Drug therapy in cardiac arrest: a review of the literature · REVIEW Disease management Drug therapy in cardiac arrest: a review of the literature Andreas Lundin1*, Therese Dja¨rv2,

REVIEW

Disease management

Drug therapy in cardiac arrest: a reviewof the literatureAndreas Lundin1*, Therese Djarv2, Johan Engdahl3, Jacob Hollenberg4,Per Nordberg4, Annika Ravn-Fischer5, Mattias Ringh4, Susanne Rysz6,Leif Svensson4, Johan Herlitz7,8, and Peter Lundgren5

1Department of Anaesthesia and Intensive Care, Sahlgrenska Universitetssjukhuset, Per Dubbsgatan 15, Gothenburg 41345, Sweden; 2Department of Medicine, Karolinska Institutet,Solna, Sweden; 3Department of Medicine, Halland Hospital, Halmstad, Sweden; 4Department of Cardiology, Center for Resuscitation Science, Karolinska Institutet, Solna, Sweden;5Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; 6Department of Anesthesiology, Surgical Services and Intensive Care Medicine, KarolinskaInstitutet, Solna, Sweden; 7The Prehospital Research Centre for Western Sweden, PreHospen, University of Boras, Boras, Sweden; and 8Deparment of Clinical and Molecular Medicine/Cardiology, Sahlgrenska University Hospital, Goteborg, Sweden

Received 15 September 2015; revised 27 October 2015; accepted 28 October 2015; online publish-ahead-of-print 26 November 2015

The aim of this study was to review the literature on human studies of drug therapy in cardiac arrest during the last 25 years. In May 2015, asystematic literature search was performed in PubMed, Embase, the Cochrane Library, and CRD databases. Prospective interventional andobservational studies evaluating a specified drug therapy in human cardiac arrest reporting a clinical endpoint [i.e. return of spontaneous cir-culation (ROSC) or survival] and published in English 1990 or later were included, whereas animal studies, case series and reports, studies ofdrug administration, drug pharmacology, non-specified drug therapies, preventive drug therapy, drug administration after ROSC, studies withprimarily physiological endpoints, and studies of traumatic cardiac arrest were excluded. The literature search identified a total of 8936 articles.Eighty-eight articles met our inclusion criteria and were included in the review. We identified no human study in which drug therapy, comparedwith placebo, improved long-term survival. Regarding adrenaline and amiodarone, the drugs currently recommended in cardiac arrest, twoprospective randomized placebo-controlled trials, were identified for adrenaline, and one for amiodarone, but they were all underpoweredto detect differences in survival to hospital discharge. Of all reviewed studies, only one recent prospective study demonstrated improvedneurological outcome with one therapy over another using a combination of vasopressin, steroids, and adrenaline as the intervention comparedwith standard adrenaline administration. The evidence base for drug therapy in cardiac arrest is scarce. However, many human studies on drugtherapy in cardiac arrest have not been powered to identify differences in important clinical outcomes such as survival to hospital discharge andfavourable neurological outcome. Efforts are needed to initiate large multicentre prospective randomized clinical trials to evaluate both cur-rently recommended and future drug therapies.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Drug therapy † Cardiac arrest

IntroductionIn clinical terms, cardiac arrest is defined as a sudden and sustainedloss of consciousness with pulselessness and apnoea or agonalbreathing.1 It is a heterogeneous condition in terms of underlyingpathology, initial rhythm, time in no flow, and concurrent health is-sues. The pathophysiology of cardiac arrest is mainly attributed toeither cardiac, metabolic, or mechanical causes.1 Rhythm at initialpresentation is the most important prognostic factor,2 dictates theimmediate treatment,3 and is affected by underlying pathology, timefrom collapse to rhythm recording, and bystander cardiopulmonary

resuscitation (CPR).4 In the majority of patients with out-of-hospital cardiac arrest (OHCA), primary cardiac pathology is theunderlying cause of the arrest and one-third present with a shock-able rhythm,5 increasing to two-thirds when time from collapse toresuscitation is within a few minutes.6 In patients with in-hospitalcardiac arrest (IHCA), the proportion of primary cardiac path-ology is lower and patients more frequently present with pulselesselectrical activity (PEA) as the initial rhythm,7 indicating differencesin patient characteristics and underlying pathology. In both groups,asystole is common when the time from collapse to resuscitation isprolonged.5,7

* Corresponding author. Tel: +46 73 5064648, Fax: +46 73 5064648, Email: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected]

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The pathophysiology of cardiac arrest of primary cardiac causehas been described by Weisfeldt and Becker8 as a time-sensitivethree-phase model. The first 4–5 min constitute the electrical phaseand with immediate defibrillation, survival is .50%.9 – 11 However,recurrent or shock-resistant ventricular fibrillation occurs in 10–25% of all OHCA12 and anti-arrhythmic drugs are often adminis-tered when defibrillation fails. Anti-arrhythmics possibly reducethe likelihood of arrhythmia being maintained or recurring afterthe return of spontaneous circulation (ROSC).13– 15 The effects ofanti-arrhythmic drugs on the defibrillation threshold are, however,inconsistent and most anti-arrhythmics also have pro-arrhythmiceffects.16,17

The circulatory phase follows after 4–5 min, when tissue hypoxiaand the accumulation of metabolites reduce the likelihood of suc-cessful defibrillation. Restoration of coronary perfusion pressure(CPP) is imperative. Animal studies have demonstrated an associ-ation with a CPP of .20–40 mmHg during resuscitation andROSC, and also an increased likelihood of conversion to PEA orasystole with defibrillation if adequate CPP is not established.18– 22

One human study demonstrated a positive correlation with initialand maximum CPP and ROSC during resuscitation, and initial CPPwas a stronger predictor of subsequent ROSC than no-flow time.23

Haemodynamic improvement during the circulatory phase providesthe rationale for vasopressor treatment during resuscitation.

In the metabolic phase (i.e. .10–15 min), survival is dismal due toglobal ischaemia and reperfusion injury, and the beneficial effects ofcirculatory supportive measures are diminished.24,25 In a survivalmodel of OHCA patients, Valenzuela et al.26 found that delayingCPR for .10 min rendered defibrillation ineffectual in terms of sur-vival. Moreover, the benefit of immediate CPR declined if defibrilla-tion was delayed for .10 min. If a large proportion of patients withprolonged circulatory arrest are included in trials of cardiac arrest,proving benefit will be difficult, as survival is dismal regardless oftreatment.

The early initiation of CPR and defibrillation has been shown toincrease survival in cardiac arrest and is well established in treatmentalgorithms.27,28 From a theoretical point of view, several drug ther-apies are appealing, but supporting clinical data in human studies areless robust.29– 31 To summarize the evidence base for drug therapyin cardiac arrest, we decided to review the literature on humanstudies of drug therapy in cardiac arrest during the last 25 years.

MethodsIn May 2015, a literature search was performed in PubMed, Embase, theCochrane Library, and CRD databases. The search terms used, in differ-ent combinations, were ‘Cardiac arrest’, ‘Heart arrest’, ‘Circulatory ar-rest’, ‘Cardiopulmonary arrest’, ‘Drug’, ‘Drugs’, ‘Drug therapy’,‘Medication’, ‘Medications’, ‘Pharmacology’, ‘Pharmaceutical’, ‘Pharma-ceutical preparations’, and ‘Cardiovascular agents’. We included articleswritten in English from 1990 and onwards. Eligible articles were pro-spective interventional studies and observational studies evaluating aspecified drug therapy during the resuscitation phase of human cardiacarrest, reporting a clinical endpoint (i.e. ROSC or survival). We ex-cluded animal studies, case series and case reports, studies of drug ad-ministration, studies of drug pharmacology, studies of non-specifieddrug therapies, studies with primarily physiological endpoints, studies

of preventive drug therapy, studies of traumatic cardiac arrest, andstudies of drug administration after ROSC.

