Delays in Cardiopulmonary Resuscitation, Defibrillation, and Epinephrine Administration in Out-of-Hospital Cardiac Arrest　― Composite Time-Dependent Effects of Prehospital Interventions on 30-Day Favorable Neurological Outcomes and Social Implications From a Prospective Nationwide Population-Based Cohort Study ―

Abstract

Background: Our study investigated the prognostic impacts of the interval between collapse and the initiation of cardiopulmonary resuscitation (CPR), and subsequent intervals to defibrillation or epinephrine administration, on 30-day favorable neurological outcomes following out-of-hospital cardiac arrest (OHCA).

Methods and Results: This nationwide population-based cohort study used the All Japan Utstein Registry, encompassing OHCA patients in Japan between January 2006 and December 2021. The primary outcome was 30-day favorable neurological outcomes, defined as Cerebral Performance Category 1 or 2. Three-dimensional plots and multivariable logistic regression models were used to assess the time-dependent prognostic impacts of prehospital CPR interventions. In all, 184,731 OHCA patients (86,246 with shockable rhythm and 98,485 with non-shockable rhythm) were included in the study. Three-dimensional plots revealed that the interval between collapse and initiation of CPR, and subsequent intervals to defibrillation or epinephrine, were independently associated with 30-day favorable neurological outcomes in the groups with shockable and non-shockable rhythms, respectively (P<0.05 for all).

Conclusions: Among patients with witnessed OHCA, there was a dose-response relationship between delays in the collapse-CPR initiation interval, and subsequent intervals to defibrillation or epinephrine administration, and 30-day favorable neurological outcomes. Our findings provide valuable insights into OHCA management.

Out-of-hospital cardiac arrest (OHCA) is a significant public health concern associated with mortality and morbidity, particularly due to neurological sequelae among survivors.¹ Timely and effective prehospital cardiopulmonary resuscitation (CPR) is crucial in improving outcomes for OHCA patients.^2–6

The American Heart Association (AHA) guidelines recommend resuscitation algorithms stratified by the initial cardiac arrest rhythms: shockable and non-shockable.⁷ Early defibrillation in the initial shockable rhythm cohort increases the chance of a prehospital return of spontaneous circulation (ROSC), leading to an increased rate of favorable neurological outcomes.⁷ Early epinephrine administration in the initial non-shockable rhythm cohort improves clinical outcomes.⁷

However, in real-world clinical practice there are often delays in these prehospital CPR interventions, and obvious gaps remain in understanding the time-dependent prognostic effects of these interventions due to a lack of detailed clinical data. Such evidence is essential to identifying problems in current clinical practices and novel therapeutic targets for improving the quality of resuscitation, educating emergency medical service (EMS) providers and the public, and improving social infrastructure, such as expanding the use of automated external defibrillator (AED)-equipped drones, emergency medical technicians, and ambulances with a doctor onboard.^8–10

Therefore, the aim of the present study was to evaluate the relationships between the collapse to initiation of CPR interval, as well as subsequent intervals to defibrillation or epinephrine administration, and 30-day favorable neurological outcomes following OHCA in distinct initial shockable rhythm and non-shockable rhythm cohorts.

Methods

Data Source and Study Population

The All-Japan Utstein Registry is a prospective nationwide population-based cohort database, aligning with the Utstein-style guidelines for reporting OHCA. Conducted by the Fire and Disaster Management Agency of Japan from 2005 onwards, this registry aims to elucidate the epidemiology of OHCA in Japan. The All-Japan Utstein Registry defines OHCA as non-responsiveness, apnea, and pulselessness, and EMS providers in Japan initiate CPR for all OHCA patients, except in cases of obvious death, such as the amputation of the neck or trunk.

The All-Japan Utstein Registry has enrolled 2,059,417 confirmed OHCA patients between January 2005 and December 2021. Patients were excluded from the present study if: (1) there was no resuscitation (n=45,552); (2) they were aged <18 years (n=26,709) or age was unidentified (n=2); (3) the arrest was not witnessed (n=1,168,608), the witness status was unidentified (n=6,110), the cardiac arrest rhythm was unidentified (n=66,452), there was external etiology (trauma, hanging, drowning, drug overdose, or asphyxia; n=91,976), defibrillation and/or epinephrine data were missing (n=48,212), time to CPR and ROCS data were unavailable (n=5,477), or outcome data were missing (n=19); and (4) time to defibrillation data were missing in the shockable rhythm cohort (n=4,628) and time to epinephrine data were missing in the non-shockable rhythm cohort (n=410,920; Figure 1).

