What do Cochrane systematic reviews say about cardiac arrest management?

ABSTRACT CONTEXT AND OBJECTIVE: Cardiac arrest is associated with high morbidity and mortality and imposes a significant burden on the healthcare system. Management of cardiac arrest patients is complex and involves approaches with multiple interventions. Here, we aimed to summarize the available evidence regarding the interventions used in cardiac arrest cases. DESIGN AND SETTING: Review of systematic reviews (SRs), conducted in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo. METHODS: A systematic search was conducted to identify all Cochrane SRs that fulfilled the inclusion criteria. Titles and abstracts were screened by two authors. RESULTS: We included nine Cochrane SRs assessing compression techniques or devices (three SRs), defibrillation (two SRs) and other interventions (two SRs on hypothermia interventions, one on airway management and one on pharmacological intervention). The reviews included found qualities of evidence ranging from unknown to high, regarding the benefits of these interventions. CONCLUSION: This review included nine Cochrane systematic reviews that provided a diverse range of qualities of evidence (unknown to high) regarding interventions that are used in management of cardiac arrest. High-quality evidence was found by two systematic reviews as follows: (a) increased survival until hospital discharge with continuous compression, compared with interrupted chest compression, both administered by an untrained person and (b) no difference regarding the return of spontaneous circulation, comparing aminophylline and placebo, for bradyasystolic patients under cardiac arrest. Further studies are needed in order to reach solid conclusions.


INTRODUCTION
Sudden cardiac arrest is an important cause of death and is responsible for 15% of total mortality in the United States. 1 Its occurrence is associated with a poor prognosis, despite the numerous interventions that are available for treating this condition. 2currences of sudden cardiac arrest are usually associated with an underlying structural heart disease, and coronary heart disease is the most frequent form (two thirds of the cases).
Other heart diseases such as myocarditis and hypertrophic cardiomyopathies are also common causes.When there is no structural disease, most cases occur due to arrhythmia, for which there are very many etiologies. 1,3,4veral criteria have been used to define cardiac arrest in the medical literature.In 2006, the American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/ AHA/HRS) established the standard definition for cardiac arrest as "sudden cessation of cardiac activity so that the victim becomes unresponsive, with no normal breathing and no signs of circulation.If corrective measures are not taken rapidly, this condition progresses to sudden death".
In current clinical practice, cardiac arrest is reversed mainly by cardiopulmonary resuscitation and/or cardioversion or defibrillation, or cardiac pacing. 5spite the importance of cardiac arrest, there is uncertainty regarding the use of most interventions that have been recommended for its management.Several guidelines for its treatment are available, but an analysis of the best evidence is always useful, to guide further studies and to update the recommendations with the best unbiased evidence.Hence, synthesis studies such as the present review are imperative for enabling critical analysis and for summarizing the results from primary research on cardiac arrest patients.
The aim of the present review was to identify and summarize the evidence from Cochrane systematic reviews (SRs) relating to interventions for managing cardiac arrest in any setting.

Design and setting
This was a review of Cochrane systematic reviews (SRs), conducted within the Discipline of Evidence-Based Medicine of Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM-Unifesp).This article was specifically developed for the section Cochrane Highlights, which is an initiative for disseminating Cochrane reviews.This initiative results from a formal partnership between the São Paulo Medical Journal and Cochrane, and it is supported by Cochrane Brazil.

Types of study
We included SRs published in the Cochrane Database of Systematic Reviews (CDSR).Protocols for SRs and withdrawn or previous versions of single SRs were not included.No limit for publication date was applied.

Types of participants
The participants comprised patients who had been diagnosed as presenting cardiac arrest, regardless of the setting (pre-hospital or in-hospital) or their age or sex.

Types of intervention
We considered SRs assessing any intervention (either pharmacological or non-pharmacological), whether applied separately or combined with others.

Types of outcomes
We considered any clinical or laboratory outcome, as evaluated by the authors of the SRs included.

Search for reviews
We conducted a sensitive search in the Cochrane Database of Systematic Reviews (CDSR) (via Wiley) on February 24, 2018, using the MeSH term "Heart Arrest" and all related variants, in titles, abstracts and keywords.The detailed search strategy is presented in Table 1.

Selection of reviews
The titles and abstracts were screened by two authors (RLP and RR) independently.Any disagreements were resolved by reaching a consensus.The SRs that met the inclusion criteria were selected and summarized by five authors (RLP, JT, CAS, BS, GA).

Presentation of results
The results from the search and the SRs included were presented through a narrative approach (qualitative synthesis).

Reviews included
We present a short individual summary of each SR included.

Details about the characteristics of interventions, comparisons,
outcomes and quality of evidence are presented in Table 2.

