a b s t r a c t

Introduction: Timely defibrillation is associated with increased survival in out-of-hospital cardiac arrest (OHCA) cases. This study aimed to determine whether the time to first defibrillation was associated with good neurolog- ical outcomes in OHCA patients with refractory ventricular fibrillation.

Methods: Bystander-witnessed adult OHCA patients with presumed cardiac etiology who presented with ventric- ular fibrillation and received >=2 successive prehospital defibrillations from emergency medical services between 2013 and 2018 were included. The times from collapse to first defibrillation were categorized into Group 1 (0-5 min), Group 2 (6-10 min), Group 3 (11-15 min), and Group 4 (16-60 min). The primary outcome was a good neurological recovery (cerebral performance category 1-2). Multivariable logistic regression analysis was performed to calculate the adjusted odd ratios (AORs) and 95% confidence intervals (CIs) for outcomes according to time group (Group 1 as the reference) and per 1-min delay.

Results: The study included 5753 patients, with overall rates of 34.4% for survival to discharge and 27.2% for good neurological recovery. The median number of prehospital defibrillations was 3 (interquartile range 2-5). Relative to Group 1, the AORs for good neurological recovery were 0.58 in Group 2 (95% CI: 0.41-0.82), 0.42 in Group 3 (95% CI: 0.29-0.60), and 0.19 in Group 4 (95% CI: 0.13-0.29). When time from collapse to first EMS defibrillation was analyzed as a continuous variable, each 1-min delay was associated with a significant decrease in the likeli- hood of good neurological recovery (AOR: 0.93, 95% CI: 0.91-0.94).

Conclusions: A short time from collapse to first defibrillation was associated with good neurological recovery among patients with OHCA and refractory ventricular fibrillation. This result suggests that a failed first shock still has a positive effect if it is delivered quickly.

(C) 2020

1. Introduction

Out-of-hospital cardiac arrest (OHCA) is a major public health bur- den because of its high mortality rate [1-3]. survival outcomes vary ac- cording to the initial rhythm, and ventricular fibrillation or pulseless ventricular tachycardia (VF/pVT) is a strong predictor of favorable OHCA outcomes [4,5]. For example, survival rates of up to 30% have been reported for OHCA patients in VF/pVT [1]. Patients with OHCA and an initial VF/pVT rhythm should promptly receive an Electrical shock that is immediately followed by chest compressions. Patients who remain in VF/pVT after standard defibrillation (i.e., refractory VF) have high mortality rate and poor neurological outcomes [6,7].

The definitions of refractory VF in previous studies include initial VF/ pVT rhythm that persists or recurs after >=1 shock [8], persistent VF after three successive standard defibrillation attempts [9,10], or failure to

* Corresponding author at: Department of Emergency Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul 03080, Republic of Korea.

E-mail address: [email protected] (J.H. Park).

sustain recovery of spontaneous circulation (ROSC) after three shocks and the administration of amiodarone and/or adrenaline [11,12]. The 2018 American Heart Association guidelines defined refractory VF as VF/pVT that persists or recurs after >=1 shock [13] and suggest that ami- odarone or lidocaine treatment may be considered to improve the ROSC rate for patients with refractory VF, although that recommendation is based on low-quality evidence [13]. Previous studies have also revealed variable results regarding treatments for patients with refractory VF, which include extracorporeal cardiopulmonary resuscitation, Beta blockers, Double sequential defibrillation, and early reperfusion [11,12,14-18].

Early defibrillation is a key factor for improving survival among pa- tients in VF/pVT [19-21] and is emphasized in the Chain of survival [22]. The Probability of survival decreases rapidly with longer times to defibrillation in patients with a shockable rhythm [20,21], and a greater number of defibrillation attempts is also associated with decreased sur- vival [6,20]. Nevertheless, electrical shocks delivered for defibrillation can change the electrophysiological characteristics of the myocardium, even when the rhythm is refractory to the shock, based on animal and

https://doi.org/10.1016/j.ajem.2020.12.019

0735-6757/(C) 2020

human studies [23-25]. Thus, a failed shock attempt may still influence the myocardial electrophysiology, even if it fails to defibrillate VF, and a ailed first shock might still have potentially positive effects if it is de- livered early in the patient’s course. However, to the best of our knowl- edge, no studies have examined the effects of time to first defibrillation among OHCA patients who remain refractory to consecutive defibrilla- tion attempts. Therefore, the present study aimed to determine whether the time from collapse to first emergency medical services (EMS) defi- brillation was associated with neurological outcomes among Korean OHCA patients with refractory VF. We hypothesized that an early first defibrillation would be associated with good neurological outcomes among these OHCA patients, even when the initial shock failed to defi- brillate the VF.

