JOURNAL OF NEUROTRAUMA Volume 7, Number 3, 1990 Mary Ann Liebert, Inc., Publishers
Editorial NASCIS Spinal Cord Injury Study (NASCIS) recently reported that high doses of methylprednisolone (MP) given within 8 h after spinal cord injury significantly improves neurological recovery in humans. (Bracken et al., 1990). The results of this trial represent a long-awaited vindication of animal studies and the first demonstration that any treatment improves recovery in human spinal cord injury. Two of the findings were unexpected and have important implications for both spinal cord injury research and care. First, high-dose MP given between 8 and 12 h after injury was not effective. This finding suggests that opportunity for treating acute spinal cord injury is limited to the first 8 h after injury. Current medical practice does not emphasize urgent medical and surgical therapy of spinal cord injury. For example, in New York City, spinal-injured patients usually are transported to the nearest emergency room and often delayed at outlying emergency rooms, awaiting radiological studies or neurosurgical consultation. Crucial hours may be lost. Between 1985 and 1989, approximately 250 spinal cordinjured patients were admitted to Bellevue Hospital, where I work. Only about 25% of the patients arrived at the hospital within 12 h. The NASCIS results strongly argue for treating spinal cord injury as a true medical emergency that should be transported immediately to centers capable of rapid diagnosis and treatment. A delay of several hours may mean loss of multiple muscle groups or sensation that the patient would recover if immediately treated with high-dose MP. Second, MP treatment improved neurological recovery in both -plegic and -paretic spinal cord injuries, i.e., patients with no function and some residual function below the lesion level, respectively. A long-standing clinical dogma states that patients with complete lesions will not respond to treatment, whereas those with incomplete lesions can recover. Many surgeons will avoid or delay surgery in complete patients but will aggressively treat incomplete patients. This practice needs to be reevaluated in light of the NASCIS findings. The trial results indicate that not only are there axons to save but there are less than 8 h to do so. Common sense suggests that any compromise of the spinal cord should be alleviated as soon as possible. One interesting possibility is that the beneficial effects of MP may be related to protection of the spinal cord against such continuing injury until definitive surgical decompression has been achieved. The NASCIS experience also shows the critical importance of preclinical animal studies to the success of clinical trials. In 1978-1984, NASCIS carried out a clinical trial based on inadequate preclinical studies. The trial compared 1000 mg and 100 mg of daily MP started within 48 h and continued for 10 days after spinal cord injury in 300 patients. The two treatment groups showed no difference in neurological recovery (Bracken et al., 1985). In retrospect, it is apparent that too little drug was given too late. The recent second trial was based on better preclinical studies showing that higher and earlier doses are necessary. Without these preclinical studies, the second NASCIS trial would not have been done. This is a shining example of the contributions of animal experimentaThe National Acute
tion to clinical trials. MP, however, is not the ultimate drug for treating acute spinal cord injury. The doses that were used and shown to be effective transcend the term of "megadose" coined to describe 1 g of MP given per day to patients. A 30 mg/kg bolus followed by 5.4 mg/kg/h for 23 h adds up to about 10 g of i.v. administered drug over a 24-h period. At these doses, the drug is unlikely to be acting solely on corticosteriod receptors. These doses are more consistent with a chemical effect of the drug, such
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lipid peroxidation inhibition. If so, more potent lipid peroxi'dation inhibitors with less side effects are available. Other mechanisms of action should be considered, as pointed out by Drs. Hsu and Dimitrijevic in this issue of the Journal of Neurotrauma. The demonstration that high-dose MP improves neurological recovery in human spinal cord injury has complicated acute spinal injury research in several respects. It is now no longer sufficient to show that a treatment is effective. Treatments must now be compared directly with MP and shown to be superior. There are no published studies directly comparing any treatment against MP in concomitant experimentation on the same spinal injury model. The need for better spinal cord injury models has never been greater. Treatment differences will be smaller when compared against each other rather than against placebo controls. Therefore, outcome measures have to be much more accurate. Animal spinal cord injury models must be more reproducible. Clinical trials will require many more subjects to show these smaller differences. Because drug effects may well depend on injury severity and time after injury, treatment protocols must be tailored carefully and rationally to the severity of injury and the time of treatment. Such is the price of progress. as
Wise
Young, Ph.D.,
M.D.
REFERENCES BRACKEN, M.B., SHEPARD, M.J., COLLINS, W.F.,
methylprednisolone or National Acute Spinal
et al. (1990). A randomized controlled trial of naloxone in the treatment of acute spinal-cord injury: Results of the Second Cord Injury Study. N. Engl. J. Med. 322, 1405-1411.
BRACKEN, M.B., SHEPARD, M.J., HELLENBRAND, K.G., et al. (1985). Methyprednisolone and logical function 1 year after spinal cord injury. J. Neurosurg. 63, 704-713.
