antiarrhythmics in cardiac arrest: a systematic review and...

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Heart, Lung and Circulation (2017) xx, 1–11

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http://dx.doi.org/10.1016/j.hlc.2017.07.004

REVIEW

HLC 2450 1–11

Antiarrhythmics in Car
diac Arrest: ASystematic Review and Meta-Analysis
[TD$FIRSTNAME]Amelia [TD$FIRSTNAME.E] [TD$SURNAME]Chowdhury [TD$SURNAME.E], MBBS a,b*, [TD$FIRSTNAME]Brian [TD$FIRSTNAME.E] [TD$SURNAME]Fernandes [TD$SURNAME.E], MBBS c,f,g,[TD$FIRSTNAME]Thomas M.[TD$FIRSTNAME.E] [TD$SURNAME]Melhuish [TD$SURNAME.E], MBBS, BMedSci b,d,[TD$FIRSTNAME]Leigh D. [TD$FIRSTNAME.E] [TD$SURNAME]White[TD$SURNAME.E], MBBS, BSc, Grad Dip (ClinUS) d,e

aSt Vincent’s Hospital Sydney, NSW, AustraliabFaculty of Medicine, University of New South Wales, NSW, AustraliacRoyal Prince Alfred Hospital, NSW, AustraliadWagga Wagga Rural Referral Hospital, NSW, AustraliaeSchool of Medicine, University of Wollongong, NSW, AustraliafSchool of Medicine, University of Sydney, NSW, AustraliagSchool of Medicine, Western Sydney University, NSW, Australia

Received 29 January 2017; received in revised form 10 June 2017; accepted 13 July 2
017; online published-ahead-of-print xxx
Introduction It is widely accepted that antiarrhythmics play a role in cardiopulmonary resuscitation (CPR) universally,

but the absolute benefit of antiarrhythmic use and the drug of choice in advanced life support remains

controversial.

Aim To perform a thorough, in-depth review and analysis of current literature to assess the efficacy of antiar-

rhythmics in advanced life support.

Material and

Methods

Two authors systematically searched through multiple bibliographic databases including CINAHL, SCO-

PUS, PubMed, Web of Science, Medline(Ovid) and the Cochrane Clinical Trials Registry. To be included

studies had to compare an antiarrhythmic to either a control group, placebo or another antiarrhythmic in

adult cardiac arrests. These studies were independently screened for outcomes in cardiac arrest assessing

the effect of antiarrhythmics on return of spontaneous circulation (ROSC), survival and neurological out-

comes. Data was extracted independently, compared for homogeneity and level of evidence was evaluated

using the Cochrane Collaboration’s tool for assessing the risk of bias. The Mantel-Haenszel (M-H) random

effects model was used and heterogeneity was assessed using the I2 statistic.

Results and

Discussion

The search of the literature yielded 30 studies, including 39,914 patients. Eight antiarrhythmic agents were

identified. Amiodarone and lidocaine, the twomost commonly used agents, showed no significant effect on

any outcome either against placebo or each other. Small low quality studies showed benefits in isolated

outcomes with esmolol and bretylium against placebo. The only significant benefit of one antiarrhythmic

over another was demonstrated with nifekalant over lidocaine for survival to admission (p = 0.003). On

sensitivity analysis of a small number of high quality level one RCTs, both amiodarone and lidocaine had a

significant increase in survival to admission, with no effect on survival to discharge.

Conclusions This systematic review andmeta-analysis suggests that, based on current literature and data, there has been

no conclusive evidence that any antiarrhythmic agents improve rates of ROSC, survival to admission,

survival to discharge or neurological outcomes. Given the side effects of some of these agents, we recom-

mend further research into their utility in current cardiopulmonary resuscitation guidelines.

Keywords Cardiac arrest � Antiarrhythmics � Cardiopulmonary resuscitation � Ventricular fibrillation

© 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).

Published by Elsevier B.V. All rights reserved.

*Corresponding author at: St Vincent’s Hospital, 390 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. Tel.: +61425259137.,

Email: [email protected]

Please cite this article in press as: Chowdhury A, et al. Antiarrhythmics in Cardiac Arrest: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.07.004

mailto:[email protected]



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2 A. Chowdhury et al.