Figure 1.

Flowchart showing patient selection. CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation.

The study protocol adhered to the ethical principles outlined in the Declaration of Helsinki and the study was approved by the Ethics Committee of the University of Toyama (Reference no. R2024023). Given the retrospective nature of the study and the impracticality of obtaining individual consent from OHCA patients and their families, the requirement for written informed consent was waived, with strict adherence to ethical guidelines.

Prehospital Care for OHCA in Japan

EMS in Japan operate 24 h/day, providing comprehensive medical care nationwide. The Fire and Disaster Management Agency of Japan indicates an average EMS response time of approximately 9 min following a call out, ensuring timely treatment for emergency patients.

In adherence to Japanese CPR guidelines based on Consensus on Resuscitation Science and Treatment Recommendations,¹¹ prehospital care is administered by a team of 3 EMS providers, including at least 1 emergency medical technician trained in managing OHCA patients. The provider can perform CPR with intravenous lines, epinephrine, and advanced airway management, under a physician’s approval.

Instructions for performing bystander CPR are provided by emergency telephone dispatchers until EMS providers arrive on the scene, enhancing the chances of early intervention. EMS providers in Japan are mandated to transport all OHCA patients to a hospital, and resuscitation efforts are not terminated at the scene. This policy underscores the commitment to maximizing patient survival and the accuracy in verifying the uniformity of quality of prehospital CPR.

Since 2001, ambulances equipped with emergency physicians, in both helicopters and cars, has become widespread across almost all prefectures in Japan, further enhancing the capacity for advanced prehospital care and rapid transport of OHCA patients to appropriate medical facilities.

Data Collection and Quality Control

Details of the data collection have been described elsewhere.^2,3,8,12 Notably, all fire stations operating EMS systems and all collaborating medical facilities participate in the All-Japan Utstein Registry. EMS personnel are mandated to diligently record OHCA data as part of their emergency operations and to ensure comprehensive data collection in cases of cardiac arrest. In this study, we used the quality-controlled database integrated by the Fire and Disaster Management Agency and reviewed by the Japanese Circulation Society With Resuscitation Science Study (JCS-ReSS) Group.

The dataset included the following items: age, sex, rescue breathing by bystander (yes/no), cause of cardiac arrest (cardiac or non-cardiac), whether the OHCA was witnessed by EMS providers or bystanders, the presence of ambulances equipped with emergency physicians (yes/no), and first documented rhythm (pulseless ventricular tachycardia, ventricular fibrillation, pulseless electric activity, and asystole). The attending physicians, collaborating with EMS personnel, determined clinically cardiogenic or non-cardiogenic causes. The first documented rhythm was diagnosed by EMS personnel with semiautomated defibrillators on the scene.

Information on the utilization of public-access AEDs, prehospital defibrillation, epinephrine administration, and advanced airway management is also included in the database.

Temporal data were recorded by EMS personnel using standardized protocols, capturing various time points, including collapse time, call receipt time, the time at which EMS providers arrived on the scene, the time of CPR initiation, the first defibrillation time, and the time of first epinephrine administration. The collapse to CPR initiation interval was limited to a maximum of 30 min, with instances exceeding this threshold indicated as ≥30 min in our study. CPR included bystander chest compression-only CPR. Both collapse time and the time of bystander CPR initiation were obtained through EMS interviews with bystanders and measured in minutes. Time intervals from collapse to CPR initiation and subsequent intervals to defibrillation or epinephrine administration were calculated based on these data.

Outcomes

Our primary endpoint was a favorable neurological outcome at 30 days, defined as Cerebral Performance Category (CPC) 1 or 2, as reported in previously.^2,3,5,6,8,12 The CPC scale, assessed by attending physicians, delineates good cerebral performance (CPC 1) and sufficient cerebral function for independent activities of daily life with mild to moderate disability (CPC 2).

Statistical Analysis

Continuous variables are presented as the mean±SD and categorical variables are presented as numbers and percentages.

