Editorial
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
REFERENCES
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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