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Hypomagnesemia in relation to digoxin intoxication in children
Hypomagnesemia in relation to digoxin intoxication in children R. B. Singh, B.Sc., M.D. K. P. Dube, B.Sc., M.D. P. K. Srivastav, M.D., D.C.H. Varanasi, India
Recently, an increased prevalence of hypomagnesemia has been demonstrated in patients treated with digitalis and diuretics. 1-4 Hypomagnesemia decreases intracellular myocardial potassium content and sensitizes it to the effects of digoxin2. ~ However, low serum magnesium level directly may also be responsible for the increased risk of digoxin intoxication among these patients. Therefore, magnesium sulfate may be used for the management of digoxin toxicity in patients associated with hypomagnesemia. 7 These observations made in experimental animals and adult patients prompt us to re-evaluate the serum magnesium concentrations in children treated with digoxin and diuretics. Material and methods
This prospective study was conducted in the Medical Wards of the University Hospital, Varanasi, India, from January, 1972, to June, 1973. Only those 19 children were included in this study who were receiving Lanoxin brand of digoxin (Burroughs Wellcome and Company). Serum magnesium estimation was done by the method of Andreason s after at least 1 week of digitalization and diuretic therapy. Patients with rheumatic heart disease (16 cases~ were on prolonged therapy with digoxin and diuretics. Serum magnesium values were obtained in 18 healthy children for controls. Serum digoxin estimation was done by radioimmunoassay? Other laboratory data. e.g., blood urea, serum creatinine, sodium, potassium, chloFrom the Department of Medicine. Institute of Medical Sciences, Benaras Hindu University, Varanasi. India. Received for publication May 27. 1975. Reprint requests: Dr. R. B. Singh, 24. Civil Lines, Moradabad, U.P., India.
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ride, and calcium, were obtained b y standard methods. Clinical, radiological, electrocardiographic, and other necessary data were obtained to determine the cause and nature of heart failure. The criteria for the presence of digoxin intoxication were similar to those found by other investigators TM (Table I). Student's t test was employed for the analysis of data. Observations
Out o f 19 children ranging between 2 and 16 years age and weighing between 10 and 44 kilograms, 10 nontoxic ones (mean age, 10.1 _+ 4.74 years; mean body weight, 24.5 _ 10.0 kilograms) were receiving 0.4 _+ 0.27 (0.125 to 0.75) mg. per day of mean digoxin and the nine toxic ones (mean age, 12,1 _+ 3.75 years; mean body weight, 28.7 _ 8.9 kilograms) were receiving 0.47 _+ 0.25 (0.125 to 0.75) mg. per day of mean digoxin and 40 to 80 mg. per day of furosemide for control of heart failure. Most of the patients were receiving prophylactic, potassium chloride in a dosage of 15 grains three times a day (Table II). Clinical data were similar in both nontoxic and toxic patients. Degree, duration and manifestations of digoxin intoxication. Table II shows the degree of' digoxin toxicity in the form of electrocardiographically documented r h y t h m disturbances in nine toxic patients. Seven of them were associated with noncardiac symptoms of digoxin intoxication. The serum digoxin level in each individual patient was more than 2.5 ng. per milliliter, excluding one patient with Mobitz type II A-V block (Table V). The duration of digoxin toxicity in all the patients before therapy was 4 to 6 hours.
August, 1976, Vol. 92, No. 2, pp. 144-147
Hypomagnesemia a n d digoxin intoxication in children
Table I. C r i t e r i a for t h e p r e s e n c e o f d i g o x i n in-
Table II. C l i n i c a l d a t a in 19 c h i l d r e n r e c e i v i n g
toxication
digoxin and diuretics
Electrocardiographically documented sinus rhythm in all the patients before administration of digoxin, and complete resolution of any of the arrhythmias given below with discontinuation of digoxin including treated patients A. Ectopic ventricular rhythm: Multifocal ventricular ectopic beats Unifocal ventricular ectopic beats more than 5 per minute Ventricular bigeminy or trigeminy or tachycardia B. Nonparoxysmal atrioventricular (A-V) tachycardia A-V junctional escape rhythm and A-V junctional exit block C. A-V dissociation with ventricular rate exceeding atrial rate D. Atrial fibrillation with ventricular response less than 50 per minute if accompanied by ectopic ventricular beats E. Sinus rhythm with second- or third-degree A-V block F. Paroxysmal atrial tachycardia with A-V block
