Introduction

Subarachnoid hemorrhage (SAH) is a clinical phenomenon caused by the abrupt rupture and bleeding of blood vessels at the surface or base of the brain, which can occur for a number of reasons. As a result, the subarachnoid membrane receives direct blood flow [1]. SAH is a debilitating neurological disorder with high morbidity and mortality [2]. Despite advancements in medicine and surgical care, patients who survive their first bleeding event are at high risk for secondary sequelae, including delayed cerebral ischemia (DCI) and cerebral vasospasm (CV) [3]. CV denotes a temporary, self-resolving constriction of the intracranial arteries that occurs several days after an SAH. This phenomenon is closely linked to clinical deterioration resulting from DCI, affecting up to 30% to 40% of patients [4]. DCI is a significant clinical event that typically manifests 3 to 14 days after the initial bleeding and is characterized by subsequent neurological deterioration [5]. These complications can lead to poor functional outcomes and long-term disability [3].

SAH treatment extensively utilizes nimodipine, a calcium channel blocker, owing to its efficacy in preventing and managing CVs, decreasing mortality, and enhancing neurological function [6]. The high lipid solubility of nimodipine, which also promotes vascular smooth muscle relaxation and decreases calcium influx in brain cells, contributes to its effectiveness in crossing the blood-brain barrier [7]. A thorough assessment of the therapeutic effectiveness of nimodipine has become necessary in recent years despite the fact that multiple meta-analyses have shown its effectiveness in lowering CV, DCI, and cerebral infarction in patients with SAH [6].

The rationale for combining magnesium with nimodipine is based on the same principle of action of inhibiting calcium channels but differs in the mechanism of action. Nimodipine mostly acts on L-type calcium channels, but magnesium can block calcium by blocking N-methyl-D-aspartic acid receptor channels without competing with them [8,9]. Magnesium has emerged as a potential neuroprotective agent against SAH. Magnesium, recognized as a cost-effective treatment for eclampsia, has attracted attention in the field of neurocritical care because of the pathophysiological similarities to DCI following SAH [10]. However, the effectiveness of magnesium in the treatment of SAH remains controversial. Some meta-analyses indicate that magnesium may diminish the incidence of DCI and CVs, whereas others report no substantial advantage in neurological recovery or mortality. There are ongoing discussions regarding the best way to provide magnesium and whether it has synergistic benefits when taken with other medications such as nimodipine [11].

Given the various results of the existing evidence, a comprehensive meta-analysis was warranted to synthesize the available data and provide a clearer understanding of the potential benefits of combining magnesium with nimodipine in SAH management. By pooling data from multiple studies, we sought to provide a more robust assessment of the efficacy and safety of this combination therapy, which could inform clinical decision-making and guide future research directions in the management of SAH.

Methods

1. Search strategy

PubMed, Science Direct, Google Scholar, and the Cochrane Library were used to perform extensive literature searches. The following keywords were used: (nimodipine AND magnesium) AND (subarachnoid hemorrhage OR SAH) AND (comparison OR comparative OR efficacy OR effectiveness OR outcomes). To identify acceptable studies, we manually examined the reference lists of the included studies and pertinent review articles.

2. Inclusion and exclusion criteria

Two investigators screened the titles and abstracts for initial eligibility, followed by full-text reviews of potentially relevant articles. Disagreements were resolved through discussion or consultation with a third investigator. Two investigators independently extracted data using a standardized form. The inclusion criteria were as follows: (1) randomized controlled trials (RCTs) and prospective cohort studies; (2) studies of patients with SAH; (3) studies comparing the use of a combination of nimodipine and magnesium versus nimodipine alone; and (4) studies reporting at least one of the following outcomes: incidence of DCI, incidence of CV, mortality rates, functional outcomes (according to the modified Rankin scale [mRS] or Glasgow Outcome Scale [GOS]), and adverse effects. The exclusion criteria were as follows: (1) case reports, case series, retrospective studies, and non-comparative observational studies; (2) studies including pediatric patients or focusing exclusively on non-aneurysmal SAH; (3) studies examining other treatment combinations or comparing nimodipine or magnesium to placebo alone; (4) studies that did not report any of the specified primary outcomes; and (5) studies with insufficient data for statistical analysis or those that did not provide separate data for combination therapy and nimodipine alone groups. There were no language constraints in the search, although the included papers were required to have English abstracts. Reviews, comments, and conference abstracts were also excluded.

