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Propafenone Overdose
CASE REPORT
Propafenone Overdose From the Division of Toxicology, Department of Emergency Medicine, * and the Department of Internal Medicine, * Carolinas Medical Center, Charlotte, North Carolina. Receivedfor publication May 4, 1993. Revision received October 4, 1993. Accepted for publication October 26, 1993. Presented at the American Association of Poison Control Centers Annual Scientific Meeting, Tampa, Florida, September 1992.
William Kerns II, MD, FACEP* Betsy English,MD* Marsha Ford, MD, FACEP,ABMT*
Propafenone is an infrequently used class IC antiarrhythmic drug. We report our experience with a patient who overdosed with propafenone and developed coma, seizures, bradycardia, hypotension, and conduction delay. The clinical manifestations and management of this patient are discussed in light of the known pharmacology of propafenone and compared with the limited number of cases that appear in the literature. [Kerns W II, English B, Ford M: Propafenone overdose. Ann ErnergMed July 1994;24:98-103.] INTRODUCTION Propafenone is a class IC antiarrhythmic agent in the Vaughn-Williams scheme, similar to encainide and flecainide. Propafenone also exhibits ]3-adrenergic and calcium channel-blocking activities. It has been used extensively in Europe for the treatment of supraventricular and ventricular arrhythmias. Experience with this drug in the United States is more limited. It has been approved for use by the Food and Drug Administration only since 1989. Because of data from the Cardiac Arrhythmia Suppression Trial, which demonstrated an unexpected increased mortality from class IC drugs, the use of propafenone has been restricted to life-threatening ventricular arrhythmias. 1 Experience with propafenone intoxication is limited primarily to the European literature. To our knowledge, only one case report, describing a toddler accidently poisoned with propafenone, appears in the US literature. 2 We report the case of an adult with a near-fatal intentional ingestion of propafenone.
CASE REPORT A previously healthy 28-year-old man ingested 8.1 g propafenone in a suicide attempt. He was not known to be on any prescription medication, and the empty bottle of propafenone did not bear his name. His only significant
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medical history was alcohol use, extent unknown. There was no known history of cardiovascular disease. Friends discovered him approximately 1 hour after ingestion and summoned emergency medical services. The paramedics found the patient unresponsive with a systolic blood pressure of 90 mm Hg and a respiratory rate of 8. IV naloxone (2 rag) and dextrose (25 g) were given without response. The patient experienced a generalized seizure that responded to 5 mg IV diazepam. He was intubated and transported to a local emergency department. On arrival, the patient was in electromechanical dissociation; CPR was begun. IV atropine (1 rag) was ineffective, but pulses returned after 1 mg epinephrine. An ECG demonstrated a QRS complex measuring 289 milliseconds and a pulse of 70 (Figure 1). Gastrointestinal decontamination was accomplished by orogastric lavage and instillation of activated charcoal. Over the next 2 hours, the patient was given 3,000 mL normal saline, 7 mg epinephrine, 50 mEq sodium bicarbonate, 1 g calcium chloride, an isoproterenol infusion at 10 ~g/min, an external pacemaker, and mechanical ventilation. Despite these measures, the QRS complex widened further to 400 milliseconds and a pulse could not be detected. Intermittent CPR was performed. Initial laboratory data during the resuscitation included glucose, 301 mg/dL (after dextrose had been given); serum bicarbonate, 16 mEq/L; sodium, 138 mEq/L; potassium, 3.9 mEqYL; chloride, 99 mEq/L; and blood urea nitrogen, 10 mg/dL. An arterial blood gas obtained 20 minutes into the resuscitation revealed pH 7.63; PCO2, 33 mm Hg; and PO2,460 mm Hg. The patient was evacuated by air to a regional medical center with a medical toxicology consultation service. During the flight, he experienced three generalized seizures and lost a palpable blood pressure. Each seizure responded to 5 mg IV diazepam. Intermittent CPR was continued, and an epinephrine infusion at 2 ~lg/min raised the blood pressure to 60 mm Hg. On arrival in the medical center KD, the patient's heart rate was 4-5, blood pressure was palpable only at the femoral site, there were no spontaneous respirations, and the external pacemaker did not capture. The patient was cool and clammy, with central cyanosis and mottled extremities. Chest examination revealed clear bilateral breath sounds and distant heart tones. The abdomen was soft and flat with active bowel sounds. The patient had a Glasgow Coma Scale score of 4-. The pupils were 6 mm and nonreactive. Intermittent decerebrate posturing was noted. An arterial blood sample, drawn immediately,
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showed pH 7.20; PCO2, 34 mm Hg; and PO2,262 mm Hg. Soon after arrival, the patient's blood pressure became undetectable and CPR was resumed. An initial sodium bicarbonate bolus of 2 mEqNg and five subsequent boluses of 1 to 2 mEq/kg did not narrow the QRS complex. Two 5-mg IV glucagon boluses did not alter the heart rate or blood pressure, but an epinephrine bolus of 5 mg restored blood pressure to 110 mm Hg. Epinephrine boluses of 1, 3, 5, and 15 mg were repeated on five occasions, and the constant infusion begun earlier was continued. A transvenous pacemaker was placed but would not capture until after a bolus of 1 mg epinephrine (Figure 2). Additional epinephrine boluses and a constant infusion at a rate of 16.6 ~g/min were required to maintain capture and blood pressure. The patient was maintained on both the pacer (settings, 15 mA and rate of 100) and constant epinephrine infusion. Dopamine (3.8 p.g/kg/min) and dobutamine (5.7 ~tg/kg/min) were added without changes in either heart rate or blood pressure. At approximately 8 hours after ingestion, the patient was transferred to the ICU with a heart rate of 100 and systolic blood pressure of 117/79 mm Hg. Over the next 6 hours, the patient's hemodynamic status improved and all cardiovascular support was gradually withdrawn. His ECG revealed a heart rate of 90, limb lead QRS width of 200 milliseconds, and a left bundle branch block. The patient became alert and was extubated 16 hours after ingestion. Over the course of resuscitation, a total of 2 mg atropine, 600 mEq bicarbonate, 37 mg epinephrine, l0 mg glucagon, and 1 g calcium chloride were administered in addition to continuously infused vasoactive agents. Three liters of crystalloid were infused during the initial 6 hours of care. Total CPR time was approximately 120 minutes. Serial ECGs performed during the patient's hospitalization showed a progressive narrowing of the QRS width to 156 milliseconds with persistent left bundle branch block.
