Cerebral Vasospasm Pharmacological Treatment: An Update

Table 2

Summary of clinical data regarding magnesium sulphate in managing cerebral vasospasm.

Authors/year of publication	Type of study	Number of patients	Results
Brewer et al. (2001) [77]	Prospective	14 patients (11 women, 3 men; mean age: 58 years)	Four patients developed cerebral vasospasm. Doubling serum magnesium levels did not affect MCA CBFV but slightly lowered mean arterial blood pressure and systemic vascular resistance. Intravenous magnesium bolus did not reduce elevated CBFV in the subset of SAH patients with clinical vasospasm.
Chia et al. (2002) [78]	Prospective	23 patients divided into 2 groups. An Mg^++ receiving and a control group	7 out of 10 patients who did not receive magnesium developed vasospasm requiring intra-arterial papaverine, compared with only 2 of 13 patients among the Mg^++ group 𝑃<0.008).
Barile et al. (2003) [79]	Case report	1 patient	Continuous infusion in order to achieve serum magnesium levels in the range of 4–4.5 mg/dL (1.65–1.85 mmol/L) resulted in a marked decrease (12.2%) of the left MCA mean blood flow velocity.
Collignon et al. (2004) [80]	Prospective	128 consecutive patients	There was no significant difference in mean, minimum, or maximum serum magnesium levels between patients with and without DIND (1.93, 1.83, and 2.02 versus 1.91, 1.84, and 1.97 mg/dL, resp.,). Similarly, no difference was found in mean serum magnesium levels among patients with severe (1.94 mg/dL), moderate (1.92 mg/dL), or no DIND (1.91 mg/dL).
Lees et al. (2004) [81]	Randomized, placebo-controlled study	2589 patients	Primary outcome was not improved by magnesium (odds ratio 0.95, 95% CI 0.80–1.13, 𝑃=0.59). Mortality was slightly higher in the magnesium-treated group than in the placebo group (hazard ratio 1.18, 95% CI 0.97–1.42, 𝑃=0.098). Secondary outcomes did not show any treatment effect.
Chan et al. (2005) [82]	Randomized, prospective study	18 patients	Magnesium infusion increased PtO2 by 34%. Following temporary artery occlusion, PtO2 and pH decreased and PtCO2 increased in both groups. However, tissue hypoxia was less severe, and the rate of PtO2 decline was slower in the magnesium group.
Prevedello et al. (2006) [83]	Prospective	72 patients, group A placebo, group B Mg^++	In group A, vasospasm was correlated with a longer hospitalization time, different from group B, in which patients with vasospasm receiving magnesium sulfate required less hospitalization time (𝑃=0.0003).
Yahia et al. (2005) [84]	Prospective, pilot study	19 patients (mean age: 55 years; range: 39–84 years; 11 males, 8 females)	Vasospasm was observed in 9 patients (by clinical examination in two, TCD in five, and angiogram in nine). The mean serum Mg level was 2.7 mM/L and was maintained during the infusion period. No clinical adverse effects, hemodynamic changes, or fluctuations in serum glucose or phenytoin. None of the patients died. No CT evidence of ischemic infarction. Most patients had good outcomes (GOS 5 in 10 patients; GOS 4 in 8 patients).
Boet et al. (2005) [85]	Randomized, double-blind study	45 patients receive either MgSO4 80 mmol/day or saline infusion for 14 days	Patients receiving MgSO4 seemed to have fewer neurological deficits, better functional recovery, and an improved outcome score. However, none of these outcome variables reached a statistical significance. The incidence of cardiac and pulmonary complications in the MgSO4 group (43%) was also similar to that in the saline group (59%).
Wong et al. (2006) [86]	Randomized, double-blind, pilot study	60 patients receive either MgSO4 80 mmol/day or saline infusion for 14 days. Patients also received intravenous nimodipine	The incidence of symptomatic vasospasm decreased from 43% in the saline group to 23% in patients receiving MgSO4 infusion, but it did not reach statistical significance, (𝑃=0.06). For patients who had transcranial Doppler-detected vasospasm, the duration was shorter in the magnesium group compared with controls (𝑃<0.01). There was, however, no difference between groups in functional recovery or outcome.
