Variation in community and ambulance care processes for out-of-hospital cardiac arrest during the COVID-19 pandemic: a systematic review and meta-analysis

Bystander cardiopulmonary resuscitation (BCPR), early defibrillation and timely treatment by emergency medical services (EMS) can double the chance of survival from out-of-hospital sudden cardiac arrest (OHCA). We investigated the effect of the COVID-19 pandemic on the pre-hospital chain of survival. We searched five bibliographical databases for articles that compared prehospital OHCA care processes during and before the COVID-19 pandemic. Random effects meta-analyses were conducted, and meta-regression with mixed-effect models and subgroup analyses were conducted where appropriate. The search yielded 966 articles; 20 articles were included in our analysis. OHCA at home was more common during the pandemic (OR 1.38, 95% CI 1.11–1.71, p = 0.0069). BCPR did not differ during and before the COVID-19 pandemic (OR 0.94, 95% CI 0.80–1.11, p = 0.4631), although bystander defibrillation was significantly lower during the COVID-19 pandemic (OR 0.65, 95% CI 0.48–0.88, p = 0.0107). EMS call-to-arrival time was significantly higher during the COVID-19 pandemic (SMD 0.27, 95% CI 0.13–0.40, p = 0.0006). Resuscitation duration did not differ significantly between pandemic and pre-pandemic timeframes. The COVID-19 pandemic significantly affected prehospital processes for OHCA. These findings may inform future interventions, particularly to consider interventions to increase BCPR and improve the pre-hospital chain of survival.

www.nature.com/scientificreports/ Sidik-Jonkman estimator and Mantel-Haenszel method to estimate the pooled effects of COVID-19, as substantial between-study heterogeneity was present. Forest plots displayed individual and pooled odds ratios (OR) and 95% confidence intervals (95% CI) for the binary outcomes: OHCA at home, unwitnessed OHCA, BCPR, AED use, EMS resuscitation attempted, endotracheal intubation and supraglottic airway, amiodarone and epinephrine, and mechanical CPR. For the continuous outcomes (resuscitation duration and EMS call to arrival time), forest plots displayed individual and pooled standardized mean difference (SMD) and 95% CI. Two-tailed statistical significance was set at p-value ≤ 0.05. The I 2 statistic was used to quantify statistical heterogeneity 18 . This statistic indicates whether variation is more likely due to chance or study heterogeneity, with I 2 values of 25%, 50%, and 75% indicating low, moderate, and high heterogeneity respectively. Whenever there was substantial statistical heterogeneity (I 2 > 50%), we evaluated for outliers by performing a set of case deletion diagnostics to identify influential studies and subsequent leave-one-out sensitivity analyses. To account for possible moderators that might contribute to statistical heterogeneity, we performed univariate meta-regression with mixed-effects models and subgroup analyses for the outcome of BCPR. Publication bias was evaluated via visual evaluation of funnel plots and Egger's regression.

