Pre-Hospital Administration of Epinephrine in Pediatric Patients With Out-of-Hospital Cardiac Arrest

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 75, NO. 2, 2020

ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

Pre-Hospital Administration of Epinephrine in Pediatric Patients With Out-of-Hospital Cardiac Arrest Tasuku Matsuyama, MD, PHD,a Sho Komukai, PHD,b Junichi Izawa, MD, DRPH,c Koichiro Gibo, MD, MSC,d Masashi Okubo, MD, MS,e Kosuke Kiyohara, DPH,f Takeyuki Kiguchi, MD, PHD,g Taku Iwami, MD, PHD,g Bon Ohta, MD, PHD,a Tetsuhisa Kitamura, MD, DPHh

ABSTRACT BACKGROUND There is little evidence about pre-hospital advanced life support including epinephrine administration for pediatric out-of-hospital cardiac arrests (OHCAs). OBJECTIVES This study aimed to assess the effect of pre-hospital epinephrine administration by emergency-medicalservice (EMS) personnel for pediatric OHCA. METHODS This nationwide population-based observational study in Japan enrolled pediatric patients age 8 to 17 years with OHCA between January 2007 and December 2016. Patients were sequentially matched with or without epinephrine during cardiac arrest using a risk-set matching based on time-dependent propensity score (probability of receiving epinephrine) calculated at each minute after initiation of cardiopulmonary resuscitation by EMS personnel. The primary endpoint was 1-month survival. Secondary endpoints were 1-month survival with favorable neurological outcome, defined as the cerebral performance category scale of 1 or 2, and pre-hospital return of spontaneous circulation (ROSC). RESULTS During the study period, a total of 1,214,658 OHCA patients were registered, and 3,961 pediatric OHCAs were eligible for analyses. Of these, 306 (7.7%) patients received epinephrine and 3,655 (92.3%) did not receive epinephrine. After time-dependent propensity score-sequential matching, 608 patients were included in the matched cohort. In the matched cohort, there were no significant differences between the epinephrine and no epinephrine groups in 1-month survival (epinephrine: 10.2% [31 of 304] vs. no epinephrine: 7.9% [24 of 304]; risk ratio [RR]: 1.13 [95% confidence interval (CI): 0.67 to 1.93]) and favorable neurological outcome (epinephrine: 3.6% [11 of 304] vs. no epinephrine: 2.6% [8 of 304]; RR: 1.56 [95% CI: 0.61 to 3.96]), whereas the epinephrine group had a higher likelihood of achieving pre-hospital ROSC (epinephrine: 11.2% [34 of 304] vs. no epinephrine: 3.3% [10 of 304]; RR: 3.17 [95% CI: 1.54 to 6.54]). CONCLUSIONS In this study, pre-hospital epinephrine administration was associated with ROSC, whereas there were no significant differences in 1-month survival and favorable neurological outcome between those with and without epinephrine. (J Am Coll Cardiol 2020;75:194–204) © 2020 by the American College of Cardiology Foundation.

From the aDepartment of Emergency Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; bDivision of Biomedical Listen to this manuscript’s

Statistics, Department of Integrated Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan; cCenter for Critical

audio summary by

Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; dDepartment of

Editor-in-Chief

Emergency Medicine, Okinawa Chubu Hospital, Okinawa, Japan; eDepartment of Emergency Medicine, University of Pittsburgh

Dr. Valentin Fuster on

School of Medicine, Pittsburgh, Pennsylvania; fDepartment of Food Science, Otsuma Women’s University, Tokyo, Japan; gKyoto

JACC.org.

University Health Service, Kyoto, Japan; and the hDivision of Environmental Medicine and Population Services, Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan. This study was supported by Japan Society for the Promotion of Science KAKENHI Grant Numbers 15H05006 and 19K09393; and by the Clinical Investigator’s Research Project in Osaka University Graduate School of Medicine. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 1, 2019; revised manuscript received October 22, 2019, accepted October 23, 2019.

ISSN 0735-1097/$36.00

https://doi.org/10.1016/j.jacc.2019.10.052

JACC VOL. 75, NO. 2, 2020

Matsuyama et al.

