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European Review for Medical and Pharmacological Sciences 2005; 9: 183-190 Use of amiodarone in emergency A. TESTA, V. OJETTI, A. MIGNECO, M. SERRA, C. ANCONA, A. DE LORENZO*, N. GENTILONI SILVERI Department of Emergency Medicine, Catholic University – Rome (Italy) *Human Nutrition Unit, Tor Vergata University – Rome (Italy) Abstract. – Amiodarone is one of the most common anti-arrhythmic drugs used in the Emergency Department. Recent guidelines on cardiac arrest with shockable rhythm [refractory ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT)] recommend amiodarone as anti-arrhythmic of first choice. Amiodarone is also first choice drug in the treatment of various ventricular and supra-ventricular tachyarrhythmias. This paper deals with the main therapeutical indications of amiodarone in emergency medicine: dosage, side effects, contraindications and pharmacological interactions are reviewed. Amiodarone is effective for control of hemodynamically stable VT, polymorphic VT and widecomplex tachycardia of uncertain origin. It is also helpful for ventricular rate control of rapid atrial arrhythmias in patients with severely impaired left ventricular (LV) function, when digitalis has been ineffective, and is an adjunct to electrical cardioversion. The major side effects of amiodarone are hypotension, bradycardia and peripheral phlebitis. Major contraindications to the intravenous (iv) injection of amiodarone are bradycardia, senoatrial block, severe disturbs of conduction, second or third degree atrio-ventricular blocks. Other contraindications are hypotension, severe respiratory failure, hepatocellular failure and hyperthyroidism. Pharmacological interactions are reported with HMG-CoA reductase inhibitors, class I antiarrhythmic agents and other drugs which contribute to prolong QT interval, digoxin, oral anticoagulants and general anaesthesia. Key Words: Amiodarone, Emergency, Arrhythmias, Tachycardias, Cardiac arrest, Ventricular tachycardia, Atrial fibrillation. drugs, frequently used in the Emergency Department. In the last decade many trials and meta-analysis described amiodarone as antiarrhythmic agent of first choice in the treatment of hemodynamically unstable ventricular tachycardia (VT), of hemodynamically stable wide-complex tachycardias 1, and of many supraventricular tachyarrhythmias1,2. The European Resuscitation Council recommends its use in shockable cardiac arrest [ventricular fibrillation (VF) and pulseless VT]3. Finally, its use has been suggested in post-infarction patients, either presenting frequent or repetitive extra systolic beats and/or VT4 or presenting low left ventricular ejection fraction (below 40%)5. Up to 2% of the patients admitted to the Emergency Department present tachyarrhythmias. In more than 90% these are narrow QRS arrhythmias, such as atrial fibrillation (AF) (45%), paroxysmal supraventricular tachycardia (35%) and atrial flutter (8%). Around 50% of large QRS tachyarrhythmias are supraventricular tachycardias. VT are in most cases hemodynamically stable, while only a small part of large QRS tachyarrhythmia are hemodynamically unstable VT or shockable cardiac arrest (VF/pulseless VT)6. Often tachyarrhythmia end spontaneously or resolve after appropriate treatment in the Emergency Department, and around half of the patients can be discharged after a short period of observation. Pharmacodynamic Properties Introduction Amiodarone, a derivative of benzofuran, is one of the most common anti-arrhythmic Electrophysiologic Effects Amiodarone exerts a non-competitive block of alpha and beta-adrenergic receptors 183 A. Testa, V. Ojetti, A. Migneco, M. Serra, C. Ancona, A. De Lorenzo, N. Gentiloni Silveri antagonizing tachycardia, hypertension and oxygen consumption of the myocardium induced by circulating catecholamines. These effects contribute to the anti-arrhythmic and anti-anginal properties of amiodarone7. After amiodarone administration there is no significant