1. Methods
   1. Study design and setting

This retrospective study evaluated data from a nationwide prospec- tive registry of Korean OHCA patients. Korea has approximately 50 mil- lion inhabitants living in an area of 100,210 km², and there are approximately 30,000 OHCA cases per year. The EMS system in Korea is exclusively operated by the National Fire Agency, and the system had 1352 ambulances with 9091 EMS providers in 2016. The EMS level is considered intermediate, as EMS providers can provide cardio- pulmonary resuscitation (CPR) with automatic external defibrillation (AED), perform advanced airway management, and administer fluid in- travenously. All EMS-assessed OHCA patients undergo CPR at the scene and during transport according to the 2015 American Heart Association guidelines. Except for areas conducting pilot trials, prehospital adminis- tration of medications for advanced cardiac life support such as epi- nephrine is not allowed by law. As only physicians can declare death in Korea, EMS providers cannot stop CPR unless ROSC occurs and must transport all OHCA patients to the nearest emergency department (ED). Prehospital mechanical CPR device was used in 15% of OHCA patients in 2018.

• 1. Data source

This study identified cases in the Korean OHCA registry, which cap- tures all Korean cases of EMS-assessed OHCA throughout the country. The OHCA registry is a prospective observational registry that was launched during 2006 through a collaboration between the National Fire Agency and the Korea Centers for Disease Control and Prevention. The registry includes ambulance run sheets, dispatch records, EMS car- diac arrest in-depth registry, and a medical record review. The medical record reviewers from the Korea Centers for Disease Control and Pre- vention extract data regarding the etiology, hospital care, and outcomes based on the Utstein guidelines. Quality management protocols, the de- tailed data collection process, and an explanation of the registry have been described in previous reports [26,27].

• 1. Study population

The study population included bystander-witnessed, EMS-treated, adult OHCA patients (>=18 years old) with presumed cardiac etiology who had an EMS-assessed Initial shockable rhythm with refractory VF. The study included cases identified between January 2013 and Decem- ber 2018. Refractory VF was defined as VF/pVT that persisted or re- curred after >=1 shock [13]. Patients were excluded if they had missing or ineligible data regarding the time from collapse to defibrillation (<0 min or > 60 min) or missing data regarding neurological outcomes. Patients with bystander defibrillation were not excluded. We hypothe- sized that chance of bystander defibrillation is increased when response time and time to first EMS defibrillation are delayed. Because outcomes

of patients with bystander defibrillation is excellent, including patients with bystander defibrillation leads to bias toward null.

• 1. Outcome measures

The primary outcome was a good neurological recovery, which was defined as Cerebral Performance Category 1-2. The secondary outcomes included survival to hospital discharge and prehospital ROSC.

• 1. Exposure and variables

The main exposure was the time from collapse to the first EMS defi- brillation, which was determined based on the defibrillation time from the detailed EMS information regarding cardiac arrest. The times from collapse to the first EMS defibrillation were categorized as Group 1 (0-5 min), Group 2 (6-10 min), Group 3 (11-15 min), and Group 4 (16-60 min). The categorization was based on the 3 phase model of car- diac arrest comprised of the electrical phase (0-5 min), the circulatory phase (6-10 min) and the metabolic phase (11- min) [28,29]. We added an additional category to divide the large volume of patients in- cluded in the metabolic phase.

We also collected data regarding age, sex, past medical history, res- idential area (metropolitan or non-metropolitan), collapse location (public, private, or others), witnessed status, bystander CPR, bystander defibrillation, EMS response times (time from call to EMS arrival, time from ambulance arrival to scene departure, and time from scene depar- ture to ED arrival), the first EMS defibrillation location (scene or ambu- lance), and the total number of EMS defibrillations before ED arrival.