JANUARY 21, 2020:194–204

Pre-Hospital Epinephrine for Pediatric OHCA

O

ut-of-hospital cardiac arrest (OHCA) is an

international Utstein-style (13,14). We con-

ABBREVIATIONS

important public health problem in indus-

ducted a retrospective analysis of this regis-

AND ACRONYMS

trialized countries (1–3). Although pediatric

try. The population of Japan in 2016 was 127

OHCA patients account for as few as 1% of all OHCA,

million inhabitants, with 20 million people

the impact of pediatric OHCA is large because of its

age <18 years. The geographic area of Japan is

emotional burden on families and the greater number

approximately 378,000 km 2 (3). There were

defibrillator

CI = confidence interval

AAM = advanced airway management

AED = automated external

of lost years of life per individual (4,5). Nevertheless,

approximately 750 fire stations equipped

less evidence supporting interventions for pediatric

with dispatch centers that provided emer-

OHCA exists compared with adult OHCA, particularly

gency services 24 h/day (3). Cardiac arrest

in

was defined as the cessation of cardiac me-

CPR = cardiopulmonary

chanical activity as confirmed by the absence

resuscitation

pre-hospital

advanced

life

support

such

as

epinephrine administration (6,7). SEE PAGE 205

Epinephrine administration for pediatric OHCA is

CPC = cerebral performance category

of circulation signs (13). The etiology of car-

EMS = emergency medical

diac arrest was presumed to be medical origin

service

unless it was caused by trauma, drug over-

recommended for nonshockable rhythms by current

dose, drowning, electrocution, or asphyxia

international guidelines as soon as vascular or intra-

(13). All EMS personnel conduct resuscitation

osseous access is obtained (6,7). For adult OHCA, a

according to the Japanese cardiopulmonary

recent clinical trial demonstrated a positive effect of

resuscitation (CPR) guideline, based on the

epinephrine on return of spontaneous circulation

International Liaison Committee on Resusci-

(ROSC) and survival (8). However, neither a ran-

tation consensus (15).

ELST = emergency life-saving technician

FDMA = Fire and Disaster Management Agency

OHCA = out-of-hospital cardiac arrest

RCT = randomized controlled trial

domized controlled trial (RCT) nor large observational

Details of the EMS system in Japan have

study has investigated the effectiveness of epineph-

been described previously (16). Briefly, each

circulation

rine for pediatric OHCA, suggesting a critical gap in

ambulance consists of a crew of 3 emergency

RR = risk ratio

our knowledge. In an observational study assessing

providers, including at least 1 emergency life-saving

intracardiac

technician (ELST), who is a highly trained pre-

arrest

interventions,

considering

ROSC = return of spontaneous

“resuscitation time bias” (i.e., patients receiving

hospital

longer resuscitation tend to have intra-arrest in-

permitted to provide advanced life support such as

terventions, resulting in worse outcome) is crucial

inserting adjunct airways or intravenous lines, or

(9). Indeed, 2 observational studies from Japan

using semiautomated external defibrillators for pa-

assessed the effect of epinephrine on adult OHCA

tients with OHCA. Certified ELSTs after further

patients, using the same national OHCA database and

training in hospital are also allowed to administer

propensity score analysis, but showed conflicting

intravenous epinephrine and to perform tracheal

findings (10,11). The one study addressing “resusci-

intubation under online medical direction. EMS

tation time bias” by using time-dependent propensity

personnel are not permitted to place intraosseous

score-sequential matching demonstrated the positive

access. EMS personnel are legally permitted to

effect of epinephrine, which is similar to the result of

administer epinephrine for only those age $8 years

emergency

195

care

provider.

They

are

recent randomized controlled trials (11), whereas the

(3). Administration of epinephrine for OHCA patients

other study using traditional propensity score matching

by ELSTs has been permitted since April 2006 (3).

showed only its negative impact on outcome (11,12).

Almost all OHCA patients cared for by EMS personnel

The All-Japan Utstein Registry is a prospective,

are transported to hospitals and enrolled in the reg-

nationwide, population-based registry of all patients

istry, because EMS personnel are not permitted to

with OHCA, and collected approximately 4,000 pe-

terminate resuscitation on scene. The institutional

diatric patients with OHCA from January 2007 to

review board of Kyoto Prefectural University of

December 2016. Using this registry, we aimed to

Medicine and Osaka University approved the sec-

assess whether pre-hospital epinephrine administra-

ondary analysis of the All-Japan Utstein Registry with

tion was associated with favorable patient outcomes,

a waiver of informed consent.

taking time-dependent factors into consideration.

STUDY PARTICIPANTS. This study included pediatric

METHODS

patients with OHCA (age 8 to 17 years), who were resuscitated by bystanders and/or EMS personnel,

STUDY DESIGN AND EMS SYSTEM IN JAPAN. The All-

and subsequently transported to medical institutions

Japan Utstein Registry of the Fire and Disaster Man-

from January 2007 to December 2016. As mentioned

agement Agency (FDMA) is a prospective, nationwide

in the previous text, we regarded pediatric OHCA

OHCA registry that collects data according to the

patients age $8 years as at risk of receiving

196

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Pre-Hospital Epinephrine for Pediatric OHCA

JANUARY 21, 2020:194–204

epinephrine as per the resuscitation algorithm. The

them to complete the form. The EMS providers in

exclusion criteria of this study were: 1) OHCA without

charge followed-up all survivors for a 1-month period

ELST involvement; 2) EMS-witnessed cardiac arrest;

after the event. Neurological outcome was evaluated

3) OHCA with unknown first documented rhythm;

by an interview at 1 month after successful resusci-

4) OHCA with unknown or inappropriate time-

tation using the Glasgow-Pittsburgh cerebral perfor-

dependent variables (e.g., time from initiation of

mance category (CPC) scale: category 1, good cerebral

EMS CPR to epinephrine administration, time from

performance;

initiation of EMS CPR to first shock delivery, time

disability; category 3, severe cerebral disability;

from initiation of EMS CPR to pre-hospital ROSC, time

category 4, coma or vegetative state; and category 5,

from emergency call to initiation of EMS CPR, and

death/brain death (18).

time from initiation of EMS CPR to hospital arrival); or

ENDPOINTS. The primary endpoint was 1-month

5) OHCA with interval between emergency call to

survival. The secondary endpoints were 1-month

initiation of EMS CPR $30 min. We regarded inap-

survival

category

with

2,

favorable

moderate

neurological

cerebral

outcome,

propriate resuscitation interval variables as any

defined as the Glasgow-Pittsburgh CPC scale of 1 or 2

negative

(18), and pre-hospital ROSC. We used CPC because

values

for

the

resuscitation

intervals

described in the previous text.

pediatric CPC was not available.