decrease of the myocardial contractility8. The most relevant effects of amiodarone on cardiac cells are the reduction of the depolarization (phase 4)9, the late repolarization, caused by a prolongation of the action potential (phase 3) and the prolongation of the effective refractory period10. Therefore amiodarone is included among class III anti-arrhythmic drugs. It is known that torsades de pointes are the classic form of proarrhythmia observed during therapy with any drug that prolongs repolarization. Among the class III drugs the proarrhythmic risk appears to be lowest for amiodarone, probably due to its complex electrophysiologic profile that may create significant myocardial electrical homogeneity. Mechanisms of Action Some chemical peculiarities of the drug (high iodine’s content and structural analogies with thyroid hormones) suggested possible influences of amiodarone on the thyroid function 11. Furthermore, it is known that some of the cardio-electrophysiologic effects of the chronic administration of amiodarone are very similar to those of hypothyroidism 12,13. Actually, it has been shown a competition or an interaction between amiodarone and the thyroid hormones at many levels (i.e. deiodases, trans-membrane ionic channels)14,15. Two main mechanisms concerning the antiarrhythmic activity of amiodarone have been suggested: • The “T3-mediated” hypothesis: amiodarone antagonizes the thyroid hormones on the nuclear receptor and/or on transmembrane carrier of T3 at cardiac level 16,17 . This T3-mediated mechanism could explain the non-competitive adrenergic block of amiodarone. •The “Membrane-active” hypothesis: amiodarone impairs the lipid environment of the cell membranes where the main ionic channels are located, directly modulating the ionic myocardial transmembran currents18-20. 184 Pharmacokynetic Properties Amiodarone’s chemical structure can be summarised in three points: (1) presence of aromatic rings; (2) a relatively high iodine content; (3) presence of an aliphatic chain with low polarity. This chemical structure highlights some specific pharmacological characteristics like the high lipophylia, the low oral absorption rate, the extended tissue distribution, the slow elimination rate and finally the late therapeutic response during oral treatment21. After intravenous (iv) administration plasma peak concentration is reached in 6-8 hours. Drug tissue distribution occurs differently after acute administration (lungs, liver, heart and kidney) 22 and after the achievement of dynamic equilibrium (mainly in the liver, fat tissue and in the lungs)21. Drug clearance occurs mainly through the liver and only 1% is excreted through the kidneys. Amiodarone cannot be dialysed and crosses easily the placenta (10-50%). N-desethyl-amiodarone (DEA) is its main active metabolite. After a single oral dose, amiodarone’s half life is calculated to be around 24 h, during long-term therapy it increases reaching 28 days21; while DEA’s half life is around 60 days23. Therapeutic Indications in Emergency Cardiac Arrest With Shockable Rhythm (Refractory FV/Pulseless VT) The Resuscitation 2000 Guidelines recommend amiodarone as the antiarrhythmic drug of choice in treatment of resistant VF or pulseless VT24. Even if the administration of amiodarone may cause a slight delay during the resurrection procedure, evidence supports its use after epinephrine administration in the treatment of shock-refractory cardiac arrest due to VF or pulseless VT (Class of evidence IIb)25. Some studies demonstrate that amiodarone, like any other antiarrhythmic agent, must be given before the fourth shock in order to be effective. In patients with out-of-hospital cardiac arrest, due to refractory ventricular arrhythmias, treatment with amiodarone resulted in Use of amiodarone in emergency a higher rate of survival to hospital admission. Whether this benefit extends to survival to discharge from the hospital merits further investigation26. In the CASCADE trial, carried out in survivors of