Join Date: Jul 2001
Location: New Brunswick, NJ, USA
Sherry, sorry... apparently the search function of the site does not allow a link... In any case, I attach all the letters and correspondence on this issue. I can comment further if you have any questions:
BMJ 2001;322:862 (¬*7¬*April¬*)
High dose methylprednisolone must be given for 24¬*or 48¬*hours after acute spinal cord injury
Short's letter about the use of steroids for acute spinal cord injury1 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 published2 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 firstname.lastname@example.org
Competing interests: Professor Bracken is principal investigator of the three North American national acute spinal cordinjury 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[Full Text]. (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: 1405-1411[Abstract].
3. Bracken MB. Methylprednisolone and spinal cord injury. J Neurosurg Spine 2000; 93: 175-178.
4. Bracken MB. Pharmacologic treatment for acute spinal cord injury. (Cochrane review.) Cochrane library. Issue 3. In: 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
This was in response to an earlier letter written by Deborah Short:
BMJ 2000;321:1224 (¬*11¬*November¬*)
Use of steroids for acute spinal cord injury must be reassessed
EDITORYates and Roberts's editorial on corticosteroids in head injury caused me considerable concern in so far as it portrayed the situation for treating acute spinal cord injury.1 Intravenous high dose methylprednisolone given within eight hours of injury has been promoted since the second American national acute spinal cord injury study. The positive benefit of this is based on conclusions derived from a selected post hoc subgroup analysis in one clinical trial. Current recommendations regarding evidence of clinical efficacy consistently advise caution in applying results from such non-randomised groups of patients.2
The evidence produced by a systematic review that colleagues and I recently carried out did not support the use of high dose methylprednisolone in acute spinal cord injury to improve neurological recovery.3 We also concluded that "a deleterious effect on early mortality and morbidity cannot be excluded by this evidence." In terms of experimental acute spinal cord injury, the functional neurological results extracted from non-rodent animal studies using high doses of either methylprednisolone or dexamethasone "constituted a body of evidence which cannot endorse a beneficial effect." A trend to increased mortality in cat models of high spinal cord lesions was of concern. On the basis of information available to them, clinicians in Canada4 and the United States5 also consider it inappropriate to advise treatment with methylprednisolone in this context.
An independent assessment of the evidence available, particularly information from the American national acute spinal cord injury studies, is long overdue.
Deborah¬*Short, consultant in spinal cord injuries and rehabilitation medicine.¬*
Midlands Centre for Spinal Injuries, Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust, Oswestry SY10 7AG email@example.com
1. Yates D, Roberts I. Corticosteroids in head injury. BMJ 2000; 321: 129-130[Full Text]. (15¬*July.)
2. Oxman AD, Guyatt GH. A consumer's guide to subgroup analyses. Ann Intern Med 1992; 116: 78-84[Medline].
3. Short DJ, El Masry WS, Jones PW. High dose methylprednisolone in the management of acute spinal cord injurya systematic review from a clinical perspective. Spinal Cord 2000; 38: 273-286[Medline].
4. Hulbert RJ. Methylprednisolone for acute spinal cord injuryan inappropriate standard of care. J Neurosurg (Spine 1) 2000; 93: 1-7.
5. Coleman WP, Benzel D, Cahill DW, Ducker T, Geisler F, Green B, et al. A critical appraisal of the reporting of the national acute spinal cord injury studies (I and II) of methylprednisolone in acute spinal cord injury. J Spinal Disord 2000; 13: 185-199[Medline].
and there was a response to Bracken's letter from Richard Lynch:
Richard M Lynch,
A&E Department, York District Hospital
Send response to journal:
Re: The efficacy of methylprednisolone in acute spinal cord injury is still unproven.
Email Richard M Lynch:
Editor - Professor Bracken's recent letter, in which he states that high dose methylprednisolone must be given for 24 or 48 hours after acute spinal cord injury , is overly prescriptive, dogmatic and not based on sound scientific research.
Following the publication of the National Acute Spinal Cord Injury Studies (NASCIS) II and III [2,3], several authors have questioned the study methods and results [4,5] but without satisfactory explanation or response from the authors of the NASCIS trials . There are no good quality studies which have replicated the findings of NASCIS II and III, but studies exist which have failed to demonstrate an improved outcome as a result of methylprednisolone administration .
While we await further scientific studies, which either prove or disprove the efficacy of methylprednisolone in acute spinal cord injury, I urge all doctors dealing with this group of patients to critically appraise the available literature and reach an informed decision. I would also welcome the production of a national guideline either by the National Institute for Clinical Excellence or by specialists treating spinal cord injury victims inorder that best practice can be applied in this controversial area.
 Bracken, MB. High dose methylprednisonole must be given for 24 or 48 hours after acute spinal cord injury. BMJ 2001;322:862-863.
 Bracken MB, Shephard MJ, Collins WF, et al. A randomised controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury. N Engl J Med 1990;322:1405-1411.
 Bracken MB, Shephard MJ, Holford TR, Theodore R, Leo-Summers L, Aldrich E, et al. Administration of methylprednisolone for 24 - 48 hours or tirilizad mesylate for 48 hours in the treatment of acute spinal cord injury. JAMA 1997;277:1597-1604.
 Coleman WP, Benzel E, Cahill DW, Ducker T, Geisler F, Green B, et al. A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of Methylprednisolone in Acute Spinal Cord Injury. J Spinal Disorders 2000;13(3):185-199.
 Nesathurai S. Steroids and Spinal Cord Injury: Revisiting the NASCIS 2 and 3 Trials. J Trauma 1998;45(6):1088-1093.
