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Magnesium Research (1994) 7, 3/4, 313-328
State-of-the-art Review

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Magnesium and therapeutics

J. Durlach*,V. Durlach†, P. Bac‡, M. Bara§ & A. Guiet-Bara§

*SDRM, Hôpital St. Vincent-de-Paul, Paris, France; †U62, Clinique Médical, CHRU, Reims, France; ‡Laboratoire de Biologie Animale, Faculté de Pharmacie, Chatenay-Malabray, France; §Laboratoire de Physiopathologie du Développement Université Pierre et Marie Curie, Groupe Interactions cellulaires, Paris, France

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Summary: Two different types of therapy with magnesium are used: physiological oral magnesium supplementation which is totally atoxic since it palliates magnesium deficiencies by simply normalizing the magnesium intake and pharmacological magnesium therapy which may induce toxicity since it creates iatrogenic magnesium overload. Primary and secondary magnesium deficiencies constitute the sole indication of physiological oral magnesium therapy. It is therefore necessary to be well acquainted with the clinical and paraclinical pattern of magnesium deficit and to discriminate between magnesium deficiency due to an insufficient magnesium intake which only requires oral physiological supplementation and magnesium depletion related to a dysregulation of the control mechanisms of magnesium status which requires more or less specific regulation of its causal dysregulation. Physiological oral magnesium load constitutes the best tool for diagnosis of magnesium deficiency and the first step of its treatment. Physiological oral magnesium supplementation (5 mg/kg/day) is easy and can be carried out in the diet or with magnesium salts, with practically only one contra-indication: overt renal failure. Specific and aspecific treatments of magnesium depletion are tricky using for example magnesium sparing diuretics, pharmacological doses of vitamin B6, physiological doses of vitamin D and of selenium. In order to use the pharmacological properties of induced therapeutic hypermagnesaemia, high oral doses of magnesium (> 10 mg/kg/day) are advisable for chronic indications and the parenteral route is suitable for acute indications. There are 3 types of indications: specific (for the treatment of some forms of magnesium deficit i.e. acute), pharmacological (i.e. without alterations of magnesium status) and mixed--pharmacological and aetiopathogenic--(for example complications of chronic alcoholism). Today pharmacological magnesium therapy mainly concerns the obstetrical, cardiological and anaesthesiological fields. The main indications are eclampsia, some dysrhythmias (torsades de pointe particularly) and myocardial ischaemias. But it is now difficult to situate the exact place of the pharmacological indications of magnesium. Magnesium infusions can only be envisaged in intensive care units with careful monitoring of pulse, arterial pressure, deep tendon reflexes, hourly diuresis, electrocardiogram and respiratory recordings. High oral magnesium doses besides their laxative action may bring latent complications which may reduce lifespan. There may remain some indications of the laxative and antacid properties of non soluble magnesium, particularly during intermittent haemodialysis. Lastly local use of the mucocutaneous and cytoprotective properties of magnesium is still valid, in cardioplegic solutions and for preservation of transplants particularly.

Key words: Magnesium, physiology, pharmacology, therapeutics, toxicity, anaesthesiology, arrhythmias, ischaemia, eclampsia, hyperventilation, nervous hyperexcitability, tetany.

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Introduction

For a long time, magnesium only had a modest place in therapeutics, being used solely for its cathartic or neutralizing properties in oral preparations or for its sedative and antispasmodic properties parenterally. Now two different types of therapy with magnesium are used: atoxic physiological oral magnesium therapy and pharmacological magnesium therapy which may induce toxicity. Today continually increased knowledge of the clinical forms of magnesium deficit in human beings¹ is showing us in what circumstances and in what manner we can remedy magnesium deficiency using physiological doses of magnesium. Chronic primary magnesium deficiency constitutes the major indication of this main form of magnesium therapy. These palliative oral doses of magnesium meant to balance magnesium deficiency are obviously devoid of any toxicity since their purpose is to restore to normal the insufficiency of the magnesium intake. Their indications rest on well founded epidemiological trials². Conversely parenteral magnesium or high oral doses of magnesium possess all the pharmacodynamic properties of magnesium overload and are capable of inducing toxicity. They must therefore always be administered with caution in more or less specific indications ³.

In this study on therapy with magnesium we will successively consider: (1) The uses of physiological oral magnesium doses, the main form of magnesium therapy, involving first and foremost adequate knowledge of this sole indication: magnesium deficiency. The technique of oral physiological magnesium supplementation will be analyzed; (2) The indications for and techniques of several pharmacological applications of magnesium: mainly the properties of a magnesium overload induced through either high doses of oral magnesium, or parenteral magnesium therapy using soluble magnesium preparations; accessorily, laxative and antacid magnesium therapy which uses most often non or little soluble magnesium salts; lastly, some types of local magnesium therapy: mucocutaneous or cytoprotective.