cardiac arrest, the administration of amiodarone in patients with an implanted automatic defibrillator significantly reduced the number of defibrillation shocks27. Amiodarone 300 mg (made up to 20 ml with dextrose) should be administered into a peripheral vein. A further dose of 150 mg may be given for recurrent or refractory VT/VF, followed by an infusion of 1 mg min-1 for 6 hours and then 0.5 mg min-1, to a maximum daily dose of 2 g. This maximum dose is larger than the current European datasheet recommendation of 1.2 g. Preloaded syringes are not available because amiodarone adheres to the plastic surface of preloaded syringes28. Hemodynamically Unstable VT and Hemodynamically Stable Wide-Complex Tachycardias VT is considered “hemodynamically stable” if there are no symptoms or clinical evidence of tissue hypoperfusion or shock. On the contrary “hemodynamically unstable” VT requires immediate resolution through synchronized cardioversion. In all patients with unstable hemodynamics, immediate direct current (DC)-cardioversion is indicated. In particular, hemodynamically unstable large QRS complex tachycardia should be treated with a series of three synchronized shocks29. Pharmacological treatment with amiodarone is indicated only after failure of electrical cardioversion. Many studies evaluated amiodarone for the treatment of hemodynamically unstable VT. Patients with clinical congestive heart failure or depressed left ventricular (LV) function should be treated cautiously with antiarrhythmic therapy. In these patients, many antiarrhythmic agents depress LV function precipitating or worsening congestive heart failure. Amiodarone and lidocaine cause the least additional impairment of LV function30. Because of its broad antiarrhythmic spectrum and lesser negative inotropic effect, amiodarone is commonly used in these cases. Empirical pharmacological therapy may be necessary for a hemodynamically stable wide- complex tachycardia of unknown origin. Procainamide, amiodarone, and sotalol are effective in the treatment of VT and supraventricular tachycardias with an accessory pathway conduction. On the other hand, depressants of the AV node conduction (such as adenosine, beta-adrenergic receptor blockers, and calcium channel blockers) are hazardous in patients with preexcited atrial arrhythmias. Therefore, the therapeutic options are reduced to DC cardioversion, or procainamide or amiodarone. At presentation in the Emergency Department, most of the patients with VT are hemodynamically stable, thus allowing first-line antiarrhythmic drug administration. However, in the course of the disease, half of the patients need electrical therapy for definitive termination of the tachycardia31. Therefore, DC-cardioversion must be available in the Emergency Department. When electrical cardioversion is not appropriated, possible therapeutic options are: procainamide (Class of evidence IIa), sotalol (Class of evidence IIa), amiodarone (Class of evidence IIb), or disopyramide (Class of evidence IIb)32. In stable and unstable large QRS tachycardias, amiodarone should be administered at a loading dose of 150 mg diluted with 5% dextrose for slow bolus injection (10 min) in peripheral or central vein, followed if necessary by a second dose of 150 mg. In order to avoid acute side effects, the second bolus should be given after a period of 15 minutes. The therapeutic effects should become evident already in the first few minutes, and decrease progressively until the next administration29,28. The maintenance dose ranges between 10 and 20 mg/kg over 24 hours (usually 600-900 mg/24 hours and up to 1200 mg/24 hours) diluted in 500 ml of dextrose 5%28. Narrow-Complex Tachycardias (Supraventricular Arrhythmias) Supraventricular arrhythmias include supraventricular tachycardia, atrial extrasystole, atrial flutter, AF, supraventricular paroxysmal reciprocant tachycardias as the Wolff-Parkinson-White syndrome. In the supraventricular paroxysmal tachycardia, amiodarone is effective because