Magnesium for aneurysmal subarachnoid hemorrhage (MASH-2): a randomised placebo-controlled trial

Phase 3 randomised, placebo-controlled trial

N=1204

To test whether magnesium therapy improves outcome after aneurysmal subarachnoid hemorrhage

Magnesium group (n=606)

Placebo group (n=597)

Patients aged 18 years or older with an aneurysmal pattern of subarachnoid hemorrhage on brain imaging, admitted to hospital within 4 days of hemorrhage

Patients with renal failure or bodyweight lower than 50 kg

Participants in the study received a fixed daily dose of 64 mmol magnesium sulphate, reconstituted in 0.9% saline, or a placebo, administered as soon as possible after obtaining consent. The study medication was delivered continuously via intravenous infusion, continuing for 20 days following hemorrhage onset, or until the patient was discharged from the hospital or passed away, if either occurred sooner. To prevent symptomatic hypermagnesemia, renal function was monitored by investigators at least every two days.

April 2004 to September 2011

Primary: Poor outcome (modified Rankin Scale score of 4 or 5) or death 3 months after hemorrhage

Secondary: No symptoms (modified Rankin Scale score of 0) 3 months after hemorrhage, difference between distribution of all scores on the modified Rankin Scale

Characteristics

Mean age (SD; years)

Female (%)

World Federation of Neurological Surgeons subarachnoid hemorrhage grade >4

Aneurysm treatment - Coiling

Aneurysm treatment - Clipping

Aneurysm treatment - None

Aneurysm treatment - Unknown

Median time to received study medication from symptom onset (IQR; h)

Poor outcome (mRS 4-5 or death)

No symptoms (mRS 0)

Study treatment was stopped for one patient due to asymptomatic hypocalcemia, for two patients due to asymptomatic hypermagnesemia, and for one patient due to suspected symptomatic hypermagnesemia, all in the magnesium group.

Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid hemorrhage, therefore routine administration of magnesium cannot be recommended.

The study was well-designed with a large sample size and high follow-up rate, enhancing its reliability. However, it did not include detailed assessments of quality of life or cognitive outcomes, which could have provided additional insights. The study's pragmatic design focused on clinical outcomes, potentially overlooking other relevant measures such as delayed cerebral ischemia.

Intravenous Magnesium Sulphate for Aneurysmal Subarachnoid Hemorrhage (IMASH)

Design

Phase III, multicenter, randomized, double-blinded, placebo-controlled trial

N= 327

Objective

To compare intravenous magnesium sulfate infusion with placebo in patients with acute aneurysmal subarachnoid hemorrhage and assess its impact on neurological outcomes

Study Groups

Magnesium sulfate group (n= 169)

Placebo  group (n= 158)

Inclusion Criteria

Patients ≥18 years with onset and radiological diagnosis of subarachnoid hemorrhage (SAH) secondary to intracranial aneurysm within 48 hours prior to the study

Exclusion Criteria

Patients with anticipated death within 48 hours, major hepatic, pulmonary, or cardiac disease, recent myocardial infarct, significant renal impairment, pre-existing neurological disability, women of childbearing potential or with a positive urine pregnancy test

Methods

Patients were randomized 1:1 to receive either intravenous (IV) magnesium sulfate (MgSO4) infusion titrated to twice the baseline serum concentration or placebo (saline) for 10 to 14 days.

The regimen for MgSO4 infusion was 20 mmol over 30 minutes followed by 80 mmol per day. Patients were also given 60 mg of oral nimodipine every 4 hours, if blood pressure remained stable, for 14 days.

Outcome measures were assessed at 3 and 6 months post-randomization using the Extended Glasgow Outcome Scale (GOSE), modified Rankin Scale (mRS), and Barthel Index score, and adverse events by a data monitoring and safety committee.

Duration

June 1, 2002, to December 31, 2008

Outcome Measures

Primary: Favorable outcome (GOSE score 5 to 8) at 6 months

Secondary: Clinical vasospasm (within 2 weeks), and mRS, Barthel Index (at least 85), and Short Form-36 at 6 months

Baseline Characteristics

MgSO4 (n= 169)

Placebo (n= 158)

Age, years

Female

Admission WFNS

5

4

3

2

1

20 (12%)

42 (25%)

17 (10%)

40 (24%)

50 (30%)

17 (11%)

39 (25%)

14 (9%)

43 (27%)

45 (29%)

Fisher CT grade

1

2

3

4

1 (1%)

8 (5%) 

141 (83%) 

19 (11%) 

1 (1%)

16 (10%)

121 (77%)

20 (13%)

Aneurysm location

ICA

ACA

MCA

PC

59 (35%)

53 (31%)

31 (20%)

16 (10%) 

57 (36%)

43 (27%)

33 (21%)

15 (10%)

Aneurysm treatment

Coiling

Clipping

No treatment

85 (50%)

72 (43%)

11 (7%) 

72 (46%)

69 (44%)

17 (11%) 

Abbreviations: MgSO4 = Magnesium sulfate. WFNS = World Federation of Neurological Surgeons. CT = Computed tomography. ICA = Internal carotid artery. ACA = Anterior cerebral artery. MCA = Middle cerebral artery. PC = Posterior circulation.

