Complications Associated with Digoxin Therapy in Low-Birth Weight Infants

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PEDIATRICS

Vol. 69

No. 4 April 1 982 463

Complications

Associated

with

Digoxin

Therapy

in Low-Birth

Weight

Infants

Gregory

L. Johnson,

MD,

Nirmala

S. Desai,

MBBS,

Thomas

H. Pauly,

MD,

and

M. Douglas

Cunningham,

MD

From the Department of Pediatrics, University of Kentucky College of Medicine,

Lexington

ABSTRACT. Eighteen infants, each weighing less than

1,500 gm, were treated with low dose digoxin therapy for

patent ductus arteriosus and signs of circulatory conges-tion. Nine ofthe 18 developed one or more signs of clinical deterioration felt to be related to digoxin therapy: eight infants experienced frequent episodes of bradycardia, six had cardiac arrhythmias, and six experienced feeding difficulties. All signs disappeared when digoxin therapy was discontinued. Digoxin, even in relatively low dosages,

can have deleterious complications in seriously ill low-birth-weight infants. Alternatives to digoxin in this

pa-tient population should be considered before institution of digoxin therapy. Pediatrics 69:463-465, 1982: digoxin,

digitalis glycosides, premature infants, cardiac arrhyth-mias.

The improved long-term prognosis for critically

ill low-birth-weight infants with respiratory distress

syndrome, patent ductus arteriosus, and signs of

circulatory congestion has maintained interest in

the use of cardiac glycosides for these patients. The

pharmacokinetics of digoxin disposition in these

infants has been well studied’3 and various dosage

regimens have been suggested.35 Reports of digoxin

toxicity in low-birth-weight infants have, however,

primarily related the incidence of toxicity to the

relatively high dosages used.3 The purpose of this

report is to describe the occurrence of clinically

deleterious effects following low-dose digoxin

ther-apy in low-birth-weight infants.

METHODS

During a 12-month period 18 premature infants

weighing less than 1,500 gm on admission to the

neonatal intensive care nursery of the University of

Received for publication Sept 15, 1980; accepted June 9, 1981. Reprint requests to (G.L.J.) Department of Pediatrics,

Univer-sity of Kentucky College of Medicine, 800 Rose St, Lexington, KY 40536.

American Academy of Pediatrics.

Kentucky Medical Center demonstrated signs of a

patent ductus arteriosus with cardiomegaly and

hepatomegaly and were treated with digoxin. No

infant received other chronotropic or ionotropic

agents. Birth weights ranged from 980 to 1,480 gm

and the birth weight of each infant was appropriate

for gestational age. Respiratory distress syndrome

was present in all infants. Urine output and urine

specific gravity, and levels of serum sodium,

potas-sium, calcium, and creatinine, and BUN were

mon-itored in all infants and were maintained within

physiologic ranges. Infants received 500 to 1,250 ml

of fluid/sq m/24 hr with added fluid for

photother-apy and radiant warmers. Parenteral furosemide

was administered when persistent signs of

circula-tory congestion were associated with decreasing

urine output and increasing urine osmolality.

Digoxin was administered parenterally in all

in-fants. Three infants received an initial loading dose

of .020 to .030 mg/kg over 24 to 36 hours, followed

by a maintenance dosage of .005 mg/kg every 12

hours. Fifteen infants received no initial loading

dose and were treated only with maintenance

dos-ages of .003 mg/kg (two infants), .004 mg/kg (three

infants), or .005 mg/kg (ten infants), administered

every 12 hours.

Following institution of digoxin therapy, infants

were continuously monitored for cardiac

arrhyth-mias, bradycardia (<100 beats per minute),

prolon-gation of PR interval over predigoxin values (.12

seconds in all) and signs of feeding intolerance

(abdominal distention with marked increase in

quantity of retained gastric contents but without

associated signs of enterocolitis).

Serum digoxin leveLs were measured utilizing a

radioimmunoassay technique.

RESULTS

Nine of the 18 infants treated developed signs of

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464

DIGOXIN

THERAPY

IN LOW-BIRTH-WEIGHT

INFANTS

TABLE. Abno rmal Clinical Signs C oncurrent with Digoxin T herapy in Low-Birth- Weight Infants*

Weight Age Digoxin Dosage Days of Ar- Brady- Feeding PR Inter- Digoxin Time to Outcome

(gm) Digoxin (mg/kg) Digoxin rhyth- cardia Intoler- val (Heart Level

Resolu-Started Therapy mia ance Rate) tion (hr)