• 1. Statistical analysis

Categorical variables were reported as number (percentage) and compared using the chi-squared test or Fisher’s exact test. Continuous variables were reported as median (interquartile range, IQR) and com- pared using the t-test or Wilcoxon rank sum test. Multivariable logistic regression was used to investigate whether outcomes were related to the time from collapse to first EMS defibrillation. The adjusted odds ra- tios (AORs) and 95% confidence intervals (95% CIs) were calculated for the outcomes after adjusting for age, sex, medical history (diabetes, hy- pertension, heart disease, stroke), residential area, collapse location, by- stander CPR, and EMS response time. Sensitivity analyses with conditional multivariable logistic regression were also performed based on subgroups of patients from Group 2 (6-10 min) and Group 3 (11-15 min), who were matched 1:1 according to response time (per 1-min interval), as early defibrillation is closely linked to response time. We also performed additional sensitivity analyses of patients with >=3 successive prehospital EMS defibrillations, given the varying definitions of refractory VF from previous studies. All tests were two- tailed and p-values of <0.05 were considered statistically significant. All statistical analyses were performed using SAS software (version 9.4; SAS Institute Inc., Cary, NC, USA).

• 1. Ethics statement

The study complies with the Declaration of Helsinki, and its protocol was approved by the Institutional Review Board with a waiver of in- formed consent (IRB no. 1103-153-357).

1. Results

We identified 152,812 Korean cases of EMS-treated OHCA during the study period, and 5753 cases fulfilled the inclusion criteria (Fig. 1). The included cases were assigned to Group 1 (169 patients, 2.9%), Group 2 (2105 patients, 36.6%), Group 3 (1992 patients, 34.6%), or

Group 4 (1487 patients, 25.8%).

Fig. 1. Study flowchart. EMS, emergency medical service; OHCA, out-of-hospital cardiac arrest.

Table 1

Demographic characteristics according to time from collapse to first EMS defibrillation

	All patients N (%)		Group 1 (0-5 min) N (%)		Group 2 (6-10 min) N (%)		Group 3 (11-15 min) N (%)		Group 4 (16-60 min) N (%)	p-value
Patients, n	5753 (100)		169 (2.9)		2105 (36.6)		1992 (34.6)		1487 (25.8)
Collapse to first EMS defibrillation, min										<0.001
Median (IQR)	12 (9-16)		5 (4-5)		9 (7-9)		12 (11-14)		20 (17-24)
Sex, n										0.100
Male	4713 (81.9)		140 (82.8)		1758 (83.5)		1609 (80.8)		1206 (81.1)
Age, years										0.006
>=65	3387 (58.9)		106 (62.7)		1256 (59.7)		1158 (58.1)		867 (58.3)
Median (IQR)	59.6 (50.4-70.9)		60.9 (53.2-72.1)		58.9 (50.1-69.4)		59.0 (49.9-70.7)		61.6 (51.7-72.3)	<0.001
Medical history, n
Diabetes	1023 (17.8)		23 (13.6)		397 (18.9)		356 (17.9)		247 (16.6)	0.165
Hypertension	1978 (34.4)		50 (29.6)		747 (35.5)		709 (35.6)		472 (31.7)	0.033
Heart disease	1434 (24.9)		35 (20.7)		548 (26)		513 (25.8)		338 (22.7)	0.057
Stroke	3,21 (5.6)		11 (6.5)		116 (5.5)		106 (5.3)		88 (5.9)	0.832
Residential area, n										<0.001
Metropolitan	2804 (48.7)		106 (62.7)		1202 (57.1)		928 (46.6)		568 (38.2)
Collapse location, n										<0.001
Public	2334 (40.6)		100 (59.2)		942 (44.8)		784 (39.4)		508 (34.2)
Private	3304 (57.4)		67 (39.6)		1123 (53.3)		1177 (59.1)		937 (63.0)
Others	15 (0.3)		1 (0.6)		4 (0.2)		5 (0.3)		5 (0.3)
Bystander CPR, n	4156 (72.2)		103 (60.9)		1527 (72.5)		1457 (73.1)		1069 (71.9)	0.008
Bystander defibrillation, n	122 (2.1)		4 (2.4)		21 (1.0)		43 (2.2)		54 (3.6)	<0.001
EMS response time, min, median (IQR)	6 (5-9)		3 (2.5-4)		5 (5-6)		7 (6-9)		9 (6-13)	<0.001
EMS scene time, min, median (IQR)	13 (9-18)		10 (8-13)		12 (9-16.5)		13 (10-18)		14 (10-20)	<0.001
EMS transport time, min, median (IQR)	7 (4-10)		5 (3-10)		6 (4-9)		7 (5-10)		8 (5-14)	<0.001
EMS defibrillation, n
Place of first defibrillation										<0.001
Scene	5536 (96.2)		164 (97.0)		2054 (97.6)		1914 (96.1)		1404 (94.4)
Ambulance	217 (3.8)		5 (3.0)		51 (2.4)		78 (3.9)		83 (5.6)
Defibrillations before ED arrival, median (IQR)	3 (2-5)		3 (2-4)		3 (2-4)		3 (2-5)		3 (2-5)	0.010
Outcomes, n
Prehospital ROSC	2122 (36.9)		98 (58.0)		1024 (48.6)		709 (35.6)		291 (19.6)	<0.001
Survival to discharge	1978 (34.4)		92 (54.4)		961 (45.7)		668 (33.5)		257 (17.3)	<0.001
Good neurological recovery	1567 (27.2)		81 (47.9)		764 (36.3)		537 (27.0)		185 (12.4)	<0.001

