Part Five, Chapter 1, Section B
Magnesium has for a long time had only a modest place in therapeutics, being used only for its cathartic or neutralizing properties in oral preparations or for its sedative and antispasmodic properties parenterally.
Today, constantly increasing knowledge of the clinical forms of magnesium deficit in human beings (Durlach, 1988) has made it possible to know under which circumstances and in what ways chronic primary magnesium deficiency can be remedied using physiological doses of magnesium. That is the main form of magnesium therapy.
These palliative oral doses of magnesium, meant to balance chronic magnesium deficiency, are obviously devoid of any toxicity since their purpose is to ameliorate insufficient magnesium intakes. Their indications rest on well-founded epidemiological trials (Durlach et al., 1992a).
Conversely, parenteral 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 (Durlach, 1988).
In this review of the diverse applications of magnesium therapy, we will successively consider:
(i) The uses of physiological oral magnesium - the main form of magnesium therapy involving, first and foremost, an adequate knowledge of the sole indication of chronic magnesium deficiency. The technique of oral physiological magnesium supplementation will be analyzed.
(ii) The indications for, and techniques of, several pharmacological applications of magnesium:
As a conclusion, we will contrast the dangers of using the pharmacological properties of iatrogenic magnesium overload with the atoxicity of oral magnesium supplementation at physiological doses palliative of magnesium deficiencies.
Today, the main form of magnesium therapy is oral magnesium physiological supplementation addressing chronic magnesium deficiency. It is therefore necessary to be well acquainted with the clinical pattern of this sole indication.
A. Clinical forms of chronic magnesium deficiency
Open and controlled trials (Durlach, 1988; 1991; 1992; Durlach et al., 1992a) have established the clinical and paraclinical pattern of chronic magnesium deficiency (CMD). Nervous system consequences irrespective of age can be studied first: 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, pseudo-allergy (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 a 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 "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, pre-cordialgia, 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 studied with various acute paroxysmal manifestations which also can 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: neurotonic, from the ."attack of nerves" to the "hysterical crises", or autonomic: lipothymia, reactive hypoglycemia, pseudo-asthmatic crisis, vago-vagal syncope or, on the contrary, paroxysmal tachycardia. Sometimes, centripetal tingling sensations and stiffness of the extremities confer on these nervous crises a tetanoid character. 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 causes hyperventilation, gaseous alkalosis, and self-perpetuation of the crisis. 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.
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 tapping 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 ischemia lasting 10 min, post-ischemia lasting 10 min after removal of tourniquet and lastly hyperventilation lasting 5 min. If the EMG shows one (or several) train(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 sub-groups, either clinical (through a positive of the Chvostek's sign alone), or electromyographic (through a positive 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 MVP (of more than 2 mm), a "hammocking" tracing of holosystolic MVP (of more than 3 mm), an isolated systolic anterior motion (SAM) observed without obstruction or any septal thickening sign and in the absence of false systolic anterior motion. Two-dimensional echocardiography appears to be more accurate than TM echocardiography. It eliminates a number of artefacts and, particularly, in the section of parasternal longitudinal cut and the apical cut of the four heart chamber. The criterion for mitral prolapse is the billowing of one or both leaflets below the level of the mitral ring. It is important to assess the leaflet thickness as well as its whole morphology and to appreciate the ventricular kinetics 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), calcemia and daily calciuria, which can be completed by the research of daily magnesuria, proteinuria and urinary infection. These must first demonstrate normocalcemia and the absence of hypercalciuria susceptible to induce 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 hypomagnesemia in one-third of the cases of latent tetany (LT) due to CMD, with or without MVP. Normal levels do not rule out the diagnosis of CMD. The histograms of LT patients (with or without MVP) and of controls overlap. If the tetanic group reveals gaussian-type magnesemia curves with significant lower means (p <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, occasionally, hypermagnesaemic. Nevertheless, one must emphasize the remarkable constancy of magnesemia which lends importance even to small variations of magnesemia (Whang et al., 1990; Classen et al., 1991). Lymphocyte Mg/cell appears as the most interesting static intra-cellular magnesium item (Durlach et al., 1991a).