3. Data extraction

The first author's name, publication year, research site, study design, sample duration, the total number of patients in the treatment and control groups, number of males and females, mean patient age, magnesium dose and route, magnesium treatment duration, magnesium intervention time window, and study results were included in the extracted data. The study results included the incidences of CV and DCI, mortality rates, functional outcomes (according to mRS or GOS), and adverse effects.

4. Statistical analysis

This meta-analysis was performed using Cochrane Review Manager (RevMan) version 5.4. Continuous outcomes were analyzed using mean differences with 95% confidence intervals (CIs), while dichotomous outcomes were assessed using odds ratios (ORs) with 95% CIs. The I² statistic was used to analyze the heterogeneity of the enrolled studies. If there was considerable heterogeneity (p<0.10 and I²>50%), the random-effects model (REM) was used for the meta-analysis; otherwise, the fixed-effects model was used. We performed a sensitivity analysis using the leave-one-out method in the event of considerable heterogeneity to evaluate the robustness of the findings and to ascertain whether any of the included studies significantly affected the outcomes. A p-value of <0.05 was considered statistically significant. We used funnel plots to evaluate publication bias.

Results

1. Study selection and characteristics

In total, 663 potentially pertinent articles were identified in the first search. Following the removal of duplicates and title and abstract screening, the eligibility of 28 full-text articles was evaluated. Finally, 12 studies met the inclusion criteria and were included in the meta-analysis. No foreign language articles with English titles or abstracts met the inclusion criteria. Fig. 1 shows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) flow diagram depicting the study selection process.

The selected investigations, which comprised 2,338 patients overall (magnesium plus nimodipine, 1,183; nimodipine only, 1,155), were published between 2002 and 2018. The sample size ranged from 23 to 1200 participants. Two studies used the same research population [12,13]. Most studies were RCTs; one was a prospective cohort study [14]. Table 1 summarizes the features of the included studies.

2. Cerebral vasospasm

A total of 825 patients were examined for CV following SAH in nine investigations [12-20]. The REM demonstrated that the incidence of CV was significantly lower in patients with SAH treated with a combination of magnesium sulfate and nimodipine than in those treated with nimodipine alone (OR, 0.53; 95% CI, 0.29–0.95; p=0.03) (Fig. 2A). Owing to the high heterogeneity (p=0.005, I²=64%), we assessed the robustness of the data using sensitivity analysis. After excluding a trial by Wong et al. [13] due to using the same study population, the heterogeneity significantly decreased (p=0.20, I²=28%); however, the significant difference in favor of magnesium with nimodipine remained unchanged (OR, 0.44; 95% CI, 0.27–0.72; p=0.001) (Fig. 2B).

3. Delayed cerebral ischemia

In three investigations [18,20,21], 213 individuals were assessed for DCI after SAH. The findings demonstrated that the incidence of DCI was considerably lower in patients with SAH treated with magnesium sulfate plus nimodipine than in those treated with nimodipine alone (OR, 0.52; 95% CI, 0.31–0.87; p=0.01) (Fig. 3A).

4. Secondary cerebral infarction

Secondary cerebral infarction was reported in four studies [17,18,20,21]. There was an important distinction between the magnesium plus nimodipine and nimodipine-only groups, as shown by the incidence rates of secondary cerebral infarction, which were 22.8% and 29.6%, respectively. These investigations demonstrated that the two groups receiving therapy for SAH did not significantly differ in terms of secondary cerebral infarction (OR, 0.38; 95% CI, 0.11–1.29; p=0.12) (Fig. 3B).

5. Functional outcomes

The adjunct magnesium did not significantly improve the functional outcome based on the mRS evaluation, according to the REM (OR, 0.97; 95% CI, 0.79–1.19; p=0.75) (Fig. 4A). The REM also revealed that magnesium did not considerably improve the good functional outcomes of patients, according to the GOS assessment (OR, 0.81; 95% CI, 0.58–1.15; p=0.24) (Fig. 4B).