It is necessary to highlight the contrast between the dangers of using the pharmacological properties of induced iatrogenic magnesium overload and the atoxicity of a supplementation with physiological oral doses of magnesium which by simply normalizing the magnesium intake palliates magnesium deficiencies.

Physiological oral magnesium therapy

Today the main form of magnesium therapy is oral magnesium physiological supplementation of magnesium deficiencies. It is therefore necessary to be well acquainted with the clinical pattern of its sole indication. Since chronic primary magnesium deficiency is the most commonly observed form of magnesium deficiency, it will serve therefore as our descriptive model.

Clinical forms of chronic magnesium deficiency^1-4

Open and controlled trials have established the clinical and paraclinical pattern of chronic magnesium deficiency (CMD). Whatever the age nervous consequences must be first studied: clinical and paraclinical symptoms of latent tetany (hyperventilation syndrome, chronic fatigue syndrome, spasmophilia, cryptotetany) with or more often without 'idiopathic' mitral valve prolapse (idiopathic Barlow's disease, Da Costa syndrome, soldier's heart, effort syndrome, neurocirculatory asthenia) with or without pseudoallergy (through peripheral hyperreceptivity) more often than allergy (type I mainly). The non-specific pattern of this symptomatology brings the patient to consult a wide range of specialists as well as the general practitioner. It includes non-specific central, peripheral and autonomic manifestations.

The neurotic, or rather, 'central' symptoms consist of anxiety, hyperemotionality, fatigue, headaches (and sometimes migraine), insomnia, light-headedness, dizziness, nervous fits, lipothymiae, sensation of a 'lump in the throat', of 'nuchalgia' and 'blocked breathing'.

The peripheral signs are acroparaesthesiae, cramps, muscle fasciculations and myalgiae. The functional disorders include chest pain, sine materia dyspnoea, blocked respiration, precordialgia, palpitations, extrasystolae, dysrhythmias, Raynaud's syndrome, trends to orthostatic hypotension or conversely to borderline hypertension. In fact, the dysautonomic disturbances involve both the sympathetic and the parasympathetic systems.

The evolution may be studded with various acute paroxysmal manifestations which can also sometimes be seen as initial signs of the illness. The major crises of acute tetany or of grand mal--even reduced to a simple loss of consciousness--remain relatively rare. It is more often a question of nervous crises: neurotic, from the 'attack of nerves' to the 'hysterical crises', or autonomic: lipothymia, reactive hypoglycaemia, pseudo-asthmatic crisis, vagovagal syncope or, on the contrary, paroxysmal tachycardia. Sometimes, centripetal tingling sensations and stiffness of the extremities confer on these nervous crisis a tetanoid character. But, essentially, they all have in common the fact that they occur in a context of fits of anxiety, even sometimes with the impression of imminent death (panic attack), which cause hyperventilation gaseous alkalosis and self perpetuation of the crises. Physical examination must systematically research the signs of neuromuscular hyperexcitability as well as the Chvostek's sign as precordial signs of mitral dyskinesia inducing mitral valve prolapse.

A genuine Chvostek's sign must be systematically sought. With a small (children's) reflex hammer the examiner percusses the soft parts of the cheek at the centre of a line running from ear lobe to the labial commissure, avoiding the lightning contraction of a 'false Chvostek's sign' by taping the bone of the zygomatic apophysis. It is important to consider the quality--and not the intensity--of this clinical criterion of neuromuscular hyperexcitability. It is only its presence or its absence which is significant, respectively quoted 1 or 0.

The examination of the precordial area will be carefully conducted in order to search either for a non-ejection systolic click, or for a mid-to end-systolic or pansystolic murmur, or both, particularly in orthostatism in complete expiration and in the left lateral decubitus position.

Two routine tracings should always be made: a neurophysiological examination (electromyogram (EMG)) and a cardiological examination (echocardiogram (ECC)). In EMG testing for latent tetany, a Bronck's needle is inserted into the first dorsal interosseous muscle of the left hand. The three classical facilitation tests are used: tourniquet-induced ischaemia lasting 10 min, post-ischaemia lasting 10 min after removal of tourniquet and lastly hyperventilation lasting 5 min. If the EMG shows one (or several) trains(s) of autorhythmic activities, 'beating' for more than 2 min of one of the three tetanic activities (uniplets, multiplets or complex tonicoclonic tracings) a positive response is defined. As determined for the clinical criterion of tetanic hyperexcitability, this neurophysiological criterion is only considered as a two-class variable. Either its presence or its absence is significant, respectively quoted 1 or 0. The 'excitability index' (EI) is defined as the sum of the two criteria of tetany. It allows different classes among tetanies to be distinguished: one with simultaneous clinical and neurophysiological criteria: EI=2, the others with only one criterion of their tetanic state: EI=1 with two subgroups, either clinical (through positivity of the Chvostek's sign alone), or electromyographic (through positivity of EMG alone). The ECC is the best tool for detecting mitral valve prolapse (MVP). With time-motion (TM) mode, three tracings are classical: a 'cuplike' tracing of mesotelesystolic mitral valve prolapse (of more than 2 mm), a 'hammocking' tracing of holosystolic mitral valve prolapse (of more than 3 mm), an isolated systolic anterior motion (SAM) observed without obstruction nor any septal thickening sign and in the absence of false systolic anterior motion. Two-dimensional echocardiography appears to be more accurate than time-motion echocardiography. It eliminates a number of artefacts and, particularly, in the section of parasternal longitudinal cut and the apical cut of the four heart chambers. The criterion for mitral prolapse is the billowing of one or both leaflets below the level of the mitral ring. It is very important to assess the leaflet thickness as well as its whole morphology and to appreciate the ventricular kinetic by calculating: ΔD = end diastolic diameter - end systolic diameter / end diastolic diameter.