Our cohort was stratified into 2 groups based on the initial cardiac arrest rhythm: shockable and non-shockable. Frequency distributions of the collapse-CPR initiation, collapse-defibrillation, and collapse-epinephrine administration intervals were graphed in the shockable and the non-shockable rhythm cohorts. To visualize the relationships between rates of 30-day favorable neurological outcomes and the interval from collapse to CPR initiation, as well as subsequent intervals to defibrillation or epinephrine administration, in each cohort, we generated 3-dimensional plots. Multiple logistic regression analysis was used to evaluate independent predictors of 30-day favorable neurological outcomes. Covariates included the collapse-CPR initiation interval and subsequent intervals to defibrillation or epinephrine, as well as age, sex, year of the arrest, cause of the cardiac arrest, and the time interval from collapse to first contact with EMS providers. To assess the time-dependent relationship between the collapse-CPR initiation interval and subsequent intervals to prehospital interventions, patients were divided into 3 groups based on the collapse-CPR initiation interval: an early CPR (0–5 min) group; an intermediate CPR (6–10 min) group; and (3) a late CPR (≥11 min) group. Based on Japan Resuscitation Council guidelines, a sensitivity analysis was performed for 3 groups according to the year of the cardiac arrest: 2005–2010, 2011–2015, and 2016–2021. The aim of this analysis was to evaluate the relationships between rates of 30-day favorable neurological outcomes and the time to CPR, as well as to defibrillation or epinephrine, in each cohort.

Color charts representing the collapse-CPR initiation interval and subsequent intervals to defibrillation or epinephrine in each prefecture were generated to evaluate variability in the quality of prehospital care based on standard protocols.

Statistical analyses were performed using SPSS Statistics 26 (IBM, Armonk, NY, USA). Two-sided P<0.05 was considered statistically significant.

Results

Baseline Characteristics

Of the 2,059,417 patients with an OHCA, 184,731 were included in our analysis. This comprised 86,246 patients with a shockable rhythm and the prehospital use of defibrillation and 98,485 patients with a non-shockable rhythm and the prehospital use of epinephrine (Figure 1).

Compared with the non-shockable rhythm cohort, patients in the shockable rhythm cohort were younger (77.5±12.9 vs. 65.7±15.2 years, respectively) and had a higher proportion of cardiac arrests caused by cardiac events (35% vs. 92%, respectively; Table 1).

Table 1.

Clinical Features Stratified by Initial Cardiac Arrest Rhythm

	Shockable rhythm (n=86,246)	Non-shockable rhythm (n=98,485)
Demographics
Age (years)	65.7±15.2	77.5±12.9
Male sex	68,142 (79)	58,887 (60)
Bystander resuscitation
Rescue breathing (n=73,925/n=76,228)	9,739 (13)	7,030 (9)
EMS-witnessed	9,837 (11)	9,538 (10)
Ambulance with physicians	4,890 (6)	4,280 (4)
Initial cardiac arrest rhythm
Pulseless ventricular tachycardia	1,605 (2)	–
Ventricular fibrillation	84,641 (98)	–
Pulseless electric activity	–	49,250 (50)
Asystole	–	49,235 (50)
Advanced airway management (n=84,067/n=96,226)	35,887 (43)	65,399 (68)
Prehospital epinephrine	21,374 (25)	98,485 (100)
Cardiac cause	79,399 (92)	34,365 (35)
Time intervals (min)
From collapse to call receipt (n=78,228/n=89,520)	1.7±4.8	2.3±6.1
From call receipt to scene (n=86,172/n=98,428)	7.3±3.2	8.3±3.6
From scene to hospital arrival (n=85,777/n=98,238)	26.3±12.3	30.3±11.1

Continuous variables are presented as the mean±SD; categorical variables are presented as as numbers and percentages. EMS, emergency medical service.

In the shockable rhythm cohort, the time interval from collapse to call receipt was 1.7±4.8 min, the time from call receipt to arrival at the scene was 7.3±3.2 min, and the time from arrival at the scene to arrival at hospital was 26.3±12.3 min; the corresponding intervals in the non-shockable rhythm cohort were 2.3±6.1, 8.3±3.6, and 30.3±11.1 min, respectively (Table 1).

Time-Dependent Analysis in the Shockable Rhythm Cohort

In the shockable rhythm cohort, the collapse-CPR initiation interval was 5.4±5.7 min and the subsequent interval to defibrillation was 6.0±5.7 min (Figure 2A). The rate of 30-day favorable neurological outcomes was 22.0% (18,962/86,246; Figure 1).

Figure 2.

