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Epidemiology and Outcome of Out-of-Hospital Cardiac Arrests during the COVID-19 Pandemic in South Korea: A Systematic Review and Meta-Analyses

Purpose To evaluate the effect of coronavirus disease 2019 (COVID-19) on out-of-hospital cardiac arrest (OHCA) outcomes in South Korea, we conducted systematic review and meta-analysis. Materials and Methods MEDLINE, Embase, KoreaMed, and Korean Information Service System databases were searched up to June 2022. We included observational studies and letters on OHCA during the COVID-19 pandemic and compared them to those before the pandemic. Epidemiologic characteristics, including at-home OHCA, bystander cardiopulmonary resuscitation, unwitnessed arrest, use of an automated external defibrillator (AED), shockable cardiac rhythm, and airway management, were evaluated. Survival and favorable neurological outcomes were extracted. We conducted a meta-analysis of each characteristic and outcome. Results Six studies including 4628 OHCA patients were included in this study. The incidence of at-home OHCA significantly increased and the AED use decreased during the COVID-19 pandemic compared to before the pandemic [odds ratio (OR), 1.29; 95% confidence interval (CI), 1.08–1.55; I2=0% and OR, 0.74; 95% CI, 0.57–0.97; I2=0%, respectively]. Return of spontaneous circulation after OHCA, survival, and favorable neurological outcomes during and before the pandemic did not differ significantly (OR, 0.90; 95% CI, 0.71–1.13; I2=37%; OR, 0.74; 95% CI, 0.43–1.26; I2=72%; OR, 0.77; 95% CI, 0.43–1.37; I2=70%, respectively). Conclusion During the COVID-19 pandemic in South Korea, the incidence of at-home OHCA increased and AED use decreased among OHCA patients. However, survival and favorable neurological outcomes did not significantly differ from before the pandemic. This insignificant effect of the pandemic on OHCA in South Korea could be attributed to the slow increase in patient count in the early days of the pandemic. OSF Registry (DOI: 10.17605/OSF.IO/UGE9D).


INTRODUCTION
have reported an increase occurring at home, a decrease in the use of bystander cardiopulmonary resuscitation (CPR) and automated external defibrillators (AEDs), and an increase in OHCA patients with nonshockable rhythm due to an increase in COVID-19 patients with respiratory failure who cause cardiac arrest. [8][9][10][11] Administering appropriate care in the emergency department to such patients was delayed due to several circumstances, including overcrowding in medical institutions, shortage of medical resources and personnel, increased workload for paramedics, and delays in reaching the site of OHCA occurrence. [8][9][10][11] Eventually, the loose chain of survival for OHCA led to poor survival and unfavorable neurological outcomes. 8,9 Several meta-analyses have already compared the epidemiological characteristics and outcomes of OHCA during the COVID-19 pandemic to those reported before the pandemic. [8][9][10][11] The results of the first and most current meta-analyses were comparable for most factors. 8,11 However, these meta-analyses did not consider an important factor. These were undertaken regardless of the pandemic phase or the region, although the environment and system for emergency care and service in the later phase of the pandemic differed from those in the earlier phase that was unsystematic and collapsing. For instance, before and after vaccination, before and after the peak surge of COVID-19 cases, and before and after changing the strategy for the use of medical resources varied by location; hence, the results of prior meta-analyses could not be generalized. 12 As a result, a detailed meta-analysis that reflects regional characteristics and outcomes of OHCA is required.
Therefore, we determined that comparing the same medical system and medical resources during and before the pandemic is critical for the meta-analysis, and hence, this study focused on studies from South Korea. The findings of this study will establish the epidemiologic characteristics of OHCA in South Korea and assess the outcomes.

Reporting guidelines and protocol registration
This study complied with the Preferred Reporting Items for Systematic reviews and Meta-analyses and the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting information from observational studies. 12,13 We prospectively registered the review protocol in the OSF Registry (https:// doi.org/10.17605/OSF.IO/UGE9D).

