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How Best to Determine Magnesium Requirement: Need to Consider Cardiotherapeutic Drugs that Affect Its Retention

This issue's paper on repairing the magnesium deficit of patients with congestive heart failure, by Bortz Costello, Moser-Veillon and DiBianco [1], confronts the problem of identifying the deficiency and meeting the magnesium needs of such patients by fust attempting to ascertain their magnesium status. They employed currently used procedures: deteinunation of levels of magnesium in serum and plasma: total and ultrafiltrate fraction, levels in whole blood and erythrocytes, and fractional urinary excretion of magnesium and its retention after an intravenous load—before and after supplementing with oral magnesium for 3 months. The use of so many procedures to assure accurate diagnosis of deficiency and of its repletion reflects the difficulties confronting clinicians when they are dealing with patients whom they suspect might have magnesium deficiency, and who wish to avoid excessive laboratory costs.

As long ago as 1954, Flink and his co-workers identified magnesium depletion of alcoholic patients and of surgical patients with and without loss of intestinal fluids who receive intravenous fluids and who develop arrhythmias and other electrocardiographic changes, on the basis of serum values that indicated hypomagnesemia, and relief of symptoms with magnesium therapy [2]. In those cases, serum magnesium levels were so low as to allow no doubt as to the diagnosis. However, when the condition is one producing less severe depletion, one must keep in mind that tissue magnesium deficiency can exist despite total serum levels in the normal range. Only 0.3% of the body's magnesium (of about 24 g or 1 mole) is present in serum, and serum magnesium comprises protein-bound, complexed and free ionic magnesium, which constitutes 55% of the amount in serum. Free ionic magnesium is the fraction that is biologically active [3,4].

A better clue to the adequacy of magnesium in the entire body was fust provided by Fitzgerald and Fourman 40 years ago when they showed that healthy young men, who had been kept on magnesium- poor diets for close to a month, retained 25% and 45% of an intravenous load of magnesium at the end of the study [5]. In 1982, Dyckner and Wester reported that patients with congestive heart failure were magnesium deficient, as indicated by retention of over 30% of an intravenously infused 30 mmole magnesium load [6]. Bortz Costello et al [1] have reviewed the recent literature on findings from magnesium load retention studies in normal subjects and in cardiac and hypertensive patients. Gullestad and co-workers [7] evaluated the magnesium status of many hospitalized patients with medical conditions that interfere with the uptake and excretion of magnesium by the load-retention test. Among their congestive heart failure patients 26 to 37% of the load was retained as compared with 2 to 8% retention in healthy controls. Rasmussen et al [8] observed comparable magnesium retentions after intravenous loading among cardiac patients who had received long-term diuretics, and as much as 57% retention among patients with chronic ischemic heart disease. The use of this test, although it provides a reliable index of magnesium deficiency, is appropriate only where active cooperation of both patient and nursing staff can be assured; it is cumbersome and is subject to procedural errors.

Neither of these tests directly indicates tissue levels of magnesium. Measurement of magnesium in blood cells: erythrocytes and white blood cells, as well as in muscle cells, has provided valuable data as to tissue levels. But there is little evidence for dynamic equilibrium among body tissues, and thus it is uncertain whether these tests provide reliable insight as to levels in the heart [3,4]. Increased external ionic magnesium [Mg2+]o, from subnormal levels (assessed with 31P nuclear magnetic resonance spectroscopy) was shown by Altura et al [10] to improve cardiac metabolism and performance of isolated perfused working rat hearts; lowering [Mg2+]o to 0.3 mmoles resulted in cardiac failure. This indicates that measurement of ionized magnesium in serum should provide insight into its influence on the heart in patients with cardiac malfunction.

There are now several ion-selective electrode (ISE) instruments and Mg2+ ionophores that are commercially available [10-13]. Although there is not yet agreement as to which of the devices is best, the use by Bella Altura of the prototype of the NOVA instrument has provided the most data [11,12]. She and her colleagues have found that their ISE is selective for Mg2+, and exhibits little or no interference from pathophysiologic concentrations of ionic calcium, sodium, potassium, hydrogen, ammonium, or heavy metals (e.g., ionic iron, copper, zinc, cadmium, mercury or lead) in serum. Importantly, silicon (as found in vacutainer tubes) does not interfere with measured levels—an important attribute in collecting and transporting samples for analysis. Using this device, she has found [Mg2+]o, to be 71 % of the total magnesium in serum; it varies from subject to subject, but has been remarkably consistent in sequential samples from an individual [12]. Use of specific ion-selective electrodes for [Mg2+]o has disclosed that Mg2+ levels often exhibit significant differences from normality, despite no change in total serum magnesium in many disorders (i.e., cardiac disease, cardiopulmonary bypass, stroke, abnormal pregnancy, renal and hepatic transplant recipients, diabetics, asthmatics, patients with migraine and other headaches, and other conditions) [14].

