Postmortem Tissue Digoxin Concentrations in Infants and Children By PU WOONG KiM, M.D., RiCHARD W. KRASULA, PH.D., LESTER F. SOYKA, M.D., AND
ALOIs R. HASTREITER, M. D.
SUMMARY The concentrations of digoxin in tissues of premature infants, full-term infants and older children ob-
tained at autopsy were determined by a radioimmunoassay procedure. Infants were found to have much higher concentrations in the right and left ventricle (about 190 ng/g) than older children (about 70 ng/g) and adults as reported in the literature. Renal concentrations were lower in the premature group which may be related to their limited excretory capacity for digoxin. The relatively high myocardial concentrations of digoxin found in this study suggest that the usually recommended doses for infants may be excessive. quots of plasma were assayed directly. Tissue samples were homogenized in absolute ethanol for 30 sec with an Omnimixer (Ivan Sorvall, Inc., Norwalk, Conn.). The homogenates were centrifuged at 1000 g for 10 min and the supernatants removed. The precipitates were re-extracted in additional ethanol. The combined supernatants were evaporated to dryness, and resuspended in phosphate-bovine serum albumin buffer. After administration of 3H-digoxin to guinea pigs, 95% of myocardial radioactivity was extracted by this method. The extracted digoxin was bound by antiserum with an affinity
T HE LITERATURE contains little information on postmortem tissue concentrations of digoxin in adults'-5 and there is only one such report in children.6 The present study is the first to analyze postmortem tissue concentrations of digoxin in three groups of children: premature infants, full-term newborn infants and older children who received digoxin prior to death. The purpose of the study was to determine if the distribution of the drug in various tissues differed
among these groups, because altered distribution may have therapeutic implications. We were particularly concerned that the limited capacity for renal excretion of drugs by the neonate, especially the premature infant, might affect the pharmacokinetics as known in older children and adults. In premature neonates, clinical and electrocardiographic signs of digitalis toxicity are observed more frequently and may follow the use of relatively small doses of digoxin.7 Doses of digoxin currently recommended for premature infants have been derived empirically for there have been to date few, if any, objective data establishing agedependent differences in the pharmacodynamics of digoxin. Assay Procedures
identical to that of nonextracted digoxin.9 Patient Material
Tissue samples were obtained at autopsy from seven premature infants, four full-term newborn infants and four older children who received digoxin because of congestive heart failure secondary to cardiac or pulmonary pathology. In most cases, digoxin concentration was also determined on plasma samples obtained one or two days prior to death. These samples were collected six to eight hours following administration of the drug. None of the patients exhibited signs or symptoms of digitalis toxicity.
Results
Age at death, body weight, route of administration, daily dose, duration of administration, plasma digoxin levels, and diagnoses are listed in table 1. While the mean age at death of the premature and full-term newborn infants studied were similar, mean body weight and surface area differed significantly (P < 0.05). The average daily dose (on a body weight basis) administered to the premature infants was less than one-half that given to full-term newborns, while the average dose for the group of older children was about two-thirds that for full-term neonates. The duration of digoxin administration was comparable in premature and full-term newborns but was considerably longer in the group of older children. Equilibrium plasma digoxin levels (six to eight hours following administration of the drug) were measured within 24 hours of the time of death. The mean concentration in premature
Materials and Methods
Digoxin was measured by a radioimmunoassay (RIA) in our laboratory." One-tenth ml ali-
procedure developed
From the Sections of Pediatric Cardiology and Clinical Pharmacology, University of Illinois Hospital, Abraham Lincoln School of Medicine, Chicago, Illinois. Supported in part by the University of Illinois Foundation, Goodenberger Medical Research Grant 2-44-33-66-3-14, and
USPHS Grant HD-08708. Dr. Soyka's present address is Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont 05401. Address for reprints: Alois R. Hastreiter, M.D., University of Illinois Hospital, 840 South Wood Street, Chicago, Illinois 60612. Received March 21, 1975; revision accepted for publication June 26, 1975.
