Pediatr Cardiol 15:22%232, 1994 Pediatric Cardiology �9 Springer-Verlag New York Inc. 1994

Single Dai ly Dose of Digoxin fo r M a i n t e n a n c e T h e r a p y o f Infants and C h i l d r e n with Cardiac Disease: Is I t Re l i ab l e?

Mustafa Bakir and Arman Bilgk;

Department of Pediatric Cardiology, Hacettepe University, Faculty of Medicine, Ankara, Turkey

SUMMARY. Between July 1990 and September 1991, 30 infants and children, most of whom had a congenital heart defect and who had been treated at least during the previous 20 days by two daily doses of digoxin and were in a stable clinical condition, were selected at random. A maintenance dose of digoxin was administered at 24-h intervals for 7 days in the study group (n = 15); no change was made in the 12-h dosage interval in the control group (n = 15). When the serum digoxin concentrations were compared, no significant difference was found between pre- and poststudy values in the study group (1.0 - 0.6 and 0.8 - 0.3 ng/mi, respectively) or between the control and study groups (0.9 - 0.6 and 0.8 +- 0.3 ng/ml, respectively) in terms of trough serum digoxin concentrations. Although the peak serum concentrations in the study group were increased significantly (2.3 -+ 0.8 ng/ml) compared with prestudy peak levels (1.6 _ 0.7 ng/ml, p < 0.05) and with the level in the control group (1.5 - 0.8 ng/ml, p < 0.05), a toxic concentration was not reached, and toxicity symptoms were not observed clinically. Blood pressure, heart rate, and liver size did not change significantly in any patient during the study.

KEY WORDS: Digoxin, single dose - - Infants - - Congenital heart disease

Despite recent controversies, digitalis preparations remain an important and accepted therapy for pa- tients with congestive heart failure [2, 4]. Although the recommended maintenance dosage interval for digoxin in infants and children is 12 h [1, 3, 12], studies comparing the serum concentration and the clinical condition of infants and children during once-daily and twice-daily administration of digoxin [11, 16] suggest that a single maintenance dose of the drug is equivalent to a twice-daily dosage regi- men in maintaining a therapeutic serum concentra- tion. The study of Olgunttirk et al. [11] compared clinical symptoms and serum digoxin concentra- tions in 12 patients on single-dose maintenance therapy and 12 patients on two divided doses. At the end of the seventh day, blood samples were obtained at 0, 6, 12, 18, and 24 h of therapy. The difference between the serum digoxin concentra- tions of the two groups at 0, 6, 12, 18, and 24 h was not statistically significant. Because the elimination half-life of digoxin averages 20 h in infants to 40 h in

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children [5, 9, 14], adequate therapeutic serum lev- els of the drug may be expected on theoretic grounds during once-daily administration. It must be noted, however, that conditions such as meta- bolic abnormalities, increased digitalis sensitivity, advanced myocardial disease, decreased renal and hepatic excretion, concomitant drug administra- tion, hypothyroidism, hypoxemia, and altered auto- nomic tone do predispose patients to digitalis tox- icity even when serum digoxin levels are within the "therapeutic" range [2, 10].

In this study we compared the serum digoxin concentration and clinical condition of infants and children selected by objective clinical and labora- tory criteria with respect to normal renal and he- patic function. The children, most of whom had congenital heart disease, received either a once- daily or a twice-daily dose of digoxin and were mon- itored to determine whether a single daily dose of the drug reaches a toxic concentration or reduces to a subtherapeutic trough level. We also evaluated the data to see if we could predict the statistical significance of potential intoxication in unstable clinical or metabolic conditions by comparing peak concentrations of digoxin.

230 Pediatric Cardiology Vol. 15, No. 5, 1994

Table 1. Group 1 patients (study group)

Patient no. Sex Age Diagnosis Digoxin dose Treatment duration Other drugs (months) (mg/kg/day) (months)

1 M 7 VSD, PDA, PH 0.012 2 - - 2 M 18 Atrial tach. 0,008 1.5 - - 3 M 18 TGA, VSD 0.010 18 S 4 M I2 VSD, PH 0.0t0 0.7 - - 5 F 24 TGA, VSD, PH 0.011 18 - - 6 F 5 VSD 0.013 3 - - 7 M 6.5 TGA, VSD, PS 0,011 6 - - 8 M 24 VSD 0.012 22 Fu + K 9 F 6 TGA, VSD, ASD 0.010 4 - -

10 M 60 PS, TR 0.009 0.7 - - 11 M 3.5 TGA 0.009 1,5 - - 12 M 15 TGA, VSD, PS 0.009 14 Fu 13 M 10 TAPVR 0.011 0.7 - - 14 F 6 AVSD 0.015 1.5 - - 15 M 30 VSD, PH 0.011 30 Fu + K

M e a n ++- S D 16.3 +-- 14.5 0.0107 -+ 0.0018 8.24 +- 9.5

VSD, ventricular septal defect; PDA, patent ductus arteriosus; PH, pulmonary hypertension; Atrial tach., atrial tachycardia; TGA, transposition of great arteries; PS, pulmonary stenosis; ASD, atrial septal defect; TR, tricuspid regurgitation; TAPVR, total anomalous pulmonary venous return; AVSD, atrioventricular septal defect; S, spironolactone; Fu, furosemide; K, potassium supplement.

