PEDIATRIC PHARMACOLOGY AND T H E R A P E U T I C S WilliamL. Nyhan, Editor, Harry C. Shirkey, Consultant
Digoxin intoxication in infants and children: Correlation with serum levels A study was made of serum digoxin levels, as determinedby radioimmunoassay, in twelve infants and four children with digitalis toxicity. Serum digoxin concentrations were significantly higher during digitalization than during maintenance therapy, but levels during digitalization did not differ between toxic and nontoxic infants. During maintenance therapy, however, the mean levels in intoxicated infants (3.6 ng. per milliliter and children (2. 9 ng. per milliliter) were significantly higher than those of nontoxic patients (1.7 and l. 1 ng. per mtTliliter, respectively). It was concluded that when properly obtained and interpreted, determination of the serum digoxin concentration is a useful proeedure for corroborating the diagnosis o f digitalis toxicity in pediatric patlents, as it is in adults.
Richard Krasula, Ruth Yanagi, Alois R. Hastreiter, Sidney Levitsky,* and Lester F. Soyka,** Chicago, Ill.
THE AVAILABILITY of radioimmunoassay methods for the measurement of digoxin, utilizing as little as 0.1 ml. of serum, makes possible the study of serum levels in infants. Such studies are apt to be particularly valuable because infants and young children are normally given larger doses of digoxin per unit of body weight or surface area than are older children and adults, and signs and symptoms of toxicity are often difficult to ascertain, especially in young infants. The present study was undertaken to analyze the serum digoxin'levels of a group of 12 infants and four children who had clinical and/or electrocardiographic findings of toxicity. A comparison of their serum levels was made with those of infants of comparable ages and duration of therapy, and with levels in children without evidence of intoxication. From the Departments o f Pediatrics, Pharmaeology, and Surgery, University of lllinois, College of Medicine. Supported in part by United States Public Health Service grants HD-05363 and GM-81, the Goodenberger Medical Research Fund o f the University o f lllnois Medical Foundation, and American Heart Association Grant-ln-Aid No. 72-925. *Establishedlnvestigator,Americanlteart Association. **Reprintaddress:Department of Pharmacology, Given Bldg., Universityof Vermont,Burlington, Vt. 05401.
MATERIALS AND METHODS Patients. All patients receiving digoxin during a oneyear period were studied by the pediatric cardiology group. Based on clinical d a t a only, and without knowledge of their serum digoxin levels, 12 infants, two clays to five months of age, and four children, five to twelve years old, were determined to have digitalis toxicity. All had congestive failure secondary to congenital cardiac malformations, except for Case 6 who had a myocardiopathy, and Cases 13 and 15 who had Cystic fibrosis. Patients were divided into two groups: those being digitalized, who had received one or two clays of therapy, and those who had been maintained on digoxin therapy for one week or longer. Digoxin serum determinations were performed on all hospitalized infants and children during the period of study; 22 nontoxic infants (8 digitalization and 14 maintenance) and 53 nontoxic children (all maintenance) were examined. Dosage. Four of the toxic infants received an oral digitalizing close of 0.08 mg. per kilogram, and two received 0.045 mg. per kilogram intramuscularly over 16 to 24 hours. Of the nontoxic infants, seven received 0.08 mg. per kilogram orally and one received 0.05 mg. per kilogram intramuscularly. Maintenance therapy routihely consisted of one fourth of the digitatizing dose (0.02 mg. per kilogram per day for infants, 0.015 mg. per
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The Journal of Pediatrics February 1974
Table I. Summary of patients, toxic manifestations, and serum digoxin values Manifestations of toxicity
Digitalization: Infants 1 2 days
3 4 5
11 days 33 days 55 days
2.6 2.8 3.4
Persistent vomiting Persistent vomiting None
6 5 too. Maintenance therapy: Infants" 7 20 days 8 22 days 9 I0 II
33 days 2 too, 2 too.
3.2 2.6 2.0
Persistent vomiting Bradycardia during feedings Persistent vomiting Persistent vomiting Episodes of bradycardia
Maintenance therapy: Children 13 5 yr. 12.7
11 yr. 12 yr.
kilogram per day for children 9 to 18 kilograms, and 0.01 mg. per kilogram per day for children over 18 kilograms given orally in divided doses every twelve hours. All infants received Lanoxin elixir (Burroughs Wellcome & Co.); children over five years of age received tablets. Assay. The radioimmunoassay procedure used was developed in our laboratory and has been previously described, t Blood samples were obtained by venipuncture (heelstick in infants under 3 kilograms) 5 to 14 hours following administration of the drug. Serum electrolytes, blood urea nitrogen, and hematocrits were determined by standard techniques in the clinical laboratory.
