Original Article
The Use of Digoxin-Specific Fab Fragments for Severe Digitalis Intoxication in Children
N Engl J Med 1992; 326:1739-1744June 25, 1992
- Abstract
- Abstract
Background.
Because life-threatening digitalis intoxication is unusual in children, treatment with digoxin-specific—antibody Fab fragments (Fab) has rarely been reported. We describe the efficacy of Fab in the treatment of children with severe digitalis intoxication.
Methods.
Twenty-nine children with intoxication due to digoxin (28) or digitoxin (1) received Fab at 21 participating hospitals between 1974 and 1986. Data were gathered about the patients' medical illnesses, doses and serum concentrations of digitalis, responses to Fab therapy, and outcomes.
Results.
In the infants and young children with acute digoxin intoxication, the digoxin doses ranged from 0.30 to 0.96 mg per kilogram of body weight; two adolescents had severe intoxication after doses of only 0.20 and 0.26 mg per kilogram. The serum digoxin concentrations ranged from 3.0 to >100 ng per milliliter (mean, 13.8). Atrioventricular block (present in 22 patients [76 percent]) was the most common sign of toxicity. All the patients in this series had severe disturbances of cardiac rhythm, hyperkalemia (mean serum potassium concentration, 5.4 mmol per liter), or both. In 27 patients (93 percent), digitalis toxicity resolved after the administration of Fab. Of the 19 patients for whom data were available on the timing of the response to Fab, 15 responded within 180 minutes. Three patients required retreatment with Fab. Seven died of complications unrelated to the administration of Fab.
Conclusions.
We recommend that Fab be used in the treatment of digitalis poisoning in infants and young children who have ingested ≥0.3 mg of digoxin per kilogram, who have underlying heart disease, or who have a serum digoxin concentration of ≥6.4 nmol per liter (≥5.0 ng per milliliter) in the elimination phase; and who also have a life-threatening arrhythmia, hemodynamic instability, hyperkalemia, or rapidly progressive toxicity. Adolescents, who are more sensitive to the toxic effects of digoxin than younger children, may require treatment with Fab after ingesting lower doses. (N Engl J Med 1992;326: 1739–44.)
Media in This Article
Table 1
Demographic and Clinical Characteristics of 29 Children with Digitalis Poisoning.*Table 2
Fab Treatment in 29 Children with Digitalis Poisoning.Article Activity
- Article
DIGITALIS preparations, widely prescribed for children and adults with heart disease,1 2 3 4 are potent medications that in excessive doses may have cardiac, gastrointestinal, neurologic, and metabolic effects. Although there are case series of digitalis poisoning in children,5 6 7 8 few exposures result in severe toxicity. Lewander et al.9 reported on 41 cases of digoxin poisoning in children that represented the combined experience of three pediatric academic medical centers over a 10-year period. None of these acutely poisoned children, whose serum digoxin concentrations ranged from 3.8 to 14.1 nmol per liter (3 to 11 ng per milliliter), had life-threatening dysrhythmias or died.9
In 1976, Smith et al. reported the successful use of digoxin-specific—antibody Fab fragments (Fab) to treat an adult with digoxin intoxication.10 There have been numerous subsequent reports of adults successfully treated with Fab,11 12 13 14 15 16 17 18 19 20 and there are reviews outlining indications for its use in adults.21 22 23 24 25
Although there are case reports of pediatric digitalis poisoning in which Fab therapy was used,26 27 28 29 30 31 32 33 34 35 indications for the treatment of children with Fab remain unclear. The purpose of this article is to describe the characteristics and outcomes of 29 children and adolescents with digitalis intoxication who received Fab in a multicenter study and to offer recommendations for the use of Fab in children.
Methods
A study of the use of Fab (Digibind, Burroughs Wellcome) was instituted in 1974 with 21 participating medical centers (see Appendix). Children were enrolled if they had evidence of severe digoxin or digitoxin toxicity from one-time exposure or long-term dosing. Each patient's underlying cardiac disease, if any, and the medications with which the patient was being treated were recorded. Clinical evidence used to define digitalis intoxication included the presence of nausea and vomiting, mental alteration, sinus bradycardia, atrioventricular block, ventricular extrasystoles, asystole, ventricular tachycardia, ventricular fibrillation, supraventricular arrhythmias, and hyperkalemia. Fab was given to patients who had a clinical history compatible with digoxin poisoning, evidence of progressive symptoms and signs, and severe bradycardia, conduction defects, dysrhythmias, or digitalis-induced hyperkalemia (as manifested by a serum potassium concentration that was higher than 5.0 mmol per liter or was rising rapidly).
Base-line measurements of electrolytes, blood urea nitrogen, creatinine, and serum digoxin levels were obtained when circumstances permitted. If the serum digoxin concentration was reported to be "greater than" a given value, that value was used in calculations.