Results
Literature retrieval. The database search yielded a total of 966 articles. After removal of duplicates, 546 abstracts were screened and subsequently 122 reports were sought for retrieval, of which 14 articles could not be retrieved. The resultant 108 full-texts were reviewed, and 20 were identified as meeting the selection criteria. The study selection process and reasons for exclusion were illustrated in the PRISMA-P 2020 Flow Diagram (Fig. 1). www.nature.com/scientificreports/ Characteristics of studies and risk of bias. The 20 included studies originated from ten countries (France, Italy, Australia, Korea, United States of America, Spain, Netherlands, United Kingdom, Singapore, and Sweden). All studies included were retrospective cross-sectional study design. There were a total of 67,815 patients with OHCA across the studies, of which 28,960 patients were evaluated during the COVID-19 pandemic and 38,855 patients were evaluated prior to the COVID-19 pandemic. Study sample sizes ranged from 101 to 19,303 patients. The study characteristics were summarized in Table 1.
All studies achieved a score from seven to nine on the Newcastle-Ottawa Scale, signifying high quality and low risk of bias for selection (Supplementary Table 1).
Community processes. Community processes-related outcomes analyzed in this study included OHCA at home, unwitnessed OHCA, BCPR, and AED use. A summary of community processes of care was shown in Table 2, while Fig. 2 depicted the forest plots of the various community processes.
OHCA location at home. Fifteen studies accounted for the outcome of OHCA at home 6,8,10,11,13,[19][20][21][22][23][24][25][26][27][28] . Amongst these, Nickles et al. reported the lowest percentage (64.2%) in the COVID-19 pandemic, while Ortiz et al. reported the lowest percentage (60.5%) of patients with OHCA at home prior to the COVID-19 pandemic 21,26 . In contrast, Fothergill et al. reported the highest percentage of patients with OHCA at home in both periods during and before the COVID-19 pandemic (92.9%, 85.5% respectively) 11 . With the exception of four studies 10,24-26 , which showed a lower percentage of patients with OHCA at home during as compared to before the pandemic, a trend was observed where the percentage of patients with OHCA at home was higher during the COVID-19 pandemic as compared to Pre-COVID-19 pandemic ( Table 2).
Meta-analysis showed that the odds of patients undergoing OHCA at home was significantly higher during the pandemic as compared to before the pandemic (OR 1.38, 95% CI 1.11-1.71, p = 0.0069, I 2 = 90%) ( Fig. 2A).
AED use. Eleven studies accounted for AED use 8,10,11,13,[19][20][21]23,[27][28][29] . The percentage of the population with AED use ranged from 0.4 to 81.4% across intervals during and before the COVID-19 pandemic. Apart from Elmer et al. 29 , a trend of lower percentage of population with AED use was observed during the COVID-19 pandemic as compared to prior to the pandemic. Across intervals during and before the COVID-19 pandemic, almost all studies reported a percentage AED use of 29.4% or less. Only Baert et al. reported relatively higher percentages during the COVID-19 pandemic and prior to the pandemic (73.3% and 81.4% respectively) ( Table 2) 19 . Metaanalysis showed that the odds of OHCA patients using AED was significantly lower during the pandemic as compared to prior to the pandemic (OR 0.65, 95% CI 0.48-0.88, p = 0.0107, I 2 = 75%) (Fig. 2D).
EMS processes. EMS processes-related outcomes analyzed in this study included EMS resuscitation attempted, resuscitation duration, EMS call to arrival time, endotracheal intubation and supraglottic airway, amiodarone and epinephrine, and use of mechanical CPR. A summary of EMS processes of care was shown in Table 3, while Figs. 3, 4 and 5 depicted the forest plots of the various EMS processes. EMS resuscitation attempted. Eight studies accounted for the outcome of EMS resuscitation attempted 6,7,10,11,13,20,30,31 . Apart from Lai et al. 7 , all other studies reported a lower percentage of population with EMS resuscitation attempted in the COVID-19 pandemic as compared to Pre-COVID-19 pandemic (Table 3).
Meta-analysis showed that the odds of EMS resuscitation attempted on OHCA patients was significantly lower during the pandemic as compared to before the pandemic (OR 0.84, 95% CI 0.73-0.97, p = 0.0247, I 2 = 68%) (Fig. 3A).
Amiodarone and epinephrine. Four studies accounted for the use of amiodarone 6,7,20,27 , while seven studies accounted for the use of epinephrine 6,7,10,11,19,20,27 . Apart from Lai et al. 7 , all other studies reported a higher percentage of amiodarone use in the COVID-19 pandemic relative to Pre-COVID-19 pandemic. The trend was not as obvious in epinephrine usage; four studies 6,10,11,27 reported a higher percentage of epinephrine use during the pandemic as compared to before the pandemic, while three studies reported an inverse occurrence ( www.nature.com/scientificreports/ www.nature.com/scientificreports/

Sensitivity analyses. Leave-one-out analyses.
After visual inspection of forest plots for potential, sensitivity analyses were performed using influential diagnostic plots and Baujat plots. Applying this approach on each outcome of community and EMS processes, none of the estimates were substantially changed in direction or statistical significance. However, the magnitude of effect was increased in six outcomes: 18 Figs. 2-34). Ultimately, the final outcomes presented in this study were not based on adjustment with sensitivity analyses as none of the estimates were substantially changed in direction or statistical significance, showing that the sensitivity analyses did not greatly influence the findings of our review and thus, no articles were determined to be excluded.
Subgroup analyses: BCPR. In order to account for possible moderators that might contribute to statistical heterogeneity, subgroup analyses were conducted for the outcome of BCPR which had the highest number of studies. The subgroup analyses were based on categorical variables, namely, publication year and study location. None of the permutations yielded a statistically significant difference. Statistical heterogeneity remained high in all subgroup analyses. We did not conduct subgroup analyses for all other outcomes due to the inadequate data (Supplementary Table 3).

Meta-regression: BCPR.
Meta-regression with a mixed-effects model was performed for the outcome of BCPR to examine if the observed heterogeneity could be contributed by possible moderators such as sample size, mean age, proportion of males, proportion of patients with OHCA at residential location, GDP per country, GDP per state and population density of study region (km 2 ). Univariate meta-regression did not reveal any statistically significant moderators. Meta-regression analyses were only conducted for the outcome of BCPR as it had the highest number of studies. We did not conduct meta-regression for other outcomes due to the inadequate data (Supplementary Table 4).  www.nature.com/scientificreports/ Publication bias. A funnel plot was generated based on the outcome BCPR which had the highest number of studies, revealing no asymmetry, hence suggesting the absence of publication bias (Supplementary Fig. 1). This was congruent with a non-significant Egger's regression test (p = 0.62).

