Magnesium sulfate for aneurysmal subarachnoid hemorrhage: the end of the road or more trials?

Delayed cerebral ischemia (DCI) is a feared complication and an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). In the current study, Wong and colleagues performed a systematic review and meta-analysis of randomized controlled trials that investigated the efficacy of magnesium sulfate in patients with aneurysmal SAH. Outcome measures were DCI, cerebral infarction, and functional outcome 3 and 6 months after SAH. Magnesium sulfate decreased the rate of cerebral infarction, but not of DCI or poor functional outcome. Regarding outcome, a beneficial effect of magnesium sulfate on outcome can not be ruled out because of sample size limitations. Even if this meta-analysis had shown an effect on outcome, the question remains which treatment protocol should be applied in daily practice, since the administration of magnesium sulfate differed between most included studies. The present meta-analysis also underlines the importance of defining clinically relevant endpoints in SAH trials. Clinical deterioration due to DCI is more subject to inter-observer bias compared to cerebral infarction, which represents the ultimate outcome of the ischemic event. The Magnesium in Aneurysmal Subarachnoid Hemorrhage-II (MASH-II: ISRCTN68742385) phase III clinical trial nears completion. It aims to include 1,200 patients, and its results are urgently awaited.

was identifi ed as a drug that decreases the risk of DCI. However, the eff ect of nimodipine is only modest. Many patients still develop this complication and suff er from its consequences. Th erefore, new drugs are under investigation, to be used as adjunct therapy. Magnesium sulfate is a promising drug that is presently being investigated in randomized trials.
In the current study, Wong and colleagues performed a systematic review and meta-analysis update of randomized controlled trials that investigated the effi cacy of magnesium sulfate in patients with aneurysmal SAH [1]. Th e present meta-analysis diff ers from previous metaanalyses in that it included the results of two recently published randomized trials [2,3]. Six trials were retrieved including 875 patients. Outcome measures were DCI, cerebral infarction, and functional outcome 3 and 6 months after SAH. Th e number of patients for the various meta-analyses ranged between 381 and 494. Th e results showed that magnesium sulfate decreased the rate of cerebral infarction, but not of DCI or poor functional outcome.
Recently, it has been proposed that the main outcome measures of clinical trials and observational studies that investigate the complication of DCI should be cerebral infarction and functional outcome [4]. Arterial narrowing (vasospasm) is a radiographic fi nding associated with clinical deterioration due to DCI, cerebral infarction, and functional outcome. However, it is still under debate if these associations represent causal relationships. Vasospasm is often asymptomatic, and a reduction of vasospasm does not result in better functional outcomes [5]. Clinical deterioration due to DCI is less reliable than cerebral infarction, since it is more likely subject to interobserver bias. Cerebral infarction represents the ultimate outcome of the ischemic event, while clinical deterioration due to DCI is a diagnosis per exclusionem. Clinical deterioration after SAH can have multiple causes, such as infections, seizures, electrolyte disturbances, and hydrocephalus. Th e present meta-analysis used both DCI and cerebral infarction as outcome measures, and only found a benefi cial eff ect on cerebral infarction. Th is eff ect on cerebral infarction did not translate to a benefi cial eff ect

Abstract
Delayed cerebral ischemia (DCI) is a feared complication and an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). In the current study, Wong and colleagues performed a systematic review and meta-analysis of randomized controlled trials that investigated the effi cacy of magnesium sulfate in patients with aneurysmal SAH. Outcome measures were DCI, cerebral infarction, and functional outcome 3 and 6 months after SAH. Magnesium sulfate decreased the rate of cerebral infarction, but not of DCI or poor functional outcome. Regarding outcome, a benefi cial eff ect of magnesium sulfate on outcome can not be ruled out because of sample size limitations. Even if this meta-analysis had shown an eff ect on outcome, the question remains which treatment protocol should be applied in daily practice, since the administration of magnesium sulfate diff ered between most included studies. The present meta-analysis also underlines the importance of defi ning clinically relevant endpoints in SAH trials. Clinical deterioration due to DCI is more subject to inter-observer bias compared to cerebral infarction, which represents the ultimate outcome of the ischemic event. The Magnesium in Aneurysmal Subarachnoid Hemorrhage-II (MASH-II: ISRCTN68742385) phase III clinical trial nears completion. It aims to include 1,200 patients, and its results are urgently awaited. on outcome, but as pointed out by the authors, an eff ect on outcome can not be ruled out because of the relatively low number of included patients.
Even if the present meta-analysis had shown a benefi cial eff ect of magnesium sulfate on functional outcome, an important unanswered question would be which treatment protocol should be applied in daily practice. Th e administration of magnesium sulfate diff ered between most included studies. Th e concentration of magnesium sulfate was either 64 or 80 mmol/day, with or without initial bolus, and with or without dosage adjustment according to serum magnesium levels. Th e Magnesium in Aneurysmal Subarachnoid Hemorrhage-II (MASH-II: ISRCTN68742385) phase III clinical trial will hopefully shed more light on the effi cacy of magnesium sulfate in this group of patients. MASH-II aims to include 1,200 patients, which is based on a relative risk reduction of poor functional outcome of 22% (with alpha = 5% and a power of 80%) [6]. In MASH-II, magnesium sulfate 64 mmol/day or placebo is started within 4 days after SAH and continued until 20 days after the hemorrhage. Th is trial nears completion and its results are to be expected soon.

Competing interests
The author declares that he has no competing interests.