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Amiodarone IV: Indications, Dosing, Clinical Studies, Efficacy, and Bibliography Sponsored by DocMD.com INDICATIONS AMIODARONE IV Amiodarone I.V. (Cordarone I.V.) ® Indication: Amiodarone I.V. is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy. Amiodarone I.V. ® (Cordarone I.V.) • Cordarone I.V. is contraindicated in patients with cardiogenic shock, marked sinus bradycardia, and second- or third-degree AV block in the absence of a functioning pacemaker. • Cordarone I.V. should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of Cordarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. Amiodarone I.V. ® (Cordarone I.V.) • Hypotension is the most common adverse effect seen with Cordarone I.V. and may be related to the rate of infusion. Hypotension should be treated by slowing the infusion or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion. • The most important treatment-emergent adverse effects are hypotension (16%), bradycardia (4.9%), liver function test abnormalities (3.4%), cardiac arrest (2.9%), VT (2.4%), CHF (2.1%), cardiogenic shock (1.3%), and AV block (0.5%). AMIODARONE IV DOSING Rapid Onset of Action 1-4 Antiarrhythmic effects are seen in minutes3,4 Hypotension is the most common adverse effect seen with Cordarone® I.V. (amiodarone HCI) and may be related to the rate of infusion. 1. Kadish A, Morady F. The use of intravenous amiodarone in the acute therapy of life-threatening tachyarrhythmias. Prog Cardiovasc Disc. 1989;31:281-294. 2. Helmy I, Herre JM, Gee G, et al. Use of intravenous amiodarone for emergency treatment of lifethreatening ventricular arrhythmias. J Am Coll Cardiol. 1988;12:1015-1022. 3. Holt P, Curry P, Way B, et al. Intravenous amiodarone; an effective anti-arrhythmic agent. Am J Cardiol. 1982;49:1001. Abstract. 4. Benjamin R, Denizeau J-P, Melon J, et al. Les effets antiarythmiques de l’amiodarone injectable: à propos de 100 cas. Arch Mal Coeur. 1976;69:513-522. Dose Recommendations -- First 24 Hours -Loading Infusions First Rapid: 150 mg over the FIRST 10 minutes (15 mg/min). Add 3 mL of Amiodarone I.V. (150 mg) to 100 mL D5W (1.5 mg/mL) and infuse over 10 minutes. Followed by Slow 360 mg over the NEXT 6 hours (1 mg/min). Add 18 mL of Amiodarone I.V. (900 mg) to 500 mL D5W concentration = 1.8 mg/mL). Dose Recommendations -- First 24 Hours -Maintenance Infusion 540 mg over the REMAINING 18 hours (0.5 mg/min). Decrease the rate of the slow loading infusion to 0.5 mg/min. Supplemental Infusion* Add 150 mg to 100 mL D5W; administer over 10 minutes (15 mg/min) PVC† or glass container •Hypotension is the most common adverse effect seen with Amiodarone I.V. and may be related to the rate of infusion •Must use volumetric pump when administering Amiodarone I.V.; an in-line filter is recommended •Store ampuls in cartons until ready for use to protect from light •Prepared solutions should not be kept for more than 24 hours * For the management of breakthrough episodes of life-threatening VT or VF. Alternatively, the rate of the maintenance infusion may be increased. † 10% loss after two hours Supplemental Infusion* Add 150 mg to 100 mL D5W; administer over 10 minutes (15 mg/min) PVC† or glass container •Concentrations greater than 3 mg/mL in D5W have been associated with a high incidence of peripheral vein phlebitis •For infusions longer than 1 hour, Cordarone I.V. concentrations should not exceed 2 mg/mL unless a central venous catheter is used •Evacuated glass containers for admixing Cordarone I.V. are not recommended A Treatment Algorithm for Cardiac Arrest* Utilizing Cordarone I.V. (amiodarone HCI) ® Pulseless VT/VF Shock x 3 Persistent or recurrent VT/VF Continue CPR Intubate Obtain IV access Epinephrine 1 mg I.V. q 3 to 5 minutes Cordarone I.V. 300 mg rapid peripheral infusion IIb Medications, e.g., Lidocaine Procainamide etc. DF 360 J within 30 to 60 sec after each drug “Drug-Shock”, “Drug-Shock” *Due to persistent VF/pulseless VT Adapted from Gonzalez ER, Kannewurf BS, Ornato JP. Resuscitation. 