it depresses the conduction through the accessory pathway (Class of evidence IIa). Amiodarone becomes the antiarrhythmic agent of 185 A. Testa, V. Ojetti, A. Migneco, M. Serra, C. Ancona, A. De Lorenzo, N. Gentiloni Silveri choice (after failure of adenosine) if cardiac function is impaired and the ejection fraction is < 40% or there are signs of congestive heart failure33. Therapeutic goals for AF include ventricular rate control, stroke prevention, conversion to normal sinus rhythm, and maintenance of normal sinus rhythm. In the treatment of AF, amiodarone is commonly used34-36. Recentely, a meta-analysis suggests that amiodarone is an effective and relatively rapid acting drug for the conversion of AF to normal sinus rhythm and recommends amiodarone as a first-line drug37. AF in young patients, with a duration of symptoms of less than 48 h and without heart failure can be managed in the Emergency Department with amiodarone in order to avoid a longer hospitalization 38. Since amiodarone shows only slight inotropic, dromotropic and chronotropic negative effects, it can be safely administered in patients with organic cardiomyopathy or heart failure in an Emergency Unit34-36. Pre-treatment with amiodarone the month before a planned electric cardioversion in patients with AF lasting more than 48 h increases the percentage of conversion and reduces the number of early recurrence of AF 35 . Moreover, amiodarone is more effective than propafenone and sotalol in the prevention of AF recidives, in patients suffering from paroxysmal and persistent AF39. In the Wolff-Parkinson-White syndrome, AF and atrial flutter are usually precipitated by an episode of atrioventricular re-entrant tachycardia. In patients with short accessory-pathway refractory periods and rapid ventricular rates during AF, class I antiarrhythmic drugs that lengthen the refractory period of the accessory pathway and reduce ventricular rates are first choice treatment. Class I drugs may be used alone or in combination with an atrioventricular nodal depressant agent. Sotalol and amio- darone have been used in high-risk symptomatic patients. However, the risk of ventricular arrhythmias and the occurrence of side effects limit their usefulness 40 . Radiofrequency ablation should be the treatment of choice in Wolff-Parkinson-White syndrome and symptomatic atrioventricular re-entrant tachycardia. As for large QRS tachycardias, amiodarone’s loading is 150 mg diluted with 5% dextrose in slow bolus injection (10 min), followed if necessary by a second dose of 150 mg. The maintenance dose ranges between 10 and 20 mg/kg over 24 hours28. Table I summarizes the main therapeutic indication of amiodarone in emergency. Side Effects, Contraindications and Pharmacological Interactions Side Effects Acute adverse effects of amiodarone include hypotension, bradycardia, chemical peripheral phlebitis and nausea41. Hypotension was the most common adverse event reported with amiodarone iv. The hypotension was not dose-dependent, but related to the rate of infusion. Therefore amiodarone should be administered over 10 minutes42. Long-term treatment can produce adverse effects presenting several degrees of severity, frequency and time of beginning, especially on the lung, the thyroid, the liver or the cornea (Table II). Lung-toxicity determines cough, dyspnoea, fever, loss of weight, chest pain, and rarely haemoptysis43. These symptoms often emerge few days after treatment beginning, but sometimes they become evident after a few years. Amiodarone causes large modifications of the peripheral metabolism of thyroid hormones. The most important effect is the inhi- Table I. The main therapeutic indications of amiodarone in emergency. Ventricular Fibrillation/pulseless Ventricular Tachycardia refractory to defibrillation (Class of evidence IIb); Wide-Complex Tachycardia haemodynamically unstable and stable, including the polymorphic VT as well as wide-complex tachycardia of uncertain origin (Class of evidence IIb); Narrow-Complex Tachycardias hemodynamically stable or instable but resistant to electric cardioversion: TPSV (Class of evidence IIa), atrial fibrillation (Class of evidence IIa), atrial tachycardia (Class of evidence IIb), atrial tachycardia due to pre-excitation (Class of evidence IIb). 