Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Management of acute coronary syndrome wikipedia , lookup
Cardiac contractility modulation wikipedia , lookup
Electrocardiography wikipedia , lookup
Antihypertensive drug wikipedia , lookup
Heart arrhythmia wikipedia , lookup
Quantium Medical Cardiac Output wikipedia , lookup
Arrhythmogenic right ventricular dysplasia wikipedia , lookup
Hong Kong Journal of Emergency Medicine Review on Flecainide poisoning ITF Cheung and CY Man Flecainide acetate is a Vaughn-Williams class IC antiarrhythmic. It is used mainly for treatment of supraventricular arrhythmias due to reentry and is highly effective in suppressing frequent premature ventricular depolarization and nonsustained ventricular tachycardia (VT). Although less than 1% of drug overdoses are fatal, severe intoxication with Vaughn-Williams class IC antiarrhythmics is associated with average mortality of 22.5% and the rate of mortality after flecainide overdose is approximately 10%. Severe flecainide overdose is frequently fatal because of the rapid onset of hypotension and ventricular arrhythmias. Its cardiotoxicity is mainly due to its sodium and potassium channels blocking effects. Commonly recommended therapies like haemolysis or haemoperfusion is not helpful because of its large volume of distribution. As a result, the treatment goals are to decrease the amount of blockade; correct aggravating conditions for arrhythmias, such as electrolytes disturbances or hypoxia; avoid drugs with sodium channels blocking effects. Recently, there are some successful data on using peripheral cardiopulmonary bypass technique in the treatment of severe flecainide intoxication. This may be a promising treatment option in this type of drug overdose. (Hong Kong j.emerg.med. 2002;9:150-153) Keywords: Class IC antiarrhythmic, flecainide, overdose, poisoning Flecainide acetate is a Vaughn-Williams class IC antiarrhythmic. (Table 1) It is used mainly for treatment of supraventricular arrhythmias due to reentry and is highly effective in suppressing frequent premature ventricular depolarization and nonsustained ventricular tachycardia ( VT ). 1-3 Although less than 1% drug overdoses are fatal, severe i n t ox i c a t i o n w i t h Va u g h n - Wi l l i a m s c l a s s I C antiarrhythmics is associated with average mortality of 22.5% and the rate of mortality after flecainide overdose is approximately 10%. 4 Severe flecainide overdose is frequently fatal because of the rapid onset of hypotension and ventricular arrhythmias. 2,4 Its cardiotoxicity is mainly due to its sodium and potassium channels blocking effects. Correspondence to: Cheung Tsz Fung, Ian, MBChB(CUHK), FRCSEd(A&E) Prince of Wales Hospital, Accident and Emergency Department, 30-32 Ngan Shing Street, Shatin, N.T., Hong Kong Email: [email protected] Man Chi Yin, FRCSEd, FHKCEM, FHKAM(Emergency Medicine) Mechanism of toxic effects Class 1 antiarrhythmics block sodium channels in cardiomyocytes and cardiac conducting tissue. Sodium channel is responsible for phase 0 or the rapid upstroke of the action potential and is reflected in the QRS duration of the ECG. Drugs that block the sodium channel will increase QRS duration. (Table 2) Class 1A drugs lengthen the duration of action potential, where class 1B drugs shorten it, and class 1C drugs have little or no effect on action potential Table 1. Vaughn-Williams classification Class I Ia - Procainamide, Quinidine, Disopyramide Ib -Lidocaine, Mexiletine, Tocainide Ic - Encainide, Flecainide (Tambocor), Propafenone (Rhythmol) Class II - Acebutalol, Propranolol, Esmolol Class III - Bretyllium, Amiodarone, Sotalol (also class II), Ibutilide Class IV - Verapamil, Diltiazem Cheung et al./Review on Flecainide poisoning Table 2. Drugs that block the sodium channel Quinine Quinidine Procainamide Disopyramide Lidocaine Phenytoin Mexiletine Tocainide Flecainide Propafenone Moricizine Class 1A Class 1B Class 1C Tricyclics Phenothiazines Thioridazine Cocaine Diphenhydramine Benadryl Propoxyphene Dologesic Carbamazepine Amantadine duration. Class 1B antiarrhythmics have rapid offset kinetics, thus the sodium channel is reactivated between contractions. On the other hand, Class 1C has slow offset kinetics and causes complete blockade of any particular sodium channel for a much longer duration.5 Potassium channel is primarily responsible for phase III or rapid repolarization of the action potential and is reflected in the QT interval of the ECG. Drugs that cause potassium channel blockade will result in an increase in the QT duration. Class III antiarrhythmics are potassium channel blockers and result in QT prolongation. Class 1A and 1C drugs, in addition to their effects on the sodium channel, also have potassium channel blocking effects, thus they cause both QRS and QT prolongation. 151 The reminder 70% is converted by the liver to metabolites, which exert weak electro-physiologic effect. 