Figure 1. Initial 12-lead ECG demonstrating a heart rate of 70 and QRS duration of 289 milliseconds. 06/04/91
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No previous ECG was available for comparison. Serial creatine kinase and lactic dehydrogenase enzymes and isozymes demonstrated no myocardial injury. Echocardiography demonstrated borderline left ventricular enlargement and an ejection fraction of 40%. Serum propafenone levels drawn 10 hours after ingestion and on hospital day 4 were 3,200 ng/mL and 0 ng/mL, respectively, The reference level for a patient taking 300 mg every 8 hours is 1,000+250 ng/mL. There was no evidence by history or serum/urine drug screen of cocaine, phenothiazines, antidepressants, ethanol, salicylate, or acetaminophen. A digoxin level drawn at the referral hospital was less than 0.2 ng/mL. The patient was discharged on hospital day 4 without evidence of neurologic or renal sequelae. He was lost to follow-up until 4 months after ingestion, when he presented to a cardiologist for evaluation of exertional lightheadedness and left arm numbness. An ECG obtained at that time revealed a persistent QRS width of 160 milliseconds and a left bundle branch block. A Holter monitor demonstrated no significant supraventricular or ventricular dysrhythmia, but, interestingly, beats with normal intraventricular conduction appeared intermittently. Stress echocardiography revealed a left ventricle at upper limits of normal for size with globally decreased function (ejection fraction, 25% to 40%). Except for ethanol use or previous, occult viral illness, no other risk factors for cardiomyopathy could be identified. DISCUSSION
Although used to control supraventricular and ventricular dysrhythmia for many years in Europe, propafenone has Figure 2. Paced rhythm with heart rate of i00 and QR5 duration of 200 milliseconds.
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only recently been approved for the management of lifethreatening arrhythmias in the United States. Its primary electrophysiologic effect is membrane stabilization by sodium channel blockade of myocytes and conduction tissue, similar to encainide and flecainide. 1,3,4 Hence, it is classified as an IC antiarrhythmic drug. However, the electrophysiologic action is not restricted to the ability to block sodium channels. In vitro and clinical studies provide evidence of [3-blockade, equivalent to 2% to 5% of the activity of propranolol. 5-7 In addition, in vitro studies reveal weak calcium channel blockade comparable to 1% of the activity of verapamil. 3 Clinical trials looking at the pharmacokinetic properties of the drug demonstrate prompt and nearly 100% absorption of an oral dose. Peak serum concentrations occur between 2 to 3 hours after administration. There is an extensive first-pass effect by a saturable enzyme, with bioavailability varying from 4.8% to 23.5%, depending on the preparation. 8 The volume of distribution is reported to be 2.5 to 4.0 L/kg. Protein binding in plasma to (x-1 glycoprotein is approximately 90%. 1 The elimination halflife ranges from 4 hours following a single dose to 2 to 30 hours in steady state, depending on the genetic predisposition to extent of metabolism. Only 1% is excreted unchanged in the urine, s-l° Based on these pharmacokinetic properties, one would expect rapid onset of signs and symptoms in an acute ingestion, as in our patient and other patients described in the literature. 2,1 t-13 In a review of experience in Germany, KOppel et a114 reported the onset of cardiovascular symptoms between 30 and 120 minutes after ingestion. The properties of negligible urinary excretion, high volume of distribution, and extensive protein binding impede the use of dialysis as a potential mode of propafenone elimination in overdose. 15 Propafenone is metabolized by the cytochrome P-450 pathway, producing the major metabolites 5-hydroxy propafenone and N-desalkyl propafenone. 8 The 5-hydroxy propafenone is the better understood of the two. It has similar antiarrhythmic potency as the parent drug 16 and conflicting studies concerning its [3-blocking effects, t 7,t8 The extent of hydroxy metabolism is determined genetically and patients can be classified as either poor or extensive metabolizers. Approximately 7% of Caucasians are poor metabolizers. Poor metabolizers have been found to have elevated propafenone concentrations and undetectable hydroxy metabolite levels compared with extensive metabolizers. Accordingly, the elimination half-life is longer for poor metabolizers (17+8 hours) than for extensive metabolizers (5+2 hours), lO This polymorphism explains
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the wide range in elimination half-life reported in early papers. The polymorphic metabolism of propafenone may play a role in the expression of toxicity. Poor metabolizers would be expected to achieve higher propafenone concentrations, perhaps attaining levels at which [3-blockade may occur, lo In clinical studies, poor metabolizers who received chronic propafenone therapy at 450 mg per day demonstrated significantly more ]3-blockade than extensive metabolizers, r However, at higher doses, there was no significant difference in the degree of ]3-blockade. In a massive ingestion of propafenone, one might expect some degree of [3-blockade, regardless of phenotype. ECG changes can be predicted from known electrophysiologic properties of propafenone. Common findings include PR prolongation, increased QRS duration, and prolonged QT interval, reflecting prolonged atrioventricular node and ventricular conduction. Mobitz Type I atrioventricular block has been reported, and right and left bundle branch block may appear during therapy. 19-21 Cardiac side effects of propafenone therapy may include congestive heart failure and ventricular tachycardia. Hodges et a119 and Dinh et a122 reported congestive failure in clinical trials. Taking into consideration multiple medications and the presence of preexisting congestive failure, it is difficult to directly relate worsening of congestive failure to propafenone in these small studies. However, Lange et a124 provided echocardiographic evidence of left ventricular dysfunction in their prospective trial of the effects on cardiac output during propafenone and mexilitine therapy. Their group included nine propafenone subjects, two of whom developed clinically evident congestive failure. Controversy exists over the role of propafenone in worsening ventricular ectopy. Case reports have attributed ventricular tachycardia to propafenone therapy. 24,25 The clinical manifestations of toxicity in our patient mirror those previously described in the European literature and the report by McHugh and Perina 2 in the American literature. Our patient experienced rapid onset of depressed mental status, generalized seizures, widened QRS complex, bundle branch block, bradycardia, and hypotension. McHugh and Perina 2 described a pediatric patient with an accidental severe ingestion of 133 mg/kg who developed seizures, right bundle branch block, widened QRS complex, and electromechanical dissociation with bradycardia. Camous et al 11 presented two patients with intoxication who experienced acidosis, conduction delay, widened QRS complexes (both 400 milliseconds), and shock. A propafenone level in one patient was reported as 3,400 ng/mL (no reference level).
