Perhaps it is to be expected that Lenzer, a Journalist, would feel the need to “sex up” her piece about purported increased mortality owing to the administration of steroids for acute spinal cord injury by comparing it to the 9/11 terrorist murders. (1) It is extraordinary that Geisler, a neurosurgeon, would create such an unnecessary and inflammatory analogy based on head injury (2) and disappointing that the BMJ should unwittingly provide a platform for doing so.
In fact, patients eligible for the CRASH trial (head injuries for whom steroid therapy was indicated) are precisely those excluded from the spinal cord injury (NASCIS) steroid trials. Extrapolation of trial results from seriously head injured patients to patients with an acute spinal cord injury is clinically naive. Even when some head injured patients did enter the NASCIS trials (about 16%) the exclusion criteria would necessarily make them mild cases. Results of the CRASH trial indicate no meaningful effect of steroids on mortality in these patients (6.3 v 5.8% mortality with and without steroid administration respectively, which could have been a chance result). (3) Because most head injury was an exclusion criterion in the NASCIS trials, no Practice Guideline should have recommended that spinal cord patients with head injury be administered steroids and I am unaware of any that did.
The randomized trial evidence, in toto, provides the best estimate for (six month all-cause) mortality owed to steroids in spinal injured patients without significant head injury. In untreated controls the mortality rate was 5.7% (essentially the same as the CRASH control group with a mild injury) and 3.0% in steroid treated patients. This estimates a decreased risk of 46% ranging with 95% confidence from a decrease in mortality of 76% to an increase of 25%. (4) The randomized spinal injury trials do not provide any evidence for a positive effect on mortality among spinal cord injured patients owed to steroids and support the lack of a steroid effect in the mild head injured CRASH patients. In sum, there is no evidence for any increase in mortality owed to steroid use in spinal cord injured patients.
Inexplicably, Lenzer cites articles criticizing the spinal injury trials (see 1) but none of the published corrections and clarifications. (5-8) Regarding spinal injury, Lenzer missed the real story which is why more than thirty years after the first RCT of pharmaceutical agents and acute spinal cord injury was launched (it was the first RCT of any therapy for this injury) (9) and two follow-up trials (10, 11) the neurosurgical community has failed to launch a single trial to address the continuing uncertainty surrounding steroid treatment but continues to publish and rely on anecdotal non-randomized clinical reports. The result being an “updated guideline” that contains no updated randomized evidence. (12)
1. Lenzer J. Why we can’t trust clinical guidelines. BMJ 2013; 346:f3830
2. Geisler BMJ letter June 24th 2013
3. Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005;365(9475):1957-1959.
4. Bracken MB. Steroids for acute spinal cord injury. Cochrane Data Base Systematic Reviews 2012; CD001046 PMID 22258943
5. Bracken MB, Aldrich EF, Herr DL, Hitchon PW, Holford TR, Marshall LF, Nockels RP, Pascale V, Shepard MJ, Sonntag VKH, Winn, HR, Young W. Clinical measurement, statistical analysis and risk-benefit: controversies from trials of spinal injury. Journal of Trauma Injury Infection and Critical Care 2000; 48:558-561,
6. Bracken MB, Eisenberg H, Herr D, Hitchon PW, Holford TR, Marshall LF, Perot P, Piepmeier J, Wagner F, Walker MW, Wilberger JE, Winn HR, Young W. Commentary on: Guidelines for Management of Acute Cervical Spinal Injuries. Neurosurgery 2002; 50: S xiv-S xix
7. Bracken MB, Shepard MJ, Collins WF, Holford TR, Baskin DS, Flamm E, Eisenberg HM, Leo-Summers L, Maroon JC, Marshall LF, Perot PL, Piepmeier J, Sonntag VKH, Wagner FC, Wilberger JL, Winn, HR, Young W. Response. J Neurosurg 1992; 77: 325-7
8. Bracken MB. Methylprednisolone and spinal cord injury. J Neurosurg Spine 2000; 93: 175-78
9. Bracken MB, Collins WF, Freeman DH, Shepard MJ, Wagner FW, Silten RM, Hellenbrand KG, Ransohoff J, Hunt WE, Perot PL, Grossman RG, Green BA, Eisenberg HM, Rifkinson N, Goodman JH, Meagher JN, Fischer B, Clifton GL, Flamm ES, Rawe SE: Efficacy of methylprednisolone in acute spinal cord injury: A multicenter randomized trial. Journal American Medical Association 1984; 251: 45 52
10. Bracken MB, Shepard MJ, Collins, WF, Holford TR, Young W, Baskin DS, Eisenberg HM, Flamm E, Leo Summers L, Maroon J, Marshall LF, Perot PL, Jr., Piepmeier J, Sonntag VKH, Wagner FC, Wilberger JE, Winn HR. 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. New England Journal of Medicine 1990; 322:1405 1411,
11. Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings M, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot Jr. PL, Piepmeier J, Sonntag VKH, Wagner F, Wilberger JE, Winn HR, Young W. Methylprednisolone administered for 24 or 48 hours, or 48 hour tirilazad mesylate, in the treatment of acute spinal cord injury; results of the third national acute spinal cord injury randomized controlled trial. Journal American Medical Association 1997; 277:1597-1604
12. Hurlbert RJ, Hadley MN, Walters BC, Aarabi B, Dhall SS, Gelb DE, et al. Pharmacological therapy for acute spinal cord injury. Neurosurgery 2013; 72: 93-105.
Competing interests:
The author was the Principal Investigator of the three spinal injury steroid trials, a Scientific Adviser to the CRASH trial, an occasional consultant to the Upjohn Corporation (one of the manufacturers of methylprednisolone) and has testified for plaintiff and defendant in litigation.