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POSTMORTEM TISSUE DIGOXIN
Table 1 Age, Weight, Diagnosis and Parameters of Digoxin Administration*
Case
Premature neonates
Full-term neonates
1 2 3 4 5 6 7 8
9 10 11
Daily digoxin dose (mcg kg'
Durat. digoxin admn. (days)
Digoxin serum level (ng/ml)
17.5 17.0 8.6 7.0 6.8 4.8 2.6
1 1 2
2.3 2.2
3
1.6 2.0 1.3 2.7
Age (days)
Weight (kg)
Route admn. digoxin
2 4 3 13 10 12 24 4 2 9 11
1.14 2.05 2.32 1.44 1.91 1.33 1.49 3.10 3.60 2.50 3.77
IB1 IV PO PO PO PO PO PO IV IM PO
30.0 33.3 10.0 21.2
6 8 9 1 1 3 7
Diagnosis
RDS, PDA RDS RiDS RDS iDS, PDA RDS RDS, PDA Myocardiopathy Meconium aspiration Coarctation of aorta, PD)A Transposition of the great arteries,
single ventricle Older children
12
3 yrs
11.80
PO
10.6
2
.3
13
3 yrs
12.83
PO
13.4
45
.4
14
11/2 yrs
8.07
PO
17.4
140
1.0
15
7 yrs
14.33
PO
17.2
180
.5
Congenital aortic stenosis and mitral insufficiency P.O. Tetralogy of Fallot with pulmonary atresia Tetralogy of Fallot with pulmonary atresia Congeniit.al mitr.al insufficiency
*Patients are listed in ascending order of duration of digoxin administration within each age group. Abbreviations: RDS = respiratory distress syndrome; PDA = patent ductus arteriosus; P.O. = postoperative. neonates was significantly higher than in older children, 1.9 ± 0.4 vs 0.6 + 0.3 ng/ml (P < 0.05). Since a plasma digoxin level had been determined in only one full-term neonate, it was not possible to make any comparison with this group. As shown in tables 2 and 3, there were considerable differences in digoxin concentrations among the various tissues, though the highest concentrations were always found in the kidney, the GI tract (stomach, small and large bowel, gall bladder and pancreas), myocardium and liver. Adipose tissue had the lowest concentrations. Heart
Myocardial concentrations of digoxin were considerably higher in the newborn period, in both the premature and full-term infants, the average level in the ventricles being about 190 ng/g in contrast to the mean concentration in older children of 70 ng/g. Analysis of individual patients yielded values higher than 100 ng/g for all newborns, with one exception, whereas two of the three older children in whom myocardial concentrations were measured had values less than 70 ng/g. The difference in concentration of digoxin in ventricular myocardium of infants versus children was significant (P < 0.05). Myocardial concentrations of digoxin were approximately equal in the right and left ventricles but were somewhat lower in the atria of neonates (122 ± 60 ng/g vs 188 ± 64 ng/g in ventricular myocardium). The ratios of ventricular myocardium to plasma were 99:1 in
premature neonates, and 114:1 in older children. The mean concentration of digoxin in the right atrium of older children in the present study, 67 ng/g, was comparable to the levels previously reported from this Table 2 Tissue Concentrations of Digoxin' Case #
Myocardium Left ventricle
Right ventricle
Premature neonates 1 282 2 136 3 117 4 228 238 .5 6 197 7 109 187 Mean 67 SD i
Skeletal muscle
323 168 103 220 169 212 142 191 71
Kidney
Liver
Fat
19 144
106
.36
358 101 24 38 23 37 -33
102 39 96 33 73 -43
19 76 82
16 3 6 3 13 7
26 31 16
228 277 121 166 198 - 69
-34
231
19 33
11
1s
39 31
36
8
-34
3
38
3 7
Full-term nconates 8 9 10 11
196
168 247
231
63
160
238 Mean 180 SD -84 Older children 44 12 64 13 14 13 71 60 Mean -14 SD
3196 =s-.36 40 69 114
74 37
32
-17 1 7 11 14 8 -6
213 232 -27
*Values are ng/g wet weight of tissue.
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KIM ET AL.
1130 Table 3
Tissue Concentrations of Digoxin* Spleen
Skin
Premiature neonates 12 13 Mean SD
-2
-7
(N)
(5)
(7)
Lung
27 -7
(4)
Full-term neonates 22 16 Mean -6 -13 SD
26 14
(N)
(3)
(4)
Older children Mean 8 -5 SD (N) (3)
(4) 38 30 (4)
17 -5
(2)
Gall Small Large Brain Adrenal Thyroid Thymus Testicle Ovary Pancreas Stomach intestine intestine bladder
7 -8
16 14
30 -9
18 -6
(4)
(6)
(5)
(4)
14
25
32
1o
-1o --7
(4) 21 -12
(3)
(3) 14 -7
(3)
(4) 21 18
(2)
(4) 6
(1)
6
14
27
23
-3
-
(2)
(1)
10 (5)
14 (7)
15 813
-
(3)
61
31
22
-21
(2) 4
(1)
21 4
(4) 71 =-67
(2)
53 431 (7)
54 -40 (7)
93 -62 (4)
70 51 (4)
14 -6 (3)
71 18 9 15
i
(4)
52 -22
75
70 -107 (4) (3)
i69 (3)
(3)
33 -36 (6)
Urinary bladder
(2)
11
(1)
*Values are ng/g wet weight of tissue.