114
neuro-
Editorial NASCIS Spinal Cord Injury Study (NASCIS) recently reported that high doses of methylprednisolone (MP) given within 8 h after spinal cord injury significantly improves neurological recovery in humans. (Bracken et al., 1990). The results of this trial represent a long-awaited vindication of animal studies and the first demonstration that any treatment improves recovery in human spinal cord injury. Two of the findings were unexpected and have important implications for both spinal cord injury research and care. First, high-dose MP given between 8 and 12 h after injury was not effective. This finding suggests that opportunity for treating acute spinal cord injury is limited to the first 8 h after injury. Current medical practice does not emphasize urgent medical and surgical therapy of spinal cord injury. For example, in New York City, spinal-injured patients usually are transported to the nearest emergency room and often delayed at outlying emergency rooms, awaiting radiological studies or neurosurgical consultation. Crucial hours may be lost. Between 1985 and 1989, approximately 250 spinal cordinjured patients were admitted to Bellevue Hospital, where I work. Only about 25% of the patients arrived at the hospital within 12 h. The NASCIS results strongly argue for treating spinal cord injury as a true medical emergency that should be transported immediately to centers capable of rapid diagnosis and treatment. A delay of several hours may mean loss of multiple muscle groups or sensation that the patient would recover if immediately treated with high-dose MP. Second, MP treatment improved neurological recovery in both -plegic and -paretic spinal cord injuries, i.e., patients with no function and some residual function below the lesion level, respectively. A long-standing clinical dogma states that patients with complete lesions will not respond to treatment, whereas those with incomplete lesions can recover. Many surgeons will avoid or delay surgery in complete patients but will aggressively treat incomplete patients. This practice needs to be reevaluated in light of the NASCIS findings. The trial results indicate that not only are there axons to save but there are less than 8 h to do so. Common sense suggests that any compromise of the spinal cord should be alleviated as soon as possible. One interesting possibility is that the beneficial effects of MP may be related to protection of the spinal cord against such continuing injury until definitive surgical decompression has been achieved. The NASCIS experience also shows the critical importance of preclinical animal studies to the success of clinical trials. In 1978-1984, NASCIS carried out a clinical trial based on inadequate preclinical studies. The trial compared 1000 mg and 100 mg of daily MP started within 48 h and continued for 10 days after spinal cord injury in 300 patients. The two treatment groups showed no difference in neurological recovery (Bracken et al., 1985). In retrospect, it is apparent that too little drug was given too late. The recent second trial was based on better preclinical studies showing that higher and earlier doses are necessary. Without these preclinical studies, the second NASCIS trial would not have been done. This is a shining example of the contributions of animal experimentaThe National Acute
tion to clinical trials. MP, however, is not the ultimate drug for treating acute spinal cord injury. The doses that were used and shown to be effective transcend the term of "megadose" coined to describe 1 g of MP given per day to patients. A 30 mg/kg bolus followed by 5.4 mg/kg/h for 23 h adds up to about 10 g of i.v. administered drug over a 24-h period. At these doses, the drug is unlikely to be acting solely on corticosteriod receptors. These doses are more consistent with a chemical effect of the drug, such
113
EDITORIAL
lipid peroxidation inhibition. If so, more potent lipid peroxi'dation inhibitors with less side effects are available. Other mechanisms of action should be considered, as pointed out by Drs. Hsu and Dimitrijevic in this issue of the Journal of Neurotrauma. The demonstration that high-dose MP improves neurological recovery in human spinal cord injury has complicated acute spinal injury research in several respects. It is now no longer sufficient to show that a treatment is effective. Treatments must now be compared directly with MP and shown to be superior. There are no published studies directly comparing any treatment against MP in concomitant experimentation on the same spinal injury model. The need for better spinal cord injury models has never been greater. Treatment differences will be smaller when compared against each other rather than against placebo controls. Therefore, outcome measures have to be much more accurate. Animal spinal cord injury models must be more reproducible. Clinical trials will require many more subjects to show these smaller differences. Because drug effects may well depend on injury severity and time after injury, treatment protocols must be tailored carefully and rationally to the severity of injury and the time of treatment. Such is the price of progress. as
Wise
Young, Ph.D.,
M.D.
REFERENCES BRACKEN, M.B., SHEPARD, M.J., COLLINS, W.F.,
methylprednisolone or National Acute Spinal
et al. (1990). A randomized controlled trial of naloxone in the treatment of acute spinal-cord injury: Results of the Second Cord Injury Study. N. Engl. J. Med. 322, 1405-1411.
BRACKEN, M.B., SHEPARD, M.J., HELLENBRAND, K.G., et al. (1985). Methyprednisolone and logical function 1 year after spinal cord injury. J. Neurosurg. 63, 704-713.
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![[Corticosteroid therapy for acute spinal cord injury: the NASCIS controversy].](/assets/img/hold.png)
