Europ. J. Pediat. 124, 217--222 (1977)
European Journal of 9
9
Pediatrnes 9 by Springer-Verlag 1977
Digoxin Elimination by Exchange Transfusion H. Rosegger*, M. Zach, H. Gleispach, and A. Beitzke The University Children's Hospital (Vorstand: Univ.-Professor Dr. E. Zweymiiller), Auenbruggerplatz, A-8036 Graz, ~)sterreich
Abstract. The report covers four cases presenting simultaneous indications for digitalisation and exchange transfusions. Intravenous administration of digoxin was followed: 1. by monitoring of the behaviour of the plasma digoxin level; 2. by determination of the total amount of glycoside eliminated by the blood exchange. Particular attention was paid to the effect of the delay between injection and exchange transfusion on the amount of digoxin eliminated. All four cases showed moderate falls in plasma levels. The amounts of digoxin eliminated by exchange transfusion were in reverse relationship to the delay between administration of digoxin and the blood exchange. At no time did the eliminated fraction exceed 5% of the total amount present in the body. Key words: Exchange transfusion - Digoxin elimination.
Zusammenfassung. Es wird von vier F~illen berichtet, bei denen sich zugleich die Indikation zur Digitalisierung und zur Austauschtransfusion ergab. Nach vorhergehender, intraven0ser Digoxingabe wurde einerseits das Verhalten der Digoxinkonzentration im Plasma gemessen, andererseits die gesamte durch den Blutaustausch eliminierte Glykosidmenge bestimmt. Besondere Beachtung galt einer Abh~ingigkeit des eliminierbaren Prozentsatzes yon dem zeitlichen Abstand der Austauschtransfusion zur vorangehenden Injektion. In allen vier F~illen wurde ein m~igiges Absinken der Plasmakonzentration beobachtet. Die dutch Austauschtransfusion eliminierte Digoxinmenge stand in einem verkehr t proportionalen Verhiiltnis zum Intervall zwischen Digoxingabe und Blutaustausch. In keinem Fall tiberstieg diese eliminierte Fraktion 5% der insgesamt im K6rper enthaltenen Menge. Introduction The introduction of the radioimmunoassay by Smith et al. in 1969 [13] has allowed a routine and reasonably reliable determination of the glycoside concen* Corresponding author
218
H. Rosegger et al.
t r a t i o n i n the p l a s m a of digitalised patients. This m e t h o d is especially useful in e x p l o r i n g a n d solving p r o b l e m s associated with the p h a r m a c o k i n e t i c s of cardiac glycosides. The object of the c u r r e n t study was to determine to what extent a definite a m o u n t of d i g o x i n in the b o d y could be reduced by exchange transfusion. P a r t i c u l a r a t t e n t i o n was to be paid to the d e p e n d e n c e of the e l i m i n a t e d a m o u n t o n the delay between a d m i n i s t r a t i o n of d i g o x i n a n d c o m m e n c e m e n t of the e x c h a n g e t r a n s f u s i o n (ET). I n n e w b o r n i n f a n t s r e q u i r i n g digitalisation as well as exchange transfusions, the t h e r a p e u t i c p r o d e d u r e could be j e o p a r d i s e d w i t h o u t exact knowledge of the a m o u n t by which the digitalis level is reduced by ET. A t the same time, this study could supply i n f o r m a t i o n to help in the e v a l u a t i o n of the practical value of E T in the t r e a t m e n t of accidental digitalis intoxications.
Patients and Methods In 1975, a total of four patients required digitalis treatment as well as exchange transfusion. Three were newborn infants at the time of the transfusion; the fourth was aged 3 years 7 months. The Table shows the clinical data, indication for digitalisation and ET, together with the delay between digitalis treatment and the exchange transfusion. In the three newborn infants,~the exchange transfusion was carried out following the first i.v. administration of a digoxin preparation (Lanicor| The amount adiministered represented 50% of the recommended saturation dose [8, 9, 10, 12]. In the older child, the exchange transfusion was carried out in the maintenance stage of digoxin treatment, after saturation was completed. In order to avoid measuring errors, the injection was in each case given into a peripheral vein and not via the i.v. ET route (umbilical vein and cava catheter). Blood samples were taken before, half-way through, and at the end of the ET, centrifuged, and the plasma stored at minus 20~ C until the determination was carried out. In addition, we determined the plasma amount of the withdrawn blood, and a sufficient aliquot was stored as described above for determination of the glycoside concentration. The digoxin level was determined with the Digoxin-3HRadioimmunoassay Kit of NEN (New England Nuclear). In view of any possible effects of various plasma parameters on the measuring values [2], we carried out quench corrections of the bilirubin-induced errors.
