Despite recent advances in medical technology and therapeutics, the morbidity and mortality of cardiac arrest remain high [
1]. According to contemporary reports, the estimated mortality rate for OHCA is still in the range of 92% to 96% [
1],[
2]. In recent years, the focus of resuscitative efforts in cardiac arrest has moved toward continuous chest compressions and the quality of basic life support maneuvers [
3]-[
5]. Nevertheless, the use of IV medications remains an integral part of advanced life support (ALS) algorithms [
6],[
7]. However, the safety and efficacy of such medications are increasingly questioned [
8],[
9]. Last year saw the publication of several articles related to cardiac arrest that raised additional concerns regarding the utility of IV medication administration in ALS algorithms.
Anti-arrhythmic drugs for out-of-hospital cardiac arrest
Despite a paucity of evidence of long-term benefit, anti-arrhythmic agents are recommended as a part of standard resuscitation algorithms for persistent ventricular arrhythmias without palpable pulses following attempted cardioversion [
6],[
7]. In addition, new agents have been used for ventricular fibrillation (VF) and ventricular tachycardia (VT) in the years following the most recent iterations of international guidelines. Therefore, Huang and colleagues [
10] undertook a systematic literature review and meta-analysis evaluating studies of cardiac arrest in patients over age 18 in which an anti-arrhythmic was used, regardless of the presenting cardiac rhythm. The final analysis included 14 studies of varying quality. The populations studied were heterogeneous in terms of in-hospital cardiac arrest and OHCA as well as initial rhythm.
Pooled results from evaluated randomized trials did not demonstrate any significant improvement in survival to discharge for any agent, including amiodarone (risk ratio (RR) = 0.82, 95% confidence interval (CI) = 0.54 to 1.24), magnesium (RR = 1.07, 95% CI = 0.62 to 1.86), or lidocaine (RR = 2.26, 95% CI = 0.93 to 5.52). Although there was no long-term advantage, lidocaine was associated with improved survival to admission whereas amiodarone and magnesium were not. Nevertheless, pooled analysis demonstrated no significant difference in survival to either hospital admission or discharge when amiodarone was compared directly with lidocaine (P = 0.28). None of the evaluated studies reported neurologic outcome measures.
In addition to these more traditional anti-arrhythmic agents, newly introduced potassium channel blockers such as nifekalant were analyzed as well. Four observational studies were evaluated, and all demonstrated inferior survival compared with amiodarone. Although these studies did indicate a possible benefit over lidocaine in terms of return of spontaneous circulation (ROSC), they demonstrated no benefit in survival to discharge.
In essence, this meta-analysis provided no distinct evidence for a survival benefit from any anti-arrhythmic medication in the management of cardiac arrest. This work mirrors previously published literature suggesting the limited, if any, benefit of ALS interventions in cardiac arrest [
8],[
11],[
12]. Although this article reviewed a smaller number of studies than another recent meta-analysis [
13], the results are similar. There may indeed be some utility of these drugs in certain populations, but routine use is of questionable utility and further large randomized trials will need to be conducted. Fortunately, one such clinical trial is under way [
14].
Epinephrine for out-of-hospital cardiac arrest
Epinephrine has been standard practice in cardiac arrest management for decades [
15],[
16]. Epinephrine increases coronary perfusion pressure [
17] and has shown benefit in animal models for ROSC after cardiac arrest [
15]. However, epinephrine may also have deleterious effects, including myocardial dysfunction, decreased microcirculation, and cerebral hypoperfusion [
16],[
18]. Furthermore, although epinephrine has been shown to improve rates of ROSC, there is limited evidence of long-term benefit [
19],[
20]. In a study by Goto and colleagues [
21], the utility of epinephrine for OHCA was again examined, with a particular focus on those patients initially presenting with a `no shock indicated' rhythm.
This study design was a retrospective analysis of prospectively collected data from an OHCA registry in a Japanese cohort. In this system, there is no field termination protocol and all patients are transported to hospital. A single dose of epinephrine may be administered by protocol, and additional doses may be provided only after discussion with a physician. The study endpoint was 1-month survival among those receiving epinephrine. Secondary endpoints were prehospital ROSC and 1-month favorable neurologic outcome, defined as a cerebral performance category (CPC) score of 1 or 2. Of the 209,577 patients evaluated, 92.6% had an initial cardiac rhythm in which a defibrillatory shock was not indicated. Survival at 1 month with intact neurologic status was 1.8%. In the subset of patients with an initial rhythm of VF or VT, those receiving epinephrine had significantly worse 1-month neurologic outcomes (7.0% versus 18.6% with CPC score of 1 or 2, P <0.0001). Those with `no shock advised' had improved prehospital ROSC with epinephrine (18.7% versus 3.0%, P <0.0001) but had similar rates of good 1-month neurologic outcomes (0.59% versus 0.62%, P =0.605). However, those patients receiving epinephrine after 10 minutes had worse 1-month neurologic outcomes (odds ratio (OR) 0.51, 95% CI 0.44 to 0.59). In those receiving rapid drug administration, after adjustment for initial rhythm, epinephrine was independently associated with worse 1-month neurologic outcomes (OR 0.71, 95% CI 0.54 to 0.92).
Although ostensibly the results indicate worse outcomes when epinephrine is administered, this retrospective review examines a univariate analysis, not a controlled clinical trial. A patient presenting with VF, for example, should be expected to fare poorly if they do not respond to initial cardiopulmonary resuscitation (CPR) and defibrillation attempts and thus move on to the epinephrine step of the protocol. Likewise, one could presume the same outcome, though less pronounced, in those non-VT/VF patients refractory to initial basic CPR and airway interventions. In addition, this review is a retrospective database analysis from the unique prehospital care system of Japan, and generalizability to other cohorts may not be possible.
This study by Goto and colleagues adds to the controversy surrounding the utility of epinephrine administration in OHCA and mirrors several previously published studies [
16],[
19],[
20]. Although there is no clear demonstration of improvement in long-term outcomes, epinephrine has still been associated with an increase in ROSC and 1-month survival. With the recent increase in utilization of novel therapies, including induced hypothermia and extracorporeal life support, further studies are necessary to determine a possible benefit of epinephrine in these cohorts as well. Finally, the addition of nitrates, vasopressin, or steroids to epinephrine may have some utility but these are not yet in widespread use for the purpose of evaluation [
22],[
23]. Until further research is conducted and alternative therapies established, the current consensus is that epinephrine should not be abandoned. However, its utility in cardiac arrest must continue to be investigated, and there is growing skepticism as to its benefits. A much-anticipated, double-blind, placebo-controlled trial planned to begin in 2014 in the UK [
24] will hopefully provide some definitive conclusions.