ResultsThe literature search identified a total of 8936 articles (after the re-moval of duplicates). After screening of titles and abstracts by two ofthe authors (A.L. and P.L.), 769 were considered to be potentiallyrelevant for research on drug therapy in cardiac arrest. Of these,681 were excluded, whereas 88 articles met our inclusion criteriaand were included in the review (Figure 1). Reasons for exclusionwere case series (n ¼ 45), review article (n ¼ 326), study of drug ad-ministration or pharmacology (n ¼ 11), study with physiologicaloutcome (n ¼ 18), animal studies (n ¼ 263), and preventive orpost-resuscitative intervention (n ¼ 18). Of 88 included studies,40 were classified as observational studies and 48 as interventionalstudies. Sixty-three studies enrolled patients with OHCA, 16 studiesenrolled patients with IHCA, and 9 studies enrolled both. The in-cluded studies comprised 17 different drugs such as adrenaline(n ¼ 33), vasopressin (n ¼ 14), methoxamine (n ¼ 1), iso-proterenol (n ¼ 1), amiodarone (n ¼ 7, two studies presented in ni-fekalant section), lidocaine (n ¼ 6, three studies presented inlidocaine and nifekalant section), sotalol (n ¼ 1, presented in lido-caine section), procainamide (n ¼ 2), atropine (n ¼ 1), aminophyl-line (n ¼ 3), nifekalant (n ¼ 4), beta-blockers (n ¼ 1), magnesium(n ¼ 5), thrombolytics (n ¼ 6), corticosteroids (n ¼ 1), sodium bi-carbonate (n ¼ 3), erythropoietin (n ¼ 1), and crystalloid and col-loids (n ¼ 2). Of the interventional studies, the median and meanstudy size were 199 and 442 patients (range 30–3327 patients), re-spectively. Of the interventional studies, 38 reported time from col-lapse to study drug administration (or a proximate surrogate), withan average time interval of 16 min (range 1–43 min). Most interven-tional studies allowed only intravenous drug administration, al-though a few allowed intraosseous or endotracheal administrationif intravenous access could not be established. Details of studiesare summarized in Tables 1 and 2.

Vasopressor drugs

AdrenalineAdrenaline is an a- and b-adrenergic agonist and its cardiovasculareffects include venous and arterial vasoconstriction, increased ino-tropy, and chronotropy.32 Studies of adrenaline in animal models ofcardiac arrest have demonstrated increased diastolic blood pressureand CPP,20,33,34 but also pulmonary vasoconstriction,35 increasedmyocardial oxygen demand, and myocardial oxygen imbalance36

as well as cerebral vasoconstriction and diminished cerebral bloodflow.37 Clinical effects from adrenaline in animal studies include anincreased rate of ROSC and short-term survival,22,38 but also post-resuscitative myocardial dysfunction,39 cerebral ischaemia,40 andpoor neurological outcome as well as decreased short-term sur-vival.41 Less myocardial dysfunction has been demonstrated withpure a-agonists38 and with adrenaline plus b-adrenergic antago-nists.42,43 Both beneficial and harmful effects of adrenaline wereaugmented with higher doses.44–46 The electrophysiological effectsof adrenaline are complex, and animal studies have demonstrated

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increased myocardial instability47,48 as well as beneficial electro-physiological effects.49 In humans, adrenaline has been associatedwith more rhythm transitions to ventricular arrhythmias afterROSC.50

We found 33 studies51– 83 evaluating adrenaline administration inhuman cardiac arrest. Fifteen were interventional and 18 were ob-servational studies. Thirteen interventional studies compared high-dose adrenaline (i.e. .0.02 mg/kg) with a standard dose (i.e. 0.01–0.02 mg/kg).51 – 63 Although four of these reported higher rates ofROSC,53 – 56 only one small study of paediatric patients found in-creased survival to hospital discharge with a higher dose of adren-aline.53 In the largest study, Gueugniaud et al. randomized 3327adult patients with OHCA to 5 or 1 mg of adrenaline. The higherdose increased the rate of ROSC (40.4 vs. 36.4%, P ¼ 0.02), but sur-vival to hospital discharge was not statistically different.56 Further-more, two other large multicentre trials did not demonstrate anysignificant benefit from higher dosages.51,55

We found two studies that compared adrenaline with pla-cebo.64,65 Woodhouse et al. randomized 194 patients to high-dose

adrenaline (10 mg) or placebo. There were more rhythm transitionsin the adrenaline group but no difference in survival. The results aredifficult to interpret, as there were major imbalances in baselinecharacteristics between groups.64 Jacobs et al. randomized 500OHCA patients to standard treatment with adrenaline (1 mg) vs. sa-line placebo. The adrenaline group had a higher rate of ROSC (23.5vs. 8.4%, P , 0.001), but there was no significant difference in sur-vival to hospital discharge. The trial was underpowered, as the en-rolment of 5000 patients was planned to detect a 2% absolutedifference in survival to hospital discharge, from a baseline survivalrate of 5%.65

Of 18 observational studies,66 – 83 8 retrospectively comparedoutcome in patients with cardiac arrest depending on whether ornot adrenaline was administered.71,73,74,77,78,80,82 Three studiesfound no difference in survival,69,74,78 while three reported reducedsurvival associated with adrenaline administration71,73,82 and two re-ported increased survival.75,77 Three of the studies used data fromthe same national registry in Japan, with inconsistent findings.73,77,80

Hagihara et al.73 found that adrenaline was associated with increased

Figure 1 PRISMA 2009 flow diagram.

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ROSC, but reduced overall and neurologically intact survival at1 month. In contrast, Nakahara et al.,80 using the same registry, re-ported increased 1-month survival in patients receiving adrenalinebut no difference in neurologically intact survival. Both studiesused propensity scoring to adjust for confounders, but Nakaharaet al. used time-dependent statistics which, according to the authors,could explain the different findings. Recently, Dumas et al.,82 usingvarious statistical methodologies, reported a significantly poorerneurological outcome in resuscitated OHCA patients who receivedadrenaline. This association was observed, regardless of length of re-suscitation, and there was an inverse linear relationship between to-tal dose (i.e. dose effect), as well as the timing of first dose, andneurological outcome.

Five studies looked at the association between the timing ofadrenaline administration and survival.75,76,79,81,83 Three reportedan association between the earlier administration of adrenalineand ROSC or survival,75,76,81 whereas one small study was unableto find any association.79 One recent retrospective study of 20000 patients with IHCA found a correlation between increasing dos-age intervals of adrenaline and survival to hospital discharge.83 Com-pared with a dosage period of 4–5 min, the adjusted odds ratio forsurvival to hospital discharge was 2.17 (95% CI: 1.62–2.92) for dos-age intervals of 9–10 min.

Two studies evaluated the association between total adrenalinedose and outcome, and both reported that the cumulative doseof adrenaline is independently associated with poor outcome.70,72

Finally, three small studies reported on survival in adult and paediat-ric patients receiving high-dose or standard-dose adrenaline, withno significant difference in ROSC or survival.66– 68

VasopressinVasopressin is a neurohypophysical hormone84 and its cardiovascu-lar effects include increased inotropy, systemic and coronaryvasoconstriction,85 and the potentiation of catecholaminergic ef-fects.86,87 In animal models of cardiac arrest, vasopressin increaseddiastolic blood pressure and CPP.88– 90 Compared with adrenaline,vasopressin has been associated with less impairment of cerebralblood flow,91 less attenuation from acidosis,92 less tachyphylaxiaand pulmonary vasoconstriction,93 as well as longer effect dur-ation.94 Vasopressin mediates ACTH release and, in animal studiesof cardiac arrest, the levels of ACTH and cortisol were higher afterthe administration of vasopressin compared with adrenaline.86,95

High endogenous vasopressin levels, as well as increased cortisol le-vels, have been associated with improved survival after cardiacarrest.96,97

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Table 1 Included studies

Study drug Design OHCA/IHCAa

No. ofstudies

Interventional Observational

Randomizedprospective

Non-randomizedprospective

Prospective withhistorical controls

Adrenalineb 13 1 1 18 27/6 33

Vasopressinc 8 2 4 8/6 14

Methoxamine 1 0/1 1

Isoproterenol 1 1/0 1

Amiodaroned 2 3 2/3 5

Lidocainee,f 2 1 3/0 3

Aminophylline 3 3/0 3

Sodium bicarbonate 1 2 2/1 3

Magnesium 4 1 3/2 5

Beta-blocker 1 1/0 1

Thrombolytics 3 1 4 7/1 8

Erythropoietin 1 0 1/0 1

Corticosteroids 1 0 1/0 1

Crystalloids 1 1 2/0 2

Procainamide 2 1/1 2

Atropine 1 0/1 1

Nifekalant 4 3/1 4

48 40 64/23 88

aStudies enrolling both IHCA and OHCA patients are classified as OHCA if the primary setting was emergency department, and if the primary setting was in-hospital (includingemergency department), studies are classified as IHCA.bIn total, 41 studies evaluated adrenaline as an intervention, and 8 are classified in other sections (vasopressin).cIn two studies, intervention included corticosteroids.dIn total, seven studies evaluated amiodarone, and two studies are classified in other sections (nifekalant).eIn total, six studies evaluated lidocaine, and three studies are classified in other sections (nifekalant and amiodarone).fOne study included comparison with sotalol.




