The therapeutic use of magnesium ...
Purpose: P u r p o s e : To review current knowledge concerning the use of mag- nesium in anesthesiology, intensive care and emergency medicine. Methods: M e t h o d s : References were obtained from Medline�� (1995 to 2002). All categories of articles (clinical trials, reviews, or meta- analyses) on this topic were selected. The key words used were magnesium, anesthesia, analgesia, emergency medicine, intensive care, surgery, physiology, pharmacology, eclampsia, pheochromo- cytoma, asthma, and acute myocardial infarction. Principal P r i n c i p a l findings: f i n d i n g s : Hypomagnesemia is frequent postoperatively and in the intensive care and needs to be detected and corrected to prevent increased morbidity and mortality. Magnesium reduces catecholamine release and thus allows better control of adrenergic response during intubation or pheochromocytoma surgery. It also decreases the frequency of postoperative rhythm disorders in car- diac surgery as well as convulsive seizures in preeclampsia and their recurrence in eclampsia. The use of adjuvant magnesium during perioperative analgesia may be beneficial for its antagonist effects on N-methyl-D-aspartate receptors. The precise role of magnesium in the treatment of asthmatic attacks and myocardial infarction in emergency conditions needs to be determined. Conclusions: C o n c l u s i o n s : Magnesium has many known indications in anesthe- siology and intensive care, and others have been suggested by recent publications. Because of its interactions with drugs used in anesthesia, anesthesiologists and intensive care specialists need to have a clear understanding of the role of this important cation. Objectif : Mise au point sur les indications du magn��sium en anesth��sie, en r��animation ou en service d'urgence. M��thode : R��alisation d'une revue de la litt��rature r��cente (1995 �� 2002) concernant le magn��sium, par le syst��me Medline. Les articles, type ��tude clinique prospective, revue ou m��ta-analyses ont ��t�� recherch��s. Les mots cl��s utilis��s ��taient : ���magnesium, anesthesia, analgesia, emergency medicine, intensive care, surgery, physiology, pharmacology, eclampsia, pheochromocytoma, asthma, et acute myocardial infarction���. Principaux r��sultats : Les hypomagn��s��mies sont fr��quentes en postop��ratoire et en r��animation. Elles sont responsables d'une aug- mentation de la morbidit�� et de la mortalit�� et devraient ��tre d��tec- t��es et corrig��es. Le magn��sium diminue la lib��ration des cat��cholamines, il permet ainsi un meilleur contr��le de la r��ponse adr��nergique lors de l'intubation ou au cours de la chirurgie du ph��ochromocytome. En chirurgie cardiaque, il diminue la fr��quence de survenue des troubles du rythme postop��ratoires. Il diminue la sur- venue des crises convulsives chez les femmes ayant une pr��-��clamp- sie et diminue les r��cidives convulsives chez les femmes ayant une ��clampsie. Il poss��de des effets antagonistes des r��cepteurs N- methyl-D-aspartate et on pourrait assister �� un d��veloppement de ses indications en tant qu'adjuvant dans l'analg��sie p��riop��ratoire. En urgence, sa place dans le traitement de la crise d'asthme et de l'in- farctus du myocarde m��rite d'��tre pr��cis��e. Conclusion : Cet ion important de l'organisme a de nombreuses indications reconnues en anesth��sie r��animation et de nouvelles indi- cations pourraient appara��tre au vue de publications r��centes. Ces interactions avec les drogues utilis��es en anesth��sie en font une mol��cule importante �� conna��tre des anesth��sistes-r��animateurs. AGNESIUM (Mg) is the fourth most common mineral salt in the human organism and second among intracellu- lar cations. It has calcium antagonist effects, is involved in the regulation of different ion channels and phosphorylation reactions, and serves as a cofactor in many enzymatic systems. Dysmagnesemia, 732 NEUROANESTHESIA AND INTENSIVE CARE CAN J ANESTH 2003 / 50: 7 / pp 732���746 The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review [L'usage th��rapeutique du magn��sium en anesth��siologie, r��animation et m��decine d'urgence] Laurent Dub�� MD, Jean-Claude Granry MD PhD From the Department of Anesthesiology, University Hospital, Angers, France. Address correspondence to: Dr. Laurent Dub��, D��partement d'Anesth��sie R��animation, CHU Angers, 4, rue Larrey, 49033 Angers C��dex 1, France. Phone: 33 2 41 35 36 35 Fax: 33 2 41 35 39 67 E-mail: Ladube@chu-angers.fr Accepted for publication December 23, 2002. Revision accepted March 19, 2003. M
