Use of Amiodarone in Emergency

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 drugs, frequently used in the Emergency De- most common anti-arrhythmic drugs used in the partment. In the last decade many trials and Emergency Department. Recent guidelines on meta-analysis described amiodarone as anti- cardiac arrest with shockable rhythm [refractory ventricular fibrillation (VF)/pulseless ventricular arrhythmic agent of first choice in the treat- tachycardia (VT)] recommend amiodarone as an- ment of hemodynamically unstable ventricu- ti-arrhythmic of first choice. Amiodarone is also lar tachycardia (VT), of hemodynamically first choice drug in the treatment of various ven- stable wide-complex tachycardias1, and of tricular and supra-ventricular tachyarrhythmias. many supraventricular tachyarrhythmias1,2. This paper deals with the main therapeutical in- The European Resuscitation Council recom- dications of amiodarone in emergency medi- mends its use in shockable cardiac arrest cine: dosage, side effects, contraindications and pharmacological interactions are reviewed. [ventricular fibrillation (VF) and pulseless 3 Amiodarone is effective for control of hemody- VT] . Finally, its use has been suggested in namically stable VT, polymorphic VT and wide- post-infarction patients, either presenting fre- complex tachycardia of uncertain origin. It is al- quent or repetitive extra systolic beats and/or so helpful for ventricular rate control of rapid VT4 or presenting low left ventricular ejec- atrial arrhythmias in patients with severely im- tion fraction (below 40%)5. paired left ventricular (LV) function, when digital- is has been ineffective, and is an adjunct to elec- Up to 2% of the patients admitted to the trical cardioversion. The major side effects of Emergency Department present tach- amiodarone are hypotension, bradycardia and yarrhythmias. In more than 90% these are peripheral phlebitis. Major contraindications to narrow QRS arrhythmias, such as atrial fibril- the intravenous (iv) injection of amiodarone are lation (AF) (45%), paroxysmal supraventric- bradycardia, senoatrial block, severe disturbs of ular tachycardia (35%) and atrial flutter conduction, second or third degree atrio-ventric- (8%). Around 50% of large QRS tach- ular blocks. Other contraindications are hypotension, severe respiratory failure, hepatocel- yarrhythmias are supraventricular tachycar- lular failure and hyperthyroidism. Pharmacologi- dias. VT are in most cases hemodynamically cal interactions are reported with HMG-CoA re- stable, while only a small part of large QRS ductase inhibitors, class I antiarrhythmic agents tachyarrhythmia are hemodynamically unsta- and other drugs which contribute to prolong QT ble VT or shockable cardiac arrest (VF/pulse- interval, digoxin, oral anticoagulants and gener- less VT)6. al anaesthesia. Often tachyarrhythmia end spontaneously Key Words: or resolve after appropriate treatment in the Amiodarone, Emergency, Arrhythmias, Tachycar- Emergency Department, and around half of dias, Cardiac arrest, Ventricular tachycardia, Atrial fib- the patients can be discharged after a short rillation. period of observation.