RESULTS Onset. Manifestations of toxicity in infants occurred from one to 37 days following the onset of digoxin therapy (Table I). In five infants, manifestations were observed from 8 to 14 hours after completion of digitalization. In a single infant (Case 1), toxicity was seen 8 hours
First and second degree AV block Ventricular premature beats None None Atrial flutter; second degree A-V block None
Rec'd 1/2 of digitalizing dose
Premature junctional beats Sinus bradycardia with premature atrial beats None None Atrial tachycardia with variable block S u p r a v e n t r i c u l a r premature beats
2.5 3.6 I0.0
16 37 7
Supraventricular tachycardia A-V dissociation; A-V block Variable A-V block 2:1 - 3:1 Variable A-V block 2:l - 3:1
2.1 3.7 2.9 3.5 3.2
after receiving the first one half of the total digitalizing dose. Toxicity occurred in children following 15 days to over one year of therapy. M a n i f e s t a t i o n s . In seven infants, three in the digitalization group and four in the maintenance therapy group, toxicity was diagnosed on the basis of electrocardiographic findings (Table I). One infant (Case 12) had supraventricular premature beats prior to administration of digoxin, but therapy resulted in an increased frequency of ectopic beats which reverted to the previous frequency when the dose was reduced. In the remaining five, the diagnosis was made by the finding of persistent vomiting in the absence of fever, signs of infection, gastroenteritis, other drug therapy, etc., and seemed unrelated to the presence of congestive heart failure. Vomiting promptly ceased following discontinuance or decrease in dosage. Four children all had cardiac rhythm disturbances but not vomiting. Toxic manifestations were mild and generally disappeared with discontinuance of the drug for 24 to 48 hours.
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ChT ldren Toxic
% . . . . ~ e
Fig. 1. Individual determinations of Serum digoxin concentration in infants and children. Line indicates mean and bar S.E.M. Values of 8.1 and 10.0 ng. per milliliter not included in calculation of mean. One infant (Case 10) was receiving diuretic drugs (hydrochlorothiazide and spironolactone) at the time of diagnosis of toxicity, but his serum electrolyte values were normal. Serum concentrations of sodium and potassium, blood urea nitrogen, and hematocrits were within normal limits for age in all patients except Case 11, who had mild azotemia (52 mg. per 100 ml.), hyperkalemia (6.3 mEq. perliter), and hyponatremia (129 mEq. per liter), and Cases 7 and 9 who had slight hyponatremia (130 and 129 mEq. per liter, respectively). Serum levels. During the initial digitalization period the six infants manifesting toxicity had serum digoxin concentrations (3.7 + 1.6 ng. per milliliter, mean • S.D.) equivalent to those of eight nonintoxicated infants of the same age (4.0 __+1.8 rig. per milliliter), but about twice that seen during maintenance therapy (1.7 • 0.9 ng. per
milliliter). However, levels in infants who developed toxicity during maintenance therapy differed significantly (3.6 ___0.9 vs. 1.7 __+0.9 ng. per milliliter, p (0.01) from those in nonintoxic infants. Serum digoxin concentrations in the toxic infants ranged from 2.1 to 10.0 ng. per milliliter (Table I). For statistical analysis, t h e values in Case 11, whose very high level (10.0 ng. per milliliter) was associated with renal failure, and in Case 7 were considered to be extraordinary and therefore omitted in calculation of the mean. Only one of 17 values in 14 nontoxic infants during maintenance therapy was /> 3 rig. per milliliter, whereas levels in five of the six toxic infants were ~ 3 ng. per,milliliter and the other was 2.5 ng~ per milliliter (Fig. 1). Fifty-three children from one to 15 years Qf age had a mean serum concentration during maintenance therapy
Krasula et aL
The Journal of Pediatrics february 1974
Table II. Summary of serum digoxin concentrations determined by radioimmunoassay during maintenance therapy in patients to two years of age Serum digoxin
Authors (reference) '
Hayes et al.4 Rodgers et al.9 O'Malley et alJ ~ Coltart 11 Cree et al. 14 Krasula et al. 1 Present study
No. of patients
Maintenance digoxin dose (mg./kg./day)
Nontoxic patients (ng./ml.) (mean ++_S.D.)