(A) Distribution of the time from collapse to initiation of cardiopulmonary resuscitation (CPR) and the subsequent interval to defibrillation in patients with a shockable rhythm. (B) Distribution of the collapse-CPR initiation interval and the subsequent interval to epinephrine administration in patients with a non-shockable rhythm.

Three-dimensional plots illustrating the relationship between rates of 30-day favorable neurological outcomes and both collapse-CPR initiation and subsequent defibrillation intervals revealed that shorter collapse-CPR initiation and subsequent defibrillation intervals were associated with a greater probability of favorable 30-day neurological outcomes (Figure 3A).

Figure 3.

(A) Three-dimensional plot illustrating the relationship between rates of favorable 30-day neurological outcomes, the time from collapse to initiation of cardiopulmonary resuscitation (CPR), and the subsequent interval to defibrillation in patients with a shockable rhythm. (B) Three-dimensional plot illustrating the relationship between rates of favorable 30-day neurological outcomes, the collapse-CPR initiation interval, and the subsequent interval to epinephrine in patients with a non-shockable rhythm.

In multivariable analysis, both the collapse-CPR initiation and subsequent defibrillation intervals were independently associated with 30-day favorable neurological outcomes. For each additional 5-min delay in the CPR initiation-defibrillation interval, the likelihood of achieving a favorable 30-day neurological outcome decreased significantly in the early CPR cohort (i.e., CPR initiation within 5 min; adjusted odds ratio [aOR] for 6–10 min, 1.144 [P<0.001]; aOR for 11–15 min, 0.821 [P<0.001]; aOR for 16–20 min, 0.496 [P<0.001]; aOR for ≥21 min, 0.326 [P<0.001]; Table 2). Similar trends were observed across the intermediate and late CPR cohorts.

Table 2.

Relationship Between Favorable 30-Day Neurological Outcomes and the Time From Collapse to Initiation of CPR and Subsequent Defibrillation in Unadjusted and Adjusted Logistic Regression Models in the Shockable Rhythm Cohort

Time interval from CPR to defibrillation	Crude OR (95% CI)	P value	aOR (95% CI): Model 1	P value	aOR (95% CI): Model 2	P value
Early CPR (0–5 min) cohort (n=51,440)
0–5 min	Ref.		Ref.		Ref.
6–10 min	0.822	<0.001	0.786	<0.001	1.144	<0.001
11–15 min	0.571	<0.001	0.542	<0.001	0.821	<0.001
16–20 min	0.357	<0.001	0.344	<0.001	0.496	<0.001
≥21 min	0.225	<0.001	0.230	<0.001	0.326	<0.001
Intermediate CPR (6–10 min) cohort (n=20,060)
0–5 min	Ref.		Ref.		Ref.
6–10 min	0.863	0.004	0.836	0.001	0.820	0.006
11–15 min	0.485	<0.001	0.469	<0.001	0.440	<0.001
16–20 min	0.231	<0.001	0.241	<0.001	0.228	<0.001
≥21 min	0.312	<0.001	0.355	0.001	0.382	0.005
Late CPR (≥11 min) cohort (n=14,746)
0–5 min	Ref.		Ref.		Ref.
6–10 min	0.844	0.097	0.843	0.101	0.835	0.127
11–15 min	0.772	0.146	0.781	0.171	0.908	0.639
16–20 min	0.193	0.193	0.226	0.011	0.207	0.029
≥21 min	0.366	0.366	0.418	0.009	0.476	0.213

Adjusted (aOR) and unadjusted (OR) odds ratios of the logistic regression model depicting the relationship between favorable 30-day neurological outcomes and the intervals to cardiopulmonary resuscitation (CPR) and subsequent defibrillation. Model 1 was adjusted for age, sex, and interval to epinephrine administration. In Model 2, covariates included interval to epinephrine administration, age, sex, emergency medical service (EMS)-witnessed out-of-hospital cardiac arrest, the use of public-access defibrillators and advanced airway management, the cause of cardiac arrest, ambulance with physician, and time interval from collapse to first contact with EMS providers. CI, confidence interval.

Time-Dependent Analysis in the Non-Shockable Rhythm Cohort

In non-shockable rhythm cohort, the collapse-CPR initiation interval was 6.6±7.1 min and the subsequent interval to epinephrine was 18.7±8.8 min (Figure 2B). The rate of favorable 30-day neurological outcomes was 0.9% (943/98,485; Figure 1).