Rapid Response:
Re: Why we can’t trust clinical guidelines
To the Editor:
Perhaps it is to be expected that Lenzer, a Journalist, would feel the need to “sex up” her piece about purported increased mortality owing to the administration of steroids for acute spinal cord injury by comparing it to the 9/11 terrorist murders. (1) It is extraordinary that Geisler, a neurosurgeon, would create such an unnecessary and inflammatory analogy based on head injury (2) and disappointing that the BMJ should unwittingly provide a platform for doing so.
In fact, patients eligible for the CRASH trial (head injuries for whom steroid therapy was indicated) are precisely those excluded from the spinal cord injury (NASCIS) steroid trials. Extrapolation of trial results from seriously head injured patients to patients with an acute spinal cord injury is clinically naive. Even when some head injured patients did enter the NASCIS trials (about 16%) the exclusion criteria would necessarily make them mild cases. Results of the CRASH trial indicate no meaningful effect of steroids on mortality in these patients (6.3 v 5.8% mortality with and without steroid administration respectively, which could have been a chance result). (3) Because most head injury was an exclusion criterion in the NASCIS trials, no Practice Guideline should have recommended that spinal cord patients with head injury be administered steroids and I am unaware of any that did.
The randomized trial evidence, in toto, provides the best estimate for (six month all-cause) mortality owed to steroids in spinal injured patients without significant head injury. In untreated controls the mortality rate was 5.7% (essentially the same as the CRASH control group with a mild injury) and 3.0% in steroid treated patients. This estimates a decreased risk of 46% ranging with 95% confidence from a decrease in mortality of 76% to an increase of 25%. (4) The randomized spinal injury trials do not provide any evidence for a positive effect on mortality among spinal cord injured patients owed to steroids and support the lack of a steroid effect in the mild head injured CRASH patients. In sum, there is no evidence for any increase in mortality owed to steroid use in spinal cord injured patients.
Inexplicably, Lenzer cites articles criticizing the spinal injury trials (see 1) but none of the published corrections and clarifications. (5-8) Regarding spinal injury, Lenzer missed the real story which is why more than thirty years after the first RCT of pharmaceutical agents and acute spinal cord injury was launched (it was the first RCT of any therapy for this injury) (9) and two follow-up trials (10, 11) the neurosurgical community has failed to launch a single trial to address the continuing uncertainty surrounding steroid treatment but continues to publish and rely on anecdotal non-randomized clinical reports. The result being an “updated guideline” that contains no updated randomized evidence. (12)
1. Lenzer J. Why we can’t trust clinical guidelines. BMJ 2013; 346:f3830
2. Geisler BMJ letter June 24th 2013
3. Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005;365(9475):1957-1959.
4. Bracken MB. Steroids for acute spinal cord injury. Cochrane Data Base Systematic Reviews 2012; CD001046 PMID 22258943
5. Bracken MB, Aldrich EF, Herr DL, Hitchon PW, Holford TR, Marshall LF, Nockels RP, Pascale V, Shepard MJ, Sonntag VKH, Winn, HR, Young W. Clinical measurement, statistical analysis and risk-benefit: controversies from trials of spinal injury. Journal of Trauma Injury Infection and Critical Care 2000; 48:558-561,
6. Bracken MB, Eisenberg H, Herr D, Hitchon PW, Holford TR, Marshall LF, Perot P, Piepmeier J, Wagner F, Walker MW, Wilberger JE, Winn HR, Young W. Commentary on: Guidelines for Management of Acute Cervical Spinal Injuries. Neurosurgery 2002; 50: S xiv-S xix
7. Bracken MB, Shepard MJ, Collins WF, Holford TR, Baskin DS, Flamm E, Eisenberg HM, Leo-Summers L, Maroon JC, Marshall LF, Perot PL, Piepmeier J, Sonntag VKH, Wagner FC, Wilberger JL, Winn, HR, Young W. Response. J Neurosurg 1992; 77: 325-7
8. Bracken MB. Methylprednisolone and spinal cord injury. J Neurosurg Spine 2000; 93: 175-78
9. Bracken MB, Collins WF, Freeman DH, Shepard MJ, Wagner FW, Silten RM, Hellenbrand KG, Ransohoff J, Hunt WE, Perot PL, Grossman RG, Green BA, Eisenberg HM, Rifkinson N, Goodman JH, Meagher JN, Fischer B, Clifton GL, Flamm ES, Rawe SE: Efficacy of methylprednisolone in acute spinal cord injury: A multicenter randomized trial. Journal American Medical Association 1984; 251: 45 52
10. Bracken MB, Shepard MJ, Collins, WF, Holford TR, Young W, Baskin DS, Eisenberg HM, Flamm E, Leo Summers L, Maroon J, Marshall LF, Perot PL, Jr., Piepmeier J, Sonntag VKH, Wagner FC, Wilberger JE, Winn HR. 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. New England Journal of Medicine 1990; 322:1405 1411,
11. Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings M, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot Jr. PL, Piepmeier J, Sonntag VKH, Wagner F, Wilberger JE, Winn HR, Young W. Methylprednisolone administered for 24 or 48 hours, or 48 hour tirilazad mesylate, in the treatment of acute spinal cord injury; results of the third national acute spinal cord injury randomized controlled trial. Journal American Medical Association 1997; 277:1597-1604
12. Hurlbert RJ, Hadley MN, Walters BC, Aarabi B, Dhall SS, Gelb DE, et al. Pharmacological therapy for acute spinal cord injury. Neurosurgery 2013; 72: 93-105.
Competing interests: The author was the Principal Investigator of the three spinal injury steroid trials, a Scientific Adviser to the CRASH trial, an occasional consultant to the Upjohn Corporation (one of the manufacturers of methylprednisolone) and has testified for plaintiff and defendant in litigation.