Pharmacodynamic Properties Introduction Electrophysiologic Effects Amiodarone, a derivative of benzofuran, is Amiodarone exerts a non-competitive one of the most common anti-arrhythmic 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 Pharmacokynetic Properties oxygen consumption of the myocardium induced by circulating catecholamines. These Amiodarone’s chemical structure can be effects contribute to the anti-arrhythmic and summarised in three points: (1) presence of anti-anginal properties of amiodarone7. After aromatic rings; (2) a relatively high iodine amiodarone administration there is no signifi- content; (3) presence of an aliphatic chain cant decrease of the myocardial contractility8. with low polarity. The most relevant effects of amiodarone This chemical structure highlights some on cardiac cells are the reduction of the depo- specific pharmacological characteristics like larization (phase 4)9, the late repolarization, the high lipophylia, the low oral absorption caused by a prolongation of the action poten- rate, the extended tissue distribution, the tial (phase 3) and the prolongation of the ef- slow elimination rate and finally the late ther- fective refractory period10. Therefore amio- apeutic response during oral treatment21. darone is included among class III anti-ar- After intravenous (iv) administration plas- rhythmic drugs. It is known that torsades de ma peak concentration is reached in 6-8 pointes are the classic form of proarrhythmia hours. Drug tissue distribution occurs differ- observed during therapy with any drug that ently after acute administration (lungs, liver, prolongs repolarization. Among the class III heart and kidney)22 and after the achieve- drugs the proarrhythmic risk appears to be ment of dynamic equilibrium (mainly in the lowest for amiodarone, probably due to its liver, fat tissue and in the lungs)21. complex electrophysiologic profile that may Drug clearance occurs mainly through the create significant myocardial electrical homo- liver and only 1% is excreted through the geneity. kidneys. Amiodarone cannot be dialysed and crosses easily the placenta (10-50%). N-de- Mechanisms of Action sethyl-amiodarone (DEA) is its main active Some chemical peculiarities of the drug metabolite. After a single oral dose, amio- (high iodine’s content and structural analo- darone’s half life is calculated to be around 24 gies with thyroid hormones) suggested possi- h, during long-term therapy it increases ble influences of amiodarone on the thyroid reaching 28 days21; while DEA’s half life is function11. Furthermore, it is known that around 60 days23. some of the cardio-electrophysiologic effects of the chronic administration of amiodarone are very similar to those of hypothy- roidism12,13. Actually, it has been shown a Therapeutic Indications in Emergency competition or an interaction between amiodarone and the thyroid hormones at many Cardiac Arrest With Shockable Rhythm levels (i.e. deiodases, trans-membrane ionic (Refractory FV/Pulseless VT) channels)14,15. Two main mechanisms concern- The Resuscitation 2000 Guidelines recom- ing the antiarrhythmic activity of amiodarone mend amiodarone as the antiarrhythmic drug have been suggested: of choice in treatment of resistant VF or pulseless VT24. • The “T3-mediated” hypothesis: amio- Even if the administration of amiodarone darone antagonizes the thyroid hormones may cause a slight delay during the resurrec- on the nuclear receptor and/or on trans- tion procedure, evidence supports its use af- membrane carrier of T3 at cardiac lev- ter epinephrine administration in the treat- el16,17. This T3-mediated mechanism ment of shock-refractory cardiac arrest due could explain the non-competitive adren- to VF or pulseless VT (Class of evidence ergic block of amiodarone. IIb)25. Some studies demonstrate that amio- •The “Membrane-active” hypothesis: amiodarone, like any other antiarrhythmic agent, darone impairs the lipid environment of must be given before the fourth shock in or- the cell membranes where the main ionic der to be effective. channels are located, directly modulating In patients with out-of-hospital cardiac ar- the ionic myocardial transmembran cur- rest, due to refractory ventricular arrhyth- rents18-20. mias, treatment with amiodarone resulted in