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Friocourt et a126 described their experience with a young man taking propafenone for ventricular ectopy who acutely ingested 2,700 mg. He suffered rapid onset of a seizure, hypotension, bradycardia, QRS prolongation (120 milliseconds), and atrioventricular block. The patient's drug level 2 hours after ingestion was 3,185 ng/mL (therapeutic values, 500 to 2,000 ng/mL). Lanquetot et a112 published an account of an occult propafenone ingestion. Clinical manifestations included rapid onset of coma, seizures, widened QRS complex (180 milliseconds), bradycardia, hypotension, and, terminally, asystole. A drug level drawn 30 minutes after ingestion was 3,620 ng/mL (therapeutic range, 120 to 1,000 ng/mL). Olm et aP 3 reported the case of an elderly man who suffered coma, myoclonus, acidosis, widened QRS complex, conduction delay, and hypotension following a 4-g intentional ingestion. The intoxication was confirmed by plasma levels. Picciotto et a127 reported a 3-g suicidal ingestion by an adolescent girl. She developed shock and atrioventricular and interventricular conduction delay. The most extensive review of propafenone toxicity appears in the published experience of the Berlin Poison Control Center. K0ppel et al ]4 compiled data on 120 cases of isolated class IC antiarrhythmic drug ingestion occurring over a 14-year period, including 34 propafenone intoxications. Of the 34 propafenone cases, 18 involved children; almost one-half were male, and the reported amounts ingested ranged from 300 to 3,000 mg. Signs and symptoms, in decreasing order of observed frequency, included bradycardia, nausea, vomiting, and hypotension. The authors reported at least a 25% QRS prolongation in 55% of their total review population. Deaths were attributed mainly to electromechanical dissociation. With a reported mortality rate of 9% for propafenone, the review clearly emphasizes the severe cardiovascular toxicity that may occur with these agents. Our patient may be the first acute ingestion to demonstrate delayed and possibly permanent cardiac sequelae. Evaluation just before discharge and at 4 months after ingestion, including repeat ECGs and echocardiography, revealed a persistent left bundle branch block, mild global hypokinesis, and an ejection fraction of approximately 40%. Right and left bundle branch blocks have been noted in patients taking therapeutic doses. Coumel et a121 described 3 of 71 patients who developed left bundle branch block. This was transient in two patients and did not necessitate discontinuing propafenone. The course of the third patient was not reported. Hodges et a119 reported that 1 of 12 patients under evaluation for suppression of ventricular ectopy developed
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intermittent right bundle branch block. This resolved in temporal relationship to reduction of the dose. New left bundle branch block developed in two of 32 patients enrolled in a clinical study of propafenone therapy in stable ventricular ectopy. 22 Unfortunately, in our patient, no ECG predating the ingestion was available for comparison and confirmation of new changes. Regarding the echocardiographic changes in a 28-year-old, previously healthy man, other etiologies of an underlying, previously undetected cardiomyopathy would include his known ethanol abuse and occult viral illness. Abundant commentary appears in the pharmacology literature and in case reports concerning the physiologic basis of cardiac toxicity, but there is a paucity of comment on the occurrence of central nervous system toxicity, specifically, seizures. Two plausible explanations exist for seizures in acute toxicity. First, cerebral hypoperfusion and hypoxia may occur due to hypotension, bradycardia, and respiratory depression. Second, seizures occur frequently with toxicity of other class I drugs, such as tricyclic antidepressants, lidocaine, and encainide. 28 This may be a direct drug effect, although the mechanism remains to be elucidated. Various therapies for propafenone intoxication are reported in the literature, and success varies from case to case. Pharmacologic modalities have included atropine, sodium bicarbonate, dopamine, dobutamine, isoproterenol, methoxamine and sodium lactate solution. Quantities of the medications often are not reported, making it difficult to draw any conclusion as to efficacy of these agents in reversing toxicity. The use of a pacemaker was reported in two cases; one patient survived. 12,27 K0ppel et al's review 14 briefly mentioned the administration of 100 mmoles of sodium bicarbonate in each of 29 patients who suffered cardiac arrest; only two survivors were reported. They also mentioned eight patients with bradyarrhythmia treated with sodium bicarbonate, but correlation with the effects of other drugs and improvement of ECGs were not available. 14 Treatment of systemic acidosis with sodium bicarbonate may ameliorate worsening of cardiac conduction; McHugh and Perina 2 reported QRS widening during generalized seizure activity. Plasmapheresis was reported as beneficial in the management of two cases. ~1 There are no other reports of enhanced elimination therapies, and the pharmacologic behavior of the drug suggests that hemodialysis or hemoperfusion would not be beneficial. The modality that appeared to have the most clinical benefit in reversing the bradycardia and hypotension was the combination of an internal pacemaker and IV epinephrine. Neither of these agents alone provided adequate
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perfusion. There are two references to patients taking propafenone therapeutically who required permanent pacemakers that would not capture until drug dosages were decreased. 21.29 Perhaps the addition of epinephrine in our patient facilitated pacer capture by lowering the amount of energy required for membrane depolarization. 3° Our patient still required a relatively high (15) milliamp setting for successful capture. SUMMARY