Table 1. Weights, gestation periods, and ages of the four patients, together with indications for ET and digitalis treatment. Sequence according to delays between glycoside dose and ET Patient
Weight (G)
Gest. age/age
Indication of exchange transf,
Bilirubin . . . . . mg digoxin Interval: (rag/100 ml) (indication) injection exchange
H. Ch.
3 070
38 weeks
Severe rhisoimmunisation
16.5
0.05 mg heart failure
150 min
Z.M. c~
2 970
40 weeks
Severe rhisoimmunisation
11.4
0.06 mg heart failure
200 min
K.
1 360
34 weeks
Hyperbilirubinemia
15.5
0.03 mg heart failure
375 min
13 300
37/12years
Poisoning with Amanita phalloides
8.0
0.51 mg heart failure
M.A.
25 h
Digoxin Elimination by Exchange Transfusion
219
10 -ng/ml Pat. H. 6.0 5
4.6 3.4
i
I 1
i
i 2
JR 4
3
hrs after injection Fig. 1. The reduction in plasma digoxin concentration measured in Patient 1 in the course of the ET
L 3.4% 2.9%
o
63~s2~
~6
04
1.0~ "]
1 I 1
I 2
I 3
I z,
[ 5
F 6
0.48%
R iJ 24
hrs after injection Fig. 2. The amounts of glycoside eliminated for each individual patient by ET, expressed as percentage of the total amount present in the body. Sequence according to the delay between injection and commencement of ET
Results In all 4 cases, the plasma concentrations showed moderate falls in the course of the ET. An example is shown in Figure 1. The total glycoside amount eliminated by the ET (calculated from the amount of pooled plasma determined in ml, and the digoxin concentration of the aliquot) was expressed as a percentage of the digoxin present in the body. N o allowance was made in the case of the three newborn infants for the small renal excretion between the i.v. dose and the beginning of the exchange transfusion. In the case of the older child, the total amount present in the body was calculated on the basis of the doses administered and a 30% daily elimination rate. Figure 2 represents the percentages obtained, in sequence according to the length of the interval between injection and ET. As this interval increased, the percentage eliminated was markedly decreased.
H. Rosegger et al.
220 100.0
T5o = 3L hrs
g lo.o
g u I
E 1.0 :-E
0.1
100
i ~"i.v.
500 1000 Minutes cffter injection
Fig. 3. Curve showing behaviour of the plasma concentration following a single, i.v. dose of digoxin (Doherty, 1969)
Discussion Pharmacokinetics
The pharmacokinetics of digoxin in the human body formed the theoretical basis for the classification of the above results. As administration of the glycoside was in all four cases by the i.v. route, we can exclude the problems of enteral absorption for the purposes of this study. The very high plasma concentration following injection is subsequently reduced by binding of the glycoside to receptors in the tissues. The distribution time, which continues until the tissue binding process is complete, is reported as being between 6 and 8 h [7]. After completion of distribution, less than 1% of the administered dose is recovered from the plasma [5]. Digoxin is predominantly excreted via the kidneys, by glomerular filtration without tubular reabsorption [121]. This means that the elimination rate is affected by the plasma concentration but not by the quantity of urine produced [ 15]. The average half-life of digoxin is quoted as 34 h [6]. Figures on the relative elimination rate, i.e., the daily elimination as a percentage of the total amount present in the body, range from 18% [11] to 37% [14, 15]. The behaviour of the plasma concentration after i.v. administration of digoxin can be deduced from the above data (Fig. 3). The concentration curve reaches its maximum value immediately after completion of the injection; after that the level steadily declines. The slope is very steep in the first few hours after injection; after that, reduction is slower and the curve
Digoxin Elimination by Exchange Transfusion
221
becomes flatter. The initial steep slope is chiefly due to the distribution to the tissue receptors; the other factor is renal elimination. The subsequent slower reduction in concentration shows that the renal elimination only slowly changes the equilibrium between tissue and plasma levels.