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Table 2 Prospective interventional studies of drug therapy in human cardiac arrest

Author (year) Study design Study size Setting Inclusion ofparticipants

Intervention1 Control1 Time to studydrugadministration(min)

Admin. route Primaryoutcome(s)

Results

Adrenaline Goetting et al.(1991)

Prospectiveinterventionvs. historicalcontrolgroup

40 patients Prehospital Paediatric patientsw/ witnessedcardiac arrest,refractory totwo standarddoses ofadrenaline

HDE (0.2 mg/kg) afterfailure of two dosesSDE

SDE (0.01 mg/kg) 4 iv ROSC ROSC: 70 vs. 0%(P , 0.001) andsurvival to discharge40 vs. 0% in theintervention groupand control group,respectively

Lindner et al.(1991)

Prospective,randomizedtrial

68 patients Emergencydepartment

Adult patients w/IHCA orOHCA andasystole orPEA

HDE (5 mg), followed bystandard ACLStreatment

SDE (1 mg) Not stated iv ROSC, survival tohospitaldischarge.

ROSC: 57 vs. 15%(P , 0.01) andsurvival to discharge11 vs. 4% (P ¼ NS) inthe intervention andcontrol groups,respectively

Brown et al.(1992)


1280 patients Prehospital Adult patients w/OHCA

HDE (0.2 mg/kg), onedose, followed bystandard ACLStreatment

SDE (0.02 mg/kg) 17 iv ROSC ROSC: 22 vs. 23% andsurvival to discharge5 vs. 7% in theintervention andcontrol groups,respectively(P ¼ NS)

Callaham et al.(1992)



HDE (15 mg), maximumthree doses, followedby standard ACLStreatment

SDE (1 mg) 16 iv ROSC ROSC: 13 vs. 8%(P ¼ 0.01) andsurvival to hospitaldischarge 1.7 vs. 1.2%(P ¼ NS) in theintervention andcontrol groups,respectively

Stiell et al. (1992) Prospective,randomizedtrial

650 patients In hospital Adult patients w/IHCA orOHCA inhospital ortreated in theED

HDE, 7 mg every 5 min upto five doses. followedby standard ACLStreatment

SDE (1 mg), repeateddoses

15 min (OHCApatients), 7 min(IHCApatients)

iv or endotracheal ROSC ROSC: 18 vs. 23% andsurvival to hospitaldischarge 3 vs. 5% inthe intervention andcontrol groups,respectively(P ¼ NS)

Lipman et al.(1993)


40 patients In hospital Adult ICUpatients w/IHCA andasystole

HDE (10 mg) every 5 min.Maximum threedoses, followed bystandard ACLStreatment

SDE (1 mg), every5 min

Not reported iv Not reported ROSC: 68 vs. 68% and24 h survival 21 vs.31% in theintervention andcontrol groups,respectively(P ¼ NS). Onepatient in the controlgroup survived todischarge

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Polglase et al(1994)



5 mg (30 patients) or10 mg (34 patients)adrenaline, repeateddoses

SDE (1 mg) 41patients, repeateddoses

Not reported iv Not reported ROSC: 14 vs. 20 vs. 20%in 1, 5, and 10 mggroups, respectively(P ¼ NS). No patientsurvived to hospitaldischarge

Choux et al.(1995)



HDE (5 mg), repeateddoses

SDE (1 mg), repeateddoses

22 iv ROSC, survival tohospitaladmission andsurvival tohospitaldischarge

ROSC: 35.5 vs. 32% andsurvival to hospitaladmission: 24 vs. 20%in the interventionand control groups,respectively(P ¼ NS)

Woodhouse et al.(1995)

Prospective,randomized,placebo-controlledtrial


Adults patients w/OHCA ofcardiacaetiology

Adrenaline 10 mg Saline placebo Not reported iv Immediate survival(i.e. stablecardiac rhythmw/a palpablepulse)

Immediate survival: 9.7vs. 7% and survival tohospital discharge: 2vs. 0% in theintervention andcontrol groups,respectively(P ¼ NS)

Carvolth et al.(1996)


1174 patients (594patients in thehistoricalcontrol group)

Prehospital Adult patients w/OHCA

HDE: 5, 10, and 15 mgdosing to a total doseof 30 mg

SDE (1 mg) repeateddoses to amaximum of 4 mg

Not reported iv or endotracheal Survival to hospitaladmission,survival todischarge

Survival to hospitaladmission: 15.3 and14.5% and survival tohospital discharge 4.8and 4.9% in theintervention andcontrol groups,respectively(P ¼ NS)

Sherman et al.(1997)



Adult patients w/OHCArefractory toSDE

HDE (0.1 mg/kg),repeated every 5 min

SDE (0.01 mg/kg),repeated every5 min

23 (time torandomization)

iv Improvement incardiac rhythmor ROSC

ROSC: 19 vs. 11% in theintervention andcontrol groups,respectively(P ¼ NS), no patientsurvived to hospitaldischarge

Gueugniaud et al.(1998)


3327 patients Prehospital Adult patients w/OHCA andshock-resistant VF,asystole orPEA

HDE; 5 mg, repeateddosing (maximum 15doses)

SDE; 1 mg, repeateddoses

20 iv or endotracheal ROSC, survival tohospitaladmission anddischarge

ROSC: 40.4 vs. 36.4%(P , 0.05) andsurvival to hospitaldischarge: 2.3 vs.2.8% (P ¼ NS) in theintervention andcontrol groups,respectively

Perondi et al.(2004)


68 patients In hospital Paediatric patientsw/ IHCArefractory toinitial SDE

HDE (0.1 mg/kg),repeated doses

SDE (0.01 mg/kg) 2 iv 24 h survival ROSC: 44 vs. 24%(P ¼ NS) and 24 hsurvival 3 vs. 21%(P ¼ 0.05) in theintervention andcontrol groups,respectively

Continued

Drug

therapyin

cardiacarrest

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Table 2 Continued




Results

Patterson et al.(2005)



Paediatric patients(,22 years) inED w/ OHCArefractory toprehospitalresuscitation

HDE, 0.1 mg/kg for theinitial dose and 0.2 mg/kg for subsequentdoses

SDE (0.01 mg/kg) Not reported iv or endotracheal Survival todischarge andneurologicaloutcome

Survival to hospitaldischarge: 7 vs. 2% inthe intervention andcontrol groups,respectively(P ¼ NS)

Jacobs et al.(2011)


534 patients Prehospital Adult patents w/OHCA

SDE (1 mg), repeateddosing every 3 min

Placebo (0.9% saline) 10 (time to EMSarrival)

iv Survival to hospitaldischarge

ROSC: 23.5 vs. 8.4%(P , 0.05) andsurvival to hospitaldischarge 4.0 and1.9% (P ¼ NS) in theintervention andcontrol groups,respectively

Vasopressin Lindner et al.(1997)


40 patients Prehospital Adult patients w/OHCA andshock-resistant VF

Vasopressin (40 IU), onedose, followed bystandard ACLStreatment

Standard ACLStreatment.