186 Use of amiodarone in emergency Table II. Most important side effects of amiodarone administration. Side effects Amiodarone administration Frequency (%) Major effects Proarrhythmia Bradycardia Short-term Short-term <1 2 to 4 Hypotension Short-term Unknown Peripheral phlebitis Pulmonary toxicity Short term Long-term Unknown 2 to 17 Hyperthyroidism Long-term 1 to 23 Hypothyroidism Liver toxicity Long-term Long-term 5 to 32 1 Optic neuropathy Long-term Unknown Short-term Long-term Long-term Long-term 30 Long-term <9 Minor effects Nausea, anorexia Corneal microdeposits Photosensitivity Blue discoloration of skin > 90 4 to 9 bition of the enzyme 5’-monodeiodinase type I that removes the iodine from the fenolic T4 ring, forming T3, and resulting in a relevant increase of the serum concentration of fT4 and the contemporary reduction of fT3. Other effects are an alteration of the “reverse T3” due to a decreased clearance and a change of serum levels of pituitarythyroid axis hormones with a TSH increase44. Moreover, since amiodarone contains iodine its administration may cause a modification of the thyroid function, either hypothyroidism or thyrotoxicosis, especially at the beginning of the treatment and on pre-existing thyroid disease (autoimmune thyroiditis or nodular goiter)11. Regarding liver dysfunction, some cases of chronic hepatitis, with histopathological features similar to alcoholic hepatitis, have been observed. In patients with clear signs of liver failure amiodarone is best avoided45. After prolonged treatment it is possible to observe corneal microstores, normally asymptomatic which don’t contraindicate Method of diagnosis ECG Physical examination, ECG Physical examination, Blood pressure Physical examination Chest radiograph Pulmonary function tests FT3, FT4, TSH levels FT3, FT4, TSH levels Liver enzyme levels (three times higher than normal) Ophthalmologic examination History, physical examination Slit-lamp examination History, physical examination Physical examination Treatment Stop amiodarone If severe, stop amiodarone and Insert pacemaker Stop/ reduce amiodarone Central vein cannulation Stop amiodarone Corticosteroid therapy Antithyroid drug therapy Stop amiodarone Thyroid hormone therapy Stop amiodarone Stop amiodarone Reduce dosage None Use sunblock Reduce dosage the continuation of the therapy. These microstores, formed by complex lipids, are irreversible, even after treatment discontinuation43. Contraindications Main contraindications to the iv administration of amiodarone are synus bradycardia, senoatrial block and severe conduction disturbances like second or third degree atrioventricular block. Other contraindications are hypotension, severe respiratory failure, thyroid disease, liver failure, cardiomyopathy and cardiac failure. Amiodarone is best avoided during pregnancy since it may induce fetal thyroid diseases, and during breast-feeding since significant amounts of amiodarone are eliminated trough the breast milk during the treatment (Table III). Pharmacological Interactions Administration of amiodarone in patients taking HMG inhibitors-CoA reductase inhibitors, in particular simvastatin, may in187 A. Testa, V. Ojetti, A. Migneco, M. Serra, C. Ancona, A. De Lorenzo, N. Gentiloni Silveri Table III. Most important contraindications to acute amiodarone administration. Absolute contraindications Bradycardia of the synus Senoatrial block Severe second or third degree atrio-ventricular blocks (unless paced) Pregnancy Breast-feeding Relative contraindications Hypotension Cardiomyopathy or cardiac failure Severe respiratory failure Thyroid disease Hepatocellular failure Possible drug interaction causing the risk of torsades de point crease the risk of myopathy. The