- Email: [email protected]
Steroids CRASH out of head-injury treatment
Reflection & Reaction Steroids CRASH out of head-injury treatment In 1961, Galicich and French1 showed the beneficial effects of steroids in the significant reduction of oedema produced by brain tumours. It seemed logical that steroids would also decrease oedema associated with traumatic brain injury, and steroids became a standard part of management protocols. Over the course of 40 years, 16 clinical trials (excluding CRASH [corticosteroid randomisation after significant head inhury]) showed no proof of steroid efficacy in reducing death and disability in severe traumatic brain injury. The evidence led authors of the Guidelines for the management of traumatic brain injury to recommend against steroid use in patients with traumatic brain injury.2 Despite this recommendation, a survey of US trauma centres, done 5 years after dissemination of the guidelines, found that about 50% routinely gave steroids to patients with severe traumatic brain injury. The CRASH trial3 puts the final nail in the coffin of steroid use for patients with traumatic brain injury. Originally designed to enroll 20 000 patients randomly allocated to receive either steroids or placebo, the trial was halted after enrollment of 10 008 patients because of a significant increase in mortality in the steroid group (21% compared with 18% in the placebo group) giving a 1·18 times increased risk of mortality. In comparison to, the 16 other steroid trials, the CRASH trial had the second highest dose of steroid administration, a 2 g loading dose of methylprednisolone or placebo followed by 0·4 g for 48 h, similar to the spinal-cord injury steroid protocol. In contrast to a prior trial recommending steroids for focal contusions,4 subgroup analyses of the CRASH trial showed that steroids were associated with the highest relative risk for death in patients with normal scans or scans showing cortical contusions. A metaanalysis of the 16 previous trials showed no beneficial or adverse effects of steroids, and inclusion of the CRASH trial (27 times larger than the largest of the others) in the metaanalysis, showed an adverse effect of steroids in traumatic brain injury.
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The cause of the increased deaths in the steroid arm is unknown, because cause of death was not recorded. Many factors that are predictive of poor outcome after traumatic brain injury (ie, age, Glasgow-coma-scale score, pupilary reactivity, abnormal intracranial CT scan results) were balanced in the treatment and placebo arms, making it unlikely that the increased deaths were because of increased injury severity in the steroid arm. However, no data were provided on hypotension, which is known to be strongly associated with mortality after traumatic brain injury.2 Turning to data from the Third National Acute Spinal Cord Injury (NASCIS-3) trial5 for clues to explain the increased mortality, severe pneumonia, severe sepsis, and severe gastrointestinal haemorrhage were more common when steroid infusion lasted 48 h compared with 24 h (5·8% vs 2·6% for pneumonia; 2·6% vs 0·6% for sepsis; and 0·6% vs 0·0% for gastrointestinal hemorrhage), raising the question of whether such complications may have contributed to the increased mortality observed in the steroid arm of the CRASH trial. The authors of the CRASH trial state that there was no evidence of a large rise of these complications. Further analyses of the CRASH trial are clearly needed to clarify the reasons for the observed increase in deaths. Before the CRASH trial, most studies in traumatic brain injury did not have a sufficient number of patients to detect the observed difference in outcome as statistically significant. In a review of 208 randomised controlled trials in traumatic brain injury, Dickinson and co-workers6 highlighted the following weaknesses: a mean loss to follow-up of 19%; a mean sample size of 82; no trials powered to detect an absolute difference of less than 5%; and only 4% of trials powered to detect an absolute difference between 5% and 10%. Regrettably, effect sizes in trials in traumatic brain injury have been less than 10% and may have been attenuated due to practice variation, which is associated with differences in patients’ outcomes. Thus, over 22 compounds or therapies developed
from basic neuroscience research tested in traumatic brain injury have also failed. Implementation of acute-care protocols based upon the guidelines for the patients enrolled in trials in traumatic brain injury would help reduce the variability associated with care of patients in future trials. In sharp contrast to previous traumatic-brain-injury studies, the CRASH trial enrolled a large number of participants, and required the involvement of 239 hospitals in 49 countries to achieve the necessary sample size. Taking into account the shortcomings of other traumatic-braininjury studies, the CRASH trial was designed to have more than 90% power to detect a 2% absolute difference in mortality at an p<0·01. This design brings traumatic-brain injury-studies into the arena of large clinical trials for other diseases that also substantially affect public health—eg, heart disease and stroke. Overall the CRASH trial is a tour-de-force of clinical trial administration and a resounding defeat for the therapeutic efficacy of high-dose steroids in traumatic brain injury. Jamshid Ghajar and Dale C Hesdorffer JG is at Weill Medical College of Cornell University and the Brain Trauma Foundation; and DCH is at the GH Sergievsky Center, Columbia University, New York, NY and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA. Email [email protected] Conflict of interest
We have no conflicts of interest. References 1
2 3
4
5
6
Galicich JH, French LA. Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brain surgery. Am Pract Dig Treat 1961; 12: 169–74. Bullock RM, Chesnut RM, Clifton GL, et al. Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2000; 17: 451–553. Roberts I, Yates D, Sandercock P, et al. Effect of Intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomized placebocontrolled trial. Lancet 2004; 364: 1321–28. Grumme T, Baethmann A, Koloziejczyk D, et al. Treatment of patients with severe head injury by triamcinolone: a prospective, controlled multicenter clinical trial of 396 cases. Res Exp Med (Berl) 1995; 195: 217–29. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the third national acute spinal cord injury randomized controlled trial. JAMA 1997; 277: 1597–604. Dickinson K, Bunn F, Wentz R, Edwards P, Roberts I. Size and quality of randomized controlled trials in head injury: review of published studies. BMJ 2000; 320: 1308–11.
