Limited observational data have suggested that amantadine, an indirect dopamine agonist and N-methyl-D-aspartate antagonist, may have favorable neurobehavioral effects for patients with severe traumatic brain injury (TBI). The favorable effects may be due to enhanced neurotransmission during a period of dopamine depletion and neuronal hypoexcitability following brain injury. In the March issue of  The New England Journal of Medicine, Giancino et al designed a multicenter, prospective, double-blind, randomized, placebo-controlled trial, funded by the National Institutes of Health, to determine the effectiveness of four weeks of amantadine therapy in promoting recovery from a post-traumatic vegetative or minimally conscious state.

A total of 184 patients were enrolled (n=87 in the amantadine group) at 11 clinical sites. Eligible patients were 16 to 65 years old who had sustained a non-penetrating TBI. Patients were enrolled four weeks after injury. Amantadine was started at 100 mg twice daily and gradually increased to 200 mg twice daily by week four of the treatment protocol. All patients were treated in a rehabilitation unit, where an intention-to-treat analysis was performed.

In a comparison of the two groups, more patients in the amantadine group had favorable outcomes according to the Disability Rating Scale score (DRS), and fewer remained in a vegetative state. Recovery was faster in the amantadine group as measured by the DRS score (slope, 0.24 points per week; P = 0.007). No significant difference in the incidence of adverse events was reported between the amantadine and placebo groups.

The authors concluded that administration of amantadine between four and 16 weeks after brain injury significantly improved the rate of functional recovery over a four-week treatment period. The results of this study might be confounded by the effect of concomitant psychoactive drugs and individual responses to rehabilitation therapy, as well as other factors. Although amantadine was not given until four weeks following injury –a time when patients had already been discharged from the intensive care unit — this is an important study because, to date, no intervention has been shown to accelerate the rate of recovery and functional outcome in severe TBI and the vegetative state that ensues in 10% to15% of patients.

Concise Critical Appraisal is a regular feature authored by SCCM member Samuel M. Galvagno Jr., DO. Each installment highlights journal articles most relevant to the critical care practitioner.