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EMERGENCY MEDICAL SERVICES/ORIGINAL RESEARCH

Manual Cardiopulmonary Resuscitation Versus CPR Includinga Mechanical Chest Compression Device in Out-of-Hospital

Cardiac Arrest: A Comprehensive Meta-analysis FromRandomized and Observational Studies

Judith L. Bonnes, MD*; Marc A. Brouwer, MD, PhD; Eliano P. Navarese, MD, PhD; Dominique V. M. Verhaert, BSc;Freek W. A. Verheugt, MD, PhD; Joep L. R. M. Smeets, MD, PhD; Menko-Jan de Boer, MD, PhD

*Corresponding Author. E-mail: [email protected] or [email protected].

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Study objective: Mechanical chest compression devices have been developed to facilitate continuous delivery of high-quality cardiopulmonary resuscitation (CPR). Despite promising hemodynamic data, evidence on clinical outcomesremains inconclusive. With the completion of 3 randomized controlled trials, we conduct a meta-analysis on the effect ofin-field mechanical versus manual CPR on clinical outcomes after out-of-hospital cardiac arrest.

Methods: With a systematic search (PubMed, Web of Science, EMBASE, and the Cochrane Libraries), we identified alleligible studies (randomized controlled trials and nonrandomized studies) that compared a CPR strategy includingan automated mechanical chest compression device with a strategy of manual CPR only. Outcome variables weresurvival to hospital admission, survival to discharge, and favorable neurologic outcome.

Results: Twenty studies (n¼21,363) were analyzed: 5 randomized controlled trials and 15 nonrandomized studies, pooledseparately. For survival to admission, the pooled estimate of the randomized controlled trials did not indicate a difference(odds ratio 0.94; 95% confidence interval 0.84 to 1.05; P¼.24) between mechanical and manual CPR. In contrast,meta-analysis of nonrandomized studies demonstrated a benefit in favor of mechanical CPR (odds ratio 1.42; 95%confidence interval 1.21 to 1.67; P<.001). No interaction was found between the endorsed CPR guidelines (2000 versus2005) and the CPR strategy (P¼.27). Survival to discharge and neurologic outcome did not differ between strategies.

Conclusion: Although there are lower-quality, observational data that suggest that mechanical CPR used at therescuer’s discretion could improve survival to hospital admission, the cumulative high-quality randomized evidencedoes not support a routine strategy of mechanical CPR to improve survival or neurologic outcome. These findings areirrespective of the endorsed CPR guidelines during the study periods. [Ann Emerg Med. 2016;67:349-360.]

Please see page 350 for the Editor’s Capsule Summary of this article.

A feedback survey is available with each research article published on the Web at www.annemergmed.com.A podcast for this article is available at www.annemergmed.com.

0196-0644/$-see front matterCopyright © 2015 by the American College of Emergency Physicians.http://dx.doi.org/10.1016/j.annemergmed.2015.09.023

INTRODUCTIONOut-of-hospital cardiac arrests occur frequently, with

an estimated incidence of 50 to 100 per 100,000 person-years.1,2 Survival to hospital discharge ranges between 5%and 20%.1 Both in the out-of-hospital and inhospitalsetting, several initiatives have been developed to improveoutcome. In addition to the implementation of early accessto automated external defibrillators and the initiative ofdispatcher-assisted cardiopulmonary resuscitation (CPR)with chest compressions only, the introduction ofmechanical chest compression devices respresents a newstrategy that may result in improved survival.3,4

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Given the often challenging conditions in the setting of anout-of-hospital cardiac arrest, a mechanical chest compressiondevice could assist the rescuer to deliver high-quality CPR.Since the early 2000s, new devices have become clinicallyavailable that demonstrated improved blood pressure andcoronary perfusion pressure compared with manual CPR.5-7

Thereafter, the first series of observational studies reportedpromising findings with regard to survival to admission.8,9

Given the firm association between return of spontaneouscirculation at hospital admission and survival to hospitaldischarge, a strategy that improves survival in the field isexpected to result in higher survival to discharge.

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http://dx.doi.org/10.1016/j.annemergmed.2015.09.023

Manual CPR Versus CPR With a Mechanical Chest Compression Device Bonnes et al

Editor’s Capsule Summary

What is already known on this topicMechanical cardiopulmonary resuscitation (CPR)devices seem to improve outcome for out-of-hospitalcardiac arrest in observational studies, but not inrandomized controlled trials.

What question this study addressedThis meta-analysis pooled data from 5 randomizedcontrolled trials and 15 observational studies onmechanical CPR in out-of-hospital cardiac arrest.

