BRACKEN I (NASCIS I): High-Dose Steroids in Spinal Cord Injury (1990)

“We conclude that this trial provides no evidence to support the use of high-dose methylprednisolone in the first 48 hours after acute spinal cord injury.”

  • Adapted from Bracken MB, et al.

1. Publication Details

  • Trial Title: 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
  • Citation: Bracken MB, Shepard MJ, Collins WF, 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(20):1405-1411. DOI: 10.1056/NEJM199005173222001. Note: The trial known as “Bracken I” or NASCIS I was published in 1984/1985. The more definitive and widely cited trial is NASCIS II, published in 1990, which this summary focuses on as it directly compares to NASCIS III and is the most influential of the series.
  • Published: May 17, 1990, in The New England Journal of Medicine
  • Author: Michael B. Bracken, Ph.D., M.P.H.
  • Funding: National Institute of Neurological Disorders and Stroke.

2. Keywords

  • Spinal Cord Injury, Methylprednisolone, Corticosteroids, Naloxone, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute spinal cord injury (Population), does treatment with high-dose methylprednisolone or naloxone (Intervention) compared to placebo (Comparison) improve neurologic recovery at 1 year (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Acute spinal cord injury often involves a secondary injury cascade of inflammation and ischemia that worsens the initial neurologic damage. Based on animal studies, it was hypothesized that high-dose corticosteroids could mitigate this secondary injury and improve outcomes.
  • Knowledge Gap: There was no high-quality evidence from large randomized controlled trials in humans to support the use of high-dose steroids for spinal cord injury. The potential benefits and risks were unknown. The first NASCIS trial (NASCIS I) had been inconclusive.
  • Proposed Hypothesis: The authors hypothesized that high-dose methylprednisolone or naloxone, administered early after acute spinal cord injury, would improve neurologic recovery compared to placebo.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 10 medical centers in the United States.
  • Trial Period: Enrollment ran from 1985 to 1987.
  • Population:
    • Inclusion Criteria: Adult patients (13-75 years) with acute, blunt spinal cord injury who could be treated within 12 hours of the injury.
    • Exclusion Criteria: Included pregnancy, life-threatening associated injuries, and gunshot wounds to the spine.
  • Intervention: Patients were randomized to one of three groups:
  • Methylprednisolone: An initial bolus of 30 mg/kg, followed by an infusion of 5.4 mg/kg/hr for 23 hours.
  • Naloxone: An initial bolus of 5.4 mg/kg, followed by an infusion of 4.0 mg/kg/hr for 23 hours.
  • Placebo: A matching placebo infusion.
  • Control: The placebo group served as the control.
  • Management Common to Both Groups: All patients received standard trauma and supportive care for acute spinal cord injury.
  • Power and Sample Size: The authors calculated that a sample size of 450 patients would provide 80% power to detect a clinically meaningful difference in neurologic recovery. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: Change in neurologic function (motor and sensory scores) at 6 weeks, 6 months, and 1 year after injury.
    • Secondary Outcomes: Included mortality and rates of complications.

6. Key Results

  • Enrollment and Baseline: 487 patients were randomized. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: In the overall analysis, there was no statistically significant difference in motor or sensory recovery at 1 year among the three groups.
  • Secondary Outcomes: There was no significant difference in mortality between the groups.
  • Adverse Events: Patients in the methylprednisolone group had a higher rate of wound infections and gastrointestinal bleeding, although these differences were not statistically significant.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcomes were analyzed using analysis of variance (ANOVA).
  • Primary Outcome Analysis: The primary outcome was a comparison of the mean change in motor and sensory scores among the three groups.
  • Key Statistic(s) Reported: The key statistics were the mean changes in neurologic scores and the associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-values for the primary outcome comparisons in the overall population were not statistically significant.
  • Clinical Impact Measures: As the trial was neutral in its primary analysis, ARR and NNT are not applicable.
  • Subgroup Analyses: A post-hoc (unplanned) subgroup analysis was performed based on the timing of treatment. In the subgroup of patients treated within 8 hours of injury, those who received methylprednisolone had a statistically significant improvement in motor recovery at 1 year compared to placebo. This benefit was not seen in patients treated after 8 hours.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design was a major strength and represented the highest level of evidence for this question at the time.
  • Generalizability: The inclusion of patients from 10 different centers increased the applicability of the findings.
  • Statistical Power: The study was large and adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of neurologic function is a highly relevant and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The primary analysis of the trial was negative. The only positive finding was in a post-hoc, unplanned subgroup analysis. Such analyses are at high risk of being false-positive findings due to the play of chance and are generally considered hypothesis-generating only.
  • External Validity (Generalizability): The findings of the subgroup analysis, even if real, would only apply to a select group of patients treated very early after injury.
  • Other: The study showed a trend towards increased harm (infections, bleeding) in the steroid group, which raises concerns about the overall risk-benefit balance.

10. Conclusion of the Authors

  • The authors concluded that while the overall results were negative, the subgroup analysis suggested that high-dose methylprednisolone is an effective treatment for acute spinal cord injury if administered within 8 hours of the injury.

11. To Summarize

  • Impact on Current Practice: This trial was profoundly influential and controversial. Based almost entirely on the positive subgroup analysis, the high-dose methylprednisolone protocol became the standard of care for acute spinal cord injury for over two decades, despite the trial’s overall negative result. In recent years, this practice has been largely abandoned due to a re-evaluation of the evidence and concerns about side effects.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute spinal cord injury.
    • Actionable Intervention: Current guidelines no longer recommend the routine use of high-dose methylprednisolone for acute spinal cord injury.
  • What This Trial Does NOT Mean: This trial does NOT provide definitive evidence that steroids are beneficial. Its primary finding was negative.
  • Implementation Caveats: The use of high-dose steroids is associated with an increased risk of complications, including infection and gastrointestinal bleeding.

12. Context and Related Studies

  • Building on Previous Evidence: The NASCIS II trial (1990) was a follow-up to the inconclusive NASCIS I trial.
  • Influence on Subsequent Research: The controversial subgroup finding of NASCIS II led to the NASCIS III trial (1997), which investigated extending the duration of steroid therapy. The legacy of this trial is a case study in the dangers of basing widespread clinical practice on a post-hoc subgroup analysis.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial left the true role of corticosteroids in acute spinal cord injury unresolved and highly debated.
  • Future Directions: Decades of subsequent research have failed to find a definitively effective neuroprotective agent for acute spinal cord injury. The focus has largely shifted to optimizing surgical timing, rehabilitation, and novel regenerative therapies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a devastating condition with no effective treatments.
  • Methods: The multicenter, double-blind RCT design was of high quality. The main methodological issue is the interpretation of the results.
  • Results: The study’s primary analysis was negative. The only positive finding emerged from a post-hoc subgroup analysis, which is not a robust form of evidence and is at high risk for being a chance finding.
  • Conclusions and Applicability: The authors’ conclusion, which emphasized the subgroup finding over the negative primary result, is a major point of controversy. This trial is a classic example of how a statistically fragile finding can, through influential publication and guideline inclusion, become a widespread and durable standard of care, even when the evidence is weak. It serves as a powerful lesson in the importance of critically appraising not just the methods of a trial, but also the authors’ interpretation of their own results.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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