Results of Multicenter Studies of Digoxin-Specific Antibody Fragments in Managing Digitalis Intoxication in the Pediatric Population ALAN D. WOOLF, MD, MPH,* THOMAS L. WENGER, MD,* THOMAS W. SMITH, MD,t FREDERICK H. LOVEJOY, JR, MD*
Digitalis toxicity continues to be a problem for pediatric patients undergoing therapy with cardiac glycosides for heart failure or arrhythmias, as well as in accidental ingestions. In this article the previous use of digoxinspecific antibody Fab fragments to treat digitalis overdose or intoxication in children is reviewed. The case reports cited in the medical literature and the 57 pediatric cases gathered as a result of the multicenter clinical trial and postmarketing surveillance study reported here indicate that digoxin-specific antibody Fab fragments are effective in ameliorating signs of digitalis poisoning in children. Not only can Fab fragments rapidly eradicate potentially life-threatening arrhythmias and conduction defects, but they are also effective in treating hyperkalemia and other noncardiac manifestations of digitalis toxicity. In the small samples of patients studied to date, complications have been minimal and no allergic reactions to digoxinspecific Fab fragments have been observed. Recommendations for the management of digitalis intoxication in children are outlined. (Am J Emerg Med 1991;9:16-20 [suppl 1). Copyright 0 1991 by W.B. Saunders Company)
Digoxin is commonly used to treat congestive heart failure and supraventricular arrhythmias in infants and children. The total loading dose, calculated in micrograms per kilogram, can be given parenterally or by mouth in divided doses over 24 hours: the usual loading dose is about 3 times the amount of the maintenance dose. Both the digitalizing and maintenance doses vary according to age, with preterm infants and children older than 2 years requiring less drug than term infants. Perhaps because the dosage of digitalis in children is age-dependent and calculated in micrograms. while the drug itself is dispensed in milligrams, errors in the calculation or administration of both the digitalizing and maintenance doses are common and result in episodes of intoxication. Additionally, accidental poisonings occur most often in young children who find an adult’s medication: less commonly. adolescents may intentionally overdose themselves on digitalis. Finally, children treated with digoxin may also be taking other medications, such as quinidine, verapamil, or amiodarone, that are known to inhibit the elimination of digoxin. resulting in toxic serum concentrations.’ More than 1,751 cases of poisoning with cardiac glycosides were reported to the American Association of Poison Control
From the *Division of Medicine, The Children’s Hospital, the ‘Department of Pediatrics, Harvard Medical School, the tDepartment of Medicine, Brigham & Women’s Hospital and Harvard Medical School, the *Massachusetts Poison Control System, Boston, MA, and S&rroughs Wellcome Co., Research Triangle Park, NC. Address reprint requests to Dr Woolf, Assistant in Medicine, The Children’s Hospital, 320 Longwood Ave, Boston, MA 02115. Key Words: Pediatrics, digitalis, toxicity, digoxin-specific Fab. Copyright Cl 1991 by W.B. Saunders Company 0735-6757/91/0902-l 004$5.00/0 16
Centers in 1988. 978 of these in children less than 17 years old.’ Although the severity of these poisonings was not broken out by age, only 20 I of I75 I cases developed moderate to severe toxic effects; 23 deaths attributed to cardiac glycosides were reported.’ Many acute digitalis intoxications in infants or young children are accompanied by few clinical effects and require only close monitoring and nonspecific therapy. A retrospective review of 10 years of experience with cases of acute pediatric digitalis poisoning at three academic insritutions revealed only 41 cases, none of which developed life-threatening symptoms or signs.’ Most patients developed only sinus bradycardia or first- or second-degree atrioventricular block. and their serum digoxin concentrations ranged from 0.2 to I 1.6 ng/mL. None ofthe patients in this series developed the severe ventricular ectopy or hyperkalemia seen in adults. However, there are reports of children overdosed or intoxicated with cardiac glycosides who developed life-threatening arrhythmias, cardiac conduction defects, and secondary hypotension.‘-’ These patients required such interventions as cardiopulmonary resuscitation, atropine. antiarrhythmic medications. and/or ventricular pacing. Early signs of digitalis intoxication in the child include those summarized in Table I. While hyperkalemia and refractory hypotension are seen. these symptoms are uncommon in children. A fuller description of the development of antidigoxin Fab fragments is presented elsewhere in this supplement. This approach was first used successfully to treat an adult patient with life-threatening digitalis toxicity in 1976.’ The first children treated with digoxin-specific Fab fragments were reported in 1982.9,‘”
Recently there have been scattered reports of the use of antidigoxin Fab fragments in the treatment ofchildren with digitalis intoxication.‘-‘5 A summary of these case reports is shown in Table 2. The dosage ofdigoxin-specific Fab fragments in children. like adults, is related to the calculated total body burden of digitalis. either from the known amount of drug ingested or from a calculation using the serum digoxin (or digitoxin) concentration. These previously reported cases documented the effectiveness ofdigoxin-specific Fab fragments in selected pediatric cases of severe digitalis intoxication. In all of these cases. resolution of symptoms followed the administration of the digoxin-specific Fab within hours. A case report of digitalis toxicity in an infant which seemed refractory to Fab therapy has also been documented.” It is possible that the antidote was administered too late in this case or that the child’s underlying congenital heart disease was terminal.
WOOLF ET AL m SPECIFIC
TABLE 1.
Symptoms
FAB FOR PEDIATRIC
DIGITALIS
TOXICITY
and Signs of Pediatric Digitalis Intoxication
Gastrointestinal Symptoms Nausea and vomiting Diarrhea Anorexia Visual Changes (Older Children) Blurred vision Photophobia Decreased red-green perception Transient blindness Neurological Signs and Symptoms Headache Confusion and disorientation Hallucinations, delirium Acute psychosis Paresthesias and neuritis Seizures (rare) Aphasia Cardiac Toxicity Sinus arrhythmia/bradycardia Sinoatrial pause or arrest First-degree heart block Second-degree heart block Third-degree heart block Supraventricular arrhythmias Premature ventricular contractions Ventricular bigeminy Ventricular tachycardia Ventricular fibrillation Metabolic Signs
Hyperkalemia (acute) Other Hypotension Malaise Fatigue Weakness Rashes
As part of a broader study of the clinical use of digoxin-specific Fab fragments in the treatment of digitalis poisoning, we have reviewed cases of pediatric digitalis toxicity in which digoxinspecific Fab fragments were used.