DATA COLLECTION AND QUALITY CONTROL. The

STATISTICAL ANALYSES. Data were presented as

following resuscitation-related data were prospec-

medians with interquartile ranges for continuous

tively collected, using the Utstein Resuscitation

variables and as proportions for categorical variables.

Registry Templates for OHCA: age, sex, date of ar-

The main exposure was intravenous epinephrine

rests, etiology of arrests, witnessed status, first

administration by EMS personnel. We conducted

documented

(chest-

propensity score-sequential matching analyses, ac-

compression only or CPR with rescue breathing),

rhythm,

bystander

CPR

counting for the timing of epinephrine administra-

dispatcher CPR instruction, public-access automated

tion

external defibrillators (AEDs) shock delivery, pre-

confounders. A similar methodology was applied for

hospital advanced airway management (AAM), pre-

investigating the effect of epinephrine and AAM on

and

adjusting

for

measured

potential

hospital administration of intravenous fluids and

adult patients with OHCA (10,19). Propensity scores

epinephrine administration, and resuscitation time-

were calculated as the estimated risk scores that

course, as well as outcome measures, including pre-

predict probability of receiving epinephrine using

hospital ROSC, 1-month survival, and neurological

Fine-Grey regression model with time-dependent

status at 1 month after the event (13,14). The resus-

and time-independent covariates and competing

citation time-course variables included time of

risk event (20). In the regression model, we treated

receipt of an emergency call, initiation of CPR by EMS

pre-hospital ROSC before epinephrine administration

personnel,

personnel,

as the competing risk. We considered pre-hospital

epinephrine administration by EMS personnel, pre-

ROSC before epinephrine administration as informa-

hospital ROSC, and hospital arrival. These resuscita-

tive censoring in the time-dependent propensity

tion time-course variables were recorded with the

score model, because epinephrine administration

clock by each EMS system. When bystanders deliv-

during CPR never occurs after ROSC except in rare

ered a shock with a public-access AED, the first

cases including rearrest. We also included hospital

documented rhythm was regarded as ventricular

arrival as censoring because our main exposure was

fibrillation/pulseless ventricular tachycardia (4,16).

pre-hospital epinephrine administration, and data

The registry did not systematically collect informa-

after hospital arrival were not available in the regis-

tion of the analyzed rhythms by public-access AEDs.

try. The time-dependent covariate included shock

However, because the sensitivity and specificity of

delivery by EMS personnel. In the propensity score-

shock delivery by an AED for shockable rhythm are

predicting model, the following time-independent

high, missing or overdiagnosing shockable rhythm

covariates were included: age (continuous), sex

would be rare (17). The data form was filled out by the

(male or female), year of occurrence (2007 to 2016),

EMS providers in cooperation with the physicians in

day of occurrence (weekday [Monday to Friday] or

charge of the patients; data were integrated into the

weekend [Saturday and Sunday]), time of occurrence

registry system on the FDMA database server. The

(daytime [9:00

data had computer review for missing or errant en-

8:59

tries; when the data was incomplete, the FDMA

of patients who received epinephrine, etiology of

returned to the respective fire station and requested

arrests (medical or nonmedical), witness status (yes

defibrillation

by

EMS

AM ])

AM

to 4:59

PM ]

or nighttime [5:00

PM

to

(21), tertiles of prefecture by the proportion

JACC VOL. 75, NO. 2, 2020

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Pre-Hospital Epinephrine for Pediatric OHCA

or no), first documented rhythm (shockable [ventricular fibrillation or pulseless ventricular tachy-

T A B L E 1 Characteristics of the Study Population

No Epinephrine (n ¼ 3,655)

cardia] or nonshockable [pulseless electrical activity or asystole]), bystander CPR (chest compression–only CPR, conventional CPR with rescue breathing, or none), public access AED shock delivery (yes or no), pre-hospital physician involvement (yes or no), and time from call to initiation of EMS CPR (continuous) as presented in Table 1. We included the prefecture

Epinephrine (n ¼ 306)

Age group Children (8–12 yrs) Adolescents (>12 yrs)

797 (21.8)

37 (12.1)

2,858 (78.2)

269 (87.9)

2,304 (63.0)

232 (75.8)

Sex Male Year of arrest

categories to address regional variations in outcomes

2007

377 (10.3)

6 (2.0)

(22). These covariates were determined a priori ac-

2008

347 (9.5)