184 Use of amiodarone in emergency a higher rate of survival to hospital admis- complex tachycardia of unknown origin. Pro- sion. Whether this benefit extends to survival cainamide, amiodarone, and sotalol are effec- to discharge from the hospital merits further tive in the treatment of VT and supraventric- investigation26. ular tachycardias with an accessory pathway In the CASCADE trial, carried out in sur- conduction. On the other hand, depressants vivors of cardiac arrest, the administration of of the AV node conduction (such as adeno- amiodarone in patients with an implanted au- sine, beta-adrenergic receptor blockers, and tomatic defibrillator significantly reduced the calcium channel blockers) are hazardous in number of defibrillation shocks27. patients with preexcited atrial arrhythmias. Amiodarone 300 mg (made up to 20 ml Therefore, the therapeutic options are re- with dextrose) should be administered into a duced to DC cardioversion, or procainamide peripheral vein. A further dose of 150 mg or amiodarone. At presentation in the Emer- may be given for recurrent or refractory gency Department, most of the patients with VT/VF, followed by an infusion of 1 mg min-1 VT are hemodynamically stable, thus allow- for 6 hours and then 0.5 mg min-1, to a maxi- ing first-line antiarrhythmic drug administra- mum daily dose of 2 g. This maximum dose tion. However, in the course of the disease, is larger than the current European half of the patients need electrical therapy for datasheet recommendation of 1.2 g. Pre- definitive termination of the tachycardia31. loaded syringes are not available because Therefore, DC-cardioversion must be avail- amiodarone adheres to the plastic surface of able in the Emergency Department. preloaded syringes28. When electrical cardioversion is not ap- propriated, possible therapeutic options are: Hemodynamically Unstable VT and procainamide (Class of evidence IIa), sotalol Hemodynamically Stable Wide-Complex (Class of evidence IIa), amiodarone (Class of Tachycardias evidence IIb), or disopyramide (Class of evi- VT is considered “hemodynamically sta- dence IIb)32. ble” if there are no symptoms or clinical evi- In stable and unstable large QRS tachycar- dence of tissue hypoperfusion or shock. On dias, amiodarone should be administered at a the contrary “hemodynamically unstable” VT loading dose of 150 mg diluted with 5% dex- requires immediate resolution through syn- trose for slow bolus injection (10 min) in pe- chronized cardioversion. ripheral or central vein, followed if necessary In all patients with unstable hemodynam- by a second dose of 150 mg. In order to avoid ics, immediate direct current (DC)-cardiover- acute side effects, the second bolus should be sion is indicated. In particular, hemodynami- given after a period of 15 minutes. The thera- cally unstable large QRS complex tachycar- peutic effects should become evident already dia should be treated with a series of three in the first few minutes, and decrease pro- synchronized shocks29. Pharmacological treat- gressively until the next administration29,28. ment with amiodarone is indicated only after The maintenance dose ranges between 10 failure of electrical cardioversion. Many stud- and 20 mg/kg over 24 hours (usually 600-900 ies evaluated amiodarone for the treatment mg/24 hours and up to 1200 mg/24 hours) di- of hemodynamically unstable VT. Patients luted in 500 ml of dextrose 5%28. with clinical congestive heart failure or de- pressed left ventricular (LV) function should Narrow-Complex Tachycardias be treated cautiously with antiarrhythmic (Supraventricular Arrhythmias) therapy. In these patients, many antiarrhyth- Supraventricular arrhythmias include mic agents depress LV function precipitating supraventricular tachycardia, atrial extrasys- or worsening congestive heart failure. Amio- tole, atrial flutter, AF, supraventricular darone and lidocaine cause the least addition- paroxysmal reciprocant tachycardias as the al impairment of LV function30. Because of its Wolff-Parkinson-White syndrome. broad antiarrhythmic spectrum and lesser In the supraventricular paroxysmal tachy- negative inotropic effect, amiodarone is com- cardia, amiodarone is effective because it de- monly used in these cases. presses the conduction through the accessory Empirical pharmacological therapy may be pathway (Class of evidence IIa). Amio- necessary for a hemodynamically stable wide- darone 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 darone have been used in high-risk sympto- function is impaired and the ejection fraction matic patients. However, the risk of ventric- is < 40% or there are signs of congestive ular arrhythmias and the occurrence of side heart failure33. effects limit their usefulness40. Radiofre- Therapeutic goals for AF include ventricu- quency ablation should be the treatment of lar rate control, stroke prevention, conversion choice in Wolff-Parkinson-White syndrome to normal sinus rhythm, and maintenance of and symptomatic atrioventricular re-entrant normal sinus rhythm. In the treatment of AF, tachycardia. amiodarone is commonly used34-36. As for large QRS tachycardias, amio- Recentely, a meta-analysis suggests that darone’s loading is 150 mg diluted with 5% amiodarone is an effective and relatively dextrose in slow bolus injection (10 min), fol- rapid acting drug for the conversion of AF to lowed if necessary by a second dose of 150 normal sinus rhythm and recommends amio- mg. The maintenance dose ranges between darone as a first-line drug37. AF in young pa- 10 and 20 mg/kg over 24 hours28. Table I sum- tients, with a duration of symptoms of less marizes the main therapeutic indication of than 48 h and without heart failure can be amiodarone in emergency. managed in the Emergency Department with amiodarone in order to avoid a longer hospi- talization38. Since amiodarone shows only slight inotropic, dromotropic and chronotrop- Side Effects, Contraindications and ic negative effects, it can be safely adminis- Pharmacological Interactions tered in patients with organic cardiomyopathy or heart failure in an Emergency Unit34-36. Side Effects Pre-treatment with amiodarone the month Acute adverse effects of amiodarone in- before a planned electric cardioversion in pa- clude hypotension, bradycardia, chemical pe- tients with AF lasting more than 48 h increas- ripheral phlebitis and nausea41. Hypotension es the percentage of conversion and reduces was the most common adverse event report- the number of early recurrence of AF35. ed with amiodarone iv. The hypotension was Moreover, amiodarone is more effective than not dose-dependent, but related to the rate of propafenone and sotalol in the prevention of infusion. Therefore amiodarone should be AF recidives, in patients suffering from administered over 10 minutes42. Long-term paroxysmal and persistent AF39. treatment can produce adverse effects pre- In the Wolff-Parkinson-White syndrome, senting several degrees of severity, frequency AF and atrial flutter are usually precipitat- and time of beginning, especially on the lung, ed by an episode of atrioventricular re-en- the thyroid, the liver or the cornea (Table II). trant tachycardia. In patients with short ac- Lung-toxicity determines cough, dyspnoea, cessory-pathway refractory periods and fever, loss of weight, chest pain, and rarely rapid ventricular rates during AF, class I an- haemoptysis43. These symptoms often emerge tiarrhythmic drugs that lengthen the refrac- few days after treatment beginning, but tory period of the accessory pathway and sometimes they become evident after a few reduce ventricular rates are first choice years. treatment. Class I drugs may be used alone Amiodarone causes large modifications of or in combination with an atrioventricular the peripheral metabolism of thyroid hor- nodal depressant agent. Sotalol and amio- mones. 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 Frequency Method of Treatment administration (%) diagnosis