Pulsed Doppler echocardiography allows the detection of associated mitral regurgitation. Four routine ionic investigations should always be made: plasma Mg (pMg), erythrocyte Mg (eMg), calcaemia and daily calciuria, which can be completed by the research of daily magnesuria, proteinuria and of urinary infection. These must first demonstrate normocalcaemia and the absence of hypercalciuria susceptible to induce a secondary magnesium deficit. Next, the evaluation of pMg and eMg with reliable methods, such as atomic absorption spectrophotometry, allows the diagnosis of primary magnesium deficit through hypomagnesaemia in one-third of the cases of latent tetany due to chronic magnesium deficiency, with or without mitral valve prolapse. Normal levels do not rule out the diagnosis of chronic magnesium deficiency. The histograms of latent tetany patients (with or without mitral valve prolapse) and of controls overlap. If the tetanic group reveals gaussian-type magnesaemia curves with significant lower means (P less than 0.001) both for pMg and eMg, their constitutive elements can be individually hypomagnesaemic (one-third of the cases), normomagnesaemic (almost two-thirds of the cases) and even, although seldom, hypermagnesaemic. Nevertheless one must emphasize the remarkable constancy of magnesaemia which lends importance even to small variations of magnesaemia^5,6,7. Lymphocyte Mg/cell appears as the most interesting static intra-cellular magnesium item⁸. In particular clinical forms, record should be completed with corresponding clinical and paraclinical explorations. Rhinoscopy in rhinitis to discriminate between pseudo-allergic vasomotor and allergic rhinitis, skin tests with not only allergens but also with histamine, acetylcholine and plasma IgE in allergic or pseudo-allergic forms, electroencephalogram and head scan in convulsive forms, psychometric investigations in psychic forms, electronystagmogram and optokinetic test in dizziness, electropolygraphic study of afternoon sleep in dyssomnia, lipid profile in atheromatous dyslipidaemias^9,10,11.

Several risk populations require special attention. Pregnant women because of the consequences of deficiency on mother, foetus, neonate and infant¹² and perhaps on the adult¹³. Geriatric^14,15 and sport¹⁶ populations where magnesium deficiency is most often associated with magnesium depletion. These last two examples illustrate the necessity of distinguishing between two types of inducing mechanisms of magnesium deficit^1,4. In the case of magnesium deficiency, the disorder corresponds to an insufficient magnesium intake: it merely requires oral physiological magnesium supplementation. In the case of magnesium depletion the disorder which induces magnesium deficit is related to a dysregulation of the control mechanisms of magnesium metabolism: either failure of the mechanisms which insure magnesium homeostasis or intervention of endogenous or iatrogenic perturbating factors of magnesium status. Magnesium depletion requires more or less specific correction of its causal dysregulation.

This differential diagnosis between these two types of magnesium deficit is of major importance in case of primary magnesium deficit. It is also interesting in case of secondary magnesium deficit. Although they initially always require their own specific aetiologic treatment, this major therapeutic measure cannot always be performed. It may not be possible to get an alcoholic to quit drinking or to manage diabetes mellitus perfectly. In such cases, a careful analysis of the mechanisms inducing the magnesium deficit can lead to an effective therapy. In chronic alcoholism, magnesium deficiency secondary to an insufficient magnesium entry is frequent¹ whilst in diabetes mellitus the part of the deficiency appears usually much more accessory than the dysregulations inducing magnesium depletion¹. In chronic alcoholism oral magnesium supplementation frequently constitutes an interesting adjuvant treatment^1,17a, while it is much more rarely efficient in diabetes mellitus. However in magnesium depletion it is always wise to maintain a sufficient magnesium intake to allow the means of correcting the dysregulation to have a substrate. It may thus constitute a necessary adjunct to the treatment ^1,17b,17c.