METHODS Two separate studies have been conducted. In the first study, 22 collaborating medical centers reported cases in which Fab antibody fragments were used on protocol in a clinical trial between 1978 and 1986. This protocol required that the patient demonstrate life-threatening toxic effects and that other conventional treatments (eg, antiat-rhythmic drugs, ventricular pacing, cardioversion) precede the use of Fab fragments (some of the cases in the multicenter trial had been previously described in the literature and are included in Table 2). The second clinical investigation was undertaken as a postmarketing surveillance study of the safety and efficacy of digoxinspecific Fab fragments in the management of digitalis intoxication. Voluntary reporting of all cases of digoxin poisoning requiring Fab fragments was solicited between 1986 and 1988. Circumstances of the intoxication and the clinical outcome, as well as any adverse effects which might be attributable to Fab fragments, were carefully documented by questionnaire.
17
RESULTS There were 29 children between the ages of 1 day and 18 years old recruited into the first multicenter clinical trial. Reports on the treatment of 28 children between the ages of 4 days and 7 years old were included in the more recent postmarketing surveillance study. Thus, 57 total cases form the basis for this report. Conduction defects (first-degree. second-degree, and thirddegree atrioventricular block) were the most common manifestations of cardiac toxicity in these children (58% of the 57 patients), with second-degree heart block having the highest incidence. Patients in the multicenter clinical trial had, as expected, more severe manifestations of digitalis toxicity than those in the postmarketing surveillance study: refractoriness to other conventional modalities of management was a condition of entry into the study. More patients had signs of extreme cardiac rhythm instability (supraventricular or ventricular arrhythmias, ventricular fibrillation, asystole) than did those in the postmarketing survey. More patients in the multicenter trial also required such therapies as antiarrhythmic agents, ventricular pacing, and cardiopulmonary resuscitation prior to treatment with digoxinspecific Fab fragments. Results of these two clinical studies confirmed the efficacy of digoxin-specific Fab fragments. Almost 90% of the patients in both groups had partial or total resolution of cardiac conduction disturbances or arrhythmias attributable to digitalis intoxication after treatment with Fab fragments. In most cases beneficial effects were observed within 30 minutes to 4 hours of the therapy; reversal of cardiotoxic effects of digitalis poisoning was complete within 24 hours. Noncardiac signs of digitalis intoxication, such as hyperkalemia. vomiting, and depressed consciousness, also improved or resolved after the use of digoxin-specific Fab fragments. Three patients had recrudescence of conduction defects within 24 hours of therapy, which resolved with a second dose of Fab fragments. Therefore, close monitoring of these patients with serial electrocardiograms and serum potassium measurements for 48 hours after Fab fragment administration is recommended, although most children will not need more than one dose of Fab fragments. The postmarketing surveillance study has confirmed the safety of pediatric therapy with digoxin-specific Fab fragments. While 23% of the total patients ultimately had a fatal outcome, none of these deaths were attributable to the digitalis itself, but rather reflected the serious nature of their underlying medical conditions. There were no reports of allergic reactions or immunecomplex related complications in these children. While apparent exacerbation of underlying congestive heart failure has been observed in adults, no such complications were reported from either pediatric sample. Hypokalemia, requiring intravenous potassium supplementation, was reported in one pediatric patient.
DISCUSSION It is well recognized that, in contrast to adults, children without intrinsic heart disease will often tolerate an acute overdose of digitalis with few clinical effects. The emergency physician should recognize that children who are chronically intoxicated with digitalis, or who receive an acute on chronic overdose during loading or maintenance therapy, may be at heightened risk for life-threatening adverse effects of the drug. Those with underlying congenital heart disease may be at a particularly high risk for
18
AMERICAN
TABLE 2.
JOURNAL
OF EMERGENCY
Previous Case Reports of Digitalis Intoxication
Gender
Age
Zucker 1982
M
30 mos
A
NO
Murphy 1982 Rossi 1984
M M
20 mos 34 mos
A A
NO NO
Autret 1985
M
1 mo
L
COARCT CHF
Hussain 1985
M
30 mos
L
NO
Presti 1985
A
L
36
Congenital Disease
Schaumann
1986
F
16 yrs
A
Gonadaldysgenesis PDA Papillary necrosis AVM RF NO
Schaumann
1986
M
17 yrs
A
NO
M
1 mo
C
CAVO PS
Rose 1987
Kearns 1989
F
24 mos
A
Nollett 1989
-
4 yrs
A
Kaufman 1990
M
7d
L
n Volume 9, Number 2 (Supplement
Treated With Digoxin-Specific
Acute v Loading v Chronic
Ref
MEDICINE
Hype RV CHF NO
TGV PS sv PS PDA VT
Antibody
1) n March 1991
Fab Fragments Serum Digoxin Concentration
Fab Dose
(ng/mL)
(mg)
Survival
800
Y
960 480
Y Y
80
Y
27.5
325
Y
6.5
160
N
?
13.0
400
Y
?