15 (4.9)

cording to previous studies (21,23,24). Based on the predicted time-dependent propensity

2009

337 (9.2)

20 (6.5)

2010

360 (9.8)

30 (9.8)

2011

378 (10.3)

26 (8.5)

scores, a patient receiving epinephrine at any given

2012

352 (9.6)

29 (9.5)

minute (from min 0 to 59) after initiation of CPR by

2013

313 (33.4)

34 (11.1)

EMS

(1:1

2014

400 (10.9)

40 (13.1)

matching without replacement) with a patient who

2015

411 (11.2)

48 (28.1)

was at risk of receiving epinephrine and had the

2016

380 (10.4)

58 (19.0)

3,153 (86.3)

260 (85.0)

502 (13.7)

46 (15.0)

personnel

were

sequentially

matched

nearest propensity score within the same minute (9,10). In sequential risk-set matching, at-risk patients included those who were still receiving CPR on

Day of arrest Weekday (Monday to Friday) Weekend (Saturday and Sunday) Time of arrest

scene and had not yet received epinephrine before or

Daytime (9:00

within the same minute. Therefore, at-risk patients

Nighttime (5:00

also included patients who received epinephrine later, because the sequential matching should not depend on future events to avoid selection bias (9,25,26). Risk-set sequential matching is known to address resuscitation time bias (9,26). We set the

AM

to 4:59

PM

PM)

to 8:59

AM)

1,176 (32.2)

93 (30.4)

2,479 (67.8)

213 (69.6)

Tertiles of prefecture preference for performing epinephrine Tertile 1 (0.0%–3.1%)

764 (20.9)

56 (18.3)

Tertile 2 (3.1%–10.0%)

1,375 (37.6)

56 (34.6)

Tertile 3 (10.3%–33.3%)

1,516 (41.5)

144 (47.1)

Etiology

caliper-width for the nearest neighbor matching at

Medical

1,642 (44.9)

134 (43.8)

0.2 of SDs of the risk score (27,28). In propensity

Nonmedical

2,013 (55.1)

172 (56.2)

score-matched cohort, we calculated standardized

Witness status Yes

1,235 (33.8)

119 (38.9)

No

2,420 (66.2)

187 (61.1)

difference for each covariate to assess the balance of covariates

between

groups

with

and

without

epinephrine. We considered SDs <0.1 as having wellmatched balance at first (27), but we could not achieve well-matched balance even if the caliper-width

First documented rhythm Shockable Nonshockable

278 (7.6)

43 (14.1)

3,377 (92.4)

263 (85.9)

1,433 (39.2)

132 (43.1)

Bystander CPR

was too narrow (¼ 0.001). If we tried to achieve bet-

Chest compression only CPR

ter balancing of SDs (<0.1) by setting a much narrower

Chest compression with ventilation

caliper-width (<0.001), we lost a great number of

None

534 (14.6)

60 (19.6)

1,688 (46.2)

114 (37.3)

Pre-hospital physician involvement

187 (5.1)

39 (12.7)

Time from call to EMS CPR, min

8 (7–11)

9 (7–12)

Advanced airway management

933 (25.5)

184 (60.1)

value of 0.25 rather than 0.1 of SDs, as suggested in

EMS shock delivery

358 (9.8)

63 (20.6)

the published data (28), before performing our final

Time from EMS CPR to EMS shock delivery, min

analyses.

Time from EMS CPR to epinephrine, min

patients. We finally decided not to lose a number of patients with a narrow range of target and chose the

2 (1–5)

3 (2–8)

N/A

15 (10–21)

In the original cohort, we estimated unadjusted risk ratios (RRs) with 95% confidence intervals (CIs) of epinephrine for the outcomes by univariable log-

Values are n (%) or median (interquartile range). AAM ¼ advanced airway management; CPR ¼ cardiopulmonary resuscitation; EMS ¼ emergency medical services; N/A ¼ not applicable.

binomial regression model. In the matched cohort, we applied log-binomial link function in generalized estimating equations to calculate RRs with 95% CIs of

duplications between patients with epinephrine and

epinephrine for outcomes (29). We used generalized

without epinephrine (28). We did not include cova-

estimating equations to account for potential corre-

riates in the models in the original and matched co-

lation within-pair of risk set matching. We adjusted

horts to avoid overfitting of models due to our limited

for frequency weights to address a number of the

sample size.

197

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Pre-Hospital Epinephrine for Pediatric OHCA

JANUARY 21, 2020:194–204

F I G U R E 1 Patient Flowchart of This Study

All OHCAs between 2007 and 2016 in Japan n = 1,214,658 Age <8 or ≥18 years old (n = 1,208,736) Pediatric OHCA n = 5,922 No resuscitation attempt (n = 419) EMS-resuscitated Pediatric OHCA n = 5,503 No emergency life-saving technicians involvement (n = 181) EMS witnessed arrest (n = 427) Initial rhythm unknown (n = 145) Time-dependent variables unknown (n = 558) Inappropriate data in time-dependent variables (n = 21) Interval from call to initiation of EMS CPR ≥30 minutes (n = 210) Eligible for analyses n = 3,961

CPR ¼ cardiopulmonary resuscitation; EMS ¼ emergency medical service; OHCA ¼ out-of-hospital cardiac arrest.