14 iv Survival to hospitaladmission

Survival to hospitaladmission: 70 vs. 35%(P ¼ 0.06) andsurvival to hospitaldischarge: 40 vs. 15%in the interventionand control groups,respectively(P ¼ NS)

Stiell et al. (2001) Prospective,randomizedtrial

200 patients In hospital Adult patients w/IHCA

Vasopressin (40 mg) onedose, followed bystandard ACLStreatment

Standard ACLStreatment

6 iv Survival to hospitaldischarge

Survival to hospitaldischarge: 12 vs. 14%in the interventionand control groups,respectively(P ¼ NS)

Wenzel et al.(2004)


1219 patients Prehospital Adult patents w/out-of-hospitalcardiac arrest

Two injections of 40 IU ofvasopressin, followedby additionaltreatment w/adrenaline if needed



ROSC: 25 vs. 28%(P ¼ 0.19) andsurvival to hospitaladmission: 36 vs. 31%(P ¼ 0.06) in theintervention andcontrol groups,respectively

Callaway et al.(2008)


325 patients Prehospital Adult patients w/OHCA,requiring atleast one doseof adrenaline


One dose salineplacebo in additionto standard ACLStreatment

14 iv ROSC, presence ofpulses athospital arrival

ROSC: 31 vs. 30% andsurvival to hospitaladmission: 19 vs. 23%in the interventionand control groups,respectively(P ¼ NS)

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Gueugniaud et al.(2008)



Adrenaline (1 mg) andvasopressin (40 IU),maximum two doses,followed by standardACLS treatment

1 mg adrenaline andsaline placebo,maximum twodoses, followed bystandard ACLStreatment


ROSC: 28.6 vs. 29.5%and survival tohospital admission20.7 vs. 21.3%; in theintervention groupand control groups,respectively(P ¼ NS)

Mentzelopouloset al. (2009)



Vasopressin (20 IU) plusadrenaline (1 mg) inrepeated doses(maximum 5 cycles)w/ methyl-prednisolone (40 mg)on the first cycle.Additional adrenalineif needed. Post-resuscitation shocktreated w/hydrocortisone2

Adrenaline (1 mg) plussaline placebo formaximum fivecycles. Salineplacebo forpatients w/ post-resuscitation shock

1 (time to ACLS) iv ROSC and survivalto hospitaldischarge

ROSC: 81 vs. 52%(P ¼ 0.003) andsurvival to hospitaldischarge 19 vs. 4%(P ¼ 0.02) in theintervention andcontrol groups,respectively

Mukoyama et al.(2009)



Adult patients inED w/ OHCArefractory toprehospitalresuscitation

Vasopressin (40 IU)repeated every5–10 min untilcumulative dose of160 IU

Adrenaline (1 mg),repeated every5–10 min untilcumulative dose of4 mg

33 iv Survival to hospitaldischarge

ROSC: 28.7 vs. 26.6%and survival tohospital discharge 5.6vs. 3.8% in theintervention andcontrol groups,respectively(P ¼ NS)

Carroll et al.(2012)


30 patients (20patients inhistoricalcontrol group)

In hospital Paediatric patientsin ICU w/cardiac arrestrefractory toat least onedoseadrenaline

Vasopressin (0.8 mg/kg),one dose, followed bystandard ACLStreatment

Historical controlgroup (paediatricpatients in the ICUthat received atleast two doses ofvasopressormedication, but notvasopressin)

1 iv or io Assess feasibility ofa futurerandomizedcontrolled trial

24-h survival: 80 vs. 30%,(P , 0.05) andsurvival to discharge:60 vs. 25% (P ¼ 0.07)in the interventionand control groups,respectively

Ong et al. (2012) Prospective,randomizedtrial


Adult patients w/OHCA(includingarrest in theED)



35 (time to EDarrival)

iv Survival to hospitaldischarge

ROSC: 30 vs. 31% andsurvival to discharge:2.3 vs. 2.9% in theintervention andcontrol groups,respectively(P ¼ NS)

Mentzelopouloset al. (2013)



See Mentzelopoulos(2009)

See Mentzelopoulos(2009)

2 (time to ACLS) iv Survival to hospitaldischarge w/favourableneurologicalrecovery

ROSC: 83.9 vs. 65.9%(P ¼ 0.005) andneurologicallyfavourable survival13.9 vs. 5.1%(P ¼ 0.02) in theintervention andcontrol groups,respectively

Continued

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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 2 Continued




Results

Methoxamine Patrick et al.(1995)


199 patients In hospital Adult patients w/witnessedIHCA andOHCApresenting tothe ED

Methoxamine (40 mg),repeated doses

Adrenaline (2 mg),repeated doses

3 iv ROSC ROSC: 42 vs. 53% in theintervention andcontrol groups,respectively(P ¼ NS)

Isoproterenol Jaffe et al. (2004) Prospective,randomizedtrial

79 patients Prehospital Adult patients w/OHCA andasystole

Isoprenaline (200 mg)every 3–5 min,maximum 600 mg

Standard ACLStreatment[including atropine1 mg (total 3 mg)every 3–5 min]

7 iv ROSC ROSC: 46 vs. 45% andsurvival to hospitaldischarge 3 vs. 7%, inthe intervention andcontrol groups,respectively(P ¼ NS)

Amiodarone Kudenchuk et al.(1999)



One dose of 300 mg ofintravenousamiodarone

Saline placebo 21 iv Survival to hospitaladmission

Survival to hospitaladmission 44 vs. 34%(P ¼ 0.03) andsurvival to hospitaldischarge: 13.4 and13.2% in theintervention andcontrol groups,respectively

Dorian et al.(2002)


347 patients Prehospital Adult patients w/shock-resistant VF/VT

Amiodarone (5 mg/kg)plus saline placebo. IfVF persisted a seconddose of amiodarone(2.5 mg/kg) plusplacebo was given

Lidocaine (1.5 mg/kg)plus amiodaroneplacebo. If VFpersisted, a seconddose of lidocaine(1.5 mg/kg) wasgiven


Survival to hospitaladmission: 22.8 vs.12.0% (P ¼ 0.009)and survival tohospital discharge: 5vs. 3% (P ¼ NS) inthe intervention andcontrol groups,respectively

Lidocaine Weaver et al.(1990)



100-mg bolus of lidocaine.A second doselidocaine (100 mg)was given before thenext shock if VFpersisted

Adrenaline (0.5 mg).Additionaladrenaline (0.5 mg)was given if VFpersisted

9 (time todefibrillation)

iv Not reported ROSC: 48 vs. 54% andsurvival to discharge:19 vs. 20% in theintervention andcontrol groups,respectively(P ¼ NS)

Aminophylline Mader et al.(1999)


82 patients Prehospital Adult patients w/OHCA andasystole

Aminophylline (250 mg),one dose

Saline placebo 12 iv ROSC ROSC: 27 vs. 20% in theintervention andcontrol groups,respectively(P ¼ NS)

Mader et al.(2003)


112 patients Prehospital Adult patients w/OHCA andasystole aftertreatment w/adrenaline andatropine

One dose ofaminophylline(250 mg)

Saline placebo 12 iv ROSC ROSC: 22.7 vs. 15.6% inthe intervention andcontrol groups,respectively(P ¼ NS). No patientsurvived to hospitaldischarge

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Abu-Laban et al.(2006)


971 patients Prehospital Adult patients w/OHCA andasystole orPEA,refractory toinitialtreatment w/adrenaline andatropine

Aminophylline (250 mg),up to two doses

Saline placebo 27 iv ROSC ROSC: 24.5 vs. 23.7%and survival tohospital admission:6.6 and 7.6% in theintervention andcontrol groups,respectively(P ¼ NS)

Sodiumbicarbonate

Dybvik et al.(1995)


502 patients Prehospital Adult patients w/OHCA andasystole orshock-resistant VF

250 mL of Tribonat(sodium bicarbonate-trometamol-phosphate), bufferingcapacity 500 mmol/L

250 mL of salineplacebo

6 (time to EMSarrival)

iv Survival to hospitaladmission andto hospitaldischarge

Survival to hospitaladmission: 36 vs. 36%and survival todischarge: 10 vs. 14%in the interventionand control groups,respectively(P ¼ NS)

Magnesium Miller et al.(1995)



Emergencydepartment

Adult patients w/cardiac arrestand shock-resistant VF

One dose intravenousmagnesium-sulphate(2.5–5 g)


13 iv ROSC . 30 min ROSC: 35 vs. 21%(P ¼ 0.21) andsurvival to discharge:5.2 vs. 4.5% in theintervention andcontrol groups,respectively

Fatovich et al.(1997)

Prospectiverandomized,placebo-controlledtrial


Adult patients w/in the ED w/OHCArefractory toprehospitalresuscitation

Magnesium (5 g), onedose

Saline placebo 33 iv ECG rhythm 2 minafter drugadministration

ROSC: 23 vs. 22% andsurvival to discharge3 and 0% in theintervention andplacebo groups,respectively(P ¼ NS)

Thel et al. (1997) Prospective,randomizedplacebo-controlledtrial


Magnesium (2 g bolus),followed by 8 g over24 h

Saline placebo 11 iv ROSC ROSC: 54 vs. 60%(P ¼ 0.44) andsurvival to hospitaldischarge 21 vs. 21%(P ¼ NS) in theintervention andcontrol groups,respectively

Allegra et al.(2001)


116 patients Prehospital Adult patients w/OHCA and VF

Magnesium (2 g) one dose Saline placebo andadrenalineaccording toguidelines

28 iv ROSC in the fieldand a perfusingpulse on arrivalat the ED

ROSC 25.5 vs. 18.5%and survival todischarge: 3.6 and3.7% in theintervention andcontrol groups,respectively.(P ¼ NS)