laboratory for 17 surgical patients on chronic digoxin maintenance therapy, 62 ± 6 ng/g.9 Skeletal Muscle
Skeletal muscle concentrations of digoxin were also considerably higher in the newborn groups than in older children, 37 and 32 ng/g vs 8 ng/g. Analysis of individual patients revealed values higher than 20 ng/g in most newborn infants and values lower than 15 ng/g in the older age group. Skeletal muscle to plasma digoxin ratios were 19:1 in premature neonates and 13:1 in older children. Kidney
In contrast to myocardium and skeletal muscle, the concentration of digoxin in the kidney was much lower in premature neonates (73 ng/g) than in full-term neonates and older children (198 and 232
mean
ng/g, respectively). All premature infants, with
one
exception, had renal tissue concentrations of digoxin lower than 102 ng/g, while, excluding one patient, all full-term and older children had renal concentrations above 166 ng/g. The difference in concentration of digoxin in prematures versus full-term infants and children was significant (P < 0.05). In four patients in
whom both renal cortex and medulla were analyzed, no significant difference in the two regions was found.
the organs of the GI tract, stomach, small and large bowel, gall bladder and pancreas had relatively high concentrations. However, these varied considerably from case to case, probably due to differences in the time and mode of administration of the drug and whether elixir or tablets were used. It is interesting to note that digoxin concentrations ranging from 11-86 ng/g were found in the GI tract following parenteral administration, suggesting biliary excretion. In the liver, mean digoxin concentrations ranged from 41-56 ng/g, and did not differ among the three groups. Discussion
Few studies have systematically examined digoxin concentrations in human tissues obtained at autopsy. Available studies are summarized in table 4. Doherty et al.1 administered 3H-digoxin to adults near expected time of death and found the highest concentrations occurred in the heart, kidney and liver, similar to our findings. In patients with normal renal function digoxin concentrations were higher in the kidney than in the myocardium, while the reverse was true with patients who were in renal failure. Jelliffe and Stephenson2 used a fluorometric method for measurement of left ventricular digoxin concentration Table 4 Summary of Previous Studies of Postmortem Tissue Digoxin
Other Tissues
With the exception of the kidney, skin, brain and stomach, all other organs had higher concentations of digoxin in tissues from both prematures and full-term neonates (table 3). In most tissues, the digoxin concentration ranged from 5-25 ng/g in all age groups. In addition to skeletal muscle, the spleen and adipose tissue also had levels below 12 ng/g in older children. Conversely,
Group
Tissue
Adults Myoc ardium Adults LV LV Adtults Elderly LV aduilts LV Adults Abbreviations: LV assav.