Interpretation of the Results In accordance with the pharmacokinetics described, after the end of the distribution period, dialysis [1] or a heart-lung machine [3] can eliminate only small amounts of digoxin from the body. The effects of exchange transfusions on the plasma digoxin levels of two newborn infants were described as early as 1972 [4]. However, the extremely high plasma levels described in that study, the dosage used--which was very much higher than o u r s - - a n d the overlapping in time of several doses of digoxin and repeated exchange transfusions,do not allow a definite correlation between time factor and the size of the eliminated digoxin dose. Particular attention was paid to this correlation in our own study. In theory, the percentage of digoxin removed from the body by ET should be in direct proportion to the plasma level. Consequently, in view of the behaviour of the plasma curve, it should be the higher, the shorter the delay between injection and ET. Interpretation of plasma concentration in the course of ET: the fall in the plasma concentration measured in the three newborn infants (Fig. l), where the ET was carried out within the distribution period, can be attributed to three separate mechanisms: 1) tissue binding; 2) elimination by ET; 3) renal elimination. The case of the older child represents an example of the situation after completion of digoxin binding to the tissue receptors: here the reduction in plasma level was due only to elimination via the kidneys, and the ET. The multiple factors involved in reducing the plasma levels precluded quantitative determination of the effect of the ET. The desirable quantitative determination can, however, be carried out by the simple and precise method of calculating the pooled plasma digoxin, as described. The measured values (Fig. 2) represent a clear confirmation of the theory that the amount of glycoside eliminated must be related to the delay between injection and exchange transfusion. The fact that even the exchange transfusion carried out nearest in time to the injection was able to eliminate less than 5% of the total amount present in the body, permits two practical conclusions: 1) where digitalisation coincides with exchange transfusions, it is not necessary to replace the amount withdrawn by ET; 2) in case of accidental digitalis intoxication, the amount of glycoside removed by even a very early exchange transfusion would be in no way related to the therapeutic expenditure.
References
1. Ackermann, G. L., Doherty, J. E., Flanigan, W. J.: Peritoneal Dialysis and Hemodialysis of Tritiated Digoxin. Ann. Intern. Med. 67, 718 (1967) 2. Belpaire, F. M., Bogart, M. G., Broe, M. E.: Radioimmunassay of Digoxin in Renal Failure. A Comparison of Different Commercial Kits. Clin. Chim. Acta 62, 255 (1975)
222
H. Rosegger et al.
3. Coltart, D. J., Chamberlain, D. A., Howard, M. R., Kettlewell, M. G., Mercer, J. L., Smith, R. W.: Effect of Cardiopulmonary Bypass on Plasma Digoxin Concentrations. Br. Heart J. 33, 334 (1971) 4. Coltart, D. J., Watson, D., Howard, M. R.: Effect of Exchange Transfusions on Plasma Digoxin Levels. Arch. Dis. Child. 47, 814 (1972) 5. Doherty, J. E.: The Clinical Pharmacology of Digitalis Glykosides. A. Review. Amer. J. Med. Sci. 225, 382 (1968) 6. Doherty, J. E.: Determinants of Digitalis Dosage. J. Ark. Med. Soc. 66, 120 (1969) 7. Gilfrich, H. J., Sch61merich, P.: Digitalisintoxikation. Neuere Gesichtspunkte zur Entstehung und Bewertung. Dtsch. med. Wschr. 100, 831 (1975) 8. Klaus, M. H., Fanaroff, A. A.: Care of the High-Risk Neonate. Philadelphia-LondonToronto: W. B. Saunders Company 1973 9. Levine, O. R., Blumenthal, S.: Digoxin Dosage in Premature Infants. Pediatrics 29, 18 (1962) 10. Nadas, A. S., Fyler, D. C.: Pediatric Cardiology. Philadelphia-London-Toronto: W. B. Saunders Company 1972 11. Niedner, R.: Digitalistherapie. Stuttgart: Georg Thieme Verlag 1973 12. Rudolph, A. M.: The Circulatory System. In: Barnett, H. L.: Pediatrics, 15th ed., New York: Appleton-Century-Crofts 1972 13. Smith, T. W., Butler, V. P., Haber, E.: Determination of Therapeutic and Toxic Serum Digoxin Concentrations by Radioimmunassay. N. Engl. J. Med. 281, 1212 (1969) 14. Smith, T. W.: Digitalis Glycosides (First of Two Parts). N. Engl. J. Med. 288, 719 (1973) 15. Smith, T. W., Haber, E.: Digitalis (Third of Four Parts). N. Engl. J. Med. 289, 1063 (1973)
Received August 30, 1976
European Journal of 9
9
Pediatrnes 9 by Springer-Verlag 1977
Digoxin Elimination by Exchange Transfusion H. Rosegger*, M. Zach, H. Gleispach, and A. Beitzke The University Children's Hospital (Vorstand: Univ.-Professor Dr. E. Zweymiiller), Auenbruggerplatz, A-8036 Graz, ~)sterreich
Abstract. The report covers four cases presenting simultaneous indications for digitalisation and exchange transfusions. Intravenous administration of digoxin was followed: 1. by monitoring of the behaviour of the plasma digoxin level; 2. by determination of the total amount of glycoside eliminated by the blood exchange. Particular attention was paid to the effect of the delay between injection and exchange transfusion on the amount of digoxin eliminated. All four cases showed moderate falls in plasma levels. The amounts of digoxin eliminated by exchange transfusion were in reverse relationship to the delay between administration of digoxin and the blood exchange. At no time did the eliminated fraction exceed 5% of the total amount present in the body. Key words: Exchange transfusion - Digoxin elimination.
