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Abstract & Commentary
Synopsis: Administration of GH has been suggested to modify the catabolic response to critical illness. Two European studies with a total of 535 patients demonstrate a doubling of mortality with high doses of GH as compared to placebo.
Source: Takala J, et al. N Engl J Med 1999;341: 785-792.
The loss of protein that accompanies critical illness contributes to morbidity and mortality. Growth hormone (GH) resistance has been suggested as one possible mechanism contributing to the negative nitrogen balance observed. Therapeutic administration of GH, at 5-20 times the normal replacement dose, in some patient groups (burns, trauma, other critically ill patients on hyperalimentation) is associated with improvement in nitrogen retention. However, the latter result is not the same as an improvement in overall outcome. The effect of therapeutic GH administration on survival was investigated in the two studies reported in this paper.
These two randomized, prospective, double-blind, placebo-controlled evaluations were carried out in parallel in Finland (247 patients) and in several other European countries (285 patients). Patients were enrolled on the fifth to seventh ICU day if they were expected to require at least 10 days of ICU care. Patients received 0.10 mg/kg of GH per day, or placebo, until ICU discharge or for 21 days. Forty-seven of the 119 patients receiving GH in the Finnish group expired (39%), as compared to 25 of the 123 controls (20%), while 61 of the 139 treated patients in the European study died (44%) compared to 26 of 141 controls (18%). Txhese differences are highly significant.
Patients in the treatment and control groups were similar in diagnosis, reason for ICU admission, and severity of illness (APACHE II Score). Most of them were male (74% and 65%), elderly (61 years), and admitted following cardiac (26%) or abdominal surgery (25%), after trauma (10%), or for acute respiratory failure (39%). The average APACHE II score was 18. The increased mortality occurred earlier in the European group, which also initiated GH therapy at the full therapeutic level, while in the Finnish group the dose was increased to treatment levels over a three-day period. The increased mortality was associated with an increased incidence of sepsis, septic shock, and multiple organ failure. It persisted through hospital discharge and at three months. Ventilator length of use, ICU length of stay, and hospital length of stay were longer in the survivors who received GH. No early or late benefit could be identified in patients who received GH.
Comment by Charles G. Durbin, Jr., MD, FCCM
Preliminary reports of improvement in survival and nitrogen retention from administration of GH to small groups of critically ill patients were not supported by these two large, placebo-controlled, randomized trials. The use of GH was associated with a much worse outcome and demonstrated no value to any subgroup of these patients. GH administration was associated with more hyperglycemia and this may have been a contributing factor to the higher incidence of systemic infectious complications. There may be a role for GH in the critically ill, but given at a high dose after the first week of illness it doubles mortality with no benefit. Until additional information is available, this convincing report should be believed.
a. increase mortality in the critically ill.
b. improve outcome of the most seriously ill patients.
c. reduce the incidence of infection in critically ill patients.
d. improve renal function but not mortality in severely ill patients.
e. reduce the time on mechanical ventilation.