What this study adds to our knowledgeThe pooled randomized controlled trials confirm thatthere is no apparent benefit to mechanical CPR overstandard manual CPR in out-of-hospital cardiacarrest.

How this is relevant to clinical practiceThis study supports manual CPR in out-of-hospitalcardiac arrest, which is cheaper and technically easierto implement.

Unexpectedly, the first large randomized trial was haltedbecause of evidence of unfavorable clinical outcome atdischarge for the CPR strategy including a mechanical chestcompression device.10 It has been suggested that studydesign and the choice of CPR algorithms affected thefindings.11 In the past year, the results of 3 largerandomized controlled trials comparing mechanical withmanual chest compressions in the out-of-hospital cardiacarrest setting have been published, thereby improving theavailable evidence on this topic.12-14

The present analysis addresses the collective evidenceon this in-field intervention, presented for randomizedand observational studies separately. In the context thatdifferences in postresuscitation care may affect the initialadvantage of a new out-of-hospital intervention and that alarge part of the available data stems from observationalstudies, this meta-analysis primarily addresses survival toadmission. Where this endpoint most directly reflects theacute effect of the intervention, the ultimate outcomemeasures concern survival to discharge and neurologicoutcome. Evidence on these endpoints will besummarized as well for the studies with available data.

MATERIALS AND METHODSThe methodology and report of the present meta-analysis

are based on the recommendations of the Cochrane

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Collaboration, the Preferred Reporting Items for SystematicReviews and Meta-Analyses (PRISMA) statement, and theMoose group.15-18

Study DesignA systematic search was performed with PubMed,

Web-of-Science, EMBASE, and the Cochrane Librariesto identify all eligible studies. References of all relevantarticles were searched for additional studies. The searchstrategy included the following key words: (1) “cardiacarrest OR heart arrest,” (2) “cardiopulmonary resuscitationOR CPR,” and (3) “mechanical OR load distributing bandOR piston driven OR Lucas OR Autopulse.” The searchterms were combined as follows: (1) AND (2) AND (3)(Figure E1, available online at http://www.annemergmed.com). The search covered the period after January 1, 2000.Two researchers performed the searches independently;the last search was performed on December 12, 2014.

The included randomized and nonrandomized studieswere selected according to the presence of all 3 of thefollowing criteria: (1) controlled study comparing a strategyof manual CPR with a strategy using an automatedmechanical chest compression device whether or not incombination with manual CPR; (2) out-of-hospital cardiacarrest setting; and (3) reporting at least 1 of the followingoutcome parameters: return of spontaneous circulation,survival to hospital admission, or survival to hospitaldischarge (either with or without reported neurologicoutcome). Both articles, as well as abstracts, were included.We excluded studies reporting no original study data orreporting incomplete outcome data (eg, no absolute eventrates). No language restrictions were applied.

The primary endpoint was survival to hospitaladmission. Secondary endpoints were the presence ofany return of spontaneous circulation before hospitaladmission, survival to hospital discharge, and favorableneurologic outcome at discharge. The latter was defined assurvival to hospital discharge with a cerebral performancecategory score of 1 or 2 or modified Rankin Scale scoreof less than or equal to 3.

The methodological quality of the randomized andnonrandomized studies was assessed by 2 reviewers (J.L.B.and D.V.M.V.) independently, using the CochraneCollaboration’s tool for assessing risk of bias and theNewcastle-Ottawa Scale, respectively.15 Extraction of datafrom the included studies was performed by 1 investigator(J.L.B.) using a prespecified data collection form (AppendixE1, available online at http://www.annemergmed.com). Todouble check the extracted data, a second investigator repeatedthis process (D.V.M.V.). In case of any disagreements,the opinion of a third reviewer was decisive (M.A.B.).

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Bonnes et al Manual CPR Versus CPR With a Mechanical Chest Compression Device

To assess a potential difference in relative efficacy ofboth strategies in relation to the endorsed CPR guidelinesduring the study, we prospectively planned a sensitivityanalysis on this subject. The included studies werecategorized according to the endorsed CPR guidelines,either European Resuscitation Council/American HeartAssociation guidelines 2000 or 2005/2010.19-23 Forobservational studies that did not explicitly report whichresuscitation protocol was adopted, we used a preplannedcategorization: In case the study was initiated beforeDecember 2005, we appointed it to the group of studiesthat followed the guidelines 2000; studies initiated afterDecember 2005 were considered to be performed afterimplementation of CPR guidelines 2005 (Table).

