Ionic biology and ionic medicine in cardiac arrhythmias with particular reference to magnesium Lloyd T. Iseri, MD,? Byron J. Allen, MD, Mark L. Ginkel, Michael A. Brodsky, MD. Orange, Calif. In this day and age, when so much advancement is being made in molecular biology, we tend to lose sight of the importance of basic ions in clinical medicine. This report deals with the concept of ionic biology involving Na+, K+, Ca++, and Mg++ ions with respect to the membrane and action potential of cardiac cells in the genesis of tachyarrhythmias. Various clinical disorders leading to arrhythmias will be examined as examples of ionic medicine, and treatment protocols will be recommended according to these concepts. Basic concepts. The cell membrane separates the various ions, and the concentrations of these ions vary considerably outside and inside the cell. Naf and K+ are fully ionized so that their concentrations represent their total ionic concentrations. Ca++ and Mg++, on the other hand, form complexes with proteins, organic acids, and phosphates so that their total extracellular and intracellular concentrations do not represent their ionic concentrations. The extracellular concentration of Na+ is as high as 140 mmol/L, whereas the intracellular concentration is only about 10 to 20 mmol/L. The reverse is true of K+. Extracellular K+ is approximately 4 mmol/L, whereas intracellular K+ is approximately 140 mmol/L. More than half of serum Ca++ is complexed so that its ionic strength is only about 1.3 mmol/L (5.2 mg/ dl). This extracellular Ca++ concentration, however, is still much greater than the micromolar (0.1 pmol/L) ionic concentration inside the cell. It is interesting to note that an ionic Mg++ concentration of 0.5 mmol/L (1.2 mg/dl) is approximately the same outside and

From

the University

Received

Reprint requests: College of Medicine, CA 92668. TDeceased. 4/1/36980

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of CaIiiornia,

for publication

Irvine

Oct. 24, 1991;

College accepted

Michael Brodsky, MD, Division of Cardiology,

of Medicine. Dec.

University 101 City

10, 1991. of California, Drive South,

Irvine Orange,

MD, and

inside the cell even though the total extracellular magnesium concentration is approximately 0.8 mmol/L (2.0 mg/dl) and the total intracellular magnesium level, is approximately 15 mmol/L (36 mg/dl). The Na+ gradient is maintained solely by the magnesium-dependent Naf-K+-adenosine triphosphatase (ATPase) enzyme system. The K+ gradient is maintained by the same enzyme system and the Mg++-controlled Na:K:Cl and KC1 cotransport and K transport systems.l The Ca++ gradient is maintained by the magnesium-dependent Ca++-ATPase enzyme and Na+-Ca++ exchange systems.i Although there is no appreciable gradient of Mg++ ions across the cell membrane, the ultimate intracellular concentration of total and ionic Mg++ is controlled by cytoplasmic buffering systems such as adenosine triphosphate and 2,3-diphosphog1ycerate.i In addition, there is some evidence that a Mg++ transport system exists to maintain a low rate of efflux.2 Normal cardiac rhythm is initiated by spontaneous depolarization of negatively charged sinus node cells, which apparently results from a slow inward current carried by an influx of sodium and calcium ions.3 This depolarization then spreads rapidly through the atria, slowly through the atrioventricular node, and rapidly again through the His-Purkinje system and the ventricles inscribing characteristic action potentials along the way. The resting membrane potential (phase 4) of a cardiac cell is negatively charged primarily as a result of flow of K+ ions from high intracellular to low extracellular levels. This negativity (-90 mV) is then abruptly decreased by the arrival of a depolarization wave. When a threshold of -60 mV is exceeded, sodium channels open and Na+ ions rush in to completely depolarize the cell. A small amount of Ca++ ions also rush in. This phase of the action potential is designated phase 0. In the Purkinje cell, depolarization may exceed neutrality, and a transient positive potential may be