6.1
480
Y
30 ug/d
19.9
120
N
22.5 mg
26.0
1280
Y
30 mg
12.8
160
Y
600 ug
25.0
40
Y
Symptoms Signs
Digoxin Dose
Jet Tachy Lethargy N&V V fib 2” SAB SA Block 2” AVB 1” AVB 2” AVB N&V PAC 1” AVB N&V Coma VES
10mg
12mg 6mg
>lOO
16.7 21.7
200 ug/k
4.5 mg
25 ug/k
V-tach/fib :; 3” AVB PAT VES 3” AVB VES CHF Asystole N&V Lethargy 1” AVB 2” AVB
N&V VES Bigeminy 3” AVB
(est)
ABBREVIATIONS:TGV, transposition of great vessels; CAVO, common atrioventricular orifice; VES, ventricular extra systoles; PS, pulmonary stenosis; CHF, congestive heart failure; AVB, atrioventricular block; SAB, sinoatrial block; N & V, nausea and vomiting; PAC, premature atrial contractions; Jet Tachy, AV junctional tachycardia; V tach, ventricular tachycardia; COARCT, coarctation of the aorta; V fib, ventricular fibrillation; PAT, paroxysmal atrial tachycardia; PDA, patient ductus arteriosus; Hypo RV, hypoplastic right ventricle; SV, single ventricle; AVM, arteriovenous malformation; RF, renal failure; A, ambiguous genitalia.
of digitalis toxicity for several reasons. Use of concomitant potassium-wasting diuretics without supplemental potassium may increase cardiac sensitivity to digitalis. The treatment of these patients with other antiarrhythmic agents that interact with digoxin may precipitate toxicity. Those patients who, as part of their medical condition, have impaired renal function may become intoxicated with digoxin unless their maintenance dose is adjusted based on creatinine clearance. The combined experience between the two multicenter pediatric studies described in this paper includes 57 children who received digoxin-specific Fab fragments for the treatment ofdigcomplications
italis toxicity. It is evident that the antidote was used earlier in the course of therapy for those children in the postmarketing survey and that those children were less severely toxic than those in the multicenter clinical trial. In these two studies, rapid resolution of symptoms and signs of cardiac toxicity was observed in a substantial majority of patients after Fab was administered. Both conduction defects and ventricular or supraventricular ectopy resolved within 24 hours, and often within 4 hours, of the administration of Fab fragments. This therapy was also effective in decreasing serum potassium levels to the normal range, usually within 4 hours of administration.
WOOLF ET AL n SPECIFIC
FAB FOR PEDIATRIC
DIGITALIS
19
TOXICITY
There were no cases reported of acute hypersensitivity or other allergic reactions to digoxin-specific Fab fragments among these children. No adverse effects that could be directly attributable to Fab fragments were reported, although one patient developed hypokalemia. In three children there appeared to be a recrudescence of cardiac conduction defects posttreatment that resolved upon administration of a repeated dose of Fab fragments.
RECOMMENDATIONS The emergency physician is advised to obtain as accurate a history as possible concerning the total dose of digitalis taken in a poisoning situation. The dosing of digoxin in small infants should be carefully reviewed for possible errors in calculation or preparation. In all patients an attempt should be made to rid the gastrointestinal tract of unabsorbed drug if the cardiac glycoside was ingested within 2 hours of presentation to the emergency department. While ipecac or lavage may be performed, clinicians must be aware of the hazards of vagal stimulation, either by vomiting or during passage of an orogastric tube, potentially exacerbating a conduction defect or bradycardia in symptomatic patients. Activated charcoal is an effective agent to adsorb digitalis and should be administered (at 1 gram per kilogram ofbody weight) to prevent further absorption from the gastrointestinal tract. Repetitive doses of charcoal are not known to enhance elimination of digoxin. 2o Cholestyramine has also been advocated for use as a possible binder with good affinity for the cardiac glycosides,*’ but evidence that it is more effective than charcoal is lacking. All patients deserve careful monitoring of vital signs and serial electrocardiography. Repeated measurement of arterial blood gases, serum electrolytes including potassium, serum glucose. and renal function tests may be necessary. A serum digoxin (or digitoxin) concentration should be performed at least 6 to 8 hours after the ingestion to insure steady-state sampling after the rapid initial phase of drug redistribution into body tissues. Antiarrhythmic agents, a&opine, bretyllium. amiodarone, and ventricular pacing have all been tried in pediatric patients with severe digitalis poisoning who demonstrate life-threatening cardiac symptoms and signs. Secondary hypotension may respond to fluids and pressors or digoxin-specific Fab fragments. Level of consciousness must be monitored clinically; seizures, while unusual, should be treated with standard anticonvulsants such as benzodiazepines. barbiturates, or phenytoin. Hyperkalemia can be treated by conventional means including sodium polystyrene sulfonate (Kayexalatea) or. if life-threatening, digoxinspecific Fab fragments. Hemodialysis or hemofiltration are not considered helpful in lowering serum digitalis concentrations. It is recommended that digoxin-specific Fab fragments be reserved for pediatric cases of severe digitalis (either digoxin or digitoxin) intoxication, confirmed by history or serum digoxin or digitoxin concentration. The pediatric patient who ingests acutely more than 0.1 mg/kg of digoxin, or who has a steady state serum concentration greater than 5 ng/mL is likely to have symptoms and signs of toxicity. The clinical definition of a serious intoxication should include either a potentially life-threatening arrhythmia or a cardiac conduction defect. A severe digitalis poisoning might also be defined to include potentially lifethreatening hyperkalemia. refractory hypotension, or emergence or progression of cardiac manifestations after a known massive ingestion. Table 3 summarizes these recommendations.
TABLE3.