Primary Data AnalysisOdds ratios (ORs) and95%confidence intervals (CIs)were

used as summary statistics and are reported for mechanicalversus manual CPR. Heterogeneity was assessed by theCochran’sQ test. Statistical heterogeneity was summarized bythe I2 statistic, which quantifies the percentage of variation instudy results that is due to heterogeneity rather than to chance.Pooled ORs were calculated with the more conservativeDerSimonian and Laird random-effects model. Potentialpublication bias was examined by constructing a funnel plot,in which the standard error of the OR was plotted against theOR of the selected outcomes. With preplanned meta-regression analyses, we assessed the relationship between therelative efficacy of mechanical versus manual CPR and theeffect on survival to admission in relation to (1) emergencymedical services (EMS) response times (as reported by theindividual studies and in conformity with the time from call toambulance arrival); (2) the proportion of patients with ashockable first observed rhythm, either ventricular tachycardiaor ventricular fibrillation; (3) the proportion of patients withwitnessed arrests; and (4) the proportion of patients receivingbystander CPR. P<.05 is considered statistically significantand reported as 2-sided. Stata (StataCorp, 2009, StataStatistical Software: Release 11. College Station, TX: StataCorpLP) was used for statistical computations.

RESULTSTwenty studies were included in the meta-analysis

(Figure 1), of which 5 had a randomized design. The studiesinvolved a total of 21,363 patients, of whom 9,391 wereallocated to the mechanical arm and 11,972 to the manualarm. The former patients received AutoPulse CPR (ZOLLMedical Corporation, Chelmsford, MA) in 11 studies,whereas the LUCAS device (Physio-Control Inc./Jolife AB,Sweden) was used in 8 studies. In one study, both devices


were used. Characteristics of the analyzed studies, includingthe endorsed CPR guidelines, are outlined in the Table.

The 5 randomized controlled trials involved 12,206patients, of whom approximately half of the patients(n¼5,520) were allocated to mechanical CPR.

Of the 15 controlled studies with a nonrandomized design,8 were published as full-text articles8,24-30 and 7 as conferenceabstracts.9,31-36 Outcomes reported comprise a total of 9,157patients, divided into 3,871 patients who received mechanicalCPR and 5,286 treated with manual CPR only.

The randomized studies were composed of high-qualitytrials, with a low risk of bias. The quality of thenonrandomized studies was good to moderate. A limitationof 10 of the 15 nonrandomized studies was that onlycrude survival rates without adjustment were reported.The risk-of-bias assessments are presented in Tables E1and E2, available online at http://www.annemergmed.com.

The primary endpoint was survival to hospital admission.In total, 16 studies reported on 19,190 patients: 28% survivedin the mechanical arm (2,406/8,749) versus 26% in themanual arm (2,707/10,441) (Figure 2). In the 4 randomizedcontrolled trials (n¼11,439), no benefit in survival to hospitaladmission was found for mechanical versus manual CPR (OR0.94; 95% CI 0.84 to 1.05; P¼.24). In contrast, the 12nonrandomized studies (n¼7,751) demonstrated a survivalbenefit in favor ofmechanical CPR (OR1.42; 95%CI1.21 to1.67; P<.001). Meta-regression indicated that the benefit ofmechanical over manual CPR decreased with increasing EMSresponse times (b –.12; 95% CI –.13 to –.10; P¼.01)(Figure 3). There was no interaction between the endorsedCPR guidelines and the type of CPR delivery in thenonrandomized studies (P for interaction¼.27). No evidenceof publication bias was found.

Secondary endpoints included out-of-hospital returnof spontaneous circulation, survival to hospital discharge,and favorable neurologic outcome. Eleven studies reportedon out-of-hospital return of spontaneous circulation(n¼11,871), of which 3 were randomized controlled trials(n¼7,208). In total, 32% of patients (3,800/11,871)had out-of-hospital return of spontaneous circulation atany time. The pooled estimate of the randomizedcontrolled trials demonstrated no difference betweenstrategies (OR 1.03; 95% CI 0.93 to 1.14; P¼.60),whereas nonrandomized data indicated a significant benefitin favor of mechanical CPR (OR 1.74; 95% CI 1.23 to2.45; P¼.002) (Figure 4). Nine studies reported on survivalto discharge (n¼9,568), of which 4 were randomizedcontrolled trials (n¼7,735). In total, 9% of patients(865/9,568) survived to discharge. CPR including amechanical device versus manual CPR only did not resultin improved outcomes in either the randomized controlled



Table. Characteristics of the included studies.