Technique of physiological oral magnesium therapy

Effect of oral physiological magnesium supplementation is the best tool for establishing the diagnosis of magnesium deficiency. Physiological oral doses of magnesium are totally devoid of the pharmacodynamic effects of parenteral magnesium which are observed irrespective of magnesium status: they are without clinical effects when magnesium status is normal. But correction of symptoms by this oral magnesium load will not only be studied on extra- and intra-cellular magnesium parameters, but also on all the well known--but non specific--clinical and paraclinical items. For example stigma of neuromuscular hyperexcitability should be integrated in the protocol of physiological oral magnesium supplementation concerning allergic, vascular, pregnant or sport patients^1,2,14-16,18.

Chronic primary magnesium deficit affects a large proportion of the population (15-20 per cent). This prevalence seems consistent with the estimation of nutrient deficiency using probability analysis in populations where the mean magnesium daily intake is slightly above 4 mg/kg/day versus a recommended dietary amounts of magnesium set a 6 mg/kg/day^1,19-22. The first step of physiological oral supplementation should be achieved through dietetic means. But usually magnesium and energy content of food correlate^1,2,6: magnesium rich products are also rich in energy. Except for some vegetarian diets^1,15 supplementation should be achieved using a high magnesium density nutrient with the best possible availability^1,19-21. This requirement is met by magnesium in water, which must have a probable link with the importance of its hexahydrated form in biological systems^{1,19,20,24-26}. It is possible in natural form, rarely in tap water, sometimes in bottled mineral water. Most often, the treatment is medicinal using addition of soluble magnesium salts to ordinary water ^{1,19,20,27-29}. If it is only a question to correct in vivo an experimental magnesium deficiency, all magnesium salts have a comparable bioavailability, either mineral salts i.e. chloride, or organic salts i.e. acetate, citrate, methionate, aspartate, lactate, glutamate, pyrrolidone-carboxylate. Evidently the specific properties of their anions may have their own importance: for example a supply of chloride is interesting in case of coexistent hypochloremic alkalosis^1,21 or the anions may act differently on various targets: for example at the membranous level^30,31. Tolerance of these physiological doses is excellent. Acceleration of intestinal transport is observed only in susceptible subjects: for example patients with colitis¹. The contraindications are obvious¹. Two are exceptional: myasthenia and hypermagnesaemic periodic paralysis. There is only one contraindication: overt renal insufficiency (creatinine clearance less than 15 ml). Urinary infection with elevated urinary phosphates is a transient contraindication with the risk of precipitating ammonium-magnesium phosphates. Urinary residues must be cleared up prior to any magnesium therapy¹. Magnesium may impair the properties of several drugs: for example 4-quinolones, tetracyclines, several aminoglycosides, vancomycin. The use of these antibiotics constitutes another transient contraindication^1,32.

Lastly, within the limits of our present knowledge, we can eventually consider as a relative contraindication of magnesium therapy, magnesium solid tumours in a state of development since their growth may be stimulated by magnesium^1,33. But palliative control of poorly tolerated magnesium deficiency is permissible if it coincides with a well known antagonism between magnesium and the carcinogen or with an effective cystotatic treatment--such as Cis-Pt--which prevents the risk of inducing magnesium excess in the sites where magnesium excess is noxious ^1,33. If one finds at the first monthly monitoring of a treatment of a chronic magnesium deficit that a simple increase in oral magnesium intake is ineffective or insufficient it is necessary to proceed to the treatment of this magnesium depletion¹: in the case of renal loss of magnesium, use of agents that reduce urinary magnesium either magnesium-sparing diuretics i.e. amiloride (5 to 10 mg/day), spironolactone (100 to 200 mg/day), or antistress hygienic or medicinal prescriptions; if these fail or immediately in the case without urinary magnesium leakage, use of magnesium fixing agents: i.e. pharmacological doses of vitamin B6 and physiological doses of vitamin D, progesterone in particular cases of luteal insufficiency or high-risk pregnancies¹. Further research on the tricky problem of treatment of magnesium depletion might bear upon diverse genetic or acquired models of magnesium depletion in order to study their physiopathological mechanisms and aim at their control¹⁸. Various types of more or less severe magnesium depletion are used: genetic models^34-38 and acquired models which associate low magnesium intake with diverse types of stress: aluminium load, cardiac or nervous insults^{39-42,43,44-48}. Models which may be cured appear particularly appropriate to screen treatments of magnesium depletion^34,47,48. Recent experimental data have stressed the links between magnesium and selenium status^14,49. Glutathione peroxidase may be lowered either by selenium deficiency--whose classical marker it is--or by magnesium deficiency. In some cases in which magnesium deficit was not controlled by simple physiological oral magnesium supplementation, magnesium depletion was cured by the addition of 200 Ý/day of oral selenium as seleno-methionine to the same magnesium supplementation. This treatment simultaneously normalized reduced erythrocyte magnesium and glutathione peroxidase concentrations⁵⁰.

In case of failure of these two initial stages of therapy for magnesium depletion, we use either partial magnesium 'analogues' i.e. propranolol, verapamil, several anticonvulsants as phenytoin, baclofen ..., antioxidants i.e. sulphur compounds, selenium, vitamins C and E^{1,9,10,14,15,18,32,49,51,52a,b} or parenteral magnesium therapy.