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IntroductionOut-of-hospital cardiac arrests (OHCAs) have a reported

incidence of 395,000 events in the US with only 5.5% of

patients surviving to hospital discharge, whilst in-hospital

cardiac arrests (IHCAs) have an estimated incidence of

200,000 in the US with 24.4% surviving to discharge [1,2].

High mortality rates and associated complications such as

irreversible neurological disability explain the significant

public health burden of cardiac arrest [2,3]. Thus, the need

for a standardised approach to resuscitation to improve

cardiac and cerebral perfusion during cardiopulmonary

resuscitation (CPR) has been recognised formany years, with

the aim of improving cardiac arrest outcomes [3].

Pharmacological therapy is universally employed as a

resuscitative measure to enhance myocardial perfusion pres-

sure and peripheral blood flow and additionally improve

defibrillation success. Antiarrhythmics (AAs) play a role in

shock-refractory ventricular fibrillation (VF) and pulseless

ventricular tachycardia (VT) in the restoration and mainte-

nance of a spontaneous perfusing rhythm during shock ter-

mination [4,5]. The American Heart Association (AHA)

guidelines recommend the use of AA agents, however there

is limited evidence on the associated short-term and long-

term outcomes [4–8].

In light of this, we conducted a systematic review and

meta-analysis to appraise randomised controlled trials and

cohort studies around the efficacy of AAs in adult cardiac

arrest, and their effects on short- and long-term patient

outcomes.

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Methods

Search StrategyA systematic search was conducted on multiple biblio-

graphic databases including CINAHL, SCOPUS, PubMed,

Web of Science, The Cochrane Trials Registry and Medline

(Ovid) from the inception of the databases until December

2016. Two independent reviewers used the following combi-

nations of search terms (1) ((‘‘Cardiac Arrest”) OR (‘‘Cardiac

Arrhythmias”) OR (‘‘Cardiopulmonary Resuscitation”) OR

(‘‘Ventricular Tachycardia”) OR (‘‘Ventricular Fibrillation”)

OR (‘‘Advanced Life Support”)) AND ((‘‘Antiarrhythmics”)

OR (‘‘Antiarrhythmia agents”) OR (‘‘Amiodarone”) OR

(‘‘Lignocaine”) OR (‘‘Lidocaine”) OR (‘‘Magnesium”) OR

(‘‘Potassium-channel blockers”)). For completeness, a man-

ual reference check of systematic reviews and recent articles

was performed to identify any additional studies.

Inclusion CriteriaFor a study to be included, the patient population was any

adult (over 18 years of age) with a cardiac arrest, either an

OHCA or IHCA. All AA agents were considered as an

intervention including amiodarone, lidocaine, magnesium,

in addition to potassium-channel blockers such as nifekalant

Please cite this article in press as: Chowdhury A, et al. AntiarrhyAnalysis. Heart, Lung and Circulation (2017), http://dx.doi.org

and bretylium in comparison to a placebo. Outcomes that

were measured included ROSC; short-term survival: sur-

vival to hospital admission for OHCA patients, survival to

hospital discharge; and neurologic outcomes at discharge.

Study designs were limited to randomised controlled trials

(RCTs) or prospective/retrospective cohort designs. Two

reviewers (AC and BF) assessed and agreed upon each study

for inclusion in this systematic review and any discrepancies

were discussed with LW and TM.

Data ExtractionTwo reviewers (AC and BF) independently extracted data

from each article that met the inclusion criteria. The data

extracted from each study included the first author’s last

name and publication year, the study design, number of

participants, patient population, intervention and clinical

outcome results. The data collected by each reviewer was

then compared for homogeneity and any discrepancies were

addressed by discussion with LW and TM.

Level of Evidence and Risk of BiasEach article was evaluated using the Centre for Evidence

Based Medicine (CEBM): Levels of Evidence Introduction

Document [9]. These studies were then assessed for risk of

bias and methodological quality using the Cochrane Col-

laboration’s tool for assessing the risk of bias [10]. The

results from each study were then grouped into individual

AAs.