(days) Loading

Mainte-nance

1,000 6 . . . .003 4 + + + .14 (160) 3.5 48 Survived

1,050 4 . . . .005 4 - + + .16 (130) 4.1 48 Survived

1,100 21 . . . .005 10 - + + .14 (150) NA 24 Survived

1,130 4 . . . .005 5 + + - -j. 4.0 48 Died with

DIC

1,180 7 .030 .004 4 + + + .14 (140) 4.0 48 Survived

1,200 14 .020 .005 14 + + - 3.6 48 Survived

1,230 3 . . . .005 11 + + - .13 (140) NA 48 Survived

1,270 3 . . . .005 4 + + + .13 (140) 3.5 48 Died with

1,280 3 . . . .005 5 - - + .14 (150) 3.7 72

sepsis

Survived

*Abbreviations used are: NA, not available; DIC, disseminated intravascular coagulopathy.

t PR interval not available due to arrhythmia.

therapy (Table). Eight of the nine infants

experi-enced repeated episodes of bradycardia; two

dem-onstrated periods of nodal rhythm, three had

inter-mittent second degree atrioventricular block and

one had complete atrioventricular dissociation. Six

infants developed signs of feeding intolerance. None

of these findings was demonstrable in any of the

nine remaining infants.

Sinus rhythm could be demonstrated at some

point in the continuous electrocardiographic

trac-ings in seven of the nine infants who developed

signs suggestive of digoxin-mediated effects. The

PR interval was prolonged over pretreatment

val-ues in each case and the mean PR interval for the

affected group was statistically different both from

pretreatment values (paired t = 8.65, P < .001) and

from values observed in the other nine infants (t =

6.07 P < .001). In the nine infants who did not

develop findings suggestive of digoxin-related

de-terioration, pretreatment PR intervals ranged from

.10 to .12 second and posttreatment intervals ranged

from .09 to .12 second (paired t = 0.78; P values

were not significant).

A serum digoxin level was obtained ten to 12

hours following the most recent administration of

digoxin in seven infants with clinical findings felt to

be related to digoxin and was 3.5 ng/ml in each

case. Measurements of serum levels were not

avail-able in the remaining 11 infants.

In infants who developed signs thought to be

related to digoxin administration, six developed

these signs following four to five days of therapy

and in three infants, signs were observed following

ten to 14 days of therapy. Of those who developed

signs at four to five days, all six were between 3 and

7 days of age when digoxin therapy was instituted.

In contrast, two of three infants who became

symp-tomatic after ten to 14 days of therapy were 14 days

of age or older before digoxin was administered.

Digoxin therapy was discontinued at the time of

development of the signs noted above. In all nine

infants, these signs resolved completely 24 to 72

hours following cessation of digoxin therapy. Seven

of the nine patients survived. There were two late deaths from noncardiac-related causes.

No significant differences were noted (Student’s

unpaired t test) in weight (mean 1,160 vs 1,191 gm),

gestational age (mean 29.6 vs 29.8 weeks), amount

of parenteral fluids administered (mean 915 vs 890

mi/sq m/24 hr), age at which digoxin was started

(mean 7.2 vs 7.8 days), or presence of an initial

digitalizing dose between infants who developed

signs suggestive of digoxin-mediated effects and

those who did not. Furosemide had been

adminis-tered to seven of the nine infants who developed

findings and to eight of the nine who did not. There

was no difference noted between the two groups

either in duration of furosemide therapy or in total

dose of furosemide received.

DISCUSSION

It is a fact that full-term infants more than 28

days of age and less than 1 year of age require more

digoxin per unit of body weight and tolerate high

serum levels of digoxin better than do older children

or adults.6’7 Whereas it is generally understood that

both full-term and premature infants are somewhat

more sensitive to digoxin in the first 28 days of life

than are these older infants, there are few clinical

reports of digoxin usage in low-birth-weight

new-borns. This report describes a high incidence of

cardiac arrhythmias and frequent episodes of

bradycardia in premature infants weighing less than

1,500 gm receiving low-dose digoxin therapy.

Whereas significant serum digoxin levels were

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ARTICLES

465

ent in these infants, levels were not within the

ranges generally associated with overt digoxin

tox-icity in the newborn, nor were levels available for

comparison in the infants who did not develop signs

of clinical deterioration. The findings noted in our

patients did, however, resolve with discontinuance

of digoxin therapy, further suggesting that the low

doses initially administered may have been

toxi-genic.

In adults, the most ominous clinical

manifesta-tions of digoxin toxicity are those related to

drug-mediated effects on cardiac automaticity. The

car-diac findings noted in our group of patients, in

contrast, would seem to be related simply to the

effects of digoxin on conduction, either directly or

indirectly through the vagotonic effects of the drug.