Serum magnesium. T h e m e a n s e r u m m a g n e s i u m c o n c e n t r a t i o n in 19 c h i l d r e n r e c e i v i n g d i g o x i n a n d d i u r e t i c s w a s l o w e r t h a n in 18 healthy control subjects. The magnesium levels w e r e f u r t h e r l o w e r e d w h e n m e a n v a l u e s in t o x i c and hypomagnesemic patients were compared w i t h t h o s e in h e a l t h y c o n t r o l s u b j e c t s ( T a b l e I V ) . M a g n e s i u m d e f i c i e n c y (less t h a n 1.5 m E q . p e r liter) w a s e n c o u n t e r e d in five o u t of n i n e t o x i c p a t i e n t s a n d in t h r e e o u t o f 10 n o n t o x i c subjects. Serum digoxin and dosage. T h e m e a n s e r u m d i g o x i n level in 10 n o n t o x i c c h i l d r e n w a s 2.24 • 0.46 (1.5 t o 2.8) ng. p e r m i l l i l i t e r a n d in n i n e t o x i c o n e s i t w a s 4.4 • 2.51 (1.3 t o 10.1) ng. per milliliter. The difference was statistically s i g n i f i c a n t (P < 0.05) b u t t h e r e w a s n o s i g n i f i c a n t d i f f e r e n c e in d o s a g e s c h e d u l e s b e t w e e n t h e t w o groups. Other laboratory data. Mean concentrations of other laboratory data did not show much abnormality (Table III). Serum sodium and chloride were s l i g h t l y l o w e r e d . M e a n b l o o d u r e a w a s s i g n i f i c a n t l y h i g h e r ( P < 0.05) i n t h e t o x i c g r o u p (40.6 • 15.3 mg. p e r 100 m l . ) a s c o m p a r e d t o n o n t o x i c p a t i e n t s (28.7 • 7.0 mg. p e r 100 m l . ) a n d t h i s m a y be t h e c a u s e of h i g h e r d i g o x i n l e v e l s in toxic patients. Management. P o t a s s i u m c h l o r i d e o r a l l y a n d m a g n e s i u m s u l f a t e i n t r a v e n o u s l y w e r e u s e d for t h e m a n a g e m e n t of d i g o x i n t o x i c i t y .
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Age, 10 years and less Sex, male Class III and IV heart failure Other medications: F(lrosemide Prednisolone Potassium chloride Etiological diagnosis: Rheumatic heart disea~ Congenital heart disease Cardiomyopathy Risk factors: Subacute bacterial endocarditis Acute rheumatic carditis Sinus rhythm Toxic manifestations (9 cases): Extracardiac Cardiac: Ventricular bigeminy or trigeminy Multifocal ventricular ectopic beats Second-degree (Mobitz type I[) A-V-block Deaths
i Percent 7 14 10
36.8 73.6 52.6
13 4 13
68.4 21.0 68.4
16 2 1
84.2 10.5 5.2
1 5 19
5.2 26.3 100.0
7
36.8
3 2 4
15.7 10.5 21.5
-
-
Table III. L a b o r a t o r y d a t a in 19 c h i l d r e n r e c e i v i n g digoxin
Datum
Blood urea (mg./1O0 ml.) Serum creatinine (mg./100 ml.) Serum sodium (mEq./L.) Serum potassium (mEq./L.) Serum chloride (mEq/L.) Serum calcium (rag./100 ml.)
Normal
Mean +_S.D. (range)
20-40
34.3 +_ 1 2 . 9
(18-75)
0.6-1.2
1.03 _+ 0 . 1 7
(0.8-1.5)
120-135
123 _+ 6.4
(112-133)
3.5-5.0
4.0 - 0 . 3 9
(3.5-4.8)
85-110
90.8 • 5.6
(80-102)
9.0-11.0
9.6 • 0 . 4 1
(9.0-10.4)
D i g o x i n a n d d i u r e t i c s w e r e s t o p p e d in a l l t h e p a t i e n t s as s o o n a s t o x i c i t y w a s d e t e c t e d . N o specific a n t i a r r h y t h m i c drug was given to patients with Mobitz type II A-V block. In three p a t i e n t s w h o h a d h y p o m a g n e s e m i a 10 to 20 ml. o f 20 p e r c e n t m a g n e s i u m s u l f a t e w a s a d m i n i s t e r e d s l o w l y i n t r a v e n o u s l y in 10 t o 25 m i n u t e s . I n t w o cases a r r h y t h m i a s d i s a p p e a r e d w i t h i n 15 m i n u t e s a n d in one a f t e r 30 m i n u t e s o f i n f u s i o n of m a g n e s l u m s u l f a t e ( T a b l e V). I n t w o p a t i e n t s w h o h a d
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Singh, Dube, and Srivastav
Table IV. S e r u m m a g n e s i u m levels in different
groups of controls
patients
in
relation
to
Table V. Results of t r e a t m e n t in toxic )atients
healthy Serum levels
Various groups Healthy controls
Number Mean• (ng/ml) Range P value
Total
Toxic
Hypomagnesemic
18 19 9 8 1.76 + 0.13 1.58 • 0.24 1.5 _+ 0.20 1.36 _+ 0.05 1.5-2.1 -
1.3-2.1 < 0.01
1.3-1.8 < 0.001
1.3-1.4 < 0.001
no magnesium deficiency potassium chloride orally in double the dosage (30 grains thrice daily) was continued. M u c h more time was required by these patients t h a n by m a g n e s i u m - t r e a t e d ones for the disappearance of cardiac a r r h y t h m i a s (Table V). Discussion
It is known t h a t dosages of digitalis and therapeutic serum digoxin c o n c e n t r a t i o n s vary from patient to patient. T h e y m a y also v a r y from time to time in the same patient, the cause being electrolyte disturbances, metabolic alterations, drugs, hormones, and a u t o n o m i c influences which m a y influence the u p t a k e of digoxin and m a y render the m y o c a r d i u m more sensitive to the effects of drug21 T o the c o n t r a r y , some p a t i e n t s (e.g., children) tolerate a relatively higher digoxin concentration as compared to a d u l t s Y However, this property of children's m y o c a r d i u m m a y be 10st in the presence of h y p o k a l e m i a and h y p o magnesemia sensitizing it to the toxic effects of digoxin, 7 ':~ Similarly, renal insufficiency as a risk of toxicity has been observed by m a n y investigators. TM. . . . . :' The dosage of digoxin should be reduced because the drug is n o t excreted. I t is interesting to note t h a t the m e a n serum digoxin concentration in toxic patients of this s t u d y was significantly higher t h a n in nontoxic ones, b u t there was no significant difference in the m e a n dosage of digoxin between the two groups. T h e cause m a y be t h a t renal functions in the toxic patients were impaired (mean blood urea, 40.6 _+ 15.3 mg. per 100 ml.). H y p o k a l e m i a was not found in our patients as most of t h e m were receiving p r o p h y l a c t i c potassium chloride along with diuretics. However,
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No. rhythm
Dig. K Mg (ng./ (mEq. (mEq. ml.) / L.) / L.) Treatment
Magnesium sulfate Magnesium sulfate Potassium chloride Magnesium sulfate
Duration of therapeutic response
1. Bigeminy
2.6
4.6
1.3
15 min.