We report our experience with a man who survived a near-fatal, acute propafenone ingestion. Clinical manifestations were predictable based on pharmacologic knowledge and were similar to those previously described in the literature. Aggressive, prolonged resuscitation was instituted with sodium bicarbonate, glucagon, calcium, atropine, and inotropic-chronotropic agents. A combination of bolused and continuously infused epinephrine with temporary internal pacing proved the most beneficial therapy. The patient's history, a drug screen negative for commonly ingested drugs, and an elevated serum propafenone confirmed this as an isolated propafenone ingestion. Four months after the acute ingestion, the patient exhibited evidence of mild cardiomyopathy and a persistent left bundle branch block that may have been due to the propafenone. REFERENCES 1. Funk-Brentano C, Kroemer HK, Lee JT: Drug therapy: Propafenone. N EnglJ Med 1990;322:518-525. 2. McHugh TP, Perina DG: Propafenone ingestion. Ann ErnergMed 1987;16:437-440. 3. Ledda F, Mantelli L, Manzini S, et al: Electrephysiological and antiarrhythmic properties of propafenone in isolated cardiac preparations. J CardiovascPharmacol1981 ;3:1162-1173. 4. Kelhardt M: Basic electrophysiologic actions of propafenone in heart muscle, in Schlepper M, Olssen B (eds): CardiacArrhythmias: Diagnosis,Prognosis, Therapy.Proceedings, 1st International Rytmonorm-Congress.Berlin, Springer-Verlag, 1983, p 91-101. 5. MiJller-Peltzer H, Greger G, Neugebauer G, et al: Beta-blocking and electrophysiological effects of propafenone in volunteers, Eur J Clin Pharmacol1983;25:831-833. 6. McLeod AA, Stiles GL, Shand DG: Demonstration of beta adrenereceptor blockade by propafenone hydrochloride: Clinical pharmacologic, radioligand binding and adenyl cyclase activation studies. J PharmacolExp Ther1983;228:461-466. 7. Lee JT, Lineberry MD, Funck-Brentano C, et al: Propafenone-induced ~-blockade in extensive and poor metabolizer subjects. Circulation1988;78(supp111):11-499. 8. Siddoway LA, Roden DM, Woosley RL: Clinical pharmacology of propafenone: Metabolism and concentration-response relations, Am J Cardio11984;54:9D-12D. 9, Connolly SJ, Kates RE, Lebsack CS, et al: Therapy and prevention: Arrhythmia: Clinical pharmacology of propafenone. Circulation1983;68:589-596. 10. Siddoway LA, Thompson KA, McAIlister CB, et al: Therapy and prevention: Pharmacology: Polymorphism of propafenone metabolism and disposition in man: Clinical and pharmacokinetic consequences. Circulation 1987;75:785-791.
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11. CamousJP, Meyer IP, Gibelin P, et al: Correspondance:Traitement des intoxicationsaux nouveauxantiarythmiques(cibenzoline,flGca'inide,propafGnone).La PresseMedicale 1987;16:2076. 12. LanquetotH, FurorY, KerourGdanV, et al: Intoxication rnortelle par associationpropaf~noneamitriptyline; ,&,preposd'un cas. Allressolollie1988;29:39-42.
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13. OIm M, JimenezMJ, Munne P: Correspondance:Efficacit~ de la methoxaminepar vole veineuse lots des intoxications~ la propafenone.La PresseMedical1989;18:1124.
William Kerns II, MD, FACEP
14. KOppelC, OberdisseU, HeinerneyerG: Clinical course and outcome in class IC antiarrhythmic overdose. Clin Toxico11990;28:433-444.
Department of Emergency Medicine
15. BurgessED, Duff HJ: Brief reports: Hemodialysisremovalof propafenone.Pharmacotherapy 1989;9:331-333.
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16. ThompsonKA, Siddoway LA, Weosley RL, et al: Potentdose-dependentelectrophysiolegic effects of the major metabelite of propafenone.Circulation1985;72(supp1111):111-233.
Division of Toxicology
Carolinas Medical Center
Charlotte, North Carolina 28232-2861 704-355-2000
17. Lee JT, KroemerHK, Silberstein DJ, ot al: The role of genetically determinedpolymerphic drug metabolism in the beta-blockadeproducedby propafeeone.N Enlll J Med 1990;322:17641768. 18. Funk-BrentanoC, KroemerHK, PavlouH, et al: Genetically-determinedinteraction between propafenoneand low-dosequinidine: Role of active metabolites in modulating net drug effect. Br J Clin Pharmacol1989;27:435-444. 19. HodgesM, SalernoD, Granrud6: Double-blindplacebo-controlledevaluation of propafenone in suppressingventricular ectopic activity. Am J Cardio11984;54:45D-50D. 20. de SoyzaN, Terry L, Murphy ML, et al: Effect of propafenonein patients with stable ventricular arrhythmias.Am HeartJ 1984;108:285-289. 21. OoumelP, LeclercqJE, AssayagP: Europeanexperiencewith the antiarrhythmic efficacy of propafenonefor supraventricularand ventricular arrhythmias.Am J Cardio11984;54:60D-66D. 22. Dinh H, BakerBJ, de SoyzaN, et al: Sustainedtherapeutic efficacy and safety of oral propafenonefor treatment of chronic ventricular arrhythmias: A 2-year experience.Am HeartJ 1988;115:92-96. 23. LangeH, LampertS, Sutton MSJ, et al: Changesin cardiac output determined by continuouswave Dopplerechocardiographyduring propafenoneor mexilitine drug testing. Am J Cardiol 1990;65:458-462. 24. Nathan AW, BextonRS, HellestrandKJ. et al: Fatal ventricular tachycardia in association with propafenone,a new class IC antiarrhythmic agent. PostgradMed J 1984;60:155-156. 25. BussJ, Neuss H, Bilgin Y, et al: Malignant ventricular tachyarrhythmiain associationwith propafenonetreatment. Eur HeartJ 1985;6:424-428. 26. Friocourt P, Martin C, Lozac'hL: Intoxicationvolontaire par la propaf~none:A propasd'un cas. Ann Cardiol.4ng#io11968;37:133-136. 27. Picciotto G, SiragusaV, Cellura M, et al: Acute propafenonepoisoning:Descriptionof a case. Minerva-Cardioangiol1990;38:555-558. 28. Ellenhora MJ, BarcelouxDG: Medical ToxicologFDiallnosisand Treatmentof Human Poisoning.New York, Elsevier,1988, p 184, 186, 408. 29. Levy:Propafenonesymposium:Discussion IL Am J Cardie11984;54:51D-52D. 30. Ruffy R: Pharmacologicmodulation of ventricular defibrillation, in Zipes DP,Jaliffe J (eds): CardiacElectrophysiololly:FromCell to Bedside.Philadelphia,WB Saunders, 1990, p 959-962.