Major effects Proarrhythmia Short-term < 1 ECG Stop amiodarone Bradycardia Short-term 2 to 4 Physical examination, If severe, stop amiodarone ECG and Insert pacemaker Hypotension Short-term Unknown Physical examination, Stop/ reduce amiodarone Blood pressure Peripheral phlebitis Short term Unknown Physical examination Central vein cannulation Pulmonary toxicity Long-term 2 to 17 Chest radiograph Stop amiodarone Pulmonary function tests Corticosteroid therapy Hyperthyroidism Long-term 1 to 23 FT3, FT4, TSH levels Antithyroid drug therapy Stop amiodarone Hypothyroidism Long-term 5 to 32 FT3, FT4, TSH levels Thyroid hormone therapy Liver toxicity Long-term 1 Liver enzyme levels Stop amiodarone (three times higher than normal) Optic neuropathy Long-term Unknown Ophthalmologic Stop amiodarone examination

Minor effects Nausea, anorexia Short-term 30 History, physical Reduce dosage Long-term examination Corneal microdeposits Long-term > 90 Slit-lamp examination None Photosensitivity Long-term 4 to 9 History, physical Use sunblock examination Blue discoloration Long-term < 9 Physical examination Reduce dosage of skin

bition of the enzyme 5’-monodeiodinase the continuation of the therapy. These mi- type I that removes the iodine from the crostores, formed by complex lipids, are ir- fenolic T4 ring, forming T3, and resulting in reversible, even after treatment discontinu- a relevant increase of the serum concentra- ation43. tion of fT4 and the contemporary reduction of fT3. Other effects are an alteration of the Contraindications “reverse T3” due to a decreased clearance Main contraindications to the iv adminis- and a change of serum levels of pituitary- tration of amiodarone are synus bradycardia, thyroid axis hormones with a TSH increase44. senoatrial block and severe conduction dis- Moreover, since amiodarone contains iodine turbances like second or third degree atrio- its administration may cause a modification ventricular block. Other contraindications of the thyroid function, either hypothy- are hypotension, severe respiratory failure, roidism or thyrotoxicosis, especially at the thyroid disease, liver failure, cardiomyopathy beginning of the treatment and on pre-exist- and cardiac failure. Amiodarone is best ing thyroid disease (autoimmune thyroiditis avoided during pregnancy since it may induce or nodular goiter)11. fetal thyroid diseases, and during breast-feed- Regarding liver dysfunction, some cases of ing since significant amounts of amiodarone chronic hepatitis, with histopathological fea- are eliminated trough the breast milk during tures similar to alcoholic hepatitis, have been the treatment (Table III). observed. In patients with clear signs of liver failure amiodarone is best avoided45. Pharmacological Interactions After prolonged treatment it is possible Administration of amiodarone in patients to observe corneal microstores, normally taking HMG inhibitors-CoA reductase in- asymptomatic which don’t contraindicate hibitors, in particular simvastatin, may in-

