This randomized clinical trial (RCT) continues the work of the National Acute Spinal Cord Injury Study (NASCIS) group in attempting to treat patients with acutely injured spinal cords by pharmacologic therapy. Previous animal work has suggested that some of the permanent disability from this injury results from biochemical and physical degradation of the spinal cord in the hours following injury. Several mechanisms are likely to be responsible for this """"""""secondary injury"""""""" including decreased blood flow, metabolic dysfunction, protein degradation, and lipid peroxidation. The notion that early drug therapy may improve permanent neurologic recovery after acute spinal cord injury recently received support from the results of a prior RCT (NASCIS 2) conducted by us. The proposed RCT of 495 patients will compare the best treatment arm of NASCIS 2 (30 mg/kg bolus of methylprednisolone followed by a 23-hour infusion of 5.4 mg/kg) with the same dose of methylprednisolone extended for 48 hours. A third treatment arm will use the aminosteroid tirilazad at a dose of 1.5 mg/kg every six hours for 48 hours after an initial bolus of methylprednisolone (30 mg/kg). Tirilazad is a new class of aminosteroid which has proven to be efficacious in animal models of acute spinal cord injury. An escalating dose phase 2 study at three NASCIS centers has shown tirilazad to be free of toxicity at the planned study dose. Neurological function is assessed in the emergency room and 72 hours, 6 weeks, 6 months and one year post injury. Functional status is evaluated during the last three follow-up exams. NASCIS has over twelve years of experience in conducting RCTs in acute spinal cord injury. While this injury is now known to be amenable to treatment, recovery of lost function is modest, and further significant improvements in recovery from the catastrophic injury need to be empirically documented in properly controlled studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS015078-12
Application #
3395952
Study Section
Neurological Disorders Program Project Review A Committee (NSPA)
Project Start
1979-02-01
Project End
1996-06-30
Budget Start
1991-07-31
Budget End
1992-06-30
Support Year
12
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Bracken, Michael B; Holford, Theodore R (2002) Neurological and functional status 1 year after acute spinal cord injury: estimates of functional recovery in National Acute Spinal Cord Injury Study II from results modeled in National Acute Spinal Cord Injury Study III. J Neurosurg 96:259-66
Bracken, M B (2001) Methylprednisolone and acute spinal cord injury: an update of the randomized evidence. Spine (Phila Pa 1976) 26:S47-54
Bracken, M B (2000) Methylprednisolone and spinal cord injury. J Neurosurg 93:175-9
Shepard, M J; Bracken, M B (1999) Magnetic resonance imaging and neurological recovery in acute spinal cord injury: observations from the National Acute Spinal Cord Injury Study 3. Spinal Cord 37:833-7
Bracken, M B; Shepard, M J; Holford, T R et al. (1998) Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the third National Acute Spinal Cord Injury randomized controlled trial. J Neurosurg 89:699-706
Shepard, M J; Saftlas, A F; Leo-Summers, L et al. (1998) Maternal anthropometric factors and risk of primary cesarean delivery. Am J Public Health 88:1534-8
Bracken, M B; Shepard, M J; Holford, T R et al. (1997) 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. National Acute Spinal Cord Injury JAMA 277:1597-604
Zhang, H; Bracken, M B (1996) Tree-based, two-stage risk factor analysis for spontaneous abortion. Am J Epidemiol 144:989-96
Shepard, M J; Bracken, M B (1994) The effect of methylprednisolone, naloxone, and spinal cord trauma on four liver enzymes: observations from NASCIS 2. National Acute Spinal Cord Injury Study. Paraplegia 32:236-45
Duh, M S; Shepard, M J; Wilberger, J E et al. (1994) The effectiveness of surgery on the treatment of acute spinal cord injury and its relation to pharmacological treatment. Neurosurgery 35:240-8;discussion 248-9

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