Hassan et al.(2002)


105 patients Prehospital(includingemergencydepartment)

Adult patients w/OHCA andshock-resistant orrecurrent VF

Magnesium-sulphate (2–4 g)

Saline placebo 8 (time to EMSarrival)

iv ROSC ROSC: 17 vs. 13% andsurvival to hospitaldischarge 4 vs. 2% inthe intervention andcontrol groups,respectively(P ¼ NS)

Continued

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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 2 Continued




Results

Thrombolytics Bottiger et al.(2001)



Prehospital Adult patients w/OHCA ofcardiacaetiologywithout ROSCafter 15 min

5000 U of heparin bolusand tPA (50 mg),intervention wasrepeated if no ROSCafter 30 min

ACLS treatment 8 (time to EMSarrival)

iv Safety of theprotocol (i.e.,bleedingcomplications),ROSC andsurvival tohospitaladmission

ROSC: 68 vs. 44%(P ¼ 0.026) andsurvival to discharge15 vs. 8% (P ¼ NS) inthe intervention andcontrol groups,respectively

Abu-Laban et al.(2002)

Prospectiverandomized,placebo-controlledtrial

233 patients Prehospital Adult patients w/OHCA andPEA refractoryto initialtherapy

Tenecteplase (100 mg),one dose. Afterenrolment standardresuscitation wascontinued for at least15 min

Saline placebo 35 iv. Survival to hospitaldischarge

ROSC: 21.4 vs. 23.3%and survival todischarge 0.8 and 0%in the interventionand control groups,respectively(P ¼ NS)

Fatovich et al.(2004)



Adult patients inED w/ OHCArefractory toprehospitalresuscitation

Tenecteplase (50 mg) asfirst drug, one dose

Saline placebo,followed by ACLStreatment

43 iv ROSC ROSC: 42 vs. 6%(P , 0.05) andsurvival to discharge5 vs. 6% (P ¼ NS) inthe intervention andcontrol groups,respectively

Bottiger et al.(2008)

Prospectiverandomizedplacebo-controlledtrial

1050 patients Prehospital Adult patients w/witnessedOHCA andinitiation ofACLS within10 min

Tenecteplase (50 mg),one dose

Saline placebo. 18 iv 30-day survival ROSC: 55.0 vs. 54.6%and survival todischarge: 15.1 vs.17.5% in theintervention andcontrol groups,respectively(P ¼ NS)

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Erythropoietin Grmec et al.(2009)

Prospective,non-randomizedtrial w/prospectiveandhistoricalcontrolgroup

54 prospectivelyincludedpatients (24erythropoietinand 30 saline),48 patients inthe historicalcontrol group

Prehospital Adult patients w/OHCA

Erythropoietin (90 000 IUof beta-epoetin), onedose0

Saline placebo(prospectivecontrols), standardACLS treatment(historicalcontrols)

6 (time to CPR) iv Survival to ICUadmission

ROSC: 92 vs. 53%(P ¼ 0.03) in theintervention andconcurrent controlgroups. ICUadmission: 92 vs. 50%and 65% (adjustedP ¼ NS) in theintervention group,concurrent controlsand matchedcontrols, respectively

Corticosteroids Tsai et al. (2007) Prospective,non-randomized,trial


Adult patient inthe ED w/OHCArefractory toprehospitalresuscitation

100 mg Hydrocortisone,one dose

Saline placebo Not reported iv Not reported ROSC: 61 vs. 39%(P ¼ 0.038) andsurvival to hospitaldischarge 8 vs. 10%(P ¼ NS) in theintervention andcontrol groups,respectively

Crystalloids/colloids

Breil et al. (2012) Prospectiverandomizedtrial

203 patients Prehospital Adult patents w/OHCA

2 mL/kg of 7.2% NaCl w/6% HES (200 000/0.5),infused over 10 min

2 mL/kg of 6% HES(200 000/0.5),infused over 10 min

14 iv Survival to hospitaladmission andhospitaldischarge

Survival to hospitaladmission: 50 vs. 47%and survival tohospital discharge 23vs. 21% in theintervention andcontrol groups,respectively(P ¼ NS)

ACLS: advanced cardiac life support; OHCA: out-of hospital cardiac arrest; IHCA: in-hospital cardiac arrest; ED: emergency department; PEA: pulseless electrical activity; EMS: emergency medical services; ROSC: return of spontaneouscirculation; iv: intravenous; HES: hydroxyethyl starch; NS: non-significant; ICU: intensive care unit; VF: ventricular fibrillation; HDE: high-dose adrenaline; SDE: standard-dose adrenaline 1: standard ACLS treatment (adrenaline 1 mg repeatedevery 3–5 min) was provided in the intervention and control groups if not stated otherwise; 2: 300 mg hydrocortisone daily for 7 days maximum, w/ gradual taper.

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Our search yielded 1498 –111 studies involving vasopressin duringhuman resuscitation, including 10 prospective interventionaltrials.90 – 99,98 – 107 Two small, randomized, controlled trials (total240 patients) compared adrenaline (1 mg) with vasopressin(40 IU), and neither ROSC nor survival to discharge differed be-tween groups.98,99 Callaway et al. randomized 325 patients to thecombination of adrenaline and vasopressin (40 IU) or adrenalinealone. The rates of ROSC and survival to discharge were similar.100

Mukoyama et al.101 randomized 336 OHCA patients after pro-longed cardiac arrest to repeated doses of vasopressin (40 IU) oradrenaline (1 mg). There were no differences in ROSC or survivalto hospital discharge.

Three large, multicentre studies evaluated vasopressin and adren-aline.102– 104 Wenzel et al.102 randomized 1219 OHCA patients totwo doses of either 40 IU of vasopressin or 1 mg of adrenaline andadditional treatment with adrenaline was added if needed. Overall,there was no difference in survival to discharge. In a prespecifiedsubgroup of patients with asystole, vasopressin resulted in a signifi-cantly higher rate of ROSC and survival to hospital discharge (29 vs.20%, P ¼ 0.02, and 4.7 vs. 1.5%, P ¼ 0.04, respectively). Gueugniaudet al. randomized 1442 OHCA patients to either adrenaline (1 mg)and vasopressin (40 IU) or adrenaline and placebo. There was nodifference in the primary outcome, i.e. survival to hospital admis-sion103 This study differed from the former, as rates of asystolewere higher (83 vs. 44%) and time to drug administration was longer(21 vs. 10 min). Ong et al.104 randomized 727 OHCA patients to asingle dose of adrenaline (1 mg) or vasopressin (40 IU) at presenta-tion in the emergency department (ED). There was no difference inthe primary outcome, survival to hospital discharge, although therewas a trend towards improved survival with vasopressin in a sub-group with shockable rhythm. More than 90% of patients in bothgroups received additional open-label adrenaline. In two placebo-controlled studies, a group from Greece randomized patients to re-peated doses of adrenaline (1 mg) or a combination of vasopressin(20 IU) and adrenaline every 3–5 min.105,106 Concurrent with thefirst injection, one dose methyl-prednisolone (40 mg), was adminis-tered to the intervention group. If haemodynamic instability devel-oped after resuscitation, hydrocortisone (300 mg) daily, withgradual tapering, was administered to the intervention group. Thefirst study enrolled 99 patients and there was a significant benefitin the treatment group for the primary endpoints of ROSC (81 vs.52%, P ¼ 0.003) and survival to hospital discharge (19 vs. 4%, P ¼0.02). The second study, powered to detect a difference in neuro-logically favourable survival, enrolled 268 adult IHCA patients.Haemodynamic parameters, during and after resuscitation, ROSC(83.9 vs. 65.9%, P ¼ 0.005), and neurologically favourable survivalto hospital discharge (13.9 vs. 5.1%, P ¼ 0.02) improved significantlyin the intervention group. The cause of arrest was deemed to behypotension or respiratory failure in .70% of patients, 16% hadan initial shockable rhythm, and the median time to resuscitationfrom collapse was 2 min.

