CASE REPORT
encainide, overdose
Encainide Overdose in an Infant
From the Divisions of Clinical
Mary E Mortensen, MD**
Pharmacology~Toxicology*
Claire E Bolon, MD *~
and Cardiologyt and the
Michael T Kelley, MD *~§
Departments of Pediatrics~: and Emergency Medicine,§ The Ohio
Philip D Walson, MD *~ Steven Cassidy, MD t *
State University, Columbus. Received for publication September 20, 1991. Revision received February 13, 1992. Acceptedfor publication February 27, 1992.
We describe a near-fatal case of encainide toxicity in a 6-month-old infant who reportedly ingested a single 25-mg tablet. Within 30 minutes he had a wide-complex sinus tachycardia (QRS, 0.16 second)and then acutely decompensated with the development of ventricular tachycardia. Electroshock cardioversion (probably synchronized but not documented) was performed, but the ventricular tachycardia returned. Intraosseous fluids, sodium bicarbonate, and phenytoin were administered, and defibrillation was performed. The resultant wide-complex tachyarrhythmia gradually normalized. Serum encainide and metabolite concentrations obtained at the time of resuscitation (60 minutes after ingestion) exceeded the therapeutic adult range. History and blood concentration data were consistent with ingestion of as little as a single 25-mg tablet, which was nearly fatal to this child. [Mortensen ME, Bolen CE, Kelley MT, Walson PD, Cassidy S: Encainide overdose in an infant. Ann EmergMedAugust1992;21:998-1001 .] INTRODUCTION Serious unintentional medication ingestions it] children often involve a drug prescribed for an adult. One or two tablets may seem unlikely to produce serious toxicity. However, for some antiarrhythmic medications, ingestion of a single tablet by a child could result in serious and potentially fatal cardiovascular effects. Many antiarrhythmics have a rapid onset of action, which can rapidly lead to life-threatening arrhythmias. We describe the successful management of a life-threatening encainide overdose in an infant.
CASE
REPORT
A 6-month-old boy was transported to the emergency department by ambulance approximately 30 minutes after his mother found him being fed one of her encainide tablets by a 2-year-old child of a neighbor. One tablet was thought to have been ingested. Transport was delayed because the emergency medical services providers were reluctant to transport the asymptomatic child, despite the poison center recommendation and concerns of the mother. The infant was awake and alert in the triage area, with an apical pulse of 140 and respirations of 24. (.Weight of 7.6 kg was recorded after resuscitation.) Other than a rapid heart
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rate, the triage nurse noted no other physical abnormalities. Within ten minutes of arrival the child became pale, diaphoretic, and cyanotic. Cardiac monitoring was begun, and a wide-complex sinus tachycardia was noted initially (QRS, 0.16 second) (Figure 1A). Femoral pulses were not palpable; the monitor showed ventricular tachycardia (Figure 1B). Chest compressions were started, and 1 J/kg cardioversion (probably synchronized but not documented) was administered; ventricular fibrillation was then observed. Defibrillation was performed, with conversion to a wide-complex sinus tachycardia that quickly deteriorated to ventricular tachycardia. The patient was intubated. Because p e r i p h e r a l venous access was unsuccessful, a tibial intraosseous line was inserted; 20 mg/kg phenytoin was given. Sodium bicarbonate 2.6 mEq/kg and an unrecorded volume of 50% dextrose were administered. Periods of ventricular tachycardia alternated with a wide-complex t a c h y a r r h y t h m i a (Figure 1C). Shortly after fluid and medications were administered, the child's color improved, pulses became palpable, and a blood pressure of 108/63 mm Hg was obtained. He began to open his eyes, and became agitated. Two milligrams of diazepam was administered for sedation. Gastric lavage was performed; no pills or fragments were noted. Ten grams of activated charcoal was then given. The infant remained in sinus rhythm with gradual normalization of the QRS interval. He was t r a n s f e r r e d to the ICU, and on arrival was opening his eyes and reaching for his mother. Vital signs were blood pressure, 89/75 mm Hg; pulse, 188; and respirations, 30. Extremities were cool and pale, and the remainder of his physical examination was normal.
