Resuscitation Today - Autumn 2018

Volume 5 No. 3

Autumn 2018

Resuscitation Today A Resource for all involved in the Teaching and Practice of Resuscitation

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In this issue Mechanical versus Manual Chest Compressions How Does the Length of Cardiopulmonary Resuscitation Affect Brain Damage in Patients Surviving Cardiac Arrest Life Connections 2019: More Choice and Great Value for Money

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EDITORS COMMENT

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CLINICAL PAPER

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compressions in the treatment of inDelivery Systems hospital• cardiac patients in a nonAirwayarrest Management shockable Oxygen rhythm: aTherapy randomised controlled • trial (COMPRESS-RCT) feasibility

CLINICAL PAPER How does the length of cardiopulmonary resuscitation affect brain damage in patients surviving cardiac arrest? A systematic review

CONTENTS

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RESUSCITATION TODAY - AUTUMN 2018

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EDITORS COMMENT “Our aim as with each of our titles, is to provide our readers with a publication they can both read and enjoy, but to achieve this we need your input and support by way of providing us with material for editorial consideration.�

EDITORS COMMENT Regrettably due to unforeseen work circumstances, our editor has been unable to provide us with his comments for this issue, therefore to avoid the publication being delayed, I am stepping in with my thoughts.

Our aim as with each of our titles, is to provide our readers with a publication they can both read and enjoy, but to achieve this we need your input and support by way of providing us with material for editorial consideration. This edition again contains 2 articles sourced and, published with permission from The Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine due to a lack of home grown material being available to us and, whilst we are sure you will enjoy both articles, we would prefer to be publishing material submitted by yourselves for the benefit of our readers working within Resuscitation and Accident & Emergency Departments, other related Hospital Departments etc, our submission requirements are set out below.

Our next issue will be published in February and in addition to our normal distribution will also be circulated from our stands at Life Connections Harrogate and Trauma Care therefore anything submitted for this edition will be seen and read by a wide and varied audience, if you have anything to submit we would appreciate receiving it by no later than early January.

On behalf of everyone involved with Resuscitation Today, I would like to thank those that have made editorial submissions and, the trade for supporting this well regarded title, without your valued input we would not have achieved what we have done to date.

Best wishes to everyone Terry Gardner, Publisher, Resuscitation Today

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The publication is mailed to all resuscitation, A&E and anaesthetic departments plus all intensive care, critical care, coronary care and cardiology units.

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If you have any queries please contact the publisher Terry Gardner via: info@mediapublishingcompany.com

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CLINICAL PAPER

MECHANICAL VERSUS MANUAL CHEST COMPRESSIONS IN THE TREATMENT OF IN-HOSPITAL CARDIAC ARREST PATIENTS IN A NON-SHOCKABLE RHYTHM: A RANDOMISED CONTROLLED FEASIBILITY TRIAL (COMPRESS-RCT) Keith Couper1,2*, Tom Quinn3, Ranjit Lall1, Anne Devrell4, Barry Orriss4, Kate Seers5, Joyce Yeung1,2, Gavin D. Perkins1,2 On behalf of the COMPRESS-RCT collaborators Reproduced with permission from the Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. (2018) 26:70 doi: 10.1186/s13049-018-0538-6

Abstract Background Mechanical chest compression devices consistently deliver highquality chest compressions. Small very low-quality studies suggest mechanical devices may be effective as an alternative to manual chest compressions in the treatment of adult in-hospital cardiac arrest patients. The aim of this feasibility trial is to assess the feasibility of conducting an effectiveness trial in this patient population.

Methods COMPRESS-RCT is a multi-centre parallel group feasibility randomised controlled trial, designed to assess the feasibility of undertaking an effectiveness to compare the effect of mechanical chest compressions with manual chest compressions on 30-day survival following in-hospital cardiac arrest.

Over approximately two years, 330 adult patients who sustain an in-hospital cardiac arrest and are in a non-shockable rhythm will be randomised in a 3:1 ratio to receive ongoing treatment with a mechanical chest compression device (LUCAS 2/3, Jolife AB/Stryker, Lund, Sweden) or continued manual chest compressions. It is intended that recruitment will occur on a 24/7 basis by the clinical cardiac arrest team. The primary study outcome is

the proportion of eligible participants randomised in the study during site operational recruitment hours. Participants will be enrolled using a model of deferred consent, with consent for follow-up sought from patients or their consultee in those that survive the cardiac arrest event.

The trial will have an embedded qualitative study, in which we will conduct semi-structured interviews with hospital staff to explore facilitators and barriers to study recruitment.

Discussion The findings of COMPRESS-RCT will provide important information about the deliverability of an effectiveness trial to evaluate the effect on 30-day mortality of routine use of mechanical chest compression devices in adult in-hospital cardiac arrest patients.

Trial registration ISRCTN38139840, date of registration 9th January 2017.

Keywords: Cardiac arrest, Cardiopulmonary resuscitation, Advanced cardiac life support, Mechanical chest compression device

Background RESUSCITATION TODAY - AUTUMN 2018

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Each year, approximately 35,000 patients have a cardiac arrest in

hospital cardiac arrest (odds ratio of hospital/30-day survival 2.34, 95%

UK hospitals, of which less than one in five patients survives to leave

confidence interval 1.42 to 3.85) [11].

hospital [1]. Observational studies report the association between highquality cardiopulmonary resuscitation (CPR) and improved survival, as

This apparent discrepancy in findings between the in-hospital and out-

well as the challenge of delivering high-quality manual CPR in clinical

of-hospital setting may reflect differences in evidence quality or clinical

practice [2–5].

factors, such that mech-CPR is more effective than man-CPR in the hospital setting [12, 13]. Examples of such factors include opportunity

Mechanical chest compression devices consistently deliver high-quality

for early optimal device deployment by a clinical team with frequent

chest compressions [6]. In the out-of-hospital setting, large, high-quality

cardiac arrest exposure and the challenge of delivering effective manual

randomised controlled trials have found no evidence of improved

chest compressions on a hospital bed, due to the compressibility of the

patient outcome in patients treated with mechanical CPR (mech-CPR),

underlying mattress [2, 14, 15].

compared with manual CPR (man-CPR) [7–10]. In contrast, very lowquality small randomised and observational studies report evidence

Based on this ongoing uncertainty, there is a need for a clinical trial

of an association between mech-CPR and increased survival in in-

to evaluate the effect of the routine use of mech-CPR, compared

* 1 2

Correspondence: k.couper@warwick.ac.uk Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK Full list of author information is available at the end of the article

CLINICAL PAPER with man-CPR, on 30-day survival in adults that sustain an in-hospital

The trial is conducted in accordance with the Medical Research Council

cardiac arrest. However, such a trial would require a large sample size

(MRC) guidelines on Good Clinical Practice, applicable UK legislation

and might be beset by a number of practical challenges, such that is

and the Warwick University Clinical Trials Unit Standard Operating

prudent to first undertake a feasibility trial.

Procedures. The trial sponsor is the University of Warwick.

The study is co-ordinated by Warwick Clinical Trials Unit. It is run in

Methods/design COMPRESS-RCT is a multi-centre parallel group feasibility randomised controlled trial, in which adult patients that sustain a non-shockable in-hospital cardiac arrest are randomised in a 3:1 ratio to receive either mech-CPR or ongoing man-CPR (Fig. 1). The aim of the trial is to assess whether it is feasible to undertake an effectiveness trial to examine the effect of the use of mech-CPR on 30-day survival following in-hospital cardiac arrest. A qualitative study is embedded in the trial, in which semi-structured interviews are conducted with clinicians involved in the trial to explore potential facilitators and barriers to recruitment.

The trial flow diagram is presented in figure one.

collaboration with five English acute hospital research sites: Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust; University Hospital, University Hospitals Coventry and Warwickshire NHS Trust; Warwick Hospital, South Warwickshire NHS Foundation Trust; Sandwell General Hospital, Sandwell and West Birmingham Hospitals NHS Trust; and Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Foundation Trust.

Outcome measures The primary outcome for this feasibility trial is the proportion of eligible patients randomised during site operational recruitment hours.

We will measure a range of secondary outcome measures, grouped as study feasibility outcomes, patient outcomes, process outcomes, and safety outcomes, which are summarised in Table 1.

Eligibility criteria Participants are eligible to be included in the trial if they: 1. Sustain an in-hospital cardiac arrest and resuscitation is attempted by a hospital cardiac arrest team trained in the use of the mechanical chest compression device (excludes cardiac arrests in the emergency department).

2. In a non-shockable rhythm (pulseless electrical activity or asystole) at the time of eligibility assessment.

3. Known or believed to be aged 18 years or over.

A team is categorised as being trained in device use if at least two clinicians present have been trained in device use.

Exclusion criteria are: 1. Patient has valid do not attempt cardiopulmonary resuscitation order.