Recommendations For Digoxin-Specific Use in Children With Digoxin Poisoning
Fab Fragment
1. Known Digoxin Intoxication (A) Strong historical evidence of an acute ingestion 7 0.1 mg/kg or (B) Elevated (steady-state) serum dgoxin concentration > 5 ng/ mL AND 2. Rapidly progressing symptoms/signs of digoxin toxicity or. 2. Potentially life-threatening arrhythmias including cardiac conduction disturbances or 2. Severe hyperkalemia (K+ z 6.0 mEq/L)
While it is not recommended that Fab fragments be used prophylactically. we believe that it is desirable to institute therapy early in the course of a severe poisoning to forestall progression to more refractory, damaging cardiac arrhythmias. At times, it may be desirable to use Fab before other modalities such as antiarrhythmic agents, ventricular pacing, or cardioversion in the treatment of pediatric digitalis intoxication; however, digoxin-specific Fab should not contraindicate the use of these valuable adjuncts to treatment. Whenever Fab fragments are used, prior skin testing for hypersensitivity reactions is recommended (time permitting) for children as well as adults if there is a known allergic predisposition to immunoglobulin proteins or prior history of Fab antibody use. Precautionary monitoring for allergic reactions should be instituted during administration of the antidote. Although the two clinical studies described here demonstrated the safety of this antidote in a small sample of children, more uncommon, idiosyncratic reactions are still possible. The development of urticaria or other rashes, wheezing, or angioedema should be treated with diphenhydramine, epinephrine, and/or steroids. The use of epinephrine must be balanced against its potential for worsening the effects of digoxin intoxication. Such episodes, as well as any other suspected adverse reactions. should be reported to the manufacturer (Burroughs-Wellcome Company) and the Food and Drug Administration. All pediatric patients with severe digitalis intoxication should be admitted to an intensive care setting for at least 24 hours after the administration of digoxin-specific Fab fragments. Close monitoring of vital signs, electrocardiogram, serum electrolytes (particularly serum potassium). and renal function is suggested. Serum total digoxin concentrations are markedly elevated and hence generally misleading after administration of Fab fragments: if there is a laboratory capability of assaying serum free digoxin concentration. then this may be useful when combined with close observation of the patient’s clinical course. Patients in whom all symptoms of digitalis toxicity resolve may be safely redigitalized after it can be demonstrated by serum measurements that digoxin-specific Fab fragments have been completely eliminated. This will require at least several days or longer if the patient has impaired renal function. The efforts of the Advisory Panel to the Postmarketing Surveillance Study of Digibinda are acknowledged with deep appreciation. Anne
20
AMERICAN
JOURNAL
OF EMERGENCY
Hickey, MS, the staff epidemiologist at Burroughs Wellcome Co., assisted with the analysis of data from the postmarketing surveillance study and reviewed the manuscript.
REFERENCES 1. Koren G: Interaction between digoxin and commonly coadministered drugs in children. Pediatrics 1985;75:1032-1037 2. Litovitz TL, Schmitz BF, Holm KC: 1988 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1988;7:495-545 3. Lewander WJ, Gaudreault P, Einhorn A, et al: Acute pediatric digoxin ingestion: A ten-year experience. Am J Dis Child 1986;140: 770-773 4. McNamara DG, Brewer EJ, Ferry GD: Accidental poisoning of children with digitalis. N Engl J Med 1964;271: 1106-l 108 5. Fowler RS, Rathi L, Keith JD: Accidental digitalis intoxication in children. J Pediatr 1964;64: 188-200 6. Duke M: Atrioventricular block due to accidental digoxin ingestion treated with atropine. Am J Dis Child 1972;124:754-756 7. Hastreiter AR, van Der Horst RL, Chow-Tung E: Digitalis toxicity in infants and children. Pediatr Cardiol 1984;5:131-142 8. Smith TW. Haber E. Yeatman L, et al: Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976;294:797-800 9. Zucker AR, Lacina SJ, DasGupta DS, et al: Fab fragments of digoxin-specific antibodies to reverse ventricular fibrillation induced by digoxin ingestion in a child. Pediatrics 1982;70:468-471 10. Murphy DJ, Bremner WF, Haber E, et al: Massive digoxin poisoning treated with Fab fragments of digoxin-specific antibodies. Pediatrics 1982;70:472-473 11. Rossi R, Leititis JU, Hagel KJ, et al: Severe digoxin intoxication in a child treated by infusion of digoxin-specific Fab-antibody-fragments. Eur J Pediatr 1984;142: 138-l 40
MEDICINE
n Volume 9, Number 2 (Supplement
1) n March 1991
12. Autret E, Chantepie A, Bloc D, et al: Utilisation des anticorps antidigoxine an tours dune intoxication digitalique chez un nourrisson. Archives Francaises de Pediatrie 1985;42:803-804 13. Hussain MI, Murray R, Williams BP: Purified digoxin specific Fab fragments. Indiana Med 1985;780:781 14. Presti S, Friedman D, Saslow J, et al: Digoxin toxicity in a premature infant: treatment with Fab fragments of digoxin-specific antibodies. Pediatr Cardiol 1985;6:91-93 15 Schaumann W, Kaufmann 6, Neubert P, et al: Kinetics of the Fab fragments of digoxin antibodies and of bound digoxin in patients with severe digoxin intoxication. Eur J Clin Pharmacol 1986;30:527533 16. Rutherfoord Rose S, Gorman RL, McDaniel J: Fatal digoxin poisoning: an unsuccessful resuscitation with use of digoxin-immune Fab. Am J Emerg Med 1987;5:509-511 17. Kearns GL, Moss MM, Clayton BD, et al: Pharmacokinetics and efficacy of digoxin specific Fab fragments in a child following massive digoxin overdose. J Clin Pharmacol1989;29:901-908 18. Nollet H, Verhaaren H, Stroobandt R, et al: Delayed elimination of digoxin antidotum determined by radioimmunoassay. J Clin Pharmacol 1989;29:41-45 19. Kaufman J, Leikin J, Kendzierski D, et al: Use of digoxin Fab immune fragments in a seven-day old infant. Pediatr Emerg Care 1990;6:118-121 20. Park GD, Goldberg MJ, Spector R, et al: The effects of activated charcoal on digoxin and digitoxin clearance. Drug Intel1 Clin Pharm 1985;19:937-941 21. Hastreiter AR, van der Horst RL, Chow-Tung E: Digitalis toxicity in infants and children. Pediatr Cardiol 1984;5:131-142 22. Hursting MJ, Raisys VA, Opheim KE, et al: Determination of free digoxin concentrations in serum for monitoring Fab treatment of digoxin overdose. Clin Chem 1987;33:1652-1655