Figure 1. ECG recordings during resuscitation o f infant with encainide intoxication A. Shortly after ED arrival and about 30 minutes after ingestion, when pale, diaphoretic, and cyanotic B. After acute decompensation when peripheral pulses were no longer palpable C. After fluid resuscitation, intraosseous phenytoin and sodium bicarbonate administration, and cardioshock of l J/kg
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L a b o r a t o r y results from blood drawn at the time of cardiac stabilization (about 45 minutes after the event) included the following: serum sodium, 137 mmol/L; potassium, 3.2 mmol/L; chloride, 98 mmol/L; bicarbonate, .17 mmol/L; blood urea nitrogen, 10 mg/dL (3.6 mmol/L); creatinine, 0.1 mg/dL (8.8 mmol/L); glucose, 338 mg/dL (16.7 mmol/L); calcium, 9.0 mg/dL (2.2 mm.ol/L); and phosphorus, 5.7 mg/dL (1.6 mmol/L). Arterial blood gas obtained ten to 15 minutes after intubation (on 100% oxygen) showed p H 7.43, Pco2, 23 mm Hg; and P02,443 mm Hg. WBC count was 21,200, with 12% segmented neutrophils, 78% lymphocytes, 2% bands, 6% monocytes, and 2% eosinophils. The platelet count was 673,000. Hemoglobin was 10.1 g/dL, and hematocrit was 31%. An ECG recorded 72 hours after admission demonstrated normal sinus rhythm with normal P R and QRS intervals (Figure 2). Chest radiograph showed a normal cardiac silouhette and clear lung fields. Serum and urine toxicology screens were negative. The remainder of his hospitalization was unremarkable. Results of initial and subsequent serum encaiuide and metabolite levels are shown (Table). Encainide and metabolite assays were performed at a reference laboratory using a modified high-pressure liquid chromatography method. 2
DISCUSSION To date, encainide overdose with life-threatening toxicity has not been reported in a child. In fact, few data are available concerning treatment of encainide overdose, presumably because of its limited availability. Other related antiarrhythmic drugs are more widely used, however, and may have similar potential for toxicity. Encainide, an analogue of lysergic acid, is a benzanilide compound that has been demonstrated to have five to ten times the antiarrhythmic potency of procainamide. 3 It is a class Ic antiarrhythmic agent that blocks sodium channels of the myocardium and P u r k i n j e fibers, manifested by doserelated slowing of phase zero depolarization. It has minimal effects on either repolarization or action potential duration.4, 5 Sodium channel blocking prolongs the QRS interval and slows intraventricular conduction, a This slowing of cellular depolarization permits conduction delays and ventricular arrhythmias that may be life threatening at high doses. Other adverse effects include hypotension, b r a d y c a r d i a , Figure 2. Normal ECG obtained three days after the overdose, with PR interval 0.11 second and QRS interval 0.06 second (paper speed, 50 mm/sec)
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atrioventricular dissociation, and asystole. 3 Similar cardiac effects have been seen in overdoses of other drugs with sodium channel-blocking activity, including the tricyclic antidepressants and class Ia antiarrhythmic agents. 6 Absorption of encainide after oral dosing is rapid. It is metabolized extensively in the liver. In adults, within 30 minutes to four hours, encainide is metabolized to its major active metabolites, O-desmethyl encainide and 3-methoxy0-desmethyl encainide, both which are more potent antiarrhythmics than the p a r e n t compound.7, a About 7% of the general population has a genetic deficiency in encainide metabolism. In these nonmetabolizers, encainide elimination halflife is eight to 22 hours, there is no conversion to O-desmethyl encainide, and encainide is renally eliminated as n-desmethyl encainide.9,1o Encainide was approved for treatment of ventricular arrhythmias in adults, particularly those arrhythmias resistant to other s t a n d a r d therapies. 3 It a p p e a r e d to be effective for preventing supraventricular tachycardia in patients with Wolff-Parkinson-White syndrome n and showed promise in treating children with medically refractory supraventricular tachycardia. 12 However, paradoxical worsening of ventricu|ar arrhythmias was reported in some patients.13 In the Cardiac A r r h y t h m i a Suppression Trial, a muhicenter, randomized, placebo-controlled clinical trial, both encainide and flecainide were associated with excess deaths from arrhythmias and nonfatal arrhythmias.]4 Death rates were highest in the encainide-treated group. This provided evidence that both drugs h a d p r o a r r h y t h m i c potential, and both were discontinued.]S Approved indications for encainide and flecainide were restricted to life-threatening arrhythmias.16 Recent evidence indicates that similar p r o a r rhythmic effects occur in pediatric patients treated with encainide to suppress supraventricular tachycardias or ventricular arrhythmias.17 In December 1991, encainide was withdrawn from the m a r k e t and now is available only from the manufacturer for patients with life-threatening arrhythmias.
Table. Serum encainide and metabolite concentrations*
Therapeutic Adult Ranget
Patient (ng]mL)
Encainide O-Desmethyl encainide 3-Methoxy-O-desrnethyl encainide
(ng/mL)
Initial
Repeat
180 464
< 100 < 100
15-100 100-300
126
< 100
60-300
*Initial values were obtained during resuscitation in the ED approximately 60 minutes after ingestion. Repeat values were obtained approximately 24 hours later when the patient was asymptomatic. Usual assay detection limits are 5 ng/ml, but since the initial patient values were high, the repeat samples were assayed at a sensitivity of 100 ng/mL. Because of insufficient volume, these samples could not be reanalyzed atthe lower (5 ng/ml) detection limit. A recommended therapeutic range for encainide is 3OOto 1,200ng/mL in patients with a genetic deficiency in encainide metabolism. tTherapeutic range as reported by the clinical laboratory and based on unpublished data (personal communication, HG McCoy, PharmD, MedTox Laboratories, St Paul, Minnesota).
