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

Cardiac arrest is the cessation of effective contraction of the myocardium leading to sudden loss of consciousness and absence of pulse and respiratory function [1]. In 2010, Berdowski et al. estimated that the global incidence of out of hospital cardiac arrests was 55 arrests per 100,000 person-years [2]. Since the 1960s, cardiopulmonary resuscitation (CPR) has been used to attempt to restart the heart following cardiac arrest [3], however prognosis is poor, with a global average survival rate of 7% [2]. There is currently limited evidence available to clinicians to guide their decisions about continuation of CPR and its possible impact on outcomes.

Cardiac arrest followed by CPR and subsequent return of spontaneous circulation (ROSC) leads to global ischaemia-reperfusion injury. The abrupt cessation of blood flow causes ischaemia and hypoxia. Cell membrane ion transporters, which require oxygen-dependent adenosine triphosphate, stop functioning. Calcium floods into the cells [4], promoting apoptosis, in addition to excitotoxicity, whereby neurotransmitters are over-stimulated leading to neuronal damage [5]. Reperfusion injury occurs when CPR is commenced, bringing about oxidative stress and the formation of free radicals and reactive oxygen species [6]. These are very damaging and react with many macromolecules, including DNA, proteins and lipids. In addition, global reperfusion leads to activation of leukocytes causing an inflammatory stress response, disrupting the blood-brain barrier, causing further damage by fluid leaking into the intracellular space leading to cerebral oedema [6]. CPR partially reverses the ischaemia but it is not as effective as the heart, and cerebral perfusion pressure remains low until ROSC is achieved, at which point further reperfusion damage occurs [7].

Brain damage can seriously impact the lives of survivors of CPR sometimes causing permanent disability. Studies have demonstrated that psychosocial and cognitive impairment are more common in those surviving cardiac arrest with a brain injury; anxiety, depression and post-traumatic stress disorder are increased; and social interaction is reduced [8, 9]. In addition, memory loss is particularly common after cardiac arrest [10]. It is unclear whether ischaemic-reperfusion damage is the direct cause, due to the life-changing impact any critical illness may have. However, it has been demonstrated that the brain regions associated with these problems are more susceptible to anoxic injury [5].

Considering the damaging effects of CPR, the difficult decision about when to terminate resuscitation attempts in those with no ROSC must be made by healthcare professionals. Although extensive research has been conducted in order to create and validate the Termination of Resuscitation rule for the prehospital setting [11], current guidelines for the hospital setting are ambiguous. Both the UK and European Resuscitation Councils suggest considering terminating CPR after 20 min of asystole [12, 13], however this has little empirical support. The American Heart Association (AHA) guidelines simply 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 to explore the effects of duration of CPR on neurological outcome in 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.

In order to conduct a systematic review in a way that minimised bias, the PRISMA statement, which is designed for the reporting of systematic reviews, particularly intervention studies, was followed [15]. A protocol for this systematic review was developed by the author and a reviewer experienced in systematic reviews.

Search methods

A search of Cinahl, Medline, PubMed, Scopus and Web of Science was conducted in March 2016. Since not all databases used medical subject headings (MeSH), a combination of MeSH terms and keywords were used (Table 1). An example of this is given in Additional file 1: Appendix 1. Creation of the search string was overseen by a subject specific librarian. In addition, reference lists of relevant papers and the journals Resuscitation and Circulation, which are the European Resuscitation Council and AHA’s journals respectively, were hand searched. All retrieved papers were entered on a reference management software (RefWorks), and duplicates were removed. Potentially relevant articles were then screened based on title and then on reading the abstract. If they appeared relevant, the full-text articles were assessed for eligibility (Fig. 1). The literature search period was from January 2010 to March 2016. Inclusion and exclusion criteria for the review are presented in Table 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].