Digitalis toxicity continues to be a problem for pediatric patients undergoing therapy with cardiac glycosides for heart failure or arrhythmias, as well as in accidental ingestions. In this article the previous use of digoxinspecific antibody Fab fragments to treat digitalis overdose or intoxication in children is reviewed. The case reports cited in the medical literature and the 57 pediatric cases gathered as a result of the multicenter clinical trial and postmarketing surveillance study reported here indicate that digoxin-specific antibody Fab fragments are effective in ameliorating signs of digitalis poisoning in children. Not only can Fab fragments rapidly eradicate potentially life-threatening arrhythmias and conduction defects, but they are also effective in treating hyperkalemia and other noncardiac manifestations of digitalis toxicity. In the small samples of patients studied to date, complications have been minimal and no allergic reactions to digoxinspecific Fab fragments have been observed. Recommendations for the management of digitalis intoxication in children are outlined. (Am J Emerg Med 1991;9:16-20 [suppl 1). Copyright 0 1991 by W.B. Saunders Company)
Digoxin is commonly used to treat congestive heart failure and supraventricular arrhythmias in infants and children. The total loading dose, calculated in micrograms per kilogram, can be given parenterally or by mouth in divided doses over 24 hours: the usual loading dose is about 3 times the amount of the maintenance dose. Both the digitalizing and maintenance doses vary according to age, with preterm infants and children older than 2 years requiring less drug than term infants. Perhaps because the dosage of digitalis in children is age-dependent and calculated in micrograms. while the drug itself is dispensed in milligrams, errors in the calculation or administration of both the digitalizing and maintenance doses are common and result in episodes of intoxication. Additionally, accidental poisonings occur most often in young children who find an adult’s medication: less commonly. adolescents may intentionally overdose themselves on digitalis. Finally, children treated with digoxin may also be taking other medications, such as quinidine, verapamil, or amiodarone, that are known to inhibit the elimination of digoxin. resulting in toxic serum concentrations.’ More than 1,751 cases of poisoning with cardiac glycosides were reported to the American Association of Poison Control
From the *Division of Medicine, The Children’s Hospital, the ‘Department of Pediatrics, Harvard Medical School, the tDepartment of Medicine, Brigham & Women’s Hospital and Harvard Medical School, the *Massachusetts Poison Control System, Boston, MA, and S&rroughs Wellcome Co., Research Triangle Park, NC. Address reprint requests to Dr Woolf, Assistant in Medicine, The Children’s Hospital, 320 Longwood Ave, Boston, MA 02115. Key Words: Pediatrics, digitalis, toxicity, digoxin-specific Fab. Copyright Cl 1991 by W.B. Saunders Company 0735-6757/91/0902-l 004$5.00/0 16
Centers in 1988. 978 of these in children less than 17 years old.’ Although the severity of these poisonings was not broken out by age, only 20 I of I75 I cases developed moderate to severe toxic effects; 23 deaths attributed to cardiac glycosides were reported.’ Many acute digitalis intoxications in infants or young children are accompanied by few clinical effects and require only close monitoring and nonspecific therapy. A retrospective review of 10 years of experience with cases of acute pediatric digitalis poisoning at three academic insritutions revealed only 41 cases, none of which developed life-threatening symptoms or signs.’ Most patients developed only sinus bradycardia or first- or second-degree atrioventricular block. and their serum digoxin concentrations ranged from 0.2 to I 1.6 ng/mL. None ofthe patients in this series developed the severe ventricular ectopy or hyperkalemia seen in adults. However, there are reports of children overdosed or intoxicated with cardiac glycosides who developed life-threatening arrhythmias, cardiac conduction defects, and secondary hypotension.‘-’ These patients required such interventions as cardiopulmonary resuscitation, atropine. antiarrhythmic medications. and/or ventricular pacing. Early signs of digitalis intoxication in the child include those summarized in Table I. While hyperkalemia and refractory hypotension are seen. these symptoms are uncommon in children. A fuller description of the development of antidigoxin Fab fragments is presented elsewhere in this supplement. This approach was first used successfully to treat an adult patient with life-threatening digitalis toxicity in 1976.’ The first children treated with digoxin-specific Fab fragments were reported in 1982.9,‘”
Recently there have been scattered reports of the use of antidigoxin Fab fragments in the treatment ofchildren with digitalis intoxication.‘-‘5 A summary of these case reports is shown in Table 2. The dosage ofdigoxin-specific Fab fragments in children. like adults, is related to the calculated total body burden of digitalis. either from the known amount of drug ingested or from a calculation using the serum digoxin (or digitoxin) concentration. These previously reported cases documented the effectiveness ofdigoxin-specific Fab fragments in selected pediatric cases of severe digitalis intoxication. In all of these cases. resolution of symptoms followed the administration of the digoxin-specific Fab within hours. A case report of digitalis toxicity in an infant which seemed refractory to Fab therapy has also been documented.” It is possible that the antidote was administered too late in this case or that the child’s underlying congenital heart disease was terminal.
WOOLF ET AL m SPECIFIC
TABLE 1.
Symptoms
FAB FOR PEDIATRIC
DIGITALIS
TOXICITY
and Signs of Pediatric Digitalis Intoxication
Gastrointestinal Symptoms Nausea and vomiting Diarrhea Anorexia Visual Changes (Older Children) Blurred vision Photophobia Decreased red-green perception Transient blindness Neurological Signs and Symptoms Headache Confusion and disorientation Hallucinations, delirium Acute psychosis Paresthesias and neuritis Seizures (rare) Aphasia Cardiac Toxicity Sinus arrhythmia/bradycardia Sinoatrial pause or arrest First-degree heart block Second-degree heart block Third-degree heart block Supraventricular arrhythmias Premature ventricular contractions Ventricular bigeminy Ventricular tachycardia Ventricular fibrillation Metabolic Signs
Hyperkalemia (acute) Other Hypotension Malaise Fatigue Weakness Rashes
As part of a broader study of the clinical use of digoxin-specific Fab fragments in the treatment of digitalis poisoning, we have reviewed cases of pediatric digitalis toxicity in which digoxinspecific Fab fragments were used.