Because Bortz Costello et al [1] maintained their patients on digoxin, diuretics and angiotensin converting enzyme-inhibitors (ACE-I) during their magnesium supplementation study, they make reference to studies that considered the influence of cardiotherapeutic medications on magnesium. They referred to its wastage by diuretics and its retention by ACE-I. It should be noted that digoxin is also a magnesium waster [15], that congestive heart failure patients' hypomagnesemia worsens while receiving digitalis even without concomitant diuretic therapy, and that magnesium deficiency contributes to digitalis toxicity [16-18]. Their demonstration that such combination therapy did not interfere with repair of the pre-existing magnesium deficit by 3 months' magnesium supplementation, on repetition of the load test, supports fmdings from studies that showed that ACE-I protects against lowering of magnesium in serum, red blood cells, platelets, lymphocytes, and mononuclear blood cells, whether or not in combination with diuretics [19-23]. It is not widely appreciated that ACE-I conserves magnesium, as has been shown in patients with hypertension and/or congestive heart failure [20-23] and which might contribute to their salutary effects in cardiovascular disease, including acute myocardial infarction, magnesium therapy having been shown to be effective in hypertension, arrhythmias, and congestive heart failure, ischemic heart disease, and during open heart surgery, both in experimental models and clinically [24-26].

However, the clinical demonstration of apparent sparing of magnesium by ACE-I paradoxically provides insight into a potential risk of combination therapy—such as might have contributed to adverse effects in studies of magnesium treatment of acute myocardial infarction. When high dosage intravenous infusion of magnesium is accompanied by ACE-inhibition, the hypermagnesemia caused by the infusion can be intensified by the drug and be sufficient to cause systemic generalized vasodilatation, and to retard impulse generation in the sinus node, and slow conduction in the heart [27]. Hypotension, shock, bradycardia and heart block are, in fact, adverse effects encountered in the two studies that infused high dosage magnesium (80 mmoles over 24 hours) for suspected acute myocardial infarction in combination with an ACE-inhibitor and/or a nitrate vasodilator [27,28]. The mechanism might involve suppression, by angiotensin II of stimulation of aldosterone secretion [30] which in turn has long been known to increase urinary loss of magnesium [31]. The direct effect of angiotensin II on intracellular magnesium has also been demonstrated in a study in which addition of angiotensin II to platelets of hypertensive patients caused significant fall in ionized magnesium content [20].

Cardiac patients are at risk of magnesium loss. The difficulties and uncertainties physicians encounter, in making the diagnosis of magnesium deficiency and in evaluating response to therapy, are largely accountable for delays in accepting low magnesium as an important contributor to morbidity and mortality, and in attempting to correct it. Now that clinically available means to determine ionic magnesium levels are more widely available, the substantial knowledge of the importance of diagnosing magnesium deficiency in patients, determining the effects of drugs that affect its levels, and ascertaining success in its repletion. should be increasingly applied to patient care.

Mildred Seelig, MD, MPH, MACN
Atlanta, GA

Burton M. Altura, PhD, FACN
SUNY Health Science Center at Brooklyn
Brooklyn, NY


1. Bortz Costello R, Moser-Veillon PB, DiBianco R: Magnesium supplementation in patients with congestive heart failure. J Am Coll Nutr 16:22-31, 1997.

2. Flink EB, Stutzman FL, Anderson AR, Konig T, Fraser R: Magnesium deficiency after prolonged parenteral fluid administration and after chronic alcoholism complicated by delirium tremens. J Lab Clin Med 43:169-183, 1954.

3. Elin RJ: Assessment of magnesium status. In Itokawa y, Durlach J (eds): "Magnesium in Health and Disease." London: J. Libbey, pp 137-146, 1989.

4. Altura BM, Altura BT: Magnesium in the cardiovascular biology. Sci Am 2:28-37, 1995.

5. Fitzgerald MG, Fourman P: An experimental study of magnesium deficiency in man. Clin Sci 15:635 647, 1956.

6. Dyckner T, Wester PO: Magnesium deficiency-guidelines for diagnosis and substitution therapy. Acta Med Scand (Suppl) 661: 37-41, 1982.

7. Gullestad L, Dolva LO, Waage A, Falch D, Fagerthun H, Kjekshus J: Magnesium deficiency diagnosed by an intravenous loading test. Scand J Clin Lab Invest 52:245-253, 1992.

8. Rasmussen HS, McNair P, Goransson L, Balslav S, Larsen OG, Aurup P: Magnesium deficiency in patients with ischemic heart disease with or without acute myocardial infarction uncovered by an intravenous loading test: Arch Intern Med: Feb., 1988.

9.-31. We are missing these references.

Journal of the American College of Nutrition, Vol. 16, No.1, 4-6 (1997)
Published by the American College of Nutrition

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