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The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

Out-of-Hospital Cardiac Arrest Are Drugs Ever the Answer?


JoseA. Joglar, M.D., and RichardL. Page, M.D.

Out-of-hospital cardiac arrest accounts for ap- the effect purely of the drug had not been evalu-
proximately 356,000 deaths per year in the United ated. In this context, the Resuscitation Outcomes
States,1 with many patients having ventricular Consortium (ROC) conducted a trial to address
fibrillation or pulseless ventricular tachycardia an important question: are drugs the answer?
as the presenting rhythm. In an effort to reduce The results of this trial are now reported by
mortality, the American Heart Association (AHA) Kudenchuk et al.8 in the Journal.
developed the Chain of Survival,2 including The ROC is a network of regional centers across
early cardiopulmonary resuscitation (CPR), rapid North America, supported by the National Insti-
defibrillation, and effective advanced life sup- tutes of Health and other organizations, that
port as central links in management. However, allows for well-powered randomized studies of
the rate of survival of out-of-hospital cardiac ar- out-of-hospital cardiac arrest and trauma. The
rest with good neurologic function remains poor, trial is the first randomized, multicenter, double-
averaging just 8.5%.1 Geographic variation ex- blind comparison of intravenous saline placebo
ists, and higher rates of survival are reported in versus amiodarone versus lidocaine, along with
specific locations such as aircraft3 and casinos.4 standard care, in patients with out-of-hospital car-
Defibrillation is effective at terminating most diac arrest and ventricular fibrillation or pulseless
sustained ventricular fibrillation or pulseless ventricular tachycardia that recurs or persists
ventricular tachycardia, but the arrhythmia per- after one or more electrical shocks. Although the
sists in some patients, and many have immedi- lidocaine preparation is standard, the formula-
ate recurrence. Antiarrhythmic medication, typi- tion of amiodarone with a solvent that does not
cally intravenous amiodarone or lidocaine, is cause hypotension (Nexterone, Baxter Healthcare)
often used with the goal of restoring and main- is novel and allows for isolated evaluation of the
taining a stable rhythm. Both agents have a class pharmacologic effect of the drug.
IIb recommendation in the 2015 American Heart In the trial, neither amiodarone nor lidocaine
Association Guidelines Update for Cardiopulmonary Re- resulted in a significantly higher rate of survival
suscitation and Emergency Cardiovascular Care,5 which to hospital discharge (the primary outcome) or
states that these drugs may be considered for favorable neurologic function at discharge (the
ventricular fibrillation or pulseless ventricular secondary outcome) than the rate with placebo
tachycardia that is unresponsive to CPR, defi- among the 3026 patients studied. On the other
brillation, and a vasopressor therapy.5 The un- hand, there were nonsignificant differences be-
certainty in these recommendations is based on tween each drug and placebo in the survival rate
previous trials6,7 that were not powered to make (a difference of 3.2 percentage points for amio-
comparisons with respect to overall survival and darone vs. placebo and 2.6 percentage points for
that showed no survival benefit. Furthermore, lidocaine vs. placebo). Further evidence of an
all previous trials of intravenous amiodarone were antiarrhythmic effect was the significant benefit
potentially undermined by a formulation that of both drugs over placebo in several measures:
included a solvent that causes hypotension; thus, fewer shocks were administered after the first

n engl j mednejm.org 1
The n e w e ng l a n d j o u r na l of m e dic i n e

dose of the trial drug; fewer patients received We commend the ROC investigators for their
rhythm-control medications during hospitaliza- efforts to provide scientific evidence to support
tion; and fewer patients required CPR during emergency care, and we agree with the Institute
hospitalization. of Medicine recommendations10 that research must
How might we explain the negative results of continue, with efforts to coordinate emergency
the trial? One possibility, as the authors suggest, care and quickly implement best practices on the
is that the trial was underpowered for the smaller- basis of contemporary data. Finally, we empha-
than-predicted drug effect. A further possibility is size the benefit of bystander-initiated CPR, for
that drug delivery was provided too late to over- which the current trial showed an absolute sur-
come the metabolic consequences of prolonged vival benefit of almost 10 percentage points,
arrest. Rates of conversion to sinus rhythm and eclipsing any effect of drug intervention.
survival rates are highest immediately after out- Disclosure forms provided by the authors are available with
of-hospital cardiac arrest, with up to 74% sur- the full text of this article at NEJM.org.
vival among patients with ventricular fibrillation
From the University of Texas Southwestern Medical Center,
or pulseless ventricular tachycardia if a shock is Dallas (J.A.J.); and the University of Wisconsin School of Medi-
administered within 3 minutes.4 This brief elec- cine and Public Health, Madison (R.L.P.).
trical phase is followed by a hemodynamic
This article was published on April 4, 2016, at NEJM.org.
phase; however, after 10 minutes, the metabolic
phase dominates and the chances of survival are 1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and
reduced.9 stroke statistics 2016 update: a report from the American
Heart Association. Circulation 2016;133(4):e38-360.
For the vast majority of the trial patients (for 2. Travers AH, Rea TD, Bobrow BJ, et al. CPR overview: 2010
whom emergency medical services [EMS] person- American Heart Association guidelines for cardiopulmonary re-
nel were not present at the time of arrest), the suscitation and emergency cardiovascular care. Circulation
2010;122:Suppl 3:S676-84.
mean time to drug treatment was 19.3 minutes 3. Page RL, Joglar JA, Kowal RC, et al. Use of automated exter-
well into the metabolic phase. What if the drug nal defibrillators by a U.S. airline. N Engl J Med 2000;343:1210-
therapy were administered sooner, as we might 6.
4. Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hard-
presume would occur for the substantial sub- man RG. Outcomes of rapid defibrillation by security officers
group (66%) whose arrest was witnessed by a after cardiac arrest in casinos. N Engl J Med 2000;343:1206-9.
bystander? For these patients, the rate of survival 5. Link MS, Berkow LC, Kudenchuk PJ, et al. Adult advanced
cardiovascular life support: 2015 American Heart Association
to hospital discharge was significantly higher with Guidelines update for cardiopulmonary resuscitation and emer-
amiodarone (27.7%) or lidocaine (27.8%) than with gency cardiovascular care. Circulation 2015;132:Suppl 2:S444-
placebo (22.7%) a clinically important differ- 64.
6. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for
ence of 5 percentage points. resuscitation after out-of-hospital cardiac arrest due to ventricu-
What can we conclude from the current trial, lar fibrillation. N Engl J Med 1999;341:871-8.
and how might we modify care for out-of-hospital 7. Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas R, Barr
A. Amiodarone as compared with lidocaine for shock-resistant
cardiac arrest with ventricular fibrillation or pulse- ventricular fibrillation. N Engl J Med 2002;346:884-90.
less ventricular tachycardia that either recurs or 8. Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, lido-
persists despite electrical shock? The data do not caine, or placebo in out-of-hospital cardiac arrest. N Engl J Med.
DOI:10.1056/NEJMoa1514204.
support the use of amiodarone or lidocaine for all 9. Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest:
patients, but, although they are not absolutely a 3-phase time-sensitive model. JAMA 2002;288:3035-8.
conclusive, the data suggest that EMS personnel 10. Institute of Medicine. Strategies to improve cardiac arrest
survival: a time to act. Washington, DC:National Academies
should consider these agents when the arrest is Press, 2015.
witnessed. There is no signal from the data as to DOI: 10.1056/NEJMe1602790
which drug might be preferable, however. Copyright 2016 Massachusetts Medical Society.

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