2. Known or clinically apparent pregnancy.

3. Cardiac arrest where use of a mechanical chest compression device is contra-indicated (e.g. following cardiac surgery, thoracic trauma, patient size).

4. Known previous study participation.

Trial approvals and conduct COMPRESS-RCT is approved by the West Midlands – Coventry and Warwickshire National Health Service Research Ethics Committee (16/

5. Patient requiring use of mechanical chest compression device as part of routine clinical care.

6. Patient known to be detained by Her Majesty’s Prison Service.

WM/0299). The Health Research Authority Confidentiality Advisory Group has approved the processing and transfer of data without

Recruitment and randomisation

consent, under The Health Service (Control of Patient Information)

It is intended that, where possible, the recruitment process is led 24-h

Regulations 2002 (16/CAG/0088). The trial is registered with the ISRCTN

a day by the hospital cardiac arrest team. On arrival of the mechanical

Trial Registry (ISRCTN08233942). The trial is funded by a National

device at the cardiac arrest location, a trained member of the cardiac

Institute for Health Research Post-Doctoral Research Fellowship (PDF-

arrest team assesses patient eligibility for study inclusion. If a patient is

2015-08-109).

identified as being eligible, then the patient proceeds to randomisation.

RESUSCITATION TODAY - AUTUMN 2018

Fig. 1 Trial flow diagram

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CLINICAL PAPER Table 1 Study secondary outcomes

make decisions, this approach is made to the participant’s designated personal or professional consultee.

Study feasibility outcomes (formulae detailed summary in Additional file 1) • Proportion of patients randomised outside of weekday daytime hours).

• Device deployment time- measured as the pause in chest compressions associated with device deployment.

• Proportion of patients/consultees providing agreement to ongoing study participation.

• Success of study blinding procedures.

• Proportion of patients with complete follow-up data.

• Proportion of patients with analysable chest compression quality data.

Patient outcomes • Return of spontaneous circulation- defined as the return of a spontaneous circulation for at least twenty minutes.

• Duration of critical care and hospital stay.

• Survival- measured at hospital discharge, 30-days, and 6-months.

• Quality of life- measured using EQ-5D-5 L (EuroQOL- 5 dimensions- 5 levels) and SF-12 (12-item short form survey) questionnaires at hospital discharge and 6-months.

• Good neurological outcome measured using cerebral performance category (CPC) at discharge and the modified Rankin score (mRS) at discharge and at six-months. Good neurological outcome will be defined as a CPC of 1 or 2 or return to baseline (pre-admission) CPC, or mRS of 0–3 or return to baseline (pre-admission) mRS. Process outcomes • Cardiopulmonary resuscitation (CPR) quality (chest compression rate, chest compression depth, flow-fraction, pre-shock pause, post-shock pause, peri-shock pause).

Safety outcomes • Device related adverse events

Patients are individually randomised in a 3:1 ratio in favour of the use of the mech-CPR, using a sequentially numbered sealed opaque envelope system. An unequal randomisation ratio was chosen to increase clinician exposure to device use during the trial. A single envelope is stored with each mechanical device at all times. The randomisation sequence was created by the study statistician, using the centre as strata and using random blocks to ensure that a 3:1 allocation was maintained for both interventions for a given strata. Envelopes are packed by a Warwick Clinical Trials Unit staff member who is independent of the study team.

At the point that the envelope is opened, the patient is categorised as being randomised for the intention-to-treat analysis. Following envelope use, the next sequentially numbered envelope is allocated to that device.

Consent RESUSCITATION TODAY - AUTUMN 2018

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Cardiac arrest is a sudden, unpredictable event, in which the patient immediately loses consciousness. Furthermore, the need for immediate treatment makes it impractical to obtain informed consent from the

We consulted in detail with a group of patient research ambassadors regarding the approach that should be adopted in relation to trial information provision to family members in the event that the participant dies. The group carefully considered the three main options: active information (e.g. letter); passive information (e.g. poster in hospital bereavement office), or no information. The patient research ambassadors recommended that family members should not be informed about trial participation. In forming this view, the group considered factors such as the nature of the intervention being studied and the balance of benefit and harm in providing information at a time of bereavement. This reflects the approach that has been adopted in similar trials [8, 16, 17].

Sources of bias Compliance and contamination Compliance with allocated study treatment is being monitored, together with reasons for non-compliance, throughout the trial. It is acknowledged that non-compliance may be unavoidable in some circumstances, such as where a participant has return of spontaneous circulation following randomisation and prior to initiation of mech-CPR. Where possible, defibrillator download data is used to corroborate compliance information recorded on the case report form.

Potential causes of contamination are dependent on study allocation.

In the mech-CPR arm, contamination is most likely attributable to compliance issues. In the man-CPR arm, crossover may occur if a special circumstance arises following randomisation where local policy requires use of mech-CPR (e.g. post-randomisation decision for intraarrest coronary angiography). Such events are likely to be rare and are recorded and monitored throughout the trial.

Blinding The nature of the intervention makes it impossible to blind clinical personnel present at the cardiac arrest event. It is not possible to blind clinical and site research teams to treatment allocation as the intervention is recorded in the participant’s medical record and clinical examination may indicate device use (e.g. chest bruising). However, it is not considered likely that knowledge of treatment allocation will influence delivery of other intra-arrest or post-arrest interventions.

Participants will be initially blinded as they will be unconscious throughout the cardiac arrest event. An active attempt is made to maintain this

patient’s consultee prior to trial enrolment. On this basis, a Research

blinding, although participants may nevertheless subsequently become

Ethics Committee has approved the initial enrolment of trial participants

unblinded (e.g. if they access their medical records). The rationale for

under a waiver of consent in accordance with the English law.

maintaining blinding will be explained during the consent process and in study information. The success of participant blinding is measured

Participants that survive the cardiac arrest are approached at the

through study questionnaires distributed at hospital discharge and six-

earliest reasonable opportunity following the cardiac arrest event.

months by asking participants whether they are aware of their study

Following explanation of the trial, the participant or their consultee is

allocation and which treatment they believe that they received.

offered one of three options: 1) use of routine health data sources for data collection and completion of questionnaires at discharge and six-

Trial interventions/treatment

months; 2) use of routine health data sources for data collection without

All patients initially receive manual chest compressions. Following

questionnaire completion; or 3) declination of further study involvement

commencement of the trial intervention, the intervention will continue for

and data collection. In the event that the participant lacks capacity to

the duration of the cardiac arrest event. Aside from the trial intervention

CLINICAL PAPER Table 2 Schedule of intervention delivery and data collection Assessment points

1

Assessment point window

Cardiac arrest 2 days (± 3 days) Regular in-hospital 30-day (± 2 days) Hospital Six-months (± 1 m) event after assessment 1 reviews after assessment 1 discharge† after assessment 1

2

3

4

Eligibility assessment

✓

Intervention

✓

Cardiac arrest event data

✓

✓

Defibrillator record download

✓

Post-cardiac arrest treatment

✓

✓

✓

Length of hospital stay

✓ ✓

✓

✓

✓

Quality of life (SF-12 and EQ-5D-5 L) Assessment of blinding Consent to continue‡ Adverse events

6

✓

Patient demographics/past medical history

Survival status

5

✓

✓

✓

✓

✓

✓

✓

✓

✓

✓

✓

✓

✓

✓

✓

† − May occur before visit four; ‡ − Seek at first appropriate opportunity SF-12- 12-item short form survey; EQ-5D-5 L- EuroQOL- 5 dimensions- 5 levels

being tested (method of chest compression delivery), it is expected that

not expected to survive, and those that do will require a prolongation

all cardiac arrest interventions in both groups is delivered in accordance

of their hospital stay and may have long-term incapacity and disability.

with Resuscitation Council (UK) guidelines [18].

These events will be recorded as outcome measures. As such, adverse events and adverse device events will only be recorded where the event

Mech-CPR (intervention group)

is potentially related to trial participation (i.e. may have resulted from study

In participants randomised to the mechanical chest compression trial arm, a

treatment) and the event is unexpected. Events are only recordable if they

LUCAS-2 or LUCAS-3 device (Jolife AB/Stryker, Lund, Sweden) is deployed

occur prior to the participant being discharged from hospital.

as early as possible following randomisation. The device is used in place of manual chest compressions as long as continued resuscitation is indicated.

Expedited reporting is required for recordable adverse events and adverse device events that meet standardised criteria for seriousness,

Cardiac arrest teams are trained to minimise pauses in chest

namely events that: result in death, are immediately life-threatening,

compression delivery during device deployment. The device is deployed

require hospitalisation or prolongation of existing hospitalisation, result

in two phases (1- insertion of the back plate; 2- deployment of the upper

in persistent or significant disability or incapacity, result in congenital

part of the device), with chest compressions delivered between the two

abnormality or birth defect, or result in an important medical condition.

phases. Teams aim for the maximum chest compression pause during each phase to be less than ten seconds. The training method being

Sample size

used is modelled on our preparatory manikin work [19].

