Since the creation of the American Heart Association Advanced Cardiac Life Support Guidelines, antiarrhythmic medications have enjoyed a prominent spot in the treatment of cardiac arrest associated with ventricular fibrillation or pulseless ventricular tachycardia.
Physiology
The electrical impulses that produce these lethal arrhythmias involve ion channels on the surface of the myocytes. With ischemia, ion channels become unstable and may not function properly. In some cases, ion channel instability enhances automaticity, thereby causing pacemaker cells to depolarize prematurely. If this premature impulse occurs during a vulnerable period where the heart muscle has not recovered sufficiently from the previous depolarization, ventricular tachycardia or fibrillation may develop.
Obviously, definitive treatment for lethal arrhythmias resulting from myocardial ischemia is correction of the ischemic state. However, under ischemic conditions, controlling ion channels may be the key to preventing sudden cardiac death or reversing it once it occurs.
How antiarrhythmic medications work
Antiarrhythmic medications work by altering ion permeability across the myocardial membranes, which changes impulse conduction through the myocardium.[1] Amiodarone acts on multiple ion channels simultaneously to slow ventricular conduction, suppress ventricular premature complexes, depress AV node automaticity, and prevent atrial or ventricular reentrant arrhythmias.[2]
Additionally, because of its calcium channel blocking properties, amiodarone does not produce torsade de pointes as often as other antiarrhythmic drugs, despite its propensity to increase the QT interval.[3]
Early animal studies suggested that amiodarone raised the electrical threshold necessary to produce ventricular fibrillation.[4,5] Canine studies describe successful conversion with amiodarone administration following protracted resuscitation efforts involving multiple defibrillation attempts, epinephrine and alternative antiarrhythmics.[6]
Soon human case studies highlighted the effectiveness of rapid loading does of intravenous amiodarone in controlling lethal ventricular arrhythmias,[7] even when refractory to other antiarrhythmic medications.[8,9]
ARREST-ing evidence
In 2000, the American Heart Association recommended amiodarone as the primary antiarrhythmic agent for persistent ventricular tachycardia or ventricular fibrillation.[10] The results of the ARREST trial heavily influenced the AHA’s recommendation of amiodarone over lidocaine in Guidelines 2000.
The ARREST trial was a 27-month randomized, double-blind comparison of 300 milligrams of intravenous amiodarone to placebo for out-of-hospital cardiac arrest patients with shock-refractory VF/pVT.[11] The results demonstrated that patients receiving amiodarone were significantly more likely to achieve a return of spontaneous circulation and be admitted to the hospital compared to the patients receiving a placebo.
However, when researchers tracked the patients to see if they lived long enough to be discharge from the hospital, amiodarone provided no survival advantages over placebo for all patients, for those who presented in ventricular fibrillation, or for those who achieved a transient return of a pulse before antiarrhythmic treatment. By design, the trial lacked the statistical power to detect the significance of these observations.
In a follow-up trial, researchers compared intravenous amiodarone to intravenous lidocaine in a group of out-of-hospital cardiac arrest patients with shock-resistant ventricular fibrillation. In the Amiodarone vs. Lidocaine in Prehospital Ventricular Fibrillation Evaluation (ALIVE) trial, patients were randomized to receive either 1.5 milligrams of lidocaine or 5 milligrams per kilogram of amiodarone.[12] Patients receiving amiodarone were more likely to survive to hospital admission compared to patients receiving lidocaine. Once again, though, when patients were tracked to see if they survived to hospital discharge, amiodarone offered no survival advantages over lidocaine.
However, in both the ARREST and ALIVE trials, amiodarone was administered late in the resuscitation event, which may explain the inability to demonstrate an improvement in long-term survival.
AHA recommendations
Current American Heart Association guidelines recommend amiodarone for VF/pVT refractory to CPR, countershock, and vasopressor therapy.[13] That recommendation is labeled as a class IIb recommendation, which means that the evidence in favor of the recommendation identifies only short-term or weakly positive benefits or mixed results.[14]
The recommended intravenous dose is 300 mg administered as a bolus, followed by a 150 mg bolus dose. The medication is usually stored in glass ampules or glass syringes due to the drug’s propensity to adhere to the plastics used to make other types of containers.[15-17]
Amiodarone also has a propensity to foam when prepared for intravenous injection, especially if the ampule is agitated or the medication is aspirated too quickly.[18] This can lead to inaccurate dosing and reduced efficacy. To reduce the risk, paramedics should use a large-bore needle and aspirate the medication slowly from the vial, taking care to handle the ampules gently.