6. Mortality

The combined findings of eight investigations [12–15,20,22] including 950 patients demonstrated that there was no significant difference in mortality rates between the two groups when SAH was treated (OR, 0.97; 95% CI, 0.75–1.26; p=0.83) (Fig. 5A).

7. Adverse events

Three articles [13,18,20] reported the incidence of adverse events. These studies showed marked heterogeneity (I²=85%, p=0.001), prompting the use of REM to pool the effect size. We found that the magnesium plus nimodipine group (n=260) had more adverse events than the nimodipine-only group (n=245), but the difference was not statistically significant (OR, 3.14; 95% CI, 0.31–31.96; p=0.33) (Fig. 5B).

The reported adverse events varied across the studies. Hypotension was the most commonly reported side effect, with one study showing a significantly higher incidence in the magnesium plus nimodipine group (48%) than in the nimodipine-only group (11%) [18]. Other cardiovascular complications included bradycardia, arrhythmias, and, in rare cases, myocardial infarction. In one study, metabolic disturbances were also observed, particularly hypocalcemia, in patients receiving combination therapy. The less frequent adverse events included fever, palpitations, dizziness, and severe limb weakness. Most adverse events were managed by adjusting the infusion rates or discontinuing the treatment, and no mortality was directly attributed to the study medications [13,18,20].

Discussion

This meta-analysis aimed to evaluate the efficacy and safety of combining magnesium with nimodipine for the management of SAH. Our findings indicate that the adjunctive use of magnesium sulfate with nimodipine may significantly reduce the incidence of CV and DCI in patients with SAH, while not demonstrating a notable impact on functional outcomes and mortality rates.

Several guidelines and protocols were documented across the included studies regarding the administration of magnesium as an adjunct therapy. However, detailed magnesium dosing protocols are not specifically outlined in the latest 2023 American Heart Association/American Stroke Association guidelines for the management of aneurysmal SAH [23]. Typically, magnesium sulfate is administered at an initial loading dose, followed by continuous infusion [22]. The loading dose generally ranges from 16 to 20 mmol, given over 1,530 minutes, followed by a continuous infusion of 8 to 16 mmol per day for 10 to 14 days post-hemorrhage [12,13,15,17,18,24]. Dose adjustments based on serum levels, renal function, and clinical responses may be necessary [18].

Our findings demonstrated a significant reduction in the incidence of CV in patients treated with magnesium plus nimodipine compared to those treated with nimodipine alone (OR, 0.53; 95% CI, 0.29–0.95). This effect may be attributed to the complementary actions of magnesium and nimodipine on calcium channels, with magnesium acting as a natural calcium antagonist and blocking calcium influx through N-methyl-ᴅ-aspartic acid receptor channels [8,9]. The neuroprotective properties and dose-dependent risk profile of magnesium sulfate are well established, and low serum magnesium levels have been associated with an increased risk of intraparenchymal hemorrhage progression and rupture of incidental aneurysms in patients with SAH [25-27]. The potential mechanisms by which magnesium ions may prevent and improve CV include inhibiting blood vessel contraction, enhancing the role of nitric oxide (which is weakened after the onset of SAH), preventing the release of excitatory amino acids from brain cells, and acting as a vasodilator in cerebral arteries. These multifaceted actions suggest that magnesium, when combined with nimodipine, offers a more comprehensive approach to preventing vasospasms and improving outcomes in patients with SAH [20,28].

The combination therapy of magnesium and nimodipine showed a significant reduction in the incidence of DCI (OR, 0.52; 95% CI, 0.31–0.87), which is a crucial finding given that DCI is a major cause of morbidity and mortality in patients with SAH. Magnesium ions primarily act as vasodilators, potentially improving vasospasms and ischemia tolerance [29]. Furthermore, magnesium may reduce inflammation and oxidative stress, both of which contribute to secondary brain injury [30].

In contrast, our analysis did not find significant differences in functional outcomes, as assessed by the mRS and GOS. The ORs for both scales indicated no substantial improvement in functional recovery with the addition of magnesium (mRS: OR, 0.97; p=0.75; GOS: OR, 0.81; p=0.24). This suggests that although magnesium may mitigate some of the acute complications associated with SAH, it does not translate into improved long-term functional outcomes.