The dose of Fab was based on a stoichiometric ratio of the amount of Fab needed for a total-body burden of digoxin; the pediatric dose was extrapolated empirically from experience in adults.36 For digoxin intoxication, the following formula was used: dose of Fab in milligrams = (serum digoxin concentration in nanograms per milliliter × 5.6 × the body weight in kilograms/1000) × 64. For digitoxin intoxication, the following formula was used: dose of Fab in milligrams = (serum digitoxin concentration in nanograms per milliliter × 0.56 × the body weight in kilograms/1000) × 64. If the steady-state serum digoxin concentration was unknown but there was reliable information on the amount ingested, the dose of Fab was based on the fact that 40 mg (one vial) of Fab binds approximately 0.66 mg of digoxin. Fab was infused intravenously; skin testing for hypersensitivity reactions was advised before administration. The time that Fab therapy began was noted, and when possible in the case of acute intoxications, the length of time from digoxin exposure to the initiation of Fab therapy was also recorded. Serum potassium levels were monitored for 48 to 72 hours after Fab therapy. Each patient's subsequent course and survival were also described.
Data were analyzed with both descriptive and inferential statistics. Univariate statistics for categorical data used the chi-square test or Fisher's exact test, and continuous variables were compared with use of Student's t-test.37 All analyses consisted of two-tailed tests, with an alpha level of 0.05 used to demonstrate statistical significance. Informed consent for participation in the study was obtained from a parent of each child before enrollment; the study was approved by the investigational review board of each participating institution.
Results
Twenty-one medical institutions reported that 29 children were treated with Fab from 1974 through 1986. Information on three patients in this series (Patients 1, 2, and 16) has been published as case reports.26 , 27 , 29
Age, Sex, and Underlying Cardiac Problems
The age and sex of the children and the presence or absence of underlying heart disease are shown in Table 1Table 1
Demographic and Clinical Characteristics of 29 Children with Digitalis Poisoning.*. The median age was 1.5 years. Four patients were receiving other cardiac medications at the time of the intoxication (two propranolol, one isosorbide dinitrate, and one quinidine).Dose and Serum Concentration of Digoxin
Eighteen exposures to digitalis (17 to digoxin and 1 to digitoxin) were classified as single-dose poisonings (resulting from the use of someone else's medication in 13 cases and from overdose with the patients' own medication in 5); in the other 11 cases, the patients were intoxicated during long-term use of their own medication. In 10 of the 17 acute digoxin intoxications, the amount taken was known (mean dose, 0.4 mg per kilogram of body weight). In two poisonings in adolescents, doses of 0.20 and 0.26 mg per kilogram were taken. In the six younger children without underlying heart disease (excluding Patient 12, whose case was complicated by quinidine intoxication), the doses of digoxin ranged from 0.30 to 0.96 mg per kilogram. The mean (±SD) serum digoxin concentration in 27 patients was 17.7±23.2 nmol per liter (13.8±18.1 ng per milliliter); 15 of the 16 children with underlying cardiac disease had serum digoxin concentrations above 6.4 nmol per liter (5.0 ng per milliliter).
Clinical Toxicity and Early Treatment
Table 2Table 2
Fab Treatment in 29 Children with Digitalis Poisoning. lists the patients who had each of the 10 clinical symptoms and signs of digitalis toxicity. Atrioventricular block, manifested in 22 of the 29 patients (76 percent), was the most common sign of digitalis toxicity. Twenty-seven of the 29 patients had two or more signs of toxicity in addition to nausea and vomiting.Of the 24 patients for whom data were available, all received antiarrhythmic medications, ventricular pacing, or both before Fab therapy. Four patients were reported to have received only ventricular pacing; six received only antiarrhythmic medications; three received both antiarrhythmic drugs and ventricular pacing; five received direct-current cardioversion, cardiopulmonary resuscitation, and antiarrhythmic medications; four received cardioversion, cardiopulmonary resuscitation, antiarrhythmic medications, and ventricular pacing; and two received both cardiopulmonary resuscitation and antiarrhythmic drugs.
Dose of Fab
Table 2 shows the doses of Fab in the 29 patients. In 10 patients with acute intoxication, the mean interval between the last dose of digoxin and Fab treatment was 20±23.5 hours (range, 6 to 84).