Stippler et al. (2006) [87]	Comparative matched-cohort study	Seventy-six adults (mean age 54.6 years; 71% women; 92% Caucasian)	Symptomatic vasospasm was present at a significantly lower frequency in patients who received MgSO4 infusion (18%) compared with patients who did not receive MgSO4 (42%) (𝑃=0.025). There was no significant difference in mortality rate at discharge (𝑃=0.328). A trend toward improved outcome as measured by the modifed Rankin Scale (𝑃=0.084), but not the Glasgow Outcome Scale (𝑃=1.0), was seen in the MgSO4 treated group.
Muroi et al. (2008) [88]	Prospective, randomized, single-blind, placebo-controlled study	58 patients; 27 received placebo and 31 MgSO4	The difference in the occurrence of DIND and secondary infarction was not significant. The intention-to-treat analysis revealed a trend toward a better outcome (𝑃=0.083) after 3 months. On-treatment analysis showed a significantly better outcome after 3 months (𝑃=0.017) and a trend toward a better outcome after 1 year (𝑃=0.083). Significantly more often hypotension (𝑃=0.040) and hypocalcemia (𝑃=0.005) occurred as side effects in the MgSO4 group. In 16 patients (52%), the MgSO4 therapy had to be stopped before day 12 because of side effects.
Zhao et al. (2009) [89]	Meta-analysis study	Five previously published clinical studies	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)).
Wong et al. (2010) [90]	Prospective, randomized, placebo-controlled study	Of the 327 patients recruited, 169 were randomized to receive treatment with i.v. MgSO4 and 158 to receive saline (placebo)	The results do not support a clinical benefit from intravenous magnesium sulfate infusion.
Westermaier et al. (2010) [91]	Prospective, randomized, placebo-controlled study	110 patients receive i.v. MgSO4 or placebo	The incidence of delayed ischemic infarction was significantly lower in magnesium-treated patients (22% versus 51%; 𝑃=0.002); 34 of 54 magnesium patients and 27 of 53 control patients reached a good outcome (𝑃=0.209). Delayed ischemic neurologic deficit was reduced (9 of 54 versus 15 of 53 patients; 𝑃=0.149) and transcranial Doppler-detected vasospasm was significantly reduced in the magnesium group (36 of 54 versus 45 of 53 patients; 𝑃=0.028).
Suarez (2011) [92]	Review study	Seventeen articles were identified and reviewed, including one phase-III randomized-controlled clinical trial and six phase-II randomized-controlled trials	Due to inconsistently reported benefits and the occurrence of side effects, phase-II data suggested that intravenous magnesium for SAH provided either no overall net benefit or uncertain tradeoffs. Benefit was likewise not supported in the single phase-III clinical trial.
Muroi et al. (2012) [93]	Prospective study	15 patients. Eight patients were treated with standard therapy alone (group 1) and seven patients were treated with an additional, high-dose of MgSO4 (group 2)	Serum Mg^++ levels in group 2 were significantly higher compared to group 1: 1.48 ± 0.04 mmol/L versus 0.90 ± 0.01 mmol/L, 𝑃<0.001. Interleukin-6 (IL-6) in the CSF was significantly lower in group 2 compared to group 1: 6680 ± 989 versus 11079 ± 1277 pg/mL, 𝑃=0.021. A trend towards lower systemic IL-6 levels was found in group 2: 58 ± 7 versus 104 ± 21 pg/mL, 𝑃=0.052. Systemic IL-1β levels were significantly lower in group 2: 0.66 ± 0.11 and 0.15 ± 0.01 pg/mL (𝑃<0.001), while the CSF levels did not differ.
Mees et al. (2012) [94]	Phase-III randomized, placebo-controlled	1204 patients—606 patients were assigned to the magnesium group (two lost to followup) and 597 to the placebo group (one lost to followup)	158 patients (26.2%) had poor outcome in the magnesium group compared with 151 (25.3%) in the placebo group (risk ratio (RR) 1.03, 95% CI 0.85–1.25). Their updated meta-analysis of seven randomized trials involving 2047 patients shows that magnesium is not superior to placebo for the reduction of poor outcome after aneurysmal subarachnoid haemorrhage (RR 0.96, 95% CI 0.86–1.08).