1998;39:33-42. AMIODARONE IV EFFICACY Suppresses Highly Malignant Ventricular Arrhythmias in Patients 1 With Severe Underlying Heart Disease In clinical studies • Decreased median number of life-threatening events by 71%2 • Increased median time to first event to 13.7 hours2 • 85% of patients in controlled studies survived the critical first 24 hours.3 Without a placebo comparison, a mortality benefit could not be established. 1. 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. Circulation. 1995;92:3255-3263. 2. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrhythmias. Circulation. 1995;92:3264-3272. 3. Data on file, Wyeth-Ayerst Laboratories. Reduction of VT/VF Events During Double-Blind Therapy1 Events/hr (median) 0.10 0.07 P=0.067 71% Reduction 0.04 0.05 0.02 0.00 125 mg 500 mg 1000 mg Cordarone I.V. Dosing (mg/24 Hours) • The 125 mg dose group was used as a control group. • Due to administration of supplemental infusions, the 1000 mg dose group actually received 1185 mg/24 hours compared to the 125 mg dose group, which received 428 mg/24 hours Reproduced with permission. Circulation. Copyright 1995 American Heart Association. 1. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with lifethreatening ventricular tachyarrhythmias. Circulation. 1995;92:3264-3272. Reduction from Baseline in VT/VF Events1 Baseline Median VT/VF Events per 24 Hours Cordarone I.V. 1000 mg Cordarone I.V. 125 mg 4.0 3.52 (88% reduction) 3.0 1.68 1.32 (44% reduction) 0.48 1000 mg 125 mg Difference from baseline P=0.0425 No significant difference observed between the 1000 mg dose and the 500 mg dose or the 125 mg dose and the 500 mg dose Reproduced with permission. Circulation. Copyright 1995 American Heart Association. 1. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with lifethreatening ventricular tachyarrhythmias. Circulation. 1995;92:3264-3272. AMIODARONE IV CLINICAL STUDIES Amiodarone in out-of-hospital Resuscitation of REfractory Sustained ventricular Tachyarrhythmias (ARREST) A prospective, randomized, double-blind, placebocontrolled comparison of ACLS guidelines with and without intravenous amiodarone in out-of-hospital cardiac arrest due to shock-refractory VF/VT Kudenchuk PJ, Cobb LA, Copass LA, et al. New Engl J Med. 1999. 341:871-878. ARREST Eligibility Criteria • Age >18 years • Nontraumatic out-of-hospital cardiac arrest • Ongoing VF/VT after 3+ shocks • Medics and study drug on scene • I.V. access ARREST Study End Points •Primary - Admission to hospital with a spontaneously perfusing rhythm (assigned to a hospital bed) ARREST Study End Points •Secondary -Adverse effects -Total duration of resuscitative efforts -Number of shocks after study drug -Need for additional antiarrhythmic drugs •Also Evaluated -Survival to hospital discharge* -Neurologic status at hospital discharge* * Due to sample size, trial was not powered to detect significant differences between treatment groups. Study Algorithm Cardiac Arrest VF or Pulseless VT Shock x 3 Persistent or Recurrent VF/VT Stable Rhythm ETT I.V. EPI Study Drug Standard ACLS Care Placebo I.V. amiodarone Asystole or PEA Excluded From Study ETT: endotracheal intubation I.V.: intravenous access established EPI: epinephrine PEA: pulseless electrical activity November 1994 – February 1997 Out-of-Hospital Cardiac Arrest (n=3954) Met Study Criteria (n=667) Eligible/Treated (n=507) Study Group (n=504) Ineligible/Not Treated (n=3260) Ineligible/Treated (n=27) Eligible/Not Treated (n=160) Drug Assignment Unknown (n=3) • • • • BLS Only/DOA Age/Trauma PEA/Asystole <3 Shocks • Insufficient number of shocks ROSC at time of Rx Trauma • • • • VF/VT terminated before Rx Protocol violation