Search strategy
Two experienced reviewers (J.H.K. and C.A.) systematically searched five electronic databases, including local databases (MEDLINE, Embase, Cochrane Library, KoreaMed, and Korean Information Service System) for studies on the epidemiology and outcome of OHCA during COVID-19 pandemic, which included those reported before the pandemic and through June 2022. We included medical subject headings (MeSH), Embase subject headings, and other relevant keywords in our search strategy. We combined the MeSH terms and free terms related to "out-of-hospital cardiac arrest" and "COVID-19. " Supplementary Table 1 (only online) summarizes the search strategy in detail.

Study selection
Two reviewers (J.H.K. and C.A.) independently screened the titles, abstracts, and the type of each of the identified articles, excluding irrelevant studies. First, we eliminated duplicate studies. Studies were considered duplicates if their titles, authors, and publication years were the same. We then excluded all articles meeting the following criteria: reviews, case reports, case series, editorials, comments, or meta-analyses; animal studies; irrelevant populations; and inappropriate controls. In case the two reviewers disagreed about the study selection, the third reviewer (M.N.) intervened, and differences were discussed until consensus was achieved. Finally, we included studies which evaluated the epidemiologic factors and outcomes of patients with OHCA during COVID-19 and compared them to those reported before the pandemic. We also excluded studies that 1) included patients aged <18 years, 2) provided no comparison or outcomes, and 3) were non-original articles. We subsequently reviewed the full text of potentially relevant articles that met the inclusion criteria.

Data extraction
The two reviewers independently extracted the following information from the included studies: authors, year of publication, location of study, information about the medical institution, population, age, sex, OHCA at home, bystander CPR, unwitnessed state, AED usage, shockable cardiac rhythm, airway management, paramedic related factors, etiology, and CPR time. In addition, we extracted the study outcomes including return of spontaneous circulation (ROSC), survival to hospital admission, survival to hospital discharge, and favorable neurological outcome. Discrepancies between reviewers were resolved by consensus.

Quality assessment in individual studies
The Newcastle-Ottawa Scale is a quality assessment tool used to evaluate non-randomized studies based on an eight-point score divided across three domains. 14 Each report is scored with a number of stars for three domains: 1) selection (maximum of four stars), 2) comparability (maximum of two stars), and 3) outcome (maximum of three stars). Two reviewers (J.H.K. and C.A.) independently assessed the included six studies; any unresolved disagreements between reviewers were resolved by discussion with the third author.

Statistical analysis
This meta-analysis investigated the epidemiological charac-  15 Ahn (2021) 16 Lee (2021) 17 Lim (2021) 18 Chung (2022) 19 Lim (2022) 20  teristic and outcomes of OHCA during the COVID-19 pandemic comparing to before the pandemic. For dichotomous variables, we calculated the pooled odds ratio (OR) with a 95% confidence interval (CI) using a random-effects model. We estimated the proportion of inter-study inconsistency using the I 2 statistic to assess heterogeneity, considering I 2 values of 25%, 50%, and 75% as low, moderate, and high heterogeneity, respectively. We performed the meta-analysis using the statistical analysis software R (version 4.0.0, The R Foundation for Statistical Computing, Vienna, Austria), using the packages "meta" (version 4.11-0) and "metaphor" (version 2.1-0); a p val-ue<0.05 was considered statistically significant. Each comparison was conducted using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) analysis (GRADEpro Guideline Development Tool, McMaster University, USA). We did not assess for publication bias, given the small number of included studies.

RESULTS
In total, 419 studies were identified from the database search, and 368 papers remained after removing duplicates. Subsequently, 351 studies were excluded for irrelevance after assessing the titles and abstracts; 17 relevant studies remained, which were subjected to full-text retrieval. From those, we excluded 11 studies due to irrelevant population (n=5), irrelevant control (n=4), irrelevant outcome (n=1), and duplicated data [n=1; Supplementary Table 2 (only online)]. Finally, we conducted the meta-analysis and systematic review including six eligible studies with 4628 patients with OHCA. [15][16][17][18][19][20] Table 1 shows the baseline characteristics of included studies and Fig.  1 presents the study selection flowchart.

Quality assessment
When assessing the quality of articles according to the Newcastle-Ottawa Scale, only one had a score of 6. Of the remaining studies, two scored 7 and three scored 8 (Supplementary  Table 3, only online).