Three-dimensional plots illustrating the relationship between rates of favorable 30-day neurological outcomes, collapse-CPR initiation intervals, and subsequent intervals to epinephrine administration indicated that shorter collapse-CPR initiation and subsequent epinephrine administration intervals were weakly associated with improved favorable 30-day neurological outcomes (Figure 3B).

In multivariable analysis, both the collapse-CPR initiation interval and CPR initiation–epinephrine administration interval were independently associated with favorable 30-day neurological outcomes. Each additional 5-min delay in the CPR initiation to epinephrine administration interval was associated with a decreased likelihood of favorable 30-day neurological outcomes in the early CPR cohort (aOR for 11–15 min, 0.600 [P=0.005]; aOR for 16–20 min, 0.428 [P<0.001]; aOR for ≥21 min, 0.283 [P<0.001]; Table 3). Similar trends were observed across the intermediate and late CPR cohorts.

Table 3.

Relationship Between Favorable 30-Day Neurological Outcomes and the Time From Collapse to Initiation of CPR and Subsequent Epinephrine Administration in Unadjusted and Adjusted Logistic Regression Models in the Non-Shockable Rhythm Cohort

Time interval from CPR to epinephrine administration	Crude OR (95% CI)	P value	aOR (95% CI): Model 1	P value	aOR (95% CI): Model 2	P value
Early CPR (0–5 min) cohort (n=53,962)
0–10 min	Ref.		Ref.		Ref.
11–15 min	0.573	<0.001	0.573	<0.001	0.600	0.005
16–20 min	0.363	<0.001	0.363	<0.001	0.428	<0.001
≥21 min	0.2227	<0.001	0.227	<0.001	0.283	<0.001
Intermediate CPR (6–10 min) cohort (n=19,757)
0–10 min	Ref.		Ref.		Ref.
11–15 min	0.865	0.400	0.865	0.400	0.955	0.821
16–20 min	0.460	<0.001	0.460	<0.001	0.603	0.041
≥21 min	0.286	<0.001	0.286	<0.001	0.358	0.001
Late CPR (≥11 min) cohort (n=24,787)
0–10 min	Ref.		Ref.		Ref.
11–15 min	0.647	0.037	0.647	0.037	0.719	0.164
16–20 min	0.511	0.006	0.511	0.006	0.577	0.05
≥21 min	0.303	<0.001	0.303	<0.001	0.368	0.002

aOR and OR of the logistic regression model depicting the relationship between favorable 30-day neurological outcomes and the time to CPR initiation and subsequent epinephrine administration. Model 1 was adjusted for age, sex, and the interval to epinephrine administration. In Model 2, covariates included interval to epinephrine administration, age, sex, EMS-witnessed out-of-hospital cardiac arrest, the use of public-access defibrillators and advanced airway management, the cause of cardiac arrest, ambulance with physician, and the time interval from collapse to first contact with EMS providers. Abbreviations as in Table 2.

Sensitivity Analysis for Time-Dependent Prognostic Impact of Prehospital CPR Interventions

Based on Japan Resuscitation Council guidelines, our study was divided into 3 time periods: 2006–2010, 2011–2015, and 2016–2021. Identical results were obtained across all time periods (Supplementary Figure).

Geographical Distribution of Prehospital Intervention Times in Japan

The color charts revealed variations in the collapse-CPR initiation interval and subsequent intervals to defibrillation and epinephrine administration among regions.

Specially, Miyazaki and Fukushima prefectures had shorter intervals to the initiation of CPR but longer intervals to defibrillation and epinephrine administration, whereas Tokyo had a longer interval to CPR initiation but shorter intervals to defibrillation and epinephrine administration. Conversely, Osaka and Aichi had shorter intervals for all 3 intervals (i.e., CPR administration, defibrillation, and epinephrine administration; Figure 4).

Figure 4.

Color charts illustrating the (A) time from collapse to initiation of cardiopulmonary resuscitation (CPR) and subsequent intervals to (B) defibrillation and (C) epinephrine administration in each prefecture.