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Propafenone Overdose From the Division of Toxicology, Department of Emergency Medicine, * and the Department of Internal Medicine, * Carolinas Medical Center, Charlotte, North Carolina. Receivedfor publication May 4, 1993. Revision received October 4, 1993. Accepted for publication October 26, 1993. Presented at the American Association of Poison Control Centers Annual Scientific Meeting, Tampa, Florida, September 1992.
William Kerns II, MD, FACEP* Betsy English,MD* Marsha Ford, MD, FACEP,ABMT*
Propafenone is an infrequently used class IC antiarrhythmic drug. We report our experience with a patient who overdosed with propafenone and developed coma, seizures, bradycardia, hypotension, and conduction delay. The clinical manifestations and management of this patient are discussed in light of the known pharmacology of propafenone and compared with the limited number of cases that appear in the literature. [Kerns W II, English B, Ford M: Propafenone overdose. Ann ErnergMed July 1994;24:98-103.] INTRODUCTION Propafenone is a class IC antiarrhythmic agent in the Vaughn-Williams scheme, similar to encainide and flecainide. Propafenone also exhibits ]3-adrenergic and calcium channel-blocking activities. It has been used extensively in Europe for the treatment of supraventricular and ventricular arrhythmias. Experience with this drug in the United States is more limited. It has been approved for use by the Food and Drug Administration only since 1989. Because of data from the Cardiac Arrhythmia Suppression Trial, which demonstrated an unexpected increased mortality from class IC drugs, the use of propafenone has been restricted to life-threatening ventricular arrhythmias. 1 Experience with propafenone intoxication is limited primarily to the European literature. To our knowledge, only one case report, describing a toddler accidently poisoned with propafenone, appears in the US literature. 2 We report the case of an adult with a near-fatal intentional ingestion of propafenone.
CASE REPORT A previously healthy 28-year-old man ingested 8.1 g propafenone in a suicide attempt. He was not known to be on any prescription medication, and the empty bottle of propafenone did not bear his name. His only significant
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medical history was alcohol use, extent unknown. There was no known history of cardiovascular disease. Friends discovered him approximately 1 hour after ingestion and summoned emergency medical services. The paramedics found the patient unresponsive with a systolic blood pressure of 90 mm Hg and a respiratory rate of 8. IV naloxone (2 rag) and dextrose (25 g) were given without response. The patient experienced a generalized seizure that responded to 5 mg IV diazepam. He was intubated and transported to a local emergency department. On arrival, the patient was in electromechanical dissociation; CPR was begun. IV atropine (1 rag) was ineffective, but pulses returned after 1 mg epinephrine. An ECG demonstrated a QRS complex measuring 289 milliseconds and a pulse of 70 (Figure 1). Gastrointestinal decontamination was accomplished by orogastric lavage and instillation of activated charcoal. Over the next 2 hours, the patient was given 3,000 mL normal saline, 7 mg epinephrine, 50 mEq sodium bicarbonate, 1 g calcium chloride, an isoproterenol infusion at 10 ~g/min, an external pacemaker, and mechanical ventilation. Despite these measures, the QRS complex widened further to 400 milliseconds and a pulse could not be detected. Intermittent CPR was performed. Initial laboratory data during the resuscitation included glucose, 301 mg/dL (after dextrose had been given); serum bicarbonate, 16 mEq/L; sodium, 138 mEq/L; potassium, 3.9 mEqYL; chloride, 99 mEq/L; and blood urea nitrogen, 10 mg/dL. An arterial blood gas obtained 20 minutes into the resuscitation revealed pH 7.63; PCO2, 33 mm Hg; and PO2,460 mm Hg. The patient was evacuated by air to a regional medical center with a medical toxicology consultation service. During the flight, he experienced three generalized seizures and lost a palpable blood pressure. Each seizure responded to 5 mg IV diazepam. Intermittent CPR was continued, and an epinephrine infusion at 2 ~lg/min raised the blood pressure to 60 mm Hg. On arrival in the medical center KD, the patient's heart rate was 4-5, blood pressure was palpable only at the femoral site, there were no spontaneous respirations, and the external pacemaker did not capture. The patient was cool and clammy, with central cyanosis and mottled extremities. Chest examination revealed clear bilateral breath sounds and distant heart tones. The abdomen was soft and flat with active bowel sounds. The patient had a Glasgow Coma Scale score of 4-. The pupils were 6 mm and nonreactive. Intermittent decerebrate posturing was noted. An arterial blood sample, drawn immediately,
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showed pH 7.20; PCO2, 34 mm Hg; and PO2,262 mm Hg. Soon after arrival, the patient's blood pressure became undetectable and CPR was resumed. An initial sodium bicarbonate bolus of 2 mEqNg and five subsequent boluses of 1 to 2 mEq/kg did not narrow the QRS complex. Two 5-mg IV glucagon boluses did not alter the heart rate or blood pressure, but an epinephrine bolus of 5 mg restored blood pressure to 110 mm Hg. Epinephrine boluses of 1, 3, 5, and 15 mg were repeated on five occasions, and the constant infusion begun earlier was continued. A transvenous pacemaker was placed but would not capture until after a bolus of 1 mg epinephrine (Figure 2). Additional epinephrine boluses and a constant infusion at a rate of 16.6 ~g/min were required to maintain capture and blood pressure. The patient was maintained on both the pacer (settings, 15 mA and rate of 100) and constant epinephrine infusion. Dopamine (3.8 p.g/kg/min) and dobutamine (5.7 ~tg/kg/min) were added without changes in either heart rate or blood pressure. At approximately 8 hours after ingestion, the patient was transferred to the ICU with a heart rate of 100 and systolic blood pressure of 117/79 mm Hg. Over the next 6 hours, the patient's hemodynamic status improved and all cardiovascular support was gradually withdrawn. His ECG revealed a heart rate of 90, limb lead QRS width of 200 milliseconds, and a left bundle branch block. The patient became alert and was extubated 16 hours after ingestion. Over the course of resuscitation, a total of 2 mg atropine, 600 mEq bicarbonate, 37 mg epinephrine, l0 mg glucagon, and 1 g calcium chloride were administered in addition to continuously infused vasoactive agents. Three liters of crystalloid were infused during the initial 6 hours of care. Total CPR time was approximately 120 minutes. Serial ECGs performed during the patient's hospitalization showed a progressive narrowing of the QRS width to 156 milliseconds with persistent left bundle branch block.