METHODS Two separate studies have been conducted. In the first study, 22 collaborating medical centers reported cases in which Fab antibody fragments were used on protocol in a clinical trial between 1978 and 1986. This protocol required that the patient demonstrate life-threatening toxic effects and that other conventional treatments (eg, antiat-rhythmic drugs, ventricular pacing, cardioversion) precede the use of Fab fragments (some of the cases in the multicenter trial had been previously described in the literature and are included in Table 2). The second clinical investigation was undertaken as a postmarketing surveillance study of the safety and efficacy of digoxinspecific Fab fragments in the management of digitalis intoxication. Voluntary reporting of all cases of digoxin poisoning requiring Fab fragments was solicited between 1986 and 1988. Circumstances of the intoxication and the clinical outcome, as well as any adverse effects which might be attributable to Fab fragments, were carefully documented by questionnaire.
17
RESULTS There were 29 children between the ages of 1 day and 18 years old recruited into the first multicenter clinical trial. Reports on the treatment of 28 children between the ages of 4 days and 7 years old were included in the more recent postmarketing surveillance study. Thus, 57 total cases form the basis for this report. Conduction defects (first-degree. second-degree, and thirddegree atrioventricular block) were the most common manifestations of cardiac toxicity in these children (58% of the 57 patients), with second-degree heart block having the highest incidence. Patients in the multicenter clinical trial had, as expected, more severe manifestations of digitalis toxicity than those in the postmarketing surveillance study: refractoriness to other conventional modalities of management was a condition of entry into the study. More patients had signs of extreme cardiac rhythm instability (supraventricular or ventricular arrhythmias, ventricular fibrillation, asystole) than did those in the postmarketing survey. More patients in the multicenter trial also required such therapies as antiarrhythmic agents, ventricular pacing, and cardiopulmonary resuscitation prior to treatment with digoxinspecific Fab fragments. Results of these two clinical studies confirmed the efficacy of digoxin-specific Fab fragments. Almost 90% of the patients in both groups had partial or total resolution of cardiac conduction disturbances or arrhythmias attributable to digitalis intoxication after treatment with Fab fragments. In most cases beneficial effects were observed within 30 minutes to 4 hours of the therapy; reversal of cardiotoxic effects of digitalis poisoning was complete within 24 hours. Noncardiac signs of digitalis intoxication, such as hyperkalemia. vomiting, and depressed consciousness, also improved or resolved after the use of digoxin-specific Fab fragments. Three patients had recrudescence of conduction defects within 24 hours of therapy, which resolved with a second dose of Fab fragments. Therefore, close monitoring of these patients with serial electrocardiograms and serum potassium measurements for 48 hours after Fab fragment administration is recommended, although most children will not need more than one dose of Fab fragments. The postmarketing surveillance study has confirmed the safety of pediatric therapy with digoxin-specific Fab fragments. While 23% of the total patients ultimately had a fatal outcome, none of these deaths were attributable to the digitalis itself, but rather reflected the serious nature of their underlying medical conditions. There were no reports of allergic reactions or immunecomplex related complications in these children. While apparent exacerbation of underlying congestive heart failure has been observed in adults, no such complications were reported from either pediatric sample. Hypokalemia, requiring intravenous potassium supplementation, was reported in one pediatric patient.
DISCUSSION It is well recognized that, in contrast to adults, children without intrinsic heart disease will often tolerate an acute overdose of digitalis with few clinical effects. The emergency physician should recognize that children who are chronically intoxicated with digitalis, or who receive an acute on chronic overdose during loading or maintenance therapy, may be at heightened risk for life-threatening adverse effects of the drug. Those with underlying congenital heart disease may be at a particularly high risk for
18
AMERICAN
TABLE 2.
JOURNAL
OF EMERGENCY
Previous Case Reports of Digitalis Intoxication
Gender
Age
Zucker 1982
M
30 mos
A
NO
Murphy 1982 Rossi 1984
M M
20 mos 34 mos
A A
NO NO
Autret 1985
M
1 mo
L
COARCT CHF
Hussain 1985
M
30 mos
L
NO
Presti 1985
A
L
36
Congenital Disease
Schaumann
1986
F
16 yrs
A
Gonadaldysgenesis PDA Papillary necrosis AVM RF NO
Schaumann
1986
M
17 yrs
A
NO
M
1 mo
C
CAVO PS
Rose 1987
Kearns 1989
F
24 mos
A
Nollett 1989
-
4 yrs
A
Kaufman 1990
M
7d
L
n Volume 9, Number 2 (Supplement
Treated With Digoxin-Specific
Acute v Loading v Chronic
Ref
MEDICINE
Hype RV CHF NO
TGV PS sv PS PDA VT
Antibody
1) n March 1991
Fab Fragments Serum Digoxin Concentration
Fab Dose
(ng/mL)
(mg)
Survival
800
Y
960 480
Y Y
80
Y
27.5
325
Y
6.5
160
N
?
13.0
400
Y
?
