a b s t r a c t

Background: The effects and relative benefits of advanced airway management and epinephrine on patients with out-of-hospital cardiac arrest (OHCA) who were defibrillated are not well understood.

Methods: This was a prospective observational study. Using data of all out-of-hospital cardiac arrest cases occur- ring between 2005 and 2013 in Japan, hierarchical logistic regression and conditional logistic regression along with time-dependent propensity matching were performed. Outcome measures were survival and minimal neu- rological impairment [Cerebral Performance Category 1 or 2] at 1 month after the event.

Results: We analyzed 37,873 cases that met the inclusion criteria. Among propensity-matched patients, advanced airway management and/or prehospital epinephrine use was related to decreased rates of 1-month survival (ad- justed odds ratio 0.88, 95% confidence interval 0.80 to 0.97) and CPC (1, 2) (adjusted odds ratio 0.56, 95% confi- dence interval 0.48 to 0.66). Advanced airway management was related to decreased rates of 1-month survival (adjusted odds ratio 0.89, 95% confidence interval 0.81to 0.98) and CPC (1, 2) (adjusted odds ratio 0.54, 95% con- fidence interval 0.46 to 0.64) in patients who did not receive epinephrine, whereas epinephrine use was not re- lated to the outcome measures.

Conclusions: In defibrillated patients with OHCA, advanced airway management and/or epinephrine are related to reduced long-term survival, and advanced airway management is less beneficial than epinephrine. However, the proportion of patients with OHCA who responded to an initial shock was very low in the study subjects, and the external validity of our findings might be limited.

(C) 2017

1. Introduction

Advanced life support for patients with out-of-hospital cardiac arrest (OHCA) by emergency medical services (EMS) consists of semi- automated defibrillation, advanced airway management, and epineph- rine administration. ALS by EMS has been regarded as an important el- ement of the response to OHCA in many countries [1]. A meta-analysis of ALS and basic life support (BLS) revealed that the administration of ALS to patients with non-Traumatic cardiac arrest increased survival to hospital discharge [2]. Several findings indicate that prehospital ad- vanced airway management can be effective under certain conditions, including cases of return of spontaneous circulation (ROSC) before hos- pital arrival [3-5]. Some reports have indicated that prehospital epi- nephrine use is related to increased survival to hospital arrival and 1- month survival [6,7].

However, findings revealing the negative effects of ALS are domi- nant. Although one meta-analysis conducted in the 1990s to examine

* Corresponding author.

E-mail address: [email protected] (A. Hagihara).

EMS systems including the administration of ALS to patients with OHCA showed that ALS was beneficial [8], the analysis had several lim- itations because of the quality and completeness of existing literature [8, 9]. A robust before-and-after study conducted in Ontario, Canada, showed that ALS did not improve the rate of survival to hospital dis- charge [10]. Two observational studies conducted in Taiwan and the USA showed that patients with OHCA who received BLS had higher rates of survival to hospital discharge than those who received ALS [11,12]. Similarly, most studies have shown that advanced airway man- agement has negative effects or no effect on Survival and neurological outcome of patients with OHCA [13,14]. Negative effects of prehospital epinephrine use on long-term outcomes have also been reported [6,15]. Resuscitation guidelines recommend the administration of ad- vanced airway management and epinephrine after defibrillation to pa- tients with OHCA of presumed Cardiac origin whose initial rhythms are shockable. The efficacy of Early defibrillation has been established [10]. However, we know little about the effects of advanced airway management and/or epinephrine on defibrillated patients with OHCA. The optimal response intervals for advanced airway management and epinephrine administration are also less clear than that of defibrillation

http://dx.doi.org/10.1016/j.ajem.2017.07.018

0735-6757/(C) 2017

[10]. We also do not know whether advanced airway management and epinephrine interact. Thus, using national data from the whole sample

Table 1

Baseline characteristics of patients with OHCA who were defibrillated.

of OHCAs occurring between 2005 and 2013 in Japan, we performed time-dependent propensity matching and evaluated the effects, interac- tion, and time modification of advanced airway management and epi- nephrine in patients with OHCA who were defibrillated.

Variable No ALS

(n = 14,621)

Patients with OHCA cases by year, n (%)^a

2005	1906	(13.04)	2275	(9.79)	0.00
2006	1882	(12.87)	2595	(11.16)
2007	1598	(10.93)	2430	(10.45)
2008	1824	(12.48)	2608	(11.22)
2009	1746	(11.94)	2721	(11.70)
2010	1777	(12.15)	2836	(12.20)
2011	1362	(9.32)	2357	(10.14)
2012	1437	(9.83)	2984	(12.84)
2013	1088	(7.44)	2441	(10.50)
Sex (male), n (%)	10,919	(74.68)	18,223	(78.37)	0.00
Age (years), mean (SD)	67.80	(15.42)	66.82	(15.13)	0.00
Emergency life-saving technician in	13,224	(90.45)	23,137	(99.51)	0.00

ALS

(n = 23,252)

P

value

1. Methods

This prospective observational study was conducted using national registry data. The study was approved by the ethics committee of Kyu- shu University Graduate School of Medicine. The requirement for writ- ten informed consent was waived.