Figure 1. Initial 12-lead ECG demonstrating a heart rate of 70 and QRS duration of 289 milliseconds. 06/04/91
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No previous ECG was available for comparison. Serial creatine kinase and lactic dehydrogenase enzymes and isozymes demonstrated no myocardial injury. Echocardiography demonstrated borderline left ventricular enlargement and an ejection fraction of 40%. Serum propafenone levels drawn 10 hours after ingestion and on hospital day 4 were 3,200 ng/mL and 0 ng/mL, respectively, The reference level for a patient taking 300 mg every 8 hours is 1,000+250 ng/mL. There was no evidence by history or serum/urine drug screen of cocaine, phenothiazines, antidepressants, ethanol, salicylate, or acetaminophen. A digoxin level drawn at the referral hospital was less than 0.2 ng/mL. The patient was discharged on hospital day 4 without evidence of neurologic or renal sequelae. He was lost to follow-up until 4 months after ingestion, when he presented to a cardiologist for evaluation of exertional lightheadedness and left arm numbness. An ECG obtained at that time revealed a persistent QRS width of 160 milliseconds and a left bundle branch block. A Holter monitor demonstrated no significant supraventricular or ventricular dysrhythmia, but, interestingly, beats with normal intraventricular conduction appeared intermittently. Stress echocardiography revealed a left ventricle at upper limits of normal for size with globally decreased function (ejection fraction, 25% to 40%). Except for ethanol use or previous, occult viral illness, no other risk factors for cardiomyopathy could be identified. DISCUSSION
Although used to control supraventricular and ventricular dysrhythmia for many years in Europe, propafenone has Figure 2. Paced rhythm with heart rate of i00 and QR5 duration of 200 milliseconds.
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only recently been approved for the management of lifethreatening arrhythmias in the United States. Its primary electrophysiologic effect is membrane stabilization by sodium channel blockade of myocytes and conduction tissue, similar to encainide and flecainide. 1,3,4 Hence, it is classified as an IC antiarrhythmic drug. However, the electrophysiologic action is not restricted to the ability to block sodium channels. In vitro and clinical studies provide evidence of [3-blockade, equivalent to 2% to 5% of the activity of propranolol. 5-7 In addition, in vitro studies reveal weak calcium channel blockade comparable to 1% of the activity of verapamil. 3 Clinical trials looking at the pharmacokinetic properties of the drug demonstrate prompt and nearly 100% absorption of an oral dose. Peak serum concentrations occur between 2 to 3 hours after administration. There is an extensive first-pass effect by a saturable enzyme, with bioavailability varying from 4.8% to 23.5%, depending on the preparation. 8 The volume of distribution is reported to be 2.5 to 4.0 L/kg. Protein binding in plasma to (x-1 glycoprotein is approximately 90%. 1 The elimination halflife ranges from 4 hours following a single dose to 2 to 30 hours in steady state, depending on the genetic predisposition to extent of metabolism. Only 1% is excreted unchanged in the urine, s-l° Based on these pharmacokinetic properties, one would expect rapid onset of signs and symptoms in an acute ingestion, as in our patient and other patients described in the literature. 2,1 t-13 In a review of experience in Germany, KOppel et a114 reported the onset of cardiovascular symptoms between 30 and 120 minutes after ingestion. The properties of negligible urinary excretion, high volume of distribution, and extensive protein binding impede the use of dialysis as a potential mode of propafenone elimination in overdose. 15 Propafenone is metabolized by the cytochrome P-450 pathway, producing the major metabolites 5-hydroxy propafenone and N-desalkyl propafenone. 8 The 5-hydroxy propafenone is the better understood of the two. It has similar antiarrhythmic potency as the parent drug 16 and conflicting studies concerning its [3-blocking effects, t 7,t8 The extent of hydroxy metabolism is determined genetically and patients can be classified as either poor or extensive metabolizers. Approximately 7% of Caucasians are poor metabolizers. Poor metabolizers have been found to have elevated propafenone concentrations and undetectable hydroxy metabolite levels compared with extensive metabolizers. Accordingly, the elimination half-life is longer for poor metabolizers (17+8 hours) than for extensive metabolizers (5+2 hours), lO This polymorphism explains
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the wide range in elimination half-life reported in early papers. The polymorphic metabolism of propafenone may play a role in the expression of toxicity. Poor metabolizers would be expected to achieve higher propafenone concentrations, perhaps attaining levels at which [3-blockade may occur, lo In clinical studies, poor metabolizers who received chronic propafenone therapy at 450 mg per day demonstrated significantly more ]3-blockade than extensive metabolizers, r However, at higher doses, there was no significant difference in the degree of ]3-blockade. In a massive ingestion of propafenone, one might expect some degree of [3-blockade, regardless of phenotype. ECG changes can be predicted from known electrophysiologic properties of propafenone. Common findings include PR prolongation, increased QRS duration, and prolonged QT interval, reflecting prolonged atrioventricular node and ventricular conduction. Mobitz Type I atrioventricular block has been reported, and right and left bundle branch block may appear during therapy. 19-21 Cardiac side effects of propafenone therapy may include congestive heart failure and ventricular tachycardia. Hodges et a119 and Dinh et a122 reported congestive failure in clinical trials. Taking into consideration multiple medications and the presence of preexisting congestive failure, it is difficult to directly relate worsening of congestive failure to propafenone in these small studies. However, Lange et a124 provided echocardiographic evidence of left ventricular dysfunction in their prospective trial of the effects on cardiac output during propafenone and mexilitine therapy. Their group included nine propafenone subjects, two of whom developed clinically evident congestive failure. Controversy exists over the role of propafenone in worsening ventricular ectopy. Case reports have attributed ventricular tachycardia to propafenone therapy. 24,25 The clinical manifestations of toxicity in our patient mirror those previously described in the European literature and the report by McHugh and Perina 2 in the American literature. Our patient experienced rapid onset of depressed mental status, generalized seizures, widened QRS complex, bundle branch block, bradycardia, and hypotension. McHugh and Perina 2 described a pediatric patient with an accidental severe ingestion of 133 mg/kg who developed seizures, right bundle branch block, widened QRS complex, and electromechanical dissociation with bradycardia. Camous et al 11 presented two patients with intoxication who experienced acidosis, conduction delay, widened QRS complexes (both 400 milliseconds), and shock. A propafenone level in one patient was reported as 3,400 ng/mL (no reference level).