6,7 The main metabolite meta-0-dealkylated lactum contribute little to the efficacy or toxicity of the drug. Renal clearance is enhanced in acidic urine, however, a systemic acidosis is likely to exacerbate cardiac toxicity and must be avoided. Clinical features of flecainide overdose Daily therapeutic dose of flecainide is 200-300 mg. Doses in excess of 400 mg per day are associated with a high incidence of adverse effects and are usually not required for the control of arrhythmias. In the first 30 minutes after overdose, nausea and vomiting are common early symptoms. After 30 minutes to 2 hours of ingestion, cardiotoxicity will appear and bradyarrhythmias are more common than tachyarrhythmias. Other cardiac arrhythmias include various heart block, Torsade de pointes, other ventricular arrhythmias, VF and asystole. Cardiac arrest has been reported in 1/4 of all patients with flecainide overdose. 4,8 Serious ventricular tachyarrhythmias may be provoked in 5-25% of patients, who had depressed left ventricular function, sustained VT or taking a daily dose of more than 400 mg. Other clinical features like dizziness, headache, blurred vision, seizure and hypotension had been reported. Flecainide may elevate pacing or defibrillation thresholds, therefore, higher energy level will be required during resuscitation. Kinetics in overdose Investigation Flecainide is well absorbed with bioavailability of 95%. It is a weak base with moderate protein binding (40%) and has a high volume of distribution of 9 L/kg. Its distribution half-life is 10 mins whereas its elimination half-life is dose dependent, ranging from 7 to 23 hours. After complete absorption, about 30% of an oral dose is excreted unchanged by the kidneys. Urgent electrolytes and acid-base (Na +, K + , Mg 2+ , HCO3-) should be measured and corrected, in order to prevent exacerbating toxicity. ECG will show progressive prolongation of QRS, often well over 200 ms. Some authors suggested that 152 prolongation of PR or QRS of more than 50% indicates toxicity. 2 Drug level may be of prognostic significance though are unlikely to alter initial management. Treatment As an emergency physician, the paramount initial treatment is supportive, which includes the basic Airway, Breathing and Circulation. The aim is to prevent hypoxia and maintain fluid balance, which will aggravate the toxicity. Secondly, we should decrease further drug absorption. Gastrointestinal decontamination like gastric lavage should be considered in all patients who are unconscious and presented within 1 hour after ingestion of more than two times the recommended daily dose. However, atropine or pacing should be given prior to intubation and lavage, in order to prevent vagal stimulation. Activated charcoal should be given to ALL patients unless contraindicated.8 Thirdly, we need to minimize cardiac toxicity by 1) decreasing the amount of blockade (e.g. NaHCO3 for sodium channel blockade); 2) correct aggravating conditions for arrhythmias, such as electrolytes disturbance or hypoxia; 3) avoid drugs with sodium channel blocking effects. (Table 2) Early and large doses of NaHCO 3 should be given. Total doses of 3-6 mEq/kg NaHCO 3 showed efficacy in animal studies.9-12 We should aim at maintaining a pH of 7.5-7.55. Some authors recommended that NaHCO 3 should be given in patients with QRS>160 ms or any arrhythmias.10 Lastly, we need to increase the elimination of the drugs. Forced diuresis should be avoided because this may be complicated by the antiarrhythmic-induced cardiac insufficiency. Urinary acidification will increase flecainide elimination, however, a systemic acidosis is likely to exacerbate cardiac toxicity and must be avoided. Haemoperfusion and haemodialysis Hong Kong j. emerg. med. ! Vol. 9(3) ! Jul 2002 is unlikely to be helpful as flecainide has a very large volume of distribution, although there is one case report in which this seems to be more effective.13,14 Although cardiopulmonary bypass (CBS) continues to be an experimental procedure in the treatment of poisoning, 15,16 there are two recently published cases of successful use of CBS in the treatment of flecainide overdose. In May 1997 Annals of Emergency Medicine published the first reported use of CBS in flecainide overdose.17 The patient had an agonal rhythm and a flecainide level of 5.4 mug/ml (normal range 0.2-1.0 mug/ml). After 10 hours of CBS, the level dropped to 1.4 mug/ml and the patient had a stable rhythm and blood pressure. However, treatment was discontinued because the patient already sustained an irreversible neurologic damage before effective circulation was restored. In 2001 Crit Care Med published a successful case of using extracorporeal membrane oxygenation (ECMO) in treatment of flecainide overdose. 