Data collection

The EMS system in Japan has been described elsewhere [16]. Briefly, EMS is provided by municipal governments through about 800 fire sta- tions with dispatch centers. The Japanese guidelines do not allow EMS providers to terminate resuscitation in the field. Thus, all patients with OHCA who are treated by EMS personnel are transported to hospitals

ambulance (yes), n (%)

Medical doctor in ambulance (yes), n

(%)^a

Advanced life support by MD (yes), n

(%)^a

Relationship of bystander to patient (family member), n (%)

571 (3.91) 1130 (4.86) 0.00

2420 (16.56) 3082 (13.26) 0.00

7282 (49.81) 14,053 (60.44) 0.00

with OHCA, summarize each OHCA case in the standardized Utstein

[17]. The Fire and Disaster Management Agency (FDMA) has main- tained a prospective, nationwide, population-based registry of all	CPR initiated by Bystander chest compression (yes), n (%)a	5674	(39.28)	10,121	(44.58)	0.00
OHCA cases in Japan using a standardized Utstein-style template. EMS personnel, in cooperation with the physicians in charge of patients	rescue breathing (yes), n (%)a Life support by EMS personnel	2000	(13.91)	3043	(13.57)	0.35

Time from call to first defibrillation

14.51 (8.25) 14.28 (8.36) 0.01

style [17,18]. Data from the 800 fire stations with dispatch centers in the 47 prefectures of Japan are then integrated into the national registry	(min), mean (SD)b Time from call to arrival at hospital	29.78	(11.89)	35.74	(12.13)	0.00
system on the FDMA database server. The data are checked electronical- ly by the FDMA, and returned to the respective fire stations for error cor- rection when problems are detected.	(min), mean (SD)b Number of attempted defibrillations, n (%) 1, 2	10,058	(68.79)	14,209	(61.11)	0.00
	>= 3	4563	(31.21)	9043	(38.89)
2.2. Subjects	Insertion of intravenous line (yes), n (%)a	0	(0.00)	12,948	(55.69)	0.00

The patients were aged 18-100 years and had OHCAs of presumed cardiac origin before the arrival of EMS personnel between 1 January 2005 and 31 December 2013 in Japan (Supplementary Fig. S1). Intervals from calls to EMS arrival at the scene and at hospital were <= 60 min and

<= 120 min, respectively. OHCAs were witnessed, bystanders did not pro- vide Automated external defibrillation, no epinephrine was adminis- tered after ROSC, and EMS personnel performed defibrillation. Intervals from calls to first defibrillation by EMS personnel were

<= 60 min, and patients were transported to medical institutions thereafter.

Study variables

n (%)

ROSC (yes), n (%)b ALSb	8	(0.05)	1994	(8.58)	0.00
Epinephrine use (yes), n (%)	0	(0.00)	3041	(13.08)	0.00
Advanced airway management (yes),	0	(0.00)	14,044	(60.40)

Epinephrine use & advanced airway management (yes), n (%)

Endpoints^b

1-month survival after cardiac arrest (yes), n (%)

Cerebral performance category 1 or 2 (good performance/moderate disability) 1 month after the event (yes), n (%)

0 (0.00) 6167 (26.52)

1648 (11.27) 2505 (10.77) 0.13

863 (5.90) 954 (4.10) 0.00

The “ALS” group included cases in which advanced airway manage- ment and/or epinephrine was used, and the “no ALS” group included cases in which neither measure was used. Advanced airway manage- ment includes endotracheal intubation and use of supraglottic airway devices (i.e., laryngeal mask airway, laryngeal tube, esophageal-tracheal twin-lumen airway device). Table 1 shows the variables used in the study by ALS status. “Advanced support by MD” is a variable that indi- cates if ALS was performed by MD. The origins of cardiac arrests (i.e., presumed cardiac or non-cardiac) were determined clinically by physi- cians in charge with the aid of EMS personnel.

When patients survived cardiac arrest, they were followed for up to 1 month after the event, and information on survival and neurological function at 1 month after the event or at hospital discharge, whichever was earlier, was collected. Neurological outcomes 1 month after suc- cessful resuscitation were evaluated using the Cerebral Performance Category (CPC) scale (1: good cerebral performance, 2: moderate cere- bral disability, 3: severe cerebral disability, 4: coma or vegetative state, 5: death) [17-19].

The ALS group included cases in which advanced airway management and/or epinephrine was used, and the no ALS group included cases in which neither measure was used.

ROSC: return of spontaneous circulation before hospital arrival.

^a Numbers do not add up to totals due to missing values.