Statistical AnalysesThe combined data was analysed using RevMan 5.3 software

(The Nordic Cochrane Centre, Copenhagen, Denmark). The

odds ratio (OR) with 95% confidence interval (CI) was used

for dichotomous outcomes, and the weighted mean differ-

ence (WMD) with 95% CI for continuous outcomes. The

Mantel-Haenszel (M-H) random effects model was used.

Heterogeneity was assessed using the I2 [1_TD$DIFF] statistic, with an

I2>50% indicating significant heterogeneity. P value of<0.05

provided evidence of significant OR and WMD. We then

conducted sensitivity analyses to assess how variance in

rhythms and location of cardiac arrest may affect our results.

As part of the sensitivity analysis, each outcome was also

analysed using only level one RCTs.

Results

Literature Search ResultsThe initial systematic literature search yielded 1110 citations,

of which 340 abstracts were reviewed. Based on a review of

their abstract, 54 articles appeared to meet the search criteria.

Of these 54 articles, 31 met the inclusion criteria (Figure 1).

These 31 articles included eight interventionmedications and

42,808 patients (Appendix 1). Each study was then screened

for risk of bias and methodological quality (Figure 2). Of

these, 11 were high quality level one RCTs, two were low

thmics in Cardiac Arrest: A Systematic Review and Meta-/10.1016/j.hlc.2017.07.004


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Figure 1 Study identification algorithm. This diagramoutlines the filtering process from the literature searchthrough to study inclusion.

Figure 2 Screening of bias and methodological qualitybased on the Cochrane Collaboration’s tool for assessingthe risk of bias.

Antiarrhythmics in Cardiac Arrest 3

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quality level one RCTs, seven were low quality level two

prospective cohort studies and 11 were low quality level

three retrospective cohort studies.

AmiodaroneFour studies reported on the use of amiodarone versus

placebo (n = 27,616) [11–14]. Of these four studies, two

reported on return of spontaneous circulation (ROSC)

[12,13]. Administration of amiodarone was not associated

with an improved ROSC (OR = 1.04; 95%CI 0.87–1.24;

I2 = 0%; p = 0.68). All four studies reported on survival to

admission and survival to discharge. Amiodarone had no

significant effect on survival to admission (OR = 1.33; 95%CI

0.91–1.97; I2 = 92%; p = 0.14; Figure 3) or survival to dis-

charge (OR = 1.25; 95%CI = 0.60–2.58; I2 = 97%; p = 0.55;

Figure 4). Two studies reported on neurological outcomes

in the surviving patients, showing no significant difference

with the use of amiodarone (OR = 0.94; 95%CI 0.63–1.40;

I2 = 0%; p = 0.75) [11,12].

LidocaineFive studies reported on lidocaine versus placebo

(n = 22,285) [12,14–17]. Two reported on ROSC, showing

no significant difference with the use of lidocaine

(OR = 1.73; 95%CI = 0.85–3.51; I2 = 84%; p = 0.13) [12,15].

All five studies showed that lidocaine had no impact



Figure3 Survival to admission with A) Amiodarone; B) Lidocaine; C) Magnesium; D) Esmolol; E) Bretylium F) Vasopressin.


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Figure 4 Survival to discharge with A) Amiodarone; B) Lidocaine; C) Magnesium; D) Esmolol; E) Bretylium F) Vasopressin.


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on survival to admission (OR = 1.32; 95%CI = 0.86–2.03;

I2 = 90%; p = 0.21; Figure 3) and survival to discharge

(OR = 1.54; 95%CI = 0.83–2.86; I2 = 90%; p = 0.17; Figure

4). Of the 455 patients to survive to discharge in the

study by Kudenchuck et al., lidocaine had no impact on

neurological outcomes (OR = 0.76; 95%CI = 0.49–1.17;

p = 0.21).

MagnesiumFive studies investigated the use of magnesium (n = 485)

[18–22]. All five studies reported on ROSC, showing no

advantage with the use of magnesium (OR = 1.04; 95%

CI = 0.68–1.59; I2 = 0%; p = 0.79). Magnesium showed no

effect on survival to admission (OR = 1.16; 95%CI = 0.60–

2.23; I2 = 0%, p = 0.67; Figure 3), survival to discharge

(OR = 1.10; 95%CI = 0.57–2.10; I2 = 0%; p = 0.78; Figure 4)

or survival to one year (OR = 3.59; 95%CI = 0.14–91.35;

p = 0.44). The use of magnesium had no beneficial effect

on neurological outcomes (OR = 1.52; 95%CI = 0.37–6.33;

I2 = 0%; p = 0.56).