Discussion

Our nationwide cohort study underscored the critical importance of timely interventions in improving outcomes following witnessed OHCA. There were several key findings. First, the collapse-CPR initiation interval and subsequent interval to defibrillation were independently correlated with favorable 30-day neurological outcomes among patients with shockable rhythm. Second, in patients with non-shockable rhythm, the collapse-CPR initiation interval and subsequent interval to epinephrine administration showed weaker associations with favorable 30-day neurological outcomes. Third, there were significant regional disparities in both the collapse-CPR initiation interval and subsequent intervals to defibrillation or epinephrine administration across prefectures in Japan.

Time Sensitivity of CPR Initiation and Defibrillation in Patients With Shockable Rhythm

In the case of ventricular fibrillation/pulseless ventricular tachycardia, myocardial reserves of oxygen and other energy substrates are quickly depleted, rendering the myocardium refractory to defibrillation.^7,13–15 Therefore, early defibrillation or the administration of CPR before defibrillation could be vital for improving outcomes in OHCA.

Our study elucidated a dose-response effect between early CPR initiation and prompt defibrillation, contributing significantly to favorable neurological outcomes in patients with shockable rhythms. This underscores the critical role of a rapid response, including prompt defibrillation, and seamless coordination between bystanders and EMS providers, as well as the importance of widespread defibrillator availability to optimize patient outcomes.^8,10 Notably, in the cohort with CPR initiation within 5 min, a subsequent interval to defibrillation of 5–10 min was associated with improved favorable 30-day neurological outcome. These results could suggest that the success rates of defibrillation improved significantly after a period of CPR, allowing replenishment of myocardial reserves of oxygen and other energy substrates.^7,14,16

Our findings emphasize the time sensitivity of interventions in the management of OHCA, particularly in the case of shockable rhythm. Consistent with a previous study by Nguyen et al., we found a dose-response relationship between delays in the collapse-CPR initiation interval and favorable neurological survival rates.¹⁷ Specifically, Nguyen et al. reported that a collapse-CPR initiation interval >10 min was associated with an 8.8% decrease in favorable 30-day neurological outcomes, aligning with our findings. Moreover, although shorter subsequent intervals to defibrillation were deemed important,¹⁸ our study highlighted that a shorter collapse-CPR initiation interval was a more crucial factor in achieving favorable 30-day neurological outcomes. Our study may offer a threshold for one of the greatest challenges during CPR: determining the optimal duration of treatment or performing extracorporeal CPR when conventional CPR fails to elicit a response.

These results highlight the importance of minimizing the time to intervention to maximize the likelihood of successful neurological recovery, emphasizing the criticality of early, continuous, and high-quality CPR.

Time Sensitivity of CPR Initiation and Epinephrine Administration in Patients With Non-Shockable Rhythm

Epinephrine holds promise during cardiac arrest primarily due to it effects on α-adrenergic receptors, augmenting coronary and cerebral perfusion pressure during CPR.^7,19 A systematic review and meta-analysis indicated significant increases in survival rates following OHCA with epinephrine administration.²⁰ However, a randomized control study and observation studies have not definitively established whether neurological outcomes improve with epinephrine administration.^20,21 This ambiguity may be due to delayed epinephrine administration, with administration times exceeding 20 min in the OHCA cohort.

We observed an association between shorter intervals from collapse to CPR initiation and subsequent epinephrine administration and improved neurological outcomes in patients with non-shockable rhythms, suggesting a potential window for intervention optimization. This underscores the complexity of managing this patient population, and future research could explore novel strategies, such as advanced hemodynamic support, timing of peripheral intravenous routes, route of drug administration, and targeted pharmacotherapy, to enhance outcomes in patients with a non-shockable rhythm. In particular, advanced care planning may be essential in patients with advanced cancer and respiratory diseases.^22,23

Although the impact of early interventions may be less pronounced in patients with non-shockable compared with shockable rhythms, our study emphasizes the importance of timely and coordinated efforts in optimizing patient outcomes. Tailored approaches in OHCA management, with a focus on optimizing response times and intervention strategies for different rhythm presentations, are imperative. Our study elucidates the challenges in and opportunities for improving outcomes in patients with non-shockable rhythms. The implications of our findings extend to clinical practice and prehospital care protocols, particularly in the case of non-shockable rhythms.