Pharmacological magnesium therapy

Induced magnesium overload

In order to induce a therapeutic magnesium overload and to use the pharmacological properties of the ion, it is necessary to go beyond the mechanisms of magnesium homeostasis. Large doses of magnesium given orally are advisable for chronic indications and the parenteral route is suitable for acute applications.

The pharmacodynamic properties of magnesium are antispasmodic curariform and ganglioplegic, bradycardic, antiarrhythmic, vasodilating and hypotensive, antithrombotic, antianoxic, stabilizing, antitoxic versus several pollutants, cytoprotective and thus antistress^{1,27,33,53-56}.

To prevent magnesium overload accidents, one must understand the symptoms of magnesium overload¹.

• Up to 1.5 mM of plasma Mg (pMg) magnesium overload remains clinically latent.

• At 1.5 mM, cardiovascular signs (hypotension and after a transient tachycardia-bradycardia) and cutaneous flushing appear.

• Digestive signs, nausea and vomiting are observed below 1.5 mM.

• Nervous signs of neuromuscular hypoexcitability only occurs when pMg is more than twice the normal. Beginning at 2 mM/l deep tendon hyporeflexia appears. At the same time, urinary signs and non specific changes in the electrocardiogram: lengthening of the PR interval followed by prolongation of the QT interval may occur. Well-monitored therapy with magnesium infusion must never lead to respiratory arrest which is only observed after the occurrence of deep tendon hyporeflexia and oliguria. Without assisted ventilation death occurs through asphyxia due to respiration paralysis.

• If artificial respiration permits survival while magnesium perfusion continues the patient enters hypothermic coma. The same as in hibernation, hyperglycaemia occurs that appears to be a linear function of hypothermia, low blood calcium and phosphorus and a tendency to reduced coagulation mainly linked to platelet¹ and vascular endothelium^58-62b disorders. Hypermagnesaemia may clinically mimic a central brain-stem herniation syndrome⁵⁷. Above 7.5 mM/litre death occurs from diastolic cardiac arrest¹. In magnesium excess it should be emphasized that the blood brain barrier gives priority to the peripheral action of magnesium overload (described as early as 1869⁶³ and which resembles the Lambert-Eaton syndrome⁶⁴) rather than to the pseudo 'central anesthesic effect' (erroneously claimed from 1905⁶⁵). The brain magnesium concentration remains unaltered⁶⁶. In overt magnesium overload, the failure of the homeostatic regulations replaces a parallel slowing of insulin and adrenaline secretions with hypoinsulinism coupled with a strong release of adrenaline. It also induces urinary loss of taurine while the increased release of calcitonin and the low PTH secretion exceed their goal¹.

Indications

They are of three types: specific, pharmacological or mixed.

Specific indications

Parenteral magnesium treatment is specifically used for the treatment of magnesium deficit in its acute form often with magnesium-dependent hypocalcaemia and/or hypokalaemia, when the oral route is prohibited (parenteral nutrition, anaesthesias, coma) or after the failure of oral magnesium therapy¹.

Pharmacological indications

The pharmacological properties of magnesium have enabled it to be used in many illnesses where no magnesium deficit has been described: intoxication with anticholinesterases (especially TEPP or DFP), aconitine or strychnine; treatment for convulsions in hyperoxia, decompression disorders (caisson disease), or gas embolism and treatment in porphyria that does not increase ALA synthetase activity; treatment for certain forms of migraine and hiccups; as a relaxant that facilitates certain kinds of psychological or neurologic examination and is used in anesthesiology or during kinesitherapy; antihypoxic treatment, especially with high altitude sickness or for carbon monoxide poisoning; antiarrhythmic treatment in any kind of tachyarrhythmia, for example, in digitalis excess, in lithium poisoning, in alcoholism, in cardiac failure, in post-myocardial infarction period and particularly in ventricular dysrhythmia such as in 'torsade de pointes'; and treatment of cases of tissue calcinosis such as ossifying myositis (neurotic, traumatic or progressive) or para-articulatory ossification after the implantation of articular endoprostheses ^{1,9,10,18,27,32,44-46,67,70a,70b}.

