ArticlesMagnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial
Introduction
Acute stroke is the third leading cause of mortality in developed countries and the largest single cause of disability. Treatment options in the immediate hours after stroke are limited. Recombinant tissue plasminogen activator (rtPA) greatly improves chances of full recovery if given intravenously within 3 h of stroke onset1 but the short time window and bleeding risks restrict rtPA to a few stroke patients. Aspirin has a small absolute benefit (about 1% reduction in death or disability) if started within 48 h of stroke, but absence of evidence of a time-dependent effect suggests its probable mode of action to be prevention of early recurrent stroke.2
Results of imaging studies and animal models of stroke have given rise to the notion of the ischaemic penumbra, a region of hypoperfused tissue surrounding the infarct core in which blood flow is between the thresholds of cell viability and functional activity. Metabolic and neurochemical events within the penumbra lead to cell death unless reperfusion takes place. In animal models, pharmacological modulation of various aspects of penumbral pathophysiology reduces infarct volume and improves outcome. Such neuroprotective treatments are attractive since they promise benefit without the potential bleeding risk of thrombolysis. However, no neuroprotective agent has yet been translated successfully from animal models into clinical practice.3 Some agents have been associated with important toxic effects and worsening of clinical outcomes.
Magnesium is neuroprotective in various animal models. It is a potentially safe and inexpensive treatment. In permanent or transient middle cerebral artery occlusion (MCAO) models in rodents, systemically administered magnesium reduces infarct volume.4, 5 Serum concentrations of magnesium as low as 1·49 mmol/L are associated with maximum infarct volume reduction.5 In embolic MCAO, magnesium significantly reduced infarct volume even when given 6 h after onset of ischaemia, a time window considerably longer than for other neuroprotective agents.6 The mechanism of neuroprotection by magnesium remains uncertain: increasing magnesium concentration reduces presynaptic release of the neurotransmitter glutamate,7 blocks glutamatergic N-methyl-D-aspartate receptors,8 potentiates adenosine action, improves mitochondrial calcium buffering, and blocks calcium entry via voltage-gated channels. Furthermore, it has cardiovascular effects, notably enhanced cerebral perfusion after MCAO9 and raised cardiac output. Antiplatelet actions are not relevant in clinical use.10
Workers on several small pilot trials in stroke have reported reduced proportions of magnesium-treated patients being dead or disabled at 3–6 months.11, 12, 13, 14, 15 The odds ratio for death or disability in a systematic review of these pilot trials was 0·73, but with a wide 95% CI (0·38–1·41).16 Potential neuroprotective effects have been identified in preterm perinatal hypoxic injury.17
We aimed to test whether intravenous magnesium sulphate, given within 12 h of stroke onset, reduces death or disability at 90 days.
Section snippets
Participants
Between October, 1997, and April, 2003, we enrolled and randomised patients in the Intravenous Magnesium Efficacy in Stroke (IMAGES) trial. This study was an international, multicentre, double-blind, placebocontrolled, parallel group study. Trial entry was based on a clinical diagnosis of stroke with treatment to begin within 12 h of the time the participant was last known to be well. Patients had to be conscious, aged 18 years or older, and previously independent (estimated premorbid modified
Results
Of 2589 patients randomised, 2543 (98%) received at least part of the trial infusion. Of the 46 participants who received no trial treatment, the reason was most usually because of clinical deterioration between randomisation and planned commencement of infusions. These individuals were excluded a priori from the efficacy analysis. Nine participants (0·3%) were lost to follow-up (figure 1). Three people received treatment that differed from that allocated (none of those allocated magnesium).
Discussion
Despite promising findings of animal studies and preliminary clinical trials that provided a solid rationale for our trial, intravenous magnesium sulphate did not reduce death or disability at 90 days when given within 12 h of clinically diagnosed stroke. Prespecified hypotheses that treatment within 6 h would be better than treatment within 6–12 h, that ischaemic stroke would benefit rather than intracerebral haemorrhage, and that cortical strokes would benefit more than lacunes were not
References (30)
Neuroprotection in acute ischaemic stroke: a tale of for whom the bell tolls?
Lancet
(2000)- et al.
Survival and histological evaluation of therapeutic window of post-ischemia treatment with magnesium sulfate in embolic stroke model of rat
Neurosci Lett
(2000) - et al.
Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual-probe microdialysis technique
Life Sci
(2002) - et al.
Classification and natural history of clinically identifiable subtypes of cerebral infarction
Lancet
(1991) - et al.
Design of future acute-stroke treatment trials
Lancet Neurol
(2003) Tissue plasminogen activator for acute ischemic stroke
N Engl J Med
(1995)- et al.
Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40 000 randomized patients from the Chinese acute stroke trial and the international stroke trial
Stroke
(2000) - et al.
Reduction of infarct volume by magnesium after middle cerebral artery occlusion in rats
J Cereb Blood Flow Metab
(1991) - et al.
Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia
J Neurosurg
(1996) - et al.
Magnesium gates glutamate-activated channels in mouse central neurones
Nature
(1984)
Effects of magnesium sulfate and nifedipine on regional cerebral blood flow during middle cerebral artery ligation in the rat
Arch Int Pharmacodyn Therap
ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction
Lancet
Infusion of magnesium in patients with acute brain infarction
Acta Neurol Scand
A randomised, double-blind, placebo-controlled pilot trial of intravenous magnesium sulfate in acute stroke
Stroke
Dose optimization of intravenous magnesium sulfate after acute stroke
Stroke
Cited by (0)
Study investigators listed at end of report