Dub�� et al.: MAGNESIUM THERAPY 733 particularly hypomagnesemia, is frequent perioperative- ly and in intensive care and causes considerable mor- bidity. Different serum Mg concentrations and dosages will be used, depending on whether they are intended to correct a deficit or for pharmacological purposes. Mg is used in different surgical situations, obstetrics and perioperative analgesia and has various interactions with the drugs used in anesthesia. In emergency depart- ments, it is being studied in the treatment of myocardial infarction and asthmatic attacks. This review considers Mg physiology and the implications of dysmagnesemia for anesthetic practice. Recent studies of known indica- tions or promising developments of Mg therapy in anesthesiology, intensive care and emergency medicine are reviewed and discussed. Mg M g physiology p h y s i o l o g y Mg in the organism Mg is a bivalent ion, like calcium, with an atomic weight of 24.312. The human body contains 1 mole (24 g of Mg). It is the fourth most common mineral salt in the organism after phosphorus, calcium and potassium,1���3 the second intracellular cation after potassium, and the fourth plasma cation after sodium, potassium and calcium.4 It is concentrated mainly in bone (60%), muscle (20%) and soft tissues (20%). Only a fourth of the Mg contained in bone and mus- cle is exchangeable.2 Extracellular Mg represents only 1% of the total. In serum, Mg is divided into three fractions: ionized (active form), protein-bound and that contained in anion complexes (phosphates and citrates). These three fractions account respectively for 65, 27 and 8% of serum content. Three-fourths of plasma Mg is ultrafiltrable.2,4 The daily recommended Mg requirement is 250 to 350 mg (10.4���14.6 mmol) in adults4,5 and an addi- tional 100 to 150 mg in children and pregnant or nursing women.2 Food input is ensured essentially by cocoa powder, chocolate, almonds, peanuts, walnuts, vegetables, cereals and seafood. From 30 to 50% of ingested Mg is absorbed (5 mmol��day���1) in decreasing quantity from the small intestine to the colon. Fibres, phytates and oxalic acid appear to reduce Mg absorp- tion moderately through the formation of a complex that cannot be easily dissociated. The binding of Mg to anions (phosphates) or fatty acids reduces the quan- tity of absorbable Mg. The fraction of absorbed Mg decreases as the quantity ingested increases.2 Mg depletion corresponds to obligatory and uncontrol- lable digestive losses (around 60% of ingested Mg) and variable losses through renal excretion. Digestive losses are increased by diarrhea or biliary fistula. Urinary excretion of Mg is normally 5 mmol��day���1, but can be reduced to 0.5 mmol��day���1 in the event of severe deficiency. The level is regulated by variations in renal reabsorption, as a function of magnesemia, rela- tive to inputs and bone mobilization.2 Around 75% of plasma Mg is filtered at the glomerular level. Only 5% of filtered Mg is excreted, with reabsorption of 15 to 25% in the proximal convoluted tubule and 50 to 60% in the ascending limb of Henle's loop. Diuretics, thi- azides, cisplatin, gentamicin and cyclosporine inhibit renal reabsorption.3,5 Mg is mainly intracellular, existing largely (90%) in bound form in adenosine triphosphate (ATP) mole- cules of the cytoskeleton (nucleus, mitochondria and reticulum), in nucleotides, or in enzyme complexes. A small portion of intracellular Mg (5���14%, depending on the cells) is found in ionized free form within the cell. Heart muscle cells have a high concentration of total Mg (11���17 mmol��L���1 of intracellular water).2,6 Knowledge about the hormonal regulation of Mg homeostasis is incomplete. Several hormones are involved in the regulation of Mg metabolism, namely parathyroid hormone (PTH), calcitonin, vitamin D, insulin, glucagon, epinephrine, antidiuretic hormone, aldosterone and sex hormones. PTH and vitamin D increase intestinal absorption, PTH favours renal reab- sorption of Mg and facilitates its bone reuptake, insulin increases cellular uptake of Mg, and glucagon is conducive to its renal reabsorption.7,8 Biological considerations Assay of total plasma Mg by spectrophotometry is pre- cise and easy to perform (0.7���1.1 mmol��L���1 or 1.4���2.2 mEq��L���1, or 16.8���26.4 mg��L���1). However, owing to the intracellular nature of this ion, these values are not exactly indicative of the Mg pool in the organism or of a possible state of deficiency.4 Other concentrations have been studied to allow better assessment of true Mg deficiencies, namely intracellular (8���10 mmol��L���1)6 and ionized plasma Mg (0.65 �� 0.1 mmol��L���1) concentra- tions. Interferences with calcium ions at the level of the Mg electrode reduce the relevance of the ionized Mg assay.4 Because of the long life of Mg and its slow turnover, erythrocytic Mg might be a better indicator of deficiency (values in the literature: 2.10 �� 0.4 mmol��L���1)1,3 Lymphocytic Mg would appear to be a better indicator of the Mg content of muscle and myocardium and of ionized Mg.1 However, the relation between these last evaluations and the Mg pool of the organism remains uncertain.4 Urinary excretion of Mg is highly variable, ranging from 5 mmol��day���1 in the normomagnesimic subject to 0.5 mmol��day���1 in the deficient subject. Measurement of urinary excretion helps separate renal
