setting (see also Baxter, page 67). Furthermore, the question of whether the metabolic responses that occur in ICU patients should be regarded as advantageous or disadvantageous should also be taken into account. The current Correspondence to: O. G. P. Isaksson, Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, SE-41345 GSteborg, Sweden. Tel: +46 31 342383; Fax: +46 31 821524; Email: [email protected]
1096-6374/99/0A0083 + 02 $18.00/0
Table 1 Nutritional dogmas in ICU patients
nutritional dogmas for the treatment of ICU patients could be questioned as outlined in Table 1. A P P R A I S A L OF R E S U L T S OF G H T R E A T M E N T ICU PATIENTS
IN
Results from two recent, as yet unpublished, randomized, placebo-controlled, prospective studies demonstrated significantly increased mortality rates in critically ill patients treated with large doses of GH compared with controls. These well-designed and properly executed studies may serve as a good example for the design of future studies in ICU patients. A contributing factor to the negative outcome of these studies may have been the high doses of GH (16-24 IU/day; 5.3-8.0 rag/day) used in these patients. These doses are 10-20 times higher than normal GH replacement doses given to adults with GH deficiency (1-3 IU/day; 0.3-1.0 mg/day). One of the reasons for the high GH doses used in the ICU studies was that critically ill patients are thought to be GH resistant. However, while the term GH resistance might have some relevance for short GH-deficient children who receive GH replacement therapy, it is poorly defined in
© 1999 Churchill Livingstone
84
O.G.P. Isaksson
terms of the effects of GH on the metabolism of adult patients. In these patients, GH resistance may imply a decreased n u m b e r of GH receptors, impaired secretion of insulin-like growth factor I or a lower than expected increase in plasma insulin and glucose levels following the start of GH treatment. At present, the factors underlying the presumed GH resistance in critically ill patients have not been identified (see also Van den Berghe, page 77). With the benefit of hindsight, it is easy to criticise the rationale for treating critically ill patients with GH at such high doses. However, a n u m b e r of lessons can be learnt from these studies. Indeed, these results demonstrate that GH - a h o r m o n e that is usually considered to be 'gentle', with the primary effect of stimulating anabolism and b o d y growth in children can have serious deleterious effects in certain conditions. The o u t c o m e of the ICU studies do, however, demonstrate the importance of having an independent safety committee who have no vested interest in the study, but who have unblinded access to all the study data.
CONCLUSIONS
Although these studies have shown, without doubt, that treatment of critically ill patients with high doses of GH can have harmful effects, it would be premature to conclude that there is no beneficial role for GH in such patients. It may be that GH treatment is beneficial at a later stage in the patient's illness, when the patient has started to recover towards an 'anabolic' phase spontaneously. The negative outcome observed in these studies may have been due to the high GH doses used. Thus, a lower dose of GH with doses adjusted individually in order to achieve a defined degree of clinical/metabolic response may not cause the negative effects observed.
REFERENCES
1. Palazzo M, Soni N. Critical-care studies: redefining the rules. Lancet 1988; 352: 1306-1307. 2. Prudden JF, Pearson E, SoroffHS. Studies on growth hormone. II. The effect on the nitrogen metabolism of severely burned patients. Surg Gynecol Obstet 1956; 102: 695-700.