As the timing of epinephrine or witnessed status

who received epinephrine, 206 (87.9%) were adoles-

may change the effect size of epinephrine, we per-

cents, 232 (75.8%) were male, and 184 (60.1%)

formed subgroup analyses stratified by the timing of

received AAM, while among those who did not

epinephrine (within 15 min or later) and witnessed

receive epinephrine, 2,858 (78.2%) were adolescents

status (witnessed or unwitnessed arrests). In the

and 2,304 (63.0%) were male, and 933 (25.5%) had

subgroup analyses, we recalculated RRs with 95% CIs

AAM. In both groups with or without epinephrine,

for outcomes in the original and matched cohorts. In

approximately 45% had medical etiology of arrests,

all models, we used B-splines for continuous vari-

one-third had witnessed arrest, approximately 90%

ables. All statistical analyses were performed with R

had nonshockable first documented rhythm, and

software, version 3.5.1 (R Foundation for Statistical

more than one-half had any type of bystander CPR.

Computing, Vienna, Austria).

Median time from initiation of EMS CPR to epinephrine administration was 15 min.

RESULTS

After time-dependent propensity score matching, 608 patients were matched. There was substantial

During the study period, a total of 5,922 pediatric

overlap in propensity scores (Online Figure 1). Patient

patients with OHCA age 8 to 17 years were docu-

characteristics of the matched cohort are presented in

mented. After excluding those who met exclusion

Table 2. The distribution of each variable included in

criteria, 3,961 patients were included in our study

the propensity score calculation was well-balanced

(Figure 1). Among them, there were 306 (7.7%) pa-

(all SDs <0.25).

tients who received epinephrine and 3,655 (92.3%) who did not receive epinephrine.

In the original cohort, no significant differences were observed in 1-month survival with favorable

Patient characteristics with or without epinephrine

neurological outcome (epinephrine: 3.6% [11 of 306]

administration are shown in Table 1. Among those

vs. no epinephrine: 3.1% [112 of 3,655]; RR: 1.17

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Pre-Hospital Epinephrine for Pediatric OHCA

[95% CI: 0.64

to

2.16]) and 1-month survival

(epinephrine: 10.1% [31 of 306] vs. no epinephrine:

T A B L E 2 Characteristics of the Study Population in the Matched Cohort

No Epinephrine (n ¼ 304)

8.9% [325 of 3,655]; RR: 1.14 [95% CI: 0.80 to 1.62]), while the epinephrine group was more likely to achieve pre-hospital ROSC compared with the no

Epinephrine (n ¼ 304)

Standardized Difference

<0.001

Age group 37 (12.2)

37 (12.2)

267 (87.8)

267 (87.8)

230 (75.7)

230 (75.7)

the epinephrine and no epinephrine groups in favor-

2007

7 (2.3)

6 (2.0)

able neurological outcome (epinephrine: 3.6% [11 of

2008

22 (7.2)

15 (4.9)

2009

13 (4.3)

20 (6.6)

2010

33 (10.9)

30 (9.9)

2011

34 (11.2)

26 (8.6)

(epinephrine: 10.2% [31 of 304] vs. no epinephrine:

2012

20 (6.6)

29 (9.5)

7.9% [24 of 304]; RR: 1.13 [95% CI: 0.67 to 1.93]),

2013

36 (11.8)

34 (11.2)

whereas the epinephrine group had higher likelihood

2014

37 (12.2)

39 (12.8)

of achieving pre-hospital ROSC (epinephrine: 11.2%

2015

51 (16.8)

48 (15.8)

2016

51 (16.8)

57 (18.8)

254 (83.6)

258 (84.9)

50 (16.4)

46 (15.1)

89 (29.3)

93 (30.6)

215 (70.7)

211 (69.4)

epinephrine group (epinephrine: 11.1% [34 of 306] vs. no epinephrine: 3.7% [137 of 3,655]; RR: 2.96 [95% CI: 2.07 to 4,24]) (Table 3). Similarly, in the matched cohort, there were no significant differences between

304] vs. no epinephrine: 2.6% [8 of 304]; RR: 1.56 [95% CI:

0.61 to

3.96])

and

1-month survival

[34 of 304] vs. no epinephrine: 3.3% [10 of 304]; RR:

Children (8–12 yrs) Adolescents (>12 yrs) Sex Male Year of arrest

Table 4 shows the results of the subgroup analyses stratified by the timing of epinephrine and witnessed status. In the earlier time of epinephrine administration group in the matched cohort, we observed that epinephrine administration was associated with 1-month survival and pre-hospital ROSC. In witnessed and unwitnessed groups, epinephrine administration was associated with pre-hospital ROSC, but not associated with 1-month survival and favorable neurological outcome.