^b These variables were not included in the logistic regression model for the generation of the propensity score.

Endpoints

Endpoints were survival at 1 month after the event and survival with minimal neurological impairment, defined as CPC category 1 or 2 (Table 1) [17-19].

Statistical analysis

Using data for all 37,873 patients, hierarchical logistic regression models with the endpoints listed in Table 1 serving as dependent vari- ables were fitted to examine the association between ALS and long-

term survival using the time from call to first defibrillation (60 strata, 0- 60 min). With projected 1-month survival and CPC (1 or 2) rates of 11.27% and 5.90%, respectively, in the control group and 10.77% and

Table 2

Baseline characteristics of propensity-matched patients with OHCA who were defibrillated.

4.10%, respectively, in the ALS group (Table 1), 37,873 samples provided power levels of 32.9% for 1-month survival and 100.0% for CPC (1 or 2) with a type I error rate of 5% [20].

The effect of ALS may be influenced by the time of defibrillation, and ALS administration was not randomized in the patient population. Thus, we also performed time-dependent propensity score matching to ob- tain ALS and control pairs. Specifically, because a proportional hazard assumption was not realistic for the data, a stratified analysis was per- formed [21,22]. Using a time-dependent covariate (i.e., time from call to first defibrillation), subjects were categorized into 10 strata (each containing 10% of observations). A full non-parsimonious logistic re- gression model with ALS serving as the dependent variable and almost all variables listed in Table 1 (i.e., 64 variables, including 8 dummy var- iables for “cases by year” and 46 dummy variables for prefectures in Japan) serving as independent variables was fitted. Based on propensity scores, ALS cases were matched to unique control patients in each of the 10 strata [21,22]. Using data from propensity-matched subjects, three types of conditional logistic regression model of ALS, with endpoints listed in Table 2 serving as the dependent variables, were fitted. With projected 1-month survival and CPC (1 or 2) rates of 11.16% and 5.39%, respectively, in the control group and 8.92% and 2.87%, respec- tively, in the ALS group (Table 2), 20,256 samples provided power levels of 100.0% for 1-month survival and CPC (1 or 2) with a type I error rate of 5% [20].

To evaluate the effects of the interaction between advanced airway management and epinephrine administration on survival and minimal neurological impairment at 1 month after the event in propensity- matched patients, measures of effect modification on an additive scale, relative excess risk due to interaction (RERI), and interaction on a mul- tiplicative scale (the ratio of odds ratios [ORs]), were calculated [23,24].

Variable No ALS

(n = 10,128)

Patients with OHCA Cases by year, n (%)

2005	1583	(15.63)	1811	(17.88)	0.00
2006	1449	(14.31)	1632	(16.11)
2007	1182	(11.67)	1194	(11.79)
2008	1316	(12.99)	1202	(11.87)
2009	1200	(11.85)	1059	(10.46)
2010	1204	(11.89)	1061	(10.48)
2011	875	(8.64)	769	(7.59)
2012	832	(8.21)	866	(8.55)
2013	487	(4.81)	534	(5.37)
Sex (male), n (%)	7671	(75.74)	7714	(76.17)	0.48
Age (years), mean (SD)	67.18	(15.42)	66.94	(15.08)	0.25
Emergency life-saving technician in	10,080	(99.53)	10,088	(99.61)	0.39
ambulance (yes), n (%)
Medical doctor in ambulance (yes), n	405	(4.00)	445	(4.39)	0.16
(%)
Advanced life support by MD (yes), n	1467	(14.48)	1426	(14.08)	0.41
(%)
Relationship of bystander to patient	5848	(57.74)	6047	(59.71)	0.01
(family member), n (%)
CPR initiated by bystander
Chest compression (yes), n (%)	4230	(41.77)	4326	(42.71)	0.17
Rescue breathing (yes), n (%)	1491	(14.72)	1524	(15.05)	0.52
Life support by EMS personnel
Time from call to first defibrillation (min), mean (SD)a	13.56	(7.49)	13.57	(7.46)	0.90
Time from call to arrival at hospital (min), mean (SD)a	29.29	(11.54)	32.98	(11.35)	0.00
Number of attempted defibrillations,
n (%)
1, 2	6709	(66.24)	6594	(65.11)	0.09
>= 3	3419	(33.76)	3534	(34.89)

ALS

(n = 10,128)

