High dose methylprednisolone must be given for 24 or 48 hours after acute spinal cord injury

British Medical Journal, April 7, 2001 by Michael B Bracken

EDITOR--Short's letter about the use of steroids for acute spinal cord injury[1] leads me to question the quality of the purported systematic review that she and colleagues carried out. Trials were missed, and the authors relied heavily on uncontrolled or historically controlled case series and seemed to depend on cat experiments to evaluate risk of mortality.

Since the original trial of high dose methylprednisolone was published[2] it has been repeatedly documented that the second national acute spinal cord injury study included a subgroup analysis, which was specified in the protocol. This analysis was to test the rather obvious hypothesis that earlier administration of methylprednisolone might lead to greater efficacy.[3] Eight hours was the (only) dichotomy analysed because it was the closest whole number to the median time between injury and the start of methylprednisolone. Subsequent trials in the national study, and other trials, used the eight hour window as an eligibility criterion and in so doing also specifically tested the eight hour hypothesis. Contrary to Short's statement, all the tested and reported comparisons were conducted in randomised patients.

Mortality data are available from three trials and show a relative risk of 0.54 (95% confidence interval 0.24 to 1.25) for death by six months after injury when 24 hour high dose methylprednisolone is compared with placebo or nothing.[4] The relative risk of overall mortality at one year in patients treated with 48 hour versus 24 hour high dose methylprednisolone is 1.11 (0.46 to 2.66). Thus there is no evidence in the literature on human spinal cord trials to raise concern about mortality. In all of these trials the absolute mortality among all patient groups is lower than might be expected from previously reported case series.

Evidence from all trials of acute spinal cord injury continues to indicate significant improvement in neurological motor function after high dose methylprednisolone is given for 24 or 48 hours.[4 5] Any new assessment of methylprednisolone and spinal cord injury might consider why the only documented pharmacological treatment to offer some improvement in neurological recovery without significant risk of harm is being denied some patients. People who continue to be uncertain about the role of methylprednisolone should conduct randomised controlled trials that address their concerns.

Michael B Bracken professor of epidemiology and neurology Yale University School of Medicine, Department of Epidemiology and Public Health, PO Box 208034, New Haven, CT 06520-8034, USA michael.bracken@yale.edu

Competing interests: Professor Bracken is principal investigator of the three North American national acute spinal cord injury trials, which were funded by the United States National Institutes of Health. He is an occasional paid consultant to Pharmacia-Upjohn, which is one of the manufacturers of methylprednisolone.

[1] Short D. Use of steroids for acute spinal cord injury must be reassessed. BMJ 2000;321:1224. (11 November.)

[2] Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, et al. A randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury: results of the second national acute spinal cord injury study. N Engl J Med 1990;322:1405-11.

[3] Bracken MB. Methylprednisolone and spinal cord injury. J Neurosurg Spine 2000;93:175-8.

[4] Bracken MB. Pharmacologic treatment for acute spinal cord injury. (Cochrane review.) Cochrane library. Issue 3. Oxford: Update Software, 2000.

[5] Tator CH, Fehlings MG. Review of clinical trials of neuroprotection in acute spinal cord injury. Neurosurgical Focus 1999;6:1-14(article 8). Available at www.neurosurgery.org/ focus/jan99/6-1-8.html