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|Year : 2003 | Volume
| Issue : 3 | Page : 361-363
Evaluation of nimodipine in the treatment of severe diffuse head injury: A double-blind placebo-controlled trial
Pillai SV, Kolluri VR, Mohanty A, Chandramouli BA
Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bangalore - 560029
Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore - 560029
Aims: The aim of this study was to establish whether nimodipine given orally soon after severe diffuse head injury for a period of three weeks improved outcome.
Material and Methods: The present report analyzes the results of a prospective randomized double–blind placebo-controlled trial of nimodipine in 97 severe head injury patients (GCS Score <\=8) treated at the Department of Neurosurgery, NIMHANS, between January 1995 and June 1996. The patients were randomly assigned to two groups which were matched for age, sex, mode of injury, time interval from injury to admission, neurological status and CT scan findings. One group was given nimodipine 30 mg Q6H and the other group was given a placebo. The outcome of these patients at 6 months was evaluated using the Glasgow Outcome Score by and a psychologist. Results: Results showed no significant difference in the functional and psychological outcome between the two groups, even in patients with subarachnoid hemorrhage. No adverse drug events were recorded. Conclusion: Oral nimodipine given for three weeks does not improve outcome in patients with severe diffuse head injury.
|How to cite this article:|
Pillai S V, Kolluri V R, Mohanty A, Chandramouli B A. Evaluation of nimodipine in the treatment of severe diffuse head injury: A double-blind placebo-controlled trial. Neurol India 2003;51:361-3
|How to cite this URL:|
Pillai S V, Kolluri V R, Mohanty A, Chandramouli B A. Evaluation of nimodipine in the treatment of severe diffuse head injury: A double-blind placebo-controlled trial. Neurol India [serial online] 2003 [cited 2021 Feb 27];51:361-3. Available from: https://www.neurologyindia.com/text.asp?2003/51/3/361/1169
Calcium channel blockers have been shown to improve outcome after subarachnoid hemorrhage and to decrease vasospasm following head injury., Previous studies on the efficacy of nimodipine in head injury included patients with relatively less severe head injuries and their study population comprised significant proportions of patients with operable mass lesions.,,,. Moreover these trials used nimodipine for short periods whereas traumatic vasospasm has been documented to last up to two weeks. ,,,., No study has focussed on the efficacy of nimodipine in patients with severe diffuse head injury (SDHI). We conducted a prospective, randomised double-blind placebo-controlled trial with the aim of establishing whether nimodipine given orally for three weeks improved outcome in patients with SDHI.
The trial was conducted between January 1995 and June 1996 in the Department of Neurosurgery, NIMHANS. Consecutive adults (16-70 years), with a highest post-resuscitation Glasgow Coma Scale score (GCS) 8 or less, who had sustained injury less than 24 hours prior to admission were entered into the trial if their CT scan at the time of admission showed evidence of only diffuse head injury without any operable mass lesion like intracerebral hematoma or contusion more than 1 cm in diameter, or extradural and acute subdural hematomas more than 1 cm in maximum thickness. Patients were excluded if they were pregnant, had an unstable systemic condition or severe multiple injuries, if no brainstem reflexes were elicitable and if subsequent CT scans revealed evidence of an operable lesion as defined above. Patients who had hypotension prior to or after admission were excluded from the trial. Informed consent (which included explanation regarding the nature of the trial, the process of randomisation, the potential effects and side-effects of the drug, the treatment of any side-effects, and their right to withdraw from the trial at any time) for entry into the trial and randomization was taken from the patients' relatives before including them in the trial.
The patients were randomly assigned to the two treatment groups using a randomization table. All patients, relatives, nursing staff, doctors and those responsible for the analysis were blinded to the treatment coding. The test drug (nimodipine or placebo) was initially administered through a nasogastric tube or orally in a dose of 30 mg every 6 hours for a period of 3 weeks. Subsequently, depending on improvement, the drug was administered either by a nasogastric tube or orally. Treatment with the trial drug could be stopped if the treating surgeon considered that any adverse event was due to the drug. All patients were treated with Mannitol 1gm/kg/day for 5 days, prophylactic anticonvulsants and antibiotics. Patients were ventilated mechanically when required. No patient received barbiturate therapy. Serial daily recording of the level of consciousness (by GCS scoring), blood pressure, reactivity of pupils to light, presence of extraocular movements and any limb weakness was done. Cranial CT scan was done on Day 1,3 and 7 and as necessitated by the condition of the patient. Hematological and serum biochemical parameters (hemoglobin, packed cell volume, platelet count, prothrombin time, activated partial thromboplastin time, serum electrolytes including calcium, liver and renal function tests) were analyzed on the lst, 3rd and 7th days of entry into the trial to document any evidence of deviation due to nimodipine therapy. Any adverse event was also documented.