Four observational studies evaluated vasopressin in cardiac ar-rest.108 – 111 Two studies reported an association between onedose of vasopressin (40 IU), alone or in combination with adren-aline, and increased ROSC, but none demonstrated a significant dif-ference in survival.108,109 Duncan et al.110 found an associationbetween vasopressin use and a reduced likelihood of ROSC in

paediatric ICU patients. The second study comprised only 10 pa-tients.104 Finally, one study reported an increased rate of ROSC(63 vs. 37%, P ¼ 0.01) in a subgroup of cardiac arrest patientswith acidosis, when vasopressin and adrenaline were administeredcompared with adrenaline alone.111

MethoxamineMethoxamine is an a1-adrenergic receptor agonist, similar in struc-ture to phenylephrine. It increases peripheral resistance and after-load through vasoconstriction, and can cause reduced cardiacoutput and reflexive bradycardia.112 In animal studies, methoxamineresulted in increased coronary blood flow and ROSC,33,113 and inone study, there was less myocardial oxygen imbalance and impair-ment of cerebral blood flow compared with adrenaline.114 Wefound only one human trial of methoxamine. Patrick et al.115 rando-mized 199 adult patients (of whom 145 were analysed) with IHCAto either 2 mg of adrenaline or 40 mg of methoxamine every 4 min.Return of spontaneous circulation, survival to discharge, and neuro-logical outcome did not differ significantly between groups.

IsoproterenolIsoproterenol is a pure b-adrenergic agonist with inotropic andchronotropic effects. It increases cardiac output and myocardialoxygen consumption, and can exacerbate ischaemia and arrhyth-mias in patients with ischaemic heart disease or impaired ventricularfunction.116 It is primarily used for the temporary treatment of bra-dyarrhythmias.3 Animal studies have reported a reduction in bloodpressure and CPP with isoproterenol during resuscitation.33,117 Wefound one study by Jaffe et al.,118 evaluating isoproterenol in humancardiac arrest. Seventy-nine patients with asystole as the initialrhythm were included in an open-label randomized trial. Patients re-ceived standard advanced cardiac life support (ACLS) treatment in-cluding atropine and were randomized to 200 mg of open-labelisoproterenol every 3–5 min or no isoproterenol. There was no dif-ference in the rate of ROSC or survival to hospital admission and thestudy was terminated prematurely due to futility.

Anti-arrhythmic drugs

AmiodaroneAmiodarone is classified as a class III anti-arrhythmic, although itspharmacodynamic effects are pleiotropic and include blockage ofsodium channels, calcium channels, and a- and b-antagonisticeffects.114 –116,119 – 121 Acute intravenous amiodarone has been re-ported to increase, cause no change in, and reduce the defibrillationthreshold in animal studies of ventricular fibrillation.14,16

We found seven studies of amiodarone in human cardiac ar-rest.14,16,117 – 128 Two compared amiodarone with nifekalant andwill be discussed in another section.127,128 Two randomized, con-trolled trials compared amiodarone with placebo and lidocaine,respectively.122,123 Both studies evaluated a dose of 300 mg of amio-darone in shock-resistant ventricular arrhythmia and the primaryoutcome was survival to hospital admission. Kudenchuk et al.122

enrolled 504 patients in cardiac arrest who were randomly assignedto 300 mg of intravenous amiodarone or placebo. Survival tohospital admission was higher with amiodarone (44 vs. 34%,

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P ¼ 0.03). In the ALIVE trial, Dorian et al.123 randomized 347patients with shock-resistant ventricular fibrillation or relapse ofventricular fibrillation to lidocaine (1.5 mg/kg) or amiodarone(5 mg/kg). If ventricular fibrillation persisted, another dose of amio-darone (2.5 mg/kg) could be administered. The survival to hospitaladmission was higher with amiodarone than with lidocaine (22.8 vs.12%, P , 0.05). Neither study was powered to detect differencesin survival to discharge.

We found three observational studies of amiodarone.124 – 126

One small retrospective study evaluated the use of amiodaroneand reported no statistically significant difference in survival, regard-less of whether or not amiodarone was given, and only 36 patientsreceived amiodarone.124 In a retrospective study, Rea et al.125 com-pared survival in 194 patients who received lidocaine, amiodarone,or a combination of the two. Twenty-four-hour survival did not dif-fer statistically between the three groups. Finally, one study re-viewed paediatric patients with IHCA and survival in relation towhether amiodarone, lidocaine, both or none were adminis-tered.126 Only lidocaine was associated with improved ROSC andshort-term survival.

LidocaineLidocaine is a class Ib anti-arrhythmic; it prolongs conduction vel-ocity and shortens action potential duration and the effective refrac-tory period.13 Prior to the ALIVE trial in 2002, lidocaine wasrecommended for shock-resistant arrhythmias.123

We found seven studies of lidocaine in cardiac arrest. Four com-pared lidocaine with amiodarone or nifekalant and are discussed inother sections.123,125,126,129 Weaver et al.130 randomized 192 pa-tients with shock-resistant ventricular fibrillation to either adren-aline or lidocaine. There was no significant difference in the rate ofROSC or survival between the groups. Patients who receivedlidocaine had a three times higher rate of asystole following defib-rillation. A small randomized trial compared sotalol (100 mg) andlidocaine (100 mg) in shock-resistant ventricular fibrillation andfound no significant difference in survival to hospital admissionor discharge.131 Finally, a retrospective study of 1212 patients,33% of whom received lidocaine, reported an association be-tween lidocaine and survival to hospital admission (38 vs. 18%,P , 0.01), although there was no difference in survival to hospitaldischarge.132

ProcainamideProcainamide is a class Ia anti-arrhythmic and, unlike lidocaine, it alsoblocks potassium channels, prolonging action potential duration andQT time.13 It has been used since the 1950s to treat various arrhyth-mias, including ventricular fibrillation. Whereas early animal studiesof cardiac arrest found it inferior to vasopressors,33 others have de-monstrated beneficial electrophysiological effects and, in a humanstudy, procainamide was superior to lidocaine in converting sus-tained monomorphic ventricular tachycardia in humans.15,133

We found two observational studies of procainamide in humancardiac arrest.134,135 In a small comparison study of 20 patients, pro-cainamide was associated with increased survival in undifferentiatedcardiac arrest.134 The second study retrospectively compared out-come in 665 patients with shock-resistant ventricular fibrillation, ofwhom 176 had received procainamide and, after adjustment for

baseline imbalances, there was no association between treatmentwith procainamide and survival.135

AtropineAtropine is an anticholinergic drug used to treat bradyarrhythmiasand its cardiac effects are mainly on the sinus and the atrioventricu-lar nodes.136 It was introduced in the treatment for bradyasystolicarrests after a case series in the 1970s.137 In 2010, atropine was re-moved from European Resuscitation Council Guidelines for Resus-citation due to the lack of evidence. Animal studies of atropine inPEA report contradictory results in terms of ROSC.138,139 Wefound one, retrospective study of atropine in human cardiac ar-rest,140 in which 7448 adult patients, 6419 with asystole and 1029with PEA, were included. Patients with asystole had a significantlyhigher rate of ROSC if atropine and adrenaline were given, whencompared with adrenaline alone (adjusted OR 1.6; P , 0.05). Thetwo groups had similar 30-day favourable neurological outcomes.In the PEA group, atropine and adrenaline were associated withsignificantly lower 30-day survival compared with only adrenaline(adjusted OR 0.4, P ¼ 0.016).

AminophyllineAminophylline has complex cardiovascular effects dependent onthe effect of theophylline, as both a phosphodiesterase inhibitorand an adenosine receptor antagonist.141 Cardiac effects include in-creased inotropy, chronotropy, and coronary vasoconstriction.During myocardial ischaemia, the accumulation of endogenous ad-enosine can result in bradycardia, vasodilation, and negative inotro-py, and could perpetuate asystole.142 Aminophylline couldtheoretically prevent bradyasystolic arrest and post-defibrillatoryasystole and PEA. This latter theory was tested in two animal modelswith prolonged ventricular fibrillation.143,144 Aminophylline admin-istration, in addition to adrenaline, neither increased the rate ofROSC nor reversed PEA after defibrillation.

We identified three studies of aminophylline in human cardiac ar-rest.145– 147 Two small studies randomized a total of 184 patients incardiac arrest to aminophylline or placebo in addition to standardACLS treatment.145,146 Both were negative for the primary out-come, rate of ROSC. Abu-Laban et al.147 studied the effect of ami-nophylline in patients with bradyasystolic arrest or PEA and 971patients, refractory to treatment with adrenaline and atropine,were randomized to aminophylline or placebo. There was no differ-ence in the rates of ROSC or survival to hospital discharge.