AuthorYear of

Publication N Study PeriodMain Inclusion

CriteriaMain Exclusion

Criteria DeviceCPR

Guidelines VT/VFWitnessedArrest*

ResponseTime,

MinutesMain Outcome

Measures

Nonrandomized studiesCasner24† 2005 262 2003 Adult cardiac arrests

patientsNot reported AutoPulse Not

reported28% man,

33% mechNot reported 7 Sustained ROSC

Ong8 2006 783 2001–2005 Adult patients with anontraumatic OHCAwho received CPR,defibrillation, or bothin Richmond

Patients withoutresuscitationattempt, obviousmajor trauma,<18 y, pregnantwoman, prisoners,mentally disabled

AutoPulse Notreported

21% man,24% mech

47% man,52% mech

6.5 man,6.1 mech

ROSC, survival tohospital admission,survival to discharge,neurologic outcomeat discharge

Axelsson25 2006 328 2003–2005 Patients with awitnessed OHCA ofpresumed cardiaccause

<18 y, trauma,pregnancy,hypothermia,intoxication,hanging,drowning, ROSCbefore arrivalsecond tier

LUCAS Notreported

32% man,30% mech

100% man,100% mech

8 man, 7mech

ROSC at any time,survival at hospitaladmission, survival todischarge, neurologicrecovery

Maule26 2007 290 2004–2006 Patients with an OHCA Not reported LUCAS ERC 2000,2005

Not reported Not reported Notreported

ROSC

Steinmetz27‡ 2008 419‡ 2006–2007 Patients with an OHCAresuscitated by theMECU

Noncardiac cause,missing data

AutoPulse ERC 2005 37% 74% 5 ROSC at hospitaladmission, 1-mosurvival

Jennings28† 2012 286 2006–2010 Adults with an OHCA Not reported AutoPulse Notreported

36% man,30% mech

72% man,71% mech

9 man, 9mech

Survival to hospital,survival to hospitaldischarge

Satterlee29 2013 572§ 2008–2010 Patients with an OHCAfor whom the EMSattemptedresuscitation

<18 y, presumednoncardiac cause,pregnancy

LUCAS Notreported

18% man,21% mech

61% man,53% mech

7 man, 7mech

Out-of-hospital ROSC,arrival at the EDwith ROSC

Axelsson30 2013 2,401 1998–2003;2007–2011

OHCA patients for whomthe EMS attemptedresuscitation

None LUCAS Notreported

32% man,26% mech

70% man,73% mech

5 man, 9mech

Survival to admission,1-mo survival

Lairet31 2005 406 2004 Patients with acardiopulmonaryarrest

Not reported AutoPulse Notreported


ROSC, admission to ED,survival to discharge

Ornato32 2005 1,086 Circa1998–2004

Adult nontraumaticcardiac arrest casesof presumed cardiacorigin



Field ROSC

Swanson9 2006 876 OHCA patients Not reported AutoPulse AHA 2000 Not reported Not reported Notreported

Survival to ED admission

Wilde33 2008 220 2005–2007 Patients with an OHCA Not reported LUCAS Notreported

58% man,65% mech

Not reported 7 man, 6mech

ROSC on admission,3-mo survival

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Paradis34 2009 1,024 2007–2009 Patients with cardiacarrest receivingmanual CPR,AutoPulse CPR, or both


21% 39% Notreported

ROSC, ROSC sustainedto ED admission

Truhlar35 2010 30 2010 Patients with anontraumatic OHCA

Not reported LUCASAutoPulse

Notreported


Survival to hospitaldischarge, survival todischarge with CPC1–2, injuries

Morozov36 2012 188 2009–2011 OHCA patients Not reported AutoPulse Notreported


ROSC at the scene,survival to hospitaladmission

Randomized studiesHallstrom10

(ASPIRE)2006 767 2004–2005 Adults with an OHCA of

cardiac origin for whomthe EMS attemptedresuscitation

<18 y, trauma,recent surgery,prisoners, DNR,obviously dead

AutoPulse AHA 2000 32% man,31% mech

49% man,44% mech

5.7 man,5.6 mech

Survival to 4 h, survivalto hospital discharge,neurologic status ofsurvivors

Smekal37 2011 148 2005–2007 Out-of-hospital suddencardiac arrest patients

Known pregnancy,<18 y, trauma

LUCAS ERC 2000 27% man,27% mech

74% man,68% mech

6.4 man,7.3 mech

ROSC, survival tohospital admission,survival to hospitaldischarge

Rubertsson12

(LINC)2014 2,589 2008–2013 Adults with an

unexpected OHCATraumatic arrest,

<18 y, knownpregnancy, bodysize too largeor small to fitthe chestcompressiondevice