N
Mean i SEM
7 11
(ng/g)
Method
Reference
8S5 5-202
3H-digoxin
1 2
FluIoIonietric
4
158
-
43
ItLA
3
13 15
112 97
-
13 16
1IA RIAe
4
=
-
left venitricle; ItIA
=
radioimmuno-
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POSTMORTEM TISSUE DIGOXIN
and found a wide range of 5-202 ng/g. Toxicity was associated with levels of 210 and 262 ng/g. The wide variability probably was due to the time between dosage and death and possibly methodologic factors. Isalo and Nuutila3 found rather higher levels in four adults using the radioimmunoassay procedure. These levels were lower than adults dying in situations believed to represent digitalis toxicity. The studies of Karjalainen et al.4 and of Jusko and Weintraub5 are probably the best data in adults since they contain a reasonable number of patients and utilize the radioimmunoassay procedure. It is impressive that their mean values are very similar, both being about 100 ng/g. The only previous report which presents data on tissue concentrations of digoxin in children is that of Hernandez et al.6 Tritiated digoxin was administered to nine children prior to cardiac surgery and extracorporeal circulation. Two of these children died postoperatively and the digoxin concentrations were determined in heart, liver and kidney. Unfortunately the results were expressed in percent of total radioactivity and cannot be directly compared with the literature data for adults or with the data in the present report. It can be seen that the mean concentrations for ventricular digoxin in both premature and full-term newborns in this study exceed those described above in adults by almost a factor of two-fold. In contrast, the mean level of 74 ng/g in the older children, though somewhat lower than the mean for adults, is more compatible with those values. The high tissue concentrations in infants may correlate with the frequent observation of electrocardiographic and other clinical signs of digitalis toxicity.7' 10 High concentrations relative to findings in older children and adults were not limited to the myocardium but were found also in skeletal muscle; in fact in almost all tissues analyzed the concentrations of digoxin were higher for neonates than older children or adults. A remarkable exception was the renal concentration of digoxin which was found to be markedly lower in premature infants than in full-term newborns or older children. As noted above, Doherty et al.1 found that adults with renal failure had lower concentrations of digoxin in the kidney than those with normal renal function. However, Karjalainen et al.4 found concentrations in the renal cortex of patients with high serum creatinine concentrations not to differ significantly from patients with normal serum creatinine concentrations, though concentrations in papillary muscle, left ventricle, right ventricle, etc., were higher in the patients with reduced renal function. Thus from these studies it is not clear whether the concentration of digoxin in the kidney reflects
1131
renal function. Nonetheless, many investigators have shown that in newborn infants renal function, as measured by creatinine or inulin clearance, is greatly decreased compared to older children.1" The limited ability of the newborn tot excrete various antibiotics and other drugs via the renal route has also been well recognized and this limited function is more pronounced in premature infants. The present data suggest that, in the premature, decreased renal function, perhaps reflected by the low renal concentrations of digoxin, contributes importantly to the increased levels of the drug in plasma and other tissues despite the relatively small doses administered as compared to the older infant. These doses may in fact be excessive and our present data force one to re-evaluate the safety and necessity of commonly recommended digoxin doses. In full-term neonates the high tissue and plasma concentrations of digoxin probably result from both somewhat impaired renal excretion and high doses of digoxin routinely administered to such infants. Again, the high myocardial concentrations lead one to speculate that such doses may be harmful. Acknowledgment We gratefully acknowledge the expert technical assistance of Mrs. Shirley Green and excellent secretarial assistance of Mrs. Bernice Senger.
References 1. DOHERTY JE, PERKINS WH, FLANNIGAN WJ: The distribution and concentration of tritiated digoxin in human tissues. Ann Intern Med 66: 116, 1967 2. JELLIFFE RE, STEPHENSON RG: A fluorometric determination of myocardial digoxin at autopsy, with identification of digitalis leaf, digitoxin and gitoxin. Am J Clin Pathol 51: 347, 1969 3. ISALo E, NULTILA M: Myocardial digoxin concentrations in fatal intoxications. Lancet 1: 257, 1973 4. KARJALAINEN J, OJALA K, REISSEL P: Tissue concentrations of digoxin in autopsy material. Acta Pharmacol Toxicol 34: 385, 1974 5. JUSKO WJ, WEINTRAUB M: Myocardial distribution of digoxin and renal function. Clin Pharmacol Ther 16: 449, 1974 6. HERNANDEZ A, KOUCHOUKos N, BURTON RM, GOLDRING D: The effect of extracorporeal circulation upon the tissue concentration of digoxin-H'. Pediatrics 31: 952, 1963 7. LEVINE OR, BLUMENTHAL S: Digoxin dosage in premature infants. Pediatrics 29: 18, 1962 8. KRASULA RW, PELLEGRINO PA, HASTREITER AR, SOYKA LF: Serum levels of digoxin in infants and children. J Pediatr 81: 566, 1972 9. KRASULA RW, HASTREITER AR, LEVITSKY S, YANAGI R, SOYKA LF: Serum, atrial and urinary digoxin levels during cardiopulmonary bypass in children. Circulation 49: 1047, 1974 10. KRASULA RW, YANAGI R, HASTREITER AR, LEVITSKY S, SOYKA LF: Digoxin intoxication in infants and children. J Pediatr 84: 265, 1974 11. M( CRORY WW: Renal function in the postnatal period. In Developmental Nephrology. Cambridge, Harvard University Press, 1972, pp 123-161
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Postmortem tissue digoxin concentrations in infants and children. P W Kim, R W Krasula, L F Soyka and A R Hastreiter Circulation. 1975;52:1128-1131 doi: 10.1161/01.CIR.52.6.1128 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1975 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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ALOIs R. HASTREITER, M. D.