2. Bigeminy
3.2
4.8
1.3
3. Trigeminy
3.9
3.8
1.7
4. Multifocal ectopic beats 5. Multifocal ectopic beats 6. Mobitz type II A-V block 7. Mobitz type II A-V block 8. Mobitz type II A-V block 9. Mobitz type II A-V block
3.0
4.2
1.4
10.1
3.8
1.8
Potassium chloride
12 hr.
1.3
3.9
1.4
No specific treatment
24 hr.
4.8
4.0
1.7
No specific treatment
8 hr.
4.9
4.0
1.6
No specific treatment
12 hr.
3.2
4.2
1.3
No specific treatment
10 hr.
10 min. 8 hr. 30 min.
magnesium deficiency was quite fl'equent (eight out of 19 children). M e a n serum m a g n e s i u m concentration was significantly lowered (P < 0.01) in 19 children and it was f u r t h e r diminished in toxic patients (nine cases) as well as in hypomagnesemic patients (eight cases) t h a n healthy controls (Table IV). Five of nine toxic patients had frank h y p o m a g n e s e m i a (serum magnesium < 1.5 mEq. per liter). These observations confirm the previously held view t h a t h y p o magnesemia is highly prevalent in a d u l t patients treated with digoxin and diuretics and also in those who had digoxin toxicity. 1-4 It is likely t h a t magnesium defficiency has predisposed these patients to digoxin intoxication. The mechanism could be t h a t digitalis inhibits cell m e m b r a n e adenosine t r i p h o s p h a t a s e (ATPase) activity, resulting in decreased intracellular potassium, and m a g n e s i u m is a m e t a l l o - c o e n z y m e that activates ATPase. ~GI t is likely t h a t magneslum deficiency contributes digitalis-induced A T Pase blockade, resulting in a greater loss of intracellular potassium, G and sensitizes the m y o -
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Hypomagnesemia and digoxin intoxication in children
c a r d i u m to digitalis, i n c r e a s e s its u p t a k e , a n d i n d u c e s digoxin t o x i c i t y w i t h doses w h i c h a r e o r d i n a r i l y n o n t o x i c . 17-1~ T h e c a u s e of m a g n e s i u m d e f i c i e n c y a m o n g t h e s e p a t i e n t s is p o s s i b l y i n c r e a s e d diuresis a n d m a g n e s u r i a . ~' 20 I n t h r e e p a t i e n t s w h o h a d m a g n e s i u m deftciency, a r r h y t h m i a s d i s a p p e a r e d w i t h m a g n e s i u m s u l f a t e t h e r a p y ( T a b l e V). I t is l i k e l y t h a t m a g n e sium a d m i n i s t r a t i o n resulted in a rapid decrease in arterial p o t a s s i u m c o n c e n t r a t i o n , i n d i c a t i n g t h a t t h e r e is a c e l l u l a r u p t a k e of p o t a s s i u m . T h i s effect of m a g n e s i u m s u l f a t e m a y be o n e of t h o s e overcoming the ATPase inhibition induced by digitalis b e c a u s e w h e n it is a d m i n i s t e r e d a l o n e it does n o t c a u s e a n i n f l u x of m y o c a r d i a l p o t a s sium.6, 7 A t t h e e n d it s h o u l d be n o t e d t h a t h y p o m a g n e s e m i a is very c o m m o n i n c h i l d r e n r e c e i v i n g digoxin a n d d i u r e t i c s a n d t h a t p a t i e n t s w i t h m a g n e s i u m deficiency are p r e d i s p o s e d t o a h i g h e r risk of d i g o x i n toxicity. M a g n e s i u m r e p l a c e m e n t m a y b e preferred a m o n g t h e s e p a t i e n t s for t h e m a n a g e m e n t of d i g o x i n - i n d u c e d c a r d i a c a r r h y t h mias.
