Antiarrhythmics in Cardiac Arrest: A Systematic Review and...
Transcript of Antiarrhythmics in Cardiac Arrest: A Systematic Review and...
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Heart, Lung and Circulation (2017) xx, 1–11
1443-9506/04/$36.00
http://dx.doi.org/10.1016/j.hlc.2017.07.004
REVIEW
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Antiarrhythmics in Car
diac Arrest: ASystematic Review and Meta-Analysis[TD$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 xxxIntroduction 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
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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
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
Figure3 Survival to admission with A) Amiodarone; B) Lidocaine; C) Magnesium; D) Esmolol; E) Bretylium F) Vasopressin.
4 A. Chowdhury et al.
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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
Figure 4 Survival to discharge with A) Amiodarone; B) Lidocaine; C) Magnesium; D) Esmolol; E) Bretylium F) Vasopressin.
Antiarrhythmics in Cardiac Arrest 5
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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
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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).
Please cite this article in press as: Chowdhury A, et al. AntiarrhyAnalysis. Heart, Lung and Circulation (2017), http://dx.doi.org
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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Antiarrhythmics in Cardiac Arrest 7
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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,
Please cite this article in press as: Chowdhury A, et al. AntiarrhyAnalysis. Heart, Lung and Circulation (2017), http://dx.doi.org
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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8 A. Chowdhury et al.
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
Please cite this article in press as: Chowdhury A, et al. AntiarrhyAnalysis. Heart, Lung and Circulation (2017), http://dx.doi.org
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
thmics in Cardiac Arrest: A Systematic Review and Meta-/10.1016/j.hlc.2017.07.004
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Antiarrhythmics in Cardiac Arrest 9
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.
557558559560561562563564565566567568569570571572573574575576577ConclusionWe 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
Please cite this article in press as: Chowdhury A, et al. AntiarrhyAnalysis. Heart, Lung and Circulation (2017), http://dx.doi.org
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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