SUMMARY The concentrations of digoxin in tissues of premature infants, full-term infants and older children ob-
tained at autopsy were determined by a radioimmunoassay procedure. Infants were found to have much higher concentrations in the right and left ventricle (about 190 ng/g) than older children (about 70 ng/g) and adults as reported in the literature. Renal concentrations were lower in the premature group which may be related to their limited excretory capacity for digoxin. The relatively high myocardial concentrations of digoxin found in this study suggest that the usually recommended doses for infants may be excessive. quots of plasma were assayed directly. Tissue samples were homogenized in absolute ethanol for 30 sec with an Omnimixer (Ivan Sorvall, Inc., Norwalk, Conn.). The homogenates were centrifuged at 1000 g for 10 min and the supernatants removed. The precipitates were re-extracted in additional ethanol. The combined supernatants were evaporated to dryness, and resuspended in phosphate-bovine serum albumin buffer. After administration of 3H-digoxin to guinea pigs, 95% of myocardial radioactivity was extracted by this method. The extracted digoxin was bound by antiserum with an affinity
T HE LITERATURE contains little information on postmortem tissue concentrations of digoxin in adults'-5 and there is only one such report in children.6 The present study is the first to analyze postmortem tissue concentrations of digoxin in three groups of children: premature infants, full-term newborn infants and older children who received digoxin prior to death. The purpose of the study was to determine if the distribution of the drug in various tissues differed
among these groups, because altered distribution may have therapeutic implications. We were particularly concerned that the limited capacity for renal excretion of drugs by the neonate, especially the premature infant, might affect the pharmacokinetics as known in older children and adults. In premature neonates, clinical and electrocardiographic signs of digitalis toxicity are observed more frequently and may follow the use of relatively small doses of digoxin.7 Doses of digoxin currently recommended for premature infants have been derived empirically for there have been to date few, if any, objective data establishing agedependent differences in the pharmacodynamics of digoxin. Assay Procedures
identical to that of nonextracted digoxin.9 Patient Material
Tissue samples were obtained at autopsy from seven premature infants, four full-term newborn infants and four older children who received digoxin because of congestive heart failure secondary to cardiac or pulmonary pathology. In most cases, digoxin concentration was also determined on plasma samples obtained one or two days prior to death. These samples were collected six to eight hours following administration of the drug. None of the patients exhibited signs or symptoms of digitalis toxicity.
Results
Age at death, body weight, route of administration, daily dose, duration of administration, plasma digoxin levels, and diagnoses are listed in table 1. While the mean age at death of the premature and full-term newborn infants studied were similar, mean body weight and surface area differed significantly (P < 0.05). The average daily dose (on a body weight basis) administered to the premature infants was less than one-half that given to full-term newborns, while the average dose for the group of older children was about two-thirds that for full-term neonates. The duration of digoxin administration was comparable in premature and full-term newborns but was considerably longer in the group of older children. Equilibrium plasma digoxin levels (six to eight hours following administration of the drug) were measured within 24 hours of the time of death. The mean concentration in premature
Materials and Methods
Digoxin was measured by a radioimmunoassay (RIA) in our laboratory." One-tenth ml ali-
procedure developed
From the Sections of Pediatric Cardiology and Clinical Pharmacology, University of Illinois Hospital, Abraham Lincoln School of Medicine, Chicago, Illinois. Supported in part by the University of Illinois Foundation, Goodenberger Medical Research Grant 2-44-33-66-3-14, and
USPHS Grant HD-08708. Dr. Soyka's present address is Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont 05401. Address for reprints: Alois R. Hastreiter, M.D., University of Illinois Hospital, 840 South Wood Street, Chicago, Illinois 60612. Received March 21, 1975; revision accepted for publication June 26, 1975.