P

value

To study whether the effect of ALS on long-term survival was modified by the timing of ALS administration in propensity-matched patients, measures of effect modification on an additive scale, RERI, and interac-	Insertion of intravenous line (yes), n (%) ROSC (yes), n (%)a	0 6	(0.00) (0.06)	0 78	(0.00) (0.77)	- 0.00
tion on a multiplicative scale (the ratio of ORs in strata of time from call to first defibrillation, examined using a 2 x 2 table) were calculated	ALSa Epinephrine use (yes), n (%)	0	(0.00)	164	(1.62)	0.00
[23,24]. In the analysis, time from call to first defibrillation was split into	Advanced airway management (yes),	0	(0.00)	9817	(96.93)
two categories by the median (i.e., <= 11 min and N 11 min). Ninety-five percent confidence intervals (CIs) of RERI were calculated by the delta method [24]. All analyses were performed using the STATA software (ver. 14.1; Stata Corp., College Station, TX, USA). The significance level for all tests	n (%) Epinephrine use & advanced airway management (yes), n (%) Endpointsa 1-Month survival after cardiac arrest (yes), n (%)	0 1130	(0.00) (11.16)	147 903	(1.45) (8.92)	0.00
was P b 0.05 (two-sided).	Cerebral performance category 1 or 2	546	(5.39)	291	(2.87)	0.00
	(good performance/moderate
3. Results	disability) 1 month after the event (yes), n (%)

Patient characteristics

Among patients with OHCAs registered between 1 January 2005 and 31 December 2013 in Japan (n = 1,024,425), 37,873 cases met the in- clusion criteria and were included in the analysis (Supplementary Fig. S1, Table 1). Significant differences between the ALS and control groups were observed for all variables except rescue breathing and 1-month survival after the event (P b 0.0001 and b 0.05) (Table 1).

Characteristics of propensity-matched patients

In this study, 10,128 ALS cases were matched with 10,128 unique no-ALS cases. Of variables included in the time-dependent propensity score calculation, propensity matching could not balance the distribu- tions of year, relationships of bystanders to patients, and prefecture (data not shown) (P = 0.00, 0.01, and 0.00, respectively) (Table 2). However, absolute standardized differences in covariates after propen- sity score matching indicated that the distributions of covariates were

The ALS group included cases in which advanced airway management and/or epinephrine was used, and the no ALS group included cases in which neither measure was used.

ROSC: return of spontaneous circulation before hospital arrival.

^a These variables were not included in the logistic regression model for the generation of the propensity score.

balanced between the two groups in the 10 strata (Supplementary Fig. S2).

Logistic regression analyses of outcomes

Hierarchical logistic regression analyses showed that ALS was relat- ed to decreased 1-month survival (all covariates adjusted OR, 0.82; 95% CI, 0.75-0.90) and CPC (1 or 2) (all covariates adjusted OR, 0.49; 95% CI, 0.42-0.56) (Table 3). Three types of conditional logistic regression anal- ysis using time-dependent propensity-matched samples also showed that ALS was related to decreased 1-month survival (all covariates

Table 3 Logistic regression analyses of outcomes in the ALS group (vs. no ALS group) among all and propensity-matched patients who had out-of-hospital cardiac arrests and were defibrillated.

CPC (1 or 2) (adjusted OR, 0.54; 95% CI, 0.46-0.64 in the stratum of no epinephrine use, and adjusted OR, 0.37; 95% CI, 0.13-0.99 in the stratum of epinephrine use), whereas epinephrine use was not related to the

outcome measures in every stratum of advanced airway management.

1-Month survival CPC (1 or 2)

OR (95% CI) P OR (95% CI) P

Hierarchical logistic regression analysis of ALS using all patients (reference: no ALS)

Crude 0.93 (0.87-0.99) 0.024 0.67 (0.61-0.74) 0.000

Adjusted for all covariates^b 0.82 (0.75-0.90) 0.000 0.49 (0.42-0.56) 0.000

Conditional logistic regression analysis of ALS using propensity-matched patients (reference: no ALS)

The RERIs for 1-month survival and CPC (95% CI, 1 or 2) were -0.72 (95% CI, -1.57-0.13) and -0.76 (-95% CI, -2.11-0.59), respectively.

The measure of interaction on a multiplicative scale, the ratio of ORs, was 0.71 (95% CI, 0.42-1.21) for one month survival and 0.98 (95% CI, 0.47-2.01) for CPC (1 or 2) and was not significant.

3.5. Effects of ALS by time

Adjusted for propensity score

Adjusted for propensity score and significant covariates^a

Adjusted for propensity score and all covariates^b

0.76 (0.70-0.84) 0.000 0.51 (0.44-0.59) 0.000

0.90 (0.82-0.99) 0.035 0.57 (0.49-0.67) 0.000

0.88 (0.80-0.97) 0.011 0.56 (0.48-0.66) 0.000

ORs for each stratum of ALS and time from call to first defibrillation are presented in Table 5, with control and <=11 min serving as reference values. ALS was related to decreased 1-month survival in the stratum of N 11 min from call to defibrillation (adjusted OR, 0.75; 95% CI, 0.62-0.90) and to CPC (1 or 2) in the <= 11-min and N 11-min strata (adjusted OR, 0.63; 95% CI, 0.53-0.76 and adjusted OR, 0.42; 95% CI, 0.31-0.58, respec-

The ALS group included cases in which advanced airway management and/or epinephrine was used, and the no ALS group included cases in which neither measure was used.

