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(Stroke. 1995;26:1183-1188.)
© 1995 American Heart Association, Inc.

Articles

A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of Intravenous Magnesium Sulfate in Acute Stroke

Keith W. Muir, MRCP Kennedy R. Lees, BSc, MD, FRCP

From the Acute Stroke Unit, University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland.

Correspondence to Dr Keith W. Muir, Acute Stroke Unit, University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, Scotland.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Magnesium ions act as endogenous vasodilators of the cerebral circulation and act pharmacologically as noncompetitive antagonists of the N-methyl-D-aspartate receptor by virtue of their role as endogenous voltage-sensitive blockers of the ion channel. The preclinical efficacy of magnesium has been demonstrated in standard models of stroke.

Methods Sixty patients were randomized to magnesium sulfate (8 mmol IV over 15 minutes and 65 mmol over 24 hours) or placebo within 12 hours of clinically diagnosed middle cerebral artery stroke. Pulse, blood pressure, and serum magnesium levels were monitored. Primary outcome was death or significant functional impairment (Barthel Index score <60) at 3 months.

Results Magnesium was well tolerated, with no significant adverse effects and no change in blood pressure or pulse rate. Laboratory and electrocardiographic variables did not differ significantly between placebo- and magnesium-treated groups. Serum magnesium rose from 0.76 mmol/L to 1.42 mmol/L over 24 hours and remained significantly higher than in the placebo group at 48 hours. Thirty percent of magnesium-treated and 40% of placebo-treated patients were dead or disabled (Barthel Index score <60) at 3 months (P=.42). There was a decrease in the number of early deaths in the magnesium-treated group (P=.066, log-rank test).

Conclusions Magnesium sulfate is well tolerated after acute stroke and has no deleterious hemodynamic effects at this dose. Further trials are required to determine efficacy.

Key Words: clinical trials • magnesium • treatment outcome • neuroprotection

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Parenteral administration of magnesium has potential therapeutic roles in cardiovascular and neurological disease. A number of small trials suggested benefits of elevating the serum magnesium concentration after acute myocardial infarction (MI)¹ ; postulated mechanisms of action included vasodilatation and antidysrhythmic and antithrombotic effects.² The larger second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2)^{3 4} found improved early and late mortality after MI in patients treated with magnesium given as the sulfate (MgSO₄) in doses sufficient to double serum magnesium levels and suggested that magnesium may be predominantly cytoprotective.

The Mg²⁺ ion regulates cellular energy metabolism, vascular tone, and cell membrane ion transport.⁵ Its effects are generally antagonistic to those of calcium.⁶ Magnesium may regulate ATP concentrations,⁵ and adequate magnesium concentration is a prerequisite for ATP regeneration after ischemia and reperfusion.^{7 8} Magnesium causes vasodilatation by stimulation of endothelial prostacyclin release⁹ and in vivo prevents vasoconstriction both of carotid arteries by a variety of mediators¹⁰ and of intracranial vessels after experimental subarachnoid hemorrhage.¹¹ Administration of magnesium to humans decreases total peripheral resistance by 20% to 30%, with a compensatory rise in cardiac output.² Transcranial Doppler ultrasound changes in magnesium-treated preeclamptic patients are consistent with vasodilatation of small cerebral arterioles distal to the middle cerebral artery.¹²

The Mg²⁺ ion blocks the ion channel of the N-methyl-D-aspartate (NMDA) receptor in a voltage-dependent fashion,¹³ and increasing extracellular magnesium concentrations in vitro cause noncompetitive NMDA blockade.¹⁴ These NMDA antagonist properties may be responsible for the anticonvulsant effect of parenteral MgSO₄, which has led to its use as standard therapy in preeclampsia in the United States.¹⁵ Its efficacy in preeclampsia implies that magnesium may have broader clinical applications as a neuroprotective agent.¹⁶ In vitro and in vivo models of focal and global ischemia have demonstrated neuronal protection that in some instances is as great as that seen with noncompetitive NMDA antagonists.

