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 [38,39,40]. 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 [41,42,43] 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.
Strengths and limitations
To find all the literature on this topic, thorough, systematic searches 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 which is a limitation of this study, however this was overseen by a subject specific librarian and approved by a second reviewer.
The inclusion and exclusion criteria may be a further limitation for this study. The search was limited to papers in English which could introduce language bias. Due to frequent changes in CPR guidelines and ever-improving outcomes, the search was limited to studies published after 2010 in order to keep a relatively narrow time-frame in which practices could be assumed to remain fairly consistent. Wang et al. [45] found a higher probability of favourable neurological outcome with CPR conducted after 2010 due to the vast changes in guidelines that year, however only two of the studies were based entirely on data collected since 2010 with some including results reported in 2000. There is clearly a risk of variation associated with changes in practice. Therapies supplementary to advanced life support such as extracorporeal resuscitation or therapeutic hypothermia were excluded from the review. These may have an important effect on outcomes, but would have led to a much more complex review with difficulty isolating the findings. Excluding this potentially large volume of literature means that caution should be used in extrapolating the findings to this population. Excluding patients who achieved prehospital ROSC may have introduced bias, however papers investigating prehospital ROSC report similar findings to those studies included for review [28,29,30].
The similarity in the design and methods of the studies allowed comparisons to be drawn using the same appraisal tool across the studies, maintaining objectivity and minimising bias. All parameters in the chosen appraisal tool were equally weighted despite the possibility of some having greater influence in the overall quality than others. The appraisal tool highlighted the main areas in which bias could have been introduced but did not discriminate between large and small flaws. An alternative may have been to use a scale however this may be more subjective.
The included studies relied on retrospective collection of registry data. There is potential for errors in data collection, variation of recording methods between hospitals or misinterpretation of data [22, 35]. It would be highly unethical to conduct experimental studies in this area of research. As with any systematic review, there is a risk of publication bias as many papers will only report significant findings. With only a small number of relevant studies, it proved impossible to restrict studies to only those of the highest quality. The limited similarity between studies prevented conducting a meta-analysis.
Overall this literature review included a number of steps to maintain quality. Bias was minimised by following the PRISMA procedure with minimal deviation. Reporting of methods was transparent throughout to increase replicability. Consistency of findings amongst the majority of the studies increases confidence in the findings of this review. The findings are generalisable to the study population, as both IHCA and OHCA in most hospital settings, all arrest types and a wide variety of hospitals and locations were included. The review sought only to study the adult population and therefore the findings cannot be applied to paediatrics.