6.1
480
Y
30 ug/d
19.9
120
N
22.5 mg
26.0
1280
Y
30 mg
12.8
160
Y
600 ug
25.0
40
Y
Symptoms Signs
Digoxin Dose
Jet Tachy Lethargy N&V V fib 2” SAB SA Block 2” AVB 1” AVB 2” AVB N&V PAC 1” AVB N&V Coma VES
10mg
12mg 6mg
>lOO
16.7 21.7
200 ug/k
4.5 mg
25 ug/k
V-tach/fib :; 3” AVB PAT VES 3” AVB VES CHF Asystole N&V Lethargy 1” AVB 2” AVB
N&V VES Bigeminy 3” AVB
(est)
ABBREVIATIONS:TGV, transposition of great vessels; CAVO, common atrioventricular orifice; VES, ventricular extra systoles; PS, pulmonary stenosis; CHF, congestive heart failure; AVB, atrioventricular block; SAB, sinoatrial block; N & V, nausea and vomiting; PAC, premature atrial contractions; Jet Tachy, AV junctional tachycardia; V tach, ventricular tachycardia; COARCT, coarctation of the aorta; V fib, ventricular fibrillation; PAT, paroxysmal atrial tachycardia; PDA, patient ductus arteriosus; Hypo RV, hypoplastic right ventricle; SV, single ventricle; AVM, arteriovenous malformation; RF, renal failure; A, ambiguous genitalia.
of digitalis toxicity for several reasons. Use of concomitant potassium-wasting diuretics without supplemental potassium may increase cardiac sensitivity to digitalis. The treatment of these patients with other antiarrhythmic agents that interact with digoxin may precipitate toxicity. Those patients who, as part of their medical condition, have impaired renal function may become intoxicated with digoxin unless their maintenance dose is adjusted based on creatinine clearance. The combined experience between the two multicenter pediatric studies described in this paper includes 57 children who received digoxin-specific Fab fragments for the treatment ofdigcomplications
italis toxicity. It is evident that the antidote was used earlier in the course of therapy for those children in the postmarketing survey and that those children were less severely toxic than those in the multicenter clinical trial. In these two studies, rapid resolution of symptoms and signs of cardiac toxicity was observed in a substantial majority of patients after Fab was administered. Both conduction defects and ventricular or supraventricular ectopy resolved within 24 hours, and often within 4 hours, of the administration of Fab fragments. This therapy was also effective in decreasing serum potassium levels to the normal range, usually within 4 hours of administration.
WOOLF ET AL n SPECIFIC
FAB FOR PEDIATRIC
DIGITALIS
19
TOXICITY
There were no cases reported of acute hypersensitivity or other allergic reactions to digoxin-specific Fab fragments among these children. No adverse effects that could be directly attributable to Fab fragments were reported, although one patient developed hypokalemia. In three children there appeared to be a recrudescence of cardiac conduction defects posttreatment that resolved upon administration of a repeated dose of Fab fragments.
RECOMMENDATIONS The emergency physician is advised to obtain as accurate a history as possible concerning the total dose of digitalis taken in a poisoning situation. The dosing of digoxin in small infants should be carefully reviewed for possible errors in calculation or preparation. In all patients an attempt should be made to rid the gastrointestinal tract of unabsorbed drug if the cardiac glycoside was ingested within 2 hours of presentation to the emergency department. While ipecac or lavage may be performed, clinicians must be aware of the hazards of vagal stimulation, either by vomiting or during passage of an orogastric tube, potentially exacerbating a conduction defect or bradycardia in symptomatic patients. Activated charcoal is an effective agent to adsorb digitalis and should be administered (at 1 gram per kilogram ofbody weight) to prevent further absorption from the gastrointestinal tract. Repetitive doses of charcoal are not known to enhance elimination of digoxin. 2o Cholestyramine has also been advocated for use as a possible binder with good affinity for the cardiac glycosides,*’ but evidence that it is more effective than charcoal is lacking. All patients deserve careful monitoring of vital signs and serial electrocardiography. Repeated measurement of arterial blood gases, serum electrolytes including potassium, serum glucose. and renal function tests may be necessary. A serum digoxin (or digitoxin) concentration should be performed at least 6 to 8 hours after the ingestion to insure steady-state sampling after the rapid initial phase of drug redistribution into body tissues. Antiarrhythmic agents, a&opine, bretyllium. amiodarone, and ventricular pacing have all been tried in pediatric patients with severe digitalis poisoning who demonstrate life-threatening cardiac symptoms and signs. Secondary hypotension may respond to fluids and pressors or digoxin-specific Fab fragments. Level of consciousness must be monitored clinically; seizures, while unusual, should be treated with standard anticonvulsants such as benzodiazepines. barbiturates, or phenytoin. Hyperkalemia can be treated by conventional means including sodium polystyrene sulfonate (Kayexalatea) or. if life-threatening, digoxinspecific Fab fragments. Hemodialysis or hemofiltration are not considered helpful in lowering serum digitalis concentrations. It is recommended that digoxin-specific Fab fragments be reserved for pediatric cases of severe digitalis (either digoxin or digitoxin) intoxication, confirmed by history or serum digoxin or digitoxin concentration. The pediatric patient who ingests acutely more than 0.1 mg/kg of digoxin, or who has a steady state serum concentration greater than 5 ng/mL is likely to have symptoms and signs of toxicity. The clinical definition of a serious intoxication should include either a potentially life-threatening arrhythmia or a cardiac conduction defect. A severe digitalis poisoning might also be defined to include potentially lifethreatening hyperkalemia. refractory hypotension, or emergence or progression of cardiac manifestations after a known massive ingestion. Table 3 summarizes these recommendations.
TABLE3.