Magnesium protects both hippocampal neurons from glutamate-mediated necrosis¹⁷ and white matter tracts from prolonged ischemia.¹⁸ A rapid decrease of intracellular free magnesium concentration occurs after focal fluid-percussion injury in rats, which is associated with a decline in intracellular high-energy phosphate stores and is in proportion to the severity of injury.¹⁹ Increasing extracellular magnesium concentration enhances the recovery of hippocampal neuronal high-energy phosphates after ischemia.^{8 20}

Infarct size was reduced by a degree equivalent to that of NMDA antagonists in a rat NMDA injection model of focal ischemia,²¹ and direct administration of magnesium as the chloride salt (MgCl₂) significantly decreased rat hippocampal CA1 necrosis even when administered 24 hours after 20 minutes of four-vessel forebrain ischemia.²² Systemic MgCl₂ decreased cerebral infarct volume by 20% after permanent middle cerebral artery occlusion in the rat.²³ Immediate and longer-term neurological recovery was significantly greater in MgCl₂-treated rats after focal fluid-percussion brain injury when magnesium was administered 30 minutes after injury.²⁴

If magnesium is even moderately effective as a neuroprotective agent in humans, there are significant advantages. It is widely available, inexpensive, and has an established safety profile. This contrasts with concerns over the safety of noncompetitive NMDA antagonists in particular. We undertook a randomized, double-blind, placebo-controlled pilot trial of intravenous MgSO₄ to assess the safety and feasibility of magnesium therapy.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The study was approved by the West Ethics Committee of Greater Glasgow Health Board. Written informed consent was obtained from either patients or their next of kin. All patients older than 18 years of age presenting within 12 hours of onset of a clinically diagnosed acute middle cerebral artery stroke were eligible. Exclusion criteria were pregnancy, known renal failure (serum creatinine >200 µmol/L), or preexisting functional impairment such that poststroke assessment would be impaired (modified Rankin Scale score 3).

All patients had pretreatment electrocardiogram (ECG), serum biochemistry, complete blood count, and coagulation screen. Baseline assessment included physical examination and scoring on two separate stroke scales: the Middle Cerebral Artery Neurological Score (N score)²⁵ and the National Institutes of Health (NIH) Stroke Scale.²⁶ Strokes were classified with the use of the Oxfordshire Community Stroke Project classification.²⁷

Magnesium and placebo were prepared as solutions of identical volume and appearance by the hospital pharmacy sterile supplies unit. Randomization was performed in blocks of 10 according to a code devised and held by the pharmacy. Medical staff and patients were blind to treatment. The code was broken only after final follow-up was complete for all subjects. We administered MgSO₄ 8 mmol IV in 50 mL normal saline over 15 minutes, followed by 65 mmol in 100 mL over 24 hours as a continuous infusion. The placebo group received equal volumes of normal saline alone.

Repeated ECGs were performed after the bolus and at 24 and 48 hours. Blood studies were repeated at 24 hours. All subjects had CT scanning performed within 72 hours of admission.

Follow-up visits were conducted by the same investigators, and repeated scores on the Barthel Index, Rankin Scale, N score, and NIH Stroke Scale were obtained at day 5 and after day 90. An additional assessment of 10-m walking time was made. The primary outcome measure was death or significant functional impairment (Barthel Index score <60) at 3 months.

Categorical data were compared with ² tests. One-sample t tests were used to compare change from pretreatment to posttreatment for laboratory values. Blood pressure, pulse rate, the ECG variables PR and corrected QT intervals, and serum magnesium levels were compared by repeated-measures ANOVA. Survival data were analyzed with the use of the log-rank test on Kaplan-Meier survival curves. Median stroke scale scores were compared by Friedman ANOVA by ranks.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Sixty-one of 260 patients admitted to the Acute Stroke Unit of the Western Infirmary were eligible and were randomized into the trial during a 6-month period beginning January 1993. One patient was subsequently excluded from the trial as a result of the finding of a brain tumor on CT scanning. A total of 60 patients were thus assessable; 30 received magnesium and 30 placebo.

Demography, medical history, and clinical and CT diagnoses are detailed in Table 1. There were no significant differences between the baseline clinical characteristics of the placebo- and magnesium-treated populations. Two patients presented with clinical features compatible with middle cerebral stroke but subsequently developed clinical features localizing the event to the brain stem. One patient had significant cardiac failure (New York Heart Association class IV) at trial entry, and one other was undergoing acute MI.

