Paradoxical behavior of serum digoxin concentrations in an anuric neonate

Paradoxical behavior of serum digoxin concentrations in an anuric neonate

September 1977 The J o u r n a l o f P E D I A T R I C S 487 Paradoxical behavior o f serum digoxin concentrations in an anuric neonate Serum digoxi...

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September 1977 The J o u r n a l o f P E D I A T R I C S

487

Paradoxical behavior o f serum digoxin concentrations in an anuric neonate Serum digoxin values were determined in a newborn infant with severe heart failure and renal failure. The half-life o f digoxin in the serum appeared to change, possibly the result o f prolonged distribution and~or absorption owing to circulatory insufficiency, or to the accumulation o f cross-reacting metabolites of digoxin in the serum. No clinical toxicity was apparent, and no cardiac arrhythmia was observed. The need for monitoring serum digoxin concentration and clinical effect in newborn infants is emphasized.

Stanley J. Szefler, M.D.,* Jeffrey R. Koup, Pharm.D., and George P. Giacoia, M.D., Buffalo, N. Y.

THE PHARMACOLOGY AND PHARMACOKINETICS of digoxin have been the subject of extensive research. Available data have been reviewed by Smith and H a b e r 1 for adults and by Morselii and associates ~ in children. Digoxin distributes extensively into muscle tissue and is primarily eliminated by glomerular filtration. N o m o grams for the adjustment of the dose of digoxin based on estimates of renal function have been useful in the reduction of digoxin toxicity in adults.:' The continuous state of change of renal and hepatic function during the neonatal period confounds predictive methods and necessitates close monitoring of therapy in the individual patient. We recently had the opportunity to treat a newborn infant with severe renal failure and heart failure secondary to coarctation of the aorta. The changing halflife of digoxin in the serum of this anuric patient was totally unexpected and emphasizes the need for careful clinical observation and frequent analysis of serum digoxin concentration in this type of patient.

METHODS All serum digoxin concentrations were measured by the A b - T R A C digoxin solid-phase radioimmunoassay From the Departments o f Pediatrics and Pharmaceutics, State University o f New York at Buffalo, and Children's Hospital o f Buffalo. *Reprint address': Regional Intensive Care Unit, Division of Neonatology, Children's Hos)vital of Bz{ff'alo, 219 Bryant St., Buffalo, N Y 14222.

(Schwarz/Mann). The concentration of digoxin in peritoneal fluid was measured by the above method after appropriate addition of blank plasma.

CASE REPORT Patient D. N., a two-day-old male infant, was admitted for evaluation of cyanosis and tachypnea. He was the 6 pound, i ounces (2.65 kg), product of a term, uncomplicated pregnahcy, delivered by cesarean section because of previous cesarean section. After two uneventful days the infant became lethargic and was feeding poorly; he subsequently developed cyanosis and Abbreviations used SDC: serum digoxin concentration im: intramuscular SGOT: serum glutamic oxalacetic transaminase SGPT: serum glutamic pyruvic transaminase PT: prothrombin time PTT: partial thromboplastin time BUN: blood urea nitrogen respiratory distress. He was pale, ashen-gray, and in severe respiratory distress with poor peripheral pulses; femoral pulses were difficult to palpate. Auscultation revealed an S~ gallop with no murmur. The liver was palpable 4 cm below the right midclavicular line. Cardiomegaly and increased pulmonary vascular markings were noted on a chest radiograph. Arterial blood gas values were: pH 7.12, Po~ 80, Pco~ 14, total CO~ 5, and base excess -25. An electrocardiogram demonstrated biventricular hypertrophy with a QRS axis of + 120~ Cardiac catheterization revealed coarctation of the aorta, muscular ventricular septal defect, pulmonary

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Szefler, Koup, and Giacoia

The Journal of Pediatrics September 1977

Serum Digoxin 6T

kidneys, the first scan did show a relatively heavier deposit of isotope in the liver as compared to that in the second scan, suggesting deterioration of liver function. Other indices of liver function also indicated deterioration: Values observed on day one were SGOT 1145, SGPT 309, PT 26.4/12.4 (control) seconds, PTT 54.4/34.4 (control) seconds, fibrinogen 69 mg/dl, direct bilirubin 0.7 mg/dl, and total bilirubin 3.5 mg/dl. Values obtained on day 10 were: SGOT 185, SGPT 139, PT 18.9/11.8 seconds, PTT 73.9/31.4 seconds, fibrinogen 36 mg/dl, direct bilirubin 14.0 mg/dl, and total bilirubin 16.8 mg/dl. A renal arteriogram performed on day 17 demonstrated a lack of renal perfusion. The patient's condition continued to deteriorate, leading to death. Digoxin doses, SDC, and serum creatinine values are summarized in Fig. 1.