Results

Endpoint

MgSO4 (n= 169)

Placebo (n= 158)

95% CI

Favorable outcome

Clinical vasospasm

mRS score

Good outcome (0-2)

Excellent outcome (0-1)

97 (57%)

77 (46%)

91 (58%)

71 (45%)

OR 1.0: 95% CI (0.6 to 1.5)

OR 1.0: 95% CI (0.7 to 1.6)

Barthel Index

Short Form-36

Physical health

Mental health

67.3 ± 26.1*

65.4 ± 22.0* 

65.5 ± 25.3**

64.5 ± 24.1**

MD 3.8: 95% CI (-5.6 to 9.2)

MD 3.4: 95% CI (-5.7 to 7.6)

*n= 99

**n= 90

Abbreviations: MgSO4 = Magnesium sulfate. CI = Confidence interval. mRS = modified Rankin Scale. OR = Odds ratio. MD = Mean difference.

Adverse Events

Hypotension occurred in 15% of the MgSO4 group and 13% of the placebo group (p= 0.590).

There was no significant difference in the incidence of cardiac failure, acute renal failure, pneumonia, sepsis, pulmonary embolism, myocardial infarction, or gastrointestinal bleeding between the groups.

Study Author Conclusions

Our results do not support a significant clinical benefit of IV magnesium sulfate infusion over placebo infusion in patients with acute aneurysmal SAH.

InpharmD Researcher Critique

The study's lack of significant findings may be due to low cerebrospinal fluid penetration of magnesium sulfate or the timing of administration.

The study was limited by the lack of on-site trial monitoring and the use of the last observation carried forward method, which could introduce bias. Additionally, the study did not incorporate daily blood pressure data, which could have impacted outcomes.

Magnesium Sulfate in Aneurysmal Subarachnoid Hemorrhage: A Randomized Controlled Trial

Randomized, double-blind, placebo-controlled multicenter trial

N= 283

To assess whether intravenous magnesium sulfate reduces the frequency of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (SAH)

Magnesium treatment group (n= 139)

Placebo group (n= 144)

Patients randomized within 4 days after aneurysmal SAH; diagnosis based on positive CT scan or xanthochromia of cerebrospinal fluid; aneurysm confirmed by angiography or typical pattern on CT

Nonaneurysmal causes for SAH, renal failure (serum creatinine >150 µmol/L), age <18 years, no informed consent, or imminent death

Patients received a continuous intravenous dose of 64 mmol/L magnesium sulfate per day, starting within 4 days after SAH and continuing until 14 days after aneurysm occlusion or a maximum of 18 days after SAH onset. The placebo was 50 mL of normal saline. 

November 2000 to January 2004

Primary: Occurrence of DCI within 3 months after SAH

Secondary: Any new hypodensity on brain CT, poor outcome (Rankin score ≥4), nonexcellent outcome (Rankin score ≥1)

Characteristics

Mean age

Women (%)

WFNS I (%)

WFNS II (%)

WFNS III (%)

WFNS IV (%)

WFNS V (%)

WFNS ≥4 (%)

Cisternal blood above median (%)

Ventricular blood above median (%)

Intracranial hematoma amount (%)

Surgery (%)

Endovascular treatment (%)

Outcome

DCI (%)

New hypodensities on CT (%)

Poor outcome, Rankin ≥3 (%)

Excellent outcome, Rankin 0 (%)

No major side effects occurred. Discontinuation reasons included hypotension, phlebitis, bradycardia, atrial fibrillation, hypermagnesemia, and renal failure.

This study suggests that magnesium reduces DCI and subsequent poor outcome in patients with SAH, but the results are not yet definitive. A phase III trial is needed to confirm the beneficial effect of magnesium therapy, with poor outcome as the primary outcome.

The study was well-designed as a randomized, double-blind, placebo-controlled trial, which strengthens the validity of the findings. However, the study was underpowered due to the lower than expected frequency of the primary outcome in the control group, which may limit the conclusiveness of the results. Additionally, the study did not include silent infarctions in the primary outcome measure, which could have provided a more comprehensive assessment of magnesium's effects. A larger phase III trial is necessary to confirm these findings and establish magnesium's role in clinical practice.

The Safety and Feasibility of Continuous Intravenous Magnesium Sulfate for Prevention of Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage

Design

Prospective, single-cohort, pilot study

N= 19

Objective

To study the safety and feasibility of a continuous, high-dose intravenous (IV) infusion of magnesium sulfate (MgSO4) in conjunction with standard subarachnoid hemorrhage (SAH) management for the prevention of cerebral vasospasm and ischemic cerebral injury in patients with aneurysmal SAH

Study Groups

All patients (n= 19)

Inclusion Criteria

Patients ≥18 years with aneurysmal SAH documented by a non-contrast computed tomography (CT) head scan and a cerebral angiogram obtained within 72 hours of ictus

Exclusion Criteria

Patient with known chronic renal impairment (serum creatinine >2.0 mM/L), intracerebral pathological condition (e.g., intracranial abscess), brain tumor, pregnancy

Methods

Patients received a continuous IV infusion of 12 g of MgSO4 in a 500-mL solution of 0.9% NaCl administered at a rate of 4.06 mM (0.5 g) every hour over a 24-hour period for 10 days.