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Friocourt et a126 described their experience with a young man taking propafenone for ventricular ectopy who acutely ingested 2,700 mg. He suffered rapid onset of a seizure, hypotension, bradycardia, QRS prolongation (120 milliseconds), and atrioventricular block. The patient's drug level 2 hours after ingestion was 3,185 ng/mL (therapeutic values, 500 to 2,000 ng/mL). Lanquetot et a112 published an account of an occult propafenone ingestion. Clinical manifestations included rapid onset of coma, seizures, widened QRS complex (180 milliseconds), bradycardia, hypotension, and, terminally, asystole. A drug level drawn 30 minutes after ingestion was 3,620 ng/mL (therapeutic range, 120 to 1,000 ng/mL). Olm et aP 3 reported the case of an elderly man who suffered coma, myoclonus, acidosis, widened QRS complex, conduction delay, and hypotension following a 4-g intentional ingestion. The intoxication was confirmed by plasma levels. Picciotto et a127 reported a 3-g suicidal ingestion by an adolescent girl. She developed shock and atrioventricular and interventricular conduction delay. The most extensive review of propafenone toxicity appears in the published experience of the Berlin Poison Control Center. K0ppel et al ]4 compiled data on 120 cases of isolated class IC antiarrhythmic drug ingestion occurring over a 14-year period, including 34 propafenone intoxications. Of the 34 propafenone cases, 18 involved children; almost one-half were male, and the reported amounts ingested ranged from 300 to 3,000 mg. Signs and symptoms, in decreasing order of observed frequency, included bradycardia, nausea, vomiting, and hypotension. The authors reported at least a 25% QRS prolongation in 55% of their total review population. Deaths were attributed mainly to electromechanical dissociation. With a reported mortality rate of 9% for propafenone, the review clearly emphasizes the severe cardiovascular toxicity that may occur with these agents. Our patient may be the first acute ingestion to demonstrate delayed and possibly permanent cardiac sequelae. Evaluation just before discharge and at 4 months after ingestion, including repeat ECGs and echocardiography, revealed a persistent left bundle branch block, mild global hypokinesis, and an ejection fraction of approximately 40%. Right and left bundle branch blocks have been noted in patients taking therapeutic doses. Coumel et a121 described 3 of 71 patients who developed left bundle branch block. This was transient in two patients and did not necessitate discontinuing propafenone. The course of the third patient was not reported. Hodges et a119 reported that 1 of 12 patients under evaluation for suppression of ventricular ectopy developed
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intermittent right bundle branch block. This resolved in temporal relationship to reduction of the dose. New left bundle branch block developed in two of 32 patients enrolled in a clinical study of propafenone therapy in stable ventricular ectopy. 22 Unfortunately, in our patient, no ECG predating the ingestion was available for comparison and confirmation of new changes. Regarding the echocardiographic changes in a 28-year-old, previously healthy man, other etiologies of an underlying, previously undetected cardiomyopathy would include his known ethanol abuse and occult viral illness. Abundant commentary appears in the pharmacology literature and in case reports concerning the physiologic basis of cardiac toxicity, but there is a paucity of comment on the occurrence of central nervous system toxicity, specifically, seizures. Two plausible explanations exist for seizures in acute toxicity. First, cerebral hypoperfusion and hypoxia may occur due to hypotension, bradycardia, and respiratory depression. Second, seizures occur frequently with toxicity of other class I drugs, such as tricyclic antidepressants, lidocaine, and encainide. 28 This may be a direct drug effect, although the mechanism remains to be elucidated. Various therapies for propafenone intoxication are reported in the literature, and success varies from case to case. Pharmacologic modalities have included atropine, sodium bicarbonate, dopamine, dobutamine, isoproterenol, methoxamine and sodium lactate solution. Quantities of the medications often are not reported, making it difficult to draw any conclusion as to efficacy of these agents in reversing toxicity. The use of a pacemaker was reported in two cases; one patient survived. 12,27 K0ppel et al's review 14 briefly mentioned the administration of 100 mmoles of sodium bicarbonate in each of 29 patients who suffered cardiac arrest; only two survivors were reported. They also mentioned eight patients with bradyarrhythmia treated with sodium bicarbonate, but correlation with the effects of other drugs and improvement of ECGs were not available. 14 Treatment of systemic acidosis with sodium bicarbonate may ameliorate worsening of cardiac conduction; McHugh and Perina 2 reported QRS widening during generalized seizure activity. Plasmapheresis was reported as beneficial in the management of two cases. ~1 There are no other reports of enhanced elimination therapies, and the pharmacologic behavior of the drug suggests that hemodialysis or hemoperfusion would not be beneficial. The modality that appeared to have the most clinical benefit in reversing the bradycardia and hypotension was the combination of an internal pacemaker and IV epinephrine. Neither of these agents alone provided adequate
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perfusion. There are two references to patients taking propafenone therapeutically who required permanent pacemakers that would not capture until drug dosages were decreased. 21.29 Perhaps the addition of epinephrine in our patient facilitated pacer capture by lowering the amount of energy required for membrane depolarization. 3° Our patient still required a relatively high (15) milliamp setting for successful capture. SUMMARY