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POSTMORTEM TISSUE DIGOXIN
Table 1 Age, Weight, Diagnosis and Parameters of Digoxin Administration*
Case
Premature neonates
Full-term neonates
1 2 3 4 5 6 7 8
9 10 11
Daily digoxin dose (mcg kg'
Durat. digoxin admn. (days)
Digoxin serum level (ng/ml)
17.5 17.0 8.6 7.0 6.8 4.8 2.6
1 1 2
2.3 2.2
3
1.6 2.0 1.3 2.7
Age (days)
Weight (kg)
Route admn. digoxin
2 4 3 13 10 12 24 4 2 9 11
1.14 2.05 2.32 1.44 1.91 1.33 1.49 3.10 3.60 2.50 3.77
IB1 IV PO PO PO PO PO PO IV IM PO
30.0 33.3 10.0 21.2
6 8 9 1 1 3 7
Diagnosis
RDS, PDA RDS RiDS RDS iDS, PDA RDS RDS, PDA Myocardiopathy Meconium aspiration Coarctation of aorta, PD)A Transposition of the great arteries,
single ventricle Older children
12
3 yrs
11.80
PO
10.6
2
.3
13
3 yrs
12.83
PO
13.4
45
.4
14
11/2 yrs
8.07
PO
17.4
140
1.0
15
7 yrs
14.33
PO
17.2
180
.5
Congenital aortic stenosis and mitral insufficiency P.O. Tetralogy of Fallot with pulmonary atresia Tetralogy of Fallot with pulmonary atresia Congeniit.al mitr.al insufficiency
*Patients are listed in ascending order of duration of digoxin administration within each age group. Abbreviations: RDS = respiratory distress syndrome; PDA = patent ductus arteriosus; P.O. = postoperative. neonates was significantly higher than in older children, 1.9 ± 0.4 vs 0.6 + 0.3 ng/ml (P < 0.05). Since a plasma digoxin level had been determined in only one full-term neonate, it was not possible to make any comparison with this group. As shown in tables 2 and 3, there were considerable differences in digoxin concentrations among the various tissues, though the highest concentrations were always found in the kidney, the GI tract (stomach, small and large bowel, gall bladder and pancreas), myocardium and liver. Adipose tissue had the lowest concentrations. Heart
Myocardial concentrations of digoxin were considerably higher in the newborn period, in both the premature and full-term infants, the average level in the ventricles being about 190 ng/g in contrast to the mean concentration in older children of 70 ng/g. Analysis of individual patients yielded values higher than 100 ng/g for all newborns, with one exception, whereas two of the three older children in whom myocardial concentrations were measured had values less than 70 ng/g. The difference in concentration of digoxin in ventricular myocardium of infants versus children was significant (P < 0.05). Myocardial concentrations of digoxin were approximately equal in the right and left ventricles but were somewhat lower in the atria of neonates (122 ± 60 ng/g vs 188 ± 64 ng/g in ventricular myocardium). The ratios of ventricular myocardium to plasma were 99:1 in
premature neonates, and 114:1 in older children. The mean concentration of digoxin in the right atrium of older children in the present study, 67 ng/g, was comparable to the levels previously reported from this Table 2 Tissue Concentrations of Digoxin' Case #
Myocardium Left ventricle
Right ventricle
Premature neonates 1 282 2 136 3 117 4 228 238 .5 6 197 7 109 187 Mean 67 SD i
Skeletal muscle
323 168 103 220 169 212 142 191 71
Kidney
Liver
Fat
19 144
106
.36
358 101 24 38 23 37 -33
102 39 96 33 73 -43
19 76 82
16 3 6 3 13 7
26 31 16
228 277 121 166 198 - 69
-34
231
19 33
11
1s
39 31
36
8
-34
3
38
3 7
Full-term nconates 8 9 10 11
196
168 247
231
63
160
238 Mean 180 SD -84 Older children 44 12 64 13 14 13 71 60 Mean -14 SD
3196 =s-.36 40 69 114
74 37
32
-17 1 7 11 14 8 -6
213 232 -27
*Values are ng/g wet weight of tissue.
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61 11 90
3(0
32 77 41
2;5)
4 9 6 -2 1 1 4 10 4 4
KIM ET AL.
1130 Table 3
Tissue Concentrations of Digoxin* Spleen
Skin
Premiature neonates 12 13 Mean SD
-2
-7
(N)
(5)
(7)
Lung
27 -7
(4)
Full-term neonates 22 16 Mean -6 -13 SD
26 14
(N)
(3)
(4)
Older children Mean 8 -5 SD (N) (3)
(4) 38 30 (4)
17 -5
(2)
Gall Small Large Brain Adrenal Thyroid Thymus Testicle Ovary Pancreas Stomach intestine intestine bladder
7 -8
16 14
30 -9
18 -6
(4)
(6)
(5)
(4)
14
25
32
1o
-1o --7
(4) 21 -12
(3)
(3) 14 -7
(3)
(4) 21 18
(2)
(4) 6
(1)
6
14
27
23
-3
-
(2)
(1)
10 (5)
14 (7)
15 813
-
(3)
61
31
22
-21
(2) 4
(1)
21 4
(4) 71 =-67
(2)
53 431 (7)
54 -40 (7)
93 -62 (4)
70 51 (4)
14 -6 (3)
71 18 9 15
i
(4)
52 -22
75
70 -107 (4) (3)
i69 (3)
(3)
33 -36 (6)
Urinary bladder
(2)
11
(1)
*Values are ng/g wet weight of tissue.