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The effects of encainide overdose have not been well described, so specific treatment recommendations have not been published. However, in one adult who intentionally overdosed on encainide, hypertonic (1 M) sodium bicarbonate was associated with a p r o m p t improvement in cardiac rhythm and blood pressure and a decrease in QRS duration. 18 Hypertonic saline (3 M) was used in the successful treatment of encainide-induced ventricular tachycardia in an adult taking the drug therapeutically. 19 Adverse metabolic effects of the hypertonic saline included h y p e r n a t r e m i a , hyperosmolality, hypocalcemia, and hypophosphatemia. In experimental models, hypertonic sodium bicarbonate also appears to reverse QRS prolongation and hypoteusion caused by tricyclic antidepressant poisoning. 17,20 Experimentally, sodium loading with either the bicarbonate or chloride salt shortens the prolonged QRS interval in dogs pretreated with O-desmethyl encainide, a potent metabolite of encainide. 21 In our patient, serum encainide a n d metabolite concentrations were higher than the adult therapeutic range r e p o r t e d by the l a b o r a t o r y (Table), but these concentrations were consistent with the ingestion of approximately 25 mg (one tablet). 10 It is possible that more tablets had been ingested if a significant amount of drug was removed by orogastric lavage; nevertheless, the amount of drug in the child at the time of his toxic event was unlikely to have been more than one tablet. Conduction delay, manifested as a prolonged QRS interval, was seen approximately 30 minutes after ingestion and rapidly progressed to ventricular tachycardia. Reports of seizures and ventricular tachyarrhythmias in encainide toxicity led to the empiric use of p h e n y t o i n l n this patient. Similarities between encainide and trieyclic antidepressant cardiotoxicity may support the use of phenytoin for such ventricular arrhythmias; 22 however, the efficacy of phenytoiu is unproven and disputed. 23 Phenytoin administered before an amitriptyline infusion to experimental animals a p p e a r e d to enhance tricyclic antidepressant cardiotoxicity, a finding that has discouraged the clinical use of phenytoin.23,24 In this case, the decision to administer sodium bicarbonate was based on the known sodium channel-blocking effect of encainide. This p r o p e r t y is shared with tricyclic antidepressants, and sodium bicarbonate appears to reverse the ECG signs of tricyclic antidepressant eardiotoxicity, including impaired depolarization, conduction delays, ventricular tachycardia, and depressed cardiac contractility. 6,2° Because of the numerous interventions made in r a p i d succession, we cannot evaluate the independent effects of phenytoin or sodium bicarbonate in this case. Immediate transfer to a medical facility for evaluation and monitoring is essential for any patient who has ingested even a small amount of a substance that may have a r a p i d onset of potentially life-threatening toxic effects. Transport personnel should not delay t r a n s p o r t until toxic signs appear, especially in infants or children in whom a 'single tablet could be lethal. Prehospital care providers must guard against trivial-
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E N C A I N I D E OVERDOSE M o r t e n s o n et al
izing a "minimal" pediatric ingestion. Similarly, an adult who reports intentionally ingesting "just a minimal" dose of a rapidly and highly toxic substance deserves prompt transport for evaluation and treatment. Early and effective decontamination is a priority. Because encainide is readily absorbed and has a rapid onset of action, induced emesis is probably contraindicated. Gastric lavage may be considered. However, theoretical complications of orogastric intubation in proarrhythmia drug overdose include vagal stimulation and asystole. Activated charcoal may have limited efficacy when an ingestant is absorbed rapidly. Thus, by the time the patient reaches a medical facility, it may be too late to retard absorption of a drug such as encainide. Because of this child's acute decompensation and our inability to obtain rapid peripheral venous access, an intraosseous line was inserted. At our institution, policy dictates that an intraosseous line be inserted in critically ill patients if peripheral venous access is not successful after two attempts or within 90 seconds. This access was crucial to our resuscitation efforts, given that the fluids and medications can be rapidly administered by this route. 25,26 Our patient apparently ingested just one 25-rag tablet, contradicting a common misconception that one tablet of an adult medication is unlikely to produce serious toxicity in a child. Our experience also emphasizes that physicians must closely monitor cardiac status and rhythm and be prepared for rapid intervention and resuscitation. Although we can make no conclusions regarding optimal therapy, experimental evidence and very limited clinical experience suggest that hypertonic sodium bicarbonate or sodium chloride may be beneficial in reversing encainide cardiotoxicity in overdose. SUMMARY
