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Home > Topics > Trauma
December 01, 2013
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The Research Review
by Kenny Navarro

Amiodarone in the Prehospital Environment

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

By Kenny Navarro

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

1. Lau, W., Newman, D., & Dorian, P. (2000). Can antiarrhythmic agents be selected based on mechanism of action? Drugs, 60(6), 1315-1328.
2. Essebag, V. (1995).Class I and class III antiarrhythmic agents: mechanisms of action and the problem of proarrhythmic activity. Retrieved from http://www.medicine.mcgill.ca/mjm/v01n02/anti.html
3. Nattel, S. (1993). Comparative mechanisms of action of antiarrhythmic drugs. American Journal of Cardiology, 72(16), 13F-17F.
4. Lubbe, W. F., McFadyen, M. L., Muller, C. A., Worthington, M., & Opie, L. H. (1979). Protective action of amiodarone against ventricular fibrillation in the isolated perfused rat heart. American Journal of Cardiology, 43(3), 533-540.
5. Lubbe, W. F., Nguyen, T., & West, E. J. (1983). Modulation of myocardial cyclic AMP and vulnerability to fibrillation in the rat heart [abstract]. Federation Proceedings, 42(8), 2460-2464.
6. Anastasiou-Nana, M. I., Nanas, J. N., Nanas, S. N., Rapti, A., Poyadjis, A., Stathaki, S., & Moulopoulos, S. D.(1994).Effects of amiodarone on refractory ventricular fibrillation in acute myocardial infarction: experimental study [abstract]. The Journal of the American College of Cardiology, 23(1), 253–258.
7. Mostow, N. D., Rakita, L., Vrobel, T. R., Noon, D., & Blumer, J. (1984). Amiodarone: intravenous loading for rapid suppression of complex ventricular arrhythmias. Journal of the American College of Cardiology, 4(1), 97-104.
8. Chapman, J. R., & Boyd, M. J. (1981). Intravenous amiodarone in ventricular fibrillation. British Medical Journal (Clinical Research Edition), 282(6268), 951-952. doi:10.1136/bmj.282.6268.951
9. Leak, D. (1986). Intravenous amiodarone in the treatment of refractory life-threatening cardiac arrhythmias in the critically ill patient. American Heart Journal, 111(3), 456-462. doi:10.1016/0002-8703(86)90048-7
10. American Heart Association. (2000). Part 7: The era of reperfusion: Section 1: Acute coronary syndromes (acute myocardial infarction). Circulation, 102(suppl 1), I-172-I-203, doi:10.1161/01.CIR.102.suppl_1.I-172
11. Kudenchuk, P. J., Cobb, L. A., Copass, M. K., Cummins, R. O., Doherty, A. M., Fahrenbruch, C. E., Hallstrom, A. P., Murray, W. A., Olsufka, M., & Walsh, T.(1999). Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. New England Journal of Medicine, 341(12), 871-878. doi:10.1056/NEJM199909163411203
12. Dorian, P., Cass, D., Schwartz, B., Cooper, R., Gelaznikas, R., & Barr, A.(2002). Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. New England Journal of Medicine, 346(12), 884-890. doi:10.1056/NEJMoa013029
13. Neumar, R. W., Otto, C. W., Link, M. S., Kronick, S. L., Shuster, M., Callaway, C. W., Kudenchuk, P. J., Ornato, J. P., McNally, B., Silvers, S. M., Passman, R. S., White, R. D., Hess, E. P., Tang, W., Davis, D., Sinz, E., & Morrison, L. J. (2010). Part 8: Adult advanced cardiovascular life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation, 122[suppl 3], S729–S767. doi:10.1161/CIRCULATIONAHA.110.970988
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
15. Campbell, S., Nolan, P. E. Jr., Bliss, M., Wood, R., & Mayersohn, M. (1986). Stability of amiodarone hydrochloride in admixtures with other injectable drugs. American Journal of Hospital Pharmacy, 43(4), 917-921.
16. Peters, P. G., & Hayball, P. J. (1990). A comparative analysis of the loss of amiodarone from small and large volume PVC and non-PVC infusion systems. Anaesthesia and Intensive Care, 18(2), 241-245.
17. Weir, S. J., Myers, V. A., Bengtson, K. D., & Ueda, C. T. (1985). Sorption of amiodarone to polyvinyl chloride infusion bags and administration sets. American Journal of Hospital Pharmacy, 42(12), 2679-2683.
18. Van Herendael, H., & Dorian, P. (2010). Amiodarone for the treatment and prevention of ventricular fibrillation and ventricular tachycardia. Vascular Health and Risk Management, 6, 465-472.
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.
22. Gallik, D. M., Singer, I., Meissner, M. D., Molnar, J., & Somberg, J. C. (2002). Hemodynamic and surface electrocardiographic effects of a new aqueous formulation of intravenous amiodarone. American Journal of Cardiology, 90(9), 964-968. doi:10.1016/S0002-9149(02)02662-0
23. Somberg, J. C., Bailin, S. J., Haffajee, C. I., Paladino, W. P., Kerin, N. Z., Bridges, D., Timar, S., & Molnar, J.(2002). Intravenous lidocaine versus intravenous amiodarone (in a new aqueous formulation) for incessant ventricular tachycardia. American Journal of Cardiology, 90(8), 853–859. doi:10.1016/S0002-9149(02)02707-8
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

About the author

Kenny Navarro is an Assistant Professor in the Emergency Medicine Education Department at the University of Texas Southwestern Medical Center at Dallas. He coordinates all continuing education activities and assists in medical oversight for BioTel, a multi-jurisdictional EMS system composed of 14 fire/rescue agencies and more than 1,500 paramedics. Mr. Navarro serves as a Content Consultant for the AHA ACLS Project Team for Guidelines 2010 and served on two education subcommittees for NIH-funded research projects, as the Coordinator for the National EMS Education Standards Project, and as an expert writer for the National EMS Education Standards Implementation Team. Send correspondence concerning any articles in this section to Kenneth W. Navarro, The University of Texas Southwestern Medical School at Dallas, 6300 Harry Hines Blvd, MC 9134, Dallas, Texas 75390-9134, or e-mail kenny.navarro@ems1.com.
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