EsmololOne study by Driver et al. reported on the use of esmolol

against placebo (n = 25) [23]. This study showed a near sig-

nificant increase in ROSC (OR = 17.59; 95%CI = 0.87–356.81;

p = 0.06). There was no significant difference in survival to

admission (OR = 4.33; 95%CI = 0.61–30.57; p = 0.14; Figure 3)

or survival to discharge (OR = 5.33; 95%CI = 0.71–40.22;

p = 0.10; Figure 4). Of the six patients to survive to discharge,

esmolol had no effect on neurological outcomes (OR = 4.20;

95%CI = 0.12–151.97; p = 0.43).

BretyliumTwo studies investigated the effect of bretylium compared to

placebo (n = 108) [24,25]. Bretylium significantly improved

survival to admission (OR = 4.04; 95%CI = 1.22–13.43;

I2 = 0%; p = 0.02; Figure 3). Therewas no significant improve-

ment in survival to discharge (OR = 4.44; 95%CI = 0.51–39.03;

p = 0.18; Figure 4).

VasopressinOne study by Gueugniaud et al. assessed the effect of

vasopressin versus placebo (n = 2894) [26]. This study

showed no effect on ROSC (OR = 0.96; 95%CI = 0.82–

1.13; p = 0.62), survival to admission (OR = 0.96; 95%

CI = 0.81–1.15; p = 0.68; Figure 3), survival to discharge

(OR = 0.73; 95%CI = 0.43–1.24; p = 0.24; Figure 4), survival

to one year (OR = 0.60; 95%CI = 0.33–1.08; p = 0.09) or neu-

rological outcome in survivors (n = 55; OR = 0.56; 95%

CI = 0.19–1.65; p = 0.30).

Amiodarone versus NifekalantFour studies compared amiodarone with nifekalant

(n = 1532) [27–30] and showed no difference in ROSC

(OR = 1.14; 95%CI = 0.67–1.94; I2 = 0%; p = 0.62), survival

to admission (OR = 0.79; 95%CI = 0.62–1.01; I2 = 0%;

p = 0.06), survival to discharge (OR = 1.08; 95%CI = 0.58–

2.04; I2 = 22%, p = 0.81) or neurological outcome in survivors

(OR = 0.15; 95%CI = 0.01–1.54, I2 = 0%, p = 0.11).


Amiodarone versus LidocaineSeven studies looked at amiodarone versus lidocaine

(n = 11,616) [12,14,29,31–34]. There was no difference in

ROSC (OR = 0.95; 95%CI = 0.61–1.08; I2 = 68%; p = 0.81), sur-

vival to admission (OR = 1.18; 95%CI = 0.93–1.50; I2 = 66%;

p = 0.18), survival to discharge (OR = 0.99; 95%CI = 0.83–

1.18, I2 = 31%, p = 0.90) or neurological outcome in surviving

patients (OR = 1.17; 95%CI = 0.77–1.79, p = 0.45).

Lidocaine versus BretyliumThree studies investigated lidocaine versus bretylium

(n = 486) [35–37]. There was no difference in ROSC

(OR = 1.78; 95%CI = 0.95–3.34; I2 = 43%; p = 0.07), survival

to admission (OR = 0.98; 95%CI = 0.37–2.60; p = 0.97) or sur-

vival to discharge (OR = 1.14; 95%CI = 0.46–2.82; I2 = 28%;

p = 0.78).

Lidocaine versus NifekalantFour studies compared lidocaine with nifekalant (n = 317)

[29,38–40]. These studies showed no significant increase in

ROSC (OR = 2.92; 95%CI = 0.63–13.47; I2 = 76%; p = 0.12).

