Journal of Clinical Neuroscience 16 (2009) 1394–1397

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Journal of Clinical Neuroscience

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Review

A meta analysis of treating subarachnoid hemorrhage with magnesium sulfate

Xu-Dong Zhao a, Yi-Ting Zhou b, Xin Zhang a, Zong Zhuang a, Ji-Xin Shi a,*
a
Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China
b
Department of Radiology, Wuxi Integrated Traditional Chinese and Western Medicine Hospital, Wuxi, Jiangsu Province, China

a r t i c l e i n f o a b s t r a c t

Article history: Despite the publication of several randomized controlled studies, there is still much debate on whether
Received 25 March 2009 magnesium sulfate improves outcome in patients with aneurysmal subarachnoid hemorrhage. Here we
Accepted 6 May 2009 present data to assess the clinical effectiveness of magnesium sulfate in the prevention of cerebral
vasospasm in patients who have suffered from aneurysmal subarachnoid hemorrhage. The EMBASE
and PubMed databases were searched using the following terms: ‘‘magnesium sulfate” or ‘‘MgSO4” with
Keywords: ‘‘subarachnoid hemorrhage” or ‘‘cerebral vasospasm”. A manual search of the bibliographies of relevant
Subarachnoid hemorrhage
articles was also conducted. Two co-authors of the present study designed the meta analysis of published
Cerebral vasospasm
Magnesium sulfate
randomized clinical trials and extracted the data. Data were analysed by using Review Manager 4.2 from
the Cochrane Collaboration (Oxford, UK). Five published manuscripts were identified according to the
screening criteria. The occurrence of poor outcome (death, vegetative state, or dependency) in patients
treated with magnesium sulfate was less likely than control group patients (odds ratio [OR] 0.54 [95%
confidence interval, CI 0.36–0.81]). Mortality rates did not differ between magnesium sulfate (14%)
and control treated (12%) patients (OR 1.16 [95% CI 0.51–2.65]). Our results indicate that although there
was reduced likelihood of a poor outcome for patients treated with magnesium sulfate after SAH, patient
mortality was not improved.
Ó 2009 Elsevier Ltd. All rights reserved.

1. Introduction
Cerebral vasospasm and delayed cerebral ischemia (DCI), asso-
ciated with high morbidity and mortality rates, are major compli-
cations of aneurysmal subarachnoid hemorrhage (SAH). Although
much research has aimed to find ways of preventing these compli-
cations, the management of vasospasm in patients who have expe-
rienced an aneurysmal SAH remains a significant clinical
problem.1–3 DCI occurs in about 30% of patients with SAH from
rupture of an intracranial aneurysm and it is an important cause
of poor outcome.4 Because DCI usually occurs 4 to 10 days after
the hemorrhage,5 neuroprotective treatment can be started before
the onset of ischemia, but it must be administered for an extended
period.
Magnesium is known as a neuroprotective agent that might
prevent or reverse delayed cerebral ischemia after SAH. It is bene-
ficial in the treatment of eclampsia, a condition that has some sim-
ilarities with DCI.6,7 Neuroprotective mechanisms of magnesium
include inhibition of release of the excitatory amino acid gluta-
mate, and a blockade of the N-methyl-D-aspartate–glutamate
receptor and voltage-dependent calcium channels. Finally, magne-
sium increases cardiac contractility, which may improve cerebral
perfusion in dysautoregulated brain tissue.8,9 The use of magne-
* Corresponding author. Tel./fax: +86 25 51805369.
E-mail address: jxshi@yahoo.cn (J.-X. Shi).
sium sulfate in aneurysmal SAH has a sound theoretical basis, with
enough circumstantial evidence in the obstetric and neurologic lit-
erature to warrant clinical investigation in neurosurgical practice
to establish its role in the treatment of vasospasm after aneurysmal
SAH.3,10 To assess the clinical effectiveness and safety of magne-
sium sulfate in the prevention of cerebral vasospasm in patients
who have suffered from aneurysmal SAH, we have searched using
electronic and manual methods to find all relevant studies for a
meta analysis. We then combined these studies to assess the effec-
tiveness of magnesium sulfate on the prevention of cerebral vaso-
spasm after aneurysmal SAH.
2. Methods
2.1. Search strategy and selection criteria
We systematically searched EMBASE and PubMed databases
(from 1 Jan. 1989 to Dec. 2008) using the following terms: ‘‘magne-
sium sulfate” or ‘‘MgSO4” with ‘‘subarachnoid hemorrhage” or
‘‘cerebral vasospasm”. Included studies reported the effects of
magnesium sulfate for cerebral vasospasm after aneurysmal SAH.
Where there were insufficient data presented for inclusion, authors
were contacted for further details. All randomized controlled trials
investigating the effect of magnesium sulfate in patients with SAH
were included, irrespective of dose, route of administration, and
duration of treatment. The Glasgow Outcome Scale (GOS) score