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inscribed. This is quickly quenched, however, by the recently discovered transient outflow of K+ ions4 This phase is designated phase 1. During phase 2 or the plateau phase, electroneutrality is maintained by slow inflow of Ca++ and Na+ ions and limited outflow of K+ ions. This outflow of K+ ions has been shown recently to be inhibited by ATPase activity.5 Repolarization of the cells during phase 3 then takes place. This is accomplished by increasing the outflow of K+ and decreasing the inflow of Caf+ and Na+. During phase 4, sodium is expelled and cell potassium is replenished by the magnesium-dependent Na+-K+-ATPase enzyme system, the so-called “sodium pump.” Inasmuch as three Na+ ions are pumped out for every two Kf ions pumped in, extra Na+ ions can change places with Ca++ and allow Ca++ ions to be expelled.6 Additional Ca++ ions are removed from the cells by the Mg++-dependent Cat+-ATPase system. Thus although phase 4 appears quite stable, albeit negatively charged, considerable exchange of ions is taking place. It now becomes essential to correlate movements of Ca++, Na+, and Kf ions with development of tachyarrhythmias. Tachyarrhythmias can occur (1) by repetitive automatic or triggered impulses or (2) by reentrant circus movement. An automatic or a triggered impulse, whether single or multiple, may also initiate reentrant tachycardia by producing delayed asynchronous propagation of the impulse. Automatic impulses occur when rapid diastolic depolarization during phase 4 exceeds the threshold and incites the cell to depolarize. This rapid diastolic depolarization is seen in hypopotassemia. Hypopotassemia, contrary to the Nernst equation but consistent with the “constant field” equation of Goldman, Hodgkin, and Katz, decreases the resting membrane potential7 Triggered impulses occur when afterpotentials during phase 4 or late phase 3 exceed the threshold. These afterpotentials are created by hypomagnesemia, which apparently allows Ca++ ions to enter the cells.8 Afterpotentials are also created by phasic movement of ionic calcium in and out of the sarcoplasmic reticulum.g It would appear from the data reported thus far that a decrease in Mg++ ions can induce triggered ectopic impulses, and a decrease in K+ ions can delay conduction of these impulses to set up reentrant tachycardia. Although it is beyond the scope of this discussion, the possibility that magnesium deficiency might induce coronary spasm and create an ischemic environment for ionic imbalance should also be considered.iO Clinical observations. Usually but not always tachyarrhythmias occur in diseased hearts. Disease pro-

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cesses such as ischemia, infarction, fibrosis, myocardial failure, inflammation, hypertrophy, and dilatation, as well as drugs and metabolites, make the heart susceptible to ionic imbalance by virtue of their effect on regeneration of adenosine triphosphate, which is essential to maintain that balance. Furthermore, these disease processes may cause aberrations in conduction and dispersion of refractoriness so that reentry tachycardia can occur with minimal disruption of ionic balance. In acute myocardial infarction and ischemia, the frequency of ventricular tachycardia is inversely correlated with serum K+ levels.li Of interest is the observation that intravenous potassium replacement does not always suppress these malignant arrhythmias.ii In contrast to the regularity with which hypopotassemia is found in acute myocardial infarction, hypomagnesemia does not seem to occur consistently. Kafka et a1.,12 in a study of 211 cases of acute myocardial infarction, found hypopotassemia in 59 % of patients and hypomagnesemia in only 6 % patients. Hypopotassemia and hypomagnesemia occurred together in only 8 of 211 (4%) patients, but most important all eight of these patients had ventricular tachycardia (VT) or ventricular fibrillation (W. Hypomagnesemia appears to develop after hospitalization in approximately 30% of patients with AMI. It is suspected that the acute stress of infarction results in release of catecholamines, which causes lipolysis and formation of free fatty acids.i3 The free fatty acids then remove the Mg++ from circulation by chelation. Experimentally epinephrine has been shown to reduce serum magnesium levels presumably through chelation with free fatty acids.14 From a therapeutic standpoint, the results of at least four double-blind randomized studies have now been reported to show that infusion of magnesium during the first 24 hours after acute myocardial infarction will reduce the development of VT and VF.i5-i8 Of 512 patients reported, 32% had tachyarrhythmias when given placebo and only 16% when given magnesium. Although specific use of K+ was not mentioned in the treatment protocols, most patients with hypopotassemia undoubtedly received K+ infusion. These studies therefore support the use of Mg++ and K+ in acute myocardial infarction. There have been numerous studies in which diuretics have caused K+ and Mg++ deficiency. The classical studies of Dyckner and Westerlgs 2o have shown that muscle analyses were often needed to demonstrate depletion of K+ and Mg++ after prolonged use of hydrochlorothiazide diuretics. They also showed that the number of VEB ectopic beats

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1.3

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1.0

4.2

16:34

2.5

4.0

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mEq/L I.H. 56 yr F Fig. 1. Effects of potassium(K) and magnesium(Mg) infusions in atrial fibrillation. (From Iseri LT, et al. Magnesium 1989;8:299.Reproduced with permission.)