The planned sample size is 330 participants. This number is based on two separate calculations.

Man-CPR (control group) Firstly, in relation to the primary outcome, we project a total eligible

receive manual chest compressions. Where available, the cardiac arrest

sample size of 550 participants at study sites over the study period.

team may use a real-time audiovisual feedback device to guide the

Based on a recruitment rate of 60%, a sample size of 330 randomised

quality of manual chest compressions.

patients will allow us to estimate the 95% confidence interval of the recruitment rate with sufficient precision (i.e. 55.9 to 64.1%) to support

Data collection and management

progression to an effectiveness trial.

Study data are collected by site research teams. Anonymised data are transferred securely to the trial co-ordinating centre. Study data items and

Secondly, we will use the approach of comparing groups using an 80%

definitions match, as far as possible, those used for the UK-based National

one-sided confidence interval, as described by Cocks and Torgerson,

Cardiac Arrest Audit [1]. Table 2 shows an overview of data to be collected

to establish if a clinically meaningful difference between groups in an

and the corresponding assessment time-point. In participants that consent to

effectiveness trial can be ruled out, thereby precluding progression to

follow-up, the period of follow-up is six months after the cardiac arrest event.

an effectiveness trial [20]. For an effectiveness trial, a sample size of 3554 patients would be required to detect a 3.5% absolute improvement

Adverse events/adverse device events

in 30-day survival at a power of 90% and a significance level of 0.05. As

COMPRESS-RCT enrols a population of participants who are in an

such, 9% of 3554 (320) is required for our feasibility study, which has

immediately life-threatening situation. The majority of participants are

been slightly increased to account for patients lost to follow-up [20].

RESUSCITATION TODAY - AUTUMN 2018

In patients randomised to the man-CPR arm, patients continue to

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CLINICAL PAPER Statistical analysis

high-quality large randomised controlled trials have produced consistent

Feasibility outcomes will be reported using descriptive statistics. Categorical

results, showing no benefit in the routine use of mech-CPR compared

data will be described as frequency and percentage. Continuous data will

with man-CPR [10]. Such data highlights the value of using high-quality

be assessed for normality, and described as mean and standard deviation

randomised controlled trials, where available, as a basis for policy-

or median and interquartile range as appropriate.

making.

We will report and analyse patient and process outcomes as we

To date, cardiac arrest randomised controlled trials have tended to focus

would for an effectiveness trial. Analyses will be undertaken on an

on the out-of-hospital setting. A systematic review of cardiac arrest

intention-to-treat basis. For dichotomous outcomes, we will describe

randomised controlled trials published between 2002 and 2012 identified

differences between groups as risk ratio and 95% confidence interval.

61 trials, of which only three (5%) included in-hospital cardiac arrest

For continuous outcomes, we will report mean difference and 95%

patients [29]. Differences between out-of-hospital and in-hospital cardiac

confidence interval. In addition, for the outcome of 30-day survival, we

arrest in terms of patient characteristics and clinical response limit the

will compare groups using an 80% one-sided confidence interval, based

direct generalisability of research findings between these settings [1, 30].

on the approach described by Cocks and Torgerson [20]. We will report

Furthermore, it likely means that experience and lessons learned from

both unadjusted analyses, and analyses adjusted for key baseline

the successful delivery of out-of-hospital cardiac arrest research cannot

characteristics.

necessarily be directly transferred to the in-hospital setting [31].

Qualitative study

COMPRESS-RCT will provide important new information as to the

The qualitative aspect of the study will be undertaken at centres

feasibility of conducting a randomised controlled trial of mech-CPR in

participating in the clinical trial, and will explore staff member’s

the hospital setting. More broadly, we will provide new insight in to the

experiences of being involved in the trial, as well as potential barriers

challenges of both delivering cardiac arrest research on a 24/7 basis in

and facilitators to recruitment. Following written informed consent, a

an acute hospital.

researcher will conduct a digitally audio recorded face-to-face semistructured interview with the staff member about their experience of the

Trial status

COMPRESS-RCT study. Staff members will be purposively sampled to

The current approved protocol is version 3.0, dated 29th January

ensure a diverse sample based on factors such as clinical role, study

2018. The full protocol is included in the electronic supplement. Trial

site, and whether or not a patient was actually randomised to the study.

recruitment is ongoing. Trial recruitment commenced February 2017,

Recruitment will continue recruitment until data saturation is achieved,

with a scheduled end date of February 2019.

which is anticipated to be approximately 30 participants [21, 22].

Interviews will be transcribed verbatim. Data will be analysed using a constant comparative method that is informed by a grounded theory approach [23]. We will review each interview on its completion and compare it to other interview data. This process will enable us to identify patterns and themes within the dataset, and may facilitate the development of a conceptual model to describe potential and actual barriers to recruitment, together with possible solutions.

Trial oversight/monitoring The trial is managed by a trial management group that meets on a monthly basis. The management group is comprised of clinical coapplicants, a methodologist, administrative staff, and patient research ambassadors. Independent oversight is provided through a trial RESUSCITATION TODAY - AUTUMN 2018

oversight committee, comprised of an independent chair and trial management group members. The oversight committee meets on a sixmonthly basis. The oversight committee chair, trial statistician, and an independent clinical expert review unblinded outcome data in a closed meeting following each oversight committee meeting.

Discussion The time-critical nature of cardiac arrest makes research on the effectiveness of cardiac arrest interventions both practically and ethically challenging [24]. Observational studies provide useful insights in to the effectiveness of interventions, but are prone to biases, such as selection bias and the recently described resuscitation time bias [24, 25]. In the out-of-hospital setting, observational studies of mech-CPR have produced inconsistent findings [26–28]. In contrast, findings of

10

Abbreviations CPR: cardiopulmonary resuscitation; EQ-5D-5 L: EuroQOL- 5 dimensions- 5 levels; Man-CPR: manual cardiopulmonary resuscitation; Mech-CPR: mechanical cardiopulmonary resuscitation; SF-12: 12-item short form survey Acknowledgements COMPRESS-RCT collaborators.

Catherine Baldock (University Hospitals Coventry and Warwickshire NHS Trust).

Christopher Bassford (University Hospitals Coventry and Warwickshire NHS Trust).

Roger Beadle (South Warwickshire NHS Foundation Trust).

Sukhdeep Dosanjh (Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK).

Anthony Freestone (Blackpool Teaching Hospitals NHS Foundation Trust).

Jonathan Hulme (Sandwell and West Birmingham Hospitals NHS Trust).

Catherine Lawrence (Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK. Funding This research is funded by an NIHR Post-Doctoral Research Fellowship (PDF 2015-08109). A condition of funding was the use of an unequal randomisation ratio. Otherwise, the funder had no role in the design of the study, data collection, data analysis and interpretation, or the writing of the manuscript. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Some support for equipment is provided by Jolife AB/Stryker, who manufacture the LUCAS mechanical chest compression device. Jolife AB/Stryker have no role in the design of the study, data collection, data analysis and interpretation, or the writing of the manuscript.

Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analysed.

Authors’ contributions All authors contributed to the design of the trial. KC, TQ, RL, AD, KS, and GDP contributed to the application for research funding. All authors have read and approved the final manuscript.

CLINICAL PAPER Ethics approval and consent to participate The trial was approved by the West Midlands - Coventry & Warwickshire Research Ethics Committee, who waived the requirement to seek consent from patient participants prior to enrolment.

Consent for publication Not applicable Competing interests TQ, RL, and GDP were investigators on the PARAMEDIC trial, which was an NIHR funded trial that evaluated the use of mechanical chest compression devices in the prehospital setting. The remaining authors declare that they have no competing interests.

Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author details 1 Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK. 2University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. 3Emergency, Cardiovascular and Critical Care Research Group, Faculty of Health, Social Care and Education, Kingston University, London and St George’s, University of London, London, UK. 4University of Warwick, Coventry, UK. 5Warwick Research in Nursing, Warwick Medical School, University of Warwick, Coventry, UK.

RESUSCITATION TODAY - AUTUMN 2018

References 1. Nolan JP, Soar J, Smith GB, Gwinnutt C, Parrott F, Power S, Harrison DA, Nixon E, Rowan K, National Cardiac Arrest a Incidence and outcome of in-hospital cardiac arrest in the United Kingdom National Cardiac Arrest Audit. Resuscitation.

2014;85(8):987–992. doi: 10.1016/j.resuscitation.2014.04.002.

2. Abella BS, Alvarado JP, Myklebust H, Edelson DP, Barry A, O’Hearn N, Vanden Hoek TL, Becker LB. Quality of cardiopulmonary resuscitation during in-hospital cardiac arrest. JAMA. 2005;293(3):305–310. doi: 10.1001/jama.293.3.305.

3. Talikowska M, Tohira H, Finn J. Cardiopulmonary resuscitation quality and patient survival outcome in cardiac arrest: a systematic review and meta-analysis.