Standard SAH management consisted of IV normal saline, IV phenytoin, drainage of cerebrospinal fluid, and early surgery or coiling.

The effect of MgSO4 on clinical examination, heart rate, and blood pressure was measured every 2 hours, and serum glucose and phenytoin levels were monitored daily.

Duration

June 2001 to October 2002

Outcome Measures

Primary: Evidence of vasospasm on clinical examination

Secondary: Glasgow Outcome Scale (GOS) score assessment and CT scan evidence of ischemic infarction at 30 days

Baseline Characteristics

All patients (n= 19)

Age, mean (range), years

Female

Fisher Grade, mean

3

Hunt & Hess Grade

Grade II

Grade III

Grade IV

12

2

5

Hemorrhage

Intraventricular

Intracranial

8

1

Ventriculostomy

8

MgSO4 level, mean, mM/L

1.6 ± 0.30

Abbreviations: MgSO4 = Magnesium sulfate. 

Results

Endpoint

All patients (n= 19)

Vasospasm

Symptomatic

Asymptomatic

2 (11%)

7 (37%)

MgSO4 level, mean, mM/L

2.7 ± 0.37

GOS score at 30 days*

5

4

10

8

There was no CT evidence of cerebral ischemic infarction, and no deaths occurred.

*GOS score 4 and 5 represent "good outcomes".

Abbreviations: TCD = Transcranial Doppler. GOS = Glasgow Outcome Scale. CT = Computed tomography.

Adverse Events

No clinical adverse effects, hemodynamic changes, or fluctuations in serum glucose or phenytoin levels were observed.

Study Author Conclusions

Our study confirmed the safety and feasibility of a continuous infusion of high-dose intravenous MgSO4 in patients with aneurysmal SAH.

InpharmD Researcher Critique

The study was a prospective pilot study without a control group, which limits the ability to draw definitive conclusions about the efficacy of MgSO4. The small sample size further limits the generalizability of the findings. However, the study demonstrated the safety and feasibility of the treatment, providing a basis for future randomized controlled trials.

Magnesium Sulfate in the Management of Patients with Fisher Grade 3 Subarachnoid Hemorrhage: A Pilot Study

Design

Single-cohort, pilot study

N= 10

Objective

To evaluate the effect of magnesium sulfate (MgSO4) on the clinical course of patients with severe aneurysmal subarachnoid hemorrhage (SAH)

Study Groups

All patients (n= 10)

Inclusion Criteria

Patients ≥18 years with aneurysmal SAH demonstrated by angiography and computed tomography (CT) scan features consistent with Fisher Grade 3 criteria, within 5 days of ictus

Exclusion Criteria

Patients with known renal impairment, major cardiac, pulmonary, or hepatic disease, moribund condition at admission, pregnancy

Methods

Patients received a bolus (20 mmol over 20 minutes) and constant infusion (80 mmol every 24 hours) of intravenous (IV) MgSO4 in 0.9% saline, with incremental increases of 10 to 20 mmol daily as required after correlation with the daily serum magnesium levels. Goal serum level during continuous infusion was twice the baseline or a level ranging from 2 to 2.5 mmol/L.

Upon angiographic confirmation of the aneurysm, surgical clipping or endovascular coiling of the lesion was performed. Additionally, patients received nimodipine and hypervolemic therapy after the aneurysm had been secured.

Baseline and daily metabolic panel and transcranial Doppler (TCD) ultrasonography were assessed.

Duration

Treatment: Up to 10 days post-ictus

Follow-up: 3 months 

Outcome Measures

Primary: Achievement of goal serum magnesium levels

Secondary: Evidence of vasospasm on TCD ultrasonography, clinical evidence of vasospasm, Glasgow Outcome Scale (GOS) score at 3 months

Baseline Characteristics

All patients (n= 10)

Age, mean, years

Female

WFNS score

Grade I

Grade II

Grade V

8

1

1

Time to MgSO4 initiation post-hemorrhage, mean, days

Dose of MgSO4 continuous infusion, mmol/day

Abbreviations: WFNS = World Federation of Neurological Surgeons. MgSO4 = Magnesium sulfate.

Results

Endpoint

All patients (n= 10)

At goal serum MgSO4 levels

Evidence of Vasospasm

On TCD ultrasonography

Clinical

5

3

GOS score

5

3

8

2

Severe vasospasm occurred in 3 patients (velocities, >200 cm/s).

Abbreviations: MgSO4 = Magnesium sulfate. TCD = transcranial Doppler. GOS = Glasgow Outcome Scale.

Adverse Events

No adverse effects were noted during the infusions. No deaths occurred.

Study Author Conclusions

This pilot study on the effect of MgSO4 on vasospasm after aneurysmal SAH demonstrates that it can be used safely in this group of neurosurgical patients.

InpharmD Researcher Critique

This study's small sample size and lack of a control group limit the ability to draw definitive conclusions about its efficacy in reducing vasospasm.