Epidemiological characteristics of OHCA during the pandemic vs. before the pandemic
Except for the study by Chung, et al., 19 the OHCA population during the pandemic was larger in four studies. Except for the study by Lim, et al., 18 five studies included patients from the initial period immediately after the first reported case of COVID-19 in South Korea (Fig. 2).

Level of evidence
The results of this study were assigned low or very low level of evidence in each epidemiological characteristics and outcomes according to the evidence profile using the GRADE framework (Supplementary Table 4, only online). Analysis of observational studies was the main reason for the low level of evidence.

DISCUSSION
Unlike previous reports, our meta-analysis focused on the effect of the COVID-19 pandemic on OHCA in South Korea. Several previous meta-analyses have considered all during-pandemic data as one group, and compared those with data from before the pandemic. [8][9][10][11] A limitation of these studies was their inability to represent the regional differences in the medical care environment, which was addressed by our meta-analysis as we focused only on data from South Korea. For instance, the incidence and mortality of COVID-19 in South Korea increased only moderately in the early phase compared to those in other countries, owing to favorable medical conditions. 21 Considering that global data inclusion leads to high inter-study heterogeneity, to ensure accurate analysis and to better represent the characteristics of the emergency medical service response system, the prognosis of OHCA patients, and the emergency medical system established in response to the COVID-19 pandemic in South Korea, we performed a meta-analysis including reports only from South Korea. The Korean Association of Cardiopulmonary Resuscitation annually provides records of patients experiencing cardiac arrest ( Supplementary Fig. 1, only online). Although the most recent data facilitated identifying the total number of patients with OHCA and rates of survival, home isolation, bystander CPR, and defibrillation at the beginning of the pandemic in 2020, this information was limited and other factors could not be validated. Therefore, we assessed for additional variables by a meta-analysis of published research papers providing detailed statistics. This meta-analysis showed significantly increased incidence of at-home OHCA, decreased bystander use of AEDs, and decreased intubation during the COVID-19 pandemic in South Korea. In contrast, we observed no significant changes in the use of SGA devices, unwitnessed arrests, shock-able rhythm, and bystander CPR. Furthermore, ROSC, survival until discharge, and favorable neurological outcomes did not differ significantly.
Lim, et al. 8 were the first to compare the outcomes of OHCA during and before the COVID-19 pandemic. Their study included studies from several countries, including the United States, Europe, and Australia. OHCA incidence had increased during the pandemic; and particularly, the incidence of at-home OHCA increased, attributable to the need for social distancing and reduced outdoor activity. 8 The early days after the outbreak in South Korea witnessed inadequate medical response and preparedness, similar to other countries. 22,23 In this study, however, we observed an unexpected trend in the incidence of shockable rhythm. Due to an increased influx of patients with OHCA experiencing respiratory failure due to COVID-19, [24][25][26] previous studies had reported a decreased incidence of shockable rhythm compared to before the pandemic. 27,28 However, in this meta-analysis, we found no significant differences in this regard. The decrease in the rate of shockable rhythm in Europe and the United States could be attributed to the dramatic increase in the number of patients at the early phase of the pandemic, as well as the increase in the number of confirmed patient arrests due to a collapsing medical system. The aforementioned factors could have resulted in delayed paramedic response to OHCA incidents or delayed arrival of critically ill pa- tients to the medical facility with aggravated underlying pathophysiology. 8,29 Given a relatively lower COVID-19 caseload with stringent isolations policy in the early phase of the pandemic in South Korea compared to that in other countries, we hypothesized that the epidemiological features and outcomes of patients would differ. Lim, et al. 8 found an increased use of SGA devices and decreased use of ETI in prehospital airway management during the pandemic. Conversely, a recent other meta-analysis showed that ETI use has increased to pre-pandemic proportions. 11 In the early phase of the pandemic, airway treatment recommendations avoided intubation to help aerosol-led COVID-19 infection. 30 However, a recent study showed that intubation by experienced healthcare providers was associated with a low incidence of COVID-19 infection, 31,32 and recent meta-analyses likely reflect this trend. Our meta-analysis showed a significant decrease in intubation use; however, we did not observe a significant difference in the use of SGA devices. However, only two of the included studies compared intubation results, and the heterogeneity was substantial. Therefore, identifying the overall trend of airway management during the COVID-19 pandemic in South Korea is challenging, and additional analysis are needed.
