Imagine you are out for an evening jog when a young man, who is running ahead of you, collapses. You rush over and a rapid assessment suggests that he is unresponsive, has no pulse, and is not breathing. You start chest compressions and a bystander calls 911. EMS arrives soon, however, after 5 cycles of chest compressions and several attempts at defibrillation for a rhythm of ventricular fibrillation there is still no response. The ACLS algorithm next prompts the team to choose an antiarrhythmic: amiodarone or lidocaine? The team pulls amiodarone and his rhythm reverts. What led to that choice? Would lidocaine have had the same effect?
The pre-hospital period has been identified as critical to obtaining favorable outcomes in acute cardiovascular events. Currently, there are Class IIb recommendations from the American Heart Association for the use of antiarrhythmic medication, typically intravenous amiodarone and lidocaine, in cases of cardiac arrest. The agents may be considered for ventricular fibrillation or pulseless ventricular tachycardia unresponsive to CPR, defibrillation, or vasopressor treatment. However, evidence regarding the effectiveness of these agents remains inconclusive. In this week’s NEJM, Kudenchuk et al try to answer the question of the survival benefit of anti-arrhythmic agents in out-of-hospital cardiac arrest.
This randomized, double blinded, placebo-controlled trial compares parenteral amiodarone, lidocaine and saline placebo, along with standard care, in 3026 adults with non-traumatic, out-of-hospital, cardiac arrest with shock refractory ventricular fibrillation, or pulseless ventricular tachycardia. The primary outcome of interest was survival to hospital discharge, and the secondary outcome of interest was favorable neurologic function at discharge, defined as a modified Rankin score of 3 or less. The study outcomes were evaluated using a modified intention-to-treat (or efficacy) population and an intention-to-treat (or safety) population
The study did not find a statistically significant difference in either of the outcomes; neither amiodarone nor lidocaine resulted in higher survival compared to saline placebo (24.4%, 23.7%, and 21.0%, respectively) upon hospital discharge (primary outcome) nor did they result in significant difference in favorable neurological function at discharge (secondary outcome). However, there was significant benefit of both antiarrhythmic drugs over placebo in certain measures: fewer shocks were administered after the first dose of the trial drug; fewer patients received rhythm-control medications during hospitalization; and fewer patients required CPR during hospitalization.
Although the study is well designed, investigators had little control over certain aspects of the study, such as standardization of care in hospitals. The frequency of coronary catheterization, therapeutic hypothermia, and withdrawal of life-sustaining treatments demonstrated no difference between groups. The trial used only one administrative strategy; others manners with active-treatment crossover and may produce different results. However, pre-hospital trials pose unique practical, operational, ethical and analytical challenges of uncertainty. Selection bias could have influenced trial enrollment, though instances of exclusion were numerically small (6.3%). Potential confounders in clinical CPR trials are the relatively ‘open’ exclusion and inclusion criteria, where many cases with no chance of survival are enrolled; for instance, asystolic patients who do not convert to ventricular tachycardia/ventricular fibrillation. Thus, more benefit may be seen in certain sub-populations. However, it is difficult to implement strict criteria into cardiac arrest studies, because the decision to randomize has to be executed instantaneously, without much clinical data.
The study suggests the possible clinical benefit of antiarrythmic administration, with respect to fewer shocks and less need of in-hospital antiarrhythmics and CPR, which warrants further evaluation. Additionally, the accompanying editorial by Dr. Joglar and Dr. Page speculates that the antiarrhythmics may have been administered too late to ameliorate significant metabolic consequences of prolonged arrest, and it is unknown if earlier administration confers further benefit. The study raises several interesting hypotheses, which need to be explored to further expand the evidence available to support or refute current resuscitation practices.
NEJM Deputy Editor Dr. John Jarcho notes that there has been very little previous research directly comparing antiarrhythmic drug strategies in out-of-hospital cardiac arrest. “We believe that these data are very likely to influence both guidelines and clinical practice in the management of this patient population. We also consider it important to encourage the effort to conduct clinical trials in this difficult setting.”
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Bhavna Seth is a Resident in Internal Medicine at Boston University Medical Center.