CC Nerd-The Case of the Relative Insufficiency

When it comes to the efficacy of glucocorticoid therapy for the treatment of septic shock, we have existed in a state of ambiguity, torn between the results of two contradictory RCTs. The first, the Annane et al trial published in JAMA in 2002, suggested a mortality benefit in favor of the corticosteroid group in the subset of patients who were found to have relative adrenal insufficiency (1). The second, the larger CORTICUS study, published in the NEJM in 2008 found no benefit of the use of corticosteroids compared to placebo (2). Those in favor of the administration of corticosteroids have argued that the patients in the Annane et al trial represented a much sicker population, isolating the subset of patients who truly benefit from steroid supplementation. While the negative results observed in the CORTICUS trial were the consequence of enrolling a much healthier population and washing out any chance of identifying the underlying signal. The contrary opinion is simple, the results of the Annane et al trial were due to statistical noise and a small sample size, and CORTICUS was nothing more than the expected regression to the mean. We have long awaited the results of the ADRENAL trial, a pragmatic, double-blind, parallel-group, RCT, comparing hydrocortisone to placebo in patients presenting with septic shock. And while this trial’s impressive sample size and methodological rigor overshadow both the Annane et al and CORTICUS cohorts, I fear its results will deliver far less certitude than any of us had hoped.

Venkatesh et al enrolled adults, age 18 or older who required mechanical ventilation, with septic shock (two or SIRS criteria on vasoactive agents for at least 4-hours) (3). Patients were randomized to receive an intravenous infusion of hydrocortisone at a dose of 200 mg per day or matching placebo for 7-days. Over a 4-year period the authors enrolled 3800 patients in 64 ICUs. 1898 were assigned to the hydrocortisone arm and 1902 to the placebo arm.

The authors found no difference in the primary outcome, 90-day mortality, between the hydrocortisone and placebo groups (27.9% vs 28.8%, CI 0.82 to 1.10; P=0.50). Nor was there a difference in 28-day mortality (22.3% vs 24.3%; CI 0.76 to 1.03; P= 0.13). The authors noted that patients in the hydrocortisone group had a faster time to resolution of shock (3 vs 4 days), a shorter time to discharge from the ICU (10 vs 12 days), and a shorter duration of initial mechanical ventilation (6 vs 7 days). While statistically significant, it is important to remember that these are secondary endpoints, and are acutely vulnerable to the whimsies of statistical chance. For example, although time to ICU discharge was statistically shorter in patients randomized to receive hydrocortisone, the authors found no difference in number of days alive and outside the ICU, or days alive and outside the hospital. And while duration of initial mechanical ventilation was shorter in the hydrocortisone group, there was no difference in days alive and free of mechanical ventilation nor a difference in the rate of recurrent mechanical ventilation. Such inconsistencies make one wonder if these findings were simply due to multiple measurements and statistical chance. Even the improvement in time to resolution of shock seems to be of questionable clinical relevance. It did not translate into a mortality benefit, the mean difference in MAP between the two groups was only 5.39 mm Hg, and there was no difference in the daily dose of norepinephrine. Finally, the authors observed a 4.7% absolute increase in the need for blood transfusion in the patients in the placebo group (37% vs 41.7%). But at best given the secondary nature of this finding and the unclear mechanistic underpinning, it is hypothesis generating.

The authors also note a statistical significant increase in the rate of adverse events in the hydrocortisone group (1.1% vs 0.3% p= 0.009). Most of these were clinically inconsequential (hyperglycemia,hypernatremia, etc), but it is important to remember that RCTs are notoriously poor at identify rare harms and as such will underestimate the harm of the treatment in question.

Despite the methodological rigor of the ADRENAL trial, I am sure some will find minute chinks in its scientific armor in an attempt to discount its findings. Most notably, there was no minimum dose of vasopressors required prior to enrollment. And so the argument is that like the CORTICUS trial, this cohort represents a group of patients that are unlikely to benefit from hydrocortisone supplementation. But when the authors examined patients with elevated pressor requirements (both >15 mcg/min and >25 mcg/min), elevated APACHE scores (>25), and those that met the SEPSIS 3 criteria for septic shock, they were unable to identify a signal of benefit in any of these sicker subsets of patients, all of which represent a far larger sample size than the original Annane et al cohort.

It is hard to view these results as anything but a negative study. While there are some potential signals of benefit in the patients who received hydrocortisone, they were fleeting and ultimately had minimal influence on patient centered outcomes. If a true benefit does exist, it is small and would require an impossibly large trial to empirically demonstrate. In the end, the ADRENAL trial will have a nominal effect on practice. The desire to act in the face of critical illness is strong enough that we will reason away this lack of benefit simply because we have so little else to offer. When faced with a patient in refractory shock, many of us will continue to give corticosteroids in the hopes they may help the individual patient laying before us. We will just do so with an added degree of hand-wringing, knowing we have read the literature refuting our practice and simply want nothing to do with its conclusions.

Sources Cited:

Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-71.
Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111-24.
Venkatesh B, Finfer S, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med 2018. DOI: 10.1056/NEJMoa1705835