“Medicines will be well used when the doctor understands their nature, what man is, what life is, and what constitution and health are. Know these well and you will know their opposites; you will then know well how to devise a remedy.” ─ Leonardo da Vinci
Before we can intelligently discuss the antiarrhythmic properties of amiodarone, we must first review some basics about cardiac electrophysiology. Unlike every other muscle cell in the body that must receive an impulse from the central nervous system in order to contract, specialized cells within the heart muscle are capable of initiating their own electrical impulse, a property known as automaticity.
At a cellular level, electrical impulse creation and propagation occurs because of specialized proteins on the surfaces of these myocardial cells (myocytes). These specialized proteins form structures known as ion channels.
Ion channels permit movement of certain electrically charged particles into and out of the myocytes. Sodium channels permit the movement of sodium ions across the cellular membrane; potassium channels permit the movement of potassium ions, and so on.
Pacemaker cells in the heart work because the channel that permits sodium to flow into a cell slowly leaks. Each sodium ion that leaks into a particular myocyte alters the electrical charge inside the cell. When enough sodium leaks into the cell, the cell reaches the threshold and creates the electrical impulse in a process called depolarization.
Pacemaker cells then transfer the newly created impulse to adjacent cells, which then transfers the impulse to the next cells. Each cell passes the impulse to the neighboring cells until it travels throughout the heart muscle.
If the myocytes become ischemic for any reason, the ion channels become unstable and may open prematurely. When this happens, the cell and perhaps many of the surrounding cells depolarize out of synch with all of the other myocytes.
In some cases, this premature depolarization can trigger sudden cardiac arrest through the development of ventricular fibrillation or pulseless ventricular tachycardia (VF/pVT). Under ischemic conditions, controlling these ion channels may be the key to preventing sudden cardiac death or reversing it once it occurs.
How amiodarone works
Antiarrhythmic medications such as amiodarone and lidocaine alter ion permeability across the myocardial membrane, which in effect, stabilizes the ion channels and changes impulse conduction through the myocardium[1]. Lidocaine works specifically on the sodium channel while amiodarone works primarily on the potassium channel, although the drug also affects beta receptors, sodium channels, and calcium channels.
Early canine studies[2] and case reports[3]describe successful conversion of cardiac arrest with amiodarone administration following protracted resuscitation efforts involving multiple defibrillation attempts, epinephrine and alternative antiarrhythmic medications.
Soon however, retrospective evaluation of larger groups of patients found no statistical difference in return of spontaneous circulation (ROSC) or survival to hospital discharge between patients who received amiodarone or a different antiarrhythmic[4].What the medical community needed was a large randomized controlled trial to attempt to answer the question of whether amiodarone should be the antiarrhythmic of choice for patients suffering from VF/pVT cardiac arrest.
ARREST Trial
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[5]. The results demonstrated that patients receiving amiodarone were significantly more likely to achieve ROSC and be admitted to the hospital compared with 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.
For the patients who achieved ROSC in the field and had a recorded blood pressure upon arrival in the emergency department, amiodarone was also associated with significantly more hypotension compared with the placebo.
ALIVE Trial
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[6].
Patients receiving amiodarone were more likely to survive to hospital admission compared with patients receiving lidocaine. Once again, however, when patients were tracked to see if they survived to hospital discharge, amiodarone offered no long-term survival advantages over lidocaine.
A recent retrospective cohort study using the Get with the Guidelines database found the use of lidocaine during the in-hospital treatment of children less than 18 years old suffering from pulseless ventricular tachycardia or ventricular fibrillation was associated with improved ROSC and 24-hour survival rates but not survival to hospital discharge rates[7]. The use of amiodarone was not associated with ROSC, 24-hour survival, or survival to discharge.
A meta-analysis of randomized-controlled trials using antiarrhythmic medications for the treatment of both in- and out-of-hospital cardiac arrest found only short term benefits associated with the administration of lidocaine or amiodarone[8]. However, neither drug was associated with improvements in survival to hospital discharge rates.
A new amiodarone
Traditional amiodarone contains two chemical additives that help to keep the drug dissolved in the liquid[9]. Without these additives, the drug would precipitate in the vial.
Both of these chemicals are independently known to reduce the force of myocardial contraction and produce hypotension[10, 11, 12]. In an effort to reduce the harmful side effects cause by these two chemical additives, researchers have developed a new formulation in which amiodarone is stabilized in an aqueous solution without the need for these chemicals.
In a double-blind trial, researchers sought to determine whether aqueous amiodarone or lidocaine given intravenously was more effective for treating ventricular tachycardia refractory to synchronized cardioversion[9].
Aqueous amiodarone produced more cumulative conversions, more one-hour survivors, and more 24-hour survivors. In the only trial comparing aqueous amiodarone to lidocaine, researchers concluded that aqueous amiodarone is more effective at terminating shock-resistant ventricular tachycardia and producing survivors.
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[13]. The trial will enroll about 3,000 participants and involves nine locations across the United States and Canada[14]. The estimated study completion date is September 2015.
References
1. Sandski, C. A., Schoen, M. D., & Bauman, J. L. (2008). The arrhythmias. In J. T. DiPiro, R. L. Talbert, G. C. Yee, G. R. Matzke, B. G. Wells, & L. M. Posey (Eds), Pharmacotherapy: A pathophysiologic approach 7th Ed (pp. 279-314). New York: McGraw Hill.
2. 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. The Journal of the American College of Cardiology, 23(1), 253–258. doi:10.1016/0735-1097(94)90528-2
3. Petrovic, T., Adnet, F., & Lapandry, C. (1998). Successful resuscitation of ventricular fibrillation after low dose amiodarone. Annals of Emergency Medicine, 32(4), 518-519.
4. Pollak, P. T., Wee, V., Al-Hazmi, A., Martin, J., & Zarnke, K. B. (2006). The use of amiodarone for in-hospital cardiac arrest at two tertiary care centres [Abstract]. Canadian Journal of Cardiology, 22(3), 199-202.
5. 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
6. 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
7. Valdes, S. O., Donoghue, A. J., Hoyme, D. B., Hammond, R., Berg, M. D., Berg, R. A., & Samson, R. A. (2014). Outcomes associated with amiodarone and lidocaine in the treatment of in-hospital pediatric cardiac arrest with pulseless ventricular tachycardia or ventricular fibrillation. Resuscitation, 85(3), 381-386. doi:10.1016/j.resuscitation.2013.12.008
8. Huang, Y., He, Q., Yang, M., & Zhan, L. (2013). Antiarrhythmia drugs for cardiac arrest: A systemic review and meta-analysis. Critical Care, 17(4), R173. doi:10.1186/cc12852.
9. 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
10. 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.
11. 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. European Heart Journal, 9(2), 142–148.
12. Platou, E.S., & Refsum, H. (1986). Acute electrophysiologic and blood pressure effects of amiodarone and its solvent in the dog. Acta pharmacologica et toxicological, 58(3), 163–168. doi:10.1111/j.1600-0773.1986.tb00089.x
13. 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
14. 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