However, there was a significant increase in survival to

admission with nifekalant (OR = 2.91; 95%CI = 1.44–5.87;

I2 = 34%; p = 0.003). There was no significant difference in

survival to discharge (OR = 1.48; 95%CI = 0.75–2.91; I2 = 0%;

p = 0.26) or neurological outcomes in surviving patients

(OR = 2.40; 95%CI = 0.36–15.94; p = 0.36).

Lidocaine versus SotalolOne study by Kovoor et al. investigated lidocaine versus

sotalol (n = 129) [41]. There was no difference in ROSC

(OR = 0.60; 95%CI = 0.28–1.27, p = 0.18), survival to admis-

sion (OR = 0.44; 95%CI = 0.17-1.15; p = 0.09), survival to dis-

charge (OR = 0.44; 95%CI = 0.08–2.38; p = 0.34) or

neurological outcomes in survivors (n = 7; OR = 0.14; 95%

CI = 0.00-4.47; p = 0.27).

Sensitivity AnalysisAll results of the sensitivity analysis are included in Appen-

dix 2. The sensitivity analysis of level one RCTs revealed that

amiodarone had a significant improvement in survival to

admission (OR = 1.32; 95%CI = 1.13–1.55; I2 = 0%;

p = 0.0006) and a non-significant improvement in survival

to discharge (OR = 1.18; 95%CI = 0.98–1.44; I2 = 0%; p = 0.09).

However, in OHCAs there were no changes to ROSC

(OR = 1.06; 95%CI = 0.89–1.27; I2 = n/a, p = 0.52) or neuro-

logical outcomes (OR = 0.94; 95%CI = 0.63–1.40; I2 = 0%;

p = 0.75). Lidocaine in level one RCTs was shown to have

a significant improvement in ROSC (OR = 1.26; 95%

CI = 1.05–1.51; I2 = n/a; p = 0.01) and survival to admission

(OR = 1.37; 95%CI = 1.15–1.63; I2 = n/a; p = 0.0005), yet no

improvement in survival to discharge (OR = 1.16; 95%

CI = 0.94–1.42; I2 = n/a; p = 0.17) or neurological outcomes

(OR = 0.76; 95%CI = 0.49–1.17; I2 = n/a; p = 0.21). In a level

one RCT, bretylium had a non-significant increase in survival

to admission (OR = 3.17; 95%CI = 0.75–13.51; I2 = n/a;

p = 0.12), although had statistically significant results prior

to sensitivity analysis.



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For IHCAs, amiodarone had a no significant improvement

in ROSC compared to lidocaine (OR = 0.41; 95%CI = 0.15–

1.08; I2 = n/a; p = 0.07) and lidocaine was superior to brety-

lium (OR = 2.78; 95%CI = 1.04–7.45; I2 = n/a; p = 0.04). Lido-

caine improved survival to admission compared to

nifekalant (OR = 2.91; 95%CI = 1.44–5.87; I2 = n/a; p = 0.003).

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DiscussionThis is the most comprehensive review to date, combining

42,808 cardiac arrests from 31 studies to assess the efficacy of

AAs on outcomes post cardiac arrest. The included studies

took place in a wide variety of settings, with the majority

assessing OHCA, and examined a range of different agents.

To be included, the AA had to be compared to a control

group, another AA, ‘standard therapy’ or placebo.

Two level one [11,12] and two level three [13,14] papers

assessed amiodarone compared to standard practice or a

placebo, combining 27,616 patients. On meta-analysis they

showed administration of amiodarone had no significant

effect on the incidence of ROSC, survival to admission, sur-

vival to discharge or neurological outcome. On secondary

analysis of level one papers only, the two remaining studies

did find a significant increase in survival to admission and

the only level one paper to assess the outcome found a higher

rate of ROSC. No other sensitivity analyses were possible, as

none of these studies assessed IHCAs and only included VF/

VT rhythms. One of these papers [2_TD$DIFF][13] has previously been

criticised for its divergent baseline characteristics [7]. Whilst

the amiodarone group did have higher rates of ‘witnessed’

arrests and were more likely to receive more bystander CPR,

these characteristics would be likely to skew the results in

favour of the intervention group. Despite having been inde-

pendently verified as positive predictors of CA outcomes

[42,43], such bias is not apparent in their results.