The mortality rates did not differ significantly between the two treatment groups (OR, 0.97; p=0.83), indicating that the addition of magnesium did not adversely affect survival in patients with SAH. Similarly, for secondary cerebral infarction, data from four studies indicated no significant difference between the combination therapy and nimodipine alone (OR, 0.38; p=0.12). These findings suggest that although the addition of magnesium to nimodipine therapy may offer benefits in reducing CV and DCI, it does not translate into significant improvements in mortality or secondary cerebral infarction outcomes. The lack of effect on these critical endpoints highlights the complex nature of SAH management and underscores the need for further research to identify interventions that can more effectively impact these outcomes. It also raises questions regarding the potential limitations of magnesium therapy, such as optimal dosing, timing of administration, and possible interactions with other aspects of SAH management that may influence long-term outcomes.

Regarding safety, our analysis indicated a higher incidence of adverse reactions in the magnesium plus nimodipine group; however, this difference was not statistically significant (OR, 3.14; p=0.33). The marked heterogeneity observed in the reporting of adverse events underscores the need for standardized definitions and reporting criteria in future studies to better assess the safety profile of this combination therapy.

This meta-analysis has several limitations that should be considered when interpreting the results. First, the small number of studies on certain outcomes such as DCI and functional outcomes limited the robustness of these findings and prevented a thorough assessment of publication bias. Second, the included studies varied in magnesium dosing regimens, administration routes, and treatment durations, which may have influenced the overall effect of the intervention. Third, the time window for magnesium administration after SAH onset differed across studies, potentially affecting the treatment efficacy. These limitations highlight the need for further large-scale, well-designed, RCTs to confirm these findings and address the remaining uncertainties regarding the use of magnesium as an adjunct to nimodipine in SAH management.

In conclusion, this meta-analysis provides evidence supporting the use of magnesium as an adjunct to nimodipine for reducing the incidence of CV and DCI in patients with SAH. However, the combination therapy did not result in significant improvements in functional outcomes, mortality rates, or secondary cerebral infarction. Although there was a trend towards increased adverse events in the combination therapy group, this difference was not statistically significant. These findings suggest that adding magnesium to nimodipine therapy may be beneficial in preventing some of the immediate complications of SAH. However, its impact on long-term outcomes remains unclear. The heterogeneity observed in some analyses and the limitations of the included studies highlight the need for further large-scale, well-designed RCTs to confirm these findings and optimize the dosing and timing of magnesium administration in SAH management.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

The authors gratefully acknowledge financial support from the Institut Teknologi Sepuluh Nopember for this work, under project scheme of the Publication Writing and IPR Incentive Program (PPHKI) 2024.

Author contributions

Conceptualization, Methodology: all authors; Data curation, Software: YP; Formal analysis, Supervision, Validation: RR; Funding acquisition: RR, YP; Visualization: YP, II; Writing-original draft: RR; Writing-review & editing: II.

Fig. 1.

Literature screening process.

Fig. 2.

Forest plots illustrate the incidence of cerebral vasospasm in the magnesium and nimodipine study, as well as in the nimodipine-only study before (A) and after (B) sensitivity. M-H, Mantel-Haenszel; CI, confidence interval; df, degrees of freedom.

Fig. 3.

Forest plots illustrate the incidence of delayed cerebral infarction (A) and secondary cerebral infarction (B) in the magnesium and nimodipine study, as well as in the nimodipine-only study. M-H, Mantel-Haenszel; CI, confidence interval; df, degrees of freedom.

Fig. 4.

Forest plots illustrate the functional outcomes, including the modified Rankin scale (A) and the Glasgow Outcome Scale (B) in the magnesium and nimodipine study, as well as in the nimodipine-only study. M-H, Mantel-Haenszel; CI, confidence interval; df, degrees of freedom.

Fig. 5.

Forest plots illustrate the incidence of mortality (A) and adverse events (B) in the magnesium and nimodipine study, as well as in the nimodipine-only study. M-H, Mantel-Haenszel; CI, confidence interval; df, degrees of freedom.

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Figure & Data

References

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