Zusammenfassung. Es wird von vier F~illen berichtet, bei denen sich zugleich die Indikation zur Digitalisierung und zur Austauschtransfusion ergab. Nach vorhergehender, intraven0ser Digoxingabe wurde einerseits das Verhalten der Digoxinkonzentration im Plasma gemessen, andererseits die gesamte durch den Blutaustausch eliminierte Glykosidmenge bestimmt. Besondere Beachtung galt einer Abh~ingigkeit des eliminierbaren Prozentsatzes yon dem zeitlichen Abstand der Austauschtransfusion zur vorangehenden Injektion. In allen vier F~illen wurde ein m~igiges Absinken der Plasmakonzentration beobachtet. Die dutch Austauschtransfusion eliminierte Digoxinmenge stand in einem verkehr t proportionalen Verhiiltnis zum Intervall zwischen Digoxingabe und Blutaustausch. In keinem Fall tiberstieg diese eliminierte Fraktion 5% der insgesamt im K6rper enthaltenen Menge. Introduction The introduction of the radioimmunoassay by Smith et al. in 1969 [13] has allowed a routine and reasonably reliable determination of the glycoside concen* Corresponding author
218
H. Rosegger et al.
t r a t i o n i n the p l a s m a of digitalised patients. This m e t h o d is especially useful in e x p l o r i n g a n d solving p r o b l e m s associated with the p h a r m a c o k i n e t i c s of cardiac glycosides. The object of the c u r r e n t study was to determine to what extent a definite a m o u n t of d i g o x i n in the b o d y could be reduced by exchange transfusion. P a r t i c u l a r a t t e n t i o n was to be paid to the d e p e n d e n c e of the e l i m i n a t e d a m o u n t o n the delay between a d m i n i s t r a t i o n of d i g o x i n a n d c o m m e n c e m e n t of the e x c h a n g e t r a n s f u s i o n (ET). I n n e w b o r n i n f a n t s r e q u i r i n g digitalisation as well as exchange transfusions, the t h e r a p e u t i c p r o d e d u r e could be j e o p a r d i s e d w i t h o u t exact knowledge of the a m o u n t by which the digitalis level is reduced by ET. A t the same time, this study could supply i n f o r m a t i o n to help in the e v a l u a t i o n of the practical value of E T in the t r e a t m e n t of accidental digitalis intoxications.
Patients and Methods In 1975, a total of four patients required digitalis treatment as well as exchange transfusion. Three were newborn infants at the time of the transfusion; the fourth was aged 3 years 7 months. The Table shows the clinical data, indication for digitalisation and ET, together with the delay between digitalis treatment and the exchange transfusion. In the three newborn infants,~the exchange transfusion was carried out following the first i.v. administration of a digoxin preparation (Lanicor| The amount adiministered represented 50% of the recommended saturation dose [8, 9, 10, 12]. In the older child, the exchange transfusion was carried out in the maintenance stage of digoxin treatment, after saturation was completed. In order to avoid measuring errors, the injection was in each case given into a peripheral vein and not via the i.v. ET route (umbilical vein and cava catheter). Blood samples were taken before, half-way through, and at the end of the ET, centrifuged, and the plasma stored at minus 20~ C until the determination was carried out. In addition, we determined the plasma amount of the withdrawn blood, and a sufficient aliquot was stored as described above for determination of the glycoside concentration. The digoxin level was determined with the Digoxin-3HRadioimmunoassay Kit of NEN (New England Nuclear). In view of any possible effects of various plasma parameters on the measuring values [2], we carried out quench corrections of the bilirubin-induced errors.