Ingestion of as little as a single tablet of encainide resulted in life-threatening ventricular arrhythmias in a child. Insertion of an intraosseous line permitted prompt delivery of medications and fluids. Prehospital care providers must be aware that apparently trivial amounts of some adult dosage forms can be toxic to small children. The authors are grateful to MeraDee Longnecker for her preparation of the manuscript. They also thank Theodore Good, RPh; Josepha Cranen, MD; and Bobbie Jo Brooks,
3. Woosley RL, Wood A J J, Roden BM: Encainide. N Engl J Med 1988;318:1107q 115. 4. Jaillon P, Drici M: Recent antiarrhythmic drugs. Am J Cardio11989;64:65J-69J. 5. Lee JH, Rosen MR: Use-dependent actions and effects on transmembrane action potentials of flecainide, encainide and ethmozine in canine Purkinje fibers. J Cardiovasc Pharmacol 1991;18:285-292. 6. Pentel PR, Benowitz NL: Tricyclic antidepressant poisoning. Management of arrhythmias. Med Toxico11986;1:101-121. 7. Buff HJ, Roden DM, Carey EL, et al: Spectrum of antiarrhythmic response to encainide. Am J Cardio11985;56:887-891. 8. Roden DM, Reele SB, Higgins SB, et el: Total suppression of ventricular arrhythmias by encainide: Pharmacokinetic and electrocardiographic characteristics. N Engl J Med 1980; 302:877-882. 9. Wang T, Roden DM, Wolfenden HT, et el: Influence of genetic pelymorphism on the metabolism and disposition of encainide in man. J PharmacolExp Ther1984;228:605-611. 10. Roden DM, Wood A J J, Wilkinson GR, et al: Disposition kinetics of encainide and metabelites. Am J Cardio11986;58:4C-9C. 11. Markel ML, Prystowsky EN, Heger J J, et el: Encainide for treatment of supraventricular tachycardias associated with the Wolff-Parkinsen-White syndrome. Am J Cardio11986;58:41C-48C. 12. Strasburger JF, Moak JP, Smith RT, et al: Encainide for refractory supraventricular tachycardia in children. Am J Cardio11986;58:49C-54C. 13. Seyka LF: Safety of encainide for the treatment of ventricular arrhythmias. Am J Cardio11988;62:63L-68L. 14. The Cardiac Arrhythrnia Supression Trial (CAST) Investigators: Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmic suppression after myocardial infarction. N Engl J Med 1989;321:406-412. 15. Pratt CM, Moye LA: The Cardiac Arrrhythmia Suppression Trial: Background, interim results and implications. Am J Cardiol1990;65:20B-29B. 16. Anonymous: Restrictions on use of flecainide, encainide. FDA Drug Bu111989;18:16. 17. Fish FA, Billette PC, Benson DW Jr: Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. The Pediatric Electrophysiology Group. JAm Cog Cardiolt991;18:356-365. 18. Pentel PR, Goldsmith SR, Salerno DM, et el: Effect of hypertonic sodium bicarbonate on encainide overdose. Am J Cardio11986;57:878-880. 19. Gardner ML, Brett-Smith H, Batsford WP: Treatment of encainide proarrhythmia with hypertonic saline. PACE1990;13:1232-1235. 20. Pentel PR, Benowitz N: Efficacy and mechanism of action of sodium bicarbonate in the treatment of desipramine toxicity in rats. J Pharmacol Exp Ther 1984;230:12-19. 21. Bajaj AK, Woosley RL, Roden DM: Acute electrephysiologic effects of sodium administration in dogs treated with O-desmethyl encainide. Circulation 1989;80:994-1002. 22. Uhl JA: Phenytoin: The drug of choice in tricyclic antidepressant overdose? Ann Emerg Med 1981;10:270-274. 23. noldfrank LR, Lewin NA, FIomenbaum NE: Cyclic antidepressants, in Goldfrank LR, Flomenbaum NE, Lewin NA, et al (eds): Gold#anUs Toxicologic Emergencies, ed 4. Norwalk, Connecticut, Appleton and Lange, 1990, p 401-408. 24. Callaharn M, Schumaker H, Pentel P: Phenytoin prophylaxis of cardiotoxicity in experimental amitriptyline poisoning. J Pharmacol Exp Thor 1988;245:216-219.
MD, who helped manage the patient. Thanks also go to two anonymous reviewers
25. Fiser BH: Intraosseous infusion. N EnglJ Med 1990; 322:1579-1581.
for their insightful comments and recommendations to improve the manuscript.
26. Walsh-Kelly CM, Berens RJ, 61aeser PW, et el: Intraosseous infusion of phenytoin. Am J Emerg Med 1986;4:523-524.
REFERENCES 1. Litovitz TL, Bailey KM, Schmitz BF, et al: 1990 annual report of the American Association of Poison Control Centers national data collection system. Am J Emerg Med 1991;9:461-509.
Address for reprints: Mary E Mortensen, MD, Division of Clinical Pharmacology/ Toxicology, 700 Children's Drive, Columbus, Ohio 43205.
2. Bartok M J, Mayol RF, Boarrnan P, et al: Analysis of encainide and metabolites in plasma and urine by high-performance liquid chromatography. Ther Drug Monit 1988;10:446-452.