0.02

Weekday (Monday to Friday) Weekend (Saturday and Sunday) Time of arrest Daytime (9:00

0.03 AM

Nighttime (5:00

to 4:59

PM

PM)

to 8:59

AM)

Tertiles of prefecture preference for performing epinephrine

0.04

Tertile 1 (0.0%–3.1%)

60 (19.7)

56 (18.4)

Tertile 2 (3.1%–10.0%)

117 (38.5)

117 (38.5)

Tertile 3 (10.3%–33.3%)

127 (41.8)

131 (43.1)

Medical

136 (44.7)

133 (43.8)

Nonmedical

168 (55.3)

171 (56.2)

Yes

99 (32.6)

117 (38.5)

No

205 (67.4)

187 (61.5)

40 (13.2)

41 (13.5)

264 (86.8)

263 (86.5)

132 (43.4)

128 (42.1)

Etiology

0.02

Witness status

DISCUSSION Based on the time-dependent propensity scoresequential matching, using the Japanese prospective, nationwide, population-based OHCA registry between 2007 and 2016, we observed that there were

0.01

First documented rhythm Shockable Nonshockable

0.01

Bystander CPR

0.10

no significant differences in 1-month survival and

Chest compression only CPR

1-month

Chest compression with ventilation

50 (16.4)

62 (20.4)

No

122 (40.1)

114 (37.5)

34 (11.2)

37 (12.2)

survival

with

favorable

neurological

outcome between epinephrine and no epinephrine groups, while epinephrine administration was associated with pre-hospital ROSC (Central Illustration). No RCTs and very few observational studies have

Pre-hospital physician involvement Time from call to EMS CPR, min EMS shock delivery

38 (12.5)

50 (16.4)

0.11

2 (2–3)

2 (1–4)

0.17

Timing of matching (interval between EMS CPR and matching), min <5

3 (1.0)

3 (1.0)

5–9

67 (22.0)

67 (22.0)

10–14

79 (26.0)

79 (26.0)

15–19

62 (20.4)

62 (20.4)

atric patients with in-hospital cardiac arrests (30,31).

20–24

56 (18.4)

56 (18.4)

The absence of studies with large sample size and

25–29

20 (6.6)

20 (6.6)

sophisticated statistical analyses limits understand-

>29

17 (5.6)

17 (5.6)

20 (13.8–24.3)

15 (10–21)

Most observational studies in adult OHCA showed the positive effect of epinephrine administration on

Time from EMS CPR to epinephrine, min Values are n (%) or median (interquartile range). Abbreviations as in Table 1.

0.03

<0.001

revealed unadjusted descriptive analysis of 111 pedi-

ing of the effect of epinephrine for pediatric patients.

0.04

182 (59.9)

administration for pediatric cardiac arrest. The

included only 9 OHCA patients, and the other

0.031

186 (61.2)

Time from EMS CPR to EMS shock delivery, min

have limitations in sample size and confounders: one

9.0 (7.0–12.0) 9.0 (7.0–12.0)

Advanced airway management

assessed the effectiveness of intra-arrest epinephrine existing 2 observational studies, both from Australia,

<0.001 0.20

Day of arrest

3.17 [95% CI: 1.54 to 6.54]).

199

0.51

200

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T A B L E 3 Outcomes for Pediatric Patients With Out-of-Hospital Cardiac Arrest by Epinephrine Administration

Original Cohort

Propensity Score Sequentially Matched Cohort

No Epinephrine

Epinephrine

Risk Ratio (95% CI)

No Epinephrine

Epinephrine

Risk Ratio (95% CI)

325/3,655 (8.9)

31/306 (10.1)

1.14 (0.80–1.62)

24/304 (7.9)

31/304 (10.2)

1.13 (0.67–1.93)

Pre-hospital ROSC

137/3,655 (3.7)

34/306 (11.1)

2.96 (2.07–4.24)

10/304 (3.3)

34/304 (11.2)

3.17 (1.54–6.54)

Favorable neurological outcome

112/3,655 (3.1)

11/306 (3.6)

1.17 (0.64–2.16)

8/304 (2.6)

11/304 (3.6)

1.56 (0.61–3.96)

Primary outcome 1-month survival Secondary outcome

Values are n of patients with outcome/total n patients (%) unless otherwise indicated. CI ¼ confidence interval; ROSC ¼ return of spontaneous circulation.

ROSC, but reported conflicting findings on long-term

2.01 to 5.61), but did not have the associations with

survival and neurological status (32), which has

survival to hospital discharge (OR: 2.17; 95% CI: 0.74

made clinical-decision making complex and difficult.

to 6.32) and favorable neurological outcome at hos-

As for clinical trials, we identified 3 RCTs (8,33,34). A

pital discharge (OR: 1.76; 95% CI: 0.61 to 5.07) (34).

prior RCT from Norway that enrolled 851 adult pa-

The other recent RCT from the United Kingdom

tients with OHCA observed that intra-arrest intrave-

enrolled

nous

including

observed that epinephrine administration had higher

epinephrine had the positive effect on ROSC (odds

rates of ROSC (OR: 4.32; 95% CI: 3.85 to 4.85) and

ratio [OR]: 1.99; 95% CI: 1.48 to 2.67), but was not

survival to hospital discharge (OR: 1.39; 95% CI: 1.06

associated

discharge

to 1.82), but had no difference in the rate of favorable

(OR: 1.16; 95% CI: 0.74 to 1.82) or favorable neuro-

neurological outcome at hospital discharge (OR: 1.18;

logical outcome at hospital discharge (OR: 1.24;