Discussion
In this study, we elucidated several salient findings. First, there was a significant increase in OHCA occurring at home and a significant decrease in bystander AED use during the COVID-19 pandemic. Second, there was no difference in BCPR rates during the pandemic as compared to before. Third, the pandemic was associated with changes to EMS processes including a significant decrease in attempted EMS resuscitation, a significant increase in EMS call to arrival times, a significant decrease in endotracheal intubation, and a significant increase in supraglottic airway use. The increase in OHCA at home is consistent with stay-at-home and social distancing measures worldwide during the COVID-19 pandemic 33 . As more people are enforced to stay or work from home 34 , OHCA at home rates have consequently increased. Importantly, this finding also highlights that witness rates for OHCA incidence are similar during the pandemic as compared to before. This is necessary to consider for future prehospital Table 3. Summary of emergency medical services processes of care. EMS emergency medical services, OHCA out-of-hospital cardiac arrest, CPR cardiopulmonary resuscitation, ALS advanced life support, NR not reported, N number, SD standard deviation. a Difference in denominators is due to incomplete reporting of outcomes for certain patients. b Among those in whom resuscitation was attempted by the Emergency Medical Services.  www.nature.com/scientificreports/ interventions as subsequent measures should be targeted at the accessibility of services and devices and less at the detection of OHCA in the chain of survival 35 . This finding is supported by a statistically significant decrease in bystander AED use during the COVID-19 pandemic, which could be attributed to an increase of OHCA occurring at home 36,37 . The lack of AED availability in homes may principally explain this observation, along with inaccessibility of AEDs installed in public buildings due to the sudden closure of non-essential businesses and services by government policies 36 . Accordingly, new perspectives for current AED guidelines may be warranted as OHCA at home rates have increased during the pandemic, highlighting the shortcomings of current AED policies. More strategic placements of AEDs should be carried out to maximize access from individual   www.nature.com/scientificreports/ homes, with particular emphasis on rural areas where AED accessibility is relatively more limited 36,38 . Given the potentially long-lasting lifestyle changes from the COVID-19 pandemic, the rising rates of OHCA at home should be urgently addressed. Interestingly, we found no statistical difference in BCPR during the pandemic as compared to before. This is in contrast to previous literature, which suggested that observed decreases in BCPR resulted from fear of COVID-19 disease transmission from patient to bystanders or hesitancy among family members towards performing CPR for OHCA at home due to psychological and emotional reasons 8,13,39 . This result could be explained by an attitude-behavior gap whereby family members at home perform CPR despite such hesitancy 40 . Moreover, it could also be attributed to certain recommendations that CPR is not an aerosol-generating procedure [41][42][43] , thus, decreasing the likelihood for COVID-19 to be transmitted. A recent study with swine models validates such findings, where the authors found that chest compressions alone did not cause significant aerosol generation in the swine model 44 . However, our findings should be interpreted with caution as an analysis on BCPR rates for home versus non-home arrests could not be performed due to paucity of data. Furthermore, this result should be interpreted in light of significant statistical heterogeneity unexplained by the sociodemographic, economic status, and geographical location of the sample population in each study. Although no differences were found in BCPR before and after the COVID-19 pandemic, this does not mean that campaigns or interventions encouraging CPR during the pandemic should cease, which should instead be carefully tailored to each country's unique response to the pandemic at the societal and individual levels 45,46 .
The decrease in EMS resuscitation attempts was significant, contrary to previous studies 22,47 . The COVID-19 pandemic directly led to a severe strain on ambulance resources, changes in EMS workflows, and sicker OHCA patients, possibly leading to fewer patients qualifying for EMS resuscitation in an attempt to redirect scarce resources and maximize lives saved when crisis standards of care are enforced 20,48 . Additionally, protocol changes could have exacerbated the decrease in EMS resuscitation attempts during the pandemic. For example, in Detroit, EMS protocols were amended to include the termination of resuscitation in suspected COVID-19 cases after ten minutes of resuscitation without return of spontaneous circulation 25 . The scarcity of resources is also consistent with the increase in EMS call to arrival times, which could be attributed to PPE requirements during the pandemic and increased ambulance travel distance for OHCA patients at home 10 . Cho et al. reported an emphasis on high-level PPE, consistent with an exaggerated increase in EMS call to arrival time and did not modify the significance of the effect size when excluded during leave-one-out analysis 10 . Although our study found a relatively smaller magnitude of SMD estimate for EMS call to arrival times, there remained a statistically significant increase in EMS call to arrival times during the pandemic. This has added importance in a time-critical medical emergency such as OHCA, where every second counts. Interestingly, the increase in EMS call to arrival