0967-5868/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jocn.2009.05.001
 X.-D. Zhao et al. / Journal of Clinical Neuroscience 16 (2009) 1394–1397 1395

Table 1 ized protocol and data collection form. For each study and each
Characteristics of studies included in analysis and primary outcome of patients with type of treatment, the following data were extracted: number of
subarachnoid hemorrhage after three months.
patients, and number of each outcome. Disagreements were solved
YearRef No. of Mean age Poor Favorable by discussion with the third investigator (Xin Zhang).
patients (years) outcome outcome
200613 2.3. Statistical methods
Study 38 54.9 7 (18%) 31 (82%)
Control 38 54.4 19 (50%) 19 (50%)
200514
Data were analyzed and processed in Review Manager 4.2 as
Study 122 >18 32 (26%) 90 (64%) supplied by the Cochrane Collaboration (Oxford, UK). The analyses
Control 127 >18 44 (35%) 83 (65%) were performed using both fixed models11 and random-effects
200815 models12 with Statistical Analysis System software (SAS Institute,
Study 31 53.6 ± 14.4 11 (35%) 20 (65%)
Cary, NC, USA). The risk differences in each study were defined
Control 27 52.1 ± 11.3 14% (52%) 13 (48%)
200216 by the odds ratio (OR) with 95% confidence intervals (95% CI) of
Study 20 46 7 (35%) 13 (65%) the categorical outcome frequencies in the study groups and the
Control 16 51 8 (50%) 8 (50%) control groups, respectively.
200217
Study 13 51.1 3 (23%) 10 (67%)
Control 10 58.9 2 (20%) 8 (80%) 3. Results

We identified eight manuscripts by studying the title or abstract

of published reports by searching the electronic databases of Pub-
Table 2
Doses and period of administration of magnesium sulfate after subarachnoid
Med and EMBASE; however, only five met the criterion and were
hemorrhage in five studies included in analysis. included in this meta analysis.13–17 The baseline characteristics of
patients in both groups (magnesium sulfate and controls) in the
YearRef Administration of MgSO4 Dose and target level
five studies did not differ. The GOS score or mRS outcome scale
200613 After verification of SAH for 12 days 100 mmol/day score was measured after 3 months in all patients. A total of 476
200514 Within 4 days of SAH for 14–18 days 64 mmol/day
200815 Within 3 days of SAH for 14–18 days 64 mmol/day
patients from the five studies were included (224 in the magne-
200216 Within 3 days of SAH for 10 days 144 mmol/day, target [Mg2+]: sium sulfate group and 252 as controls). The administration route
1.6–2.3 mmol/L of magnesium sulfate was continuous intravenous infusion in all
200217 Within 5 days of SAH, until ICU 24–52 mmol/day, target [Mg2+]: included patients. The dose or target level of serum magnesium
discharge 1.0–1.5 mmol/L
(Mg2+) was also described. In the primary analysis, where the effect
ICU = intensive care unit, Mg2+ = magnesium, SAH = subarachnoid hemorrhage. of magnesium sulfate on the incidence of poor outcome was stud-
ied, all five studies supplied data on the incidence of poor outcome
(Tables 1 and 2). The occurrence of a poor outcome was less likely
or the modified Rankin Scale (mRS) outcome score was measured for patients treated with magnesium sulfate than for control pa-
at 3 months after aneurysmal SAH. tients (OR 0.54 [95% CI 0.36–0.81) (Fig. 1). Magnesium sulfate
The primary outcome was a ‘‘poor outcome”, defined as death, can improve poor outcome at 3 months after SAH.
vegetative state, or severe disability. A ‘‘favorable outcome” was In the secondary analysis, where we studied the effect of mag-
defined as moderate disability and good recovery. A secondary out- nesium sulfate on mortality, no data were available from the study
come of the study was mortality. of van den Bergh and coworkers. Pooled mortality and survival
data from the remaining four studies (193 patients) are listed in
2.2. Data extraction Table 3. The mortality rates were similar for patients treated with
magnesium sulfate and control patients: 14% in the magnesium
All data were extracted independently by two investigators sulfate group and 12% in the placebo group (OR 1.16 [95% CI
(Xu-Dong Zhao, Yi-Ting Zhou) in duplicate by means of a standard- 0.51–2.65] (Fig. 2).