Recommendations For Digoxin-Specific Use in Children With Digoxin Poisoning
Fab Fragment
1. Known Digoxin Intoxication (A) Strong historical evidence of an acute ingestion 7 0.1 mg/kg or (B) Elevated (steady-state) serum dgoxin concentration > 5 ng/ mL AND 2. Rapidly progressing symptoms/signs of digoxin toxicity or. 2. Potentially life-threatening arrhythmias including cardiac conduction disturbances or 2. Severe hyperkalemia (K+ z 6.0 mEq/L)
While it is not recommended that Fab fragments be used prophylactically. we believe that it is desirable to institute therapy early in the course of a severe poisoning to forestall progression to more refractory, damaging cardiac arrhythmias. At times, it may be desirable to use Fab before other modalities such as antiarrhythmic agents, ventricular pacing, or cardioversion in the treatment of pediatric digitalis intoxication; however, digoxin-specific Fab should not contraindicate the use of these valuable adjuncts to treatment. Whenever Fab fragments are used, prior skin testing for hypersensitivity reactions is recommended (time permitting) for children as well as adults if there is a known allergic predisposition to immunoglobulin proteins or prior history of Fab antibody use. Precautionary monitoring for allergic reactions should be instituted during administration of the antidote. Although the two clinical studies described here demonstrated the safety of this antidote in a small sample of children, more uncommon, idiosyncratic reactions are still possible. The development of urticaria or other rashes, wheezing, or angioedema should be treated with diphenhydramine, epinephrine, and/or steroids. The use of epinephrine must be balanced against its potential for worsening the effects of digoxin intoxication. Such episodes, as well as any other suspected adverse reactions. should be reported to the manufacturer (Burroughs-Wellcome Company) and the Food and Drug Administration. All pediatric patients with severe digitalis intoxication should be admitted to an intensive care setting for at least 24 hours after the administration of digoxin-specific Fab fragments. Close monitoring of vital signs, electrocardiogram, serum electrolytes (particularly serum potassium). and renal function is suggested. Serum total digoxin concentrations are markedly elevated and hence generally misleading after administration of Fab fragments: if there is a laboratory capability of assaying serum free digoxin concentration. then this may be useful when combined with close observation of the patient’s clinical course. Patients in whom all symptoms of digitalis toxicity resolve may be safely redigitalized after it can be demonstrated by serum measurements that digoxin-specific Fab fragments have been completely eliminated. This will require at least several days or longer if the patient has impaired renal function. The efforts of the Advisory Panel to the Postmarketing Surveillance Study of Digibinda are acknowledged with deep appreciation. Anne
20
AMERICAN
JOURNAL
OF EMERGENCY
Hickey, MS, the staff epidemiologist at Burroughs Wellcome Co., assisted with the analysis of data from the postmarketing surveillance study and reviewed the manuscript.
REFERENCES 1. Koren G: Interaction between digoxin and commonly coadministered drugs in children. Pediatrics 1985;75:1032-1037 2. Litovitz TL, Schmitz BF, Holm KC: 1988 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1988;7:495-545 3. Lewander WJ, Gaudreault P, Einhorn A, et al: Acute pediatric digoxin ingestion: A ten-year experience. Am J Dis Child 1986;140: 770-773 4. McNamara DG, Brewer EJ, Ferry GD: Accidental poisoning of children with digitalis. N Engl J Med 1964;271: 1106-l 108 5. Fowler RS, Rathi L, Keith JD: Accidental digitalis intoxication in children. J Pediatr 1964;64: 188-200 6. Duke M: Atrioventricular block due to accidental digoxin ingestion treated with atropine. Am J Dis Child 1972;124:754-756 7. Hastreiter AR, van Der Horst RL, Chow-Tung E: Digitalis toxicity in infants and children. Pediatr Cardiol 1984;5:131-142 8. Smith TW. Haber E. Yeatman L, et al: Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976;294:797-800 9. Zucker AR, Lacina SJ, DasGupta DS, et al: Fab fragments of digoxin-specific antibodies to reverse ventricular fibrillation induced by digoxin ingestion in a child. Pediatrics 1982;70:468-471 10. Murphy DJ, Bremner WF, Haber E, et al: Massive digoxin poisoning treated with Fab fragments of digoxin-specific antibodies. Pediatrics 1982;70:472-473 11. Rossi R, Leititis JU, Hagel KJ, et al: Severe digoxin intoxication in a child treated by infusion of digoxin-specific Fab-antibody-fragments. Eur J Pediatr 1984;142: 138-l 40
MEDICINE
n Volume 9, Number 2 (Supplement
1) n March 1991
12. Autret E, Chantepie A, Bloc D, et al: Utilisation des anticorps antidigoxine an tours dune intoxication digitalique chez un nourrisson. Archives Francaises de Pediatrie 1985;42:803-804 13. Hussain MI, Murray R, Williams BP: Purified digoxin specific Fab fragments. Indiana Med 1985;780:781 14. Presti S, Friedman D, Saslow J, et al: Digoxin toxicity in a premature infant: treatment with Fab fragments of digoxin-specific antibodies. Pediatr Cardiol 1985;6:91-93 15 Schaumann W, Kaufmann 6, Neubert P, et al: Kinetics of the Fab fragments of digoxin antibodies and of bound digoxin in patients with severe digoxin intoxication. Eur J Clin Pharmacol 1986;30:527533 16. Rutherfoord Rose S, Gorman RL, McDaniel J: Fatal digoxin poisoning: an unsuccessful resuscitation with use of digoxin-immune Fab. Am J Emerg Med 1987;5:509-511 17. Kearns GL, Moss MM, Clayton BD, et al: Pharmacokinetics and efficacy of digoxin specific Fab fragments in a child following massive digoxin overdose. J Clin Pharmacol1989;29:901-908 18. Nollet H, Verhaaren H, Stroobandt R, et al: Delayed elimination of digoxin antidotum determined by radioimmunoassay. J Clin Pharmacol 1989;29:41-45 19. Kaufman J, Leikin J, Kendzierski D, et al: Use of digoxin Fab immune fragments in a seven-day old infant. Pediatr Emerg Care 1990;6:118-121 20. Park GD, Goldberg MJ, Spector R, et al: The effects of activated charcoal on digoxin and digitoxin clearance. Drug Intel1 Clin Pharm 1985;19:937-941 21. Hastreiter AR, van der Horst RL, Chow-Tung E: Digitalis toxicity in infants and children. Pediatr Cardiol 1984;5:131-142 22. Hursting MJ, Raisys VA, Opheim KE, et al: Determination of free digoxin concentrations in serum for monitoring Fab treatment of digoxin overdose. Clin Chem 1987;33:1652-1655