Active chest compression-decompression with a hand-held suction device
This review 6 had the aim of evaluating the use of active compression-decompression (ACD) for cardiopulmonary resuscitation (CPR), consisting of application of a hand-held suction device to the sternum.Ten randomized clinical trials (RCTs) were included, assessing either out-of-hospital settings (eight RCTs; 4,162 participants) or in-hospital settings (two RCTs; 826 participants).
Regarding out-of-hospital settings, no differences were found between active compression-decompression for cardiopulmonary resuscitation with a hand-held suction device and standard manual cardiopulmonary resuscitation (STR) regarding mortality either immediately (relative risk [RR]

Interrupted chest compression
Non-asphyxial out-ofhospital cardiac arrest When performed by an untrained person, continuous chest compression achieved higher rates of survival until hospital discharge but no difference in neurological outcomes.When performed by a trained person, there was no difference between the groups regarding survival or neurological outcomes.

Defibrillation Intervention
Comparators Population Main findings GRADE 17 Biphasic transthoracic defibrillation 8

Out-of-hospital cardiac arrest
No difference between the groups regarding survival until hospital discharge.No difference regarding failure to defibrillate and return of spontaneous circulation.
Not assessed Delayed defibrillation 13 Immediate defibrillation Out-of-hospital cardiac arrest No difference between the groups was found regarding survival until hospital discharge, good neurological outcome and return of spontaneous circulation.

Other interventions Intervention
Comparators Population Main findings GRADE 17 Aminophylline 9 No intervention Bradyasystolic cardiac arrest No difference between the groups regarding survival until hospital discharge and return of spontaneous circulation.

Low to high
Pre-hospital cooling 7 In-hospital cooling Cardiac arrest patients There was a lack of data for quantitative synthesis, but the individual RCTs included did not find differences between the groups.

Very low
Hypothermia 11 No intervention Cardiac arrest patients Conventional cooling was more likely to achieve a positive neurological outcome, increased survival and higher rates of adverse events (pneumonia and hypokalemia).

Low to moderate
Emergency intubation 14 Other airway management techniques (bag-valvemask ventilation, esophageal gastric tube or combi-tube)

Acutely ill and injured patients
For the comparison ETI versus bag-valve-mask ventilation and subsequently ETI, there was no difference between the groups regarding survival and good neurological outcome at hospital discharge.For the comparisons ETI versus esophageal gastric tube and ETI versus combi-tube, there was no difference in survival between the groups at hospital discharge.

Not assessed
RCTs = randomized clinical trials; ETI = endotracheal intubation.*GRADE (Grading of Recommendations Assessment, Development and Evaluation) has the aim of assessing the quality of the evidence.From this, the results are classified as having high quality of evidence (high confidence that the estimated effect is close to the true effect); moderate quality of evidence (likely that the estimated effect is close to the real effect but there is a possibility that it is not); low quality of evidence (limited confidence in the effect estimate) or very low quality of evidence (the true effect is likely to be substantially different from the estimate effect).
The authors concluded that the use of ACD with a hand-held suction device for CPR was not associated with any benefit in relation to cardiopulmonary resuscitation.

Mechanical versus manual chest compression for cardiac arrest
This review 10 assessed the efficacy and safety of mechanical chest compression in comparison with manual chest compression in cardiopulmonary resuscitation.Six RCTs were included (n = 1,166), although only one study reported the main clinical outcome of survival until hospital discharge with "good neurological function" (defined as cerebral performance category scores 15 of 1 or 2).The group that underwent mechanical chest compression had shorter survival than the group with manual chest compression (RR 0.41; 95% CI 0.21 to 0.79; one RCT; 767 participants).
Three RCTs assessed survival until hospital discharge.Because of the clinical and methodological diversity between them, no pooled analysis was performed and the data were reported only narratively.
One RCT reported a higher frequency of survival favoring the mechanical compression group (OR 2.81; 95% CI 1.26 to 6.24; one RCT; 152 participants) while the other two found that there was no difference between the groups: (OR 0.76; 95% CI 0.44 to 1.41; one RCT; 767 participants) and (OR 0.81; 95% CI 0.26 to 2.53; one RCT; 147 participants).
The authors concluded that there was insufficient evidence to reach any solid conclusion between the interventions evaluated.
Further studies of good methodological quality with well-reported results would be needed to reduce the uncertainties.

Continuous versus interrupted chest compression for cardiopulmonary resuscitation of non-asphyxial out-of-hospital cardiac arrest
This review 12  The authors concluded from the results from this review that there was a lack of precision in evaluations on biphasic and monophasic waveforms.The data showed that there was no benefit from using a biphasic defibrillator, although further studies would be warranted to increase the confidence in these results.For further details, refer to the original abstract, available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006762.pub2/full.

Cardiopulmonary resuscitation (CPR) plus delayed defibrillation versus immediate defibrillation for out-of-hospital cardiac arrest
This review 13  The authors' conclusion was that the overall quality of evidence was low (mainly due to the risk of bias among the studies included and the imprecision of the results).There was no difference between the two interventions, and further studies would be needed to reduce the uncertainties of this analysis.