times occurred despite reported road traffic reduction during the pandemic 3 . This suggests that while the lighter road traffic may partially improve EMS call to arrival times during the pandemic, it did not completely offset the delay from PPE donning and COVID-19 related strain on ambulance resources. More studies are required to report the time between EMS departure and arrival time in order to arrive at more definitive conclusions. Finally, a decrease in endotracheal intubation was accompanied by an increase in supraglottic airway use, likely reflecting the perceived risks of COVID-19 transmission in endotracheal intubation 49 . Certain protocol revisions could have also contributed to the increase in intubation use, as these guidelines recommended the use of supraglottic airways over endotracheal intubation 24 . While the overload of healthcare systems is to be expected during a pandemic, this should not come at the cost of worsening outcomes for non-COVID illnesses including OHCA. More needs to be done to find a balance in resource allocation when saving lives affected by COVID-19 or other non-COVID life-threatening diseases. Better preparation and predefined protocols are needed for emergency care systems to operate under resource-scarce crisis situations.
These findings hold implications for future pre-hospital interventions. A growing body of evidence demonstrates significant changes to OHCA characteristics during the COVID-19 pandemic which impact public health and urgently need to be addressed 13,19 . Efforts to manage the effects of the pandemic, which may be the chief priority for public health institutions, should not come at the cost of worsening outcomes for non-COVID illnesses including OHCA. Future pre-hospital OHCA measures should also be targeted at the accessibility of services and devices and less at the detection of OHCA in the chain of survival. Systematic placement of AEDs should be carried out to maximize access from individual homes, with particular emphasis on rural areas where AED accessibility is relatively more limited 36,50 . Although no differences were found in BCPR before and after the COVID-19 pandemic, educational campaigns or interventions encouraging CPR during the pandemic should continue to be championed for and carefully tailored to each country. This would improve maintenance of personal safety on an individual level and increase empowerment of rescuers on a societal level 38 . The negative changes to EMS processes associated with the pandemic are worrying and suggest that better preparation and predefined protocols are needed for emergency care systems to operate under resource-scarce crisis situations, including the stockpiling and effective use of PPE 51 . A clear transition from non-crisis to crisis resource allocation coupled with clear public health messaging will likely be beneficial. Additionally, a centralized public EMS system may improve coordination between different stakeholders during the COVID-19 pandemic and reduce OHCA mortality rates 52,53 . However, more investigation is needed in this field. Further research is also needed to investigate measures for minimizing COVID-19 transmission during resuscitation, such as supraglottic airway use and mechanical CPR, as well as the barriers to implementing them during the pandemic.
The results of this study were robust to sensitivity analyses and incorporated data from several large OHCA registries from various countries. No publication bias was detected on visual inspection and statistical analysis. However, the findings of this study should be interpreted in the context of known limitations. All included studies were observational cross-sectional studies comparing the COVID-19 period to a historical control. Hence, results were vulnerable to confounding and should be interpreted carefully. Moderate to high statistical heterogeneity was encountered during analyses. Heterogeneity in the definition of the COVID-19 pandemic and www.nature.com/scientificreports/ Pre-COVID-19 pandemic may have led to varying estimates of effect size, depending on local epidemiology. Moreover, the included studies had varying time periods for the COVID-19 pandemic. Each study was unable to reflect an equal severity of the pandemic, which may have contributed to the heterogeneity encountered. Differences in study characteristics such as demographics, surveillance, and data collection processes also likely further accounted for observed heterogeneity. All included studies originated from first-world countries that comprised populations with higher income and higher socio-economic status. Hence, study results may be limited in terms of generalizability despite providing key insights into OHCA during the COVID-19 pandemic. However, this study is, to our knowledge, one of the first few systematic reviews and meta-analyses to examine the impact of the COVID-19 pandemic on community and EMS care processes. It represents a global body of literature that may inform future prehospital interventions and guide the interpretation of changes in OHCA characteristics during the COVID-19 pandemic.

Conclusion
BCPR rates remained unchanged before and during the COVID-19 pandemic, while outcomes of OHCA in the home and bystander AED increased. Ambulance processes remained largely unchanged, although EMS resuscitation attempts decreased and call to arrival times increased slightly. These findings may inform future interventions, particularly to consider interventions to increase BCPR and improve the pre-hospital chain of survival for future implementation.

Data availability
The data presented in this study are available in Supplementary  www.nature.com/scientificreports/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.