EMS, emergency medical service; IQR, interquartile range; CPR, cardiopulmonary resuscitation; ED, emergency department; ROSC, return of spontaneous circulation.

• 1. Baseline characteristics

Table 1 shows the patient characteristics and outcomes according to the time from collapse to EMS defibrillation. Patients were pre- dominantly male and had a median age of 59.6 years, although there were no significant inter-group differences in age or sex. Cases with short times from collapse to EMS defibrillation typically occurred in public places. Increased Response times were associated with a statistically significant increase in time from collapse to first EMS defibrillation. Overall, 2122 (36.9%) of patients obtained prehospital ROSC. Among them, 1708 (80.5%) and 1430 (67.4%) of pa- tients obtained survival to discharge and good neurological recovery, respectively. The proportions of good neurological recovery were 47.9% in Group 1 (81/169 patients), 36.3% in Group 2 (764/2105 pa-

tients), 27.0% in Group 3 (537/1992 patients), and 12.4% in Group 4 (185/1487 patients). Shorter times from collapse to EMS defibrilla- tion were also associated with higher proportions of prehospital ROSC and survival to discharge.

• 1. Main analysis

Table 2 shows the effects of time from collapse to first EMS defi- brillation on the various outcomes. The proportion of good neurolog- ical recovery significantly decreased for each time-based group (Group 2 OR: 0.62, 95% CI: 0.45-0.85; Group 3 OR: 0.40, 95% CI:

0.29-0.55; Group 4 OR: 0.15, 95% CI: 0.11-0.22). Similar results were observed after adjusting for covariates (Group 2 AOR: 0.58, 95% CI: 0.41-0.82; Group 3 AOR: 0.42, 95% CI: 0.29-0.60; Group 4

AOR: 0.19, 95% CI: 0.13-0.29).

When time from collapse to first EMS defibrillation was analyzed as a continuous variable, each 1-min delay was associated with a sig- nificant decrease in the likelihood of good neurological recovery (AOR: 0.93, 95% CI: 0.91-0.94). In addition, longer times from col- lapse to EMS defibrillation were associated with decreased likeli- hoods of survival to discharge (Group 2 AOR: 0.69, 95% CI: 0.49-0.97; Group 3 AOR: 0.47, 95% CI: 0.33-0.67; Group 4 AOR:

0.24, 95% CI: 0.16-0.35) and prehospital ROSC (Group 2 AOR: 0.65,

95% CI: 0.46-0.91; Group 3 AOR: 0.41, 95% CI: 0.29-0.58; Group 4

AOR: 0.22, 95% CI: 0.15-0.31).

• 1. Sensitivity analysis

Matching according to response time identified 2456 OHCA cases (Group 2: 1228 patients, Group 3: 1228 patients). The baseline charac- teristics and outcomes for the matched subsets are shown in Supple- mentary Table S1. The results from the conditional multivariable logistic regression analyses of outcomes in the matched subsets are shown in Table 3. The likelihood of good neurological recovery was sig- nificantly lower for longer times from collapse to the first EMS defibril- lation (AOR: 0.73, 95% CI: 0.60-0.88), and similar results were also observed for survival to discharge and prehospital ROSC. Additional sen- sitivity analyses were performed for 3694 patients with >=3 successive prehospital EMS defibrillations, and their baseline characteristics and outcomes are shown in Supplementary Table S2. The results of the mul- tivariable logistic regression analyses are shown in Table 4. As in the main analysis, increasing times from collapse to first EMS defibrillation were associated with significantly decreasing rates of good neurological recovery, survival to discharge, and prehospital ROSC.

