doi: 10.1161/01.STR.0000147971.14988.50
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(Stroke. 2004;35:2758.)
© 2004 American Heart Association, Inc.
Letters to the Editor |
Intravenous Magnesium for Neuroprotection in Acute Stroke: Clinical Hope Versus Basic Neuropharmacology
Dubai Police Medical Services, Dubai, United Arab Emirates
To the Editor:
Saver and colleagues investigated the neuroprotective effect of early magnesium infusion in ischemic or hemorrhagic stroke in the field; three quarters of the infarct cohort were treated within 2 hours of onset, and nearly one-third within 1 hour of onset.1 Dramatic early and good results were reported in the early (42% of <2-hour infarct patients) and 90-day global functional outcomes (69% of all patients and 75% of <2 hour infarct patients), respectively. These authors recommend large-scale trials with field initiation of magnesium for early neuroprotection in stroke.
An essential prerequisite for any pharmacological agent to offer significant brain neuronal protection during strokes is its ability to freely cross the blood–brain barrier (BBB). Transport of magnesium from blood to cerebrospinal fluid across BBB is limited in normal humans; intravenous administration of magnesium sulfate does not increase cerebrospinal fluid magnesium concentration.2 Orally or intravenously administered magnesium sulfate cannot affect brain neuronal function.3 Acute stroke is a hemodynamically highly labile clinical condition and impressive functional outcomes with magnesium supplementation should be viewed critically and cautiously.
The adaptive nature of hypomagnesemia, seen in a wide variety of clinical conditions and circumstances, including hospitalization and diabetes mellitus, is not generally appreciated.4,5,6 Magnesium impairs cardiac pump function, a physiological limitation to rapid therapeutic supplementation in acute myocardial infarction or congestive heart failure.5 With a mean patient age of 74 years (range 44 to 92 years) in this trial,1 the negative inotropic effect of magnesium infusion5 can significantly impair cardiac output and cranial perfusion pressure in this presbycardiac cohort. Informed consent from potential patients for clinical trials involving magnesium supplementation must include pharmacokinetic information about magnesium and BBB. Absence of serious side effects1 does not by itself support use of any neuroprotective agent. No large-scale trial of magnesium supplementation in stroke, in the field or in the hospital, should be envisaged without presenting this facet of magnesium pharmacology to the approving institutional review board.
References
1. Saver JL, Kidwell C, Eckstein M, Starkman S; for the FAST-MAG pilot trial investigators. Stroke. 2004; 35: e106–108.
2. Ko SH, Lim HR, Kim DC, Han YJ, Choe H, Song HS. Magnesium sulphate does not reduce postoperative analgesic requirements. Anesthesiology. 2001; 95: 640–646.[CrossRef][Medline] [Order article via Infotrieve]
3. Gupta VK. Management of migraine aura: basic theoretical and clinical reconsiderations. Headache. 2004. In press.
4. Gupta VK. Magnesium therapy for migraine: do we need more trials or more reflection? Headache. 2004; 44: 445–446.[CrossRef][Medline] [Order article via Infotrieve]
5. Gupta VK. Does magnesium supplementation have any role in acute myocardial infarction? No. Cardiovasc Drugs Ther. 1996; 10: 303–305.[Medline] [Order article via Infotrieve]
6. Gupta VK. Does hypomagnesemia have an adaptive role in hypertension? Hypertension. 2004; 43: 29.[CrossRef]
Intravenous Magnesium for Neuroprotection in Acute Stroke: Neuropharmacology Supports Clinical Hope
Response:
Department of Neurology,, UCLA Stroke Center, University of California, Los Angeles, Los Angeles, Calif
We thank Dr Gupta for his interest in our study, but we strongly disagree with his assessment of the pertinent literature. In fact, the basic neuropharmacology of magnesium sulfate provides substantial support for clinical stroke trials in humans.
Several studies show that magnesium does cross the blood–brain barrier, in both animals and in humans.1 Brain magnesium concentrations are regulated by active blood–brain barrier transport.2,3 Cerebrospinal fluid magnesium concentration increases by 20% to 25% in response to doubling of the serum concentration, and peaks around 4 hours after parenteral administration.3–5 While this overall increase in cerebrospinal fluid magnesium concentration is modest, magnesium concentration is selectively substantially increased in regions of pathology, including focal ischemia and seizures.6,7
It is also well known that the mild negative inotropic effect of magnesium sulfate is offset by its lowering of peripheral vascular resistance, resulting in no clinically substantial impairment in cardiac pump function.8,9 Several physiological studies suggest that magnesium increases cardiac output.10,11 Even in patients experiencing active myocardial ischemia, magnesium sulfate showed only a very small increase in the incidence of cardiogenic shock or congestive heart failure in the large ISIS-4 trial,12 and no adverse effect on cardiac pump function was reported in the more recent MAGIC clinical trial.13 Most saliently, among stroke patients in the phase 3 IMAGES trial, there was no excess of cardiac events related to administration of magnesium sulfate.14
In addition, magnesium sulfate is a potent cerebral vasodilator, in part due to calcium channel antagonism at vascular smooth muscle cells and possibly effects on myosin-binding proteins that regulate contraction.15,16 Consequently, magnesium sulfate typically increases, rather than decreases, cerebral perfusion.17–19
Magnesium sulfate has been demonstrated to reduce infarct volume in multiple animal models of stroke, has numerous identified beneficial neuroprotective and vascular effects, is already known to be efficacious in treating in humans a condition characterized by altered cerebral blood flow (eclampsia), and has shown a potential signal of efficacy when administered early after stroke onset (within 3 hour subgroup) in a randomized clinical trial.14 Further trials of magnesium sulfate in early time epochs in acute stroke are well-supported by preclinical and clinical neuropharmacology.20
References
1. Muir KW. Magnesium for neuroprotection in ischaemic stroke: rationale for use and evidence of effectiveness. CNS Drugs. 2001; 15: 921–930.[CrossRef][Medline] [Order article via Infotrieve]
2. Oppelt WW, MacIntyre I, Rall DP. Magnesium exchange between blood and cerebrospinal fluid. Am J Physiol. 1963; 205: 959–962.