(VEBs) was decreased markedly by Mg++ infusion and minimally by K+ infusion. When the sequence of Mg++ and K+ infusions was reversed, the final decrease in VEBs was essentially the same (75% vs 74% ).21Analysis of their data suggeststhat the combined use of Mg++ and K+ will certainly be more efficacious in controlling ventricular ectopy than K+ alone and probably more than Mg++ alone. Hollifield22 followed the serum potassium and magnesium levels in hypertensive patients treated with diuretics and counted the number of VEBs produced by a standard stress test. He found a significant correlation between the increased number of VEBs with change in serum potassium 1eveIs before and after treatment (r = 0.71, p < 0.001). He also found a significant correlation with change in serum magnesium levels (r = 0.68, p < 0.001). When changes in serum potassium and serum magnesium levels were multiplied, a better correlation (r = 0.81, p < 0.001) was found. He also found that replacement with potassium alone or with magnesium alone did not decrease the number of VEBs with exercise, but with both potassium and magnesium there was a definite decrease in VEBs. In our study of 10 patients with intractable ventricular tachyarrhythmias responding to intravenous Mg S04, four had torsades de pointes type of ventricular tachycardia. 23 Potassium infusion was inef-

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fective in controlling the rhythm even when serum potassium level was subnormal. Tzivoni et a1.24 reported on 12 patients with torsades de pointes, all responding to intravenous magnesium. Eight of their patients had subnormal serum potassium levels and were given potassium supplements “after” intravenous magnesium. The assumption is made that magnesium by itself was effective in controlling the rhythm. It is not clear from their report whether or not potassium supplements contributed to the outcome. The five cases of polymorphic VT with a normal QT interval that did not respond to magnesium had serum potassium levels ranging from 3.1 to 4.3 mEq/L (mean 3.7). Inasmuch as we have observed successful conversion of “torsades de pointes” type VT with a normal QT interval when magnesium and potassium were used together, the question arises as to whether or not magnesium and potassium used together would have aborted at least some of these arrhythmias.23 There is another potassium-magnesium relationship that we have observed in the past. In an alcoholic patient with hypomagnesemia with intractable VT and VF, we found that as we replaced magnesium and successfully aborted the recurrence of VT and VF, serum potassium levels declined progressively.25 Then in our prospective multifocal atria1 tachycardia studies, as magnesium was given serum potassium levels declined and control of multifocal atria1 tachycardia was rendered incomplete.26 When potassium supplements were also given a decrease in serum potassium levels was prevented and control of arrhythmia was made more effective. We believe that these patients were Mg++ and K+ depleted and Mg++ replacement helped K+ return to muscle cells. In other tachycardias such as atria1 fibrillation and atria1 flutter associated with hypomagnesemia and hypopotassemia, we have found that K+ replacement therapy alone was ineffective but K+ followed by Mgf+ was effective in controlling the rhythms.23 Fig. 1 shows atria1 fibrillation with a rapid ventricular rate in a patient recovering from an extensive burn. Serum magnesium and potassium levels were subnormal at 1.3 and 3.2 mEq/L, respectively. Treatment with potassium chloride raised the serum potassium level to 4.2 mEq/L but had no effect on the rapid atria1 fibrillation. Treatment with Mg SOc raised the serum magnesium level to 2.5 mEq/L and promptly converted the rhythm to a sinus mechanism. In another case of atria1 flutter with serum magnesium and potassium levels of 1.2 and 3.6 mEq/L, respectively, potassium infusion had no effect but magnesium infusion immediately corrected the arrhythmia. Numerous studies have shown that potassium de-

