Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up
Object. A randomized double-blind clinical trial was conducted to compare neurological and functional recovery and morbidity and mortality rates 1 year after acute spinal cord injury in patients who had received a standard 24-hour methylprednisolone regimen (24MP) with those in whom an identical MP regimen had been delivered for 48 hours (48MP) or those who had received a 48-hour tirilazad mesylate (48TM) regimen. Methods. Patients for whom treatment was initiated within 3 hours of injury
... urs of injury showed equal neurological and functional recovery in all three treatment groups. Patients for whom treatment was delayed more than 3 hours experienced diminished motor function recovery in the 24MP group, but those in the 48MP group showed greater 1-year motor recovery (recovery scores of 13.7 and 19, respectively, p = 0.053).A greater percentage of patients improving three or more neurological grades was also observed in the 48MP group (p = 0.073). In general, patients treated with 48TM recovered equally when compared with those who received 24MP treatments. A corresponding recovery in self care and sphincter control was seen but was not statistically significant. Mortality and morbidity rates at 1 year were similar in all groups. Conclusions. For patients in whom MP therapy is initiated within 3 hours of injury, 24-hour maintenance is appropriate. Patients starting therapy 3 to 8 hours after injury should be maintained on the regimen for 48 hours unless there are complicating medical factors. Pharmacological approaches for clinical improvement of neurological function in the treatment of acute spinal cord injury have been studied since 1977, primarily in three Phase III double-blind randomized clinical trials. In the first National Acute Spinal Cord Injury Study (NASCIS I) a 100-mg/24-hour regimen of methylprednisolone (MP) was compared with a 1000-mg/24-hour regimen, both administered over a 10-day period beginning within 48 hours after admittance to a spinal cord injury center in patients who had experienced traumatic spinal cord injury. [5, 9] No difference in efficacy was observed between these treatments. In the second trial (NASCIS II) treatment with a bolus of MP at 30 mg/kg of body weight followed by a 23-hour infusion of MP at 5.4 mg/kg or a 5.4-mg/kg bolus of naloxone followed by a 24-hour infusion at 4 mg/kg was compared with a placebo in patients randomized within 12 hours of injury. Patients treated with MP within 8 hours of injury experienced significantly improved neurological function over placebo-treated patients 6 weeks, 6 months,  and 1 year postinjury. In the third trial (NASCIS III) we examined whether 48-hour administration of MP (48MP) would provide improved neurological function compared with the 24-hour maintenance therapy (24MP). Posttraumatic lipid peroxidation, the secondary injury process hypothesized to be ameliorated by high-dose MP, [3, 18, 27] is known to last well beyond 24 hours. [18, 29, 30] In NASCIS III we also studied a 48-hour maintenance treatment with tirilazad mesylate (48TM), a potent lipid peroxidation inhibitor that was developed to treat central nervous system trauma with potentially fewer complications than anticipated from the high-dose 48MP regimen. [2, 4, 16, 21, 23, 26] Six-week and 6-month results of NASCIS III showed that patients treated within 3 hours of injury recovered equally in all three treatment groups. Among patients in whom the initiation of treatment was delayed for 3 to 8 hours after injury, the 24MP treatment showed a decline in efficacy, but this was not observed in the 48MP treatment. The neurological recovery rate for those treated with the 48TM regimen fell between that seen in the two MP regimens of the trial.  In this paper we report the final 1-year follow-up results of NASCIS III for neurological and functional status and provide details on the mortality and morbidity statistics. CLINICAL MATERIAL AND METHODS Patient Population The study methods have been detailed elsewhere and are summarized here. Sixteen medical centers at which spinal cord injuries are treated collaborated in NASCIS III.