^a Significant covariates were: year, relationship of bystander to patient, time from call to hospital arrival, and prefecture in Japan.

^b All covariates were: year, sex, age, emergency life-saving technician in ambulance, medical doctor in ambulance, advanced life support administered by MD, relationship of bystander to patient, chest compression by bystander, rescue breathing administration by bystander, time from call to first defibrillation, time from call to hospital arrival, number of attempted defibrillations, insertion of intravenous line, ROSC before hospital arrival, and prefecture in Japan.

adjusted OR, 0.88; 95% CI, 0.80-0.97) and CPC (1 or 2) (all covariates ad- justed OR, 0.56; 95% CI, 0.48-0.66) (Table 3).

Interaction between advanced airway management and epinephrine

ORs for advanced airway management only, epinephrine only, and both measures are presented in Table 4, with no advanced airway man- agement or epinephrine use serving as the reference. Advanced airway management was related to decreased 1-month survival (adjusted OR, 0.87; 95% CI, 0.79-0.97 in the stratum of no epinephrine use, and adjust- ed OR, 0.45; 95% CI, 0.22-0.92 in the stratum of epinephrine use) and

tively). The measures of interaction on a multiplicative scale were 0.83 (95% CI, 0.66-1.04) for 1-month survival and 0.69 (95% CI, 0.47-1.02) for CPC (1 or 2). The RERIs for 1-month survival and CPC (1 or 2) were

- 0.12 (95% CI, - 0.28-0.04) and 0.02 (95% CI, - 0.18-0.18),

respectively.

1. Discussion

We examined the association between advanced airway manage- ment and/or epinephrine and long-term survival in patients who suf- fered OHCA and were defibrillated by EMS personnel. There was a negative association between advanced airway management and/or epinephrine use and overall and Neurologically intact survival at 1 month. Advanced airway management was related to more decreased long-term survival as compared with epinephrine. There were some in- dications that the estimated joint effect on the additive scale of ad- vanced airway management and epinephrine was more detrimental than the sum of the estimated effects of advanced airway management alone and epinephrine alone so that there was negative interaction on the additive scale. The effects of advanced airway management and/or epinephrine were not modified by the timing of its administration.

Table 4

Interaction effects between advanced airway management and epinephrine on 1-month survival and cerebral performance category 1 or 2 among propensity-matched patients who had out-of-hospital cardiac arrests and were defibrillated.

Advanced airway management OR (95% CI) for advanced airway management within

No Yes

strata of epinephrine use

One-month survival Epinephrine use

Survival/no survival (n)

OR (95% CI) Survival/no

survival (n)

OR (95% CI)

No	1130/8998	1.0	837/8980	0.87	0.87 (0.79-0.97)
				(0.79-0.97)
Yes	44/120	1.54	22/125	0.69	0.45 (0.22-0.92)
		(0.90-2.64)		(0.37-1.28)
OR (95% CI) for epinephrine use within strata of		1.54		0.79
advanced airway management		(0.90-2.64)		(0.42-1.48)

CPC (1 or 2)

Epinephrine use

No	546/9582	1.0	257/9560	0.54	0.54 (0.46-0.64)
				(0.46-0.64)
Yes	25/139	1.92	9/138	0.70	0.37 (0.13-0.99)
		(0.95-3.88)		(0.28-1.75)
OR (95% CI) for epinephrine use within strata of		1.92		1.29
advanced airway management		(0.95-3.88)		(0.52-3.25)

Measures of effect modification on additive scale: RERIs (95% CIs) for 1-month survival and CPC (1 or 2) were -0.72 (-1.57 to 0.13) and -0.76 (-2.11 to 0.59), respectively. Measures of effect modification on multiplicative scale: ratios of ORs for 1-month survival and CPC (1 or 2) were 0.71 (0.42-1.21) and 0.98 (0.47-2.01), respectively.

ORs are adjusted for all covariates (i.e., year, sex, age, emergency life-saving technician in ambulance, medical doctor in ambulance, advanced life support administered by MD, relationship of bystander to patient, chest compression by bystander, rescue breathing administration by bystander, time from call to first defibrillation, time from call to hospital arrival, number of attempted defibrillations, insertion of intravenous line, ROSC before hospital arrival, and prefecture in Japan).

Table 5

Modification of the effects of ALS on 1-month survival and cerebral performance category 1 or 2 by the time from call to first defibrillation among propensity-matched patients who had out-of-hospital cardiac arrests and were defibrillated.