Implications for Public Health Policy and Future Directions

Our findings have significant implications for refining resuscitation protocols and optimizing healthcare infrastructure. In developed nations, emphasis should be placed on reducing response times from collapse to CPR initiation and the subsequent interval to defibrillation, as well as ensuring the widespread availability of defibrillators in public spaces. In resource-limited settings and developing countries, where access to advanced medical interventions may be limited, efforts should concentrate on community-based CPR training programs and initiatives to increase public awareness of the importance of early intervention. In districts where transportation infrastructure is needed, it may be important to expand AED-equipped drones. Although there are significant barriers to implementing these resources, community-based initiatives, targeted campaigns, and cost-effective, scalable approaches like integrating basic life support education into school curricula could enhance outreach. Telemedicine-assisted EMS and smartphone-based emergency tools offer cost-effective ways of improving response times. Further research is needed to assess the effectiveness and sustainability of these alternatives.

Even within a highly developed healthcare system like Japan’s, the provision of uniform resuscitation care remains a challenge due to regional differences in resources and access.²⁴ This highlights the need for tailored approaches that consider local healthcare contexts and available resources to improve survival rates and neurological outcomes in OHCA patients worldwide. Our results advocate for a time-based strategy prioritizing prehospital CPR interventions on a global scale.

Study Limitations

This study has several limitations. First, like all epidemiological studies, potential limitations include data integrity, validity, and ascertainment bias. However, our study used a uniform data collection method, had a substantial sample size, and adopted a population-based design encompassing all documented OHCA cases in Japan, thereby serving to mitigate these potential biases. Second, our reliance on various time intervals, including collapse time, call receipt time, the time of EMS provider arrival on the scene, and times to CPR initiation, first defibrillation, and first epinephrine administration, introduces the possibility of measurement error due to variability in recording accuracy. Any discrepancies identified due to system errors or conversions were addressed by cross-checking with individual EMS units and the JCS-ReSS Group and correcting inaccuracies. Third, although the quality of resuscitation is known to affect neurological outcomes, our study lacked data on resuscitation quality. Fourth, information regarding ongoing resuscitation efforts after hospital arrival was unavailable. Treatments like extracorporeal CPR may influence outcomes. As these treatments become more prevalent, the optimum duration of the prehospital recitation efforts may need to be re-evaluated. Fifth, neurological outcomes were measured at 30 days after OHCA based on Utstein style, potentially overlooking patients with gradual recovery trajectories. Establishing optimal follow-up times after OHCA remains challenging, and extending the follow-up period to 3 months may balance the recovery opportunity with patient follow-up feasibility. Sixth, the All-Japan Registry is specific to the Japanese population and healthcare system. However, the fundamental principles of CPR interventions align with international guidelines and the data collection follows the standardized Utstein reporting style, ensuring alignment with international OHCA registries. Although regional differences in EMS systems (e.g., physician-directed EMS care and free ambulance services)and patient demographics (e.g., an aging population) may affect generalizability, our findings may still have broader applicability. Seventh, our study was limited to patients with witnessed OHCA who received prehospital defibrillation and epinephrine. Finally, the underlying reasons for the differences in each prefecture in the time to initiation of CPR and subsequent intervals to defibrillation and epinephrine administration remain unclear, warranting further investigation to elucidate potential contributing factors. Indeed, major disasters, including the 2011 Great East Japan Earthquake and tsunami, the 2016 Kumamoto Earthquake, and Typhoon Hagibis in 2020, have had profound effects on local communities and healthcare infrastructure.^25–27 Specifically, in disaster-affected areas, the emotional toll from the loss of family members and colleagues, and disruptions to emergency services and communication systems may result in delays in bystander-initiated CPR and EMS response times. These factors likely contributed to a temporary decline in favorable neurological outcomes, particularly in rural regions.

Conclusions

Our study has provided valuable insights into the management of OHCA, emphasizing the importance of a time-based strategy prioritizing prompt CPR, defibrillation, and epinephrine administration. By shedding light on the significant impact of timely interventions on neurological outcomes in OHCA patients, our findings contribute to the development of tailored approaches that account for local healthcare contexts and available resources, including education for the public and EMS providers.

Acknowledgments

The authors thank all the EMS personnel and collaborating physicians in Japan, and the staff of the Fire Safety and Disaster Preparedness of Japan for establishing and following the Utstein database.

Sources of Funding

None.

Disclosures

K.K., Y.T., and T. Ikeda are members of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.

IRB Information

This study was approved by the Ethics Committee of the University of Toyama. Because of the retrospective nature of the study and the impracticality of obtaining individual consent from OHCA patients and their families, the requirement for written informed consent was waived, with strict adherence to ethical guidelines.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0638

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