A guest post by Rory Spiegel (@EMNerd_) who blogs on nihilism and the art of doing nothing at emnerd.com.
In 2004 the CRASH trial examining the efficacy of steroids for acute traumatic brain injury (TBI) was published in The Lancet. This massive trial included over 10,000 patients was stopped prematurely because of an increased mortality in the patients who received corticosteroids. This should have definitively closed the book on such a therapy. Despite this damning evidence, it appears all one has to do to make this question relevant again is to devise a disease-oriented endpoint with plausible clinical relevance and test it using a sample size too small to differentiate these harms from the surrounding noise of statistical chance.
Authors of the recently published Corti-TC trial did just this. Asehnoune et al examined the effect of the combination of hydrocortisone and fludrocortisone for the prevention of hopsital-acquired pneumonia (HAP) in patients with severe TBI. This is not the authors first foray into the efficacy of steroids for TBI. Their original trial was published in JAMA in 2011 and examined the effects of hydrocortisone to prevent HAP in patients having experienced poly-trauma. In this initial trial, about half the 149 patients randomized to either hydrocortisone or placebo suffered a severe TBI. The authors found that 35.6% of the patients in the active treatment arm developed HAP compared to 51.3% in the placebo group. This difference was seen exclusively in the subgroup of patients with TBI. Thus the authors set out to validate these findings by solely examining patients suffering from acute TBI. As a harbinger of things to come, the authors justified the 3% increase in mortality as statistical chance, since it failed to reach statistical significance due to the small sample size.
In what essentially is a validation cohort the Corti-TC trial was devised. Patients were randomized to either a 10 day course of both hydrocortisone and fludrocortisone or equivalent placebos. Cortisol levels were drawn before treatment was initiated, and in those found to be adrenally competent treatment was stopped. Once again the authors’ primary endpoint was the 28-day incidence of HAP as defined by a new infiltrate on chest x-ray with at least two of the following criteria; a temperature >38°C, leucocytosis >12 000 cells per mL, leucopenia <4000 cells per mL, or purulent pulmonary secretions.
Corti-TC demonstrated a similar difference in rates of HAP in patients given steroids vs those who received the placebo. Specifically 45% of the patients in the steroid group compared to 53% in the control group developed HAP over the first 28-days. Although this difference did not reach statistical significance due to a lower than anticipated overall incidence of HAP, a relevant divergence between the active and control groups is evident. This difference remained consistent whether or not patients were found to have adrenal deficiency, indicating that cortisol levels do not predict a subset of patients who will benefit from steroids. Of concern is the 2% absolute increase in mortality of patients treated with steroids. This difference was observed primarily in the subset of patients later found to be adrenally intact. The authors once again justify this increased mortality by its failure to reach statistical significance (p-value of 0.32). That this exact trend was demonstrated in their original study goes unmentioned. In fact, the same magnitude of harm caused the authors of the CRASH trial to halt their study prematurely. Given the collective consistency with which this mortality detriment has been demonstrated across trials it should not be written off as fluctuations of random chance. Interpreting this literature in its totality, it becomes obvious that these recent examinations of steroids in head trauma are vastly underpowered to detect the true harms involved with the utilization of such an intervention.
In the discussion section of both their trials, the authors question why their patients fared better than those in the CRASH cohort. They hypothesize that the overall higher acuity of their patients may be responsible for this difference in outcomes. The authors recommend further studies be performed to elucidate this uncertainty. I would argue that their cohorts fared no better than the CRASH patients. In fact, the absolute increase in mortality was identical to that of the CRASH trial. It is only because these authors defined success with a disease oriented outcome of little clinical significance(HAP), that their cohorts appear to fare better than the far more robustly powered CRASH cohort. At this point it seems clear steroids in acute TBI are harmful. Further studies to clarify the magnitude of benefit of irrelevant outcomes seem unwarranted.
“Hydrocortisone and fludrocortisone for prevention of hospital-acquired pneumonia in patients with severe traumatic brain injury (Corti-TC): a double-blind, multicentre phase 3, randomised placebo-controlled trial”
http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(14)70144-4/fulltext