LUCAS ERC 2005 30% man,29% mech

72% man,73% mech

7 man, 8mech

ROSC, arrival to ED withspontaneous palpablepulse, 4-h survival,survival to hospitaldischarge, survivalwith good neurologicoutcome, survival to1 and 6 mo

Wik13

(CIRC)2014 4,231 2009–2011 Patients �18 y with an

OHCA of presumedcardiac cause

Presumedpregnancy, DNRorder, patients toobig for the device,arrival of EMS>16 min after call

AutoPulse ERC/AHA2005

24% man,21% mech

48% man,47% mech

6.6 man,6.7 mech

Sustained ROSC, survivalto 24 h, survival todischarge, mRS scorebefore discharge

Perkins14

(PARAMEDIC)2015 4,471 2010–2013 Patients (�18 y) with

an OHCA for whomresuscitation wasattempted and forwhom the trial vehiclewas first on scene

Cardiac arrestbecause oftrauma,pregnancy

LUCAS ERC 2005/2010

22% man,23% mech

62% man,61% mech

6.3 man,6.5 mech

ROSC, survived event,30-day survival, 1-ysurvival, survival withCPC 1–2 at 3 mo

VT, Ventricular tachycardia; VF, ventricular fibrillation; man, manual; mech, mechanical; ROSC, return of spontaneous circulation; OHCA, out-of-hospital cardiac arrest; ERC, European Resuscitation Council; MECU, medicalemergency care unit; AHA, American Heart Association; CPC, cerebral performance category; DNR, do not resuscitate; mRS, modified Rankin Scale score.Nonrandomized studies: Four studies used historical controls,8,26,30,32 and in one study, the device was exchanged between different EMS units.25 The proportion of patients actually treated with the device varied per study from60% to 82%. Seven studies were categorized to the group of studies performed in an era in which guidelines 2000 were endorsed,8,9,24,25,31-33 and 6 were classified to guidelines 2005.27-29,34-36 Two studies could not beclassified because the endorsed guidelines differed between the study groups.26,30 Randomized studies: In 3 studies, randomization was performed for each patient found in cardiac arrest12,13,37; in 2 studies, individualambulance vehicles or EMS stations were used as units for randomization.10,14

*Arrest witnessed by either bystanders or EMS.†In the present meta-analysis, data reported for the unmatched cases have been used.‡Within the subset resuscitated according to guidelines 2005, outcomes were reported for patients who received mechanical versus manual CPR.§Survival percentages reported for patients for whom it was known whether mechanical or manual CRP was delivered.

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Figure 1. Flow diagram of the reviewing process.

Figure 2. Individual study and pooled estimates for survival to homanual CPR.



trials (OR 0.85; 95% CI 0.72 to 1.01; P¼.07) or in thenonrandomized studies (OR 0.68; 95% CI 0.21 to 2.19;P¼.52) (Figure 5). Six studies reported on neurologicoutcomes at discharge (n¼8,728), of which 3 wererandomized controlled trials (n¼7,587). In total, 6% ofpatients (504/8,728) survived to discharge with favorableneurologic outcome. Irrespective of study design, nodifference was observed for mechanical versus manual CPR(randomized controlled trials: OR 0.76, 95% CI 0.49 to1.17, P¼.22; nonrandomized controlled trials: OR 1.04,95% CI 0.26 to 4.22, P¼.96) (Figure 6).

LIMITATIONSThe present meta-analysis is based on the results of

both randomized and nonrandomized studies. Despite thatnonrandomized studies are by design more prone to biasand did not address a strategy of routine mechanicalCPR, we included observational studies but pooled themseparately from randomized controlled trials.

Whereas the randomized controlled trials have a designto address “efficacy” of a routine strategy of mechanical

spital admission for patients who received mechanical versus


Figure 3. Meta-regression showing a decreasing benefit of mechanical over manual CPR for survival to hospital admission withlonger response times.


CPR, the nonrandomized studies may give a mereindication of the “effectiveness” of an actual strategy.

With the rescuer having the choice to use or not to usethe device, outcomes in the nonrandomized studies may bedriven by selection bias. Because of the lack of propensity

Figure 4. Individual study and pooled estimates for out-of-hospitamechanical versus manual CPR.


score analyses, caution is warranted with regard toconclusions about a potential benefit of a selective strategyof mechanical CPR.