Aminophylline for bradyasystolic cardiac arrest among adults
This review 9 aimed to determine the effects (harm and benefits) of aminophylline administered to patients who suffered bradyasystolic cardiac arrest.Five RCTs (n = 1,186) were included.All of them were performed in pre-hospital settings.
There was no difference between aminophylline and placebo administration regarding the following outcomes: • Survival until hospital discharge (odds ratio, OR 0.58; 95% CI 0.12 to 2.74; five RCTs; 1,254 participants).
There were insufficient data to evaluate neurological outcomes and adverse events.The authors concluded that prehospital administration of aminophylline was not associated with any improvement in clinical outcomes.For further details, read the original abstract, available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006781.pub3/full.

Pre-hospital versus in-hospital initiation of cooling for survival and neuroprotection after out-of-hospital cardiac arrest
This review 7 evaluated the initiation setting (pre-hospital versus in-hospital) of cooling applied to cardiac arrest patients.Seven RCTs were included (n = 2,369).The authors' aim was to assess the major clinical outcome of survival (short and long-term), along with neurological outcomes and safety outcomes (serious adverse events).Despite the considerable number of RCTs and participants, the authors did not perform any pooled analysis (quantitative synthesis) because of the existence of methodological heterogeneity.They stated that none of the RCTs found any statistical differences between the two intervention groups, but this may have been influenced by lack of statistical power and low event rates in single studies.
Further studies with good methodological quality and preplanned outcomes need to be conducted to reduce the uncertainty regarding where to initiate cooling among patients who have suffered cardiac arrest.Another key point is that this review performed a head-to-head analysis.The use of hypothermia compared with inactive control was studied in another Cochrane systematic review, discussed below. 11r further details, and to access the full report on all the RCTs included, refer to the original abstract, available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010570.pub2/full.

Hypothermia for neuroprotection among adults after cardiopulmonary resuscitation
The purpose of this review 11 was to investigate the effects (efficacy and safety) of therapeutic hypothermia after cardiac arrest.
Six RCTs (n = 1,412) were included.The main results were the following: • Conventional cooling was more likely to achieve a positive neurological outcome (RR 1.94; 95% CI 1.18 to 3.21; four RCTS; 437 participants) than was no cooling.
• The incidence of the adverse effect of pneumonia was higher in the intervention group (RR 1.15; 95% CI 1.02 to 1.30; two RCTs; 1,205 participants).There was also higher incidence of hypokalemia (RR 1.15; 95% CI 1.03 to 1.84; two RCTs; 975 participants).
The overall quality of the evidence was considered low to moderate.The authors concluded that hypothermia was beneficial for patients who suffered out-of-hospital cardiac arrest, but they emphasized that this intervention would need to be studied in other settings.

Emergency intubation for acutely ill and injured patients
This review 14  sometimes by an untrained person.This difficulty may be partly resolved by conducting clinical trials using nested designs, such as clustered designs, rather than using the widely used parallel design.However, this may lead to higher risk of bias and should be considered in planning further studies.
Regarding clinical implications, high-quality evidence was found in two systematic reviews as follows: Further studies are needed in order to reach solid conclusions.
(a) survival until hospital discharge is increased with continuous compression, when compared to interrupted chest compression, both administered by an untrained person and (b) there was no difference regarding the return of spontaneous circulation of bradyasystolic patients under cardiac arrest, comparing aminophylline and placebo.For all other comparisons and related outcomes, only very low to moderate evidence quality was found.Thus, clinical practice may be guided from the results presented in Table 2 and from those obtained through other study designs (especially well-performed comparative observational studies), but most of these findings may be subject to change in the light of data from future studies.Regarding the implications for further research, it is highly necessary to ensure that any future RCT on interventions relating to cardiac arrest should be planned.Such studies should only assess clinically relevant outcomes.The reporting of such studies needs to rigorously follow the guidelines of the CONSORT 18 statement, in order to enhance transparency and reproducibility.CONCLUSION Most of the nine Cochrane systematic reviews assessing CPR found no evidence or only provided limited evidence to allow any practical recommendation.High-quality evidence was found by two systematic reviews as follows: (a) survival until hospital discharge was increased with continuous compression, when compared to interrupted chest compression, both administered by an untrained person; and (b) there was no difference regarding the return of spontaneous circulation of bradyasystolic patients under cardiac arrest, comparing aminophylline and placebo.

Table 1 . Search strategy #1 MeSH descriptor: [Heart Arrest] explode all trees (in titles, abstracts and keywords)
There was no difference in the frequencies of complications (such as fractures and pneumothorax or hemothorax) between the groups (RR 1.09; 95% CI 0.86 to 1.38; seven RCTs; 3,032 participants).

Table 2 .
Characteristics of interventions, comparisons, outcomes and quality of evidenceOne RCT found improved neurological function and survival until hospital discharge, favoring mechanical chest compression.This result was inconsistent with others included in the RCT but no quantitative synthesis was performed because of heterogeneity of the data.
These interventions are commonly delivered by more than one person, which requires more training and elevates the clinical diversity between studies.Even the concept of "controlled" is challenged under these conditions, since most of the interventions are implemented in out-of-hospital settings, the gold-standard primary research design for evaluating the efficacy and safety of interventions.This may have happened partially because it is more difficult and very costly to perform RCTs under emergency conditions, and even more so during management of cardiac arrest.