Considering CORTICUS: Hydrocortisone in Septic Shock
Abstract & Commentary
By Saadia R. Akhtar, MD, MSc Idaho Pulmonary Associates, Boise Dr. Akhtar reports no financial relationship to this field of study. This article originally appeared in the May 2008 issue of Critical Care Alert. It was edited by David J. Pierson, MD, and peer reviewed by William Thompson, MD. Dr. Pierson is Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, and Dr. Thompson is Staff Pulmonologist, VA Medical Center; Associate Professor of Medicine, University of Washington. Drs. Pierson and Thompson report no financial relationships relevant to this field of study.
Synopsis: A multicenter, randomized, double-blind, placebo-controlled trial of hydrocortisone replacement in patients with septic shock found no mortality benefit in those patients with inadequate baseline response to corticotropin stimulation.
Source: Sprung CL, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111-124.
This multicenter, randomized, double-blind, placebo-controlled trial of hydrocortisone replacement in septic shock aimed to evaluate 28-day mortality in non-responders to corticotropin stimulation. Secondary outcomes included death in responders and all patients at 28 days and one year, ICU and hospital length of stay (LOS) and death rates, and time to reversal of organ failure. Secondary infection rate was also measured.
Fifty-two European ICUs took part over 44 months. Eligible patients were >18 years old with clinical evidence of infection and onset of septic shock (defined by usual criteria) within 72 hours of enrollment. Exclusions included poor prognosis for short-term survival, immunosuppression, and recent systemic corticosteroids. Enrolled patients underwent corticotropin stimulation with non-responders defined as those demonstrating an increase in serum cortisol level of 9 micrograms/dL or less at 60 minutes after infusion of 250 micrograms of cosyntropin: a central study laboratory conducted the test. Study patients received hydrocortisone or placebo 50 mg IV every six hours for five days, tapered to off over six days. No other care was specified by the study. Standard statistical methods were used: a calculated sample size of 800 was needed to identify 10% mortality reduction with power of 80%.
In reality, enrollment was difficult and limited: only 499 patients took part in the study (251 received hydrocortisone, 248 placebo). Demographic and clinical characteristics were similar between the two groups. Approximately half of the patients in each group were non-responders to corticotropin stimulation. Over 25% of the patients in each group received etomidate, within a median time of 14 hours of study enrollment.
No mortality difference was identified in any group or time point defined a priori. Overall mortality rates were as expected for septic shock, at about 30-40%. Interestingly, however, there was a significantly increased mortality in patients who received etomidate (regardless of study group). Time to shock reversal was less (by 2-3 days) in patients who received hydrocortisone, regardless of response to corticotropin stimulation. Finally, patients in the hydrocortisone group had an increased risk of superinfection (odds ratio 1.37), hyperglycemia and hypernatremia, but not of neuromuscular weakness.
Commentary
Low dose, short-term hydrocortisone therapy has been in wide use since 2002 for management of patients in septic shock without adequate response to corticotropin stimulation. This practice is based primarily on the results of one clinical trial1 and the recommendations of expert panels/societies within critical care medicine.2 As I appraise CORTICUS, three questions come to mind.
1) Was there a need for further investigation of low-dose hydrocortisone in septic shock?
The availability of robust clinical trials to support practice is a relatively recent phenomenon in critical care medicine, and it is not surprising that we as a community may rush to embrace such results as provided by Annane and colleagues in 2002. As Finfer notes in his editorial, this may thwart efforts to carry out confirmatory trials.3 I believe that further investigation was certainly indicated. Although Annane et al's work was commendable and provided a great deal of information, it was a single (as yet unduplicated) study. The mortality benefit was demonstrated only after adjustment of data for baseline factors: this weakens the validity of the results from this randomized trial. There were several other concerns, such as regarding the necessity of adding fludrocortisone to the treatment regimen and the unexpectedly high mortality in the placebo group.1
2) Does CORTICUS provide definitive results that should change our practice?
I do not believe that CORTICUS clarifies the role of corticosteroids for patients in septic shock. Contrary to what Annane et al found, in the present paper, Sprung and colleagues suggest there may be no benefit and potentially some harm to treating patients in septic shock with low-dose corticosteroids.
Unfortunately, there are several serious flaws in CORTICUS that greatly limit the validity of the results. Enrollment was considerably less than originally intended and the study was ultimately greatly underpowered; that is, significant mortality differences may have easily been missed. In an effort to boost enrollment, the investigators changed the eligibility criteria to include patients who developed septic shock within a 72-hour period prior to study entry, rather than the 24-hour period initially defined (and the 8-hour window used by Annane et al): the physiology of septic shock clearly changes over time and other studies suggest that some interventions may only be beneficial within the earliest phase of septic shock.4 If this is true for corticosteroids then the broad time span used in CORTICUS may dilute and miss positive effects. Sprung et al also utilized a longer course of hydrocortisone than in the Annane study (11 vs 7 days). This may have increased the risk of superinfection as well as the period of hyperglycemia, perhaps negating any benefit of hydrocortisone (intensive glucose management was not controlled for in the study).
The most interesting result from CORTICUS may be the suggestion of worse outcome in patients who received etomidate prior to enrollment. This was seen regardless of baseline response to corticotropin stimulation or treatment group and I hope will spark further investigation.
3) Does the role of low-dose hydrocortisone in septic shock require further study?
Yes.
References
1. Annane D, Sébille V, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862-871.
2. Dellinger RP, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296-327.
3. Finfer S. Corticosteroids in septic shock. N Engl J Med. 2008;358:188-190.
4. Rivers E, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.
A multicenter, randomized, double-blind, placebo-controlled trial of hydrocortisone replacement in patients with septic shock found no mortality benefit in those patients with inadequate baseline response to corticotropin stimulation.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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