Database	Keywords			Limits
Cinahl (EbscoHost)	Resuscitation, Cardiopulmonary (MeSH)	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
	“Advanced life support”		“cerebral performance”	Health sciences
			“function* outcome”	Life sciences

	Inclusion	Exclusion
Population	Adults survivors of cardiac arrest receiving resuscitation in hospital	Animal studies; paediatrics
Intervention	CPR duration described as collapse to ROSC	Prehospital ROSC; additional interventions including but not limited to extracorporeal resuscitation, therapeutic hypothermia
Outcomes measured	Neurological outcome of survivors of CPR	Studies in which CPR duration is not compared with neurological outcome
Type of article	Research studies	Case studies
Language	English	Papers not published in English
Date	Published from 01/01/2010	Published prior to 2010

This systematic review found seven studies of varying quality reporting on duration of CPR and neurological outcome. Generally, neurological outcomes were better in patients who achieved ROSC after a shorter time, however this review has revealed no definitive 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 that gender is irrelevant were conclusive. Shockable rhythm was a significant predictor of favourable outcome.

Most of the studies confirmed that more favourable outcomes were associated with shorter duration of CPR. In part, this echoes the systematic review by Moulaert et al. [9] which investigated duration as a confounding variable to cognitive impairment following OHCA. Of the two studies which identified confounding variables, both demonstrated an association between time to ROSC and cognitive outcome. However, in contrast to our findings, four studies in Moulaert et al.’s review found no confounding variables. By using number of doses of adrenaline and number of shocks as proxy markers, Kaye [27] associated better outcomes with shorter durations, however caution must be applied as the methodology was unclear and of poor quality. Similar findings have been reported in the prehospital setting; for example both Abe et al. [28] and Grunau et al. [29] found that favourable neurological outcome is more likely with a shorter time to ROSC. There were some differences between those experiencing ROSC in the prehospital and the hospital setting. Abe et al. [28] and Matsuyama et al. [30] found when looking at patients with good outcomes, CPR duration was shorter in those with prehospital ROSC. It would be interesting to explore whether this is influenced by the Termination of Resuscitation rule for the prehospital setting.

Xue et al. [26] found that there was a significantly better neurological outcome in those who had an IHCA compared with those with OHCA. They also reported that arrests witnessed by medical staff had a significantly better neurological outcome. Both of these findings are consistent with greater likelihood that time between arrest and commencement of CPR was relatively short. Iqbal et al. [23] found that bystander CPR also had a significant impact on neurological outcome. It may be that the increased period of hypoxia whilst no CPR is being carried out leads to brain damage further exacerbated by reperfusion injury. However Storm et al. [31] when investigating the effect of cerebral oxygenation during CPR found that a low value at the beginning of treatment on arrival of emergency services was not a good predictor of ROSC or neurological outcome. In contrast, Parnia et al. [32] found that in IHCA, cerebral oxygenation values were a significant predictor of a neurologically favourable survival.

Despite generally finding a significant correlation between duration and neurological outcome, the incidence of complete recovery after prolonged CPR is high. For example Goldberger et al. [22] found that 73.8% of people receiving CPR for more than 30 min survived neurologically intact. Case studies, which often report remarkable outcomes, were excluded from this review due to the risk of publication bias however their findings can be interesting and useful. In a review of all published cases of patients who underwent prolonged CPR of greater than 20 minutes, 78% recovered with a favourable neurological outcome [33]. The median duration of resuscitation in the reviewed 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 to conclude it would be unethical to specify a maximum duration after which CPR should be terminated.