daily intake of simvastatin should not exceed in these cases 20 mg/day46. Potassium wasting diuretics and some class I anti-arrhythmic agents may contribute to prolong the QT interval and should therefore be administrated cautiously in patients taking amiodarone. Amiodarone may increase the plasma level of some anti-arrhythmic agents as chinidin, procainamide, disopyramide and flecainide. The interaction of amiodarone with non antiarrhythmic agents as vincamine, sultopride, erythromycin iv and pentamidine iv, can raise the risk of potentially lethal torsades de pointes47. Hypokaliemia may enhance the potential pro-arrhythmic action of anti-arrhythmic agents. Therefore, hypokaliemia should always be corrected before any amiodaronebased treatment is started48. Cardiopathic patients are often treated with digoxin (whose clearance decreases when associated with amiodarone49) and with oral anticoagulants (whose anticoagulant effect increases after amiodarone administration48). Dose adjustment and frequent prothrombin and electrocardiogram monitoring is mandatory in these patients. Phenytoin and cyclosporin plasma levels generally rise when patients starts the treatment with amiodarone. Careful clinical monitoring and prompt dose adjustment, if needed, are indicated in these patients50. Severe adverse reactions are reported in patients on amiodarone treatment undergoing general anaesthesia: severe bradycardia (not responsive to atropine), hypotension, conduction disturbances and decrease of the cardiac output. Some cases of severe respiratory failure were also reported, generally occurring after surgery51 (Table IV). In conclusion, amiodarone is a highly effective antiarrhythmic agent for many cardiac arrhythmias, ranging from AF to malignant ventricular tachyarrhythmias. It is considered the antiarrhythmic drug of choice in treatment of resistant VF or pulseless VT. It can be safely administered in patients with organic cardiomyopathy or heart failure because it shows only slight negative inotropic, dromotropic and chronotropic effects. Further- Table IV. Most important pharmacological interactions of amiodarone. Drug Digoxin Warfarin (Coumadin) Simvastatin Sildenafil Cyclosporine Antiarrhythmic drugs Quinolones Antidepressants Potassium-wasting drugs 188 Result of interaction Elevated digoxin plasma concentration Elevated prothrombin time Increased incidence of myopathy if simvastatin dosage is > 20 mg per day Increased sildenafil plasma concentration Increased cyclosporine plasma concentration Additive effects: possible elevated plasma concentrations of quinidine, disopyramide, flecainide, propafenone and dofetilide Additive QT effect: possible increased risk of proarrhythmia Increased plasma concentration of hepatically metabolized drugs: possible increased risk of proarrhythmia Additive QT effect: possible increased risk of proarrhytmia Use of amiodarone in emergency more, amiodarone prevents the recurrence of life-threatening ventricular arrhythmias and produces a modest reduction of sudden deaths in high-risk patients. 13) YIN Y, VASSY R, NICOLAS P, PERRET GY, LAURENT S. Antagonism between T3 and amiodarone on the contractility and the density of beta-adrenoceptor on chicken cardiac myocytes. Eur J Pharmacol 1994; 261: 97-104 References 14) FORINI F, NICOLINI G, BALZAN S, et al. Amiodarone inhibits the 3,5,3'-triiodothyronine-dependent increase of sodium/potassium adenosine triphosphatase activity and concentration in human atrial myocardial tissue. Thyroid 2004; 14: 493-499. 1) LETELIER LM, UDOL K, ENA J, WEAVER B, GUYATT GH. Effectiveness of amiodarone for conversion of atrial fibrillation to sinus rhythm: a meta-analysis. Arch Intern Med 2003; 163: 777-785. 2) CARON MF, KLUGER J, WHITE CM. Amiodarone in the new AHA guidelines for ventricular tachyarrhythmias. Ann Pharmacother 2001; 35: 1248-1254. 3) NO AUTHORS LISTED. Part 6: advanced cardiovascular life support. Section 7: algorithm approach to ACLS emergencies. 