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encainide, overdose
Encainide Overdose in an Infant
From the Divisions of Clinical
Mary E Mortensen, MD**
Pharmacology~Toxicology*
Claire E Bolon, MD *~
and Cardiologyt and the
Michael T Kelley, MD *~§
Departments of Pediatrics~: and Emergency Medicine,§ The Ohio
Philip D Walson, MD *~ Steven Cassidy, MD t *
State University, Columbus. Received for publication September 20, 1991. Revision received February 13, 1992. Acceptedfor publication February 27, 1992.
We describe a near-fatal case of encainide toxicity in a 6-month-old infant who reportedly ingested a single 25-mg tablet. Within 30 minutes he had a wide-complex sinus tachycardia (QRS, 0.16 second)and then acutely decompensated with the development of ventricular tachycardia. Electroshock cardioversion (probably synchronized but not documented) was performed, but the ventricular tachycardia returned. Intraosseous fluids, sodium bicarbonate, and phenytoin were administered, and defibrillation was performed. The resultant wide-complex tachyarrhythmia gradually normalized. Serum encainide and metabolite concentrations obtained at the time of resuscitation (60 minutes after ingestion) exceeded the therapeutic adult range. History and blood concentration data were consistent with ingestion of as little as a single 25-mg tablet, which was nearly fatal to this child. [Mortensen ME, Bolen CE, Kelley MT, Walson PD, Cassidy S: Encainide overdose in an infant. Ann EmergMedAugust1992;21:998-1001 .] INTRODUCTION Serious unintentional medication ingestions it] children often involve a drug prescribed for an adult. One or two tablets may seem unlikely to produce serious toxicity. However, for some antiarrhythmic medications, ingestion of a single tablet by a child could result in serious and potentially fatal cardiovascular effects. Many antiarrhythmics have a rapid onset of action, which can rapidly lead to life-threatening arrhythmias. We describe the successful management of a life-threatening encainide overdose in an infant.
CASE
REPORT
A 6-month-old boy was transported to the emergency department by ambulance approximately 30 minutes after his mother found him being fed one of her encainide tablets by a 2-year-old child of a neighbor. One tablet was thought to have been ingested. Transport was delayed because the emergency medical services providers were reluctant to transport the asymptomatic child, despite the poison center recommendation and concerns of the mother. The infant was awake and alert in the triage area, with an apical pulse of 140 and respirations of 24. (.Weight of 7.6 kg was recorded after resuscitation.) Other than a rapid heart
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rate, the triage nurse noted no other physical abnormalities. Within ten minutes of arrival the child became pale, diaphoretic, and cyanotic. Cardiac monitoring was begun, and a wide-complex sinus tachycardia was noted initially (QRS, 0.16 second) (Figure 1A). Femoral pulses were not palpable; the monitor showed ventricular tachycardia (Figure 1B). Chest compressions were started, and 1 J/kg cardioversion (probably synchronized but not documented) was administered; ventricular fibrillation was then observed. Defibrillation was performed, with conversion to a wide-complex sinus tachycardia that quickly deteriorated to ventricular tachycardia. The patient was intubated. Because p e r i p h e r a l venous access was unsuccessful, a tibial intraosseous line was inserted; 20 mg/kg phenytoin was given. Sodium bicarbonate 2.6 mEq/kg and an unrecorded volume of 50% dextrose were administered. Periods of ventricular tachycardia alternated with a wide-complex t a c h y a r r h y t h m i a (Figure 1C). Shortly after fluid and medications were administered, the child's color improved, pulses became palpable, and a blood pressure of 108/63 mm Hg was obtained. He began to open his eyes, and became agitated. Two milligrams of diazepam was administered for sedation. Gastric lavage was performed; no pills or fragments were noted. Ten grams of activated charcoal was then given. The infant remained in sinus rhythm with gradual normalization of the QRS interval. He was t r a n s f e r r e d to the ICU, and on arrival was opening his eyes and reaching for his mother. Vital signs were blood pressure, 89/75 mm Hg; pulse, 188; and respirations, 30. Extremities were cool and pale, and the remainder of his physical examination was normal.