187 A. Testa, V. Ojetti, A. Migneco, M. Serra, C. Ancona, A. De Lorenzo, N. Gentiloni Silveri

Table III. Most important contraindications to acute Hypokaliemia may enhance the potential amiodarone administration. pro-arrhythmic action of anti-arrhythmic agents. Therefore, hypokaliemia should al- Absolute contraindications ways be corrected before any amiodarone- Bradycardia of the synus 48 Senoatrial block based treatment is started . Severe second or third degree atrio-ventricular Cardiopathic patients are often treated blocks (unless paced) with digoxin (whose clearance decreases Pregnancy when associated with amiodarone49) and with Breast-feeding oral anticoagulants (whose anticoagulant effect increases after amiodarone administra- Relative contraindications tion48). Dose adjustment and frequent pro- Hypotension thrombin and electrocardiogram monitoring Cardiomyopathy or cardiac failure Severe respiratory failure is mandatory in these patients. Phenytoin and Thyroid disease cyclosporin plasma levels generally rise when Hepatocellular failure patients starts the treatment with amio- Possible drug interaction causing the risk of darone. Careful clinical monitoring and torsades de point prompt dose adjustment, if needed, are indicated in these patients50. Severe adverse reactions are reported in patients on amiodarone treatment undergo- crease the risk of myopathy. The daily intake ing general anaesthesia: severe bradycardia of simvastatin should not exceed in these cas- (not responsive to atropine), hypotension, es 20 mg/day46. conduction disturbances and decrease of the Potassium wasting diuretics and some class cardiac output. Some cases of severe respira- I anti-arrhythmic agents may contribute to tory failure were also reported, generally oc- prolong the QT interval and should therefore curring after surgery51 (Table IV). be administrated cautiously in patients taking In conclusion, amiodarone is a highly effec- amiodarone. tive antiarrhythmic agent for many cardiac Amiodarone may increase the plasma level arrhythmias, ranging from AF to malignant of some anti-arrhythmic agents as chinidin, ventricular tachyarrhythmias. It is considered procainamide, disopyramide and flecainide. the antiarrhythmic drug of choice in treat- The interaction of amiodarone with non anti- ment of resistant VF or pulseless VT. It can arrhythmic agents as vincamine, sultopride, be safely administered in patients with organ- erythromycin iv and pentamidine iv, can raise ic cardiomyopathy or heart failure because it the risk of potentially lethal torsades de shows only slight negative inotropic, dro- pointes47. motropic and chronotropic effects. Further-

Table IV. Most important pharmacological interactions of amiodarone.

Drug Result of interaction

Digoxin Elevated digoxin plasma concentration Warfarin (Coumadin) Elevated prothrombin time Simvastatin Increased incidence of myopathy if simvastatin dosage is > 20 mg per day Sildenafil Increased sildenafil plasma concentration Cyclosporine Increased cyclosporine plasma concentration Antiarrhythmic drugs Additive effects: possible elevated plasma concentrations of quinidine, disopyramide, flecainide, propafenone and dofetilide Quinolones Additive QT effect: possible increased risk of proarrhythmia Antidepressants Increased plasma concentration of hepatically metabolized drugs: possible increased risk of proarrhythmia Potassium-wasting drugs Additive QT effect: possible increased risk of proarrhytmia