Table 1. Weights, gestation periods, and ages of the four patients, together with indications for ET and digitalis treatment. Sequence according to delays between glycoside dose and ET Patient
Weight (G)
Gest. age/age
Indication of exchange transf,
Bilirubin . . . . . mg digoxin Interval: (rag/100 ml) (indication) injection exchange
H. Ch.
3 070
38 weeks
Severe rhisoimmunisation
16.5
0.05 mg heart failure
150 min
Z.M. c~
2 970
40 weeks
Severe rhisoimmunisation
11.4
0.06 mg heart failure
200 min
K.
1 360
34 weeks
Hyperbilirubinemia
15.5
0.03 mg heart failure
375 min
13 300
37/12years
Poisoning with Amanita phalloides
8.0
0.51 mg heart failure
M.A.
25 h
Digoxin Elimination by Exchange Transfusion
219
10 -ng/ml Pat. H. 6.0 5
4.6 3.4
i
I 1
i
i 2
JR 4
3
hrs after injection Fig. 1. The reduction in plasma digoxin concentration measured in Patient 1 in the course of the ET
L 3.4% 2.9%
o
63~s2~
~6
04
1.0~ "]
1 I 1
I 2
I 3
I z,
[ 5
F 6
0.48%
R iJ 24
hrs after injection Fig. 2. The amounts of glycoside eliminated for each individual patient by ET, expressed as percentage of the total amount present in the body. Sequence according to the delay between injection and commencement of ET
Results In all 4 cases, the plasma concentrations showed moderate falls in the course of the ET. An example is shown in Figure 1. The total glycoside amount eliminated by the ET (calculated from the amount of pooled plasma determined in ml, and the digoxin concentration of the aliquot) was expressed as a percentage of the digoxin present in the body. N o allowance was made in the case of the three newborn infants for the small renal excretion between the i.v. dose and the beginning of the exchange transfusion. In the case of the older child, the total amount present in the body was calculated on the basis of the doses administered and a 30% daily elimination rate. Figure 2 represents the percentages obtained, in sequence according to the length of the interval between injection and ET. As this interval increased, the percentage eliminated was markedly decreased.
H. Rosegger et al.
220 100.0
T5o = 3L hrs
g lo.o
g u I
E 1.0 :-E
0.1
100
i ~"i.v.
500 1000 Minutes cffter injection
Fig. 3. Curve showing behaviour of the plasma concentration following a single, i.v. dose of digoxin (Doherty, 1969)
Discussion Pharmacokinetics
The pharmacokinetics of digoxin in the human body formed the theoretical basis for the classification of the above results. As administration of the glycoside was in all four cases by the i.v. route, we can exclude the problems of enteral absorption for the purposes of this study. The very high plasma concentration following injection is subsequently reduced by binding of the glycoside to receptors in the tissues. The distribution time, which continues until the tissue binding process is complete, is reported as being between 6 and 8 h [7]. After completion of distribution, less than 1% of the administered dose is recovered from the plasma [5]. Digoxin is predominantly excreted via the kidneys, by glomerular filtration without tubular reabsorption [121]. This means that the elimination rate is affected by the plasma concentration but not by the quantity of urine produced [ 15]. The average half-life of digoxin is quoted as 34 h [6]. Figures on the relative elimination rate, i.e., the daily elimination as a percentage of the total amount present in the body, range from 18% [11] to 37% [14, 15]. The behaviour of the plasma concentration after i.v. administration of digoxin can be deduced from the above data (Fig. 3). The concentration curve reaches its maximum value immediately after completion of the injection; after that the level steadily declines. The slope is very steep in the first few hours after injection; after that, reduction is slower and the curve
Digoxin Elimination by Exchange Transfusion
221
becomes flatter. The initial steep slope is chiefly due to the distribution to the tissue receptors; the other factor is renal elimination. The subsequent slower reduction in concentration shows that the renal elimination only slowly changes the equilibrium between tissue and plasma levels.