 Bracken MB. Clinical Measurement, Statistical Analysis and Risk- Benefit; Controversies from Trials of Spinal Injury. J Trauma 2000;48(3):558-561.
 George ER, Scholten DJ, Buechler CM, et al. Failure of methylprednisolone to improve the outcome of spinal cord injuries. Am Surg 1995;61:659-663.
And all of this is response to an editorial:
Corticosteroids in head injury
It's time for a large simple randomised trial
The global epidemic of head injuries is only just beginning. Currently over a million people die each year from brain injuries, and a similar number are disabled, often with profound effects on the quality of their lives.1 Road crashes account for most of the injuries, and car use is rapidly increasing in many countries. By 2020¬*road crashes will, it is estimated, have moved from ninth to third in the world ranking of disease burden as measured in disability adjusted life years, and second in developing countries.2 Identifying effective treatments for head injury is thus of global health importance.
Corticosteroids have been used to treat severe head injury for over 30¬*years, though recently their value has been questioned because of the failure to demonstrate effectiveness in randomised trials.3 Nevertheless, corticosteroids continue to be used widely, albeit inconsistently. Two 1996¬*British surveys, one of nursing staff in 39¬*neurosurgical intensive care units and one of medical directors in 44¬*neurosurgical intensive care units, found that corticosteroids were used to treat head injury in 49% and 14% of units respectively. 4 5
If a treatment as simple and widely practicable as corticosteroids produced just a moderate benefit this would be worth while. If, for example, they reduced the absolute risk of death by 2% (say from 15% to 13% dead) and reduced the risk of permanent disability by a similar amount then treatment of 500¬*000 patients would avoid 10¬*000 deaths and prevent 10¬*000 permanent disabilities. Such a benefit would be impossible to show reliably without evidence from large randomised trials.
If 10¬*000 patients were randomly allocated to receive a corticosteroid infusion and 10¬*000 a placebo infusion then a 2% absolute reduction in the risk of death or disability should be detectable and a 3% reduction would certainly be detectable. By contrast, a trial of only 2000¬*patients would probably miss such differences. Reliable refutation of benefit is of equal importance, as it would protect patients currently treated with corticosteroids from any adverse effects.
So far all the randomised trials of corticosteroids in head injury have been too small to demonstrate or refute the possibility of moderate but clinically important benefits or harm from corticosteroids: the largest included only a few hundred patients, and even in aggregate they have included only about 2000.6 As a result, the use of corticosteroids in head injury has waxed and waned over time, with extensive variations in practice.
Evidence of benefit from corticosteroids in acute spinal cord injury has renewed interest in their role in brain injury. The second US national acute spinal cord injury study (NASCIS 2) compared 24¬*hours of corticosteroid (methylprednisolone) with placebo in 333¬*patients with acute spinal cord injury.7 At six months patients who had received corticosteroids within eight hours of injury had greater improvement in motor function and in sensation to pinprick and touch. Similar results were reported in a Japanese trial of 151¬*patients who received the same regimen.7 More recent trials of methylprednisolone in acute spinal cord injury have indicated slightly more neurological recovery with 48¬*than with 24¬*hours of treatment.7 On the basis of these results high dose methylprednisolone is now widely used in acute spinal cord injury.
The dose of corticosteroid used in these randomised trials was based on results from animal studies showing that methylprednisolone can reduce post-traumatic neuronal degeneration after spinal cord injury, with 30¬*mg/kg body weight being required for maximal effect. High dose methylprednisolone has also been shown to reduce post-traumatic neuronal degeneration and improve outcome in animals with head injury: 30¬*mg/kg methylprednisolone enhanced recovery in mice that were subjected to moderately severe brain injury when given five minutes after injury.8 To date only two small randomised trials of high dose (30¬*mg/kg) methylprednisolone have been performed in head injury. 9 10 In both there was a non-significant reduction in the risk of death in the methylprednisolone treated group, but because the trials were small the effectiveness of high dose methylprednisolone in head injury remains uncertain (pooled risk difference 3% lower mortality, 95% confidence interval 14% lower to 9% higher).
Results from animal studies also suggest that early administration of corticosteroid is important for maximal effect. Because axonal disruption after acute trauma of the central nervous system does not occur for several hours, there may be an early phase when neurological deficit is reversible.11 Timing of corticosteroid administration has also been shown to be important in acute spinal cord injury.7 The administration of corticosteroids in many of the existing trials in head injury, however, may have been outside this window of opportunity.
The CRASH trial (corticosteroid randomisation after significant head injury) is a large simple randomised placebo controlled trial of the effect of early administration of a 48¬*hour infusion of corticosteroid (methylprednisolone) on the risk of death and disability after head injury (www.crash.ucl.ac.uk). The results of the trial will inform clinical decision making in an area of increasing public health importance. Reliable demonstration of a benefit from corticosteroids has the potential to avoid thousands of deaths and disabilities. Similarly, the reliable refutation of any benefit would protect thousands of patients from possible side effects. However, the trial requires many thousands of patients with acute head injury to be randomised. This will be possible only if hundreds of doctors and nurses collaborate in the participating emergency departments. Management of the increasing global burden of head injury must be addressed in a similar way to that adopted so successfully in ischaemic heart disease. Prevention and the understanding of basic pathophysiology must be complemented by well conducted large simple trials.
Department of Accident and Emergency Medicine, Hope Hospital, Salford M6 8HD
Ian¬*Roberts, senior lecturer in epidemiology.¬*
CRASH Trial Coordinating Centre, Department of Epidemiology and Public Health, Institute of Child Health, London WC1N 1EH(CRASH@ich.ucl.ac.uk)