1. Discussion

This study evaluated data from a prospective Korean OHCA registry and revealed that the time from collapse to first EMS defibrillation was associated with good neurological outcomes among adults with witnessed OHCA and presumed cardiac etiology. These cases involved refractory VF, which was defined as VF/pVT that persisted or recurred after >=1 shock. Timely defibrillation for these patients was also associ- ated with improved rates of survival to discharge and prehospital ROSC. Similar results were also observed when we only considered pa- tients with >=3 successive prehospital EMS defibrillations. These findings support the importance of rapid defibrillation for OHCA patients in re- fractory VF. Several recent studies have focused on advanced life sup- port techniques, such as extracorporeal CPR, double sequential defibrillation, and early reperfusion for patients in refractory VF [11,12,14-16]. However, our results emphasize the importance of rapid defibrillation, which is an early link in the chain of survival [22], and agree with previous reports that OHCA patients with non- refractory VF and shockable rhythm had rapidly decreasing survival rates at longer times to defibrillation [20,21].

Table 2

Multivariable logistic regression analyses of outcomes according to time from collapse to first EMS defibrillation

	All patients		Positive outcomes		Unadjusted OR		Adjusted OR
Outcomes	N		N (%)		(95% CI)		(95% CI)
Good neurological recovery
Total	5753		1567 (27.2)
Per 1-min delay					0.91 (0.89-0.92)		0.93 (0.91-0.94)
Group 1 (0-5 min)	169		81 (47.9)		Reference		Reference
Group 2 (6-10 min)	2105		764 (36.3)		0.62 (0.45-0.85)		0.58 (0.41-0.82)
Group 3 (11-15 min)	1992		537 (27.0)		0.40 (0.29-0.55)		0.42 (0.29-0.60)
Group 4 (16-60 min)	1487		185 (12.4)		0.15 (0.11-0.22)		0.19 (0.13-0.29)
Survival to discharge
Total	5753		1978 (34.4)
Per 1-min delay					0.90 (0.89-0.91)		0.93 (0.91-0.94)
Group 1 (0-5 min)	169		92 (54.4)		Reference		Reference
Group 2 (6-10 min)	2105		961 (45.7)		0.70 (0.51-0.96)		0.69 (0.49-0.97)
Group 3 (11-15 min)	1992		668 (33.5)		0.42 (0.31-0.58)		0.47 (0.33-0.67)
Group 4 (16-60 min)	1487		257 (17.3)		0.18 (0.13-0.24)		0.24 (0.16-0.35)
Prehospital ROSC
Total	5753		2122 (36.9)
Per 1-min delay					0.91 (0.90-0.92)		0.93 (0.92-0.94)
Group 1 (0-5 min)	169		98 (58.0)		Reference		Reference
Group 2 (6-10 min)	2105		1024 (48.6)		0.69 (0.50-0.94)		0.65 (0.46-0.91)
Group 3 (11-15 min)	1992		709 (35.6)		0.40 (0.29-0.55)		0.41 (0.29-0.58)
Group 4 (16-60 min)	1487		291 (19.6)		0.18 (0.13-0.25)		0.22 (0.15-0.31)

Table 3

Multivariable conditional logistic regression analyses of outcomes in the response time-matched groups according to time from collapse to first EMS defibrillation

regardless of the initial rhythm, and evaluated the Rhythm analysis time, which also makes it difficult to determine the effects of reducing the time to first defibrillation in patients with refractory VF.

All patients

Positive outcomes

Unadjusted OR

Adjusted OR

The electrophysiological pattern of VF has been reported to be an im- portant factor that helps determine the termination of VF [33,34]. A ca-

Outcomes N N (%) (95% CI) (95% CI)