from non-renal causes of hypomagnesemia. In the presence of hypomagnesemia, high urinary excretion suggests that increased renal loss is the mechanism of Mg depletion, whereas low urinary excretion suggests miscellaneous or gastrointestinal causes. Studies of the urinary excretion of Mg after a loading test can help diagnose Mg deficiency when magnesemia is normal: the subject without deficiency excretes more than 60���70% of Mg input, whereas the subject with a defi- ciency excretes less than 50%.9,10 Various changes in Mg can occur during the peri- operative period. Plasma concentrations are decreased after abdominal11,12 or orthopedic surgery.13 After heart surgery, mean magnesemia is reduced,14,15 and the frequency of hypomagnesemia increased from 19.2% preoperatively to 71% immediately after surgery before dropping slightly to 65.6% 24 hr later.16 For Zuccala et al., the depletion of intracellular Mg would appear to be closely correlated with reduced serum concentrations. These authors found that both con- centrations decreased after orthopedic surgery.17 Cellular physiological properties of Mg ACTION ON MEMBRANE AND MEMBRANE PUMPS Mg intervenes in the activation of membrane Ca ATPase and Na-K ATPase involved in transmembrane ion exchanges during depolarization and repolariza- tion phases. Mg deficiency impairs the action of ATPase pumps and leads to a reduction of intracellu- lar ATP as well as to increased concentrations of sodi- um and calcium and decreased concentrations of potassium within the cell.5 It would thus appear to act as a stabilizer of cell membrane and intracytoplasmic organelles.18 ACTION ON ION CHANNELS Mg is considered to act as a regulator of different ion channels. A low intracellular Mg concentration allows potassium to leave the cell, thereby altering conduc- tion and cellular metabolism.5,18 Mg also exerts its effects on calcium channels of potential-dependent L type in membrane and on those of sarcoplasmic retic- ulum. A competitive antagonist action is directed against calcium inflows. By inhibiting the calcium acti- vation dependent on the sarcoplasmic channel, Mg limits the outflow of calcium from the sarcoplasmic reticulum, the main site of intracellular calcium stor- age.18 Thus, Mg is a calcium channel blocker and a modulator of calcium channel activity, which means that a rise in intracellular calcium occurs during hypo- magnesemia.2,5 ENZYMATIC ACTIVATION Intracellular free Mg is involved in the energy reac- tions of phosphorylation and is necessary for the acti- vation of hundreds of enzymatic reactions concerning ATP.18 Inorganic phosphate and ATP within the cell reduce free Mg, whereas the conversion of ATP to adenosine diphosphate (ADP) increases it.3 In fact, Mg interacts with the outer two phosphate groups of ATP to form the enzymatic substrate. Intracellular Mg deficiency is correlated with the impaired function of many enzymes utilizing high-energy phosphate bonds, as in the case of glucose metabolism.2 Clinical effects of Mg CARDIOVASCULAR EFFECTS The action of Mg on calcium channels and pumps actually serves as a regulator of transmembrane and intracellular flows. In addition, Mg has an indirect effect on cardiac muscle cells by inhibiting calcium uptake on the troponin C of myocytes and thereby influencing myocardial contractility. In a preparation of isolated animal heart, Mg, because of its anticalci- um properties, caused a dose-dependent negative inotropic effect.19 Rasmussen et al. observed a moder- ate positive inotropic effect after infusion of Mg into healthy volunteers,20 which could have been related to the vascular effect of Mg in reducing systemic arteri- al20 and pulmonary artery pressures through a decrease of vascular resistance.18 In in vitro studies on isolated aorta, the absence of Mg potentiated the vasoconstrictive effect of angiotensin and acetyl- choline, and hypermagnesemia induced the relaxation of smooth muscle.21 The role of Mg in transmem- brane movements of calcium and the activation of the adenylate cyclase involved in the synthesis of cyclic adenosine monophosphate (AMP a vasodilator) could account in part for this effect. A reduction of cyclic AMP in hypomagnesemia induced an increase of vascular tone.22 Mg deficiency may also play a role in the pathogenesis of variant angina or coronary spasm,23 and infusion of Mg can produce coronary dilatation and suppress acetylcholine-induced coro- nary spasm in patients with vasospastic angina.24 In anesthetized dogs, a dose-dependent decrease in heart rate and systolic and diastolic arterial pressures was observed after the infusion of Mg.25 In humans, hemodynamic studies have shown a peripheral (pre- dominantly arteriolar) vasodilator effect.26,27 After the rapid infusion of a dose of 3 or 4 g of sulfate (MgSO4), a reduction of systolic arterial pressure occurred, in relation to decreased systemic vascular resistance. Positive inotropic and chronotropic effects compensated for the former by increasing the heart 734 CANADIAN JOURNAL OF ANESTHESIA