BLS: basic life support PEA: pulseless electrical activity ROSC: return of spontaneous circulation ARREST Patient Characteristics I.V. Amiodarone (n=246) Male Placebo (n=258) P-value 187 (76%) 203 (79%) NS 66 14 65 14 NS Cardiac History 137 (64%) 135 (59%) NS Other Medical History 101 (47%) 119 (52%) NS Witnessed Arrest 155 (70%) 182 (77%) 0.07 Bystander CPR 155 (68%) 138 (59%) 0.06 0.42 0.2 0.45 0.2 NS Age (yrs) VF Amplitude (mV) Initial Cardiac Arrest Rhythm 100 83 I.V. Amiodarone Placebo 83 % of Patients 80 60 40 20 12 4 5 11 0 VF PEA: pulseless electrical activity Asystole VF PEA VF Response/Treatment Times From Dispatch Mean 1 SD (Median) Minutes I.V. Amiodarone Placebo P-value 1st unit (EMT-D) 4.3 2.0 (4) 4.4 2.3 (4) NS Paramedic/ALS 8.4 4.1 (7.8) 8.8 4.9 (7.9) NS 4.1 4.0 (3) 4.5 4.3 (3.3) NS 8.9 5.4 (7.6) 9.5 7.5 (7.4) NS I.V. 13.1 4.1 (12.7) 13.7 4.1 (13.2) NS Intubation 14.3 5.8 (12.7) 13.8 4.6 (13.1) NS Study drug 21.4 8.3 (19.2) 20.5 7.0 (19.3) NS EMT-D ALS 1st shock Resuscitation Characteristics Before Study Drug I.V. Amiodarone (n=246) Placebo (n=258) P-value Number of shocks 5 2 (4)* 5 2 (4)* 0.73 Transient ROSC 55 (22%) 52 (20%) 0.61 Antiarrhythmic drug 65 (26%) 91 (35%) 0.04 Bradycardia treatment 32 (13%) 51 (20%) 0.04 Pressor treatment 19 (8%) 22 (9%) 0.74 ROSC: return of spontaneous circulation *Median in parentheses. Treatment After Study Drug % of Patients 100 80 P=0.70 80 I.V. Amiodarone Placebo 82 P=0.04 59 60 48 P=0.004 41 40 25 20 0 Antiarrhythmic No. Receiving Drug/ 197/246 Total No. 211/258 Pressor* 91/153 69/145 * In patients with return of spontaneous circulation. Bradycardia treatment* 63/153 36/145 Admission to Hospital by Arrest Characteristics 70 Patients Surviving to Admission (%) Amiodarone 64 Placebo 60 49 50 44 41 39 40 34 38 33 30 17 20 12 10 0 All patients No. Surviving/ Total No. 108/246 89/258 VF 101/205 84/216 Asystole or PEA converting to VF 7/41 PEA: pulseless electrical activity ROSC: return of spontaneous circulation 5/42 ROSC 35/55 22/53 No ROSC 73/191 67/205 Patient Status at Hospital Discharge 70 % of Patients 60 I.V. Amiodarone Placebo 55 50 50 40 30 20 13.4 13.2 16 15 10 0 Outcome Alive, all patients Alive, VF only Resumed independent living This trial was not designed or powered to detect significance in survival to hospital discharge. ARREST Trial Conclusions •I.V. amiodarone is effective therapy for shock-refractory VF •Adverse effects expected, but manageable •Improving survival from cardiac arrest remains an important challenge ACC/AHA Treatment Recommendations for VT/VF Acute Myocardial Infarction •900,000 people in U.S. experience an MI annually •225,000 die - 125,000 die “in the field” - Most deaths are arrhythmic in etiology Source: Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction. J Am Coll Cardiol. 1996;28:1333. ACC/AHA Practice Guidelines 1990 – ACC/AHA Introduces “Guidelines for the Early Management of Patients with Acute MI” • Not a rigid prescription • A “guide” – to be modified by clinical judgment, patient needs, and new findings 1994 – ACC/AHA Task Force on Practice Guidelines Convenes • Purpose: to review knowledge accumulated since 1990 and recommend appropriate changes to the original guidelines • Estimated 5,000 publications reviewed over next 1 1/2 years 1996 – ACC/AHA Publishes Revised Guidelines Source: Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction. J Am Coll Cardiol. 