Good neurological recovery
Total	2456	791 (32.2)
Per 1-min delay			0.91	0.91
			(0.87-0.94)	(0.87-0.95)
Group 2 (6-10 min)	1228	446 (36.3)	Reference	Reference
Group 3 (11-15 min) Survival to discharge	1228	345 (28.1)	0.69 (0.58-0.82)	0.73 (0.60-0.88)
Total Per 1-min delay	2456	992 (40.4)	0.89	0.89
			(0.85-0.92)	(0.85-0.93)
Group 2 (6-10 min)	1228	564 (45.9)	Reference	Reference
Group 3 (11-15 min)	1228	428 (34.9)	0.62 (0.53-0.74)	0.64 (0.53-0.77)
Prehospital ROSC
Total Per 1-min delay	2456	1074 (43.7)	0.85	0.85
Group 2 (6-10 min)	1228	628 (51.1)	(0.81-0.88) Reference	(0.81-0.89) Reference
Group 3 (11-15 min)	1228	446 (36.3)	0.54 (0.45-0.64)	0.53 (0.44-0.64)

EMS, emergency medical service; OR, odds ratio; CI, confidence interval; ROSC, return of spontaneous circulation.

The EMS response time is a critical factor that influences Survival outcomes among OHCA patients [30,31], and it is also closely related to the time from collapse to first defibrillation. We performed condi- tional logistic regression analyses using subsets of patients from Groups 2 and 3 with matching according to response time, which reduced the confounding effect of response time and still revealed consistent results. A previous study has indicated that there were no differences in survival outcomes among OHCA patients with early or late rhythm analysis [32]. However, the median time difference was only 138 s between the early and late groups, which makes it difficult to evaluate the effects of the shorter time. In addition, that study included all OHCA patients,

nine study revealed that failed shocks significantly changed the activation pattern of long-duration VF (>1 min), from chaotic and reg- ular activation patterns to synchronized patterns immediately after the failed shocks were delivered [23]. Another canine study revealed that both unsuccessful and successful Electric shocks in VF produce an isoelectric window, which is shorter for unsuccessful shocks, that is followed by slowing and synchronization of the activation before fibril- lation regenerates from areas away from the defibrillation electrodes [35]. Conflicting results have been reported based on studies of rabbit and pig hearts, which suggested that electrical activity did not terminate after a failed shock, although those studies also indicated that it could be modified by the failed shock [36,37]. Thus, although there is controversy regarding the effects of failed shocks in VF, a failed shock might modu- late the Cardiac electrophysiology and influence the subsequent success of defibrillations. Moreover, in addition to electrophysiological proper- ties, transthoracic impedance might also be affected by electrical shock [24,25]. Although the change in transthoracic impedance after shock has been debated [38,39], transthoracic impedance is known to decrease between consecutive shocks. Therefore, a failed first shock might change the myocardial electrophysiology and decrease imped- ance, thereby creating a higher current flow for subsequent shocks. The association between short time from collapse to first EMS defibrilla- tion and good neurological outcomes maybe due to the change in the electrophysiological properties of the heart in refractory VF induced by the initially ineffective shock. Further studies are needed to clarify the physiological mechanisms underlying the effects of timely first defi- brillation on refractory VF.

We observed a significant gap between the response times and the times from collapse to first EMS defibrillation. In Group 4, the median time was 20 min from collapse to first EMS defibrillation, although the median response time in that group was 9 min. Furthermore, that group had the highest proportion of patients who received their first shock in the ambulance. Thus, the EMS personnel might not have imme- diately attempted defibrillation, even if the patient had a shockable rhythm, which suggests that this delay should be eliminated. Given

Table 4

Multivariable logistic regression analyses of outcomes according to time from collapse to first EMS defibrillation for patients with >=3 defibrillations

	All patients		Positive outcomes		Unadjusted OR		Adjusted OR
Outcomes	N		N (%)		(95% CI)		(95% CI)
Good neurological recovery
Total	3694		910 (24.6)
Per 1-min delay					0.91 (0.89-0.92)		0.92 (0.91-0.94)
Group 1 (0-5 min)	102		46 (45.1)		Reference		Reference
Group 2 (6-10 min)	1326		448 (33.8)		0.62 (0.41-0.93)		0.55 (0.36-0.86)
Group 3 (11-15 min)	1294		308 (23.8)		0.38 (0.25-0.57)		0.37 (0.23-0.59)
Group 4 (16-60 min)	972		108 (11.1)		0.15 (0.10-0.24)		0.18 (0.11-0.30)
Survival to discharge
Total	3694		1131 (30.6)
Per 1-min delay					0.91 (0.89-0.92)		0.93 (0.91-0.95)
Group 1 (0-5 min)	102		52 (51.0)		Reference		Reference
Group 2 (6-10 min)	1326		546 (41.2)		0.67 (0.45-1.01)		0.62 (0.40-0.96)
Group 3 (11-15 min)	1294		388 (30.0)		0.41 (0.27-0.62)		0.42 (0.27-0.67)
Group 4 (16-60 min)	972		145 (14.9)		0.17 (0.11-0.26)		0.21 (0.13-0.35)
Prehospital ROSC
Total	3694		1214 (32.9)
Per 1-min delay					0.91 (0.90-0.93)		0.93 (0.92-0.95)
Group 1 (0-5 min)	102		55 (53.9)		Reference		Reference
Group 2 (6-10 min)	1326		581 (43.8)		0.67 (0.45-1.00)		0.63 (0.41-0.97)
Group 3 (11-15 min)	1294		410 (31.7)		0.40 (0.26-0.60)		0.41 (0.26-0.64)
Group 4 (16-60 min)	972		168 (17.3)		0.18 (0.12-0.27)		0.22 (0.14-0.36)