The actual adherence to the endorsed protocols was notstudied because these data were not scored or reported in the

l return of spontaneous circulation for patients who received


Figure 5. Individual study and pooled estimates for survival to hospital discharge for patients who received mechanical versusmanual CPR.


majority of studies. To comply with the Cochrane guidelinesand to provide themost comprehensive update of all availableevidence, we included conference abstracts with, in somecases, lower-quality evidence.15 Sensitivity analyses showedthat the outcomes did not differ from the main analysis,showing consistency in both the direction and magnitude ofestimates, in case abstract data were not considered.

DISCUSSIONTo our knowledge, the present article is the most

comprehensive and updated source of evidence ofrandomized and observational study data on mechanicalversus manual CPR in out-of-hospital cardiac arrestpatients. Meta-analysis of the high-quality randomizedcontrolled trials did not demonstrate a benefit in clinicaloutcomes for a strategy of routine mechanical CPR. Resultsfrom the lower-quality observational studies, which weremore heterogeneous in design and did not require a strategyof routine use of mechanical CPR, suggested an advantageover manual CPR for survival to hospital admission. Thebenefit of mechanical compared with manual CPRdecreased with longer response times. As for survival todischarge and good neurologic outcomes, no differencesbetween strategies were observed.


Overall, the quantitative evidence of the randomizedtrials demonstrates that, compared with manual CPR, therelative efficacy of the systematic use of mechanical CPRwould vary from a 16% decrease to, at best, a 5% benefit insurvival to hospital admission. Whereas the initial absenceof benefit in the clinical trials was attributed to protocol-driven sequences, other explanations may account for thediscrepancy between clinical outcomes and promisinghemodynamic pilot data.5-7,10,11 First, available data aboutsafety are not conclusive with regard to the harm associatedwith CPR including a chest compression device.38,39 Thisis related to the fact that in the majority of studies, safetydata have not been systematically reported or collected,although it could have further improved our insights withregard to the observed clinical outcomes. Although bothmanual and mechanical chest compressions are associatedwith injuries, the pattern of injuries seems different andcould affect survival in a different way.38

A second explanation may be related to the fact thatdeployment of a chest compression device is associated witha pause in chest compression delivery and may result inlonger no-flow times in the initial phase of resuscitation.13

Related to this, the time to first shock delivery may belonger compared with that for manual CPR. Although inthe more recently performed trials emphasis was put on


Figure 6. Individual study and pooled estimates for favorable neurologic outcome for patients who received mechanical versusmanual CPR.


short CPR interruptions, the time to first shock deliverywas 1 to 1.5 minute longer in the mechanical than in themanual CPR arm.12,13

Finally, the abovementioned protocol-driven sequencesmay have had some effect on the observed outcomes andresulted in significant changes in the study designs of themore recent randomized trials.40-42 In short, subanalysis ofdata from the prematurely discontinued AutoPulse AssistedPrehospital International Resuscitation Trial (ASPIRE) trialsuggested that the negative outcomes with regard to theendpoint (favorable neurologic) survival to discharge wereprimarily driven by a single site that switched from CPRalgorithm during the trial.11 These insights resulted in newrandomized controlled trials with thorough CPR trainingand monitoring of CPR quality parameters, includingattention to short CPR interruptions during deviceapplication.12-14 In this context, the recent randomizedcontrolled trials adopted CPR algorithms that differedslightly from the endorsed guidelines during the studyperiods. These differences included delivery of 3-minuteCPR cycles instead of 2 minutes and different timingsof rhythm checks in the LUCAS in Cardiac Arrest (LINC)and Circulation Improving Resuscitation Care (CIRC)trial.12,13 In all of the more recently performed trials,shocks were preferably administered with continuous


mechanical CPR, whereas in the manual armscompressions were briefly interrupted.12-14 Althoughshorter preshock pauses are expected to be beneficial ontheoretical grounds, there are so far no compelling data thatdemonstrate superiority of an approach without anypreshock pause.43,44

In addition to safety issues associated with mechanicalCPR, the abovementioned aspects related to the usedalgorithms may have contributed to the absence of a clinicalbenefit of mechanical CPR, which was expected accordingto the promising hemodynamic data.

In contrast to the randomized controlled trials, theobservational studies addressed the use of mechanicalCPR by discretion of the rescuer. In addition, thenonrandomized studies were performed in the setting ofconventional CPR algorithms, as endorsed by theguidelines during that study period. From a methodologicalpoint of view, the randomized controlled trials provide asuperior level of evidence. Apart from the lack of randomallocation, the abovementioned aspects are an additionalargument to report the collective data from randomizedtrials separate from those of the observational studies.