laboratory for 17 surgical patients on chronic digoxin maintenance therapy, 62 ± 6 ng/g.9 Skeletal Muscle
Skeletal muscle concentrations of digoxin were also considerably higher in the newborn groups than in older children, 37 and 32 ng/g vs 8 ng/g. Analysis of individual patients revealed values higher than 20 ng/g in most newborn infants and values lower than 15 ng/g in the older age group. Skeletal muscle to plasma digoxin ratios were 19:1 in premature neonates and 13:1 in older children. Kidney
In contrast to myocardium and skeletal muscle, the concentration of digoxin in the kidney was much lower in premature neonates (73 ng/g) than in full-term neonates and older children (198 and 232
mean
ng/g, respectively). All premature infants, with
one
exception, had renal tissue concentrations of digoxin lower than 102 ng/g, while, excluding one patient, all full-term and older children had renal concentrations above 166 ng/g. The difference in concentration of digoxin in prematures versus full-term infants and children was significant (P < 0.05). In four patients in
whom both renal cortex and medulla were analyzed, no significant difference in the two regions was found.
the organs of the GI tract, stomach, small and large bowel, gall bladder and pancreas had relatively high concentrations. However, these varied considerably from case to case, probably due to differences in the time and mode of administration of the drug and whether elixir or tablets were used. It is interesting to note that digoxin concentrations ranging from 11-86 ng/g were found in the GI tract following parenteral administration, suggesting biliary excretion. In the liver, mean digoxin concentrations ranged from 41-56 ng/g, and did not differ among the three groups. Discussion
Few studies have systematically examined digoxin concentrations in human tissues obtained at autopsy. Available studies are summarized in table 4. Doherty et al.1 administered 3H-digoxin to adults near expected time of death and found the highest concentrations occurred in the heart, kidney and liver, similar to our findings. In patients with normal renal function digoxin concentrations were higher in the kidney than in the myocardium, while the reverse was true with patients who were in renal failure. Jelliffe and Stephenson2 used a fluorometric method for measurement of left ventricular digoxin concentration Table 4 Summary of Previous Studies of Postmortem Tissue Digoxin
Other Tissues
With the exception of the kidney, skin, brain and stomach, all other organs had higher concentations of digoxin in tissues from both prematures and full-term neonates (table 3). In most tissues, the digoxin concentration ranged from 5-25 ng/g in all age groups. In addition to skeletal muscle, the spleen and adipose tissue also had levels below 12 ng/g in older children. Conversely,
Group
Tissue
Adults Myoc ardium Adults LV LV Adtults Elderly LV aduilts LV Adults Abbreviations: LV assav.
