Magnesium is a naturally occurring calcium antagonist and a noncompetitive antagonist of N
-methyl-D-aspartate (NMDA) receptors30
. The exact protective mechanism of magnesium remains uncertain, but it probably acts on multiple levels of the ischemic cascade such as cerebral blood flow31
, energy conservation33,34
, and vascular homeostasis35
. The cardio-protective effect of magnesium after experimental myocardial infarction is most likely caused by its ability to enhance adenosine production19
, its anti-thrombotic effect18
, or both. Because magnesium is safe, inexpensive, and readily available, many clinicians favour its use for various ischaemic insults − despite the lack of any clear benefit of magnesium on the mortality and morbidity outcomes after stroke36
or acute myocardial infarction37-39
. Magnesium provides excellent neuro- and cardio-protection in various experimental models of ischaemia and has been shown to be an effective treatment for postoperative shivering. It was thus an attractive potential agent for facilitating induction of therapeutic hypothermia. However, magnesium at a dose sufficient to raise plasma concentration more than twofold only slightly restrained thermoregulatory defences to hypothermia. Compared with those treated with placebo, the shivering threshold in volunteers given magnesium decreased by only 0.3 °C, to a core temperature of 36.3°C.
There is currently little evidence that hypothermia protects against ischaemia in humans, although the evidence is overwhelming in animals. There is certainly little basis for recommending a specific target temperature for therapeutic hypothermia. Nonetheless, target temperatures from 33 to 34°C are being used clinically by some physicians and in ongoing clinical trials. Because magnesium reduces the shivering threshold only about a tenth of the amount necessary, it seems unlikely that magnesium has the potential to facilitate induction of therapeutic hypothermia, at least as a lone agent.
Magnesium seemed likely to induce thermoregulation tolerance because is an effective treatment for postoperative shivering14
. That then raises the question of how magnesium can be an effective treatment for postoperative shivering, yet reduce the shivering threshold by only a few tenths of a °C. The answer is that many postoperative patients have core temperatures only slightly below the normal shivering threshold. This may be the case even when core temperature is relatively low because residual anaesthetics impair thermoregulatory control. Consequently, treatments that reduce the shivering threshold by a couple of tenths of a degree centigrade may be sufficient to attenuate postoperative shivering40
. Such treatments will nonetheless be inadequate for induction of therapeutic hypothermia.
Recently, the addition of magnesium sulfate in a meperidine-based pharmacological antishivering regimen increased the cooling rate in unaesthetized volunteers13
. This effect was attributed to the observed vasodilation in the majority of the volunteers and associated with increased thermal comfort. In our study, increased thermal comfort during magnesium bolus was not related to peripheral vasodilation in our subjects, as determined by extremity temperature gradients. It seems that, despite the modest effect of magnesium on the shivering threshold, this agent could potentially play a contributing role for induction of therapeutic hypothermia.
Magnesium sulfate, as used clinically, increases cerebrospinal fluid (CSF) magnesium concentrations by only about 20-25%, with a peak concentration reached after two-to-four hours depending on the concentration gradient between plasma and CSF41
. We used an intravenous infusion of magnesium as proposed by Sibai, et al.42
for seizure prophylaxis in preeclamptic women. Relatively high plasma concentrations were achieved immediately after the bolus administration; these were maintained until the shivering threshold was reached about two hours after magnesium bolus initiation, thus ensuring adequate CSF levels. Because of this, we were unable to determine whether the observed thermoregulatory action of magnesium was of central15
or peripheral origin16
Despite the known central15
and peripheral muscle relaxation16
effects of magnesium, we were unable to demonstrate any significant changes in the sedation level or muscle strength during the bolus administration. It is likely that larger doses of magnesium sulfate would produce both greater thermoregulatory effects and a greater risk of complications. Nonetheless, previous studies indicate that the thermoregulatory response to most intravenous drugs is a linear function of plasma concentration43,44
. Thus, an even larger, potentially hazardous dose of magnesium seems unlikely to produce a useful reduction in the shivering threshold.
A limitation of our study is that it was conducted in healthy volunteers. Most results from volunteer studies can be extrapolated to patients; however, patients with underlying disease and those who are critically ill may respond differently. It thus remains possible that magnesium will prove more effective at inducing thermoregulatory tolerance in patients with stroke or other serious neurological problems.
In summary, magnesium in doses sufficient to increase plasma concentrations more than twofold reduced the shivering threshold marginally and did not significantly alter the gain of shivering in healthy volunteers. Magnesium thus exerts a clinically unimportant effect, as a sole agent; however, it remains to be studied as a potentially useful adjunct for induction of therapeutic hypothermia in patients with stroke or myocardial ischemia.