Materials and Methods

Thirty children, aged 1.5 months to 5.0 years (mean 13.25 months), were selected randomly from patients at the Depart- ment of Pediatric Cardiology, Hacettepe Children's Hospital in Ankara who were being treated with a constant twice-daily dose of digoxin and had been in a stable clinical condition for at least the previous 20 days. Serum creatinine, aspartate aminotrans- ferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase levels were measured in all patients; in addition, the serum potassium level was measured in patients receiving diuret- ics with or without a potassium supplement. Any patients with a value for any of the tests outside the normal range for their age were excluded. Patients taking any drugs such as quinidine, ve- rapamil, amiodarone, nifedipine, prazosine and propafenone that are known to increase serum digoxin concentration [10] were also excluded. All patients had been treated with a constant twice-daily dose of digoxin for 20 days to 30 months (mean 6 months) and reported good compliance. Twenty-seven patients suffered from a congenital heart defect, two had supraventr[eular tachycardia, and one had a cardiomyopathy. Patients were di- vided into a study group (group 1) and a control group (group 2), each consisting of 15 patients (Tables 1 and 2). Serum samples were obtained by brachial venipuncture just before (for trough concentration of digoxin) and 2 h after (for peak concentration of digoxin) the morning dose was given.

A physical examination was performed and recordings of pulse and respiration rate and liver size were made at every visit before and after the drug was given. In group 1, after serum samples had been obtained before and 2 h after the morning dose of the twice-daily digoxin regimen on the first day, a total daily maintenance dose of digoxin was given once in the morning for the following 7 days, by which time the drug is expected to reach a steady-state level in the serum. At the end of the study, serum samples were obtained in the same manner as on the first visit, and the physical examination was repeated. Parents were in- structed to be aware of the signs of digoxin intoxication in their

children and to record changes in their general health, behavior, sleeping patterns, appetite, and gastrointestinal tract symptoms (e.g., anorexia, nausea, diarrhea). Parents could contact us at any time during the study. In group 2, serum samples were ob- tained and physical examinations performed only once. Serum digoxin concentrations were detected in our therapeutic drug monitoring laboratory by a radioimmunoassay TDX method (Ab- bott, Maidenhead, Berks.).

Pharmacologic and clinical values were compared between the two groups and between the 12-h and 24-h dosing intervals in the first group by Student's t-test for paired results. Correlation between measurements was studied by least squares regression analysis. Data are expressed as the mean +- SD.

Results

Table 3 shows the serum digoxin concentrations for the two groups. No significant difference was found between the 12- and 24-h dosing interval in terms of trough concentration (0.8 -+ 0.3 and 1.0 -+ 0.6 ng/ml, respectively, p > 0.05) in group 1 patients. The dif- ference between the mean trough concentrations during the twice-daily dosing of group 1 and 2 pa- tients (1.0 +-- 0.6 and 0.9 +- 0.6 ng/ml, respectively) was also insignificant (p > 0.05). Peak concentra- tions were 1.6 + 0.7 ng/ml for twice-daily dosing, 2.3 -+ 0.8 ng/ml for once-daily dosing, and 1.5 -+ 0.8 ng/ml in the control group. On comparison of peak concentrations during twice-daily versus once-daily regimens and once-daily regimen versus the control group, the differences were found to be statistically significant (p < 0.05). No significant differences were observed in heart and respiration rates and

Bakir and Bilgi~: Single Daily Dose of l)igoxin in Children 231

Table 2. Group 2 pat ients (control group)

Patient no. Sex Age Diagnosis Digoxin dose Trea tmen t durat ion Other drugs (months) (mg/kg/day) (months)

1 M 4 VSD 0.008 1 - - 2 F 9 Card iomyopathy 0.0 i 0 1 - - 3 M 7 VSD, Down syndrome 0,013 5 - - 4 F 8 PDA 0.016 6 - - 5 F 8 VSD, PDA, PH 0.011 3 - - 6 F 10 TA, PH 0.006 7 Fu + K 7 M 11 VSD, CA 0.009 3 - - 8 M 5 AS, PDA 0.010 3 - - 9 F 6 ASD, VSD, MS 0.008 1 - -

10 M 10 VSD 0.015 8 - - 11 M 36 Atrial tach. 0.011 0.7 - - 12 F 30 VSD, PDA 0.010 14 - - 13 M 1,5 VSD 0.008 1.5 - - 14 M 5,5 AVSD 0.007 2 Fu 15 M 1.5 TGA, VSD 0.011 1 - -

Mean -+ SD 10.l -~ 9.7 0.0102 _+ 0.011 3.81 -+ 3.68

MS, mitral s tenosis ; TA, t runcus ar tef iosus; CA, coarctat ion of aorta; other abbreviat ions as in Table 1.