Summary S e r u m m a g n e s i u m e s t i m a t i o n w a s d o n e i n 19 c h i l d r e n who h a d h e a r t f a i l u r e of v a r i e d etiology. Five of n i n e toxic p a t i e n t s a n d t h r e e of 10 n o n toxic ones h a d m a g n e s i u m d e f i c i e n c y ( s e r u m m a g n e s i u m < 1.5 m E q . p e r liter). M e a n s e r u m m a g n e s i u m level was s i g n i f i c a n t l y l o w e r e d (P < 0.01) i n 19 c h i l d r e n a n d it w a s f u r t h e r lowered i n n i n e toxic p a t i e n t s (P < 0.001) as well as i n e i g h t h y p o m a g n e s e m i c p a t i e n t s (P < 0.001) t h a n in healthy control subjects. M e a n serum digoxin level i n toxic p a t i e n t s w a s s i g n i f i c a n t l y h i g h e r t h a n i n n o n t o x i c ones (P < 0.05). I n t h r e e cases m a g n e s i u m s u l f a t e w a s s u c c e s s f u l l y u s e d for t h e m a n a g e m e n t of c a r d i a c a r r h y t h m i a s . The authors wish to express their gratitude to Dr. B. C. Katiyar for his invaluable help in the preparation of this article.
2. Jackson, C. E., and Meir, D. W.: Routine serum magnesium analysis, Ann. Intern. Med. 69:743, 1968. 3. Lim, P., and Jacob, P.: Magnesium deficiency in patients on long term diuretic therapy, for heart failure, Br. Med. J. 3:620, 1972. 4. Singh, R. B., Srivastav, D. K., Dube, S. S., Dube, K. P., and Vais, S. K.: Hypomagnesemia and digoxin therapy, J. Assoc. Phys. India 22:427, 1974. 5. Beller, G. A., Hood, W. B., Jr., Smith, T. W., Abelmann, W. H., and Wacher, W. E.: Prevalence of hypomagnesemia in a prospective clinical study of digitalis intoxication, Am. J. Cardiol. 26:625, 1970. 6. Seller, R. H., Casiano, J., Kim, K. E., Mendelsshon, S., Brest, A. N., and Swartz, C.: Digitalis toxicity and hypomagnesemia, AM. HEARTJ. 79:57, 1970. 7. Neff,M. S., Saul, M., Kim, K. E., Banach, S., Swartz, C., and Seller, R. H.: Magnesium sulphate in digitalis toxicity, Am. J. Cardiol. 29:377, 1972. 8. Andreason, E.: On the determination of magnesium in the serum and urine by titan yellow method, Scand. Clin. Lab. In-~est. 9:138, 1957. 9. Smith, T. W., Butler, V. P., Jr., and Haber, E.: Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassy, N. Engl. J. Med. 281:1212, 1969. 10. Beller, G. A., Smith, T. W., Abelmann, W. H., Haber, E,, and Hood, W. E.: Digitalis intoxication: clinical correlations with serum levels, N. Engl. J. Med. 284:989, 1971. 11. Singh, R. B., Vais, S. K., Rai, A. N., and Dube, K. P.: Risk factors of digoxin intoxication, J. Indian Med. Assoc. 64:36, 1975. 12. Neill, C. A.: The use of digitalis in infants and children, Prog. Cardiovasc. Dis. 7:399, 1965. 13. Seller, R. H.: The role of magnesium in digitalis toxicity, AM. HEARTJ. 82:551, 1971. 14. Johnston, C. L., Pinkus, N. B., and Down, M.: Plasma digoxin levels in digitalised and toxic patients, Med. J. Aust. 1:863, 1972. 15. Singh, R. B., Rai, A. N., Dube, K. P., Somani, P. N., and Katiyar, B. C.: Radioimmunoassay of serum digoxin levels in relations to digoxin intoxication, Br. Heart J. 37:619, 1975. 16. Dunham, E. T., and Glynn, I. M.: Adenosine triphosphatase activity and the active movements of the alkali metal ions, J. Physiol. (Lond.) 156:274, 1961. 17. Lown, B., and Levine, S. A.: Current concepts in digitalis therapy, N. Engl, J. Med. 250:771, 1954. 18. Harrison, C. E., Jr., and Brown, A. L., Jr.: Myocardial digoxin 3H content in experimental hypokalaemic cardiomyopathy, J. Lab. Clin. Med. 72:118, 1968. 19. Prindle, K. H., Skeleton, C. L., Epstein, S. E., and Marcus, F. I.: Influence of extracellular potassium concentration on myocardial uptake ionotropic effect of triated digoxin, Circ. Res. 28:337, 1971. 20. Hannah, S., Harrison, M., Macintyre, J., and Frager, R.: Syndrome of magnesium deficiency in *nan, Lancet 2:172, 1960.
REFERENCES 1. Seller, R. H., Ramireg, O., Brest, A. N., and Moyer, J. H.: Serum and erythrocyte magnesium levels in congestive heart failure,'Am. J. Cardiol. 17:786, 1966.