	Control (no ALS)			ALS		OR (95% CI) for ALS within strata of time from call to first
	Survival/no survival (n)	OR (95% CI)		Survival/no survival (n)	OR (95% CI)	defibrillation
One-month survival
Time from call to first defibrillation <= 11 min	812/5143	1.0		692/5263	0.95 (0.84-1.06)	0.95 (0.84-1.06)
Time from call to first defibrillation	318/3855	0.67		211/3962	0.50	0.75 (0.62-0.90)
N 11 min		(0.55-0.82)			(0.40-0.62)
CPC (1 or 2)
Time from call to first defibrillation <= 11 min	379/5576	1.0		230/5725	0.63 (0.53-0.76)	0.63 (0.53-0.76)
Time from call to first defibrillation	167/4006	0.60		61/4112	0.25	0.42 (0.31-0.58)
N 11 min		(0.45-0.80)			(0.18-0.36)

The ALS group included cases in which advanced airway management and/or epinephrine was used, and the no ALS group included cases in which neither measure was used. Measures of effect modification on additive scale: RERIs (95% CIs) for 1-month survival and CPC (1 or 2) were -0.12 (-0.28 to 0.04) and 0.02 (-0.18 to 0.18), respectively. Measures of effect modification on multiplicative scale: ratios of ORs for 1-month survival and CPC (1 or 2) were 0.83 (0.66-1.04) and 0.69 (0.47-1.02), respectively.

ORs are adjusted for all covariates (i.e., year, sex, age, emergency life-saving technician in ambulance, medical doctor in ambulance, advanced life support administered by MD, relationship of bystander to patient, chest compression by bystander, rescue breathing administration by bystander, time from call to first defibrillation, time from call to hospital arrival, number of attempted defibrillations, insertion of intravenous line, ROSC before hospital arrival, and prefecture in Japan).

However, some indications suggest that the estimated joint effect on the additive scale of the advanced life support and its later administration was more detrimental to 1-month survival than the sum of the estimat- ed effects of the advanced life support alone and its later administration alone; thus, negative interaction on the additive scale was detected. These findings are novel.

Those propensity-matched subjects receiving no ALS had ROSC en

route to the hospital 0.06% of the time, and those with ALS had ROSC be- fore the hospital 0.77% of the time. This finding also supports our con- clusions. In addition, our study was sufficiently powered and adjusted for the time-dependent severity of cardiac arrest, due to the use of strat- ified analysis [22]. Because previous studies have compared ALS with BLS, we know little about the relative benefits of advanced airway man- agement and epinephrine [2,11,12]. In the present study, advanced air- way management was related to more decreased long-term survival as compared with epinephrine. The curriculum for paramedic certification in Japan generally includes 180 h of lectures and practice in school and experience in 30 successful cases in the operating room under the in- struction of an anesthesiologist [25]. In view of the case experience needed for paramedics to become prominent (i.e., 15-20 cases) [26], the Japanese training curriculum seems to be appropriate. ALS adminis- tration by physicians has been reported to increase the probability of long-term survival [2]. Thus, based on a systematic review of advanced airway management in the field, we need to identify factors related to poor resuscitation outcomes according to the type of advanced airway management device (i.e., endotracheal intubation and supraglottic air- way devices). We also need to examine cases in which advanced airway management was effective in terms of factors such as bystander eyewit- nesses, Initial shockable rhythm, ROSC, long-distance transportation, and respiratory failure [12,14]. These efforts will lead to the identifica- tion of subsets of patients for whom advanced airway management is beneficial.

Epinephrine was not related to overall or neurologically intact sur- vival at 1 month. With respect to the effect of epinephrine upon long- term survival of patients with OHCA, findings are mixed. A study that did not involve time-dependent propensity matching showed that prehospital epinephrine use had a negative long-term effect; [6] in con- trast, studies involving time-dependent propensity matching, including the present study, have revealed positive or no long-term effect [7]. In addition, later administration of advanced airway management and/or epinephrine was related to more decreased long-term outcome com- pared with earlier administration. Thus, the discrepancy in findings might be due to the pharmacological effects of epinephrine, such that its early administration is beneficial to short- and long-term survival

in defibrillated patients with OHCA [10,15]. As in the case of advanced airway management, efforts to identify timing and subsets of patients for whom prehospital epinephrine administration is most beneficial are necessary.

A practical implication of these findings is as follows. Advanced air- way management was related to more decreased long-term survival as compared with epinephrine, and there was negative interaction be- tween airway management and epinephrine on the additive scale. Ran- domized trials of different methods of airway management in patients with OHCA are now in progress [27,28]. If subsets of patients for whom prehospital advanced airway management or epinephrine is beneficial are not identified successfully in the future, a further shift from ALS to BLS and the investment of more resources in the first three links in the Chain of survival - early access, early CPR, and early de- fibrillation [10] - will be necessary.