Efficacy of Fab
Tables 2 and 3Table 3
Clinical Manifestations of Digitalis Poisoning in 29 Children and Resolution with Fab Treatment. summarize the effectiveness of Fab therapy in resolving the manifestations of digitalis toxicity in the patients. In 27 patients (93 percent), all symptoms and signs attributable to digitalis intoxication resolved. One child (Patient 12) improved but did not have a complete response; she had a concomitant quinidine overdose and a traumatic attempt at out-of-hospital resuscitation. Her dysrhythmias improved but were not abolished; she died one week later after failing to improve neurologically. One child (Patient 7) appeared to have no response to Fab; she had severe underlying heart disease. Three patients required a second dose of Fab within 4 to 16 hours after the initial dose. In one of these, the physicians mistakenly believed that Fab needed to be divided into two doses given four hours apart. In the second, initial improvement in cardiac toxicity after the administration of Fab was not sustained; this patient also had concomitant quinidine intoxication that complicated treatment. In the third patient, cardiac toxicity resolved after the administration of Fab, but 24 hours later the patient had an episode of ventricular fibrillation without explanation. Although conversion to normal sinus rhythm was quickly achieved, a second dose of Fab was administered empirically.In 18 patients the serum potassium concentrations were known both before Fab was given and within four hours after its administration. The mean serum potassium concentration after Fab treatment (4.3±1.2 mmol per liter) was significantly lower than the concentration before treatment (5.4±1.6 mmol per liter; range, 3.5 to 10.3; P<0.001).
Fourteen patients had impaired renal function (defined as a serum creatinine level of 88 μmol per liter [1.0 mg per deciliter] or higher in children at least one year old and a level of more than 62 μmol per liter [0.7 mg per deciliter] for younger children) that was not associated with a higher serum digoxin concentration (P = 0.17) or increased mortality (P = 0.34), but that was associated with underlying cardiac disease (P<0.001) and was marginally associated with higher serum potassium levels (P = 0.06).
There were seven deaths among the children in this series. One child (Patient 28) died of renal failure, progressive sepsis, and necrotizing enterocolitis nine days after the administration of Fab; another (Patient 14) died with candidal myocarditis and sepsis; a third (Patient 10) died six days after Fab therapy of respiratory arrest, renal failure, and complications of the original cardiac arrest. A fourth child (Patient 12), the only one to die who did not have heart disease, was declared brain-dead from a cardiac arrest that occurred before the administration of Fab; this patient had concomitant quinidine toxicity (serum quinidine concentration, 22 μg per milliliter). A fifth child (Patient 16), who had multiple congenital defects, died after an intracerebral hemorrhage from a congenital arteriovenous malformation seven days after Fab therapy. A sixth child (Patient 8), with high-output cardiac failure caused by a cavernous hemangioma and arteriovenous malformation of the carotid artery, died five days after Fab therapy from sepsis that occurred during peritoneal dialysis to treat renal failure sustained early in life. The seventh child who died (Patient 7) had a history of perinatal asphyxia, ischemic encephalopathy, respiratory distress syndrome, renal failure, and cardiac arrest, all of which preceded the diagnosis of digoxin toxicity. She died after a persistently downhill course marked by disseminated intravascular coagulation and possible sepsis. No new toxicity related to digitalis was noted in any of these patients after the completion of therapy with Fab.
Time to Response
Fifteen of the 19 patients (79 percent) for whom response times were available had a complete resolution of digitalis toxicity within 180 minutes of Fab therapy; the median time to a complete response was 90 minutes (range, 1 to 2160). The median time to an initial response after Fab (in 16 patients) was 25 minutes (range, 1 to 240).
Adverse Effects of Fab Therapy
Fourteen patients received sensitivity testing before Fab treatment; no allergic reactions to Fab were reported. No patient had an exacerbation of dysrhythmia or worsening heart failure due to the abrupt withdrawal of digitalis. One patient had both hypokalemia (potassium level, 2.0 mmol per liter) and an associated dysrhythmia that were related to Fab therapy and resolved with supplemental intravenous potassium. One neonate had transient apnea that may have been related to Fab treatment or to the insertion of the needle before the administration of Fab.
Discussion
Severe digitalis poisoning is uncommon in children and adolescents, although cases continue to be seen sporadically. The intoxication differs from that in adults because children with healthy hearts seem more resistant to the toxic effects of digitalis.9 , 38 Few children become ill with life-threatening symptoms; those who do either have taken massive overdoses or have severe preexisting cardiac disease. Whereas in adults ventricular ectopy is often the earliest cardiac sign of digitalis toxicity,20 serious toxicity in the children in our series was more often heralded by sinus bradycardia or varying degrees of atrioventricular conduction block. Although the overall mortality rate of the children in this series and their rate of response to Fab therapy were similar to those in adults,20 it is possible that young children, with more resilient hearts, can be successfully revived with Fab much later in the course of digitalis intoxication than can adults.