Interpretation of the Results In accordance with the pharmacokinetics described, after the end of the distribution period, dialysis [1] or a heart-lung machine [3] can eliminate only small amounts of digoxin from the body. The effects of exchange transfusions on the plasma digoxin levels of two newborn infants were described as early as 1972 [4]. However, the extremely high plasma levels described in that study, the dosage used--which was very much higher than o u r s - - a n d the overlapping in time of several doses of digoxin and repeated exchange transfusions,do not allow a definite correlation between time factor and the size of the eliminated digoxin dose. Particular attention was paid to this correlation in our own study. In theory, the percentage of digoxin removed from the body by ET should be in direct proportion to the plasma level. Consequently, in view of the behaviour of the plasma curve, it should be the higher, the shorter the delay between injection and ET. Interpretation of plasma concentration in the course of ET: the fall in the plasma concentration measured in the three newborn infants (Fig. l), where the ET was carried out within the distribution period, can be attributed to three separate mechanisms: 1) tissue binding; 2) elimination by ET; 3) renal elimination. The case of the older child represents an example of the situation after completion of digoxin binding to the tissue receptors: here the reduction in plasma level was due only to elimination via the kidneys, and the ET. The multiple factors involved in reducing the plasma levels precluded quantitative determination of the effect of the ET. The desirable quantitative determination can, however, be carried out by the simple and precise method of calculating the pooled plasma digoxin, as described. The measured values (Fig. 2) represent a clear confirmation of the theory that the amount of glycoside eliminated must be related to the delay between injection and exchange transfusion. The fact that even the exchange transfusion carried out nearest in time to the injection was able to eliminate less than 5% of the total amount present in the body, permits two practical conclusions: 1) where digitalisation coincides with exchange transfusions, it is not necessary to replace the amount withdrawn by ET; 2) in case of accidental digitalis intoxication, the amount of glycoside removed by even a very early exchange transfusion would be in no way related to the therapeutic expenditure.
References
1. Ackermann, G. L., Doherty, J. E., Flanigan, W. J.: Peritoneal Dialysis and Hemodialysis of Tritiated Digoxin. Ann. Intern. Med. 67, 718 (1967) 2. Belpaire, F. M., Bogart, M. G., Broe, M. E.: Radioimmunassay of Digoxin in Renal Failure. A Comparison of Different Commercial Kits. Clin. Chim. Acta 62, 255 (1975)
222
H. Rosegger et al.
3. Coltart, D. J., Chamberlain, D. A., Howard, M. R., Kettlewell, M. G., Mercer, J. L., Smith, R. W.: Effect of Cardiopulmonary Bypass on Plasma Digoxin Concentrations. Br. Heart J. 33, 334 (1971) 4. Coltart, D. J., Watson, D., Howard, M. R.: Effect of Exchange Transfusions on Plasma Digoxin Levels. Arch. Dis. Child. 47, 814 (1972) 5. Doherty, J. E.: The Clinical Pharmacology of Digitalis Glykosides. A. Review. Amer. J. Med. Sci. 225, 382 (1968) 6. Doherty, J. E.: Determinants of Digitalis Dosage. J. Ark. Med. Soc. 66, 120 (1969) 7. Gilfrich, H. J., Sch61merich, P.: Digitalisintoxikation. Neuere Gesichtspunkte zur Entstehung und Bewertung. Dtsch. med. Wschr. 100, 831 (1975) 8. Klaus, M. H., Fanaroff, A. A.: Care of the High-Risk Neonate. Philadelphia-LondonToronto: W. B. Saunders Company 1973 9. Levine, O. R., Blumenthal, S.: Digoxin Dosage in Premature Infants. Pediatrics 29, 18 (1962) 10. Nadas, A. S., Fyler, D. C.: Pediatric Cardiology. Philadelphia-London-Toronto: W. B. Saunders Company 1972 11. Niedner, R.: Digitalistherapie. Stuttgart: Georg Thieme Verlag 1973 12. Rudolph, A. M.: The Circulatory System. In: Barnett, H. L.: Pediatrics, 15th ed., New York: Appleton-Century-Crofts 1972 13. Smith, T. W., Butler, V. P., Haber, E.: Determination of Therapeutic and Toxic Serum Digoxin Concentrations by Radioimmunassay. N. Engl. J. Med. 281, 1212 (1969) 14. Smith, T. W.: Digitalis Glycosides (First of Two Parts). N. Engl. J. Med. 288, 719 (1973) 15. Smith, T. W., Haber, E.: Digitalis (Third of Four Parts). N. Engl. J. Med. 289, 1063 (1973)
Received August 30, 1976