The Glasgow Outcome Scale (GOS) was used to classify the condition of the patients at discharge and at 6 months follow-up. Patients who made a good recovery or had moderate disability were grouped under favorable outcome, whereas those who remained in a severely disabled or persistent vegetative state and those who died were grouped under unfavorable outcome. Outcome was also assessed by a psychologist to analyze memory, personality, other cognitive functions, social integration and speech disorder. The presence of limb paresis and epilepsy status were also reviewed.
Most of the patients in both the groups were young men of about 30 years who had sustained head injury in road accidents. [Table - 1] shows that the two groups were comparable in all respects. The analysis of the CT scans done at the time of admission is presented in [Table - 2] and shows that the two groups were comparable. Forty-one patients expired while in the hospital and 3 patients were discharged in the vegetative state. Only 41 of the remaining 53 patients could be followed up at 6 months. Data regarding outcome as assessed by GOS at discharge and at 6 months follow-up is presented in [Table - 3]. The patients were divided into two groups based on the GCS score at the time of entry into the trial-one with GCS 3 to 5 and the other with GCS 6 to 8. This analysis shows that there is no significant difference in outcome between the patients who were treated with nimodipine and those who were not. [Table - 4] shows that there is no significant difference in the psychological profile and physical assessment between the nimodipine treated group and the placebo treated group. Nimodipine did not significantly influence outcome even in patients with traumatic subarachnoid haemorrhage (tSAH) [Table - 5]. No adverse events were documented. Hematological and biochemical parameters remained unaffected in the patients treated with nimodipine.
In recent years axonal injury has come to be recognized as the primary injury to the brain following diffuse head injury. Ultrastructural studies suggest that the full extent of axonal separation takes at least 12 hours in humans, suggesting a time window during which the mechanisms leading to axonal detachment may be amenable to therapeutic intervention. One of the postulated mechanisms of axonal injury is that the initial stretching of the axolemma alters its ionic permeability and causes an increased influx of calcium into the cell which activates proteases that trigger neurofilament degeneration.,,
Secondary mechanisms leading to brain damage following primary brain trauma include a critical reduction in the cerebral blood flow leading to hypoxic/ischemic neuronal injury. Pathological increases in intracellular calcium have been implicated as the major final common pathway leading to neuronal death.
Several large multicenter studies,,,. have evaluated the influence of the calcium channel blocker, nimodipine, on the outcome of patients with severe head injury. However, the patients in these series were predominantly patients with contusions and intracranial hematomas, many of which required surgical evacuation. No study has documented the efficacy of nimodipine in patients with diffuse brain injury, where the primary pathology per se is related to excessive calcium entry into the neuron. Moreover, unlike the studies mentioned above, all patients in this report had a GCS score of 8 or less.
All our patients were given nimodipine orally or through a nasogastric tube unlike previous trials,,, in which intravenous nimodipine was used, because oral nimodipine has been shown to be safe and effective in patients with SAH. In contrast, intravenous nimodipine in these trials was associated with an increase in adverse reactions suggesting that the drug may be harmful in some patients. We used a smaller dose of nimodipine (30 mg Q6H) compared to the standard dose of 60 mg Q4H used in patients with SAH because the use of the latter dose in the initial pilot group of patients led to unacceptable episodes of hypotension. The smaller dose was not associated with any adverse effects. The drug was given for 3 weeks to cover the entire period during which post-traumatic vasospasm has been demonstrated.,,,,,, Only one other trial has used nimodipine for 3 weeks.
This study is in agreement with previous trials which did not demonstrate any improvement in outcome in patients treated with nimodipine. However, since the number of patients in each group were not adequate to bring out small differences in outcome, we can only state that nimodipine is unlikely to significantly improve outcome in patients with severe diffuse head injury. Only a multicentric trial involving a similar though larger group of patients can answer the question completely. Even in patients with tSAH we could not demonstrate any benefit with nimodipine. While this finding is in agreement with some reports, it contradicts several others.,, This contradiction is probably related to two factors. First, since the patients in our study had more severe head injuries than in the latter group, the primary injury probably overshadowed the effect of tSAH. Secondly, the number of patients with tSAH in our study were too few to fully analyze such a question.
Oral nimodipine given for 3 weeks is unlikely to significantly improve the outcome in patients with severe diffuse head injury. Unlike previous studies which suggested a beneficial effect of nimodipine on patients with tSAH, this study did not show any improved outcome in severe diffuse head injury patients with tSAH who were treated with nimodipine. However, these conclusions need further study.
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