Mixed indications: pharmacological and aetiopathogenic

These types constitute very interesting indications for magnesium therapy. The list of the types of treatment possible is quite long: treatment for delirium tremens and the different acute complications of alcoholism, most often in hypertonic form and associated with treatment of the various withdrawal syndromes; treatment for cranial trauma and many nervous crises, not only the tetanic forms but also 'grand mal', loss of consciousness, hypoglycaemic episodes, vagovagol syncope, swooning, 'panic attacks'; treatment for hypertensive diabetic and atherosclerotic vasculopathy or for various types of central and peripheral arteriopathies (cerebral, ocular, of the lower limbs, coronary and especially for myocardial infarction); treatment of phlebitis in association with major anticoagulation treatments; treatment for acute intoxication by citrates, by aluminum phosphide, by ricin and fluoride compounds as well as for intoxication by the major pollutants, Pb and Cd, and perhaps Hg, ultimately alternating with chelation treatment; treatment for dilutional hyponatraemia and ketosis. Finally the rarity of gynaecological indications which are in practice limited to a few cases of severe dysmenorrhea contrasts with the importance of obstetric indications: treatment for pre-eclampsia and eclampsia, tocolysis in premature labor, tetanization of the uterus, fetal distress syndrome and meconial contamination, and even, by virtue of magnesium's role in the synthesis of surfactant, prevention of hyaline membrane disease. Lastly parenteral magnesium is interesting in the treatments of anaphylactic shock and of asthmatic crisis--with possible consecutive management of a secondary acute respiratory failure--whereas the effects of magnesium aerosols are dubious for the latter indication^{1,9,10,18,27,32,58,67,71-81b}.

Today parenteral magnesium therapy mainly concerns the obstetric, cardiovascular and anaesthesiological fields.

In obstetrics, the main indication is pre-eclampsia^74-77. But prevention or treatment of eclamptic convulsions does not rely on a specific central action of magnesium, since the central nervous system is protected from hypermagnesaemia by the blood-brain barrier^{1,74,75,77,82,83}. The mechanisms of parenteral magnesium action on the brain seem indirect through the antithrombotic beneficial effects on platelet¹ and endothelial functions (↑ PGI2, ↑ EDRF (↑ NO), ↓ thromboxand, ↓ endothelin, ↓ angiotension II)^58-62b on microvascular obliteration--the hallmark of eclampsia⁵⁸--and on vasospasm by acting as a calcium antagonist^82,84,85. Analysis of the mechanisms of the protective action of parenteral magnesium on the central nervous system O2 toxicity brings to similar conclusions as to the preponderance of the systemic indirect factors over the pharmacological central anticonvulsant actions of parenteral magnesium^1,68,86. Nevertheless among the major treatments of preeclampsia, phenytoin⁷⁵ induces more rapid cervical dilatation, smaller fall in haematocrit after delivery, lower incidence of hot flushes and less dyspnoea and weakness in mother as well as less side effects on fetal heart tracings, than magnesium infusions do^87,88.

A critical and comprehensive review of tocolytic agents to stop preterm labour concludes that the only effective drugs are the prostaglandin inhibitors. An analysis of randomized, placebo-controlled, clinical trials showed that parenteral magnesium is not better than placebo⁸⁹ Moreover in a high risk group of patients, without clinical disturbances of magnesium status, physiological oral magnesium supplement was not effective which demonstrates that there is no magnesium deficiency in this population⁹⁰.

In the cardiovascular field, arrhythmias and ischaemias constitute the main indications of parenteral magnesium.

All topographical forms of primary or secondary cardiac arrhythmias may benefit form parenteral magnesium administration: atrial arrhythmias (multifocal tachycardia or fibrillation), supraventricular tachycardia (reentrant sinoatrial, reentral atrio-ventricular), ventricular arrhythmias (torsades de pointes particularly). Parenteral magnesium effects on heart functions bring together: reduced excitability due to a shift of excitable threshold to more depolarised potentials, reduced automotricity due to decrease rate of slow diastolic depolarization and delayed stimulus conduction due to increase of atrio-ventricular node conduction time. The ionic mechanisms underlying the anti-arrhythmic effects of parenteral magnesium are numerous. Among others, negative inotropism seems due to reduction of both Ca²⁺ influx from extracellular space and calcium release from intracellular calcium stores acting on both ryanodine sensitive and IP3-sensitive calcium release channels^70,91. Cardiac arrhythmias are usually pharmacological indications of parenteral magnesium. It is erroneous to claim, as, among others, Iseri et al., do ², that the efficiency of pharmacological magnesium infusions justifies oral magnesium physiological magnesium supplementation. Such supplements are only appropriate in mixed (pharmacological and aetiopathogenic) indications where primary or secondary magnesium deficiency exists for example in alcoholism and some cases of cardiac failure^1,92-94.

To determine the just place of parenteral magnesium therapy in cardiac arrhythmias randomized, double blind controlled trials vs. placebo and reference drugs are necessary. In such conditions, prophylactic magnesium infusion seems to lessen the incidence and severity of atrial fibrillation after coronary artery by-pass grafting, but remains inefficient on ventricular arrhythmias⁹⁵. However in another trial, a similar magnesium administration decreased the frequency of ventricular dysrhythmias⁹⁶. Because of the vast array of safe and effective drugs such as ATP and verapamil available for terminating supraventricular tachycardia, there appears to be little role for clinical use of parenteral magnesium in this setting^97,98. However the overall efficacy for conversion to sinus rhythm through this magnesium therapy seems at least as effective as with verapamil. It acts more rapidly and with fewer side-effects⁹⁹. In the control of warning ventricular arrhythmias, combination of magnesium infusion with low doses of lidocaine is more effective than lidocaine alone and avoids the toxic effects that higher doses of lidocaine may cause^66,100. In torsades de pointe magnesium infusion can be given safely as a first aid therapy, especially when conventional treatments might prove difficult or deleterious¹⁰¹. It does not jeopardize the therapeutic effects of artrial pacing since it does not affect the QT interval¹⁰².

