J Neurosurg 67:102-105, 1987 Evaluation of an intensive methylprednisolone sodium succinate dosing regimen in experimental spinal cord injury J. MARK BRAUGHLER, PH.D., EDWARD D. HALL, PH.D., EUGENE D. MEANS, M.D., THOMAS R. WATERS, M.S., AND DOUGLAS K. ANDERSON, PH.D. CNS Diseases Research, The Upjohn Company, Kalamazoo, Michigan, and Cincinnati Veterans Administration Medical Center, and the Departments of Neurology and Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio ~" Beginning 30 minutes after compression trauma of the upper lumbar (L-2) spinal cord, cats were treated with either a high-dose regimen of methylprednisolone (MP) administered as the sodium salt of the 21- succinate ester (Solu-Medrol sterile powder) or the MP vehicle. Animals were randomly assigned to either treatment group (10 cats per group), and all personnel were blind as to which animals received vehicle or drug. The intensive 48-hour dosing regimen was designed to maintain therapeutic tissue levels of MP and consisted of an initial 30 mg/kg intravenous bolus of MP; 2 and 6 hours later additional 15 mg/kg MP doses were administered by intravenous bolus. Immediately following the bolus given at 6 hours, a continuous MP infusion of 2.5 mg/kg/hr was started. The infusion was stopped abruptly at 48 hours with no dose tapering. Animals in the vehicle group received an equivalent volume of MP vehicle. The total MP dose administered over 48 hours was 165 mg/kg. Animals were evaluated weekly for neurological recovery based upon a 12- point functional scale which assessed general mobility, running, and stair-climbing. Mean recovery scores at 1 month after injury (-+ standard error of the mean) were: vehicle group (seven cats) 3.7 _+ 0.9, and MP group (10 cats) 8.7 _+ 0.2; (p < 0.001). Histological evaluation of the spinal cords revealed a strong negative correlation between neurological recovery and size of the spinal cord cavity at 1 month (r = -0.88). Three of 10 animals in the vehicle group became ill and had to be dropped from the study, whereas all of the 10 MP-treated animals survived in excellent health. The results demonstrate the therapeutic effectiveness and low incidence of side effects associated with an intensive MP dose regimen for treatment of experimental spinal cord injury. KEY WORDS * spinal cord injury 9 methylprednisolone 9 cat A VARIETY of potentially beneficial actions of methylprednisolone (MP) on the injured cen- tral nervous system (CNS) have been reported by a number of laboratories. In experimental models of spinal cord injury, MP has prevented posttraumatic spinal cord ischemia, t8'24 improved energy metabo- lism, 7'9 restored extracellular calcium, 7'24 inhibited tis- sue lipid peroxidation, t''5'16 improved nerve impulse conduction, 5'17'24 and blocked the release of free fatty acids, eicosanoids, and the loss of cholesterol from injured spinal cord tissueY' In all cases where the MP dose-response curve has been examined, the optimal intravenous dose of MP to achieve these varied actions was on the order of 30 mg/kg. Steroid doses such as these have recently been termed "CNS injury" doses. 8 Tissue pharmacokinetic and pharmacodynamic studies of MP and its effects in the injured spinal cord have indicated that its actions are dependent upon critical levels of drug in the injured tissue. 5,7,9,10,18Furthermore, these studies have predicted that intensive maintenance dosing would be required to assure maintenance of optimal tissue concentrations. Based upon acute pharmacokinetic and pharmaco- dynamic studies of MP in the injured spinal cord, a dosing regimen was proposed 6 that was designed to rapidly achieve and maintain optimal therapeutic levels of the steroid in CNS tissue. The development of this regimen was founded solely upon the pharmacology of MP at high doses and was not influenced by classic glucocorticoid pharmacology. Indeed, the beneficial ac- tions of MP on the injured CNS are believed to be unrelated to its glucocorticoid (hormonal) activity. 6,17 This hypothesis is supported in part by in vitro studies demonstrating acute and direct antioxidant-like and 102 J. Neurosurg. / Volume 67~July, 1987