NifekalantNifekalant is a potassium channel antagonist used in Japan to treatventricular arrhythmias. In animal studies, nifekalant prolongs the re-fractory period and has been reported to reduce the number andthe energy level of defibrillations, the adrenaline dose, and thetime to ROSC compared with placebo.148 We found four studiesof nifekalant in human cardiac arrest.127 –129,149 All were from Japan,all had a retrospective design and all compared nifekalant with eitheramiodarone or lidocaine. The studies comparing nifekalant withlidocaine found that nifekalant was associated with a higher rate ofROSC and 24-h survival.129,149 The studies comparing amiodaronewith nifekalant in patients with shock-resistant ventricular fibrilla-tion found no difference in terms of ROSC or survival,127,128




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although one study reported a significantly shorter time to ROSCwith nifekalant, 6 vs. 20 min.128

Beta-blockersBeta-blockers reduce the risk of ventricular arrhythmias and suddencardiac death in many myocardial pathologies150 –152 In animal mod-els, beta-blockade during resuscitation is associated with improvedrates of ROSC, less tachycardia, an improved myocardial oxygenbalance, less post-resuscitation myocardial dysfunction, and a highercardiac index after resuscitation.43,153 –155 Beta-blockade could po-tentially be beneficial in refractory ventricular fibrillation, as en-dogenous and exogenous catecholamines facilitate myocardialinstability,48,156 increases defibrillatory threshold, and relapse toventricular arrhythmias after ROSC.157 Furthermore, animal studiessuggest that beta-blockers reduce cardiac dysfunction afterresuscitation.43

We identified one study of beta-blockers during resuscitation inhumans. Driver et al.157 retrospectively studied 25 patients with re-fractory ventricular fibrillation; six patients received a short-actingb-1 antagonist (esmolol) during CPR and 19 did not. All patientshad multiple defibrillations and received adrenaline, amiodarone,and sodium bicarbonate. A higher rate of ROSC (66 and 32%)and survival with good neurological outcome (50 and 11%) wereachieved in the group treated with esmolol, although the differenceswere not statistically significant.

MagnesiumMagnesium is the second most common intracellular cation. Itcauses systemic and coronary vasodilatation and diminishes the con-tractility of vasopressors.158,159 The electrophysiological effects in-clude reduced ventricular conduction and suppression of early andlate after-depolarizations.160 In an animal study, magnesium admin-istration increased the threshold to induce ventricular arrhyth-mias.161,162 It is used for treating polymorphic ventriculartachycardia associated with a prolonged QT interval.163

We identified five studies of magnesium in human cardiac ar-rest.158 – 162,164 – 168 All were small randomized trials, comprising atotal of 506 patients. Three studies included only patients with ven-tricular fibrillation.164 – 166 All patients received standard ACLStreatment and magnesium was administered when defibrillationhad failed, with doses ranging from 2 to 5 g. In no study was magne-sium administration associated with a higher rate of either ROSC orsurvival to hospital discharge, although small sample sizes make itdifficult to exclude a type II error. However, a meta-analysis of mag-nesium administration in cardiac arrest did not find any significantincrease in ROSC or survival to hospital discharge with magnesiumadministration.169 This study reportedly had an 80% power to de-tect a 10% difference in survival to hospital discharge.

Miscellaneous drugs

Thrombolytic drugsThrombolytics convert plasminogen to plasmin,170 which degradesfibrin and has been shown to reduce mortality in ST-segment-elevation myocardial infarction171 and haemodynamically unstablepulmonary embolism.172 The rationale for the use of thrombolytics

in cardiac arrest is to dissolve possible blood clots in the coronary orpulmonary circulation. Furthermore, Fischer et al.173 demonstratedimproved microcirculatory cerebral perfusion in a cat model of car-diac arrest with the administration of thrombolytics duringresuscitation.

Six studies evaluated thrombolytics in human cardiac arrest.174 –

179 Four were randomized trials enrolling a total of .2700 pa-tients.174 – 176 All studies used Tenecteplase as the intervention.Two small studies reported increased rates of ROSC and one re-ported increased survival to hospital admission with Tenecte-plase.174,175 Two large randomized trials, however, found nobenefit in terms of survival to discharge in the group that receivedtissue plasminogen activator (tPA). In the first, Abu-laban et al.176

randomized 1500 patients with PEA to receive 100 mg of t-PA orplacebo. Only one patient in the intervention group and none inthe control group survived to hospital discharge. Bottiger et al.177

randomized 1050 patients with undifferentiated cardiac arrest toTenecteplase or placebo. The study was stopped early as a resultof futility. The rates of ROSC and 30-day survival did not differ be-tween groups (55.0 vs. 54.6%, P ¼ 0.96, and 14.7 vs. 17.0%, P ¼ 0.39,respectively). In a post hoc analysis of a large clinical trial, Stadlbaueret al.178 found that hospital admission rates were significantly higherin patients who received thrombolysis than in those who did not(45.5 vs. 32.7%, P ¼ 0.01). However, patients in the thrombolysisgroup were significantly younger and were more likely to have ashockable rhythm and to receive bystander CPR. Finally, a small ob-servational trial compared 50 patients with treatment-refractorycardiac arrest who received Tenecteplase with 113 concurrent con-trols.179 The rates of ROSC and survival to hospital admission weresignificantly higher in the thrombolysis group (26 vs. 12.4%, P ¼0.04, and 12 vs. 0%, P , 0.05, respectively).

CorticosteroidsCortisol affects a wide range of physiological processes, includingthe regulation of catecholamine synthesis, and their effects on thecardiovascular system.96 The potential role in resuscitation includesthe potentiation of catecholaminergic vasoconstriction and protec-tion from ischaemia–reperfusion injury.180 The vasoconstrictive ef-fects of noradrenaline are augmented within minutes aftertreatment with topical cortisone, supporting a relatively immediateeffect.181,182 In a rat model of cardiac arrest, hydrocortisone admin-istration increased ROSC.183 In observational studies, higher serumcortisol, during resuscitation and after ROSC, is associated with agreater likelihood of survival and less likelihood of circulatory shockas cause of death, in both animal models and humans.97,184 –188 Cor-tisol levels after resuscitation are inversely correlated with no-flowtime and insufficient cortisol levels are possibly a consequence of is-chaemic injury to the hypothalamic–pituitary–adrenal axis.97,189

We found three human studies evaluating corticosteroids in car-diac arrest. In a non-randomized prospective trial, Tsai et al.190 in-cluded 97 OHCA patients upon arrival at the ED, whereas 36patients received 100 mg of hydrocortisone and 61 received saline.Eighty per cent had asystole as the initial rhythm. The rate of ROSCwas higher in the hydrocortisone group (61 vs. 39%, P ¼ 0.038), butthere was no difference in survival. Two studies, mentioned previ-ously, demonstrated an improved outcome for IHCA patients ran-domized to the combination of adrenaline, vasopressin, and

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methyl-prednisolone followed by daily hydrocortisone for patientswith post-cardiac arrest syndrome.105,106 The role of corticoster-oids is difficult to delineate because of the combinatorial interven-tion. There was, however, a significantly higher rate of neurologicallyfavourable survival in the subgroup with post-cardiac arrest syn-drome who received hydrocortisone after resuscitation comparedwith placebo.

ErythropoietinErythropoietin has anti-apoptotic properties and promotes prolifer-ation and maturation of erythrocytes in the bone marrow.191 Animalmodels have demonstrated neuroprotective effects from erythro-poietin after regional CNS ischaemia,192 although not after cardiacarrest.193 Interestingly, erythropoietin improves haemodynamicvariables, increases ROSC and short-term survival, and reducespost-resuscitative myocardial dysfunction in animal models of car-diac arrest.194 – 197 The immediate effects of erythropoietin onhaemodynamic parameters during resuscitation are not wellunderstood.198

We found one study evaluating erythropoietin during resuscita-tion in humans. Grmec et al.199 prospectively compared 24 patientswith OHCA who received erythropoietin (90 000 IU of beta-epoetin) with 30 OHCA patients who received 0.9% saline. Out-come was also compared retrospectively with that of 48 matchedcontrols. In the prospective comparison, the rate of ROSC andICU admission, but not 24-h survival, was higher in the erythropoi-etin group after adjustment for baseline characteristics. Comparedwith historical controls, erythropoietin administration was asso-ciated with significantly higher rates of ROSC and ICU admission, al-though 24-h survival and survival to hospital discharge were notstatistically different.

