Abstract & Commentary
Commentary by Matthew E. Fink, MD, Vice Chairman and Professor of Clinical Neurology at Weill Medical College and Chief of Stroke and Critical Care Neurology at New York Presbyterian Hospital.
Synopsis: The use of magnesium may reduce ischemic complications after SAH and thereby may reduce the risk of poor outcome after SAH, but as yet, the evidence for its use in clinical practice is inconclusive.
Source: van den Bergh WM, et al. Magnesium Sulfate in Aneurysmal Subarachnoid Hemorrhage. A Randomized Controlled Trial. Stroke. 2005;36:1011-1015.
Hundreds of clinical trials have been performed to find an effective treatment for delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). Nimodipine is the only agent that has been shown to improve outcome from DCI in randomized, controlled, clinical trials.1 van den Bergh and colleagues, of the Magnesium and Acetylsalicylic Acid in Subarachnoid Hemorrhage (MASH) trial, have reported the first results of their placebo-controlled magnesium treatment trial. They randomized 283 patients with acute aneurysmal SAH; half received 64 mmol/L per day of magnesium sulfate by intravenous infusion, starting within the first 4 days of SAH and continuing for 14 days after obliteration of the aneurysm. van den Bergh et al previously reported that more than 50% of patients with SAH develop hypomagnesemia, and the dosage of magnesium was calculated to maintain serum magnesium levels within the normal range of 1.0 to 2.0 mmol/L. They made no attempt to increase serum levels of magnesium above normal because this might cause depression of consciousness, headache, or muscle weakness.
The primary outcome measurement was the development of DCI within 3 months of SAH. Secondary outcome measurements were functional outcome at 3 months using the modified Rankin Scale, and the occurrence of any new hypodensity on brain CT scan.
Magnesium treatment reduced the risk of DCI by 34% (hazard ratio, 0.66; 95% CI, 0.38 to 1.14). After 3 months, the risk reduction for poor outcome was 23% (RR, 0.77; 95% CI, 0.54-1.09). There was no reduction of risk for the outcome event “any new hypodensities on CT.”
van den Bergh et al conclude that the use of magnesium may reduce ischemic complications after SAH and, thereby, may reduce the risk of poor outcome after SAH but, as yet, the evidence for its use in clinical practice is inconclusive. They have suggested an international phase III trial, with poor outcome as the primary measurement of outcome.
The appropriate dose of magnesium in still not certain, since this study used a much lower dose than is typically used in pregnant women to prevent eclamptic seizures. van den Bergh et al were attempting to correct a magnesium deficit, rather than give a magnesium supplement in order to raise the serum level. If a follow-up study is performed, and the primary outcome measure will be global functional status at 3 months, a higher dose of magnesium should be considered, since the acute side-effects of high-dose magnesium will not confound the outcome measures.
Commentary
Magnesium sulfate has been used in the United States since 1925 for the prevention and treatment of eclamptic seizures, even without an understanding of its mechanism of action. For decades, neurologists and obstetricians were at odds over the use of this agent—neurologists objected to its use because it is not an effective antiepileptic, while obstetricians cited its long history of empiric and successful use in pregnant women. Finally, the arguments were silenced with the publication, in 1995, of a randomized trial that clearly demonstrated the superiority of magnesium sulfate over phenytoin in preventing eclamptic seizures in hypertensive pregnant women.2
Now, neurologists and neurosurgeons have rediscovered magnesium as a potential neuroprotective agent. Although magnesium is not an effective antiepileptic, it has multiple actions that explain its efficacy in eclampsia, as well as its potential as a neuroprotective agent in acute ischemic stroke. Magnesium is a non-competitive antagonist of voltage dependent calcium channels. It dilates cerebral arteries, inhibits the release of excitatory amino acids, and blocks the N-methyl-D-aspartate-glutamate receptor. In animal models of SAH and ischemic stroke, magnesium reversed cerebral vasospasm and reduced infarct size.
The efficacy of magnesium sulfate for acute cerebral ischemia is being actively investigated in a number of clinical trials, in addition to the study reported here in Neurology Alert. The recently published results of the Intravenous Magnesium Efficacy in Stroke trial did not show benefit in a protocol where magnesium was given within 12 hours of acute stroke.3 Only 3% of the study patients were treated within 3 hours and, therefore, it is unlikely that a positive benefit would be observed. Early administration is crucial. We await with great excitement and anticipation the results of the FAST-MAG trial, currently underway in Los Angeles. In this randomized, placebo-controlled trial, intravenous magnesium is administered in the field by emergency medical technicians within 2 hours of stroke onset. The trial design has addressed the most difficult challenge in neuroprotective trials for acute ischemic stroke—rapid delivery of the agent during the window of treatable ischemia.
In SAH, a natural window of opportunity exists, from 2-4 days, between the acute hemorrhage and the development of DCI. Therefore, we encourage van den Bergh et al to organize a large, international trial of magnesium treatment to prevent DCI. Until we are able to make a significant impact on the ischemic complications of aneurysmal SAH, we will be unable to improve the overall morbidity and mortality of a dread disease that strikes down young adults at the peak of their lives. — Matthew E. Fink
References
1. Rinkel GJ, et al. Calcium Antagonists for Aneurysmal Subarachnoid Haemorrhage. Cochrane Database Syst. Rev. 2002;(4):CD000277.
2. Lucas MJ, et al. A Comparison of Magnesium Sulfate with Phenytoin for the Prevention of Eclampsia. N Engl J Med. 1995;333:201-205
3. Muir KW, et al. Magnesium for Acute Stroke (Intravenous Magnesium Efficacy in Stroke Trial): Randomized Controlled Trial. Lancet. 2004;363:439-445.
The use of magnesium may reduce ischemic complications after SAH and thereby may reduce the risk of poor outcome after SAH, but as yet, the evidence for its use in clinical practice is inconclusive.
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