Toxic patients (ng./ml.) (mean +_ S.D.)
25 7 10 8 5 8 10 10 15 9 20
1 to 11 too. 3 to 30 day 1 to 12 too. 12 to 30 day 2 to 7 too. up to 30 days up to 30 days 1 to 30 days 30 days to 2 yr. 6 mo. to 2 yr. 20 days to 6 mo.
0.015-0.028 0.018 0.017 0.023 0.024 0:01 0.04 0.01 0.02 0.020 0.017
2.7 _+ 1.2(20) 1.8 _-4-1.2 2.1 _ 0.7 3.8 _+ 1.2 1.4 _+0.5 1.5 -+-0.3 2.5 _+ 0.4 1.5 1.6 1.0 _+ 0.6 1.7 _+0.9 (14)
4.5 _+ 2.5(5)
3.6 +_ 0.9 (4)*
*Valuesof 8.1 and 10 ng. per millimeteromittedfromcalculationof mean.Numbersin parenthesesin serumdigoxincolumnsindicatenumberof patientsin subgroup.
which was significantly lower than that of nontoxic infants (1.1 _+ 0,6 vs. 1.7 • 0.9, p < 0.01). Toxic children had a higher mean level than did other children (2.9 _+ 0.9 ng. per milliliter, p < 0.001), although one of the four values (1.7 ng: per milliliter) fell within the normal range (Fig. 1). This patient and the other toxic patient with a serum level less than 3.0 ng. per milliliter were hypoxic secondary to cystic fibrosis. DISCUSSION The incidence of digitalis toxicity is difficult to assess in children as well as i n adults. The dose administered varies, and in some instances an excessive dose may be given deliberately in an attempt to achieve therapeutic results. In a recent study in adults receiving maintenance therapy of digoxin, digitoxin, or digitalis leaf, Beller and co-workers 2 reported an incidence of 23 per cent of definite toxicity and an additional 6 per cent of possible toxicity. In infants and children receiving digoxin maintenance therapy, the incidence of toxicity may be as high as 20 to 25 per cent. 3,4 Levine and Blumenthal5 reported an incidence of toxicity of 2.5, 9.4, and 33.3 per cent in premature infants digitatized with 0.03, 0.05, and 0.075 mg. per kilogram body weight of digoxin, respectively. The high incidence in our infant patients (30 per cent) far exceeded that in the children (7 per cent), suggesting that the usually employed doses for infants under three months of age 6, 7 may be excessive. This seems especially true of the initial digitalization period, when 43 per cent of infants, but no children studied, had mild
manifestations of toxicity. The high serum concentrations found during digitalization of infants further supports this suggestion. We have previously reported 12that atrial concentrations of digoxin are significantly higher during digltalization than after one month or more of maintenance therapy (125 + 14 vs. 68 _+ 12 ng. per gram, p < 0.02), indicating that the risk of arrhythmias might be higher at this time. For these reasons, gradual digitalization by administration of the usual maintenance dose is recommended for all infants except those few whose clinical condition demands immediate, full digitalization. Support is gained for this recommendation by the findings of Levy and associates 13 who demonstrated in neonates and infants that maximal inotropic effect, as measured by pre-ejection period shortening , usually occurred after administration of a single 0.03 mg. per kilogram dose. No greater effect was found with 0.08 mg. per kilogram, the usually recommended digitalizing dose. In adults with digitalis toxicity, the serum digoxin levels have been reported to be significantly higher than in nontoxic patients. As recently reviewed by Smith, 8in nine studies utilizing the radioimmunoassay method, the mean level in adults receiving 0.25 or 0.5 mg. per day ranged from 0.8 to 1.4 ng. per milliliter, exactly bracketing our mean level for children of 1.1 ng. per milliliter. Six of seven studies found significantly higher levels (2.3 to 3.7 ng. per milliliter) in toxic adult patients, consistent with our results in infants and children. The pediatric literature also supports our finding of