Regarding OHCA outcomes during the pandemic, our findings in South Korea differed from those reported in previous studies. Other studies highlighted a decrease in survival rate and favorable neurological outcomes for OHCA. However, we found no significant difference in outcomes, including ROSC, survival, and favorable neurological outcomes, in South Korea. The national statistics data evaluating prehospital data indicated a slight decline in survival in 2020 ( Supplementary Fig. 1, only online); however, meta-analyses showed no significant change. This observation may imply that the pandemic had a relatively lesser effect on the outcome of OHCA in South Korea compared to other regions worldwide. This difference could be attributed to varying timing and trends in the occurrence of OHCA and public health system collapse compared to other countries.
It should not be overlooked that during a pandemic, awareness and altered responses to OHCA can be skewed. A pandemic is a type of disaster, and resources are focused as much as possible on those who can survive with limited medical resources. Resuscitative care was provided to as many people as possible prior to the pandemic; however, during the pandemic, resuscitative care focused on patients with a high probability of resuscitation. The characteristics of the two populations may differ. For example, during a pandemic, resuscitation may be easily terminated or not even started, particularly in patients with a low chance of ROSC. These people would be excluded from statistics, which could have an impact on the overall outcome of this meta-analysis.
Predicting a pandemic breakout is challenging; however, in recent years, unexpected infectious diseases are occurring more frequently, which has an impact on the healthcare system. Although COVID-19 was completely unknown, it led to an initial collapse of the healthcare system and adversely affected the course of treatment and outcomes for many critical diseases. In South Korea, the number of confirmed COVID-19 cases did not initially increase as quickly as it did in other countries, and the number of cases increased dramatically only later, allowing for the strengthening of the emergency medical system in the meantime. The medical system collapse seen during the COVID-19 pandemic should not be disregarded as a one-time event, and efforts should be made to systematize the medical system to prevent it from collapsing as a result of a pandemic caused by emerging and reemerging pathogens.
This study had several limitations. First, it was restricted to data only from South Korea. Hence, the total number of studies included was small, and the period of the pandemic varied in each study. In addition, despite the fact that there was an increase in at-home cardiac arrest, only two studies were included, and even those studies were not representative as they did not overlap the study period. Furthermore, although several epidemiologic factors and outcomes were compared across studies, interpreting the results of each variable was challenging since not all variables were analyzed in each study. Second, due to a lack of included studies, we were unable to conduct additional analyses, such as subgroup analysis or metaregression, to reduce the heterogeneity of each meta-analysis. Some factors in the meta-analysis had only two studies, making it difficult to conduct additional analysis. Third, the latest pandemic situation was not considered. In early 2022, South Korea had the highest number of daily confirmed COVID-19 cases and deaths. However, only data up to February 21, 2021 were included, with the study by Chung, et al. 19 being the most recent one. Hence, the most recent OHCA outcomes and characteristics were not examined in this study. Fourth, analyses based on published studies are restricted in their ability to reflect the complete trend. Negative research findings are not always disclosed, eliminating the inclusion of such data in the study. Therefore, future studies should compare the outcomes based on more comprehensive national data.
In conclusion, during the COVID-19 pandemic in South Korea, two studies found an increased tendency for home cardiac arrest, as well as a decreasing trend in the use of AED, among the rapidly increasing number of COVID-19 patients in the early phase of the pandemic. In addition, survival and favorable neurological outcomes of OHCA during the pandemic did not significantly differ compared to before the pandemic. In contrast to the deterioration of OHCA outcomes in the United States and Europe, which experienced medical system collapse and dramatic increase in the number of COVID-19 cases at the beginning of the pandemic, the caseload increased relatively slowly in South Korea during the same period, implying that the effect of the COVID-19 pandemic on OHCA was not significant. However, since there is insufficient evidence to support this, more investigation in South Korea is required.