188 Use of amiodarone in emergency more, amiodarone prevents the recurrence of 13) YIN Y, V ASSY R, NICOLAS P, P ERRET GY, LAURENT S. An- life-threatening ventricular arrhythmias and tagonism between T3 and amiodarone on the contractility and the density of beta-adrenoceptor produces a modest reduction of sudden on chicken cardiac myocytes. Eur J Pharmacol deaths in high-risk patients. 1994; 261: 97-104

14) FORINI F, N ICOLINI G, BALZAN S, et al. Amiodarone inhibits the 3,5,3'-triiodothyronine-dependent in- References crease of sodium/potassium adenosine triphos- phatase activity and concentration in human atrial 1) LETELIER LM, UDOL K, ENA J, WEAVER B, GUYATT GH. myocardial tissue. Thyroid 2004; 14: 493-499. Effectiveness of amiodarone for conversion of 15) DRVOTA V, C ARLSSON B, HAGGBLAD J, SYLVEN C. Amio- atrial fibrillation to sinus rhythm: a meta-analysis. darone is a dose-dependent noncompetitive and Arch Intern Med 2003; 163: 777-785. competitive inhibitor of T3 binding to thyroid hor- 2) CARON MF, KLUGER J, WHITE CM. Amiodarone in the mone receptor subtype beta 1, whereas disopyra- new AHA guidelines for ventricular tachyarrhyth- mide, lignocaine, propafenone, metoprolol, dl-so- mias. Ann Pharmacother 2001; 35: 1248-1254. talol, and verapamil have no inhibitory effect. J Cardiovasc Pharm 1995; 26: 222-226. 3) NO AUTHORS LISTED. Part 6: advanced cardiovascu- lar life support. Section 7: algorithm approach to 16) KENNEDY RI, GRIFFITHS H, GRAY TA. Amiodarone and ACLS emergencies. 7D: the tachycardia algo- the thyroid. Clin Chem 1989; 35: 1882-1887. rithms. European Resuscitation Council. Resusci- 17) HUANG CJ, GELLER HM, GREEN WL, et al. Acute ef- tation 2000; 23;46(1-3): 185-193. fects of thyroid hormone analog on sodium cur- 4) CAIRNS JA, CONNOLLY SJ, ROBERTS R, GENT M. Ran- rents in neonatal rat myocytes. J Mol Cell Cardiol domised trial of outcome after myocardial infarc- 1999; 31: 881-893. tion in patients with frequent or ripetitive ventricu- 18) KODAMA I, KAMIYA K, TOYAMA J. Amiodarone: ionic lar premature depolarisations: CAMIAT. Canadian and cellular mechanism of action of the most Amiodarone Myocardial Infarction Arrhythmia Tri- promising class III agent. Am J Cardiol 1999; 84: al Investigators. Lancet 1997; 349: 675-682. 20R-28R.