N
Mean i SEM
7 11
(ng/g)
Method
Reference
8S5 5-202
3H-digoxin
1 2
FluIoIonietric
4
158
-
43
ItLA
3
13 15
112 97
-
13 16
1IA RIAe
4
=
-
left venitricle; ItIA
=
radioimmuno-
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POSTMORTEM TISSUE DIGOXIN
and found a wide range of 5-202 ng/g. Toxicity was associated with levels of 210 and 262 ng/g. The wide variability probably was due to the time between dosage and death and possibly methodologic factors. Isalo and Nuutila3 found rather higher levels in four adults using the radioimmunoassay procedure. These levels were lower than adults dying in situations believed to represent digitalis toxicity. The studies of Karjalainen et al.4 and of Jusko and Weintraub5 are probably the best data in adults since they contain a reasonable number of patients and utilize the radioimmunoassay procedure. It is impressive that their mean values are very similar, both being about 100 ng/g. The only previous report which presents data on tissue concentrations of digoxin in children is that of Hernandez et al.6 Tritiated digoxin was administered to nine children prior to cardiac surgery and extracorporeal circulation. Two of these children died postoperatively and the digoxin concentrations were determined in heart, liver and kidney. Unfortunately the results were expressed in percent of total radioactivity and cannot be directly compared with the literature data for adults or with the data in the present report. It can be seen that the mean concentrations for ventricular digoxin in both premature and full-term newborns in this study exceed those described above in adults by almost a factor of two-fold. In contrast, the mean level of 74 ng/g in the older children, though somewhat lower than the mean for adults, is more compatible with those values. The high tissue concentrations in infants may correlate with the frequent observation of electrocardiographic and other clinical signs of digitalis toxicity.7' 10 High concentrations relative to findings in older children and adults were not limited to the myocardium but were found also in skeletal muscle; in fact in almost all tissues analyzed the concentrations of digoxin were higher for neonates than older children or adults. A remarkable exception was the renal concentration of digoxin which was found to be markedly lower in premature infants than in full-term newborns or older children. As noted above, Doherty et al.1 found that adults with renal failure had lower concentrations of digoxin in the kidney than those with normal renal function. However, Karjalainen et al.4 found concentrations in the renal cortex of patients with high serum creatinine concentrations not to differ significantly from patients with normal serum creatinine concentrations, though concentrations in papillary muscle, left ventricle, right ventricle, etc., were higher in the patients with reduced renal function. Thus from these studies it is not clear whether the concentration of digoxin in the kidney reflects
1131
renal function. Nonetheless, many investigators have shown that in newborn infants renal function, as measured by creatinine or inulin clearance, is greatly decreased compared to older children.1" The limited ability of the newborn tot excrete various antibiotics and other drugs via the renal route has also been well recognized and this limited function is more pronounced in premature infants. The present data suggest that, in the premature, decreased renal function, perhaps reflected by the low renal concentrations of digoxin, contributes importantly to the increased levels of the drug in plasma and other tissues despite the relatively small doses administered as compared to the older infant. These doses may in fact be excessive and our present data force one to re-evaluate the safety and necessity of commonly recommended digoxin doses. In full-term neonates the high tissue and plasma concentrations of digoxin probably result from both somewhat impaired renal excretion and high doses of digoxin routinely administered to such infants. Again, the high myocardial concentrations lead one to speculate that such doses may be harmful. Acknowledgment We gratefully acknowledge the expert technical assistance of Mrs. Shirley Green and excellent secretarial assistance of Mrs. Bernice Senger.
References 1. DOHERTY JE, PERKINS WH, FLANNIGAN WJ: The distribution and concentration of tritiated digoxin in human tissues. Ann Intern Med 66: 116, 1967 2. JELLIFFE RE, STEPHENSON RG: A fluorometric determination of myocardial digoxin at autopsy, with identification of digitalis leaf, digitoxin and gitoxin. Am J Clin Pathol 51: 347, 1969 3. ISALo E, NULTILA M: Myocardial digoxin concentrations in fatal intoxications. Lancet 1: 257, 1973 4. KARJALAINEN J, OJALA K, REISSEL P: Tissue concentrations of digoxin in autopsy material. Acta Pharmacol Toxicol 34: 385, 1974 5. JUSKO WJ, WEINTRAUB M: Myocardial distribution of digoxin and renal function. Clin Pharmacol Ther 16: 449, 1974 6. HERNANDEZ A, KOUCHOUKos N, BURTON RM, GOLDRING D: The effect of extracorporeal circulation upon the tissue concentration of digoxin-H'. Pediatrics 31: 952, 1963 7. LEVINE OR, BLUMENTHAL S: Digoxin dosage in premature infants. Pediatrics 29: 18, 1962 8. KRASULA RW, PELLEGRINO PA, HASTREITER AR, SOYKA LF: Serum levels of digoxin in infants and children. J Pediatr 81: 566, 1972 9. KRASULA RW, HASTREITER AR, LEVITSKY S, YANAGI R, SOYKA LF: Serum, atrial and urinary digoxin levels during cardiopulmonary bypass in children. Circulation 49: 1047, 1974 10. KRASULA RW, YANAGI R, HASTREITER AR, LEVITSKY S, SOYKA LF: Digoxin intoxication in infants and children. J Pediatr 84: 265, 1974 11. M( CRORY WW: Renal function in the postnatal period. In Developmental Nephrology. Cambridge, Harvard University Press, 1972, pp 123-161
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Postmortem tissue digoxin concentrations in infants and children. P W Kim, R W Krasula, L F Soyka and A R Hastreiter Circulation. 1975;52:1128-1131 doi: 10.1161/01.CIR.52.6.1128 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1975 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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