that our findings highlight the improved outcomes for early defibrilla- tion, quality control and EMS training measures should emphasize the importance of timely defibrillation for OHCA patients with shockable rhythm. We also observed that only 2.1% of the OHCA patients had re- ceived bystander-administered defibrillation, despite bystander AED use being associated with improved survival in OHCA cases [40]. Further efforts to improve bystander-administered defibrillation rates are likely warranted, as early defibrillation for OHCA patients with initial shock- able rhythm is associated with improved survival based on our findings and those of previous studies [19-21].

This study has several limitations. First, the time from collapse to first EMS defibrillation was collected based on the EMS cardiac arrest in-depth registry, which are not validated like other measures (e.g., defibrillator information). Nevertheless, the medical directors of Korean fire departments perform quality control for the time variables that are reported for each OHCA case. Second, we defined refractory VF as VF with >=2 successive prehospital EMS defibrillations, which agrees with the American Heart Association guidelines’ definition of re- fractory VF as VF/pVT that persists or recurs after >=1 shock [13]. There- fore, our study population might have included some patients with recurrent VF, which could have influenced our findings, as refractory VF and recurrent VF have different physiologies and survival outcomes [41]. However, based on data limitations, we were unable to specifically identify cases involving recurrent VF. Third, we could not evaluate the time from collapse to first bystander defibrillation, given the lack of re- lated data in the registry. Furthermore, we did not exclude the small proportion of patients with bystander defibrillation (2.1%), and we believe that their inclusion would bias the findings toward the null hypothesis. Fourth, we could not evaluate the detailed defibrillation processes and/or causes of defibrillation delay in our population. Fifth, the study’s observational nature is prone to unidentified sources of bias. Finally, the findings were based on the intermediate-level EMS system in Korea, and the findings might not generalize to other settings.

1. Conclusion

Among Korean OHCA patients in refractory VF, a short time from collapse to first EMS defibrillation was associated with improved neurological outcomes. This result suggests that a failed first shock still has a positive effect if it is delivered quickly, which highlights the importance of performing shocks as soon as possible for patients with a shockable rhythm. Further studies are needed to evaluate the physiological mechanisms underlying the effects of timely first defi- brillation on refractory VF.

Author Conflict of Interest And Source of Funding

The authors have nothing to declare regarding conflict of interest.

This study was supported by the National Fire Agency of Korea and the Korea Centers for Disease Control and Prevention (CDC). The study was funded by the Korea CDC (2014-2017). This funding source had no role in the design of this study and collection, analysis, and interpre- tation of data and in writing the manuscript.

Author contributions

Drs. Park JH and Lee GW had full access to all of the data in the study and take responsibility for the integrity of the data, as well as for the ac- curacy of the data analysis.

Study concept and design: Dr. Park JH.

Acquisition, analysis, and interpretation of the data: Drs. Lee GW, Park JH, and Ro YS.

Drafting of the manuscript: Drs. Lee GW, Ro YS and Park JH. Critical revision of the manuscript for important intellectual content:

Drs. Song KJ, Hong KJ, Ro YS, and Shin SD. Statistical analysis: Drs. Lee GW and Park JH.

Obtained funding: Dr. Shin SD. Administrative, technical, or material support: Drs. Song KJ, Hong KJ,

and Ro YS.

Study supervision: Drs. Shin SD and Song KJ. Manuscript approval: all authors

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2020.12.019.

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