Figure 1. ECG recordings during resuscitation o f infant with encainide intoxication A. Shortly after ED arrival and about 30 minutes after ingestion, when pale, diaphoretic, and cyanotic B. After acute decompensation when peripheral pulses were no longer palpable C. After fluid resuscitation, intraosseous phenytoin and sodium bicarbonate administration, and cardioshock of l J/kg
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L a b o r a t o r y results from blood drawn at the time of cardiac stabilization (about 45 minutes after the event) included the following: serum sodium, 137 mmol/L; potassium, 3.2 mmol/L; chloride, 98 mmol/L; bicarbonate, .17 mmol/L; blood urea nitrogen, 10 mg/dL (3.6 mmol/L); creatinine, 0.1 mg/dL (8.8 mmol/L); glucose, 338 mg/dL (16.7 mmol/L); calcium, 9.0 mg/dL (2.2 mm.ol/L); and phosphorus, 5.7 mg/dL (1.6 mmol/L). Arterial blood gas obtained ten to 15 minutes after intubation (on 100% oxygen) showed p H 7.43, Pco2, 23 mm Hg; and P02,443 mm Hg. WBC count was 21,200, with 12% segmented neutrophils, 78% lymphocytes, 2% bands, 6% monocytes, and 2% eosinophils. The platelet count was 673,000. Hemoglobin was 10.1 g/dL, and hematocrit was 31%. An ECG recorded 72 hours after admission demonstrated normal sinus rhythm with normal P R and QRS intervals (Figure 2). Chest radiograph showed a normal cardiac silouhette and clear lung fields. Serum and urine toxicology screens were negative. The remainder of his hospitalization was unremarkable. Results of initial and subsequent serum encaiuide and metabolite levels are shown (Table). Encainide and metabolite assays were performed at a reference laboratory using a modified high-pressure liquid chromatography method. 2
DISCUSSION To date, encainide overdose with life-threatening toxicity has not been reported in a child. In fact, few data are available concerning treatment of encainide overdose, presumably because of its limited availability. Other related antiarrhythmic drugs are more widely used, however, and may have similar potential for toxicity. Encainide, an analogue of lysergic acid, is a benzanilide compound that has been demonstrated to have five to ten times the antiarrhythmic potency of procainamide. 3 It is a class Ic antiarrhythmic agent that blocks sodium channels of the myocardium and P u r k i n j e fibers, manifested by doserelated slowing of phase zero depolarization. It has minimal effects on either repolarization or action potential duration.4, 5 Sodium channel blocking prolongs the QRS interval and slows intraventricular conduction, a This slowing of cellular depolarization permits conduction delays and ventricular arrhythmias that may be life threatening at high doses. Other adverse effects include hypotension, b r a d y c a r d i a , Figure 2. Normal ECG obtained three days after the overdose, with PR interval 0.11 second and QRS interval 0.06 second (paper speed, 50 mm/sec)
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atrioventricular dissociation, and asystole. 3 Similar cardiac effects have been seen in overdoses of other drugs with sodium channel-blocking activity, including the tricyclic antidepressants and class Ia antiarrhythmic agents. 6 Absorption of encainide after oral dosing is rapid. It is metabolized extensively in the liver. In adults, within 30 minutes to four hours, encainide is metabolized to its major active metabolites, O-desmethyl encainide and 3-methoxy0-desmethyl encainide, both which are more potent antiarrhythmics than the p a r e n t compound.7, a About 7% of the general population has a genetic deficiency in encainide metabolism. In these nonmetabolizers, encainide elimination halflife is eight to 22 hours, there is no conversion to O-desmethyl encainide, and encainide is renally eliminated as n-desmethyl encainide.9,1o Encainide was approved for treatment of ventricular arrhythmias in adults, particularly those arrhythmias resistant to other s t a n d a r d therapies. 3 It a p p e a r e d to be effective for preventing supraventricular tachycardia in patients with Wolff-Parkinson-White syndrome n and showed promise in treating children with medically refractory supraventricular tachycardia. 12 However, paradoxical worsening of ventricu|ar arrhythmias was reported in some patients.13 In the Cardiac A r r h y t h m i a Suppression Trial, a muhicenter, randomized, placebo-controlled clinical trial, both encainide and flecainide were associated with excess deaths from arrhythmias and nonfatal arrhythmias.]4 Death rates were highest in the encainide-treated group. This provided evidence that both drugs h a d p r o a r r h y t h m i c potential, and both were discontinued.]S Approved indications for encainide and flecainide were restricted to life-threatening arrhythmias.16 Recent evidence indicates that similar p r o a r rhythmic effects occur in pediatric patients treated with encainide to suppress supraventricular tachycardias or ventricular arrhythmias.17 In December 1991, encainide was withdrawn from the m a r k e t and now is available only from the manufacturer for patients with life-threatening arrhythmias.
Table. Serum encainide and metabolite concentrations*
Therapeutic Adult Ranget
Patient (ng]mL)
Encainide O-Desmethyl encainide 3-Methoxy-O-desrnethyl encainide
(ng/mL)
Initial
Repeat
180 464
< 100 < 100
15-100 100-300
126
< 100
60-300
*Initial values were obtained during resuscitation in the ED approximately 60 minutes after ingestion. Repeat values were obtained approximately 24 hours later when the patient was asymptomatic. Usual assay detection limits are 5 ng/ml, but since the initial patient values were high, the repeat samples were assayed at a sensitivity of 100 ng/mL. Because of insufficient volume, these samples could not be reanalyzed atthe lower (5 ng/ml) detection limit. A recommended therapeutic range for encainide is 3OOto 1,200ng/mL in patients with a genetic deficiency in encainide metabolism. tTherapeutic range as reported by the clinical laboratory and based on unpublished data (personal communication, HG McCoy, PharmD, MedTox Laboratories, St Paul, Minnesota).