Resuscitation. 2015;96:66–77. doi: 10.1016/j.resuscitation.2015.07.036.

4. Idris AH, Guffey D, Pepe PE, Brown SP, Brooks SC, Callaway CW, Christenson J, Davis DP, Daya MR, Gray R, et al. Chest compression rates and survival following out-of-hospital cardiac arrest. Crit Care Med. 2015;43(4):840–848. doi: 10.1097/ CCM.0000000000000824.

5. Stiell IG, Brown SP, Nichol G, Cheskes S, Vaillancourt C, Callaway CW, Morrison LJ, Christenson J, Aufderheide TP, Davis DP, et al. What is the optimal chest compression depth during out-of-hospital cardiac arrest resuscitation of adult patients? Circulation. 2014;130(22):1962–1970. doi: 10.1161/ CIRCULATIONAHA.114.008671.

6. Couper K, Smyth M, Perkins D. Mechanical devices for chest compression: to use or not to use? Curr Opin Crit Care. 2015;21(3):188. doi: 10.1097/ MCC.0000000000000200.

7. Wik L, Olsen J-A, Persse D, Sterz F, Lozano M, Jr, Brouwer MA, Westfall M, Souders CM, Malzer R, van Grunsven PM, et al. Manual vs. integrated automatic load-distributing band CPR with equal survival after out of hospital cardiac arrest.

The randomized CIRC trial. Resuscitation. 2014;85(6):741–748. doi: 10.1016/j. resuscitation.2014.03.005.

8. Perkins GD, Lall R, Quinn T, Deakin CD, Cooke MW, Horton J, Lamb SE, Slowther AM, Woollard M, Carson A, et al. Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial. Lancet. 2015;385(9972):947–955. doi: 10.1016/S01406736(14)61886-9.

9. Rubertsson S, Lindgren E, Smekal D, et al. Mechanical chest compressions and simultaneous defibrillation vs conventional cardiopulmonary resuscitation in outof-hospital cardiac arrest: the linc randomized trial. JAMA. 2014;311(1):53–61. doi: 10.1001/jama.2013.282538.

10. Gates S, Quinn T, Deakin CD, Blair L, Couper K, Perkins GD. Mechanical chest compression for out of hospital cardiac arrest: systematic review and meta-analysis. Resuscitation. 2015;94:91–97. doi: 10.1016/j. resuscitation.2015.07.002.

11. Couper K, Yeung J, Nicholson T, Quinn T, Lall R, Perkins GD. Mechanical chest compression devices at in-hospital cardiac arrest: a systematic review and metaanalysis. Resuscitation. 2016;103:24–31. doi: 10.1016/j.resuscitation.2016.03.004.

12. Savovic J, Jones HE, Altman DG, Harris RJ, Juni P, Pildal J, Als-Nielsen B, Balk EM, Gluud C, Gluud LL, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med. 2012;157(6):429–438. doi: 10.7326/0003-4819-157-6-201209180-00537.

13. Dechartres A, Boutron I, Trinquart L, Charles P, Ravaud P. Single-center trials show larger treatment effects than multicenter trials: evidence from a metaepidemiologic study. Ann Intern Med. 2011;155(1):39–51. doi: 10.7326/00034819-155-1-201107050-00006.

14. Perkins GD, Kocierz L, Smith SC, McCulloch RA, Davies RP. Compression feedback devices over estimate chest compression depth when performed on a bed. Resuscitation. 2009;80(1):79–82. doi: 10.1016/j.resuscitation.2008.08.011.

15. Nishisaki A, Nysaether J, Sutton R, Maltese M, Niles D, Donoghue A, Bishnoi R, Helfaer M, Perkins GD, Berg R, et al. Effect of mattress deflection on CPR quality assessment for older children and adolescents. Resuscitation. 2009;80(5):540– 545. doi: 10.1016/j.resuscitation.2009.02.006.

16. Couper K, Kimani PK, Davies RP, Baker A, Davies M, Husselbee N, Melody T, Griffiths F, Perkins GD. An evaluation of three methods of in-hospital cardiac arrest educational debriefing: the cardiopulmonary resuscitation debriefing study.

Resuscitation. 2016;105:130–137. doi: 10.1016/j.resuscitation.2016.05.005.

17. Couper K, Kimani PK, Abella BS, Chilwan M, Cooke MW, Davies RP, Field RA, Gao F, Quinton S, Stallard N, et al. The system-wide effect of real-time audiovisual feedback and Postevent debriefing for in-hospital cardiac arrest: the cardiopulmonary resuscitation quality improvement initiative. Crit Care Med. 2015;43(11):2321–2331. doi: 10.1097/CCM.0000000000001202.

18. Resuscitation Guidelines [https://www.resus.org.uk/resuscitation-guidelines/].

Accessed 26 Aug 2018.

19. Couper K, Velho RM, Quinn T, Devrell A, Lall R, Orriss B, Yeung J, Perkins GD. Training approaches for the deployment of a mechanical chest compression device: a randomised controlled manikin study. BMJ Open. 2018;8(2) 20. Cocks K, Torgerson DJ. Sample size calculations for pilot randomized trials: a confidence interval approach. J Clin Epidemiol. 2013;66(2):197–201. doi: 10.1016/j.jclinepi.2012.09.002.

21. Onwuegbuzie AJ, Leech NL. A call for qualitative power analyses. Quality & Quantity. 2007;41(1):105–121. doi: 10.1007/s11135-005-1098-1.

22. Onwuegbuzie AJ, Collins KMT. A typology of mixed methods sampling designs in social science research. Qualitative Report. 2007;12(2):281–316.

23. Charmaz K. Constructing grounded theory: a practical guide through qualitative analysis. Thousand oaks, California: Sage Publications; 2006.

24. Couper K, Perkins GD. Improving outcomes from in-hospital cardiac arrest. BMJ. 2016;353 25. Andersen LW, Grossestreuer AV, Donnino MW. “Resuscitation time bias”-a unique challenge for observational cardiac arrest research. Resuscitation. 2018;125:79– 82. doi: 10.1016/j.resuscitation.2018.02.006.

26. Bonnes JL, Brouwer MA, Navarese EP, Verhaert DVM, Verheugt FWA, Smeets JLRM, de Boer M-J. Manual cardiopulmonary resuscitation versus CPR including a mechanical chest compression device in out-of-hospital cardiac arrest: a comprehensive meta-analysis from randomized and observational studies. Ann Emerg Med. 2016;67(3):349–360. doi: 10.1016/j.annemergmed.2015.09.023.

27. Youngquist ST, Ockerse P, Hartsell S, Stratford C, Taillac P. Mechanical chest compression devices are associated with poor neurological survival in a statewide registry: A propensity score analysis. Resuscitation. 2016;106:102–7. doi: 10.1016/j.resuscitation.2016.06.039.

28. Zeiner S, Sulzgruber P, Datler P, Keferböck M, Poppe M, Lobmeyr E, van Tulder R, Zajicek A, Buchinger A, Polz K, et al. Mechanical chest compression does not seem to improve outcome after out-of hospital cardiac arrest. A single center observational trial. Resuscitation. 2015;96:220–225. doi: 10.1016/j. resuscitation.2015.07.051.

29. Whitehead L, Perkins GD, Clarey A, Haywood KL. A systematic review of the outcomes reported in cardiac arrest clinical trials: the need for a core outcome set.

Resuscitation. 2015;88:150–157. doi: 10.1016/j.resuscitation.2014.11.013.

30. Hawkes C, Booth S, Ji C, Brace-McDonnell SJ, Whittington A, Mapstone J, Cooke MW, Deakin CD, Gale CP, Fothergill R, et al. Epidemiology and outcomes from out-of-hospital cardiac arrests in England. Resuscitation. 2017;110:133–140. doi: 10.1016/j.resuscitation.2016.10.030.

31. Pocock H, Deakin CD, Quinn T, Perkins GD, Horton J, Gates S. Human factors in prehospital research: lessons from the PARAMEDIC trial. Emerg Med J. 2016;33(8):562–568. doi: 10.1136/emermed-2015-204916.