5) JULIAN DG, CAMM AJ, FRANGIN G, et al. Ran- 19) MALTSEV VA, SABBAH HN, UNDROVINAS AI. Late sodi- domised trial of effect of amiodarone on mortality um current is a novel target for amiodarone: stud- in patients with left-ventricular dysfunction after ies in failing human myocardium. J Mol Cell Car- recent myocardial infarction. EMIAT. European diol 2001; 33: 923-932. Myocardial Infarctions Amiodarone Trial Investi- gators. Lancet 1997; 349: 667-674. 20) KAMIYA K, NISHIYAMA A, YASUI K, HOJO M, SANGUINETTI MC, KODAMA I. Short- and long-term effects of 6) COTTINO A, FERRAUDO G, GERMENA C, et al. Aritmie amiodarone on the two components of cardiac ipercinetiche parossistiche: 836 casi. Cenni di delayed rectifier K(+) current. Circulation 2001; epidemiologia. Atti del IV Congresso Nazionale 103: 1317-1324. dell’associazione Nazionale dei Medici d’Urgen- za. Monduzzi Ed - Bologna 1989; p. 427. 21) HOLT DW, TUCKER GT, JACKSON PR, STOREY GC. Amio- darone pharmacokinetics. Am Heart J 1983; 106: 7) RIZZON P, B IASCO G, DI BIASE M, ANTONELLI G. Anti- 840-847. anginal and anti-arrhythmic properties of amio- 22) ROEKHUYSEN ARVEL ION Recherches dans darone. Boll Soc Ital Cardiol 1972; 17: 413-417. B J, L L, S R. la serie des benzofuranes. Arch Int Pharmacodyn 8) POLSTER P, B ROEKHUISEN J. The adrenergic antago- 1969; 177: 348. nism of amiodarone. Biochem Pharmacol 1976; 23) BONGIORNI MG. Amiodarone: effetti collaterali. Ital 25: 131-136. Heart J 2001; 2: 475-525. 9) GOUPIL N, LENFANT J. The effect of amiodarone on 24) THE AMERICAN HEART ASSOCIATION IN COLLABORATION the sinus node activity of the rabbit heart. Eur J WITH THE INTERNATIONAL LIAISON COMMITTEE ON RESUSCI- Pharmacol 1976; 39: 23-26. TATION (ILCOR). Guidelines 2000 for Cardiopul- 10) ROSENBAUM MB, CHIALE PA, HALPERN MS, et al. Clini- monary Resuscitation and Emergency Cardiovas- cal efficacy of amiodarone as an antiarrhythmic cular Care–An International Consensus on Sci- agent. Am J Cardiol 1976; 38: 934-944. ence. Resuscitation 2000; 46: 1-448

11) MARTINO E, BARTALENA L, BOGAZZI F, B RAVERMAN LE. 25) THE 1998 EUROPEAN RESUSCITATION COUNCIL GUIDE- The effects of amiodarone on the thyroid. Endocr LINES FOR ADULT ADVANCED LIFE SUPPORT. In: Bossaert Rev 2001; 22: 240-254. L (ed.). European Resuscitation Council Guide- lines for Resuscitation. Amsterdam: Elsevier, 12) PATTERSON E, WALDEN KM, KHAZAELI MB, MONT- 1998; 36-47 GOMERY DG, LUCCHESI BR. Cardiac electrophysiologic effects of acute and chronic amiodarone ad- 26) KUDENCHUK PJ, COBB LA, COPASS MK, et al. Amio- ministration in the isolated perfused rabbit heart: darone for resuscitation after out-of-hospital car- altered thyroid hormone metabolism. J Pharma- diac arrest due to ventricular fibrillation. N Engl J col Exp Ther 1986; 239: 179-184. 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, S ALAMAND A, DJIANE P. Role 38) ZAHIR S, LHEUREUX P. Management of new-onset of antiarrhythmic drugs in reducing the number of atrial fibrillation in the emergency department: is defibrillation shocks. Arch Mal Coeur Vaiss 2005; there any predictive factor for early successful car- 98: 140-144 dioversion? Eur J Emerg Med 2005; 12: 52-56.