1. Limitations

Several limitations and caveats of our study must be acknowledged. First, there were 6 (0.06%) and 78 (0.77%) patients with OHCA who re- spond to an initial shock in the “No ALS” and “ALS” groups in the pro- pensity-matched subjects. Although this very low number (i.e., 0.06%) might be due to local Resuscitation protocols or multiple selection criteria for subjects, we could not identify the reason. The external valid- ity of the findings might be limited, and we need to be careful interpreting the findings. In addition, patients with OHCA with cardiac arrest who respond to an initial shock will not need epinephrine OR air- way management. These patients clearly have a greater chance of a good outcome. In the analysis, we could not control for the timing of ar- rival. Second, data on In-hospital CPR after hospital arrival were not in- cluded in the analysis. The present findings may reflect a difference in in-hospital resuscitation, such as in-hospital and total epinephrine doses, between the ALS and control groups. With respect to this limita- tion, there is some evidence which disfavors this possibility. Specifically, the timing of the first epinephrine administration, but not the total dose, affects long-term survival [7,29,30]. The effects of confounding due to differences among hospitals are supposed to be small [7]. Nevertheless, we acknowledge this limitation. Third, a major limitation was that allo- cation to the ALS and control groups was not random. We performed a propensity analysis and rigorous adjustment to control for selection bias and confounding factors, which would be expected in a standard multi- variable analysis. Nevertheless, we could only partially control and ad- just for factors actually measured, and could not control for unknown confounding factors. Fourth, we did not have information about the

process of advanced airway management. The failure rate of out-of-hos- pital tracheal intubation is 20%, tops [31]. Because advanced airway management was defined as successful endotracheal intubation or supraglottic airway placement in this study, failed advanced airway management cases may have been included in the control group (i.e., bag-valve-mask ventilation), which would shift the bias toward null. Fifth, in Japan, it is reported that advanced airway devices should be considered only when the patient cannot be adequately ventilated by a bag-valve-mask or a long transportation time is expected [32]. Thus, this practice may represent a substantial confounder and can be a limi- tation to the study. Sixth, emergency care by ELT has been provided based upon the Japanese ALS protocols [33,34]. However, despite roughly 15 min mean between the first defibrillation and arrival at the hospital, with minimal ROSC, a minority of patients even in the ALS group received epinephrine. Given this deviation from accepted Ameri- can guidelines, such as those published by the AHA, the external validity of the present findings might be limited to the Japanese settings. Sev- enth, we did not have information on the skill levels of individual EMS personnel or the integrity and validity of the national registry data, as is true for all epidemiological studies. Thus, these factors were not con- trolled in the study.

1. Conclusion

In summary, advanced airway management and/or epinephrine was related to reduced long-term survival of defibrillated patients with OHCA. Advanced airway management was associated with more de- creased long-term survival compared with epinephrine. However, there was no significant difference between earlier and later ALS admin- istrations with respect to its effects on long-term outcomes.

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 15K08714 and 16H05247. The funding source had no role in the study design, data collection, data analysis, Data interpretation, or preparation of the manuscript.

Competing interests

None declared.

Appendix A. Supplementary data

Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ajem.2017.07.018.

References

1. Travers AH, Rea TD, Bobrow BJ, Edelson DP, Berg RA, Sayre MR, et al. Part 4: CPR overview: 2010 American Heart Association guidelines for cardiopulmonary resusci- tation and emergency cardiovascular care. Circulation 2010;122:S676-84.
2. Bakalos G, Mamali M, Komninos C, Koukou E, Tsantilas A, Tzima S, et al. Advanced life support versus basic life support in the pre-hospital setting: a meta-analysis. Re- suscitation 2011;82:1130-7.
3. Kellum MJ, Kennedy KW, Barney R, Keilhauer FA, Bellino M, Zuercher M, et al. Cardiocerebral resuscitation improves Neurologically intact survival of patients with out-of-hospital cardiac arrest. Ann Emerg Med 2008;52:244-52.
4. Kellum MJ, Kennedy KW, Ewy GA. Cardiocerebral resuscitation improves survival of patients with out-of-hospital cardiac arrest. Am J Med 2006;119:335-40.
5. Bobrow BJ, Clark LL, Ewy GA, Chikani V, Sanders AB, Berg RA, et al. Minimally interrupted Cardiac resuscitation by emergency medical services for out-of-hospital cardiac arrest. JAMA 2008;299:1158-65.
6. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epi- nephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012;307:1161-8.
7. Nakahara S, Tomio J, Takahashi H, Ichikawa M, Nishida M, Morimura N, et al. Evalu- ation of Pre-hospital administration of adrenaline (epinephrine) by emergency

medical services for patients with out of hospital cardiac arrest in Japan: controlled propensity matched retrospective cohort study. BMJ 2013;347:f6829.