In contrast to the children studied by Lewander et al.,9 some children in the present study had chronic digoxin intoxication. Our patients were also more severely intoxicated and frequently had other incapacitating medical problems; it is not surprising that we observed a 24 percent mortality rate, whereas Lewander et al. observed no deaths.9 Our enrollment protocol and the time needed to obtain Fab for a patient in the early years of the study explain the sometimes long interval between the diagnosis of digitalis intoxication and Fab therapy.
We observed a significant decrease in the serum potassium concentration after the administration of Fab. The inhibition of the membrane-boundsodium pump by digitalis results in a loss of intracellular potassium to the extracellular space, whence it is excreted by the kidney, causing elevated serum potassium concentrations but an overall depletion.39 When toxicity is rapidly reversed by Fab, the total-body potassium deficit is reflected as hypokalemia. This should prompt clinicians to monitor their patients' serum potassium concentrations serially, beginning immediately after the administration of Fab. No allergic reactions to Fab were noted, but this does not eliminate the need for vigilance when Fab is used in children.
Clinicians are cautioned that measurements of serum digoxin concentrations in children do not necessarily correlate with the effects of the drug. Also, the distribution of digoxin dictates that there must be sufficient time (four to six hours after a dose) for equilibration between compartments before serum levels are meaningful. After Fab is given, the serum digoxin concentration cannot be used to judge continuing tissue-level exposure to the drug, since digoxin that has been bound by Fab contributes to the level. Newer techniques of measuring unbound digoxin may be more useful,40 but decisions are more rationally based on the patients' clinical characteristics, particularly the seriousness of their rhythm disturbances.
We suggest that Fab be reserved for children in whom severe overdosing with digoxin is known with reasonable certainty to have occurred and that both clinical and laboratory measures be incorporated to assess the urgency of the clinical situation. It has been suggested that in young children without heart disease the ingestion of more than 4 mg of digoxin is likely to be life-threatening.41 On the basis of these published results and our own experience (involving six young children who became extremely ill after digoxin doses of 0.30 to 0.96 mg per kilogram), we suggest that the ingestion of 0.3 mg of digoxin or more per kilogram by a young child without heart disease portends serious toxicity. Adolescents, perhaps more similar to adults in their cardiac sensitivity to digoxin, may become symptomatic at even lower doses. In 15 of the 16 children with underlying heart disease in our series, serum digoxin levels were higher than 6.4 nmol per liter; these levels were also accompanied by signs of substantial digitalis toxicity.
Given the success of Fab therapy in this study, we support its earlier use, perhaps before cardiac pacing or treatment with antiarrhythmic agents, in children with confirmed digitalis intoxication who present with potentially life-threatening dysrhythmias, hemodynamic instability, or rapidly rising serum potassium levels, and in those with massive ingestions. Children require close monitoring after Fab therapy; a second dose may be necessary if toxicity attributable to digitalis recurs or fails to resolve.
Appendix
The institutions (and chief investigators) participating in the study were as follows: University of Alabama at Birmingham (V.J. Plumb); Health Sciences Center, University of Arizona at Tucson (F.I. Marcus); Veterans Affairs Health Center, Little Rock, Ark. (J.E. Doherty); UCLA School of Medicine, Los Angeles (K.I. Shine); Moffitt Hospital, San Francisco (K. Chatterjee and W.W. Parmley); Health Sciences Center, University of Colorado, Denver (A.S. Nies); Yale University School of Medicine, New Haven, Conn. (D. Rutlen); University of Miami School of Medicine, Miami (R.J. Myerburg); Emory University School of Medicine, Atlanta (R.C. Schlant); University of Chicago, Chicago (H.A. Fozzard); Indiana University School of Medicine, Indianapolis (A. Watanabe); Sinai Hospital, Baltimore (R. Veltri); Brigham and Women's Hospital, Boston (T.W. Smith); Massachusetts General Hospital, Boston (E. Haber and H. Garan); Washington University School of Medicine, St. Louis (A.S. Jaffee); College of Physicians and Surgeons, Columbia University, New York (V.P. Butler, Jr.); Duke University Medical Center, Durham, N.C. (R.M. Califf); University of Cincinnati Medical Center, Cincinnati (R.J. Toltzis); University of Pennsylvania Hospital, Philadelphia (F.E. Marchlinski); Baylor College of Medicine, Houston (R.J. Luchi); and University of Texas Health Sciences Center, Dallas (J.T. Willerson).
Presented in part at the annual meeting of the American Association of Poison Control Centers, Tucson, Ariz., September 14, 1990.
Source Information
From the Department of Medicine, Children's Hospital, the Department of Pediatrics, Harvard Medical School, and the Massachusetts Poison Control System, all in Boston (A.D.W., F.H.L.); the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (T.W.S.); and the Burroughs Wellcome Company, Research Triangle Park, N.C. (T.W.).
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