Fast track — ArticlesMagnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial
Introduction
Traumatic brain injuries are common and represent an important and costly health problem. The affected population includes many previously healthy young people. Moreover, these injuries are associated with high mortality and morbidity.1 The pathophysiology of severe brain injury involves a primary event and commonly a subsequent cascade of insults. The primary event is not treatable, whereas the secondary cascade substantially contributes to morbidity and mortality and thus is theoretically amenable to treatment. This theory has encouraged investigators to explore new treatment options and search for the “zauberkugel” or “magic bullet”.2
Evidence has suggested that magnesium could play a central part in the pathophysiology of traumatic brain injury.3 Magnesium can protect neurons from ischaemic damage and can support neuronal survival after traumatic brain injury through various mechanisms, including inhibition of the release of presynaptic excitatory neurotransmittors, blocking of NMDA channels and voltage-gated calcium channels, potentiation of presynaptic adenosine, and suppression of cortical spreading depression. Additionally, magnesium causes vascular smooth muscle to relax, thereby potentially increasing cerebral blood flow. After head injuries in human beings, total serum and ionised magnesium concentrations decrease.4 Experimentally, studies from several laboratories5 have documented that serum magnesium and brain magnesium are decreased after experimental traumatic brain injury6 and that magnesium supplementation improves outcome whether given before, shortly after, or hours after injury.7, 8 Outcome is worst in brain-injured animals with artificially lowered magnesium concentrations, intermediate in animals with no intentional alteration in magnesium concentrations, and best in animals given supplementary doses of magnesium. Treatment with magnesium can be successful when it is given up to 24 h after the injury and when given as a single bolus or for up to 7 days.9 Similarly, in vitro paradigms of neuronal injury and post-traumatic seizures have shown that magnesium concentrations correlate with improved tissue survival and lessened neurological excitation.10, 11
Our study was designed to test the notion that treating head-injured patients with magnesium would improve outcome. The primary hypothesis was that magnesium sulfate, given within 8 h of moderate or severe head injury, improves a composite measure of survival, seizure occurrence, and neurobehavioural functioning. Secondary aims were to assess the effects of timing of the dose (eg, starting <4 h vs 4–8 h after injury), sex, and ethnic origin and to determine the rate of treatment-associated adverse events.
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Participants
Patients with moderate to severe traumatic brain injury who were admitted to Harborview Medical Center, Seattle, WA, USA (a level 1 regional trauma centre), between August, 1998, and October, 2004, were eligible for the study. Moderate to severe traumatic brain injury was defined as: the need for intracranial surgery within 8 h of injury; a post-resuscitation Glasgow coma scale12 (GCS) score of 3–12; or, if intubated, a GCS motor score of 1–5 without pharmacological paralysis. We classified
Results
499 patients were randomly assigned to a study group, 49% of whom under waiver of consent. Only eight families (<2%) refused consent for the study before randomisation. Overall, 93% were followed up through 6 months, including 72% with full neuropsychological data at the 6 month assessment (figure 2).
Baseline characteristics were quite well balanced between the treatment and the placebo groups (table 1). However, consistent with the epidemiology of traumatic brain injury most patients were
Discussion
Consistent with a large trial in stroke,28 our findings do not lend support to the hypothesis that magnesium treatment would improve outcome after traumatic brain injury in human beings. However, whether these negative results might be associated with inadequate power should be considered. Simulations show that our study had more than 80% power to detect a percentage point difference of 10 between the treatment and placebo groups in dichotomised Glasgow outcome scale-extended scores for
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