1. Nichol G, Stiell IG, Laupacis A, Pham B, De Maio VJ, Wells GA. A cumulative meta- analysis of the effectiveness of defibrillator-capable emergency medical services for victims of out-of-hospital cardiac arrest. Ann Emerg Med 1999;34:517-25.
2. Nichol G, Detsky AS, Stiell IG, O’Rourke K, Wells G, Laupacis A. Effectiveness of emer- gency medical services for victims of out-of-hospital cardiac arrest: a meta analysis. Ann Emerg Med 1996;27:700-10.
3. Stiell IG, Wells GA, Field B, Spaite DW, Nesbitt LP, De Maio VJ, et al. Advanced cardiac life support in out-of-hospital cardiac arrest. N Engl J Med 2004;351:647-56.
4. Ma MH, Chiang WC, Ko PC, Huang JC, Lin CH, Wang HC, et al. Outcomes from out-of- hospital cardiac arrest in Metropolitan Taipei: does an advanced life support service make a difference? Resuscitation 2007;74:461-9.
5. Sanghavi P, Jena AB, Newhouse JP, Zaslavsky AM. Outcomes after out-of-hospital cardiac arrest treated by basic vs advanced life support. JAMA Intern Med 2015; 175:196-204.
6. Thomas MJ, Benger J. prehospital intubation in cardiac arrest: the debate continues. Resuscitation 2011;82:367-8.
7. Hasegawa K, Hiraide A, Chang Y, Brown DF. Association of prehospital advanced air- way management with neurologic outcome and survival in patients with out-of- hospital cardiac arrest. JAMA 2013;309:257-66.
8. Gueugniaud PY, David JS, Chanzy E, Hubert H, Dubien PY, Mauriaucourt P, et al. Va- sopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med 2008;359:21-30.
9. Kitamura T, Iwami T, Kawamura T, Nagao K, Tanaka H, Hiraide A, et al. Nationwide public-access defibrillation in Japan. N Engl J Med 2010;362:994-1004.
10. Council JR. Japanese guideline for emergency care and cardiopulmonary resuscita-

tion. Tokyo: Health Shupansha; 2007.

1. Cummins RO, Chamberlain DA, Abramson NS, Allen M, Baskett PJ, Becker L, et al. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein style. A statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Circulation 1991;84:960-75.
2. Jacobs I, Nadkarni V, Bahr J, Berg RA, Billi JE, Bossaert L, et al. Cardiac arrest and car- diopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare profes- sionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscita- tion Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Councils of Southern Africa). Circulation 2004;110:3385-97.
3. Hsieh FY, Bloch DA, Larsen MD. A simple method of sample size calculation for linear and logistic regression. Stat Med 1998;17:1623-34.
4. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983;70:41-55.
5. D’Agostino Jr RB. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998;17:2265-81.
6. Knol MJ, VanderWeele TJ. Recommendations for presenting analyses of effect mod- ification and interaction. Int J Epidemiol 2012;41:514-20.
7. Hosmer DW, Lemeshow S. Confidence interval estimation of interaction. Epidemiol-

ogy 1992;3:452-6.

1. Takei Y, Enami M, Yachida T, Ohta K, Inaba H. Tracheal intubation by paramedics under limited indication criteria may improve the Short-term outcome of out-of- hospital cardiac arrests with noncardiac origin. J Anesth 2010;24:716-25.
2. Wang HE, Yealy DM. Out-of-hospital endotracheal intubation: where are we? Ann Emerg Med 2006;47:532-41.
3. Benger JR, Voss S, Coates D, Greenwood R, Nolan J, Rawstorne S, et al. Randomised comparison of the effectiveness of the laryngeal mask airway supreme, i-gel and current practice in the initial airway management of prehospital cardiac arrest (RE- VIVE-Airways): a feasibility study research protocol. BMJ Open 2013;3.
4. Wang HE, Prince DK, Stephens SW, Herren H, Daya M, Richmond N, et al. Design and implementation of the Resuscitation Outcomes Consortium pragmatic airway resus- citation trial (PART). Resuscitation 2016;101:57-64.
5. Vandycke C, Martens P. High dose versus standard dose epinephrine in cardiac ar- rest - a meta-analysis. Resuscitation 2000;45:161-6.
6. Hayashi Y, Iwami T, Kitamura T, Nishiuchi T, Kajino K, Sakai T, et al. Impact of early intravenous epinephrine administration on outcomes following out-of-hospital car- diac arrest. Circ J 2012;76:1639-45.
7. Wang HE, Yealy DM. How many attempts are required to accomplish out-of-hospital endotracheal intubation? Acad Emerg Med 2006;13:372-7.
8. Norii T, Hatanaka T. prehospital airway management for out-of-hospital cardiac ar- rest. JAMA 2013;309:1888-9.
9. Japan Foundation for Emergency Medicine. Emergency care by emergency lifesaving technicians based on the Japan Resuscitation Council guidelines [in Japanese]. http:// www.qqzaidan.jp/jrc/jrc120831_02.pdf; 2010. [Accessed 30 May, 2017].
10. Japan Foundation for Emergency Medicine. Protocols for emergency care by emer- gency life-saving technicians based on the Japan Resuscitation Council guidelines [in Japanese]. http://www.qqzaidan.jp/jrc/jrc120831_03.pdf; 2010. [Accessed 30

May, 2017].