Sodium bicarbonateThe physiological effects of acidosis include increased sympatheticoutput, myocardial depression, and arteriolar vasodilation, with adecreased response to catecholamines.200,201 Sodium bicarbonatehas an alkalizing effect in plasma by increasing strong ion differenceand shifting the bicarbonate to carbondioxide ratio.202,203 The effecton intracellular pH, however, is uncertain, as generated carbon di-oxide diffuses readily across the cellular membrane.202,204 In animalstudies, sodium bicarbonate administration is associated with eitherunchanged or reduced aortic pressure and CPP.205 –208 It has a spe-cific role in the treatment of cardiac arrest secondary to intoxicationwith sodium channel blockers or hyperkalaemia.209

We found three studies evaluating the effect of sodium bicarbon-ate in human cardiac arrest.210 –212 Dybvik et al.210 performed a ran-domized trial of 502 patients with OHCA. The patients wererandomized to 250 mL of Tribonat (i.e. sodium bicarbonate, trome-tamol, and disodium phosphate) or saline. There was no differencein survival to hospital admission or discharge. One small retrospect-ive study found no association between ROSC and sodium bicar-bonate treatment in patients with prolonged (.15 min) cardiacarrest.211 Finally, in a retrospective study of paediatric cardiac arrest,the use of sodium bicarbonate was associated with a reduction inshort-term survival and survival to discharge, although sodium bi-carbonate administration was also associated with arrest in theICU and longer resuscitation efforts.212

Crystalloids and colloidsHypertonic solutions have been found to increase myocardial bloodflow, cerebral perfusion, and ROSC during resuscitation in an animalmodel of cardiac arrest.213,214 We identified one study examiningthe effects of hypertonic solution in human resuscitation.215 Breilet al. randomized 203 patients with OHCA to an infusion of 2 mL/kg of hypertonic saline (7.2% NaCl with 6% hydroxyethyl starch 200000/0.5) or only hydroxyethyl starch. There was no difference insurvival to hospital admission or survival. One observational studycompared ROSC and survival in relation to whether or not LactatedRinger’s was administered.216 More than 500 000 patients from alarge registry in Japan were included. The administration of LactatedRinger’s was associated with a reduced likelihood of survival withgood functional outcome after 1-month survival (adjusted oddsratio 0.764, P ¼ 0.04).

DiscussionThis review of the literature of human studies of the last 25 yearssuggests that there is still equipoise for the use of drug therapy incardiac arrest. Out of 88 studies, we identified no study in whichdrug therapy, compared with placebo, improved long-term survival.Regarding adrenaline and amiodarone, the drugs currently recom-mended in cardiac arrest,3 two prospective randomized placebo-controlled trials, were identified for adrenaline,64,65 and one foramiodarone,122 all were underpowered to detect differences in sur-vival to hospital discharge.

Our results are in line with other systematic reviews of drug ther-apy in cardiac arrest.217 – 225 They are also in line with the results oftwo studies evaluating drug therapy in cardiac arrest that were notincluded in our review, since they did not evaluate a specified drug.Olasveengen et al.29 randomized 1183 OHCA patients to intraven-ous access or no intravenous access and Stiell et al.31 enrolled 5638OHCA patients in a ‘before–after’ study evaluating the effects ofACLS implementation. Both were neutral for their primary out-come of survival to hospital discharge.

Conducting prospective trials of interventions in cardiac arrestpose several difficulties. Time constraints, prehospital environment,lack of informed consent, and preconceptions regarding treatmentpose methodological, ethical, and pedagogical obstacles to trialistsand may explain why trials in cardiac arrest, including other interven-tions than drug therapy,226 – 232 often result in neutral outcomes.Nonetheless, there is a need for placebo-controlled trials of drugtherapy in cardiac arrest. Evaluation of adrenaline is particularly war-ranted, both because of its ubiquitous use as well as animal36,37,39–41

and observational data,82,233,234 suggesting the lack of long-termbenefit and possibly direct harm with treatment. In 2010, The Inter-national Liaison Committee for Resuscitation stated that placebo-controlled trials to evaluate the use of vasopressors in adult andpaediatric cardiac arrest are needed.235

Our review identifies multiple issues with interventional studiesof human cardiac arrest. First, there were overall small sample sizesand limited statistical power to detect differences in patient import-ant outcomes (e.g. survival to hospital discharge), especially as sur-vival rates were generally low. Observational studies, while larger,often revealed inconsistent results which probably reflects




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differences in registries, variations in statistical methodology, andgeographical and temporal differences in the care of cardiac arrestpatients.73,77,80 The ongoing PARAMEDIC2 trial (ISRCTN:73485024) is planning to randomize 8000 patients to adrenalineor placebo and the ROC-ALPS trial will randomize 3000 patientswith shock-resistant OHCA to amiodarone, lidocaine, or pla-cebo.236 The studies are in OHCA patients and are planned to becompleted in 2018 and late 2015, respectively. They will hopefullyprovide valuable data on the use of drug therapy in cardiac arrest.

A second issue is time to drug administration in studies of OHCA.If circulatory arrest is prolonged .10–15 min, survival is dismal re-gardless of treatment26 and time to intervention is crucial. Thismight be one possible explanation for the discrepancy betweenfindings in animal and human studies. In a systematic review ofdrug therapy in animal studies, the average time to drug administra-tion was 9.5 min,237 but in our review of human studies it was 16 minand only one study of vasopressor therapy in OHCA patients had amedian time to drug administration ,10 min.

Third, most studies enrolled patient with undifferentiated cardiacarrest irrespective of time in no-flow, aetiology, initial rhythm, orpredicted survival. However, as outlined earlier, the pathophysi-ology of cardiac arrest is different depending on patient characteris-tics and comorbidities, aetiology of arrest, time in no-flow and initialrhythm, and likelihood of survival can range from a few per cent toover 50%.5,8 A single drug or intervention could have unequal effectsdepending on such differences, which would augment the difficultiesof demonstrating beneficial effects of a certain intervention andeffect sizes risk depletion. Meanwhile, intervention or drug recom-mendations cannot be too complicated to allow for implementationinto clinical practice. Even in the context of a clinical trial interven-tions are likely to fail if too complex.

Fourth, many of the trials were performed before the use of cur-rent post-resuscitative interventions (e.g. target temperature man-agement and percutaneous cardiac intervention) and thereforemight have had less chance of translating an improvement inROSC or survival to hospital admission into improved long-termsurvival. In fact, registries from Europe and the USA have reportedimproved survival in patients with cardiac arrest, regardless ofrhythm, during the last 10–15 years, even though no significantchange in resuscitation guidelines has taken place during thisperiod.5,7,238 – 240

Finally, in addition to, or instead of, currently recommendeddrugs in cardiac arrest our review suggests that ‘new’ drugs, suchas corticosteroids, beta-blockers, and erythropoietin, with supportfrom animal studies, but as of yet insufficient data from human trials,could be promising for future clinical trials. Of all reviewed studies,only one prospective study on IHCA demonstrated improvedneurological outcome with one therapy over another106 using acombination of vasopressin, steroids, and adrenalin as the interven-tion compared with standard adrenaline administration. However,survival in the control group was low, survival in the interventiongroup was not higher than in registries from Sweden and theUSA,5,7 and the results should probably not be generalized toOHCA patients as only IHCA patients were enrolled. The role ofeach individual drug is also unclear.

Regardless of the intervention, future trials should be well de-signed and controlled regarding timing of drug administration and

preferably conducted in large research networks to be able to enrollarge enough sample sizes in order to demonstrate differences inrelevant outcomes.

ConclusionThe evidence base for drug therapy in cardiac arrest is scarce. Manydrugs have been considered and several have shown promising re-sults in animal studies. Regarding adrenaline and amiodarone, thedrugs currently recommended in cardiac arrest, there is no evidenceof improved long-term survival with a favourable neurological out-come in humans. However, many human studies of drug therapy incardiac arrest have not been powered to identify differences in im-portant clinical outcomes such as survival to hospital discharge andfavourable neurological outcome. Efforts are needed to initiate largemulticentre, prospective, randomized, clinical trials to evaluate bothcurrently recommended and future drug therapies.

AcknowledgementsMany thanks to librarian Eva-Lotta Daxberg, Medical Library, Sahl-grenska University Hospital, Goteborg.

Conflict of interest: none declared.

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Drug therapy in cardiac arrest: a review of the literature · REVIEW Disease management Drug therapy in cardiac arrest: a review of the literature Andreas Lundin1*, Therese Dja¨rv2,