View this table: [in this window] [in a new window]   Table 1. Demography and Baseline Characteristics of Magnesium- and Placebo-Treated Groups

The mean time from stroke onset to administration of trial solution was 8.5 hours. There was no difference in time to treatment initiation between groups. Nine in the magnesium group and 5 in the placebo group were treated within 6 hours of onset. No adverse effects attributable to MgSO₄ were seen during or after administration. Serious medical events that occurred during the study period are detailed in Table 2. One subject suffered fatal hemorrhage from a known bleeding diathesis in the lung 10 days after stroke; he had been undergoing treatment for this at the time of the stroke. Cerebral edema was recorded if it was associated with a change in the patient's level of consciousness, and infections were recorded if patients required intravenous antibiotic therapy.

View this table: [in this window] [in a new window]   Table 2. Adverse Events and Outcome

Changes in systolic and diastolic blood pressure and pulse rate in the magnesium group did not differ from those in the placebo group (Fig 1). Changes in biochemistry, complete blood count, or coagulation parameters did not differ between magnesium and placebo groups. The ECG variables PR interval and corrected QT interval did not differ between magnesium and placebo groups at any time point.

View larger version (11K): [in this window] [in a new window]   Figure 1. Line graphs show cardiovascular variables during magnesium infusion. a, Systolic blood pressure (BP); b, diastolic BP; and c, pulse rate. P>.05 for all times (repeated-measures ANOVA). indicates magnesium-treated group; , placebo-treated group. Values are mean±SD.

Serum magnesium concentrations did not differ significantly between groups at baseline. Magnesium levels continued to rise throughout the 24-hour infusion and remained significantly elevated at 48 hours (Fig 2). Magnesium concentration was 130% of baseline after 15 minutes and 185% after 24 hours. Peak magnesium concentration was not related to baseline serum creatinine. There was no relationship between mean arterial pressure and serum magnesium.

View larger version (13K): [in this window] [in a new window]   Figure 2. Line graph shows serum magnesium concentration. *P<.01 (repeated-measures ANOVA). indicates magnesium-treated group; , placebo-treated group. Values are mean±SD.

Outcome data are summarized in Table 2. Fewer magnesium-treated patients were dead or disabled at 3 months (n=9, 30%) compared with the placebo group (n=12, 40%). There were 6 deaths in the magnesium group and 7 in the placebo group. Survival curve analysis indicated a trend toward an improved early outcome in the magnesium group (P=.066, log-rank test). Only one patient who received magnesium died within the first 7 days (Fig 3). Serial stroke scale scores are shown in Fig 4. No significant difference between groups was seen at any time. Mean 10-m walking time at 3 months was 14±7 seconds (mean±SD) for magnesium-treated and 17±13 seconds for placebo-treated groups (P=.73).

View larger version (9K): [in this window] [in a new window]   Figure 3. Graph shows Kaplan-Meier survival curves. There are no censored data. P=.066 (log-rank test). Solid line indicates magnesium-treated group; broken line, placebo-treated group.

View larger version (12K): [in this window] [in a new window]   Figure 4. Line graphs show median scores on (a) the Middle Cerebral Artery Neurological Score (N) and (b) National Institutes of Health (NIH) Stroke Scale at admission, 5 days, and 3 months. There were no significant differences at any time. indicates magnesium-treated group; , placebo-treated group.

When all patients with primary intracerebral hemorrhage were excluded from analysis, no significant differences in outcome measures were found compared with the group as a whole. In the magnesium group 6 of 26 patients died, and 31% were dead or disabled at 3 months; in the placebo group there were also 6 deaths, and 39% were dead or disabled at 3 months. Median stroke scale scores at 3 months were 90 versus 85 (magnesium versus placebo) (N score) and 2 versus 2.5 (NIH score). Survival curve analysis found a similar trend in favor of magnesium (P=.051, log-rank test).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have confirmed that MgSO₄ is a safe and feasible potential therapy in acute stroke. Magnesium acts as a vasodilator and has previously been found to lower systemic blood pressure. Reduction of systemic blood pressure in the acute phase after ischemic stroke is detrimental to survival, as was evident in the Intravenous Nimodipine West European Stroke Trial (INWEST),²⁸ in which the dose-dependent worsening of neurological outcome correlated with the degree of lowering of diastolic blood pressure. Reassuringly, we found no difference in blood pressure between the magnesium- and placebo-treated groups at any time. No adverse events were reported in association with MgSO₄. The LIMIT-2 trial used identical doses of MgSO₄ after acute MI and reported transient flushing and warmth in association with the bolus dose; extending the administration period to 10 to 15 minutes abolished this.³