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CLINICAL PAPER

HOW DOES THE LENGTH OF CARDIOPULMONARY RESUSCITATION AFFECT BRAIN DAMAGE IN PATIENTS SURVIVING CARDIAC ARREST? A SYSTEMATIC REVIEW Clare Welbourn1* and Nikolaos Efstathiou2 Reproduced with permission from the Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. (2018) 26:77 doi: 10.1186/s13049-018-0476-3

Abstract Background

Results

Brain injury can occur after cardiac arrest due to the effects of

Seven cohort studies were included for review. Quality scores ranged

ischaemia and reperfusion. In serious cases this can lead to

from eight to 11 out of 12. Five of the studies found a significant

permanent disability. This risk must be considered when making

association between shorter duration of resuscitation and favourable

decisions about terminating resuscitation. There are very specific

neurological outcome.

rules for termination of resuscitation in the prehospital setting however a similar rule for resuscitation in hospital does not exist. The aim of

Conclusions

this review was to explore the effects of duration of cardiopulmonary

There is generally a better neurological outcome with a shorter duration

resuscitation on neurological outcome in survivors of both in-hospital

of CPR in survivors of cardiac arrest however a cut-off beyond which

and out-of-hospital cardiac arrest achieving return of spontaneous

resuscitation is likely to lead to unfavourable outcome could not be

circulation in hospital.

determined and is unlikely to exist. The findings of this review could be considered by clinicians making decisions about terminating

Methods

resuscitation. This review has highlighted many gaps in the knowledge

A systematic review was conducted. Five databases were searched in

where future research is needed; a validated and reliable measure of

addition to hand searching the journals Resuscitation and Circulation

neurological outcome following cardiac arrest, more focused research

and reference lists, quality of the selected studies was assessed and

on the effects of duration on neurological outcome and further research

a narrative summary of the data presented. Studies reporting relevant

into the factors leading to brain damage in cardiac arrest.

outcomes were included if the participants were adults achieving return of spontaneous circulation in the hospital setting. Studies

Keywords

looking at additional interventions such as extracorporeal resuscitation

Literature review, Systematic review, Cardiopulmonary resuscitation,

and therapeutic hypothermia were not included. Case studies were

Advanced life support, Cardiac arrest, Neurological outcome, Time

excluded. The study period was from January 2010 to March 2016.

factors, Decision making

Background leading to neuronal damage [5]. Reperfusion injury occurs when CPR is

leading to sudden loss of consciousness and absence of pulse and

commenced, bringing about oxidative stress and the formation of free

respiratory function [1]. In 2010, Berdowski et al. estimated that the global

radicals and reactive oxygen species [6]. These are very damaging and

incidence of out of hospital cardiac arrests was 55 arrests per 100,000

react with many macromolecules, including DNA, proteins and lipids. In

person-years [2]. Since the 1960s, cardiopulmonary resuscitation (CPR)

addition, global reperfusion leads to activation of leukocytes causing an

has been used to attempt to restart the heart following cardiac arrest [3],

inflammatory stress response, disrupting the blood-brain barrier, causing

however prognosis is poor, with a global average survival rate of 7% [2].

further damage by fluid leaking into the intracellular space leading to

There is currently limited evidence available to clinicians to guide their

cerebral oedema [6]. CPR partially reverses the ischaemia but it is not as

decisions about continuation of CPR and its possible impact on outcomes.

effective as the heart, and cerebral perfusion pressure remains low until ROSC is achieved, at which point further reperfusion damage occurs [7].

Cardiac arrest followed by CPR and subsequent return of spontaneous circulation (ROSC) leads to global ischaemia-reperfusion injury. The abrupt

Brain damage can seriously impact the lives of survivors of CPR sometimes

cessation of blood flow causes ischaemia and hypoxia. Cell membrane

causing permanent disability. Studies have demonstrated that psychosocial

ion transporters, which require oxygen-dependent adenosine triphosphate,

and cognitive impairment are more common in those surviving cardiac

stop functioning. Calcium floods into the cells [4], promoting apoptosis,

arrest with a brain injury; anxiety, depression and post-traumatic stress

in addition to excitotoxicity, whereby neurotransmitters are over-stimulated

disorder are increased; and social interaction is reduced [8, 9].

* 1

Correspondence: clare.welbourn@btinternet.com College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Full list of author information is available at the end of the article

RESUSCITATION TODAY - AUTUMN 2018

Cardiac arrest is the cessation of effective contraction of the myocardium

17

CLINICAL PAPER

Table 1 Search strategy Database

Keywords

Cinahl (EbscoHost)

Resuscitation, Cardiopulmonary (MeSH)

Limits duration

neurolog*

Jan 10 – Mar 16

time

cogniti*

English

“cerebral performance” “function* outcome” Medline (OVID)

Cardiopulmonary resuscitation (MeSH)

duration

neurolog*

Jan 10 – Mar 16

time

cogniti*

English

“cerebral performance” “function* outcome” PubMed (NCBI)

“Cardiopulmonary resuscitation”

duration

neurolog*

Jan 10 – Mar 16

“Advanced cardiac life support”

time

cogniti*

English

“Advanced life support”

“cerebral performance” “function* outcome”

Web of science

“Cardiopulmonary resuscitation”

duration

neurolog*

Jan 10 – Mar 16

“Advanced cardiac life support”

time

cogniti*

English

“Advanced life support”

“cerebral performance” “function* outcome”

Scopus

“Cardiopulmonary resuscitation”

duration

neurolog*

Jan 10 – Mar 16

“Advanced cardiac life support”

time

cogniti*

English

“cerebral performance”

Health sciences

“function* outcome”

Life sciences

“Advanced life support”

RESUSCITATION TODAY - AUTUMN 2018

18

Fig. 1 Flowchart of the literature search and selection process

CLINICAL PAPER Table 2 Eligibility criteria for the selection of papers Inclusion

Exclusion

Population

Adults survivors of cardiac arrest receiving Animal studies; paediatrics resuscitation in hospital

Intervention

CPR duration described as collapse to ROSC

Outcomes measured

Neurological outcome of survivors of CPR Studies in which CPR duration is not compared with neurological outcome

Prehospital ROSC; additional interventions including but not limited to extracorporeal resuscitation, therapeutic hypothermia

Type of article

Research studies

Case studies

Language

English

Papers not published in English

Date

Published from 01/01/2010

Published prior to 2010

In addition, memory loss is particularly common after cardiac arrest [10].

Search methods

It is unclear whether ischaemic-reperfusion damage is the direct cause,

A search of Cinahl, Medline, PubMed, Scopus and Web of Science

due to the life-changing impact any critical illness may have. However,

was conducted in March 2016. Since not all databases used

it has been demonstrated that the brain regions associated with these

medical subject headings (MeSH), a combination of MeSH terms

problems are more susceptible to anoxic injury [5].

and keywords were used (Table 1). An example of this is given in Additional file 1: Appendix 1. Creation of the search string was

Considering the damaging effects of CPR, the difficult decision about

overseen by a subject specific librarian. In addition, reference lists

when to terminate resuscitation attempts in those with no ROSC must

of relevant papers and the journals Resuscitation and Circulation,

be made by healthcare professionals. Although extensive research

which are the European Resuscitation Council and AHA’s journals

has been conducted in order to create and validate the Termination

respectively, were hand searched. All retrieved papers were entered

of Resuscitation rule for the prehospital setting [11], current

on a reference management software (RefWorks), and duplicates

guidelines for the hospital setting are ambiguous. Both the UK and

were removed. Potentially relevant articles were then screened

European Resuscitation Councils suggest considering terminating

based on title and then on reading the abstract. If they appeared

CPR after 20 min of asystole [12, 13], however this has little empirical

relevant, the full-text articles were assessed for eligibility (Fig. 1).

support. The American Heart Association (AHA) guidelines simply

The literature search period was from January 2010 to March 2016.

state that clinical judgement should be used to make the decision [14]. Ultimately potential risks and benefits of carrying on CPR must be weighed up, therefore the possibility of a link between prolonged CPR and brain injury, should influence decisions for CPR termination when there is no ROSC. Brain injury is always a risk in cardiac arrest patients achieving ROSC, however it is possible that prolonged CPR may cause further damage due to reduced cardiac output during resuscitation. This review seeks to explore whether the risk of brain damage increases with prolonged CPR in the hospital setting. Previous research has looked at various aspects of CPR, though evidence focusing on this area has not been reviewed in a systematic way. The aims of this systematic review were therefore survivors of both in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA) achieving ROSC in hospital and to investigate whether there is a maximum duration of CPR to avoid or reduce the risk of unfavourable outcome.

2. Studies reporting CPR on children were not included due to the differences in aetiology and physiology of cardiac arrest [16].

Paediatrics tend to have a much higher survival rate but poorer neurological outcome, therefore this could bias the synthesis of findings of this review [17].

Data extraction Information from the included studies was extracted on an Excel data extraction form and consisted of the studies’ characteristics (bibliographic details, aims and objectives of the study, methodology, population and setting) and related findings (Table 3). Data extraction was completed by one author (CW) and overread by the second author (NE). The level of agreement following overreading was high (>85%) and any disagreements were discussed and resolved between the authors.

Quality appraisal The National Institute of Health’s [18] Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies which focuses on

Methods

key study components such as participants, measurement of variables and control of confounders was selected to appraise the papers, but was adapted to simplify it and increase its relevance to the studies

In order to conduct a systematic review in a way that minimised bias,

appraised (Table 4). Repeated exposure assessment and follow-up rate

the PRISMA statement, which is designed for the reporting of systematic

were removed as they were not relevant to the study type. The papers

reviews, particularly intervention studies, was followed [15]. A protocol

were given a score out of 12 based on how many questions were

for this systematic review was developed by the author and a reviewer

answered favourably. The appraisal was performed by one reviewer

experienced in systematic reviews.