The study by Goldberger et al. [22] found no significant link between the rate of favourable neurological outcome and duration of resuscitation. This was a high-quality study, with a very large sample size and has been widely referenced, including by the Resuscitation Council (UK) [34]. However they did find that mean and median CPC scores were higher in those who had a shorter duration. It is possible to reach very different conclusions depending on whether selecting mean CPC score (p = 0.0001) or proportion of people with favourable outcome (p = 0.131) when interpreting the data. Despite the similarities in data collection between the studies, there was considerable variation in data interpretation and presentation of results. Arguably, it is potentially more meaningful to focus on the proportion of people with a good or bad outcome than average CPC score because of the discrete nature of the CPC scale. Goldberger et al.’s [22] results are consistent with two separate population groups – one with a good prospect of recovery, in which duration of CPR had little effect, and a larger second group with poorer prospects of recovery, and amongst whom damage was more likely to increase with time of CPR. This hypothesis could explain their apparently conflicting results in which average CPC score correlates with CPR time, but percentage of good outcomes does not.

If this interpretation is correct, it has important implications. If the patient is likely to have a good outcome then prolonged CPR is justifiable, whereas in those cases where the arrest is likely to have a poor outcome this may worsen with prolonged CPR. It is therefore important to better understand other arrest factors which have an impact on outcome. In Youness et al.’s [33] study of prolonged CPR, the participants were generally young, with no co-morbidities and had cardiac arrest with reversible causes, however these findings are not discussed in depth and further research is needed.

Significance between shockable rhythm and favourable outcome was identified across all studies in this review. Three large (n = 30,716, 64,339 and 91,658), good quality studies, exploring CPR duration, found an association between shockable rhythm and shorter duration of resuscitation as a predictor of favourable neurological outcome [22, 35, 36]. This may be an indicator of the importance of cause of arrest in likelihood of survival with a good outcome. However, little research has been done to investigate the link between initial rhythm and neurological outcome with prolonged CPR.

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 hospitals which had a longer average duration of CPR, but found no difference between hospitals when looking at favourable neurological outcome to discharge. Cha et al. [36] similarly found a higher survival rate with longer institutional duration of CPR. This implies that if CPR were attempted for longer there may be a higher survival rate, which contradicts the majority of findings from this review. However Cha et al. did not report these findings in relation to neurological outcome of survivors. Hospitals which resuscitate for longer may give better quality resuscitation and more aggressive treatments which may lead to increased survival [36]. This is an interesting area for future research.

All the studies in this review adopted the Utstein-style for data collection. This is the internationally standardised format for reporting cardiac arrest data for both OHCA and IHCA [37], however, there is limited research demonstrating its validity and reliability. According to Utstein-style reporting, neurological outcome following cardiac arrest should be recorded using either CPC or mRS [37]. These outcome measures are used in all the studies reviewed. There is no evidence to justify the assumption that this should improve the validity of the studies’ findings. Studies have found a lack of validity and reliability of CPC and mRS due to significant variability between the two; limited ability to differentiate between levels of outcome; and lack of focus on any specific aspect of functioning [38–40]. This may have affected the quality of our findings which would have been more reliable had there been a standardised measure for neurological outcome implemented across clinical practice.

Since the searches were conducted there has been additional research published which would have met the inclusion criteria for this study. Four studies, all set in the emergency department were found; one focused on IHCA [41] two on OHCA [42, 43] and one studied both IHCA and OHCA [44]. All four studies found that increased duration of CPR led to a significantly poorer neurological outcome, which was measured by CPC in three of the studies [41–43] and by ability to follow commands in the fourth [44]. The inclusion of these more recent studies would not have changed the conclusions of this review.

This review has identified some interesting findings that require further investigation. It is unclear why some survivors of prolonged resuscitation had complete neurological recovery whilst others did not and further research focusing on duration of CPR, neurological outcome and the factors that affect these may help to answer this.

Current guidelines on terminating in-hospital resuscitation are discussed very briefly, leaving healthcare professionals to use clinical judgement as the main factor when making these decisions. It is hoped that in the future, enough conclusive evidence from quality research will lead to provision of clearer guidance on terminating resuscitation in the hospital setting. This systematic review sought to find out whether duration of CPR has an impact on neurological outcome of survivors of cardiac arrest. Seven studies were included for review. These were appraised for quality and were mostly of a high standard.