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pletion will precipitate toxic digitalis arrhythmia.27p 28 So far no conclusive evidence has been found that magnesium depletion will induce digitalis toxic arrhythmias, although in a group with arrhythmia, a higher frequency of hypomagnesemia has been noted.292 3o Although successful use of magnesium in chronic digitalis toxic tachycardia was reported many years ago,31y32 there have been no controlled studies in which Mg++ and K+ have been used concomitantly in this form of arrhythmia. In acute massive digitalis poisoning there is profound suppression of Na+-Kf-ATPase activity so that intracellular Kf pours out and threatens the patient with hyperpotassemia. Even though magnesium deficiency cannot be shown, infusion of large doses of magnesium will reverse the tendency for the serum Kf level to rise by driving K+ back into body cells and effectively controlling ventricular tachyarrhythmia. 33 This is one situation where K+ is contraindicated unless the serum Kf level is known to be subnormal. Inasmuch as concomitant deficiency of potassium and magnesium increases the frequency of tachyarrhythmia, and treatment with potassium and magnesium appears to be more effective than either alone, it would be appropriate to determine how often the two deficiencies occur together. Among hospitalized patients, approximately 40 % of hypopotassemia is associated with hypomagnesemia.34y 35 When magnesium levels in lymphocytes are examined, approximately 88% of patients with hypopotassemia show magnesium deficiency.36 In our multifactorial atria1 tachycardia study we found a significant correlation between the initial serum potassium and serum magnesium levels (r = 0.86)26 (Fig. 2). Others have found the same correlation in chronic cases.35T37 Prevention of tachyarrhythmias. Prevention of lifethreatening tachyarrhythmias should be of paramount importance in reducing the high incidence of sudden cardiac deaths (approximately 400,000 per year in the United States). It is apparent from this review that maintenance of ionic balance is essential not only in patients with known heart disease but also in normal persons who are under extreme physical and psychological stress. Because magnesium plays a key role in the maintenance of that balance, every effort should be made to prevent it’s deficiency. It has been stated that the average intake of magnesium in modern society is just sufficient to maintain a positive balance, and a minor shift in intake or output will result in a negative balance.38 Furthermore, casual and careless use of cathartics and diuretics, excessive consumption of alcohol, unsupervised crash diets for weight reduction, and unwise use of certain drugs

Ionic biology related to tachyarrhythmias

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Mg mEqlL

25

I 30

I 3.5

K

I LO mEqlL

see= 0.21 I 1 4.5 50

Fig. 2. Correlation of initial serum potassium (K) and magnesium (Mg) levels in multifocal atrial tachycardia. (From Iseri LT, et al. AM HEART J 1985;110:789.)

may cause magnesium depletion in unsuspecting persons.23 A variety of chronic disorders such as renal tubular disease, cardiac, pulmonary, and hepatic failure, steatorrhea, diabetes, and hyperthyroidism may deplete magnesium stores and suddenly cause a critical arrhythmia. 23 Just how much influence potassium depletion per se contributes to the total picture is difficult to assess, but since it is well established that magnesium deficiency itself may lead to potassium depletion,20 inadequate intake or excessive urinary or gastrointestinal loss of this element concurrently will compound the problem. Perhaps the most common iatrogenic cause of magnesium and potassium depletion is the use of common diuretics such as furosemide and hydrochlorothiazide. Use of these diuretics as a first-line treatment of hypertension and congestive heart failure should be questioned, and angiotensin converting enzyme inhibitors or aldosterone blockers such as spironolactone could be recommended instead. Because triamterene conserves both K+ and Mg++, combining this drug with hydrochlorothiazide (Dyazide, Maxide) might be considered appropriate. It must be cautioned, however, that when angiotensin converting enzyme inhibitors, aldosterone blockers, or triamterence are used by themselves, toxic retention of K+ and Mgs+ can occur. On the other hand, despite the combination of these drugs with hydrochlorothiazide and furosemide, loss of K+ and Mg++ may still occur. Chronic or recurrent stress, whether physical or psychological, may lead to loss of Kf and Mgs+ and some precautionary measures are advocated. With respect to acute stress, B-adrenergic blockade may reduce the effects of catecholamines on free fatty acid formation and prevent a decrease in the ionic magnesium concentration.

1408 her-i et al. Recognition, avoidance, and correction of these various factors leading to K+ and Mg++ depletion may prevent development of tachyarrhythmias. Oral supplementation with magnesium chloride or magnesium lactate tablets, amounting to 250 mg of elemental magnesium per day or more, together with a diet rich in magnesium (leafy green vegetables, nuts, beans, and seafood), may be adequate to maintain a positive balance. Any condition requiring more than the preceding measures (e.g., renal tubular disease or gastrointestinal fistula) may require weekly parentera1 supplementation. Tachyarrhythmias should also be anticipated in certain acute disorders such as diabetic ketoacidosis, acute pulmonary failure, congestive heart failure, and acute myocardial infarction, and measures should be undertaken to prevent ionic imbalance. Whang et a1.3g stressed the importance of routinely obtaining serum Mg++ levels in addition to K+ levels in all critically ill patients to identify those who are obviously K’ and Mg ++ deficient. It is predicted that when an ion-selective electrode becomes routinely available, not only would occult cases of magnesium deficiency be identified but Auctuations in ionic Mg++ concentrations in response to catecholamine stimulation would also be detected. Empiric infusion of K+ and Mg++ in acute myocardial infarction can be recommended in view of the favorable randomized studies reported thus far. It is suggested that 10 gm of MgS04 plus 40 mEq of potassium chloride infused over 10 hours during the first and second days after acute myocardial infarction may be helpful, provided there are no contraindications to these elements. Treatment of tachyarrhythmias. It is obvious that life-threatening tachyarrhythmias such as VF and hemodynamically compromised VT, whether polymorphic or monomorphic, should be treated with electrical therapy. If lidocaine or procainamide infusions fail to prevent a recurrence of VF or VT, magnesium therapy should be considered. Previous studies have shown that 2 to 3 gm of MgS04 (10 to 15 ml of 20% MgSOJ injected intravenously over 1 to 2 minutes and 10 gm of MgS04 (500 ml of 2 % MgS04) infused over 5 hours may be very helpfu1.25> 4o A second 10 gm over 10 hours may be necessary in selected cases. Deep tendon reflexes, blood pressure, heart rate, serum magnesium and potassium levels, and renal status should be monitored during the infusion. If the serum potassium level fall below 4.0 mMol/L, 40 mEq of potassium chloride should be added to the infusion. Conclusions. This review emphasizes the importance of Na+, K+, Ca++, and Mg++ in the maintenance of ionic balance across the cell membrane, de-