18 The patient had a pulseless electrical activity after a fatal dose of flecainide intoxication. After 26 hours of ECMO, the patient had a stable cardiac function with decreasing pump flow and an almost normalized conscious state. This patient finally survived without neurological sequelae upon hospital discharge. For treatment of arrhythmias, ALL class 1A antiarrhythmics are contraindicated. Class 1B (lignocaine and phenytoin), which may be used, may still exacerbate sodium channel blockade and potentially exacerbate arrhythmias. Therefore, they should be avoided. Magnesium is normally the drug of choice for treating Torsade de pointes, however, its calcium channel blocking activities may aggravate the hypotension and heart block. For these reasons, isoprenaline or over-drive pacing should be preferred. Second or third degree heart block should be treated with atropine, NaHCO3 and isoprenaline followed by a pacemaker. Seizures should be treated by diazepam 5-20 mg intravenously followed by phenobarbitone 15 mg/kg intravenously. Cheung et al./Review on Flecainide poisoning Late complications and prognosis In a large retrospective review of 120 cases of 1C antiarrhythmics overdose, 2 the average mortality was 22.5% (8-36%), whereas the overall mortality of drug overdose in general was less than 1%. The overall mortality rate for flecainide overdose was 10%. All patients with flecainide overdose should have cardiac monitoring for at least 24 hours or until ECG changes have resolved. Long-term sequelae have not been reported, although there is one report of persistent ECG changes. 153 References 1. 2. 3. 4. 5. 6. Summary Flecainide has a large volume of distribution and negative inotropic effect. In cases of overdose, PR and QRS inter vals correlate well with drug level. Prolongation of PR or QRS intervals of more 50% of normal indicate toxicity. 3 Cardiac complications can occur as early as 30 minutes and bradyarrhythmias are more common. In flecainide overdose, the threshold for pacing and defibrillation will be increased and class 1 antiarrhythmics and magnesium should be avoided. Aggressive use of NaHCO3 should be considered early, and atropine and pacing should be given before gastric lavage. Recent reports indicate the potential usefulness of CBS/ECMO in the treatment of flecainide overdose. 7. 8. 9. 10. 11. 12. 13. Conclusion 14. Flecainide overdose carries a high mortality. Early recognition of its cardiac toxicity and aggressive treatments in minimizing them are paramount. Avoid treating arrhythmias induced by antiarrhythmics with another antiarrhythmics. If we can improve the vital organ perfusion, maintain adequate renal and hepatic blood flow to enhance drug clearance, and allow time for drug redistribution, the chance of survival will be markedly improved. 15. 16. 17. 18. Roden DM, Woosley RL. Drug therapy. Flecainide. N Engl J Med 1986;315(1):36-41. Winkelmann BR, Leinberger H. Life-threatening flecainide toxicity. A pharmacodynamic approach. Ann Intern Med 1987;106(6):807-14. Suttorp MJ, Kingma JH, Jessurun EH, et al. The value of class 1C antiarrhythmic drugs for acute conversion of paroxysmal atrial fibrillation or flutter to sinus rhythm. J Am Coll Cardiol 1990;16(7):1722-7. Koppel C, Oberdisse U, Heinemeyer G. Clinical course and outcome in class 1C antiarrhythmic overdose. J Toxicol Clin Toxicol 1990;28(4):433-44. Ranger S, Nattel S. Determinants and mechanisms of flecainide-induced promotion of ventricular tachycardia in anesthetized dogs. Circulation 1995;92(5):1300-11. Boriani G, Strocchi E, Capucci A, et al. Flecainide: evidence of non-linear kinetics. Eur J Clin Pharmacol 1991;41(1):57-9. Funck-Brentano C, Becquemont L, Kroemer HK, et al. Variable disposition kinetics and electrocardiographic effects of flecainide during repeated dosing in humans: contribution of genetic factors, dose-dependent clearance, and interaction with amiodarone. Clin Pharmacol Ther 1994;55(3):256-69. Gotz D, Pohle S, Barckow D. Primary and secondary detoxification in severe flecainide intoxication. Intensive Care Med 1991;17(3):181-4. Bajaj AK, Woosley RL, Roden DM. Acute electrophysiologic effects of sodium administration in dogs treated with O-desmethyl encainide. Circulation 1989;80(4):9941002. Goldman MJ, Mowry JB, Kirk MA. Sodium bicarbonate to correct widened QRS in a case of flecainide overdose. J Emerg Med 1997;15(2):183-6. Keyler DE, Pentel PR. Hypertonic sodium bicarbonate partially reverses QRS prolongation due to flecainide in rats. Life Sci 1989;45(17):1575-80. Salerno DM, Murakami MM, Johnston RB, et al. Reversal of flecainide-induced ventricular arrhythmia by hypertonic sodium bicarbonate in dogs. Am J Emerg Med 1995;13 (3):285-93. Wu r z b e r g e r R , Wi t t e r E , Ave n h a u s H , e t a l . Hemoperfusion in flecainide poisoning. Klin Wochenschr 1986;64(9):442-4. Borgeat A, Biollaz J, Freymond B, et al. Hemofiltration clearance of flecainide in a patient with acute renal failure. Intensive Care Med 1988;14(3):236-7. Goodwin DA, Lally KP, Null DM. Extracorporeal membrane oxygenation support for cardiac dysfunction from tricyclic antidepressant overdose. Crit Care Med 1993;21(4):625-7. McVey FK, Corke CF. Extracorporeal circulation in the management of massive propanolol overdose. Anaesthesia 1991;46(9):744-6. Yasui RK, Culclasure TF, Kaufmann D, et al. Flecainide overdose: is cardiopulmonary support the treatment? Ann Emerg Med 1997;29(5):680-2. Auzinger GM, Scheinkestel CD. Successful extra-corporeal life support in a case of severe flecainide intoxication. Crit Care Med 2001;29(4):887-90.