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The effects of encainide overdose have not been well described, so specific treatment recommendations have not been published. However, in one adult who intentionally overdosed on encainide, hypertonic (1 M) sodium bicarbonate was associated with a p r o m p t improvement in cardiac rhythm and blood pressure and a decrease in QRS duration. 18 Hypertonic saline (3 M) was used in the successful treatment of encainide-induced ventricular tachycardia in an adult taking the drug therapeutically. 19 Adverse metabolic effects of the hypertonic saline included h y p e r n a t r e m i a , hyperosmolality, hypocalcemia, and hypophosphatemia. In experimental models, hypertonic sodium bicarbonate also appears to reverse QRS prolongation and hypoteusion caused by tricyclic antidepressant poisoning. 17,20 Experimentally, sodium loading with either the bicarbonate or chloride salt shortens the prolonged QRS interval in dogs pretreated with O-desmethyl encainide, a potent metabolite of encainide. 21 In our patient, serum encainide a n d metabolite concentrations were higher than the adult therapeutic range r e p o r t e d by the l a b o r a t o r y (Table), but these concentrations were consistent with the ingestion of approximately 25 mg (one tablet). 10 It is possible that more tablets had been ingested if a significant amount of drug was removed by orogastric lavage; nevertheless, the amount of drug in the child at the time of his toxic event was unlikely to have been more than one tablet. Conduction delay, manifested as a prolonged QRS interval, was seen approximately 30 minutes after ingestion and rapidly progressed to ventricular tachycardia. Reports of seizures and ventricular tachyarrhythmias in encainide toxicity led to the empiric use of p h e n y t o i n l n this patient. Similarities between encainide and trieyclic antidepressant cardiotoxicity may support the use of phenytoin for such ventricular arrhythmias; 22 however, the efficacy of phenytoiu is unproven and disputed. 23 Phenytoin administered before an amitriptyline infusion to experimental animals a p p e a r e d to enhance tricyclic antidepressant cardiotoxicity, a finding that has discouraged the clinical use of phenytoin.23,24 In this case, the decision to administer sodium bicarbonate was based on the known sodium channel-blocking effect of encainide. This p r o p e r t y is shared with tricyclic antidepressants, and sodium bicarbonate appears to reverse the ECG signs of tricyclic antidepressant eardiotoxicity, including impaired depolarization, conduction delays, ventricular tachycardia, and depressed cardiac contractility. 6,2° Because of the numerous interventions made in r a p i d succession, we cannot evaluate the independent effects of phenytoin or sodium bicarbonate in this case. Immediate transfer to a medical facility for evaluation and monitoring is essential for any patient who has ingested even a small amount of a substance that may have a r a p i d onset of potentially life-threatening toxic effects. Transport personnel should not delay t r a n s p o r t until toxic signs appear, especially in infants or children in whom a 'single tablet could be lethal. Prehospital care providers must guard against trivial-
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izing a "minimal" pediatric ingestion. Similarly, an adult who reports intentionally ingesting "just a minimal" dose of a rapidly and highly toxic substance deserves prompt transport for evaluation and treatment. Early and effective decontamination is a priority. Because encainide is readily absorbed and has a rapid onset of action, induced emesis is probably contraindicated. Gastric lavage may be considered. However, theoretical complications of orogastric intubation in proarrhythmia drug overdose include vagal stimulation and asystole. Activated charcoal may have limited efficacy when an ingestant is absorbed rapidly. Thus, by the time the patient reaches a medical facility, it may be too late to retard absorption of a drug such as encainide. Because of this child's acute decompensation and our inability to obtain rapid peripheral venous access, an intraosseous line was inserted. At our institution, policy dictates that an intraosseous line be inserted in critically ill patients if peripheral venous access is not successful after two attempts or within 90 seconds. This access was crucial to our resuscitation efforts, given that the fluids and medications can be rapidly administered by this route. 25,26 Our patient apparently ingested just one 25-rag tablet, contradicting a common misconception that one tablet of an adult medication is unlikely to produce serious toxicity in a child. Our experience also emphasizes that physicians must closely monitor cardiac status and rhythm and be prepared for rapid intervention and resuscitation. Although we can make no conclusions regarding optimal therapy, experimental evidence and very limited clinical experience suggest that hypertonic sodium bicarbonate or sodium chloride may be beneficial in reversing encainide cardiotoxicity in overdose. SUMMARY