Table 3. Serum digoxin concentration before and 2 h after the dose was given

Group Digoxin given Digoxin given twice daily once daily

Before After Before After

1 (study) 1.0 -+ 0.6 1.6 _-2- 0.7 0.8 -'2- 0.3 2,3 +- 0.8 2 (control) 0,9 -+ 0.6 1,5 -x-_ 0.8 - -

Resul ts are in nanograms per milliliter (mean -+ SD).

liver size between the patients on the two dose reg- imens or between the two groups. Except for two parents who complained of restlessness in their children (aged 12 and 15 months) during the second and third days of the once-daily regimen, there were no reported complaints.

Discussion

It is not obvious why digoxin should be adminis- tered twice daily to children because the trough and peak concentrations in children do not differ from those in adults and the elimination half-life is not shorter. Thus infants are less susceptible to the toxic effects of digoxin [12]. The twice-daily regi- men is recommended to reduce the potential risk of toxic peak concentrat ions and subtherapeut ic trough levels [1, 3, 13]. In adults, the therapeutic range is 1.0-2.5 ng/ml. However, children are be- lieved to be less sensitive to digoxin and need rel-

atively higher doses [7]. Excessive serum concen- trations of cardiac glycosides should not be inter- preted automatically as reflecting toxicity, as changes in drug response are not proportional to changes in the serum level of the drug [6, 8]. The lower toxic limit is known to be higher in children than in adults [6, 15].

Our study not only confirms the results of pre- vious similar studies [11, 16]; it has some important advantages with regard to the following points.

1. In contrast to previous studies [11, 16] we included only patients whose serum creatinine, ALT, AST, and (for patients on diuretics) potas- sium levels were within the normal limits for their age. These parameters provide objective criteria for the stable metabolic condition, which is mandatory for accurate assessment of the serum digoxin level and its toxicity.

2. Of the 39 patients in our study, 27 were suf- fering from nonoperated congenital cardiac malfor- mations, which are known to have complex hemo- dynamics. In contrast, of the 12 patients in the study of Zalzstein et al. [16], only 2 had transposi- tion of the great arteries and ventricular septal de- fect and 5 had undergone cardiac surgery. In this regard, we believe that the assessment of dose- toxicity and dose-serum level relations of digoxin in our patients may be more representative in terms of safety in a homogeneous group of pediatric patients with uncorrected cardiac malformations.

3. To achieve more reliable results we not only compared the serum digoxin levels obtained before and after a once-daily dose regimen in the study

232 Pediatric Cardiology Vol. 15, No. 5, 1994

group patients, but also compared the results from the study group with those in control cases of equal number and similar clinical characteristics. A pre- vious study [16] did not use such a control group.

4. In contrast to previous studies [11, 16], our study emphasizes the statistically significant in- creases in peak concentrations of digoxin during twice-daily (1.6 --- 0.7 ng/ml) versus once-daily reg- imens (2.3 - 0.8 ng/ml; p < 0.05) and in the once- daily regimen versus the control group (1.5 - 0.8 ng/ml; p < 0.05).

Although 8 of 15 patients with serum digoxin concentrations between 2.5 and 3.9 ng/ml did not present any clinical or laboratory finding of toxic- ity, it must be remembered that the patients se- lected were all in a stable clinical and metabolic condition. It must be remembered that metabolic abnormalities (e.g. hypokalemia, hypomagnesemia, hypercalcemia, severe acid-base imbalance, in- creased digitalis sensitivity), advanced myocardial disease, myocardial ischemia, decreased renal ex- cretion, concomitant drug administration (e.g., cat- echolamines, quinidine, verapamil, amiodarone, ni- fedipine, prazosine, propafenone), hypothyroidism, hypoxemia (especially in the setting of acute respi- ratory failure), and altered autonomic tone (e.g., vagotonic states) predispose patients to digitalis toxicity even when the serum digoxin levels are within the "therapeutic" range [2, 10]. A significant increase in digoxin concentration during once-daily dosing suggests that the drug should be given in divided (two) doses in these circumstances to avoid toxicity. However, in circumstances other than dig- italis sensitivity, administering a maintenance dose once daily rather than twice daily has the advantage of improving compliance.

Conclusion

Digoxin may be used safely with a once-daily dos- ing interval for maintenance therapy of infants and children with cardiac disease. A twice-daily dosage

regimen remains appropriate for digitalis-sensitive states.

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