Magnesium for Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage: Time for a Paradigm Shift?

To the Editor:
The Magnesium Sulphate in Aneurysmal Subarachnoid Hemorrhage (MASH) study group investigated continuous intravenous magnesium sulfate infusion from days 4 to 14 after subarachnoid hemorrhage (SAH); the clinical outcome of reduction of delayed cerebral ischemia (DCI) remains, however, uncertain.1 It is generally believed that magnesium supplementation reverses vasospasm and offers neuroprotection to ischemic brain tissues. Although the cardiovascular utility of magnesium supplementation is limited to hypomagnesemia-related arrythmias,2 a consensus opinion currently, eclampsia appears pathogenetically similar to hypertensive encephalopathy with forced dilatation of cerebral vessels, hyperperfusion, and cerebral edema (rather than a primary neuronal defect),3 which effects are likely to be further worsened by administration of magnesium sulfate. Sustained infusion of magnesium over 24 hours in a cohort with potential blood-brain barrier disruption produced marginal increases in total and ionized cerebrospinal fluid (CSF) magnesium concentration,4 a finding in accord with previous investigations in humans. Regulation of cerebrospinal fluid [Mg2+] is largely maintained following acute brain injury and limits the brain bioavailability of MgSO4.4,5 With this pharmacokinetic limitation of magnesium supplementation, mechanisms such as inhibition of excitatory amino acids, blockade of N-methyl-D-aspartate-glutamate receptor, and DNA stabilization1 become largely academic. In general, the scientific basis for magnesium supplementation in humans remains questionable.
The adaptive nature of hypomagnesemia in a wide variety of clinical circumstances, including the general population, hospitalized patients, hypertension, migraine, premenstrual syndrome, pancreatitis, extensive burns, and other diverse conditions, has not been appreciated.2,5 Occurrence of hypomagnesemia in >50% of patients with SAH1 does not indicate that SAH-associated vasospasm is a direct consequence of magnesium depletion. Also, magnesium is a naturally occurring calcium antagonist. Consequently, in the face of a life-threatening situation such as SAH, hypomagnesemia would optimize functioning of a host of calcium-dependent physiological processes to preserve the organism, including cardiac output and other cardio-vascular reflexes. In a holistic sense, hypomagnesemia seems to promote survival in life-threatening illnesses. Because clinical benefit of magnesium supplementation in this scenario would be difficult to establish, such an approach can prove inimical. No difference has been seen in the incidence of either new focal neurological deficits or poor outcomes in other studies comparing magnesium sulfate therapy with placebo.1
The belief that reducing the occurrence of DCI will improve outcome remains unproven despite use of the vasodilator nimodipine; besides, DCI occurs in a sizable fraction of SAH patients managed with nimodipine and maintained normovolemia.1 Although it may seem paradoxical not to use vasodilators to prevent DCI in SAH, it may be useful to reexamine our belief that cerebral vasospasm in SAH can be usefully modified by systemic vasodilators. Because SAH-associated cerebral vasospasm is probably related to the presence of blood in the CSF, any systemically administered putative therapeutic agent must freely cross the blood-brain barrier. Even more importantly, if the stimulus for cerebral vasospasm indeed lies in the CSF, regional or local measures at the level of the CSF to manage the blood-related intracranial vasospasm might yield better results in the future.