3. Fuchs-Buder T, Tramer MR, Tassonyi E. Cerebrospinal fluid passage of intravenous magnesium sulfate in neurosurgical patients. J Neurosurg Anesthesiol. 1997; 9: 324–328.[Medline] [Order article via Infotrieve]
4. Thurnau GR, Kemp DB, Jarvis A. Cerebrospinal fluid levels of magnesium in patients with preeclampsia after treatment with intravenous magnesium sulfate. Am J Obstet Gynecol. 1987: 1435–1438.
5. Fong J, Gurewitsch ED, Volpe L, Wagner WE, Gomillion MC, August P. Baseline serum and cerebrospinal fluid magnesium levels in normal pregnancy and preeclampsia. Obstet Gynecol. 1995; 85: 444–448.[Medline] [Order article via Infotrieve]
6. Hallak M, Berman RF, Irtenkauf SM, Evans MI, Cotton DB. Peripheral magnesium sulfate enters the brain and increases the threshold for hippocampal seizures in rats. Am J Obstet Gyneco. 1992; 167: 1605–1610.
7. Sjostrom LG, Wester P. Accumulation of magnesium in rat brain after intravenously induced hypermagnesemia (abstract). Cerebrovasc Dis. 1995; 4: 241.
8. Nakaigawa Y, Akazawa S, Shimizu R, Ishii R, Ikeno S, Inoue S, Yamato R. Effects of magnesium sulphate on the cardiovascular system, coronary circulation and myocardial metabolism in anaesthetized dogs. Br J Anaesth. 1997; 79: 363–368.
9. Shechter M. Does magnesium have a role in the treatment of patients with coronary artery disease? Am J Cardiovasc Drugs. 2003; 3: 231–239.[CrossRef][Medline] [Order article via Infotrieve]
10. Reinhart RA. Clinical correlates of the molecular and cellular actions of magnesium on the cardiovascular system. Am Heart J. 1991; 121: 1513–1521.[CrossRef][Medline] [Order article via Infotrieve]
11. Rasmussen HS, Larsen OG, Meier K, Larsen J. Hemodynamic effects of intravenously administered magnesium on patients with ischemic heart disease. Clin Cardiol. 1988; 11: 824–828.[Medline] [Order article via Infotrieve]
12. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet. 1995; 345: 669–685.[CrossRef][Medline] [Order article via Infotrieve]
13. Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium In Coronaries (MAGIC) trial: a randomised controlled trial. Lancet. 2002; 360: 1189–1196.[CrossRef][Medline] [Order article via Infotrieve]
14. Muir KW, Lees KR, Ford I, Davis S. Magnesium for acute stroke (intravenous magnesium efficacy in stroke trial): randomised controlled trial. Lancet. 2004; 363: 439–445.[CrossRef][Medline] [Order article via Infotrieve]
15. Kemp PA, Gardiner SM, Bennett T, Rubin PC. Magnesium sulphate reverses the carotid vasoconstriction caused by endothelin-I, angiotensin II and neuropeptide-Y, but not that caused by NG-nitro-L-arginine methyl ester, in conscious rats. Clin Sci (Lond). 1993; 85: 175–181.[Medline] [Order article via Infotrieve]
16. Alborch E, Salom JB, Perales AJ, Torregrosa G, Miranda FJ, Alabadi JA, Jover T. Comparison of the anticonstrictor action of dihydropyridines (nimodipine and nicardipine) and MG2+ in isolated human cerebral arteries. Eur J Pharmacol. 1992; 229: 83–89.[CrossRef][Medline] [Order article via Infotrieve]
17. Belfort MA, Moise KJ, Jr. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: a randomized, placebo-controlled study. Am J Obstet Gynecol. 1992; 167: 661–666.[Medline] [Order article via Infotrieve]
18. Lysakowski C, Von Elm E, Dumont L, Junod J, Tassonyi E, Kayser B, Tramer MR. Effect of magnesium, high altitude and acute mountain sickness on blood flow velocity in the middle cerebral artery. Clin Sci. 2004; 106: 279–285.[Medline] [Order article via Infotrieve]
19. Scardo JA, Hogg BB, Newman RB. Favorable hemodynamic effects of magnesium sulfate in preeclampsia. Am J Obstet Gynecol. 1995; 173: 1249–1253.[Medline] [Order article via Infotrieve]
20. Muir KW. Magnesium in stroke treatment. Postgrad Med J. 2002; 78: 641–645.
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