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Recently, an increased prevalence of hypomagnesemia has been demonstrated in patients treated with digitalis and diuretics. 1-4 Hypomagnesemia decreases intracellular myocardial potassium content and sensitizes it to the effects of digoxin2. ~ However, low serum magnesium level directly may also be responsible for the increased risk of digoxin intoxication among these patients. Therefore, magnesium sulfate may be used for the management of digoxin toxicity in patients associated with hypomagnesemia. 7 These observations made in experimental animals and adult patients prompt us to re-evaluate the serum magnesium concentrations in children treated with digoxin and diuretics. Material and methods
This prospective study was conducted in the Medical Wards of the University Hospital, Varanasi, India, from January, 1972, to June, 1973. Only those 19 children were included in this study who were receiving Lanoxin brand of digoxin (Burroughs Wellcome and Company). Serum magnesium estimation was done by the method of Andreason s after at least 1 week of digitalization and diuretic therapy. Patients with rheumatic heart disease (16 cases~ were on prolonged therapy with digoxin and diuretics. Serum magnesium values were obtained in 18 healthy children for controls. Serum digoxin estimation was done by radioimmunoassay? Other laboratory data. e.g., blood urea, serum creatinine, sodium, potassium, chloFrom the Department of Medicine. Institute of Medical Sciences, Benaras Hindu University, Varanasi. India. Received for publication May 27. 1975. Reprint requests: Dr. R. B. Singh, 24. Civil Lines, Moradabad, U.P., India.
144
ride, and calcium, were obtained b y standard methods. Clinical, radiological, electrocardiographic, and other necessary data were obtained to determine the cause and nature of heart failure. The criteria for the presence of digoxin intoxication were similar to those found by other investigators TM (Table I). Student's t test was employed for the analysis of data. Observations
Out o f 19 children ranging between 2 and 16 years age and weighing between 10 and 44 kilograms, 10 nontoxic ones (mean age, 10.1 _+ 4.74 years; mean body weight, 24.5 _ 10.0 kilograms) were receiving 0.4 _+ 0.27 (0.125 to 0.75) mg. per day of mean digoxin and the nine toxic ones (mean age, 12,1 _+ 3.75 years; mean body weight, 28.7 _ 8.9 kilograms) were receiving 0.47 _+ 0.25 (0.125 to 0.75) mg. per day of mean digoxin and 40 to 80 mg. per day of furosemide for control of heart failure. Most of the patients were receiving prophylactic, potassium chloride in a dosage of 15 grains three times a day (Table II). Clinical data were similar in both nontoxic and toxic patients. Degree, duration and manifestations of digoxin intoxication. Table II shows the degree of' digoxin toxicity in the form of electrocardiographically documented r h y t h m disturbances in nine toxic patients. Seven of them were associated with noncardiac symptoms of digoxin intoxication. The serum digoxin level in each individual patient was more than 2.5 ng. per milliliter, excluding one patient with Mobitz type II A-V block (Table V). The duration of digoxin toxicity in all the patients before therapy was 4 to 6 hours.
August, 1976, Vol. 92, No. 2, pp. 144-147
Hypomagnesemia a n d digoxin intoxication in children
Table I. C r i t e r i a for t h e p r e s e n c e o f d i g o x i n in-
Table II. C l i n i c a l d a t a in 19 c h i l d r e n r e c e i v i n g
toxication
digoxin and diuretics
Electrocardiographically documented sinus rhythm in all the patients before administration of digoxin, and complete resolution of any of the arrhythmias given below with discontinuation of digoxin including treated patients A. Ectopic ventricular rhythm: Multifocal ventricular ectopic beats Unifocal ventricular ectopic beats more than 5 per minute Ventricular bigeminy or trigeminy or tachycardia B. Nonparoxysmal atrioventricular (A-V) tachycardia A-V junctional escape rhythm and A-V junctional exit block C. A-V dissociation with ventricular rate exceeding atrial rate D. Atrial fibrillation with ventricular response less than 50 per minute if accompanied by ectopic ventricular beats E. Sinus rhythm with second- or third-degree A-V block F. Paroxysmal atrial tachycardia with A-V block
Serum magnesium. T h e m e a n s e r u m m a g n e s i u m c o n c e n t r a t i o n in 19 c h i l d r e n r e c e i v i n g d i g o x i n a n d d i u r e t i c s w a s l o w e r t h a n in 18 healthy control subjects. The magnesium levels w e r e f u r t h e r l o w e r e d w h e n m e a n v a l u e s in t o x i c and hypomagnesemic patients were compared w i t h t h o s e in h e a l t h y c o n t r o l s u b j e c t s ( T a b l e I V ) . M a g n e s i u m d e f i c i e n c y (less t h a n 1.5 m E q . p e r liter) w a s e n c o u n t e r e d in five o u t of n i n e t o x i c p a t i e n t s a n d in t h r e e o u t o f 10 n o n t o x i c subjects. Serum digoxin and dosage. T h e m e a n s e r u m d i g o x i n level in 10 n o n t o x i c c h i l d r e n w a s 2.24 • 0.46 (1.5 t o 2.8) ng. p e r m i l l i l i t e r a n d in n i n e t o x i c o n e s i t w a s 4.4 • 2.51 (1.3 t o 10.1) ng. per milliliter. The difference was statistically s i g n i f i c a n t (P < 0.05) b u t t h e r e w a s n o s i g n i f i c a n t d i f f e r e n c e in d o s a g e s c h e d u l e s b e t w e e n t h e t w o groups. Other laboratory data. Mean concentrations of other laboratory data did not show much abnormality (Table III). Serum sodium and chloride were s l i g h t l y l o w e r e d . M e a n b l o o d u r e a w a s s i g n i f i c a n t l y h i g h e r ( P < 0.05) i n t h e t o x i c g r o u p (40.6 • 15.3 mg. p e r 100 m l . ) a s c o m p a r e d t o n o n t o x i c p a t i e n t s (28.7 • 7.0 mg. p e r 100 m l . ) a n d t h i s m a y be t h e c a u s e of h i g h e r d i g o x i n l e v e l s in toxic patients. Management. P o t a s s i u m c h l o r i d e o r a l l y a n d m a g n e s i u m s u l f a t e i n t r a v e n o u s l y w e r e u s e d for t h e m a n a g e m e n t of d i g o x i n t o x i c i t y .