We report our experience with a man who survived a near-fatal, acute propafenone ingestion. Clinical manifestations were predictable based on pharmacologic knowledge and were similar to those previously described in the literature. Aggressive, prolonged resuscitation was instituted with sodium bicarbonate, glucagon, calcium, atropine, and inotropic-chronotropic agents. A combination of bolused and continuously infused epinephrine with temporary internal pacing proved the most beneficial therapy. The patient's history, a drug screen negative for commonly ingested drugs, and an elevated serum propafenone confirmed this as an isolated propafenone ingestion. Four months after the acute ingestion, the patient exhibited evidence of mild cardiomyopathy and a persistent left bundle branch block that may have been due to the propafenone. REFERENCES 1. Funk-Brentano C, Kroemer HK, Lee JT: Drug therapy: Propafenone. N EnglJ Med 1990;322:518-525. 2. McHugh TP, Perina DG: Propafenone ingestion. Ann ErnergMed 1987;16:437-440. 3. Ledda F, Mantelli L, Manzini S, et al: Electrephysiological and antiarrhythmic properties of propafenone in isolated cardiac preparations. J CardiovascPharmacol1981 ;3:1162-1173. 4. Kelhardt M: Basic electrophysiologic actions of propafenone in heart muscle, in Schlepper M, Olssen B (eds): CardiacArrhythmias: Diagnosis,Prognosis, Therapy.Proceedings, 1st International Rytmonorm-Congress.Berlin, Springer-Verlag, 1983, p 91-101. 5. MiJller-Peltzer H, Greger G, Neugebauer G, et al: Beta-blocking and electrophysiological effects of propafenone in volunteers, Eur J Clin Pharmacol1983;25:831-833. 6. McLeod AA, Stiles GL, Shand DG: Demonstration of beta adrenereceptor blockade by propafenone hydrochloride: Clinical pharmacologic, radioligand binding and adenyl cyclase activation studies. J PharmacolExp Ther1983;228:461-466. 7. Lee JT, Lineberry MD, Funck-Brentano C, et al: Propafenone-induced ~-blockade in extensive and poor metabolizer subjects. Circulation1988;78(supp111):11-499. 8. Siddoway LA, Roden DM, Woosley RL: Clinical pharmacology of propafenone: Metabolism and concentration-response relations, Am J Cardio11984;54:9D-12D. 9, Connolly SJ, Kates RE, Lebsack CS, et al: Therapy and prevention: Arrhythmia: Clinical pharmacology of propafenone. Circulation1983;68:589-596. 10. Siddoway LA, Thompson KA, McAIlister CB, et al: Therapy and prevention: Pharmacology: Polymorphism of propafenone metabolism and disposition in man: Clinical and pharmacokinetic consequences. Circulation 1987;75:785-791.
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11. CamousJP, Meyer IP, Gibelin P, et al: Correspondance:Traitement des intoxicationsaux nouveauxantiarythmiques(cibenzoline,flGca'inide,propafGnone).La PresseMedicale 1987;16:2076. 12. LanquetotH, FurorY, KerourGdanV, et al: Intoxication rnortelle par associationpropaf~noneamitriptyline; ,&,preposd'un cas. Allressolollie1988;29:39-42.
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13. OIm M, JimenezMJ, Munne P: Correspondance:Efficacit~ de la methoxaminepar vole veineuse lots des intoxications~ la propafenone.La PresseMedical1989;18:1124.
William Kerns II, MD, FACEP
14. KOppelC, OberdisseU, HeinerneyerG: Clinical course and outcome in class IC antiarrhythmic overdose. Clin Toxico11990;28:433-444.
Department of Emergency Medicine
15. BurgessED, Duff HJ: Brief reports: Hemodialysisremovalof propafenone.Pharmacotherapy 1989;9:331-333.
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16. ThompsonKA, Siddoway LA, Weosley RL, et al: Potentdose-dependentelectrophysiolegic effects of the major metabelite of propafenone.Circulation1985;72(supp1111):111-233.
Division of Toxicology
Carolinas Medical Center
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17. Lee JT, KroemerHK, Silberstein DJ, ot al: The role of genetically determinedpolymerphic drug metabolism in the beta-blockadeproducedby propafeeone.N Enlll J Med 1990;322:17641768. 18. Funk-BrentanoC, KroemerHK, PavlouH, et al: Genetically-determinedinteraction between propafenoneand low-dosequinidine: Role of active metabolites in modulating net drug effect. Br J Clin Pharmacol1989;27:435-444. 19. HodgesM, SalernoD, Granrud6: Double-blindplacebo-controlledevaluation of propafenone in suppressingventricular ectopic activity. Am J Cardio11984;54:45D-50D. 20. de SoyzaN, Terry L, Murphy ML, et al: Effect of propafenonein patients with stable ventricular arrhythmias.Am HeartJ 1984;108:285-289. 21. OoumelP, LeclercqJE, AssayagP: Europeanexperiencewith the antiarrhythmic efficacy of propafenonefor supraventricularand ventricular arrhythmias.Am J Cardio11984;54:60D-66D. 22. Dinh H, BakerBJ, de SoyzaN, et al: Sustainedtherapeutic efficacy and safety of oral propafenonefor treatment of chronic ventricular arrhythmias: A 2-year experience.Am HeartJ 1988;115:92-96. 23. LangeH, LampertS, Sutton MSJ, et al: Changesin cardiac output determined by continuouswave Dopplerechocardiographyduring propafenoneor mexilitine drug testing. Am J Cardiol 1990;65:458-462. 24. Nathan AW, BextonRS, HellestrandKJ. et al: Fatal ventricular tachycardia in association with propafenone,a new class IC antiarrhythmic agent. PostgradMed J 1984;60:155-156. 25. BussJ, Neuss H, Bilgin Y, et al: Malignant ventricular tachyarrhythmiain associationwith propafenonetreatment. Eur HeartJ 1985;6:424-428. 26. Friocourt P, Martin C, Lozac'hL: Intoxicationvolontaire par la propaf~none:A propasd'un cas. Ann Cardiol.4ng#io11968;37:133-136. 27. Picciotto G, SiragusaV, Cellura M, et al: Acute propafenonepoisoning:Descriptionof a case. Minerva-Cardioangiol1990;38:555-558. 28. Ellenhora MJ, BarcelouxDG: Medical ToxicologFDiallnosisand Treatmentof Human Poisoning.New York, Elsevier,1988, p 184, 186, 408. 29. Levy:Propafenonesymposium:Discussion IL Am J Cardie11984;54:51D-52D. 30. Ruffy R: Pharmacologicmodulation of ventricular defibrillation, in Zipes DP,Jaliffe J (eds): CardiacElectrophysiololly:FromCell to Bedside.Philadelphia,WB Saunders, 1990, p 959-962.
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