(CW) and checked by a second reviewer (NE).

RESUSCITATION TODAY - AUTUMN 2018

to explore the effects of duration of CPR on neurological outcome in

Inclusion and exclusion criteria for the review are presented in Table

19

RESUSCITATION TODAY - AUTUMN 2018

20 National CA database (GWTG-R registry)

Cohort study

to investigate whether duration of resuscitation attempt varies between hospitals and whether patients at hospitals that attempt resuscitation for longer have higher survival rates than those with shorter durations of resuscitation efforts

USA

Duration of resuscitation effors and survival after in-hospital cardiac arrest: an observational study

Goldberg et al., 2012 [22]

Medical records (Utstein format) interviewing patients, NOK, GP, neurologist

Cohort study

to identify factors associated with 90-day favourable functional outcomes in adults admitted to the ICU after succesful resuscitation of intra-operative CA

France

Predictors of functional outcome after intraoperative cardiac arrest

Constant et al., 2014 [21]

National CA database (GWTG-R registry)

Cohort study

to develop a valid and clinically useful risk prediction tool among succesfully resuscitated patients with an IHCA, to estimate favourable neurological survival

USA (Not stated in study)

A validated prediction tool for initial survivors of in-hospital cardiac arrest

Chan et al., 2012 [20]

Data collection

Study design

Aims/ objectives

Country of origin

Title

Author, year of publication

Table 3 Data extraction table for included studies

56.4

55.8

60 (46–70)

69 (57–78)

140

64,339 (8724 with CPC score)

56

68 (56–78) Mean 66

42,957

Gender (% male)

Age (yrs) median (IQR) or mean ± SD

n=

Incl: 2000–2008; adults (≥18 yrs); first CA during inpatient stay Excl: ICD; arrest location ED, OT, post-op, procedural areas, rehab areas; <2 mins arrest; incomplete data

Incl: 2000–2013; adults; received anaesthesia, admitted to ICU after succesful resuscitation

Incl: 2000–2009; adults (≥18 yrs), achieved ROSC Excl: Arrest location ED, OT, post-op, procedural areas; incomplete data

Inclusion (Incl) Exclusion (Excl)

Location

USA, multicentre, 551 hospitals

France, multicentre, 11 hospital ICUs

USA, multicentre, 435 hospitals

Type of CA

IHCA

IOCA

IHCA

Findings

Duration of CPR is a good predictor of neurological status at discharge

Shorter duration of CPR is associated with a more favourable outcome (CPC 1–2)

No significant link between duration of CPR and neurological outcome

Outcome measures

Neurologically favourable survival to discharge measured

by CPC score

Functional status at 90 days measured

by CPC score

Neurological status at discharge measured

by CPC score

CLINICAL PAPER

to describe neurological status and associated factors of survivors after CA, upon discharge and at six and twelve month follow ups

to assess the factors influencing outcome of CPR in ED

Brazil

China

One-year follow-up of neurological status of patients after cardiac arrest seen at the emergency room of a teaching hospital

Factors influencing outcomes after cardiopulmonary resuscitation in the emergency department

VanciniCampanharo et al., 2015 [25]

Xue et al., 2013 [26]

RESUSCITATION TODAY - AUTUMN 2018

Data collection

National research database (Utstein-style template) Case notes reviewed for data on functional status

Hospital CA database (Utstein-style template)

Utstein-style recording of consecutive IHCAs Neurological status evaluated with patient, family or guardian

Hospital registry Utstein-style template

Study design

Cohort study

Cohort study

Cohort study

Cohort study

Age (yrs) median (IQR) or mean ± SD 65 (56–65)

Mean 65.2

not stated

46.94 ± 19.05

n=

174

1014

16

725

Incl: 2011–2012; adults (≥17 yrs); resuscitated in ED; survivors to discharge

Incl: 2005–2011; adults (≥16 yrs) Excl: DNAR; incomplete data

71.6

Incl: 2005–2011; adults (≥18 yrs)

Incl: 2011–2013

Inclusion (Incl) Exclusion (Excl)

not stated

57.7

79.9

Gender (% male)

UK, single site, dedicated heart attack centre

USA, single site, ED

Brazil, single site, city hospital ED

China, single site, city hospital ED

Non-traumatic OHCA

OHCA

IHCA and OHCA

Location

OHCA

Type of CA

Shorter duration of CPR is independantly associated with survival to d/c with a favourable outcome (mRs of 0–3)

No significant link between duration of CPR and neurological outcome

CPR ≤15mins had significantly higher percentage of survivors with a neurologically favourable outcome

Neurological status at discharge, 1, 6 and 12 months measured

by CPC score

Neurologically favourable survival to discharge measured

by CPC score

Shorter duration of CPR is a powerful predictor of favourable functional outcome at discharge.

Functional status at discharge measured by mRS

Functional status at discharge measured by mRS

Findings

Outcome measures

Abbreviations: CA cardiac arrest, CPC cerebral performance category, CPR cardiopulmonary resuscitation, d/c discharge, ED emergency department, GWTG-R get with the guidelines-resuscitation, ICD implantable cardioverter defibrillator, ICU intensive care unit, IHCA in hospital cardiac arrest, IOCA intra-operative cardiac arrest, mRS modified Rankin scale, NOK next of kin, OHCA out of hospital cardiac arrest, OT operating theatre, post-op post-operative areas, ROSC return of spontatneous circulation

to estimate the dynamic probability of survival and functional recovery as a function of resuscitation effort duration to identify when to use novel therapies

USA

Duration of resuscitation effors and functional outcome after out-ofhospital cardiac arrest when should we change to novel therapies?

Reynolds et al., 2013 [24]

to determine the predictors of favourable functional status at discharge and long-term survival in patients experiencing out of hospital CA who are brought to a dedicated heart attack centre

UK

Predictors of survival and favourable outcomes after an out-of-hospital cardiac arrest in patients systematically brought to a dedicated heart attack cener (from the Harefield cardiac arrest study)

Iqbal et al., 2015 [23]

Aims/ objectives

Country of origin

Title

Author, year of publication

Table 3 Data extraction table for included studies (Continued)

CLINICAL PAPER

21

CLINICAL PAPER Table 4 Quality appraisal tool Research question

Are the research question and objectives clearly stated?

Recruitment

Are the recruitment methods and study population clearly described?

Baseline measured

Was the outcome of interest measured prior to exposure to gain a baseline for the participants? Was this accounted for when measuring the outcome?

Similar cohorts

Were eligibility criteria applied uniformly across cohorts and all participants recruited from the same or similar population?

Sample size

Is there a sample size justification, power description, or variance and effect estimates provided?

Causation

Was the exposure assessed prior to outcome measurement?

Time-frame

Was there sufficient time-frame to see an effect?

Exposure levels

Did the study examine different levels of the exposure of interest? (i.e. multiple categories of exposure or exposure measured as a continuous variable)?

Exposure measurement

Were the exposures (independent variables) measured in a way that minimised bias? Were they clearly defined, valid, reliable, and implemented consistently across all study participants?

Outcome measurement

Were the outcomes (dependent variables) measured in a way that minimised bias? Were they clearly defined, valid, reliable, and implemented consistently across all study participants?

Blinding

Were assessors blinded to exposure? (Where researchers are using data already collected, this would be yes)

Confounders

Were key potential confounding variables identified and controlled for in statistical analysis? (i.e. were regression models used?)

Analysis

Quality appraisal findings

Quantitative content analysis of the studies’ findings was undertaken

The papers were given quality scores ranging from eight to 11 out

as a meta-analysis was inappropriate due to the lack of homogeneity

of 12 (Table 5), using the appraisal process described. All studies

between the studies [19]. In addition to the primary outcome of interest,

had clear objectives. Appropriate approach and design were

which was the duration of CPR and associated neurological outcome,

always used, but not always clearly stated. The quality of selection

secondary outcomes including age, gender, initial rhythm and location

of participants was mixed. Five studies clearly demonstrated their

of arrest were considered in the analysis.

recruitment and sampling methods with eligibility criteria and had a clear description of the cohort in terms of age and sex [20 - 24].

Results

Other demographics such as ethnicity were not usually included.

In five of the studies it was unclear whether any neurological deficit prior to cardiac arrest was accounted for [21, 22, 23, 24,

Search outcomes

26]. However this may have had little impact as Chan et al. [20]

Following a systematic literature search in five databases, 2137 studies were

found that when restricting the cohort to include only those with a

found in total, with an additional 23 studies found from hand searching.

favourable neurological status it made little to no difference to the

After removing duplicates, 849 studies remained. These were screened for

overall results. All of the studies recruited participants from similar

relevance based on title and abstract. Based on title, 71 articles appeared relevant and a further 30 were selected based on their abstract. Twenty-three of these were discarded for not meeting the eligibility criteria for this review. The most frequent reasons for exclusion were that outcomes were not relevant to this review (Fig. 1). A total of seven studies were included in the review and were appraised for quality [20 - 26].