7D: the tachycardia algorithms. European Resuscitation Council. Resuscitation 2000; 23;46(1-3): 185-193. 4) CAIRNS JA, CONNOLLY SJ, ROBERTS R, GENT M. Randomised trial of outcome after myocardial infarction in patients with frequent or ripetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 1997; 349: 675-682. 5) J ULIAN DG, C AMM AJ, F RANGIN G, et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction. EMIAT. European Myocardial Infarctions Amiodarone Trial Investigators. Lancet 1997; 349: 667-674. 6) COTTINO A, FERRAUDO G, GERMENA C, et al. Aritmie ipercinetiche parossistiche: 836 casi. Cenni di epidemiologia. Atti del IV Congresso Nazionale dell’associazione Nazionale dei Medici d’Urgenza. Monduzzi Ed - Bologna 1989; p. 427. 7) RIZZON P, BIASCO G, DI BIASE M, ANTONELLI G. Antianginal and anti-arrhythmic properties of amiodarone. Boll Soc Ital Cardiol 1972; 17: 413-417. 8) POLSTER P, BROEKHUISEN J. The adrenergic antagonism of amiodarone. Biochem Pharmacol 1976; 25: 131-136. 9) GOUPIL N, LENFANT J. The effect of amiodarone on the sinus node activity of the rabbit heart. Eur J Pharmacol 1976; 39: 23-26. 10) ROSENBAUM MB, CHIALE PA, HALPERN MS, et al. Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 1976; 38: 934-944. 11) MARTINO E, BARTALENA L, BOGAZZI F, BRAVERMAN LE. The effects of amiodarone on the thyroid. Endocr Rev 2001; 22: 240-254. 12) PATTERSON E, WALDEN KM, K HAZAELI MB, M ONT GOMERY DG, LUCCHESI BR. Cardiac electrophysiologic effects of acute and chronic amiodarone administration in the isolated perfused rabbit heart: altered thyroid hormone metabolism. J Pharmacol Exp Ther 1986; 239: 179-184. 15) DRVOTA V, CARLSSON B, HAGGBLAD J, SYLVEN C. Amiodarone is a dose-dependent noncompetitive and competitive inhibitor of T3 binding to thyroid hormone receptor subtype beta 1, whereas disopyramide, lignocaine, propafenone, metoprolol, dl-sotalol, and verapamil have no inhibitory effect. J Cardiovasc Pharm 1995; 26: 222-226. 16) KENNEDY RI, GRIFFITHS H, GRAY TA. Amiodarone and the thyroid. Clin Chem 1989; 35: 1882-1887. 17) HUANG CJ, GELLER HM, GREEN WL, et al. Acute effects of thyroid hormone analog on sodium currents in neonatal rat myocytes. J Mol Cell Cardiol 1999; 31: 881-893. 18) KODAMA I, KAMIYA K, TOYAMA J. Amiodarone: ionic and cellular mechanism of action of the most promising class III agent. Am J Cardiol 1999; 84: 20R-28R. 19) MALTSEV VA, SABBAH HN, UNDROVINAS AI. Late sodium current is a novel target for amiodarone: studies in failing human myocardium. J Mol Cell Cardiol 2001; 33: 923-932. 20) KAMIYA K, NISHIYAMA A, YASUI K, HOJO M, SANGUINETTI MC, K ODAMA I. Short- and long-term effects of amiodarone on the two components of cardiac delayed rectifier K(+) current. Circulation 2001; 103: 1317-1324. 21) HOLT DW, TUCKER GT, JACKSON PR, STOREY GC. Amiodarone pharmacokinetics. Am Heart J 1983; 106: 840-847. 22) BROEKHUYSEN J, LARVEL L, SION R. Recherches dans la serie des benzofuranes. Arch Int Pharmacodyn 1969; 177: 348. 23) BONGIORNI MG. Amiodarone: effetti collaterali. Ital Heart J 2001; 2: 475-525. 24) THE AMERICAN HEART ASSOCIATION IN COLLABORATION WITH THE INTERNATIONAL LIAISON COMMITTEE ON RESUSCITATION (ILCOR). Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care–An International Consensus on Science. Resuscitation 2000; 46: 1-448 25) THE 1998 EUROPEAN RESUSCITATION COUNCIL GUIDELINES FOR ADULT ADVANCED LIFE SUPPORT. In: Bossaert L (ed.). European Resuscitation Council Guidelines for Resuscitation. Amsterdam: Elsevier, 1998; 36-47 26) KUDENCHUK PJ, COBB LA, COPASS MK, et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med 1999; 341: 871-878 189 A. Testa, V. Ojetti, A. Migneco, M. Serra, C. Ancona, A. De Lorenzo, N. Gentiloni Silveri 27) DEHARO JC, MOULIOM F, SALAMAND A, DJIANE P. Role of antiarrhythmic drugs in reducing the number of defibrillation shocks. Arch Mal Coeur Vaiss 2005; 98: 140-144 38) ZAHIR S, LHEUREUX P. Management of new-onset atrial fibrillation in the emergency department: is there any predictive factor for early successful cardioversion? Eur J Emerg Med 2005; 12: 52-56. 