The logistic use of parenteral magnesium seems now an essential therapy in the treatment of acute ischaemic heart disease and a potential role in cerebral ischaemia. In both animal and human studies, intravenous magnesium is useful in treatment of acute myocardial infarction^73,103,104. In earlier studies the beneficial effects on mortality were attributed to an antiarrhythmic effect of magnesium infusion^1,105, but it seems that the benefit relies mainly on anti-stress properties of parenteral magnesium^{1,9,71,72,106}. This indication of intravenous magnesium is pharmacological. Myocardial infarction is the typical example of a painful illness where stress induces magnesium depletion. The usual parenteral doses would not suffice to restore its balance. The failure of physiological oral magnesium supplementation to influence post-infarction cardiac events demonstrates that no magnesium deficiency intervenes¹⁰⁷. Nervous focal ischaemia--and trauma--seem relevant indications of magnesium infusion therapy. These insults induce local magnesium depletion, disruption of blood-brain barrier enabling a higher level of neuroprotector magnesium to reach the nervous tissue and to reduce focal impairment^{12,44-48,108,113} but these beneficial effects are observed with massively increased plasma magnesium only. Further research with lower parenteral magnesium administration is still requested. One should make the greatest reservations on the possible but unproven role of magnesium deficit in the aetiology of strokes⁹.

The pharmacological hypotensive action of parenteral magnesium should rarely be used. This transient effect⁶⁹ may be opposed to its persistent cerebral vasodilating effect ^7,82.

Lastly it will be interesting to study the pharmacological effects of magnesium in the therapy of consummation coagulopathy since it may be associated with magnesium deficits^1,114 and with reduced release of PGI2⁵⁸.

The muscle relaxant activity of magnesium infusion and its anti-stress activities may account for its use in anaesthesia. It has been used to treat postanaesthetic shivers¹¹⁵, to prepare brain-dead patients for organ donation with large fluxes of magnesium¹¹⁶, to manage sympathetic and parasympathetic overactivity in severe tetanus¹¹⁷, in phaeochromocytoma resection^60,118, in the prophylactic or curative treatment of reactive hypertension caused by endotracheal incubation⁶⁹. Among the interactions of hypermagnesaemia with anaesthetic agents, the enhancement of the non-depolarizing and depolarizing muscle relaxants should be highlighted. A pattern of Lambert-Eaton syndrome or of magnesium excess may be observed ^1,4,69.

Technique

Curiously, the most widely used preparations are those with magnesium sulphate. This salt has, among the soluble salts of magnesium, the least advantageous pharmacological properties ^1,24,30,31. The use of isotonic preparations of other soluble salts of magnesium would be better for example (MgCl₂, 6H₂O), magnesium acetate (Mg(C₂H₃O₂)2, 4H₂O), pyrrolidone carboxylate, aspartate... Intravenous route is customary because of the painful character of the intramuscular route. Bolus inducing a sensation of increased warmth should never exceed 100 mg (0.1 mM/kg/day). Rapid administration is dangerous¹¹⁹, the intravenous injection must be very slow (a minimum of 3 min for injection of 100 mg(1)). One or two bolus per day are possible. For venous perfusions we use as a normal well tolerated dose 100 mg per hour for perfusions from 4 to 6 h: 400 to 600 mg (17 to 25 mM) for each perfusion. Massive doses reach four perfusions per day: 2400 mg (or 100 mM). It is obvious that such forms of therapy are conceivable only in intensive care units with careful monitoring of pulse, arterial pressure, deep tendon reflexes, hourly diuresis and electrocardiogram and respiratory rhythm recording¹.

Contraindications for this form of pharmacological therapy are the same as for oral magnesium therapy but one must be even more cautious because of the toxicity reaching lethality of iatrogenic magnesium overload. Well monitored, iatrogenic hypermagnesaemia should never cause respiratory arrest¹²⁰ and even less cardiac arrest with assisted respiration. Hypocoagulation disturbances and hypothermia seem related to the importance of hypermagnesaemia^1,121.

These acute complications require:

• Firstly, minor drug treatments: intravenous calcium gluconate (1 g over 3 min) which usually produces prompt but transient improvement^1,64, osmotic diuresis, anticholinesterase and analeptic drugs¹.

• Secondly, in patients with life-threatening hypermagnesaemia, assisted respiration and haemodialysis are necessary^1,64. In pregnant women with prolonged parenteral magnesium therapy, magnesium excess may also concern foetus¹²², alterations of fetal heart tracings⁸⁸ and of breathing movements¹²³, neonatal bone abnormalities^124,125 with the possible deleterious role of SO₄ anion³¹.

