- Division of Neurosurgery, University of California, San Diego, California, USA
- Division of Neurosurgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
Clark C. Chen
Division of Neurosurgery, University of California, San Diego, California, USA
DOI:10.4103/2152-7806.190439Copyright: © 2016 Surgical Neurology International This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Hoshide R, Cheung V, Marshall L, Kasper E, Chen CC. Do corticosteroids play a role in the management of traumatic brain injury?. Surg Neurol Int 13-Sep-2016;7:84
How to cite this URL: Hoshide R, Cheung V, Marshall L, Kasper E, Chen CC. Do corticosteroids play a role in the management of traumatic brain injury?. Surg Neurol Int 13-Sep-2016;7:84. Available from: http://surgicalneurologyint.com/surgicalint_articles/corticosteroids-play-role-management-traumatic-brain-injury/
Neuroprotective strategies for the medical management of traumatic brain injury (TBI) have been elusive. While laboratory studies provide a conceptual framework for the potential efficacy of corticosteroids in this context, clinical trials testing this hypothesis have yielded no convincing evidence of clinical benefit. Here, we review the five key randomized control trials (RCTs) that have examined this issue. Based on the proposed primary endpoints of these RCTs, the five RCTs consistently showed that corticosteroids do not confer significant benefit in the TBI population.
Keywords: Outcomes, randomized controlled trials, steroids, TBI, traumatic brain injury
Traumatic brain injury (TBI) is a leading cause of death and disability, particularly in young adults.[
It is well-known that the vasogenic edema and swelling secondary to cerebral neoplasms can be reduced by treatment with corticosteroids.[
Braakman et al. conducted a single-centered, blinded, randomized controlled trial randomizing 161 patients with severe TBI to placebo (n = 80) versus a single bolus of 100 mg dexamethasone (n = 81) followed by a taper regimen (100 mg per day between days 1 and 4, 16 mg per day between days 5 and 7, and a taper of 12 mg, 8 mg, and 4 mg for days 8, 9, and 10, respectively).[
Grumme et al. carried out a multicenter, blinded study randomizing 396 patients with severe TBI (GCS < 8) who were admitted within 4 hours of injury to placebo (n = 187) and the corticosteroid, triamcinolone (n = 209; 200 mg intravenous given on presentation, 40 mg per day for 4 days, then 20 mg per day for the last 4 days).[
Saul et al. carried out a single-center, blinded study randomizing 100 TBI patients (GCS < 8), admitted within 6 hours of injury to placebo and steroid treatment (methylprednisolone 250 mg bolus, followed by 125 mg every 6 hours for 7–10 days).[
The German Ultrahigh Dexamethasone Head Injury Study (GUDHIS) randomized 300 patients with moderate or severe (GCS = 3–12) brain injury to placebo versus steroid treatment (500 mg of dexamethasone within the first 3 hours, followed by 200 mg after 3 hours, and 200 mg every 6 hours for 48 hours).[
Corticosteroid Randomization After Significant Head Injury (CRASH) was a multicenter, double-blinded, placebo controlled RCT that enrolled and randomized 10008 patients with head injuries and GCS < 14 to either 48 hour infusion of methylprednisolone (2 g for 1 hour followed by 0.4 mg for 48 hours) or placebo.[
“It has not been possible to demonstrate practical benefits of corticosteroids in the TBI population.” Ekkehard Kasper, Beth Israel Deaconess Medical Center, Boston
Various experimental models have confirmed the surprisingly beneficial impact of high-dose steroid application in reducing metabolic damages caused by e.g. lipid peroxidation, thus yielding improved physiological tissue recovery and function. This remains an encouraging fact that has its roots in sound laboratory studies. However, despite various attempts to replicate such observations in the clinical realm, it has not been possible to demonstrate comparable practical benefits of corticosteroids in the TBI population. Of the five pertinent RCTs, only post-hoc analysis by Grumme et al.[
“If the TBI patients that I treated are reflective of the general TBI population, I do not believe any RCT will be sufficiently powered or funded to test the efficacy of corticosteroid in the TBI setting.” Lawrence Marshall, University of California, San Diego.
The introduction of corticosteroids into neurosurgical practice by Dr. Donlin Long in the 1970s had a profound impact. Initial studies of corticosteroid in severe TBI suggest improved survival, although at the cost of increased vegetative and profoundly injured patient population. The survival benefit was not subsequently confirmed in multiple RCTs. Despite these results, corticosteroids are still favored by many neurological surgeons and critical care physicians. The rise and fall of glucocorticoid use in TBI mirrors numerous novel therapies where hope triumphs over fact. That said, in my care of TBI patients, I have witnessed two patients with an intracranial pressure (ICP) monitor in place. Both patients had reproducible reductions in ICP in response to corticosteroid administration. However, these two patients are unique among the thousands of other TBI patients that I had cared for in my career. If the TBI patients that I treated are reflective of the general TBI population, I do not believe any RCT will be sufficiently powered or funded to test the efficacy of corticosteroid in the TBI setting.
There is perhaps no drug more used and misused in neurosurgery than corticosteroids. Most severe injuries treated by neurosurgeons are accompanied by subsequent inflammation which is thought to further compromise neurologic function. Proponents of corticosteroid therapy point to their potent and well-established anti-inflammatory effects as avenues to mitigate the physiologic consequences of these injuries. It is fair to say that most practicing neurosurgeons have, at one time or another, witnessed remarkable clinical response to high dose corticosteroid treatment in trauma patients. It is also a fact that such response is not a routine phenomenon.
As mechanisms of corticosteroid function became better elucidated, we now understand that its role in neurosurgery is most efficacious against inflammation related to vasogenic edema but not cytotoxic edema. The efficacy of corticosteroids against tumor-related vasogenic edema is undisputed. We routinely observe brain tumor patients with deficit attributable to vasogenic edema to improve after corticosteroid administration. These observations contrasts those in the TBI or traumatic spinal cord injury patients, where cytotoxic edema predominates.
It remains unclear whether the pathophysiologic processes in a subset of TBI patients involve vasogenic edema. In TBIs where vasogenic edema predominates, patients may benefit from corticosteroid treatment. As such, diagnostic modalities (e.g. advanced physiologic imaging, serum biomarkers, etc.) are needed to make such determinations. Given the current level of evidence and the available diagnostic tools, we do not believe that corticosteroids should be administered routinely in TBI patients. To the extent that RCTs are expensive and consuming of clinical resources, clinical investigators have an ethical responsibility to triage hypothesis and test only therapeutic agents/strategies that are most likely to benefit TBI patients. Given this need for triage and with the available RCT data, we do not believe that further testing of corticosteroid without an understanding of the pathophysiologic processes (e.g., vasogenic versus cytotoxic edema) underlying the various forms of TBI is warranted. RCT resources and efforts should be directed toward more promising therapeutic agents or strategies.
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