28) EUROPEAN RESUSCITATION COUNCIL GUIDELINES 2000 FOR ADULT ADVANCED LIFE SUPPORT. A statement from the Advanced Life Support Working Group (1) and approved by the Executive Committee of the European Resuscitation Council. Resuscitation 2001; 48: 211-221. 39) B ORIANI G, D IEMBERGER I, B IFFI M, M ARTIGNANI C, BRANZI A. Pharmacological cardioversion of atrial fibrillation: current management and treatment options. Drugs 2004; 64: 2741-2762. 29) TRAPPE HJ, BRANDTS B, WEISMUELLER P. Arrhythmias in the intensive care patient. Curr Opin Crit Care 2003; 9: 345-355. 30) LEVINE JH, MASSUMI A, SCHEINMAN MM, et al. Intravenous amiodarone for recurrent sustained hypotensive ventricular tachyarrhythmias. Intravenous Amiodarone Multicenter Trial Group. J Am Coll Cardiol 1996; 27: 67-75. 31) DOMANOVITS H, PAULIS M, NIKFARDJAM M, et al. Sustained ventricular tachycardia in the emergency department. Resuscitation 1999; 42: 19-25. 32) KUGA K, YAMAGUCHI I, SUGISHITA Y. Effect of intravenous amiodarone on electrophysiologic variables and on the modes of termination of atrioventricular reciprocating tachycardia in WolffParkinson-White syndrome. Jpn Circ J 1999; 63: 189-195. 33) KOWEY PR, LEVINE JH, HERRE JM, et al. Randomized, double-blind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. The Intravenous Amiodarone Multicenter Investigators Group. Circulation 1995; 92: 3255-3263. 34) KERIN NZ, FAITEL K, NAINI M. The efficacy of intravenous amiodarone for the conversion of chronic atrial fibrillation: amiodarone vs quinidine for conversion of atrial fibrillation. Arch Intern Med 1996; 156: 49-53. 35) HORNER SM. A comparison of cardioversion of atrial fibrillation using oral amiodarone, intravenous amiodarone and DC cardioversion: Acta Cardiol 1992; 47: 473-480. 36) SINGH BN, SINGH SN, REDA DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352: 1861-1872. 37) CHEVALIER P, DURAND-DUBIEF A, BURRI H, CUCHERAT M, KIRKORIAN G, TOUBOUL P. Amiodarone versus placebo and classic drugs for cardioversion of recentonset atrial fibrillation: a meta-analysis. J Am Coll Cardiol 2003; 41: 255-262. 190 40) BARTLETT TG, FRIEDMAN PL. Current management of the Wolff-Parkinson-White syndrome. J Card Surg 1993; 8: 503-515. 41) VORPERIAN VR, HAVIGHURST TC, MILLER S, JANUARY CT. Adverse effects of low dose amiodarone: a metaanalysis. J Am Coll Cardiol 1997; 30: 791-798. 42) S OMBERG JC, C VETANOVIC I, R ANADE V, M OLNAR J. Comparative effects of rapid bolus administration of aqueous amiodarone versus 10-minute cordarone I.V. infusion on mean arterial blood pressure in conscious dogs. Cardiovasc Drugs Ther 2004; 18: 345-351. 43) POLLAK PT. Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations. Am J Cardiol 1999; 84: 37-45. 44) IERVASI G, CLERICO A, BONINI R, et al. Acute effects of amiodarone administration on thyroid function in patients with cardiac arrhythmias. J Clin Endocrinol Metab 1997; 82: 275-280. 45) BRAVO AE, DREWE J, SCHLIENGER RG, KRAHENBUHL S, PARGGER H, UMMENHOFER W. Hepatotoxicity during rapid intravenous loading with amiodarone: Description of three cases and review of the literature. Crit Care Med 2005; 33: 128-134. 46) R O T E N L, S C H O E N E N B E R G E R R A , K R A H E N B U H L S, S CHLIENGER RG. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother 2004; 38: 978-981. 47) YAMREUDEEWONG W, DEBISSCHOP M, MARTIN LG, LOWER DL. Potentially significant drug interactions of class III antiarrhythmic drugs. Drug Saf 2003; 26: 421-438. 48) LATINI R. TOGNONI G, KATES RE. Clinical pharmakinetics of amiodarone. Clin Pharmacokinet 1984; 9: 136-156. 49) MOYSEY JO, JAGGARAO NSV, GRUNDY EN, CHAMBERLAIN DA. Amiodarone increases plasma digoxin concentrations. Brit Med J 1981; 282: 272-275. 50) CHITWOOD KK, ABDUL-HAQQ AJ, HEIM-DUTHOY KL. Cyclosporine-amiodarone interaction. Ann Pharmacother 1993: 569-571. 51) DONALDSON L, GRANT IS, NAYSMITH MR, THOMAS JS. Acute amiodarone-induced lung toxicity. Intensive Care Med 1998; 24: 626-630.