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velopment of action potentials, and propagation of normal cardiac impulses. Deficiency of K+ causes partial diastolic depolarization as a result of decreased egress of intracellular K+, and deficiency of Mg++ causes afterpotentials as a result of inflow of Ca++ and Na+ ions. In both situations spontaneous depolarization can occur when the threshold is exceeded. The velocity of depolarization, however, is markedly reduced because of the prior partial diastolic depolarization. This leads to delayed conduction, which in turn induces reentry tachycardia. Various clinical conditions frequently complicated by tachyarrhythmias are examined from the standpoint of ionic balance, and prevention and treatment protocols are presented. We thank Michelle Guyer for her valuable contributions preparation of this manuscript.

in the

REFERENCES

1. Flatman PW. Magnesium and ion transport in red cells. In: Itokawa Y, Durlach J, eds. Magnesium in health and disease. London: JL Libbey, 1989. 2. Beyenbach KW. Transport of magnesium across biological membran 3s. Magnes Trace Elem 1990;9:233-54. 3. Jordan JL, Mandel WJ. Disorders of sinus function. In: Mande1 WJ, ed. Cardiac arrhythmias. Philadelphia: JB Lippincott, 198Oz108. 4. Kenyon JL, Gibbons WR. Effects of low chloride solutions on action potentials in cardiac Purkinje fibers. J Physiol (Lond) 1969;200:205-9. 5. Horie M. Role of intracellular magnesium ions in the regulation of mammalian cardiac potassium channels. In: Itokawa Y, Durlach J, eds. Magnesium in health and disease. London: JL Libbey & Company, 198985-42. 6. Pitts BJR, Eatman ML. ‘t’he heart and cellular potassium fluxes. In: Whang R, ed. Potassium: Its biologic significance. Boca Raton. Fla: CRC Press. 1983:109-18. 7. Gadsby DC,‘Wit AL. Normal’and abnormal electrophysiology of cardiac cells. In: Mandel WJ, ed. Cardiac arrhythmia. Philadelphia: JB Lippincott, 1980:56. 8. Roden DM, Iansmith DHS. Effects of low potassium and magnesium concentrations on isolated cardiac tissue. Am J Med 1987;82(suppl 3A):18-23. 9. Kass RS, Lederer WJ, Tsien RW, Weingart R. Role of Ca ions in transient in ward current and aftercontractions induced by strophanthidin in cardiac Purkinje fibers. J Physiol (Lond) 1978;281:187-208. 10. Friedman HS. Coronary vasospasm and its relationship to magnesium deficiency. Magnesium 1982;1:81-3. 11. Solomon RJ. Ventricular arrhythmias in patients with myocardial infarction and ischemia: relationship to serum potassium and magnesium. Drugs 1984;28(suppl-1):66-76. 12. Kafka H. Lanaren L. Armstrong PW. Serum Me and K in acute mybcard&rl infarction. ArchIntern Med 198?;147:465-9. 13. Flink EB, Brick JE, Shane SR. Alterations of long-chain free fatty acid and magnesium concentrations in acute myocardial infarction. Arch Intern Med 1981;141:441-3. 14. Ryzen E, Servis KL, Rude RK. Effect of intravenous epinephrine on serum magnesium and free intracellular red blood cell magnesium concentrations measured by nuclear magnetic resonance. J Am Co11 Nutr 1990$114-9. 15. Smith LF, Heagerty AM, Bing RF, Barnett OB. Intravenous infusion of magnesium sulfate after acute myocardial infarction: effects on arrhythmias and mortality. Int J Cardiol 1986;12:175-80.