95% CI: 0.86 to 1.61) (8). The positive effect of

95% CI: 0.77 to 1.98) (33). Another prior RCT from

epinephrine on ROSC in 3 clinical trials for adults was

medication

with

administration

survival

to

hospital

8,014

adult

patients

with

OHCA

and

Australia that included 534 adult patients with OHCA

consistent with our findings in pediatrics. Our study

demonstrated that epinephrine administration was

might have been underpowered to show difference in

positively associated with ROSC (OR: 3.36; 95% CI:

survival, given the limited sample size of 608 patients

T A B L E 4 Outcomes for Patients With Out-of-Hospital Cardiac Arrest by Epinephrine Based on Timing of Epinephrine or Witnessed Status

Original Cohort No Epinephrine

Epinephrine

Propensity Score-Matched Analysis Risk Ratio (95% CI)

No Epinephrine

Epinephrine

Risk Ratio (95% CI)

Timing of epinephrine administration #15 min 1-month survival

13/158 (8.2)

25/158 (15.8)

1.92 (1.02 to 3.61)

Pre-hospital ROSC

10/158 (6.3)

24/158 (15.2)

2.40 (1.19 to 4.83)

6/158 (3.8)

10/158 (6.3)

1.67 (0.62 to 4.48) 0.55 (0.21 to 1.44)

Favorable neurological outcome >15 min 1-month survival

11/146 (7.5)

6/146 (4.1)

Pre-hospital ROSC

0/146 (0.0)

10/146 (6.8)

Favorable neurological outcome

2/146 (1.4)

1/146 (0.7)

Unconverged 0.50 (0.05 to 5.49)

Witnessed status Witnessed arrests 1-month survival

184/1,235 (14.9)

13/119 (10.9)

0.73 (0.44 to 1.23)

13/99 (13.1)

13/117 (11.1)

0.85 (0.41 to 1.75)

Pre-hospital ROSC

86/1,235 (7.0)

14/119 (11.8)

1.69 (0.98 to 2.91)

3/99 (3.0)

14/117 (12.0)

3.95 (1.19 to 13.14)

Favorable neurological outcome

93/1,235 (7.5)

7/119 (5.9)

0.78 (0.37 to 1.64)

6/99 (6.1)

7/117 (6.0)

0.99 (0.34 to 2.86) 1.79 (0.87 to 3.70)

Unwitnessed arrests 1-month survival

141/2,420 (5.8)

18/187 (9.6)

1.65 (1.03 to 2.66)

11/205 (5.4)

18/187 (9.6)

Pre-hospital ROSC

51/2,420 (2.1)

20/187 (10.7)

5.07 (3.05 to 8.45)

7/205 (3.4)

20/187 (10.7)

3.13 (1.36 to 7.20)

Favorable neurological outcome

19/2,420 (0.8)

4/187 (2.1)

2.72 (0.93 to 7.97)

2/205 (1.0)

4/187 (2.1)

2.19 (0.41 to 11.87)

Values are n of patients with outcome/total n patients (%) unless otherwise indicated. Abbreviations as in Table 3.

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Pre-Hospital Epinephrine for Pediatric OHCA

C ENTR AL I LL U STRA T I O N Pre-Hospital Epinephrine for Pediatric Out-of-Hospital Cardiac Arrest

20

Relative Risk (RR) 1.13 (95% CI 0.67–1.93) RR 3.17 (95% CI 1.54–6.54)

(%)

RR 1.56 (95% CI 0.61–3.96) 10.2% (31/304) 10

11.2% (34/304)

7.9% (24/304)

3.3% (10/304)

0

No Epinephrine 1-Month Survival

3.6% (11/304)

2.6% (8/304)

Epinephrine Pre-Hospital Return of Spontaneous Circulation Favorable Neurological Outcome

Matsuyama, T. et al. J Am Coll Cardiol. 2020;75(2):194–204.

Outcomes of pre-hospital epinephrine administration for pediatric patients with out-of-hospital cardiac arrest: time-dependent propensity scoresequential matching analysis.

in our matched cohort (i.e., the larger trial in the

(39,40). Taking the results of experimental and clin-

United Kingdom demonstrated a positive effect on

ical studies into consideration, epinephrine adminis-

survival to hospital discharge, whereas the smaller

tration is obviously associated with increasing the

trials in Norway and Australia showed nonsignificant

chance of ROSC, whereas its impact on long-term

difference in survival).

outcomes such as survival or neurological outcome

The physiologically beneficial effect of epinephrine

may be smaller, largely depending on other factors,

is considered to increase diastolic pressure and cor-

such as patient baseline status or quality of care in

onary perfusion pressure through its strong alpha-

each element of “chain of survival.” However, ROSC

adrenergic effect, leading to the higher chance of

is a necessary first step to favorable neurological

ROSC (32,35). In contrast, the potential harmful

outcome, so there is currently no room to doubt

effects of epinephrine may come from its beta-

whether to administer epinephrine for pediatric

adrenergic

OHCA.