In particular clinical forms records should be completed with corresponding clinical and paraclinical explorations. Rhinoscopy in rhinitis to discriminate between pseudo-allergic vasomotor and allergic rhinitis, skin tests not only with 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 dyslipidemias (Durlach et al., 1992b; 1992c)
Several risk Populations require special attention: pregnant women because of the consequences of deficiency on mother, foetus, neonate and infant (Durlach et al., 1991b) and infants born of diabetic mothers (Durlach et al., 1991b). Geriatric (Rayssiguier et al., 1990a; Durlach et al., 1993) and sporting (Rayssiguier et al., 1990b) populations where magnesium deficiency is most often associated with magnesium depletion.
The last two examples illustrate the necessity of distinguishing between 2 types of inducing mechanisms of magnesium deficit (Durlach, 1988; 1992). 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 homeostatis 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 the case of primary magnesium deficit and it is also interesting in the case of secondary magnesium deficit. Although both always require their own specific etiologic treatment initially, these major therapeutic measures 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 frequent (Durlach, 1988), whilst in diabetes mellitus the deficiency appears as an adjunct to dysregulations inducing magnesium depletion (Durlach, 1988). In chronic alcoholism, oral magnesium supplementation frequently constitutes an interesting adjuvant treatment (Durlach, 1988; Gullestad et al., 1991), while it is much less efficient in diabetes mellitus. In magnesium depletion, however, it is always wise to maintain a sufficient magnesium intake to prevent the dysregulation from having a substrate. It may thus constitute a necessary adjunct to the treatment (Durlach, 1988).
B. Technique of physiological oral magnesium
The 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, the stigma of neuromuscular hyperexcitability should be integrated in the protocol of physiological oral magnesium supplementation concerning allergic, vascular, aging of sport patients (Durlach, 1988; Durlach et al., 1992a; 1993; Rayssiguier et al., 1990a; 1990b).
Chronic primary magnesium deficit affects a large proportion of the population (15 to 20 %). 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 vs recommended dietary amounts of magnesium set at 6 mg/kg/day (Durlach, 1988; 1989; Durlach and Mareschi, 1991). The first step of physiological oral supplementation should be achieved through dietetic means. But usually magnesium and energy contents of food correlate (Durlach, 1988; Durlach et al., 1992a; Classen et al., 1991): magnesium-rich products are also rich in energy. Except for some vegetarian diets (Durlach, 1988; Durlach et al., 1993), supplementation should be achieved using a high-magnesium density nutrient with the best possible availability (Durlach, 1988; 1989; Durlach and Mareschi, 1991; Fine et al., 1991). This requirement is met by magnesium in water, which is probably in relation to the importance of its hydrated form in biological systems (Durlach, 1988; 1989; Durlach and Mareschi, 1991; Bara et al., 1989; Theophanides et al., 1990; Meyer and Classen,1991). In practice, this is rarely the case in tap water,sometimes in bottled mineral water.
Most often, the treatment is medicinal using the addition of soluble magnesium salts to ordinary water (Durlach, 1988; 1989; Durlach and Mareschi, 1991; Classen, 1990; Fehlinger, 1990; 1991). If it is only a question of correcting an experimental magnesium deficiency in vivo, all highly soluble 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 the case of concomitant hypochloremic alkalosis (Durlach, 1988; Classen, 1990) or the anions may act differently at the membrane level (Durlach et al., 1992d).
Tolerance of these physiological doses is excellent. Acceleration of intestinal transport is observed only in susceptible subjects: for example patients with colitis (Durlach, 1988).
The contraindications are obvious (Durlach, 1988). Two are exceptional: myasthenia and hypermagnesemic periodic paralysis. There is only one frequent contraindication: overt renal insufficiency (creatinine clearance < 15 ml/mn). Urinary infection with elevated urinary phosphates is a transient contraindication, with the risk of the precipitation of ammonium-magnesium phosphates. Urinary residues must be cleared prior to any magnesium therapy (Durlach, 1988). Magnesium may impair the properties of several drugs: for example 4-quinolones, tetracyclines, several aminoglycosides and vancomycine. The use of these antibiotics constitutes another transient contraindication (Durlach, 1988; Günther, 1991). Finally, within the limits of our present knowledge, solid tumors in a state of development may also be considered as a contraindication of magnesium therapy since magnesium may stimulate their growth (Durlach, 1988; Durlach et al., 1990). However, palliative control of poorly tolerated magnesium deficiency is permissible if it coincides with an effective cytostatic treatment - such as Cisplatin - which prevents the risk of inducing magnesium excess in the sites where magnesium excess is noxious (Durlach, 1988; Durlach et al., 1990).