1996;28:1336. ACC/AHA Treatment Recommendations for VT/VF Class I: • Sustained monomorphic VT – Treat with one of the following: - Lidocaine: bolus 1.0 to 1.5 mg/kg - Procainamide: 20 to 30 mg/min loading infusion, up to 12 to 17 mg/kg. This may be followed by an infusion of 1 to 4 mg/min - Amiodarone IV: 150 mg infused over 10 min followed by 1.0 mg/min for 6 hrs and then a maintenance infusion of 0.5 mg/min - Synchronized electrical cardioversion starting at 50 J Amiodarone I.V. is indicated in life-threatening VT/VF refractory to other therapy. ACC/AHA Treatment Recommendations for VT/VF Class I (Cont’d.): • Sustained monomorphic VT with angina, pulmonary edema, or hypotension (<90 mm Hg) – synchronized cardioversion 100 J initial energy. Increasing energies may be used if not initially successful • VF or sustained (>30 sec) polymorphic VT – defibrillate up to 3 times if needed (200 J, 200 to 300 J, 360 J) ACC/AHA Treatment Recommendations for VT/VF Class IIa: • Infusions of antiarrhythmic drugs (discontinue after 6 to 24 hours and reassess need) • Correction of electrolyte and acid-base disturbances (to prevent VF recurrence following treatment of initial episode) ACC/AHA Treatment Recommendations for VT/VF Class IIb: • Drug-refractory polymorphic VT - Manage aggressively with -blockers, intra-aortic balloon pumping, PTCA/CABG surgery - Amiodarone I.V. Class III: • Treating isolated PVCs, couplets, runs of accelerated idioventricular rhythm, nonsustained VT • Prophylactic antiarrhythmic therapy when using thrombolytic agents • Amiodarone I.V. is indicated in life-threatening VT/VF refractory to other therapy. AMIODARONE IV SAFETY Clinically Manageable Safety Profile ~9% overall discontinuation rate due to adverse events 1 <1% incidence of proarrhythmia 1 <1% discontinuation due to CNS side 1 effects Hypotension is the most common adverse effect seen with Amiodarone I.V. and may be related to the rate of infusion. Hypotension should be treated by slowing the infusion or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion. 1. Data on file, Wyeth-Ayerst Laboratories. Most Important Treatment-Emergent Drug-Related Adverse Events (n=1836) Event % Incidence % Requiring permanent discontinuation Hypotension 16% 1.6% Bradycardia 4.9% <1% Liver function tests abnormal 3.4% <1% Heart arrest 2.9% 1.2% Ventricular tachycardia 2.4% 1.1% Congestive heart failure 2.1% <1% Cardiogenic shock 1.3% 1.0% AV block 0.5% <1% Fewer Drug-Related Adverse 1 Events Than Bretylium Event Cardiovascular events Hypotension Heart block CHF Proarrhythmia Nodal rhythm Phlebitis Other events Nausea Confusion Thrombocytopenia Fever Diarrhea Treatment Group Bretylium Cordarone I.V. Cordarone I.V. n=103 1000 mg 125 mg n=105 n=94 33 4 5 3 0 0 6 4 3 1 5 (32%) (4) (5) (3) (6) (4) (3) (1) (5) 21 (20%) 0 0 0 3 (3) 3 (3) 2 3 1 2 0 (2) (3) (1) (2) 17 (18%) 2 (2) 0 1 (1) 0 0 2 3 1 1 0 (2) (3) (1) (1) Reproduced with permission. Circulation. Copyright 1995 American Heart Association. 1. 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. Circulation. 1995;92:3255-3263. AMIODARONE IV BIBLIOGRAPHY Bibliography •Benaim R, Denizeau J-P, Melon J, et al. Les effets antiarythmiques de l´amiodarone injectable: à propos de 100 cas. Arch Mal Coeur. 1976;69:513-522. •Gonzalez ER, Kannewurf BS, Ornato JP. Intravenous amiodarone for ventricular arrhythmias: overview and clinical use. Resuscitation. 1998;39:33-42. •Helmy I, Herre JM, Gee G, et al. Use of intravenous amiodarone for emergency treatment of life-threatening ventricular arrhythmias. J Am Coll Cardiol. 1988;12:1015-1022. •Holt P, Curry P, Way B, et al. Intravenous amiodarone; an effective anti-arrhythmic agent. Am J Cardiol. 1982;49:1001. Abstract •Kadish A, Morady F. The use of intravenous amiodarone in the acute therapy of life-threatening tachyarrhythmias. Prog Cardiovasc Dis. 1989;31:281-294. Bibliography •Kowey PR, Levine JH, Herre JM, et al. Randomized, doubleblind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. Circulation. 1995;92:3255-3263. •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. •Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction. J Am Coll Cardiol. 1996;1328:1428. •Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with lifethreatening ventricular tachyarrhythmias. Circulation. 1995;92:3264-3272.