Early experimental evidence suggests that

imma-ture animals, in contrast to adult animals,

experi-ence marked depression of sinus and

atrioventric-ular nodal function without increases in ventricular

automaticity when digitalis glycosides are

admin-istered.8 In addition, most low-birth-weight infants

receiving digoxin therapy are seriously ill. The

con-sequences of frequent repeated episodes of

brady-cardia or cardiac arrhythmia in this patient group,

particularly in light of the diminished myocardial

reserve present in premature infants, may be

poten-tially as ominous as are drug-mediated effects on

cardiac automaticity in older children and adults.

Clearly, more knowledge of the effects of digoxin in

premature infants is needed. Our observations,

however, confirm previous studies suggesting that

the clinical definition of digoxin toxicity in

low-birth-weight newborns may be primarily related to

bradycardia and prolongation of PR interval.3

Feeding intolerance has not previously been

noted in premature infants receiving digoxin

ther-apy. The frequency of this finding in our patients

and its resolution when digoxin therapy was

discon-tinued suggest that this entity may be an early,

albeit nonspecific, complication of digoxin therapy

in premature infants.

The high incidence of clinical deterioration with

digoxin therapy in this group of infants may be due

to several factors. Premature infants have an

in-creased extracellular fluid volume9 and a relatively

lesser tissue space available for distribution of the

drug. Additionally, renal clearance of digoxin has

been shown to be significantly decreased in

pre-mature infants and leads to accelerated tissue

buildup.t:3 It is of interest that infants in whom

digoxin therapy was begun in the first week of life

developed signs much earlier than did those in

whom digoxin therapy was instituted in the second

or third week of life. The redistribution of body

fluids and maturation of renal function associated

with increasing postnatal age may account for some

of this difference.

Although prolongation of the PR interval is

ap-propriately considered a benign effect of digoxin in

older children, the presence of this sign in all our

infants who manifested bradycardia or arrhythmia

and its absence in those who did not would appear

to support PR interval prolongation as an easily

obtainable clinical sign that is useful in monitoring

low-birth-weight premature infants receiving

di-goxin therapy. In infants with disorders in which the use of digoxin is clinically indicated, close

mon-itoring of the PR interval may lessen the incidence

of undesirable effects of digoxin therapy.

IMPLICATIONS

Clearly, further controlled pharmacologic studies

of digoxin effects are needed to serve as a guide for

the rational use of digoxin therapy in

low-birth-weight infants. In assessing the indications for

di-goxin therapy in these infants, our preliminary

ex-perience suggests that a high frequency of

delete-rious effects of digoxin may exist in this patient

group. We currently pay close attention to fluid

balance and use judicious diuretic therapy rather

than digoxin in infants weighing less than 1,500 gm

with left-to-right shunt through a patent ductus

arteriosus. Serious consideration is given to early

pharmacologic or surgical intervention to close the

ductus if signs of circulatory congestion persist.

ACKNOWLEDGMENT

The authors thank Jacqueline A. Noonan, MD, for her

helpful suggestions and critical review of the manuscript.

REFERENCES

1. Lang D, von Vernuth G: Serum concentration and serum

half-life of digoxin in premature and mature newborns.

Pe-diatrics 59:902, 1977

2. Simonton RL, Hastreiter AR, vander Horst RL, et al:

Di-goxin disposition in premature infants, abstracted. Am J

Cardiol 45:429, 1980

3. Berman W Jr, Dubynsky 0, Whitman V, et al: Digoxin therapy in low-birth-weight infants with patent ductus ar-teriosus. J Pediatr 93:652, 1978

4. Rutkowski MM, Cohen SN, Doyle EF: Drug therapy of heart disease in pediatric patients. II. The treatment of congestive heart failure in infants and children with digitalis

preparations. Am Heart J 86:270, 1973

5. Pinsky WW, Jacobsen JR, Gillette PC, et al: Dosage of

digoxin in premature infants. J Pediatr 96:639, 1979 6. Neill CA: The use of digitalis in infants and children. Prog

Cardiovasc Dis 7:399, 1965

7. Willerson JT, Rogers M, Goldblatt A, et al: Serum digoxin

levels in children. Am J Cardiol 26:666, 1970 8. Vetter VL, Spear JF, Moore EN, et al: Electrophysiologic

responses to ouabain in puppies and adult dogs, abstracted. Pediatr Cardiol 1:80, 1979

9. Cassady G: Bromide space studies in infants of low birth

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1982;69;463

Pediatrics

Gregory L. Johnson, Nirmala S. Desai, Thomas H. Pauly and M. Douglas Cunningham