The decreases in early and late mortality after MI in magnesium-treated patients in the LIMIT-2 study were not repeated in the much larger fourth International Study of Infarct Survival (ISIS-4).²⁹ However, magnesium treatment in ISIS-4 was both delayed and administered after thrombolytic therapy,^{4 30} whereas in LIMIT-2, treatment was on average 5 hours earlier and preceded thrombolysis. Cytoprotective effects would therefore be minimized in ISIS-4.

Magnesium ions cross the intact blood-brain barrier such that intravenous MgSO₄ significantly raises cerebrospinal fluid magnesium concentrations.³¹ It is probable that greater local concentrations will be achieved when blood-brain barrier integrity is compromised by acute ischemia. The ideal dose of magnesium remains unknown: Experimental evidence suggests that the greater the local concentration of extracellular magnesium at the ischemic site, the greater will be the neuroprotective effect. The therapeutic index for magnesium is wide. Serum concentrations of 4 to 6 mmol/L are necessary before symptomatic inhibition of neuromuscular transmission is encountered,² although caution may be necessary in patients with renal impairment. The regimen chosen for this study was designed to double the serum magnesium concentration to twice physiological concentration and to maintain levels for 24 hours. It is notable that the baseline magnesium concentration in our population was low and that the bolus infusion failed to achieve the desired doubling of serum concentrations. This may represent underlying magnesium deficiency in the West of Scotland population, with the greater part of the bolus dose being rapidly taken up to compensate for intracellular magnesium lack. Having overcome the preexisting deficiency, further infusion over the 24-hour period in fact continued to bring about a rise in serum magnesium levels, such that the peak concentration was seen at 24 hours. The peak concentration achieved was unrelated to renal function, as measured by serum creatinine concentration. Further exploration of dosing regimens may be required to achieve the desired rapid elevation of serum levels. Higher doses have been given to preeclamptic patients without adverse effects,¹⁵ but changes in volume of distribution in pregnancy, particularly in preeclampsia, prevent direct comparisons with the stroke population. It is likely that the dose-limiting factor in stroke therapy will be any lowering of blood pressure.

Our study was not powered to detect differences in clinical outcome, and efficacy cannot be inferred from the results. Despite the small numbers, however, there was a trend in favor of magnesium. Although there was no significant difference in the proportion of patients dead or disabled at 3 months, the difference in early mortality between magnesium- and placebo-treated groups almost achieved significance. Although there was a greater proportion of large middle cerebral artery strokes (total anterior circulation stroke [TACS]) in the placebo group, these patients were not disproportionately represented in the mortality figures (TACS accounted for 4 of 6 deaths in magnesium-treated compared with 4 of 7 in placebo-treated groups). This suggests that the observed difference in early mortality may not result only from baseline differences in stroke size. Rates of nonneurological adverse events were similar between groups. Based on the figures obtained from this study, a trial to demonstrate the efficacy of intravenous MgSO₄ would require 712 patients for a type I error rate of 0.05, type II error rate of 0.2, and a difference in outcome of 25% (decrease from 40% to 30% in proportion dead or disabled). Clinical improvement was predominantly early in the study period, suggesting that shorter follow-up may be feasible in future trials.

The established safety profile of magnesium in women of child-bearing age and after MI offers advantages over other potential neuroprotective agents and was evident in this study. Further clinical trials of parenteral magnesium therapy after acute stroke to determine optimum dosing and ultimately efficacy are ongoing.

	Acknowledgments

 
We wish to thank Wendy Fallon for randomization, blinding, and drug preparation; Dr Richard Spooner for performing serum magnesium concentrations; Thia Begg, Claire Ritchie, and Joyce Thomson for additional assessments; and Elizabeth Colquhoun for invaluable assistance with clinical running of the trial.

Received June 23, 1994; revision received February 27, 1995; accepted March 20, 1995.

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