The discrepant results with the randomized controlledtrials are most likely driven by the limiting factors of anobservational study design. Bias may have been introduced



in several phases in the CPR process. In the absence of aregistration of eligible patients and those enrolled in thestudy, and without random allocation, the observationalstudies may be affected by rescuers’ preferences to choose aspecific form of CPR, or no CPR at all. Numerous otherexplanations have also been suggested to address thediscrepant findings between observational and randomizeddata. For example, correct use of mechanical CPR requiresadditional training, which may also have a positive effect onthe performance of all other actions required during theresuscitation process. The implementation of mechanicalCPR may stimulate renewed awareness and enhancedetermination to try to achieve high-quality CPR. Studieswith historical controls compared outcomes before andafter implementation of a chest compression device asstandard EMS equipment and may have been affected bythis phenomenon.8,26,30,32 These accompanying effectsmay all have contributed to the reported better short-termoutcomes that are not directly related to mechanicalcompressions themselves. However, the positive effectsreported in the observational studies without historicalcontrols may also be indicative of a true efficacy of thedevice itself.9,27,34,36 Even if this were true, there is noimproved survival to discharge or better neurologicoutcome.

Appreciating that the introduction of new resuscitationguidelines could affect outcome, we prespecified asensitivity analysis.45 Efficacy of mechanical CPR in studieswith guidelines 2000 did not differ from those withguidelines 2005. Additional prespecified analyses indicatethat in the observational studies the observed benefit ofmechanical versus manual CPR on survival to hospitaladmission is higher when response times are shorter(Figure 3). Hypothetically, this association may be relatedto the fact that cardiac arrest patients treated early have, apriori, a relatively less pessimistic chance of survivalcompared with patients with longer response times, whereat least subsets of patients may be beyond saving. The effectmeasures did not depend on the proportion of patientswith shockable first observed rhythms, witnessed arrests, orbystander CPR.

Meta-analysis of the available data on survival todischarge does not support a strategy of mechanical CPR toimprove outcome in either the observational or randomizedstudies. Survival during hospital stay may be affected bymany factors, such as differences in postresuscitationcare, the severity of the underlying cause, and, of course,neurologic status. In this context, survival to admission maybetter reflect the direct effect of an in-field interventionrather than survival to discharge, which also depends on theefficacy of hospital interventions that are often not fully


standardized in multicenter studies.46 The beneficial effecton survival to admission may be counteracted by adverseevents caused by device compressions. The ultimate goalof resuscitation remains survival to discharge with goodneurologic outcome. With regard to this endpoint, nodifferences were observed between mechanical and manualCPR. Unfortunately, registration of this outcome variablewas suboptimal in the majority of studies, even in therandomized controlled trials.

The results of the present meta-analysis imply that theroutine use of mechanical CPR does not contribute toimproved survival of out-of-hospital cardiac arrest patients.Additional study is warranted with regard to the effect ofadverse events associated with mechanical CPR and thesophisticated, untested algorithms including shocks withongoing compressions. In that respect, studies addressingthe influence of pre- and postshock pauses and the effectof shocks during compressions are eagerly awaited. Datacollection in the present meta-analysis shows that futurestudies need to systematically address similar endpoints,with uniform definitions. Even in the randomizedcontrolled trials, the collective evidence on most of thereported endpoints reflects only approximately 7,000 to8,000 patients of the more than 12,000 patients included.Finally, the ultimate goal is to discharge patients withoutmajor neurologic deficits, and especially informationon neurologic outcomes should be reported moresystematically.

In summary, this comprehensive meta-analysisdemonstrates that the cumulative evidence of high-qualityrandomized data does not support a routine strategy ofmechanical CPR to improve clinical outcomes. Althoughlower-quality evidence of the nonrandomized studiessuggests a survival benefit to admission for a strategy ofmechanical CPR initiated at the rescuer’s discretion, thereis no proof of improved survival to discharge or neurologicoutcomes in either the randomized or nonrandomizedstudies. These findings were irrespective of prevailingguidelines (2000 versus 2005) during the study periods.

Supervising editor: Jonathan L. Burstein, MD

Author affiliations: From the Department of Cardiology, RadboudUniversity Medical Center, Nijmegen, the Netherlands (Bonnes,Brouwer, Verhaert, Verheugt, Smeets, de Boer); and theDepartment of Internal Medicine, Division of Cardiology,Pulmonology and Vascular Medicine, Heinrich-Heine-University,Düsseldorf, Germany (Navarese).