Two level one [12,16] and three level two studies [14,15,17]

compared lidocaine to a control group, incorporating 22,285

cardiac arrests. There was no significant effect of lidocaine

administration on the incidence of ROSC, survival to hospi-

tal, survival to discharge or neurological outcomes. However

on secondary analysis of level one papers alone, lidocaine

significantly improved ROSC rates and survival to admis-

sion. There remained no improvement in survival related to

discharge or neurological outcome. As with amiodarone, no

other sensitivity analyses were possible.

Two level one [12,31] and five level three papers

[14,29,32–34] compared amiodarone to lidocaine, with

11,616 arrests analysed. Overall there was no significant

difference between the two medications in ROSC, survival

to admission, survival to discharge or neurological outcome.

There were no significant differences after sensitivity analy-

sis accounting for level of evidence or arrest location. All the

studies only included VT/VF rhythms.

Five level one papers assess the utility of magnesium

during cardiac arrest, including 485 cardiac arrests [18–22].

Overall there was no effect on ROSC, survival to admission,


survival to discharge or neurological outcomes. There were

no significant differences after sensitivity analysis account-

ing for level of evidence, arrest location or initial rhythm.

Limited numbers of studies assessed the effects of other

more novel AAs in cardiac arrest. These were mostly low

quality or small high quality studies, as such the results must

be interpreted with caution. The use of esmolol in one small

study (n = 25) showed an isolated increase in ROSC, with no

effect on survival to admission, survival to discharge or

neurological outcomes [23]. In two small studies (n = 108)

bretylium significantly improved survival to admission, with

no significant increase in survival to discharge [24,25]. How-

ever, three small studies found bretylium to be no better than

lidocaine [35–37]. One large high quality RCT showed no

effect with the addition of vasopressin to normal resuscita-

tion protocols [26].

On meta-analysis we have found either no or conflicting

evidence of superiority between different AAs, with the

exception of nifekalant. Early data suggests that potassium

channel blockers may be more effective than lidocaine, but

they still have no proven benefit in placebo-controlled trials.

In four low quality retrospective studies, nifekalant demon-

strated a significantly improved survival to admission

[29,38–40]. There was no benefit in ROSC, survival to dis-

charge or neurological outcomes.

International guidelines continue to recommend use of

amiodarone, which was introduced on the basis that it

increases the chance of ROSC and survival to admission

for patients in refractory VF or VT rhythms [4,44]. This

understanding is largely based on the findings of the

ARREST [11] and ALIVE [31] trials. The ARREST trial was

the first to show an early benefit for amiodarone; survival to

hospital increased. The ALIVE study provided support to the

concept that amiodarone increased survival to hospital, per-

forming superiorly to lidocaine. Neither paper found an

increase in survival to discharge.

Most recently, the ROC-ALPS [12] paper did suggest amio-

darone was superior to placebo in increasing ROSC and

survival to hospital but found no difference between amio-

darone and lidocaine, contradicting ALIVE’s findings. The

only consistent finding amongst all the highest quality level

one papers has been that there is no survival benefit to

discharge or improvement in neurological outcomes. The

reasons that AAs may facilitate the process of resuscitation

itself, but not improve survival would in itself be an inter-

esting area for further research.

It is these ongoing developments regarding the utility of

AAs that have additionally led to significant evolution of the

ACLS Algorithm over years [45]. The timing of pharmaco-

logical administration of antiarrhythmics during the stages

of the resuscitation protocol has greatly shifted from being a

later consideration to being administered on the third shock

in VT or VF [46]. Thus, the variability of administration time

in each study should be recognised as a limitation when

evaluating the overall efficacy of antiarrhythmics.

Many theories have developed surrounding the absence of

perseverance of amiodarone’s short-term benefits. One



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HLC 2450 1–11

suggestion has been that delays in administrationmay render

it ineffective because in the later ‘phases’ of cardiac arrest the

original cellular mechanisms of arrhythmia may no longer be

reversible pharmacologically as metabolic processes predom-

inate [7,47]. Indeed somepapers report significant associations

between early administration and survival to admission in

groups receiving AAs, moreso than those receiving placebo;

they conclude that early AAs use may confer greater benefit

[12,16]. The recent ROC-ALPS study reported a significant

increase in survival to discharge with AAs if the arrest was

witnessed by emergency medical services [12]. Some studies

don’t observe such effects however [13].