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D0y Fig. 1. Serum digoxin concentration and serum creatinine values related to doses of digoxin in Patient D. N. hypertension, and minimal flow through the ductus arteriosus. The patient was begun on digoxin therapy, receiving an initial im dose of 20 ~g/kg. At this point, he was noted to have oliguria (urine output less than 10 ml/kg/day) which persisted. Initial serum creatinine concentration was 2.9 mg/dl and BUN was 29.2 mg/dl. The second dose of digoxin was reduced to 5 mg/kg im. Eighteen hours after the second dose SDC was 4.2 ng/ml. SDC decreased without further therapy to 1.7 ng/ml on day four, suggesting a half-life of 1.5 days. In view of the apparently normal elimination, digoxin maintenance therapy was reinstituted at a dose of 5 ~g/kg im every 12 hours. A SDC of 5.2 ng/ml was reported from a sample drawn at the time of the sixth dose of digoxin. Digoxin therapy was again discontinued. SDC values remained elevated for three days and then declined, giving an apparent half-life of approximately ten days. On day eight, the serum creatinine concentration was 6.5 mg/d!, the BUN was 95.6 mg/dl, and there was clinical evidence of fluid overload. Based on these observation s peritoneal dialysis was begun. The peritoneal clearance of digoxin was measured on day nine as 0.5 ml/ minute. Despite the high serum digoxin concentrations noted during the patient's course, there was no apparent digoxin toxicity and also no evidence of cardiac arrhythmia on the cardiac monitor. A technetium sulfur colloid scan was obtained on days six and 14 [o assess renal function. Though there was no deposit in the

Several observations in this patient merit discussion. The first is the initial apparent half-life o f 1.5 days in a neonate with markedly impaired renal function. This value was estimated from the plot of five consecutive SDC determinations over two days. The resultant value is much lower than expected in view of the degree of renal impairment. The half-life of digoxin reported in neonates with normal renal function is extremely variable, but is in the range o f 1.25 to 1.5 d a y s # ~ Assuming that the same percentage of digoxin is eliminated by the kidneys in neonates as in adults (75%)? one would predict a half-life in the range of five to six days in an anuric neonate. When maintenance therapy was reinstituted at a normal dose of 5/~g/kg every 12 hours, the rate and the extent of accumulation of digoxin indicated that the true half-life of elimination in this patient must have been much longer than 1.5 days. The ten-day half-life observed after the second cessation of therapy is more consistent with the clinical findings of renal and hepatic failure. A possible explanation for the low initial estimate of half-life is that we were observing prolonged distribution as well as elimination of digoxin. The extensive distribution of digoxin into tissue is generally completed within six to eight hours after administration in adults: A similar time course of distribution has been observed in neonates. ~ " It would seem likely, however, that in a neonate with severe circulatory insufficiency, the distribution process could be markedly prolonged. The second noteworthy p h e n o m e n o n observed was the failure of SDC to decline for three days after the cessation of therapy on day seven. Prolonged absorption of digoxin from intramuscular injection sites has been reported# Absorption from im sites would be expected to be slower in patients with circulatory insufficiency. It would seem unlikely, however, that prolonged absorption alone would account for maintenance of high levels for three days. An alternative explanation would be that metabolites of

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digoxin were accumulating in the serum. K r a m e r and associates s have demonstrated cross reactivity of dihydrodigoxin, an inactive metabolite, with the antibody to digoxin used in commercial radioimmunoassay methodologies. Dihydrodigoxin concentrations of 1, 2, and 4 n g / ml in serum are measured by radioimmunoassay as 0.4, 0.8, and 1.3 n g / m l of digoxin, respectively. It would seem likely that this and other metabolites of digoxin may accumulate in an anuric patient and falsely elevate SDC. In patients with both renal and hepatic failure it is possible that the production as well as the elimination of these metabolites would be reduced. Thus, it is difficult to predict the magnitude of interference of these metabolites with SDC determination in this type of patient. The peritoneal clearance of digoxin of only 0.5 m l / minute accounts for removal of only 1.8 ~g/day via peritoneal dialysis. Assuming a body load of 30 ~g/kg of digoxin, only 2.3% of this a m o u n t would be removed per day during continuous peritoneal dialysis. This observation is in agreement with a previous report ~ which has demonstrated that dialysis is ineffective in the removal of digoxin, inefficient removal of digoxin by dialytic procedures results from the drug's extensive tissue distribution. Approximately 90% of digoxin in the body is located in the tissues and is thus not readily available for removal by dialysis? This experience demonstrates the need for monitoring digoxin serum concentration and clinical effect closely in

Paradoxical behavior o f serum digoxin

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newborn infants, especially those with renal failure. It may also serve to alert the clinician to potential sources of error in the interpretation of serum digoxin concentrations in the neonate. We acknowledge the technical assistance of Barbara Brodsky, Assoc. MbT, and Nelson Paolini, B.A., in the performance of the digoxin assays. REFERENCES

1. Smith TW, and Haber E: Digitalis, N Engl J Med 289:945, 1010, 1063, 1125, 1973. 2. Morselli PL, et al: Digoxin pharmacokinetics during human development in Morselli PL, Garattini S, and Sereni F, editors: Basic and therapeutic aspects of perinatal pharmacology, New York, 1975, Raven Press. 3. Jelliffe RW: Administration of digoxin, Dis Chest 56:56, 1969. 4. Dungan WT, et al: Tritiated digoxin XVIII studies in infants and children, Circulation 46:983, 1972. 5. Koup JR, Jusko WJ, Elwood CM, and Kohli RK: Digoxin pharmacokinetics: role of renal failure in dosage regimen design, Clin Pharmacol Ther 18:9, 1975. 6. Wettrell G: Digoxin therapy in infants, a clinical pharmacokinetic study, Acta Paediatr Scand (S):257, 1976. 7. Steiness E, Svenson O, and Rasmussen F: Plasma digoxin after parenteral administration: Local reaction after intramuscular injection, Clin Pharmacol Ther 16"430, 1974. 8. Kramer WG, Bathala MS, and Reuning RH: Specificity of the digoxin radioimmunoassay with respect to dihydrodigoxin, Res Commun Chem Pathol Pharmacol 14:83, 1976. 9. lisalo E, and Forsstr6m J: Elimination of digoxin during maintenance haemodialysis, Ann Clin Res 6:203, 1974.