28) EUROPEAN RESUSCITATION COUNCIL GUIDELINES 2000 39) BORIANI G, DIEMBERGER I, BIFFI M, MARTIGNANI C, FOR ADULT ADVANCED LIFE SUPPORT. A statement from BRANZI A. Pharmacological cardioversion of atrial the Advanced Life Support Working Group (1) fibrillation: current management and treatment and approved by the Executive Committee of the options. Drugs 2004; 64: 2741-2762. European Resuscitation Council. Resuscitation 40) BARTLETT TG, FRIEDMAN PL. Current management of 2001; 48: 211-221. the Wolff-Parkinson-White syndrome. J Card 29) TRAPPE HJ, BRANDTS B, WEISMUELLER P. Arrhythmias in Surg 1993; 8: 503-515. the intensive care patient. Curr Opin Crit Care 41) VORPERIAN VR, HAVIGHURST TC, MILLER S, JANUARY CT. 2003; 9: 345-355. Adverse effects of low dose amiodarone: a meta- 30) LEVINE JH, MASSUMI A, SCHEINMAN MM, et al. Intra- analysis. J Am Coll Cardiol 1997; 30: 791-798. venous amiodarone for recurrent sustained hy- 42) SOMBERG JC, CVETANOVIC I, RANADE V, M OLNAR J. potensive ventricular tachyarrhythmias. Intra- Comparative effects of rapid bolus administration venous Amiodarone Multicenter Trial Group. J of aqueous amiodarone versus 10-minute cor- Am Coll Cardiol 1996; 27: 67-75. darone I.V. infusion on mean arterial blood pressure in conscious dogs. Cardiovasc Drugs Ther 31) DOMANOVITS H, PAULIS M, NIKFARDJAM M, et al. Sus- 2004; 18: 345-351. tained ventricular tachycardia in the emergency department. Resuscitation 1999; 42: 19-25. 43) POLLAK PT. Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifesta- 32) KUGA K, YAMAGUCHI I, SUGISHITA Y. Effect of intra- tions. Am J Cardiol 1999; 84: 37-45. venous amiodarone on electrophysiologic vari- ables and on the modes of termination of atri- 44) IERVASI G, CLERICO A, BONINI R, et al. Acute effects oventricular reciprocating tachycardia in Wolff- of amiodarone administration on thyroid function Parkinson-White syndrome. Jpn Circ J 1999; 63: in patients with cardiac arrhythmias. J Clin En- 189-195. docrinol Metab 1997; 82: 275-280.

33) KOWEY PR, LEVINE JH, HERRE JM, et al. Random- 45) BRAVO AE, DREWE J, SCHLIENGER RG, KRAHENBUHL S, ized, double-blind comparison of intravenous PARGGER H, UMMENHOFER W. Hepatotoxicity during amiodarone and bretylium in the treatment of pa- rapid intravenous loading with amiodarone: De- tients with recurrent, hemodynamically destabiliz- scription of three cases and review of the litera- ing ventricular tachycardia or fibrillation. The In- ture. Crit Care Med 2005; 33: 128-134. travenous Amiodarone Multicenter Investigators 46) ROTEN L, SCHOENENBERGER RA, KRAHENBUHL S, Group. Circulation 1995; 92: 3255-3263. SCHLIENGER RG. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharma- 34) KERIN NZ, FAITEL K, NAINI M. The efficacy of intravenous amiodarone for the conversion of chronic cother 2004; 38: 978-981. atrial fibrillation: amiodarone vs quinidine for con- 47) YAMREUDEEWONG W, D EBISSCHOP M, MARTIN LG, LOW- version of atrial fibrillation. Arch Intern Med 1996; ER DL. Potentially significant drug interactions of class 156: 49-53. III antiarrhythmic drugs. Drug Saf 2003; 26: 421-438.

35) HORNER SM. A comparison of cardioversion of atri- 48) LATINI R. TOGNONI G, KATES RE. Clinical pharmaki- al fibrillation using oral amiodarone, intravenous netics of amiodarone. Clin Pharmacokinet 1984; amiodarone and DC cardioversion: Acta Cardiol 9: 136-156. 1992; 47: 473-480. 49) MOYSEY JO, JAGGARAO NSV, GRUNDY EN, CHAMBERLAIN 36) SINGH BN, SINGH SN, REDA DJ, et al. Amiodarone DA. Amiodarone increases plasma digoxin con- versus sotalol for atrial fibrillation. N Engl J Med centrations. Brit Med J 1981; 282: 272-275. 2005; 352: 1861-1872. 50) CHITWOOD KK, ABDUL-HAQQ AJ, HEIM-DUTHOY KL. 37) CHEVALIER P, D URAND-DUBIEF A, BURRI H, CUCHERAT M, Cyclosporine-amiodarone interaction. Ann Phar- KIRKORIAN G, TOUBOUL P. Amiodarone versus place- macother 1993: 569-571. bo and classic drugs for cardioversion of recent- 51) DONALDSON L, GRANT IS, NAYSMITH MR, THOMAS JS. onset atrial fibrillation: a meta-analysis. J Am Coll Acute amiodarone-induced lung toxicity. Intensive Cardiol 2003; 41: 255-262. Care Med 1998; 24: 626-630.

190