RESUSCITATION TODAY - AUTUMN 2018

22

All of the papers were cohort studies and generally used data collected routinely through national or hospital registries. Sample sizes ranged from 16 to 64,339. Out of the six studies which reported participants’ demographics, five had an average age of participants of over 60 years, with the sixth study’s participants considerably younger at 47 years. All had a greater number of males than females. Three studies reported findings from OHCA, three from IHCA and one study included both

cohorts. None of the studies provided justification for the choice of sample size however many of the studies had a large sample, therefore this does not necessarily reflect low quality. The study

by Vancini-Campanharo [25] had a small sample size of n = 16, and received a relatively low appraisal score, therefore it was not included in the comparative analysis due to high risk of bias.

Each of the studies reported a rigorous approach to measurement of the variables. In all studies exposure was assessed prior to outcome, which provides stronger evidence that the exposure caused the outcome. All studies had sufficient time-frame. All except one study [26] used different levels of exposure, either by using several time-categories or time as a continuous variable. All

OHCA and IHCA. Four of the studies were conducted at a single site

studies used Utstein-style reporting to minimise the risk of bias

and three were multicentre, with the majority conducted in Europe and

when measuring both CPR duration and neurological outcome. Five

the US. Five of the studies used Cerebral Performance Category (CPC)

were blinded to the outcome [20, 22, 23, 24, 26], as the data was

and two used the modified Rankin Scale (mRS) to measure neurological

not collected by the researchers; for the other two studies this is

outcome. Five studies measured the outcome at discharge, one

unclear [21, 25]. All studies had clear statistical methods and six

measured outcome at discharge with a follow-up at one, six and 12

of the studies controlled for confounding variables in their analysis

months and one measured 90 day outcome (Table 3).

[20, 21, 22, 23, 24, 26].

CLINICAL PAPER Data synthesis findings

8

8

10

10

10

9

11

favourable neurological outcome (CPC 1â&#x20AC;&#x201C;2 or mRS 0â&#x20AC;&#x201C;3) [20, 21, 23, 24, 26]. One study found no significant link between rate of favourable outcome and CPR duration but did find a worse outcome in those with a longer duration when looking at mean and median scores.

y

representative study population.

There was no obvious difference in neurological outcomes between the studies looking at OHCA and IHCA. Of the three studies looking

y

n unclear

y

y y

y

y

y y

unclear

y

y

This was one of the highest quality studies and had a very large,

solely at IHCA, two found a significant link [20, 21] and the other did not. The two studies including only OHCA both found a significant link between duration and neurological outcome. Three of the studies

y

y

y

y

y

y

looked at the average duration of favourable and unfavourable y

Outcome measurement

Blinding

Confounders

Score

Five studies found a significant link between shorter duration and

outcomes [21, 23, 24]. One of these studied IHCA and had an minutes for a poor outcome. Similarly the two OHCA studies had an average duration of four and 6.2 min for good outcome and 16

y

y

y

y

y

y

y

minutes in both studies for a poor outcome. One study including both IHCA and OCHA found that patients who had an OHCA had a

n

y

y

y

y

y

significantly worse outcome than IHCA.

y

Exposure levels

Exposure measurement

average of 6 minutes of CPR for a good outcome compared to 15

None of the studies looked at characteristics of those with and

y

y

y

y

y

y

y

of the studies did look at the association of various variables with neurological outcome. There was mixed evidence on the effect of age. Of the five studies which looked at age, three found that older

y

y

y

y

y

y

y

age is significantly linked with poorer outcome [20, 23, 24] and two found no significant link [21, 26]. Four studies also looked at gender and found no significant link to outcome [21, 23, 24, 26]. The most

n

n

n

n

n

n

notable other factor which was investigated in all studies was the n

Sample size

Causation

Timeframe

without neurological deficit at different durations, however many

relationship between neurological outcome and shockable (ventricular

y

y

y

y

y

y

(asystole or pulseless electrical activity) rhythm. Shockable rhythm y

Similar cohorts

fibrillation or pulseless ventricular tachycardia) or non-shockable was almost always associated with a significantly better neurological

unclear

y

unclear

unclear

unclear

unclear

y

non-shockable rhythms at different durations and found that duration

n

n

y

y

y

y

y

had a greater impact on shockable than non-shockable rhythms.

Discussion

y

y

y

y

y

y

This systematic review found seven studies of varying quality y

Research question

looked at the neurological outcomes of patients with shockable and

reporting on duration of CPR and neurological outcome. Generally, after a shorter time, however this review has revealed no definitive

Xue et al., 2013 [26]

Vancini-Campanharo et al., 2015 [25]

Iqbal et al., 2015 [23]

Reynolds et al., 2013 [24]

Constant et al., 2014 [21]

Goldberger et al., 2012 [22]

Chan et al., 2012 [20]

neurological outcomes were better in patients who achieved ROSC

Author, year

Table 5 Quality appraisal outcomes

only to be the case in OHCA. Only one of the highest quality studies

maximum duration, beyond which CPR may be futile. Due to the heterogeneity of data interpretation, analyses and reported outcomes, it was not possible to determine a time beyond which resuscitation would be unlikely to yield a favourable outcome. There was insufficient evidence to determine a meaningful difference between OHCA and IHCA. There was considerable variation in findings when looking at age as a factor in neurological outcome, though findings

RESUSCITATION TODAY - AUTUMN 2018

Recruitment

Baseline measured

outcome. The only exception to this was in one study which found this

that gender is irrelevant were conclusive. Shockable rhythm was a significant predictor of favourable outcome.

23

CLINICAL PAPER Most of the studies confirmed that more favourable outcomes were

different conclusions depending on whether selecting mean CPC

associated with shorter duration of CPR. In part, this echoes the

score (p = 0.0001) or proportion of people with favourable outcome

systematic review by Moulaert et al. [9] which investigated duration as

(p = 0.131) when interpreting the data. Despite the similarities in data

a confounding variable to cognitive impairment following OHCA. Of the

collection between the studies, there was considerable variation in data

two studies which identified confounding variables, both demonstrated

interpretation and presentation of results. Arguably, it is potentially more

an association between time to ROSC and cognitive outcome. However,

meaningful to focus on the proportion of people with a good or bad

in contrast to our findings, four studies in Moulaert et al.’s review found

outcome than average CPC score because of the discrete nature of

no confounding variables. By using number of doses of adrenaline

the CPC scale. Goldberger et al.’s [22] results are consistent with two

and number of shocks as proxy markers, Kaye [27] associated better

separate population groups – one with a good prospect of recovery, in

outcomes with shorter durations, however caution must be applied as

which duration of CPR had little effect, and a larger second group with

the methodology was unclear and of poor quality. Similar findings have

poorer prospects of recovery, and amongst whom damage was more

been reported in the prehospital setting; for example both Abe et al. [28]

likely to increase with time of CPR. This hypothesis could explain their

and Grunau et al. [29] found that favourable neurological outcome is

apparently conflicting results in which average CPC score correlates

more likely with a shorter time to ROSC. There were some differences

with CPR time, but percentage of good outcomes does not.

between those experiencing ROSC in the prehospital and the hospital setting. Abe et al. [28] and Matsuyama et al. [30] found when looking

If this interpretation is correct, it has important implications. If the

at patients with good outcomes, CPR duration was shorter in those

patient is likely to have a good outcome then prolonged CPR is

with prehospital ROSC. It would be interesting to explore whether this

justifiable, whereas in those cases where the arrest is likely to have

is influenced by the Termination of Resuscitation rule for the prehospital

a poor outcome this may worsen with prolonged CPR. It is therefore

setting.

important to better understand other arrest factors which have an impact on outcome. In Youness et al.’s [33] study of prolonged CPR,

Xue et al. [26] found that there was a significantly better neurological

the participants were generally young, with no co-morbidities and had

outcome in those who had an IHCA compared with those with OHCA.

cardiac arrest with reversible causes, however these findings are not

They also reported that arrests witnessed by medical staff had a

discussed in depth and further research is needed.

significantly better neurological outcome. Both of these findings are consistent with greater likelihood that time between arrest and

Significance between shockable rhythm and favourable outcome was

commencement of CPR was relatively short. Iqbal et al. [23] found that

identified across all studies in this review. Three large (n = 30,716,

bystander CPR also had a significant impact on neurological outcome.

64,339 and 91,658), good quality studies, exploring CPR duration,

It may be that the increased period of hypoxia whilst no CPR is being

found an association between shockable rhythm and shorter duration

carried out leads to brain damage further exacerbated by reperfusion

of resuscitation as a predictor of favourable neurological outcome [22,

injury. However Storm et al. [31] when investigating the effect of cerebral

35, 36]. This may be an indicator of the importance of cause of arrest in

oxygenation during CPR found that a low value at the beginning of

likelihood of survival with a good outcome. However, little research has

treatment on arrival of emergency services was not a good predictor of

been done to investigate the link between initial rhythm and neurological

ROSC or neurological outcome. In contrast, Parnia et al. [32] found that

outcome with prolonged CPR.

in IHCA, cerebral oxygenation values were a significant predictor of a neurologically favourable survival.