Author contributions: J.L.B, M.A.B, E.P.N., J.L.R.M.S., and M.J.d.B.conceived the study and designed the trial. F.W.A.V., J.L.R.M.S.,and M.J.d.B. supervised the conduct of the study and datacollection. J.L.B., M.A.B., and D.V.M.V. managed the data, including



quality control. J.L.B., M.A.B., and E.P.N. provided statistical adviceon study design and analyzed the data. J.L.B., M.A.B., and E.P.N.drafted the manuscript, and all authors contributed substantiallyto its revision. M.A.B. and M.J.d.B. take responsibility for the paperas a whole.

Funding and support: By Annals policy, all authors are required todisclose any and all commercial, financial, and other relationshipsin any way related to the subject of this article as per ICMJE conflictof interest guidelines (see www.icmje.org). Dr. Brouwerparticipated as a principal investigator in the CIRC trial, and hisinstitution received a per-patient fee from ZOLL. Dr. Verheugt hasreceived honoraria for speaker fees and consultancy honorariafrom AstraZenenca, Medtronic, Bayer Healthcare, Boehringer-Ingelheim, BMS/Pfizer, and Daiichi-Sankyo.

Publication dates: Received for publication June 20, 2015.Revision received August 7, 2015. Accepted for publicationSeptember 21, 2015. Available online November 19, 2015.

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Annals’ Toxicology Res

Digoxin toxicity can be difficin the elderly. Visit the Restreatment information at


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ource Center: Digoxin

ult to diagnose, particularlyource Center for successfulwww.annemergmed.com.

























































Figure E1. Search strategy.*


Annals of Emergency Medicine 360.e1

Table E1. Risk of bias of the included randomized studies.

DomainHallstrom10

(ASPIRE) Smekal37Rubertsson12

(LINC)Wik13

(CIRC)Perkins14

(PARAMEDIC)

Selection biasRandom sequencegeneration

Clusterrandomization*with crossover, notfurther specified

Patientrandomization, notfurther specified

Patientrandomization, notfurther specified

Patient randomizationwith permutedblocks, not furtherspecified

Clusterrandomization†

using a computer-generatedsequence

Allocationconcealment

Rescuer was awareof upcomingpatient treatment

Sealed letters Sealed opaqueenvelopes

Sealed randomizationcards

Rescuer was aware ofupcoming patienttreatment

Performance biasBlinding ofparticipants andpersonnel

Not blinded Not blinded Not blinded Not blinded Not blinded

Detection biasBlinding of outcomeassessment

Unclear Unclear Survival: unclearNeurologic outcome:CPC scores wereobtained by anurse or physicianwho had accessto the studydocumentation

Study personnelcollected outcomedata and were notalways blinded tostudy arm

Survival: unclearNeurologic outcome:Trial staff whoassessed patientneurologic outcomewere unaware ofthe randomizedallocation or thetreatment received

Attrition biasIncomplete outcomedata

Survival to discharge:0%

Neurologic outcome:0.7%

Out-of-hospital ROSC:1.4%

Survival toadmission: 0.7%

Survival to discharge:0.7%


Survival toadmission: 0%



Survival to admission:0%




Survival to admission:4.7%

Reporting biasSelective reporting No evidence No evidence No evidence No evidence No evidenceOther biasOther sources of bias Neurologic outcome

was missing for8.3% of thesurvivors todischarge

Neurologic outcomewas missing for27.7% of thesurvivors todischarge

*Clusters were based on an EMS station or group of stations.†Clusters were individual ambulance vehicles.


360.e2 Annals of Emergency Medicine Volume 67, no. 3 : March 2016

Table E2. The Newcastle-Ottawa Scale for the nonrandomized studies.*

Author Selection Comparability Outcome Score† Method of Adjustment

Casner24 **** ** *** 9/9 MatchingOng8 **** ** *** 9/9 Multivariable analysisAxelsson25 *** * *** 7/9 Matching‡

Maule26 *** *** 6/9Steinmetz27 *** *** 6/9Jennings28 *** ** *** 8/9 MatchingSatterlee29 **** *** 7/9Axelsson30 **** ** *** 9/9 Multivariable analysis§

Lairet31 **** *** 7/9Ornato32 **** *** 7/9Swanson9 **** *** 7/9Wilde33 **** *** 7/9Paradis34 **** *** 7/9Truhlar35 **** ** 6/9Morozov36 *** *** 6/9

*According to the Newcastle-Ottawa Scale, stars were assigned for the study quality items selection, comparability, and outcome. The maximum number of stars awardable forthese categories is 4, 2, and 3, respectively.†Newcastle-Ottawa Scale summary score out of a maximum of 9 points.‡The authors reported that no differences were found when comparing outcomes for patients who were mechanically resuscitated with matched controls. Because these data arenot shown, we assigned just 1 star for comparability.§For the outcome variable 1-month survival.


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