This theory could be tested by comparing an OHCAs with

IHCAs, where the in-hospital time to AAs is often consider-

ably less given earlier response times, pre-existing vascular

access and a greater number of initial responders [48–50].

However, to date we found no placebo or ‘standard practice’

controlled amiodarone study assessing in-hospital arrests;

this may be a useful point for future research. The closest

is the study by Pollack et al. who assessed the transition of

practice as amiodarone was introduced to in-hospital arrests

[33]. They hypothesised that as a ‘superior’ AA was intro-

duced, a survival benefit would be seen in those patients

receiving themedication. No such benefit eventuated despite

specifically analysing their data to assess for an ‘ARREST-

like’ short-term survival benefit. Given that there was no

survival benefit conferred by amiodarone vs lidocaine in

IHCAs or OHCAs, such an in-hospital placebo controlled

trial could be considered viable and ethically appropriate.

It has also been pointed out that AAs raise the defibrillation

[11,51–53]. Early and successful defibrillation when

attempted in conjunction with CPR within three to five

minutes of collapse has been shown to increase survival rates

[4]. This poses the question of whether administering AAs

may, in some cases, impede the success rate of a key inter-

vention which has proven benefits. Others have suggested

that lidocaine administration in certain patients may be

associated with asystole and prevent successful defibrillation

[16]. Despite this, as we have already highlighted, some

studies have shown early benefits to defibrillation with amio-

darone use.

We recognise that previous reviews postulate that there

may be marginal benefits in survival to discharge that are too

small to be detected by individual studies or through meta-

analysis to date. They claim that even a small benefit could be

clinically significant given the magnitude of annual cardiac

arrests [6]. Whilst logically sound, we believe it’s equally

important to consider the potential adverse effects fromAAs.

Several larger studies were powered to detect adverse drug

reactions associated with trial pharmacotherapy. ARREST

highlighted that the incidence of hypotension and bradycar-

dia were significantly increased in those receiving Amiodar-

one [11]. This may also result in the need for pacing as

demonstrated in Resuscitation Outcomes Consortium-Amio-

darone, Lidocaine or Placebo Study (ROC-ALPS) [12]. This

group has theorised the lack of survival benefits in AA use

might be explained by adverse impacts of these medications


counterbalancing any beneficial impacts [11]. Some have

suggested the solvent solution used in some amiodarone

formulations may be responsible for some of these side-

effects, and could be avoided by the use of alternative agents

[54–56]. However the ROC-ALPS study utilised one of these

new formulations but did not to report on hypotension and

bradycardia in their paper or supplementary material; how-

ever a greater number of amiodarone patients required tem-

porary pacing. Side effects profiles may be improving, but

these are by no means risk-free medications.

By principle, any intervention with known serious adverse

effects warrants reconsideration if there are no proven ben-

efits of administration. Whilst we acknowledge there may be

short-term survival benefit of amiodarone use, there is also

substantial potential for harm caused by the routine use of

AAs. Increasing survival to hospital admission, without sur-

vival to discharge can be viewed as serving to increase

invasive and costly medical intervention for these patients;

this could be traumatic both for the patient and their family

who often get little contact with them in an acute, intensive

therapy setting [57,58]. Alternatively, if patients are admitted

and regain consciousness, the patient may gain some valu-

able time with their loved ones. Although they may not have

a higher chance of survival to discharge, perhaps there is

merit to lengthening their last hours of life.

Our review builds on thework completed by others, which

have included subsets of the information presented here

[6–8]. This paper does, however, have a number of advan-

tages. We present the range of current evidence for the

majority of AAs, rather than one or two of the most common

agents. Our analysis includes a number of studies that seem

to have eluded prior search strategies. In addition, we have

adapted our analysis to correct for errors made by prior

groups. One prior meta-analysis contained errors in its sta-

tistical analysis, pertaining to use of fixed-effects models in

grouping diverse studies [7]. As such their results ought to be

interpretedwith great caution as theywere not analysed to be

applicable to the new populations. Another review grouped

the results of studies comparing amiodarone with both pla-

cebo and a range of alternative AAs [8]. The significant

heterogeneity present in these ‘control [3_TD$DIFF]’ groups make the

results that analysis invalid in reference to the question ‘does

amiodarone improve survival’.