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oo um
i
Age, 10 years and less Sex, male Class III and IV heart failure Other medications: F(lrosemide Prednisolone Potassium chloride Etiological diagnosis: Rheumatic heart disea~ Congenital heart disease Cardiomyopathy Risk factors: Subacute bacterial endocarditis Acute rheumatic carditis Sinus rhythm Toxic manifestations (9 cases): Extracardiac Cardiac: Ventricular bigeminy or trigeminy Multifocal ventricular ectopic beats Second-degree (Mobitz type I[) A-V-block Deaths
i Percent 7 14 10
36.8 73.6 52.6
13 4 13
68.4 21.0 68.4
16 2 1
84.2 10.5 5.2
1 5 19
5.2 26.3 100.0
7
36.8
3 2 4
15.7 10.5 21.5
-
-
Table III. L a b o r a t o r y d a t a in 19 c h i l d r e n r e c e i v i n g digoxin
Datum
Blood urea (mg./1O0 ml.) Serum creatinine (mg./100 ml.) Serum sodium (mEq./L.) Serum potassium (mEq./L.) Serum chloride (mEq/L.) Serum calcium (rag./100 ml.)
Normal
Mean +_S.D. (range)
20-40
34.3 +_ 1 2 . 9
(18-75)
0.6-1.2
1.03 _+ 0 . 1 7
(0.8-1.5)
120-135
123 _+ 6.4
(112-133)
3.5-5.0
4.0 - 0 . 3 9
(3.5-4.8)
85-110
90.8 • 5.6
(80-102)
9.0-11.0
9.6 • 0 . 4 1
(9.0-10.4)
D i g o x i n a n d d i u r e t i c s w e r e s t o p p e d in a l l t h e p a t i e n t s as s o o n a s t o x i c i t y w a s d e t e c t e d . N o specific a n t i a r r h y t h m i c drug was given to patients with Mobitz type II A-V block. In three p a t i e n t s w h o h a d h y p o m a g n e s e m i a 10 to 20 ml. o f 20 p e r c e n t m a g n e s i u m s u l f a t e w a s a d m i n i s t e r e d s l o w l y i n t r a v e n o u s l y in 10 t o 25 m i n u t e s . I n t w o cases a r r h y t h m i a s d i s a p p e a r e d w i t h i n 15 m i n u t e s a n d in one a f t e r 30 m i n u t e s o f i n f u s i o n of m a g n e s l u m s u l f a t e ( T a b l e V). I n t w o p a t i e n t s w h o h a d
145
Singh, Dube, and Srivastav
Table IV. S e r u m m a g n e s i u m levels in different
groups of controls
patients
in
relation
to
Table V. Results of t r e a t m e n t in toxic )atients
healthy Serum levels
Various groups Healthy controls
Number Mean• (ng/ml) Range P value
Total
Toxic
Hypomagnesemic
18 19 9 8 1.76 + 0.13 1.58 • 0.24 1.5 _+ 0.20 1.36 _+ 0.05 1.5-2.1 -
1.3-2.1 < 0.01
1.3-1.8 < 0.001
1.3-1.4 < 0.001
no magnesium deficiency potassium chloride orally in double the dosage (30 grains thrice daily) was continued. M u c h more time was required by these patients t h a n by m a g n e s i u m - t r e a t e d ones for the disappearance of cardiac a r r h y t h m i a s (Table V). Discussion
It is known t h a t dosages of digitalis and therapeutic serum digoxin c o n c e n t r a t i o n s vary from patient to patient. T h e y m a y also v a r y from time to time in the same patient, the cause being electrolyte disturbances, metabolic alterations, drugs, hormones, and a u t o n o m i c influences which m a y influence the u p t a k e of digoxin and m a y render the m y o c a r d i u m more sensitive to the effects of drug21 T o the c o n t r a r y , some p a t i e n t s (e.g., children) tolerate a relatively higher digoxin concentration as compared to a d u l t s Y However, this property of children's m y o c a r d i u m m a y be 10st in the presence of h y p o k a l e m i a and h y p o magnesemia sensitizing it to the toxic effects of digoxin, 7 ':~ Similarly, renal insufficiency as a risk of toxicity has been observed by m a n y investigators. TM. . . . . :' The dosage of digoxin should be reduced because the drug is n o t excreted. I t is interesting to note t h a t the m e a n serum digoxin concentration in toxic patients of this s t u d y was significantly higher t h a n in nontoxic ones, b u t there was no significant difference in the m e a n dosage of digoxin between the two groups. T h e cause m a y be t h a t renal functions in the toxic patients were impaired (mean blood urea, 40.6 _+ 15.3 mg. per 100 ml.). H y p o k a l e m i a was not found in our patients as most of t h e m were receiving p r o p h y l a c t i c potassium chloride along with diuretics. However,
146
No. rhythm
Dig. K Mg (ng./ (mEq. (mEq. ml.) / L.) / L.) Treatment
Magnesium sulfate Magnesium sulfate Potassium chloride Magnesium sulfate
Duration of therapeutic response
1. Bigeminy
2.6
4.6
1.3
15 min.