Neurology Vol 3 December 2004
http://neurology.thelancet.com
For personal use. Only reproduce with permission from Elsevier Ltd
708
The cause of the increased deaths in the steroid arm is unknown, because cause of death was not recorded. Many factors that are predictive of poor outcome after traumatic brain injury (ie, age, Glasgow-coma-scale score, pupilary reactivity, abnormal intracranial CT scan results) were balanced in the treatment and placebo arms, making it unlikely that the increased deaths were because of increased injury severity in the steroid arm. However, no data were provided on hypotension, which is known to be strongly associated with mortality after traumatic brain injury.2 Turning to data from the Third National Acute Spinal Cord Injury (NASCIS-3) trial5 for clues to explain the increased mortality, severe pneumonia, severe sepsis, and severe gastrointestinal haemorrhage were more common when steroid infusion lasted 48 h compared with 24 h (5·8% vs 2·6% for pneumonia; 2·6% vs 0·6% for sepsis; and 0·6% vs 0·0% for gastrointestinal hemorrhage), raising the question of whether such complications may have contributed to the increased mortality observed in the steroid arm of the CRASH trial. The authors of the CRASH trial state that there was no evidence of a large rise of these complications. Further analyses of the CRASH trial are clearly needed to clarify the reasons for the observed increase in deaths. Before the CRASH trial, most studies in traumatic brain injury did not have a sufficient number of patients to detect the observed difference in outcome as statistically significant. In a review of 208 randomised controlled trials in traumatic brain injury, Dickinson and co-workers6 highlighted the following weaknesses: a mean loss to follow-up of 19%; a mean sample size of 82; no trials powered to detect an absolute difference of less than 5%; and only 4% of trials powered to detect an absolute difference between 5% and 10%. Regrettably, effect sizes in trials in traumatic brain injury have been less than 10% and may have been attenuated due to practice variation, which is associated with differences in patients’ outcomes. Thus, over 22 compounds or therapies developed
from basic neuroscience research tested in traumatic brain injury have also failed. Implementation of acute-care protocols based upon the guidelines for the patients enrolled in trials in traumatic brain injury would help reduce the variability associated with care of patients in future trials. In sharp contrast to previous traumatic-brain-injury studies, the CRASH trial enrolled a large number of participants, and required the involvement of 239 hospitals in 49 countries to achieve the necessary sample size. Taking into account the shortcomings of other traumatic-braininjury studies, the CRASH trial was designed to have more than 90% power to detect a 2% absolute difference in mortality at an p<0·01. This design brings traumatic-brain injury-studies into the arena of large clinical trials for other diseases that also substantially affect public health—eg, heart disease and stroke. Overall the CRASH trial is a tour-de-force of clinical trial administration and a resounding defeat for the therapeutic efficacy of high-dose steroids in traumatic brain injury. Jamshid Ghajar and Dale C Hesdorffer JG is at Weill Medical College of Cornell University and the Brain Trauma Foundation; and DCH is at the GH Sergievsky Center, Columbia University, New York, NY and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA. Email [email protected] Conflict of interest
We have no conflicts of interest. References 1
2 3
4
5
6
Galicich JH, French LA. Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brain surgery. Am Pract Dig Treat 1961; 12: 169–74. Bullock RM, Chesnut RM, Clifton GL, et al. Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2000; 17: 451–553. Roberts I, Yates D, Sandercock P, et al. Effect of Intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomized placebocontrolled trial. Lancet 2004; 364: 1321–28. Grumme T, Baethmann A, Koloziejczyk D, et al. Treatment of patients with severe head injury by triamcinolone: a prospective, controlled multicenter clinical trial of 396 cases. Res Exp Med (Berl) 1995; 195: 217–29. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the third national acute spinal cord injury randomized controlled trial. JAMA 1997; 277: 1597–604. Dickinson K, Bunn F, Wentz R, Edwards P, Roberts I. Size and quality of randomized controlled trials in head injury: review of published studies. BMJ 2000; 320: 1308–11.
Neurology Vol 3 December 2004
http://neurology.thelancet.com
For personal use. Only reproduce with permission from Elsevier Ltd