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relatively higher values for serum d i g o x i n concentrations in neonates and infants than in children, a n d in toxic as oppose d to nontoxic patients of the same age group (Table II). Small n u m b e r s of patients, overlapping age limits, and different doses result in some differences which have caused confusion and controversy. Critical review of these data supports the general conclusions that: (1) infants up to about three m o n t h s of age have higher s e r u m concentrations t h a n d o children a n d a d u l t s , although relatively low considering the m a g n i t u d e of dosage; (2) toxic infants usually have elevated s e r u m concentrations; and (3) after about six m o n t h s of age, s e r u m levels approximate those of adults, despite a m u c h higher dose based on body weight. Viewed against this background a n d the accumulated experience of other workers, it can be seen that the s e r u m digoxin concentration in an infant with suspected digitalis toxicity can be correctly interpreted when the d e t e r m i n a t i o n has been made: (1) during m a i n t e n a n c e therapy, after administration of at least four half-lives of the drug or roughly five dayslS; (2) equilibrium, that is, b e t w e e n five and nine hours after an oral dose; a n d (3) w h e n the range of normal values for the age of the patient is k n o w n . If these conditions are met, and even though s o m e overlap o f values between 2 and 3 ng. per milliliter occurs in patients with or without toxicity, generally a value above 3 ng. per milliliter is consistent with toxicity. With neonates the upper limit might be raised to 3.5 or 4 ng. per milliliter, although again occasional infants attain such levels without electrocardiographic abnormalities. At all ages, serum concentrations below 2 ng, per milliliter virtually assure the absence of toxicity in patients free o f serious electrolyte disturbance, hypoxia, or thyroid disease. The authors wish to thank Dr. Thomas W. Smith, Massachusetts General Hospital, Boston, Mass., for a helpful review of the manuscript.
1. Krasula, R. W., Pellegrino, P. A., Hastreiter, A. R., and Soyka, L. F.: Serum levels of digoxin in infants and children, J. PEDIATR.81: 566, 1972. 2. Beller, G. A., Smith, T. W., Abelmann, W. H., Haber, A., and Hood, W. B.: Digitalis intoxication--a prospective clinical study with serum level correlations, N. Engl. J. Med. 284: 989, 1971. 3. Hauck, A. J., Ongley, P. A., and Nadas, A. S.: The use of digoxin in infants and children, Am. Heart J. 56: 443, 1958. 4. Hayes, C. J., Butler, V. P., and Gersony, W. M.: Serum digoxin studies in infants and children, Pediatrics 52: 561, 1973. 5. Levine, O. R., and Blumenthal, S.: Digoxin dosage in premature infants, Pediatrics 29: 18, 1962. 6. Nadas, A. S., and Fyler, D. C.: Pediatric cardiology, ed. 3, Philadelphia, 1972, W. B. Saunders Company, p. 271. 7. Neill, C. A.: The use of digitalis in infants and children, Prog. Cardiovasc. Dis. 7: 399, 1965. 8. Smith, T. W.: Contribution of quantitative assay techics to the understanding of the clinical pharmacology of digitalis, Curculation 46: 188, 1972. 9. Rogers, M. C., Willerson, J. T., Goldblatt, A.,and Smith T. W.: Serum digoxin concentrations in the human fetus, neonate and infant, N. Engl. J. Med. 287: 1010, 1972. 10. O'Malley, K., Coleman, E. N., Doig, W. B., and Stevenson, I. H.: Plasma digoxin levels in infants, Arch. Dis. Child. 48: 55, 1973. 11. Co.ltart, D. J.: Alterations in the sensitivity of the human heart to digoxin, Intl. Res. Comm. System, March, 1973. 12. Krasula, R. W., Levitsky, S., Yanagi, R., Hastreiter, A. R., and Soyka, L. F.: Serum and myocardial digoxin in children undergoing open-heart surgery, Fed. Proc. 32: 718, 1973. 13. Levy, A. M., Leaman, D. M., and Hanson, J. S.: Effects of digoxin on systolic time intervals of neonates and infants, Circulation 46: 816, 1972. 14. Cree, J. E., Coltart, D. J., and Howard, M. R.: Plasma digoxin concentration in children with heart failure, Br. Med. J. 1: 443, 1973. 15. Rowland, M.: Drug Administration and regimens, In Melman, K. L., and Morrelli, H. F., editors: Clinical pharmacology, New York, 1972~The Macmillan Company, pp. 21-60.