Amiodarone side effects
Amiodarone exists in a solution with two other chemicals, polysorbate 80 and benzyl alcohol. Amiodarone is not very water-soluble, and without these two chemical additives, it would precipitate in the vial. The additives help to keep the amiodarone dissolved in the solvent. However, these chemicals are not completely harmless. Independently, both chemicals can produce negative inotropy and hypotension and are likely responsible for most of the side effects seen with this medication.[19-21]
To prevent these side effects, researchers developed a new formulation in which amiodarone is stabilized in an aqueous solution without the need for detergents. Drug developers hoped to retain the beneficial effects of amiodarone while reducing the toxicity profile. In a case series of 32 adult patients undergoing cardiac catheterization, aqueous amiodarone did not produce a significant reduction in blood pressure from baseline.[22]
In a double-blind trial involving adult patients with ventricular fibrillation refractory to countershock, researchers demonstrated that aqueous amiodarone produced more cumulative conversions, more one-hour survivors, and more 24-hour survivors than did lidocaine.[23]
Current research
Researchers with the Resuscitation Outcomes Consortium are currently evaluating whether a captisol-enabled formulation of IV amiodarone improves survival to hospital discharge for patients who suffer ventricular fibrillation in the out-of-hospital environment.[24] The trial will enroll about 3,000 participants and involves nine locations across the United States and Canada.[25] The estimated study completion date is September 2015.
Summary
Despite the lack of long-term benefits, antiarrhythmic medication administration remains a part of current resuscitation recommendations for patients who present with or develop lethal ventricular arrhythmias.
Amiodarone has demonstrated improvement in short-term survival outcome measures only. Amiodarone has also produced significant side effects, owing primarily to the cosolvents used in the drug’s preparation. Newer formulations of amiodarone appear similarly effective without the risks of hypotension and bradycardia associated with the original formula.
Primary and secondary outcome measures from a large-scale randomized controlled trial currently underway may provide additional information about the short-term benefits as well as neurological benefits of amiodarone administration to victims of ventricular fibrillation in the out-of-hospital environment.
References
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14. Sayre, M. R., OConnor, R. E., Atkins, D. L., Billi, J. E., Callaway, C. W., Shuster, M., Eigel, B., Montgomery, W. H., Hickey, R. W., Jacobs, I., Nadkarni, V. M., Morley, P. T., Semenko, T. I., & Hazinski, M. F. (2010). Part 2: Evidence evaluation and management of potential or perceived conflicts of interest: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation, 122(18 Suppl 3), S657-S664. doi:10.1161/CIRCULATIONAHA.110.966861
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19. Gough, W. B., Zeiler, R. H., Barreca, P., & El-Sherif, N. (1982).Hypotensive action of commercial intravenous amiodarone and polysorbate 80 in dogs. Journal of Cardiovascular Pharmacology, 4(3), 375–380.
20. Munoz, A., Karila, P., Gallay, P., Zettelmeier, F., Messner, P., Mery, M., & Grolleau, R.(1988).A randomized hemodynamic comparison of intravenous amiodarone with and without Tween 80 [abstract].European Heart Journal, 9(2), 142–148.
21. Platou, E.S., & Refsum, H.(1986).Acute electrophysiologic and blood pressure effects of amiodarone and its solvent in the dog [abstract].Acta pharmacologica et toxicologica, 58(3), 163–168.
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24. ClinicalTrials.gov. (2013). Amiodarone, lidocaine or neither for out-of-hospital cardiac arrest due to ventricular fibrillation or tachycardia (ALPS). Retrieved from http://clinicaltrials.gov/ct2/show/NCT01401647
25. Resuscitation Outcomes Consortium. (2012). NIH launches trials to evaluate CPR and drugs after sudden cardiac arrest. Retrieved from https://roc.uwctc.org/tiki/tiki-index.php?page=roc-public-home
The author has no financial interest, arrangement, or direct affiliation with any corporation that has a direct interest in the subject matter of this presentation, including manufacturer(s) of any products or provider(s) of services mentioned.
Send correspondence concerning this article to Kenneth W. Navarro, The University of Texas Southwestern School of Health Professions, 5323 Harry Hines Blvd, MC 9134, Dallas, Texas 75390-9134. E-mail: kenneth.navarro@utsouthwestern.edu
