NASCIS III: Duration of Steroid Therapy in Spinal Cord Injury (1997)

“We conclude that patients with acute spinal-cord injury who receive methylprednisolone within three hours of injury should be maintained on that treatment for 24 hours. When methylprednisolone is initiated between three and eight hours after injury, it should be continued for 48 hours.”

  • The NASCIS III Investigators

1. Publication Details

  • Trial Title: The Third National Acute Spinal Cord Injury Randomized Controlled Trial (NASCIS 3)
  • Citation: 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(20):1597-1604. DOI: 10.1001/jama.1997.03540440031023
  • Published: May 28, 1997, in The Journal of the American Medical Association (JAMA)
  • Author: Michael B. Bracken, Ph.D., M.P.H.
  • Funding: The National Institute of Neurological Disorders and Stroke; Pharmacia & Upjohn.

2. Keywords

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

3. The Clinical Question

  • In adult patients with acute spinal cord injury treated with an initial bolus of methylprednisolone (Population), does extending the steroid infusion to 48 hours or using a different drug (tirilazad) (Intervention) compared to a 24-hour steroid infusion (Comparison) improve neurologic recovery at 1 year (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The NASCIS II trial (1990) had controversially suggested a benefit for high-dose methylprednisolone if given within 8 hours of spinal cord injury, leading to its widespread adoption. However, the optimal duration of this high-dose therapy was unknown.
  • Knowledge Gap: It was unclear if a longer duration of steroid therapy (48 hours) would provide additional benefit or if a different, non-steroidal antioxidant drug (tirilazad) would be as effective with fewer side effects.
  • Proposed Hypothesis: The authors hypothesized that a 48-hour infusion of methylprednisolone or a 48-hour infusion of tirilazad would be superior to the standard 24-hour methylprednisolone infusion in improving neurologic recovery.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, controlled trial (used to test the effectiveness of interventions).
  • Setting: 16 medical centers in North America.
  • Trial Period: Enrollment ran from 1991 to 1996.
  • Population:
    • Inclusion Criteria: Adult patients with acute, blunt spinal cord injury who could be treated within 8 hours of the injury.
    • Exclusion Criteria: Included pregnancy, life-threatening associated injuries, and gunshot wounds to the spine.
  • Intervention: All patients first received an open-label bolus of methylprednisolone (30 mg/kg). They were then randomized to one of three groups:
  • 24-Hour Methylprednisolone: Infusion of 5.4 mg/kg/hr for 23 hours (the standard of care at the time).
  • 48-Hour Methylprednisolone: Infusion of 5.4 mg/kg/hr for 47 hours.
  • 48-Hour Tirilazad: Infusion of 2.5 mg/kg every 6 hours for 48 hours.
  • Control: The 24-hour methylprednisolone group served as the control group.
  • 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 motor 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 motor function at 1 year, as measured by the motor score of the American Spinal Injury Association (ASIA).
    • Secondary Outcomes: Included functional independence (FIM score), sensory recovery, and rates of complications.

6. Key Results

  • Enrollment and Baseline: 499 patients were randomized. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: In the primary analysis, there was no statistically significant difference in motor recovery at 1 year among the three groups.
  • Secondary Outcomes: There were no significant differences in functional independence or sensory recovery among the groups.
  • Adverse Events: Patients in the 48-hour methylprednisolone group had a significantly higher rate of severe pneumonia and a higher mortality rate from respiratory complications compared to the 24-hour group.

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 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 subgroup analysis was performed based on the timing of the initial steroid bolus. Among patients who received the initial bolus 3 to 8 hours after injury, the 48-hour methylprednisolone group had significantly better motor recovery compared to the 24-hour group.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind design was of high quality.
  • Generalizability: The inclusion of patients from 16 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 motor function is a highly relevant and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): As with NASCIS II, the primary analysis of the trial was negative. The only positive finding was in a post-hoc, unplanned subgroup analysis, which is at high risk of being a false-positive finding.
  • External Validity (Generalizability): The findings of the subgroup analysis, even if real, would only apply to a select group of patients based on the timing of treatment initiation.
  • Other: The study showed a clear signal of harm (increased pneumonia and death) associated with the 48-hour steroid infusion, which raises significant safety concerns that may outweigh any potential, statistically fragile benefit.

10. Conclusion of the Authors

  • The authors concluded that patients treated within 3 hours of injury should receive the 24-hour methylprednisolone regimen, while patients treated between 3 and 8 hours after injury should receive the 48-hour regimen.

11. To Summarize

  • Impact on Current Practice: This trial further entrenched the use of high-dose steroids in spinal cord injury for another decade, with guidelines adopting the complex, time-based recommendations from the subgroup analysis. However, like NASCIS II, its reliance on a post-hoc analysis in the face of a negative primary outcome and a clear signal of harm has been heavily criticized in subsequent years, leading to the eventual abandonment of this practice.
  • 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 any duration in acute spinal cord injury.
  • What This Trial Does NOT Mean: This trial does NOT provide definitive evidence that a 48-hour steroid infusion is beneficial. Its primary finding was negative.
  • Implementation Caveats: The use of a 48-hour high-dose steroid infusion is associated with an increased risk of severe pneumonia and death.

12. Context and Related Studies

  • Building on Previous Evidence: The NASCIS III trial (1997) was a direct follow-up to the controversial subgroup finding of the NASCIS II trial (1990).
  • Influence on Subsequent Research: The legacy of the NASCIS trials is a powerful case study in the dangers of over-interpreting post-hoc subgroup analyses and the importance of weighing statistically fragile benefits against clear evidence of harm. They have been the subject of numerous subsequent systematic reviews and guideline debates.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial failed to provide a definitive answer on the optimal management of acute spinal cord injury.
  • 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 a logical follow-up to NASCIS II, seeking to optimize a therapy that was becoming the standard of care.
  • Methods: The multicenter, double-blind RCT design was of high quality. The main methodological issue, once again, is the authors’ emphasis on a post-hoc subgroup analysis over the neutral primary outcome.
  • 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. Critically, this fragile signal of benefit was accompanied by a clear and statistically significant signal of harm (increased pneumonia and death).
  • Conclusions and Applicability: The authors’ conclusion, which created a complex, time-based treatment algorithm from a subgroup analysis, is highly controversial and is not supported by the overall data, particularly when considering the increased risks. This trial serves as another powerful lesson in the importance of a holistic and critical appraisal of evidence.

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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