effect,

which

increases

myocardial

oxygen demand, causes fatal arrhythmia, and subse-

In this study, the proportion of pre-hospital

quently results in rearrest (32,36). According to pre-

epinephrine administration was much lower than

vious animal studies, epinephrine administration

that of a report from North America (about 7.7% vs.

during CPR was shown to reduce cerebral perfusion

73.3%) (41), which led to the smaller sample size of

through its alpha-1 agonist action and contribute to

this study. The difference might come partially from

greater neurological injury (37,38). More importantly,

differences in the EMS system (e.g., EMS personnel

the brain is more sensitive to ischemia and reperfu-

cannot obtain interosseous access in Japan). The po-

sion damage, and is less likely to recover from

tential residual confounders such as the quality of

ischemic-reperfusion

arrest

care delivered by ELSTs or the number of ELSTs per

compared with other organs including the heart

each patient might have resulted in the observed low

injury

of

cardiac

201

202

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JANUARY 21, 2020:194–204

proportion of epinephrine administration. Further-

the registry. Fourth, the survival outcome and

more, the subgroups analysis demonstrated that

favorable neurological outcome might have been

earlier time of epinephrine administration was asso-

underpowered in the matched analysis, as we stated

ciated with higher survival, which was consistent

in the discussion section. Last, as with all epide-

with a previous study (41). The median interval from

miological studies, potential limitations are data

EMS CPR to epinephrine was 15 min in this study and

integrity, validity, and ascertainment bias. The

was basically similar to findings in previous studies

uniform data collection according to the Utstein-

on epinephrine from North America and the United

style guidelines for reporting cardiac arrest, the

Kingdom (8,41). However, considering the effective-

nationwide population-based study, and the large

ness of early epinephrine administration, further ef-

sample size made it possible to minimize these

forts will be warranted to lead prompt epinephrine

potential biases.

administration. STUDY STRENGTHS AND LIMITATIONS. Our study

CONCLUSIONS

has several strengths. First, this is the nationwide registry covering all pediatric OHCA to directly

In this nationwide population-based study on pedi-

assess the effect of intra-arrest epinephrine admin-

atric OHCA between age of 8 and 17 years, we

istration for pediatric patients with OHCA. Given the

observed

limited existing evidence in this population, the

epinephrine administration and pre-hospital ROSC,

current CPR guideline concluded that it was impos-

while there were no significant differences in 1-month

sible to determine if epinephrine was beneficial for

survival and 1-month survival with favorable neuro-

pediatric OHCA (6,7). Instead, the current recom-

logical outcome between those with and without

mendation of epinephrine administration for pedi-

epinephrine.

atric cardiac arrest was made based on the results of adult OHCA studies (6,7). Importantly, considering the low incidence of pediatric OHCA and the small effect size of epinephrine administration on longterm

outcomes

(6–8,33,34),

the

feasibility

of

performing clinical trials for this population is questionable.

Therefore,

our

findings

provide

important knowledge to guide the use of epinephrine for this population. Second, we addressed “resuscitation time bias.” The longer the resuscitation time, the higher the likelihood of receiving epinephrine. Because longer resuscitation time is linked

to

worse

outcome

(42),

the

effect

of

the

association

ACKNOWLEDGMENTS The

between

authors

pre-hospital

are

greatly

indebted to all of the EMS personnel and concerned physicians in Japan, and to the Fire and Disaster Management Agency and Institute for Fire Safety and Disaster Preparedness of Japan for their generous cooperation in establishing and maintaining the Utstein database. ADDRESS FOR CORRESPONDENCE: Dr. Tasuku Mat-

suyama, Department of Emergency Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail: [email protected].

epinephrine administration is biased towards harmful effect, unless the timing of administration is accounted for (9,12). Our sophisticated statistical approach for eliminating the resuscitation time bias increased the robustness of our findings. Several

limitations

of

this

study

should

be

considered. First, we included only pediatric patients age $8 years, so the generalizability to those age <8 years is uncertain. Specifically, we were not able to fully assess the effect of epinephrine on younger children who require weight-based dosing. Second, intraosseous access by EMS personnel is not permitted in Japan. Generalizability to areas where intraosseous epinephrine administration is performed by EMS providers is also uncertain. Third, some potential confounders such as comorbidities and premorbid function are not available in

PERSPECTIVES COMPETENCY IN SYSTEMS-BASED PRACTICE: Pre-hospital administration of epinephrine by emergency medical personnel for pediatric patients with OHCA may improve ROSC, but its effect on 1month survival and neurological outcomes is uncertain. TRANSLATIONAL OUTLOOK: Further investigations are warranted to establish the utility of epinephrine administration to improve long-term outcomes in pediatric patients with OHCA and define its role in cardiopulmonary resuscitation.

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KEY WORDS epinephrine, out-of-hospital cardiac arrest, pediatrics, time-dependent propensity score-sequential matching analysis A PPE NDI X For a supplemental figure, please see the online version of this paper.