The use of high oral doses of magnesium for inducing chronic magnesium overload--for example to treat vascular hypertension or extra-systoles^67,126,127--appears very questionable, not so much because of possible laxative effects as because of its potential toxicity. It is erroneous to identify the atoxicity of physiological oral magnesium supplementation (5mg/kg/day) which only ensures normal equilibrium of magnesium balance with a similar tolerance of pharmacological high oral doses or magnesium (equal to or greater than 10 mg/kg/day) which are meant to induce chronic magnesium excess^16-21. It should be possible to observe, for example, diverse metabolic consequences akin to those observed with prolonged pharmacological parenteral magnesium treatment such as calcium homeostasis disturbances^124,125. They may constitute one of the factors reducing lifespan¹²⁸.

Laxative and antacid magnesium therapy

Laxative magnesium therapy

Laxative magnesium therapy traditionally uses the irritative osmotic strength of large doses of magnesium salts for example hydrated MgSO₄ or magnesium hydroxide. Any renal or digestive tract lesion must formally rule out its uses because of the risk of fatal accident of magnesium overload. But when cautiously used, laxative magnesium may also constitute an efficient therapy for magnesium-dependent disturbances of lipid, carbohydrate and electrolytes metabolism, in geriatric patients particularly^15,129,130.

Antacid therapy

Antacid therapy uses the neutralizing capacity of Mg_o or Mg carbonate. The more widespread use of magnesium-containing phosphate binders creates the risk of hypermagnesaemia. Their interest in haemodialysis patients is discussed. Theoretically their use coupled with a low magnesium dialysate may reduce phosphorus absorption. It appears better than aluminium salts with their risk of aluminium encephalopathy¹, but it is difficult to determine the use of magnesium containing antacids with an optimal magnesium dialysate which efficiently avoids either hyper- or hypomagnesaemia¹³¹.

Local magnesium therapy

Topical applications of magnesium

During the first world war, P. Delbet stressed the interest of irrigating wounds with a 'cytophlactic' solution of 1.2 per cent MgCl₂¹. Today topical use of magnesium is proposed as the best possible antagonist for hydrofluoric acid burns: bathing with a saturated ice cold solution of magnesium sulphate associated with local injections of a 10 per cent solution of magnesium acetate¹³². An ointment containing 25 per cent MgSO₄ has local decongestive osmotic effects which make it useful as a non specific anti-inflammatory agent¹. Such an ointment could be used associated with local treatment of soft tissue calcification¹³³. Lastly in ophthalmology an eye wash with 10 per cent MgSO₄ appears to have a significant effect on herpetic superficial dentritic keratitis¹.

Magnesium and cytoprotection

The cytoprotective properties of magnesium make it a theoretically important element in solutions for the irrigation and perfusion of organs destined for transplant: cornea, lungs, liver, pancreas, kidney and especially the heart^1,116. The role of magnesium in cardioplegy is still subject to discussion ^1,27,134. The protective role of magnesium in insulin secretion^135,136 makes it logical to consider its use in culture of the islets of Langerhans to make this promising treatment for insulin dependent diabetes more effective¹.

Conclusion

The applications of magnesium therapy are presently in constant progress. The range of the indications of pharmacological magnesium therapy is widening: for example in intensive care where it is advisable as well in cardiologic emergencies such as myocardial infarctions and torsades de pointe as in toxicological emergencies such as acute intoxication by aluminum phosphide. But its main indication concerns the control of chronic primary magnesium deficiency with physiological oral magnesium therapy. Its pattern has now been clearly elicited, but epidemiological intervention trials are still needed to assess its importance. There should be a follow-up of the effects of the physiological oral magnesium supplementation not only on magnesium items but also on all the well-known--but non-specific--clinical and paraclinical signs. Its specific efficiency should contribute to highlight the importance of the clinical forms of chronic marginal magnesium deficiency which constitutes the major indication of oral physiological magnesium application.

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107. Galloe, A.M., Rasmussen, H.S., Jørgensen, L.N., Balslov, S., Cintin. C., Graudal, N. & McNair, P. (1993): Influence of oral magnesium supplementation on cardiac events among survivors of an acute myocardial infarction. Br. Med. J. 307, 585-587.

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125. Smith, L.G., Burns, P.A. & Schandler, R.J. (1992): Calcium homeostasis in pregnant women receiving long-term MgSO₄ therapy for preterm labor. Am. J. Obstet. Gynecol. 167, 45-51.

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130. Kinnunen, 0. & Salokannel, J. (1989): Comparison of the effects of magnesium hydroxide and a bulk laxative on lipids, carbohydrates, vitamin A and E and minerals in geriatric hospital patients in the treatment of constipation. J. International Med. Res. 17, 442-454.

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