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16. Rasmussen HS, McNair P, Norregard P, Backer S, et al. Magnesium infusion in acute myocardial infarction. Lancet 1986;1:234-6. 17. Abraham AS. Rosenmann D. Kramer M, et al. Magnesium in the prevention of lethal arrhythmias in acute myocardial infarction. Arch Intern Med 1987;147:753-5. 18. Schecter M, Hod H, Monks N, et al. Magnesium therapy and mortality in acute myocardial infarction. Eur Heart J 1986;9:226-31. T. Wester PO. Extra-and intra cellular potassium 19. Dvckner and magnesium, diuretics, and arrhythmias. In: Whang R, ed. Potassium: Its biologic significance. Boca Raton, Fla: CRC Press, 1983:137-54. 20. Dyckner T, Wester PO. Potassium/magnesium depletion in patients with cardiovascular disease. Am J Med 1987;82(suppl 3A):ll-7. 21. Dyckner T, Wester PO. Ventricular extrasystoles and intracellular electrolytes before and after potassium and magnesium infusion in patients on diuretic treatment. AM HEART J -_I

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-,

1979;97:12-8. JW. Potassium and magnesium abnormalities: di22. Hollifield uretic and arrhythmias in hypertension. Am J Med 1984;77(suppl):28-32. 23. Iseri LT, Allen BJ, Brodsky MA. Magnesium therapy of cardiac arrhythmias in critical care medicine. Magnesium 1989;8:299-306. 24. Tzivoni D, Banai S, Schuger C, et al. Treatment of torsade de pointes with magnesium sulfate. Circulation 1988;77:392-7. 25. Iseri LT, Freed J, Bures AR. Magnesium deficiency and cardiac disorders. Am J Med 1975;58:837-46. 26. Iseri LT, Fairshter RD, Hardemann JL, Brodsky MA. Magnesium and potassium therapy in multifocal atrial tachycardia. AM HEARTJ 1985;110:789-94. glycosides. N Engl J Med 1973;288:71927. Smith TW. Digitalis

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28. Mason DT. Digitalis pharmacology and therapeutics: recent advances. Ann Intern Med 1974;80:520-30. WH, Wacker 29. Beller GA, Hood Jr WB, Smith TW, Abelmann EE. Correlation of serum Mg levels and cardiac digitalis intoxication. Am J Cardiol 197+33:225-g. 30. Singh RB, Dube KP, Srivastar PK. Hypomagnesemia in relation to digoxin intoxication in children. AM HEARTJ

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L. Magnesium and the heart. Klin Wochenschr 31. Zwillinger 1935;14:1429-33. caused by digitalis. 32. Szekely P, Wynne NA. Cardiac arrhythmia Clin Sci 1951;10:241-53. JH, Thomas RG, Siskind AP, Iseri LT. Magnesium 33. French therapy in massive digoxin intoxication. Am J Emerg Med 1984;13:562-6. A, et al. Predictors 34. Whang R, Oei TO, Aikawa JK, Watanabe of clinical hypomagnesemia, hypokalemia, hypophosphatemia, hyponatremia, and hypocalcemia. Arch Intern Med 1984;144:1794-6. 35. Boyd JC, Bruns DE, Willis MR. Frequency of hypomagnesemia in hypokalemic states. Clin Chem 1983;29:178-9. 36. Ryzen E, Elkayam U, Rude RKL. Low blood mononuclear cell magnesium in intensive cardiac care unit patients. AMHEART J 1986;111:475-80. 37. Boyd JC, Bruns DE, Dimarco JP, Sugg NK, Wills MR. Relationship of potassium and magnesium concentrations in serum to cardiac arrhythmias. Clin Chem 1984,30:754-7. 38 Seelig M. Magnesium deficiency in the pathogenesis of disease. New York: Plenum Medical. 1980. 39. Whang R, Oei TO, Watanabe’ A. Frequency of hypomagnesemia in hospitalized patients receiving digitalis. Arch Intern Med 1985;145:655-6. MA, Capparelli EV, Luckett CR, Iseri LT. 40. Allen BJ, Brodsky Magnesium sulfate therapy for sustained monomorphic ventricular tachycardia. Am J Cardiol 1989;64:1202-4.