LimitationsSince the mid-1990s global resuscitation councils have had

consensus statements over appropriate measure of the out-

comes of resuscitation and recommend outcomes be reported

as early (ROSC, survival to admission), intermediate (survival

to discharge) and long-term (survival to six months or more)

[59]. Many studies we include consistently did not report on

long-termoutcomes, and as suchwe are unable to provide any

evidence for the longer term harms or benefits of AAs.

Many of these studies also utilised other surrogate end-

points to measure the utility of AAs; common measures



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HLC 2450 1–11

included length of CPR, number of shocks delivered, number

of ‘trial’ AA boluses used and further episodes of arrest or

arrhythmia after admission to name but a few.Whilst groups

using these measures have justified their use, we did not to

include them in our analysis. These resuscitation factors have

much potential for variance as they were inconsistently

defined by different groups. In addition, the intrinsic poten-

tial pitfalls with utilising surrogate endpoints have been

extensively discussed for many years [60–62]. There may

be a reasonable theoretical basis for assuming each of these

endpoints might confer benefit to patients, but observed

changes in surrogate endpoints reported by various papers

here do not translate into clinically significant survival ben-

efits in large studies or meta-analysis. Furthermore, it is

difficult to qualify the impact of potential confounding aeti-

ology of the underlying arrhythmia, which could have a

variety of causes including ischaemic, non-ischaemic, con-

genital, idiopathic.

Resuscitation and the examination of the contributions

made by its different elements during cardiac arrest are

intrinsically challenging to study scientifically [59,63,64].

Furthermore, the heterogeneity and progression of the

underlying arrhythmia mechanism may additionally be a

confounding factor affecting survival rates. This warrants

further sensitivity analysis on antiarrhythmic administration

in VF compared to Monomorphic VT. If particular arrhyth-

mia mechanisms are proven to benefit from AAs, this war-

rants development of the ACLS algorithm into further

subcategories stemming from ‘shockable’ and ‘non-

shockable’. However, distinguishing the underlying rhythm

proves extremely difficult, given VT often degenerates into

VF and studies can only be limited to monitored settings.

Whilst there are groups who have spent the time and effort

to design rigorous trials examining the effects of AAs, there

remains insufficient RCT data to make level 1a recommen-

dations on systematic review. Particularly, the analyses of

newer AAs should be interpreted with caution – there is, to

date, a paucity of evidence of these agents. Studies of new

agents in CPR should endeavour to utilise placebo controls

given the lack of proven benefits of other agents available for

comparison.
557558559560561562563564565566567568569570571572573574575576577
ConclusionWe found no conclusive evidence that any antiarrhythmic

improves rates of ROSC, survival to admission, survival to

discharge or neurological outcomes. In short, no one antiar-

rhythmic delivered during resuscitation has been shown to

improve patients’ outcomes.

Our review particularly emphasises the lack of benefit of

AAs in improving medium term outcomes in the manner

they are currently utilised. This is a significant and pertinent

finding. Whilst the use of AAs during in hospital arrests is

likely to remain a case-by-case decision as guided by senior

clinicians, the default use of amiodarone during CPR algo-

rithms does not seem to be supported by evidence. It remains


plausible that there may be greater benefit with early AA

administration, but there is not currently adequate evidence

assessing this question.

As colleagues we must consider the potential benefits and

harms of AA use and the ethical implications of increasing

survival to hospital without improvement in longer-term

survival. The evidence surrounding newer and novel AAs

is too limited to draw any conclusions about their clinical use.

Conflict of InterestThe authors have no conflicts of interest to declare.

Uncited [4_TD$DIFF]Reference[65].

Appendix A. Supplementary dataSupplementary data associatedwith this article can be found,

in the online version, at http://dx.doi.org/10.1016/j.hlc.

2017.07.004 [5_TD$DIFF].

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