If one finds at the first monthly monitoring of a treatment of 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 depletion (Durlach, 1988): in the case of renal loss of magnesium, using agents that reduce urinary magnesium, either magnesium-sparing diuretics, i.e. amiloride (5 to 10 mg/day), spironolactone (100 to 200 mg/day), or anti-stress hygienic or medicinal prescriptions; if these fail (or immediately in the case of no urinary magnesium leakage) magnesium-fixing agents are indicated, i.e. pharmacological doses of vitamin B6 and physiological doses of vitamin D, progesterone in particular cases of luteal insufficiency or high risk pregnancies (Durlach, 1988). After failure of these 2 initial stages of therapy for magnesium depletion, we use either partial magnesium "analogues", i.e. propranolol, verapamil, several anticonvulsants as phenytoin, baclofen..., anti-oxidants, i.e. sulfur compounds, vitamin C and E (Durlach, 1988; Durlach et al., 1992b; 1992c; 1993; Günther, 1991; Freedman et al., 1991; Rayssiguier et al., 1992) or parenteral magnesium therapy.
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 curariform and ganglioplegic, bradycardic, antiarrhythmic and hypotensive, antithrombotic, antianoxic, stabilizing, antitoxic vs several pollutants (Durlach, 1988; Classen, 1990; Durlach et al., 1990; Guiet-Bara et al., 1991; Zdanowicz and Barletta, 1991; Cordova et al., 1992).
There are three types of indications: specific, pharmacological or mixed.
a. Specific indications
Parenteral magnesium treatment is specifically used for the treatment of magnesium deficit in its acute form, often with magnesium-dependent hypocalcemia and/or hypokalemia, when the oral route is prohibited (parenteral nutrition, anesthesias, coma) or after the failure of oral magnesium therapy.
b. Pharmacological indications
The pharmacological properties of magnesium apply 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, in anesthesiology or during kinesitherapy; anti-hypoxic treatment, especially with high altitude sickness or for carbon monoxide poisoning; treatment in any kind of tachyarrhythmia, for example, in lithium poisoning 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 (Durlach, 1988; Durlach and Durlach, 1992; Durlach et al., 1992b; 1992c; Classen, 1990; Günther, 1991).
c. Mixed indications: pharmacological and etiopathoenic
These types constitute very interesting indications for magnesium therapy. The list of possible types of treatment is quite long: treatment for delirium tremens and the different acute complications of alcoholism, most often in hypertonic form and associated with vitamins B1 and B6; treatment of the various withdrawal syndromes; treatment for many nervous crises, not only the tetanic forms but also "grand mal", loss of consciousness, hypoglycemic episodes, vago-vagal 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 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 hyponatremia and ketosis. The rarity of gynecologic indications, which, in practice, are limited to a few cases of severe dysmenorrhea, contrasts with the importance of obstetrical 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. Finally, parenteral magnesium is interesting in the treatments of anaphylactic shock and of asthmatic crisis, whereas the effects of magnesium aerosols are dubious for the latter indication (Durlach, 1988; Durlach and Durlach, 1992; Durlach et al., 1992b; 1992c; Classen, 1990; Günther, 1991; Rasmussen, 1988; Kaplan et al., 1990; Tetikkurt et al., 1992).
Curiously the most widely used preparations involve magnesium sulfate. Among the soluble salts of magnesium, sulfate has the least advantageous pharmacological properties (Durlach, 1988; Classen, 1990; Durlach et al., 1992d). It is better to use isotonic preparations of other soluble salts of magnesium, for example chloride (MgCl2.6H2O), acetate (Mg[C2H3O2]2. 4H2O), pyrrolidone carboxylate, aspartate, etc. The intravenous route is customary because of the painful character of the intramuscular route. A bolus, inducing a sensation of increased warmth, should never exceed 100 mg (0.1 mmol/kg/day); one or two boluses per day are possible. For venous perfusions we use as a normal well tolerated dose 100 mg per hour for perfusions of 4 to 6 hours: 400 to 600 mg (17 to 25 mmol) for each perfusion. Massive doses reach 4 perfusions per day: 2400 mg (or 100 mmol).
