Therapy Hydrocortisone Therapy for Patients with Septic Shock
This review may be edited
Summary
Posted By:	Greg Comadira
E-Mail:	gregory_comadira@health.qld.gov.au
Posted Date:	14/01/2008
Title:	Hydrocortisone Therapy for Patients with Septic Shock
Authors:	Charles L. Sprung, M.D., Djillali Annane, M.D., Ph.D., Didier Keh, M.D., Rui Moreno, M.D., Ph.D., Mervyn Singer, M.D., F.R.C.P., Klaus Freivogel, Ph.D., Yoram G. Weiss, M.D., Julie Benbenishty, R.N., Armin Kalenka, M.D., Helmuth Forst, M.D., Ph.D., Pierre-Francois Laterre, M.D., Konrad Reinhart, M.D., Brian H. Cuthbertson, M.D., Didier Payen, M.D., Ph.D., Josef Briegel, M.D., Ph.D., for the CORTICUS Study Group
Reference:	NEJM Volume 358:111-124
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	Background Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin. Methods In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test. Results Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock. Conclusions Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Yes Allocation concealment was maintained through the use of identical, sequentially numbered boxes of placebo or treatment vials that were administered by pharmacy.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	Yes. Only one of 500 patients withdrew consent. The remaining 499 were assessed.
2b. Were patients analyzed in the groups to which they were randomized?
	Yes
3. Were patients, health workers, and study personnel blind to treatment?
	Yes. Placebo vials were used that were identical to the vials containing steroids.
4. Were the groups similar at the start of the trial?
	Yes. Table 1 and Table 2 appear to demonstrate reasonable balance at baseline in the ITT population and in the sub-group analysis populations.
5. Aside from the experimental intervention, were the groups treated equally?
	Unknown. I cannot find the reporting of antibiotic use, duration of ventilation etc by study arm.
What are the Results?
1. How large was the treatment effect?
	The authors are misleading in their reporting of outcomes. Results from the entire population randomised (an ITT analysis) should always be presented and interpreted in preferance to any subgroup analysis, regardless of whether the interest in the subgroup was identified in advance-comment by Gord: Overall ITT mortality: 34.3% steroids vs 31.5% control, p=0.51 Non-responders mortality: 39.2% steroids vs. 36.1% control, p=0.69 Responders mortality: 28.8% steroids vs 28.7%, p=1.00 The reader must interpret the results of the '21 post-hoc analyses conducted to elucidate the reasons for the rates of death at 28 days in subgroups of patients' with extreme caution!! Conservative use of a Bonferroni correction (dividing the standard p-value of 0.05 by the number of subgroups evaluated) requires the author to achieve a p-value of 0.05/21 = 0.002 to declare any findings as statistically significant (likely not due to chance). Note that the authors do not provide a test of treatment x sub-group interaction to support the interpretation of p-values within each sub-group. Even if they did, it would be appropriate to correct for so many subgroups!!-comment by Gord
2. How precise was the estimate of the treatment effect?
	See paper for confidence intervals.
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	No. This is an underpowered negative trial. While it provides no positive support for the use of steroids, the power is too low to argue for practice change.
2. Were all clinically important outcomes considered?
	No. I cannot see the reporting of duration of ventilation, duration of organ dysfunction. Costs are not reported. Although the authors did show a reduction the duration of shock with steriods, they could not demonstrate any link to patient oriented outcomes such as survival.
3. Are the likely treatment benefits worth the potential harms and costs?
	Uncertain
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