Only one of the papers in this review considered institutional duration of CPR. Goldberger et al. [22] found a higher overall survival rate in those

RESUSCITATION TODAY - AUTUMN 2018

24

Despite generally finding a significant correlation between duration

hospitals which had a longer average duration of CPR, but found no

and neurological outcome, the incidence of complete recovery after

difference between hospitals when looking at favourable neurological

prolonged CPR is high. For example Goldberger et al. [22] found

outcome to discharge. Cha et al. [36] similarly found a higher survival

that 73.8% of people receiving CPR for more than 30 min survived

rate with longer institutional duration of CPR. This implies that if CPR

neurologically intact. Case studies, which often report remarkable

were attempted for longer there may be a higher survival rate, which

outcomes, were excluded from this review due to the risk of publication

contradicts the majority of findings from this review. However Cha et

bias however their findings can be interesting and useful. In a review

al. did not report these findings in relation to neurological outcome

of all published cases of patients who underwent prolonged CPR of

of survivors. Hospitals which resuscitate for longer may give better

greater than 20 minutes, 78% recovered with a favourable neurological

quality resuscitation and more aggressive treatments which may lead to

outcome [33]. The median duration of resuscitation in the reviewed

increased survival [36]. This is an interesting area for future research.

cases by Youness [33] was 75 min with a range of 20–330 min. In these cases it appears that duration had little impact on outcome. It is fair

All the studies in this review adopted the Utstein-style for data collection.

to conclude it would be unethical to specify a maximum duration after

This is the internationally standardised format for reporting cardiac

which CPR should be terminated.

arrest data for both OHCA and IHCA [37], however, there is limited research demonstrating its validity and reliability. According to Utstein-

The study by Goldberger et al. [22] found no significant link between the

style reporting, neurological outcome following cardiac arrest should

rate of favourable neurological outcome and duration of resuscitation.

be recorded using either CPC or mRS [37]. These outcome measures

This was a high-quality study, with a very large sample size and has

are used in all the studies reviewed. There is no evidence to justify the

been widely referenced, including by the Resuscitation Council (UK)

assumption that this should improve the validity of the studies’ findings.

[34]. However they did find that mean and median CPC scores were

Studies have found a lack of validity and reliability of CPC and mRS due

higher in those who had a shorter duration. It is possible to reach very

to significant variability between the two; limited ability to differentiate

CLINICAL PAPER between levels of outcome; and lack of focus on any specific aspect

introduced but did not discriminate between large and small flaws. An

of functioning [38, 39, 40]. This may have affected the quality of

alternative may have been to use a scale however this may be more

our findings which would have been more reliable had there been a

subjective.

standardised measure for neurological outcome implemented across clinical practice.

The included studies relied on retrospective collection of registry data.

There is potential for errors in data collection, variation of recording

Since the searches were conducted there has been additional research

methods between hospitals or misinterpretation of data [22, 35]. It

published which would have met the inclusion criteria for this study. Four

would be highly unethical to conduct experimental studies in this area

studies, all set in the emergency department were found; one focused

of research. As with any systematic review, there is a risk of publication

on IHCA [41] two on OHCA [42, 43] and one studied both IHCA and

bias as many papers will only report significant findings. With only a

OHCA [44]. All four studies found that increased duration of CPR led

small number of relevant studies, it proved impossible to restrict studies

to a significantly poorer neurological outcome, which was measured

to only those of the highest quality. The limited similarity between

by CPC in three of the studies [41, 42, 43] and by ability to follow

studies prevented conducting a meta-analysis.

commands in the fourth [44]. The inclusion of these more recent studies would not have changed the conclusions of this review.

Overall this literature review included a number of steps to maintain quality. Bias was minimised by following the PRISMA procedure with

This review has identified some interesting findings that require further

minimal deviation. Reporting of methods was transparent throughout

investigation. It is unclear why some survivors of prolonged resuscitation

to increase replicability. Consistency of findings amongst the majority

had complete neurological recovery whilst others did not and further

of the studies increases confidence in the findings of this review. The

research focusing on duration of CPR, neurological outcome and the

findings are generalisable to the study population, as both IHCA and

factors that affect these may help to answer this.

OHCA in most hospital settings, all arrest types and a wide variety of hospitals and locations were included. The review sought only to study

Strengths and limitations

the adult population and therefore the findings cannot be applied to

To find all the literature on this topic, thorough, systematic searches

paediatrics.

were conducted. The risk of missing potentially relevant articles when searching was minimised by searching five different databases and hand searching relevant journals and reference lists. Creating a search strategy and selection of papers was only carried out by one reviewer

Conclusions

which is a limitation of this study, however this was overseen by a

Current guidelines on terminating in-hospital resuscitation are discussed

subject specific librarian and approved by a second reviewer.

very briefly, leaving healthcare professionals to use clinical judgement as the main factor when making these decisions. It is hoped that in the

The inclusion and exclusion criteria may be a further limitation for

future, enough conclusive evidence from quality research will lead to

this study. The search was limited to papers in English which could

provision of clearer guidance on terminating resuscitation in the hospital

introduce language bias. Due to frequent changes in CPR guidelines

setting. This systematic review sought to find out whether duration of

and ever-improving outcomes, the search was limited to studies

CPR has an impact on neurological outcome of survivors of cardiac

published after 2010 in order to keep a relatively narrow time-frame

arrest. Seven studies were included for review. These were appraised for

in which practices could be assumed to remain fairly consistent.

quality and were mostly of a high standard.

Wang et al. [45] found a higher probability of favourable neurological outcome with CPR conducted after 2010 due to the vast changes in

Key findings

guidelines that year, however only two of the studies were based entirely on data collected since 2010 with some including results reported in

• There is generally a better neurological outcome with a shorter duration of CPR in survivors of cardiac arrest, however a cut-off

practice. Therapies supplementary to advanced life support such as

beyond which resuscitation is likely to lead to unfavourable outcome

extracorporeal resuscitation or therapeutic hypothermia were excluded

was not possible to determine and is unlikely to exist, as many people

from the review. These may have an important effect on outcomes,

survive prolonged cardiac arrest with minimal consequences.

but would have led to a much more complex review with difficulty isolating the findings. Excluding this potentially large volume of literature

• There is not enough evidence to create a definitive rule for termination

means that caution should be used in extrapolating the findings to this

of CPR in the hospital setting. Clinicians should continue to take into

population. Excluding patients who achieved prehospital ROSC may

account that in many cases the chance of neurologically favourable

have introduced bias, however papers investigating prehospital ROSC

survival decreases the longer CPR is continued, however this alone is

report similar findings to those studies included for review [28 - 30].

not enough to make the decision to terminate efforts.

The similarity in the design and methods of the studies allowed comparisons to be drawn using the same appraisal tool across the

• There is a need for a validated and reliable measure of neurological outcome following cardiac arrest.

studies, maintaining objectivity and minimising bias. All parameters in the chosen appraisal tool were equally weighted despite the possibility

• Future research is required in several areas in order for more specific

of some having greater influence in the overall quality than others. The

guidelines around the duration of resuscitation attempts to be

appraisal tool highlighted the main areas in which bias could have been

created.

RESUSCITATION TODAY - AUTUMN 2018

2000. There is clearly a risk of variation associated with changes in

25

CLINICAL PAPER Abbreviations AHA: American Heart Association; CPC: Cerebral performance category; CPR: Cardiopulmonary resuscitation; IHCA: In-hospital cardiac arrest; MeSH: Medical subject headings; mRS: Modified Rankin Scale; OHCA: Out-of-hospital cardiac arrest; ROSC: Return of spontaneous circulation Acknowledgements Not applicable.

Funding No funding was received for this research.

Availability of data and materials All data generated or analysed during this study are included in this published article and tables.

Authors’ contributions CW conducted the literature searches, quality appraisal and analysis and interpretation of data and drafted the manuscript. NE made substantial contributions to the design of the review and critically revising the manuscript. All authors approved the final version of the manuscript.

Ethics approval and consent to participate Not applicable.

Consent for publication Not applicable.

Competing interests The authors declare that they have no competing interests.

Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author details College of Medical and Dental Sciences, University of Birmingham,

1

Edgbaston, Birmingham B15 2TT, UK. 2College of Medical and Dental Sciences, Institute of Clinical Sciences, School of Nursing, Medical School, University of Birmingham, Room EF15, Vincent Drive, Birmingham B15 2TT, UK. RESUSCITATION TODAY - AUTUMN 2018

26

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RESUSCITATION TODAY - AUTUMN 2018

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27

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