2. Bigeminy
3.2
4.8
1.3
3. Trigeminy
3.9
3.8
1.7
4. Multifocal ectopic beats 5. Multifocal ectopic beats 6. Mobitz type II A-V block 7. Mobitz type II A-V block 8. Mobitz type II A-V block 9. Mobitz type II A-V block
3.0
4.2
1.4
10.1
3.8
1.8
Potassium chloride
12 hr.
1.3
3.9
1.4
No specific treatment
24 hr.
4.8
4.0
1.7
No specific treatment
8 hr.
4.9
4.0
1.6
No specific treatment
12 hr.
3.2
4.2
1.3
No specific treatment
10 hr.
10 min. 8 hr. 30 min.
magnesium deficiency was quite fl'equent (eight out of 19 children). M e a n serum m a g n e s i u m concentration was significantly lowered (P < 0.01) in 19 children and it was f u r t h e r diminished in toxic patients (nine cases) as well as in hypomagnesemic patients (eight cases) t h a n healthy controls (Table IV). Five of nine toxic patients had frank h y p o m a g n e s e m i a (serum magnesium < 1.5 mEq. per liter). These observations confirm the previously held view t h a t h y p o magnesemia is highly prevalent in a d u l t patients treated with digoxin and diuretics and also in those who had digoxin toxicity. 1-4 It is likely t h a t magnesium defficiency has predisposed these patients to digoxin intoxication. The mechanism could be t h a t digitalis inhibits cell m e m b r a n e adenosine t r i p h o s p h a t a s e (ATPase) activity, resulting in decreased intracellular potassium, and m a g n e s i u m is a m e t a l l o - c o e n z y m e that activates ATPase. ~GI t is likely t h a t magneslum deficiency contributes digitalis-induced A T Pase blockade, resulting in a greater loss of intracellular potassium, G and sensitizes the m y o -
A u g u s t , 1976, Vol. 92, No. 2
Hypomagnesemia and digoxin intoxication in children
c a r d i u m to digitalis, i n c r e a s e s its u p t a k e , a n d i n d u c e s digoxin t o x i c i t y w i t h doses w h i c h a r e o r d i n a r i l y n o n t o x i c . 17-1~ T h e c a u s e of m a g n e s i u m d e f i c i e n c y a m o n g t h e s e p a t i e n t s is p o s s i b l y i n c r e a s e d diuresis a n d m a g n e s u r i a . ~' 20 I n t h r e e p a t i e n t s w h o h a d m a g n e s i u m deftciency, a r r h y t h m i a s d i s a p p e a r e d w i t h m a g n e s i u m s u l f a t e t h e r a p y ( T a b l e V). I t is l i k e l y t h a t m a g n e sium a d m i n i s t r a t i o n resulted in a rapid decrease in arterial p o t a s s i u m c o n c e n t r a t i o n , i n d i c a t i n g t h a t t h e r e is a c e l l u l a r u p t a k e of p o t a s s i u m . T h i s effect of m a g n e s i u m s u l f a t e m a y be o n e of t h o s e overcoming the ATPase inhibition induced by digitalis b e c a u s e w h e n it is a d m i n i s t e r e d a l o n e it does n o t c a u s e a n i n f l u x of m y o c a r d i a l p o t a s sium.6, 7 A t t h e e n d it s h o u l d be n o t e d t h a t h y p o m a g n e s e m i a is very c o m m o n i n c h i l d r e n r e c e i v i n g digoxin a n d d i u r e t i c s a n d t h a t p a t i e n t s w i t h m a g n e s i u m deficiency are p r e d i s p o s e d t o a h i g h e r risk of d i g o x i n toxicity. M a g n e s i u m r e p l a c e m e n t m a y b e preferred a m o n g t h e s e p a t i e n t s for t h e m a n a g e m e n t of d i g o x i n - i n d u c e d c a r d i a c a r r h y t h mias.