Ingestion of as little as a single tablet of encainide resulted in life-threatening ventricular arrhythmias in a child. Insertion of an intraosseous line permitted prompt delivery of medications and fluids. Prehospital care providers must be aware that apparently trivial amounts of some adult dosage forms can be toxic to small children. The authors are grateful to MeraDee Longnecker for her preparation of the manuscript. They also thank Theodore Good, RPh; Josepha Cranen, MD; and Bobbie Jo Brooks,
3. Woosley RL, Wood A J J, Roden BM: Encainide. N Engl J Med 1988;318:1107q 115. 4. Jaillon P, Drici M: Recent antiarrhythmic drugs. Am J Cardio11989;64:65J-69J. 5. Lee JH, Rosen MR: Use-dependent actions and effects on transmembrane action potentials of flecainide, encainide and ethmozine in canine Purkinje fibers. J Cardiovasc Pharmacol 1991;18:285-292. 6. Pentel PR, Benowitz NL: Tricyclic antidepressant poisoning. Management of arrhythmias. Med Toxico11986;1:101-121. 7. Buff HJ, Roden DM, Carey EL, et al: Spectrum of antiarrhythmic response to encainide. Am J Cardio11985;56:887-891. 8. Roden DM, Reele SB, Higgins SB, et el: Total suppression of ventricular arrhythmias by encainide: Pharmacokinetic and electrocardiographic characteristics. N Engl J Med 1980; 302:877-882. 9. Wang T, Roden DM, Wolfenden HT, et el: Influence of genetic pelymorphism on the metabolism and disposition of encainide in man. J PharmacolExp Ther1984;228:605-611. 10. Roden DM, Wood A J J, Wilkinson GR, et al: Disposition kinetics of encainide and metabelites. Am J Cardio11986;58:4C-9C. 11. Markel ML, Prystowsky EN, Heger J J, et el: Encainide for treatment of supraventricular tachycardias associated with the Wolff-Parkinsen-White syndrome. Am J Cardio11986;58:41C-48C. 12. Strasburger JF, Moak JP, Smith RT, et al: Encainide for refractory supraventricular tachycardia in children. Am J Cardio11986;58:49C-54C. 13. Seyka LF: Safety of encainide for the treatment of ventricular arrhythmias. Am J Cardio11988;62:63L-68L. 14. The Cardiac Arrhythrnia Supression Trial (CAST) Investigators: Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmic suppression after myocardial infarction. N Engl J Med 1989;321:406-412. 15. Pratt CM, Moye LA: The Cardiac Arrrhythmia Suppression Trial: Background, interim results and implications. Am J Cardiol1990;65:20B-29B. 16. Anonymous: Restrictions on use of flecainide, encainide. FDA Drug Bu111989;18:16. 17. Fish FA, Billette PC, Benson DW Jr: Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. The Pediatric Electrophysiology Group. JAm Cog Cardiolt991;18:356-365. 18. Pentel PR, Goldsmith SR, Salerno DM, et el: Effect of hypertonic sodium bicarbonate on encainide overdose. Am J Cardio11986;57:878-880. 19. Gardner ML, Brett-Smith H, Batsford WP: Treatment of encainide proarrhythmia with hypertonic saline. PACE1990;13:1232-1235. 20. Pentel PR, Benowitz N: Efficacy and mechanism of action of sodium bicarbonate in the treatment of desipramine toxicity in rats. J Pharmacol Exp Ther 1984;230:12-19. 21. Bajaj AK, Woosley RL, Roden DM: Acute electrephysiologic effects of sodium administration in dogs treated with O-desmethyl encainide. Circulation 1989;80:994-1002. 22. Uhl JA: Phenytoin: The drug of choice in tricyclic antidepressant overdose? Ann Emerg Med 1981;10:270-274. 23. noldfrank LR, Lewin NA, FIomenbaum NE: Cyclic antidepressants, in Goldfrank LR, Flomenbaum NE, Lewin NA, et al (eds): Gold#anUs Toxicologic Emergencies, ed 4. Norwalk, Connecticut, Appleton and Lange, 1990, p 401-408. 24. Callaharn M, Schumaker H, Pentel P: Phenytoin prophylaxis of cardiotoxicity in experimental amitriptyline poisoning. J Pharmacol Exp Thor 1988;245:216-219.
MD, who helped manage the patient. Thanks also go to two anonymous reviewers
25. Fiser BH: Intraosseous infusion. N EnglJ Med 1990; 322:1579-1581.
for their insightful comments and recommendations to improve the manuscript.
26. Walsh-Kelly CM, Berens RJ, 61aeser PW, et el: Intraosseous infusion of phenytoin. Am J Emerg Med 1986;4:523-524.
REFERENCES 1. Litovitz TL, Bailey KM, Schmitz BF, et al: 1990 annual report of the American Association of Poison Control Centers national data collection system. Am J Emerg Med 1991;9:461-509.
Address for reprints: Mary E Mortensen, MD, Division of Clinical Pharmacology/ Toxicology, 700 Children's Drive, Columbus, Ohio 43205.
2. Bartok M J, Mayol RF, Boarrnan P, et al: Analysis of encainide and metabolites in plasma and urine by high-performance liquid chromatography. Ther Drug Monit 1988;10:446-452.
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