It is obvious that such forms of therapy are possible only in intensive care units, with careful monitoring of pulse, arterial pressure, deep tendon reflexes, hourly diuresis and electrocardiogram and respiratory rhythm recordings (Durlach, 1988). 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 (approaching lethality) of iatrogenic magnesium overload.
The use of high oral doses of magnesium for inducing chronic magnesium overload for example to treat extrasystoles or vascular hypertension (Durlach and Durlach, 1992) appears very questionable because of its potential toxicity (Durlach and Durlach, 1992; Ganguli et al., 1990). Conversely, the use of induced acute magnesium overload appears well-founded after control with double-blind studies: for example in acute myocardial infarction, ventricular tachycardias, tocolysis and in asthma crises (Durlach, 1988; Durlach and Durlach, 1992; Durlach et al., 1992b; 1992c; Classen, 1990; Rasmussen, 1988; Kaplan et al., 1990; Tetikkurt et al., 1992).
B. Laxative and antacid magnesium
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 formally rules out its use because of the risk of a fatal magnesium overload. When cautiously used, however, laxative magnesium may also constitute an efficient therapy for magnesium-dependent disturbances of lipid, carbohydrates and electrolyte metabolism, in geriatric patients particularly (Durlach et al., 1993; Kinnunen et al., 1989; Kinnunen and Salokannel, 1989).
Antacid therapy uses the neutralizing capacity of Mgo or Mg carbonate. The more widespread use of magnesium-containing phosphate binders creates the risk of hypermagnesemia. Its interest in hemodialysis patients is controversial. Theoretically, its use, coupled with a low-magnesium dialysate, may reduce phosphorus absorption. It appears better than aluminum salts with their risk of aluminum encephalopathy (Durlach, 1988), but it is difficult to determine the use of magnesium-containing antacids with an optimal magnesium dialysate to efficiently avoid hyper- as well as hypomagnesemia (Gonelia and Calabrese, 1989).
C. Local magnesium therapy
1. Topical applications of magnesium
During the first world war, P. Delbet stressed the interest of irrigating wounds with a "cytophylactic" solution of 1.2% MgCl2 (Durlach, 1988). Today, the topical use of magnesium is proposed as the best possible antagonist for hydrofluoric acid burns: bathing with a saturated ice cold solution of magnesium sulfate associated with local injections of a 10% solution of magnesium acetate (Harris and Rumack, 1981). An ointment containing 25% MgSO4 has local decongestive osmotic effects which make it useful as a non specific anti-inflammatory agent (Durlach, 1988).
Such an ointment could be used associated with local treatment of soft tissue calcifications (Steidl and Ditmar, 1990). Finally, in ophtalmology an eye wash with 10% MgSO4 appears to have a significant effect on herpetic superficial dentritic keratitis (Durlach, 1988).
2. 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. The role of magnesium in cardioplegy is still subject to discussion (Durlach, 1988; Classen, 1990). The protective role of magnesium in insulin secretion (Ziegler et al., 1983) makes it logical to consider its use in cultures of the islets of Langerhans to make this promising treatment for insulin-dependent diabetes more effective (Durlach, 1988).
The applications of magnesium therapy are constantly progressing. The range of the indications for pharmacological magnesium therapy is widening: for example in intensive care as well as in cardiologic emergencies such as myocardial infarctions and torsades de pointe, and in toxicological emergencies such as acute intoxication by aluminum phosphide.
Its main indication still concerns the control of chronic primary magnesium deficiency through physiological oral magnesium therapy. The pattern of this therapy has now been clearly delineated, but epidemiological intervention trials are still needed to better 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 nonspecific--clinical and paraclinical signs. Its specific efficiency should contribute to the importance of the clinical forms of chronic marginal magnesium deficiency, which constitutes the sole indication for oral physiological magnesium application.
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