Summary S e r u m m a g n e s i u m e s t i m a t i o n w a s d o n e i n 19 c h i l d r e n who h a d h e a r t f a i l u r e of v a r i e d etiology. Five of n i n e toxic p a t i e n t s a n d t h r e e of 10 n o n toxic ones h a d m a g n e s i u m d e f i c i e n c y ( s e r u m m a g n e s i u m < 1.5 m E q . p e r liter). M e a n s e r u m m a g n e s i u m level was s i g n i f i c a n t l y l o w e r e d (P < 0.01) i n 19 c h i l d r e n a n d it w a s f u r t h e r lowered i n n i n e toxic p a t i e n t s (P < 0.001) as well as i n e i g h t h y p o m a g n e s e m i c p a t i e n t s (P < 0.001) t h a n in healthy control subjects. M e a n serum digoxin level i n toxic p a t i e n t s w a s s i g n i f i c a n t l y h i g h e r t h a n i n n o n t o x i c ones (P < 0.05). I n t h r e e cases m a g n e s i u m s u l f a t e w a s s u c c e s s f u l l y u s e d for t h e m a n a g e m e n t of c a r d i a c a r r h y t h m i a s . The authors wish to express their gratitude to Dr. B. C. Katiyar for his invaluable help in the preparation of this article.
2. Jackson, C. E., and Meir, D. W.: Routine serum magnesium analysis, Ann. Intern. Med. 69:743, 1968. 3. Lim, P., and Jacob, P.: Magnesium deficiency in patients on long term diuretic therapy, for heart failure, Br. Med. J. 3:620, 1972. 4. Singh, R. B., Srivastav, D. K., Dube, S. S., Dube, K. P., and Vais, S. K.: Hypomagnesemia and digoxin therapy, J. Assoc. Phys. India 22:427, 1974. 5. Beller, G. A., Hood, W. B., Jr., Smith, T. W., Abelmann, W. H., and Wacher, W. E.: Prevalence of hypomagnesemia in a prospective clinical study of digitalis intoxication, Am. J. Cardiol. 26:625, 1970. 6. Seller, R. H., Casiano, J., Kim, K. E., Mendelsshon, S., Brest, A. N., and Swartz, C.: Digitalis toxicity and hypomagnesemia, AM. HEARTJ. 79:57, 1970. 7. Neff,M. S., Saul, M., Kim, K. E., Banach, S., Swartz, C., and Seller, R. H.: Magnesium sulphate in digitalis toxicity, Am. J. Cardiol. 29:377, 1972. 8. Andreason, E.: On the determination of magnesium in the serum and urine by titan yellow method, Scand. Clin. Lab. In-~est. 9:138, 1957. 9. Smith, T. W., Butler, V. P., Jr., and Haber, E.: Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassy, N. Engl. J. Med. 281:1212, 1969. 10. Beller, G. A., Smith, T. W., Abelmann, W. H., Haber, E,, and Hood, W. E.: Digitalis intoxication: clinical correlations with serum levels, N. Engl. J. Med. 284:989, 1971. 11. Singh, R. B., Vais, S. K., Rai, A. N., and Dube, K. P.: Risk factors of digoxin intoxication, J. Indian Med. Assoc. 64:36, 1975. 12. Neill, C. A.: The use of digitalis in infants and children, Prog. Cardiovasc. Dis. 7:399, 1965. 13. Seller, R. H.: The role of magnesium in digitalis toxicity, AM. HEARTJ. 82:551, 1971. 14. Johnston, C. L., Pinkus, N. B., and Down, M.: Plasma digoxin levels in digitalised and toxic patients, Med. J. Aust. 1:863, 1972. 15. Singh, R. B., Rai, A. N., Dube, K. P., Somani, P. N., and Katiyar, B. C.: Radioimmunoassay of serum digoxin levels in relations to digoxin intoxication, Br. Heart J. 37:619, 1975. 16. Dunham, E. T., and Glynn, I. M.: Adenosine triphosphatase activity and the active movements of the alkali metal ions, J. Physiol. (Lond.) 156:274, 1961. 17. Lown, B., and Levine, S. A.: Current concepts in digitalis therapy, N. Engl, J. Med. 250:771, 1954. 18. Harrison, C. E., Jr., and Brown, A. L., Jr.: Myocardial digoxin 3H content in experimental hypokalaemic cardiomyopathy, J. Lab. Clin. Med. 72:118, 1968. 19. Prindle, K. H., Skeleton, C. L., Epstein, S. E., and Marcus, F. I.: Influence of extracellular potassium concentration on myocardial uptake ionotropic effect of triated digoxin, Circ. Res. 28:337, 1971. 20. Hannah, S., Harrison, M., Macintyre, J., and Frager, R.: Syndrome of magnesium deficiency in *nan, Lancet 2:172, 1960.
REFERENCES 1. Seller, R. H., Ramireg, O., Brest, A. N., and Moyer, J. H.: Serum and erythrocyte magnesium levels in congestive heart failure,'Am. J. Cardiol. 17:786, 1966.
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