Fig. 1. The effect of magnesium sulfate versus control treatment on the odds of a poor outcome after subarachnoid hemorrhage (SAH) showing that a poor outcome is less
likely for patients treated with magnesium sulfate. A poor outcome is classified as death, vegetative state, or dependency as assessed by the Glasgow Outcome Scale (GOS)
score and the modified Rankin scale (mRS) score at 3 months after SAH.
1396 X.-D. Zhao et al. / Journal of Clinical Neuroscience 16 (2009) 1394–1397
Table 3
Pooled mortality rates for all patients in four studies valid for treatment analysis.
Magnesium sulfate group Control group
Survival 88 (86%) 80 (88%)
Death 14 (14%) 11 (12%)
Total 102 91
4. Discussion
SAH is a common condition with a relatively poor clinical out-
come, as 20–35% of SAH patients die with a few days.18 The cere-
bral vasospasm that follows SAH and DCI induced by cerebral
vasospasm has a major role in SAH.19 Despite many years of re-
search, the effectiveness of treatment to prevent or reverse cere-
bral vasospasm is modest.20 The current mainstay of treatment is
nimodipine administration, ‘‘triple H” therapy, or interventional
therapy, but even with this strategy, DCI occurs in about 27% of pa-
tients. Reducing the frequency and consequences of DCI will im-
prove the outcome after SAH. Nevertheless, none of such
therapies have been reported as an efficient treatment. Magnesium
sulfate has been widely used on pre-eclampsia and eclampsia
vasospasm.21,22 Magnesium exerts inhibitory activity on calcium
influx by blocking calcium channels or competing with calcium
receptors;3 thus, magnesium may have an important role in neuro-
protection, acting as a preventive factor of cerebral vasospasm be-
cause of its antagonism of calcium intracellular influx.
Magnesium is a neuroprotective agent with a well-established
clinical profile, and is commonly used in obstetric medicine.6,8
Hypomagnesemia occurs in more than half of patients with SAH
and is related to the occurrence of DCI.23 Controversial data have
been reported regarding the efficacy of magnesium sulfate3,16,17,24
and the exact mechanism of magnesium-related neuroprotection
remains speculative.25,26
This meta-analysis of magnesium sulfate in patients with SAH
represents a systematic review of this subject. We sought to deter-
mine whether magnesium sulfate as a positive strategy for cerebral
vasospasm after SAH could affect clinically important outcomes.
This study suggests that magnesium sulfate reduces poor outcome
in patients with SAH, but that mortality is not affected. Magnesium
has received much interest since 2007, specifically related to its
potential role in aneurysmal SAH. The magnesium sulfate in aneu-
rysmal SAH (MASH) study group investigated continuous intrave-
nous magnesium sulfate infusion from days 4 to 14 after SAH;
the clinical outcome of reduction of DCI remains, however, uncer-
tain. Recently, a randomized, placebo-controlled phase II trial with
magnesium sulfate in patients with SAH was conducted. Magne-
sium therapy reduced the occurrence of DCI by 34% (95% CI 14–
Fig. 2. The effect of magnesium sulfate versus control treatment on the odds of mortality after subarachnoid hemorrhage showing no effect of magnesium sulfate treatment.
62) and of poor outcome by 23% (95% CI 9–46).15 It is generally be-
lieved that magnesium supplementation reverses vasospasm and
offers neuroprotection to ischemic brain tissues.
Based on the results of the phase II study sample size, 1,200 pa-
tients are needed to give a statistically significant result. The
MASH-II study is a phase III randomized, clinical international mul-
ticenter trial to study the effect of magnesium sulfate after aneu-
rysmal SAH.27 The authors aim to include results from the phase
III trial before 2010.
Acknowledgments
We gratefully acknowledge the Jinling Hospital for financially
supporting this study. The funding source had no involvement in
the study design, collection, analysis, and interpretation of data
in writing the report or in the decision to submit the article for
publication.
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