Elsevier

The Lancet Neurology

Volume 6, Issue 1, January 2007, Pages 29-38
The Lancet Neurology

Fast track — Articles
Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial

https://doi.org/10.1016/S1474-4422(06)70630-5Get rights and content

Summary

Background

Traumatic brain injuries represent an important and costly health problem. Supplemental magnesium positively affects many of the processes involved in secondary injury after traumatic brain injury and consistently improves outcome in animal models. We aimed to test whether treatment with magnesium favourably affects outcome in head-injured patients.

Methods

In a double-blind trial, 499 patients aged 14 years or older admitted to a level 1 regional trauma centre between August, 1998, and October, 2004, with moderate or severe traumatic brain injury were randomly assigned one of two doses of magnesium or placebo within 8 h of injury and continuing for 5 days. Magnesium doses were targeted to achieve serum magnesium ranges of 1·0–1·85 mmol/L or 1·25–2·5 mmol/L. The primary outcome was a composite of mortality, seizures, functional measures, and neuropsychological tests assessed up to 6 months after injury. Analyses were done according to the intention-to-treat principle. This trial is registered with Clinicaltrials.gov, number NCT00004730.

Findings

Magnesium showed no significant positive effect on the composite primary outcome measure at the higher dose (mean=55 average percentile ranking on magnesium vs 52 on placebo, 95% CI for difference −7 to 14; p=0·70). Those randomly assigned magnesium at the lower dose did significantly worse than those assigned placebo (48 vs 54, 95% CI −10·5 to −2; p=0·007). Furthermore, there was higher mortality with the higher magnesium dose than with placebo. Other major medical complications were similar between groups, except for a slight excess of pulmonary oedema and respiratory failure in the lower magnesium target group. No subgroups were identified in which magnesium had a significantly positive effect.

Interpretation

Continuous infusions of magnesium for 5 days given to patients within 8 h of moderate or severe traumatic brain injury were not neuroprotective and might even have a negative effect in the treatment of significant head injury.

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.

Section snippets

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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