Article, Emergency Medicine

Association of the time to first epinephrine administration and outcomes in out-of-hospital cardiac arrest: SOS-KANTO 2012 study

a b s t r a c t

Objective: This study assessed the association between the timing of first epinephrine administration (EA) and the neurological outcomes following out-of-hospital cardiac arrests (OHCAs) with both initial shockable and non-Shockable rhythms.

Methods: This was a post-hoc analysis of a multicenter prospective cohort study (SOS-KANTO 2012), which reg- istered OHCA patients in the Kanto region of Japan from January 2012 to March 2013. We included consecutive adult OHCA patients who received epinephrine. The primary result included 1-month favorable neurological out- comes defined as Cerebral Performance Category 1 or 2. Secondary results included 1-month survival and return of spontaneous circulation (ROSC) after arrival at the hospital. Multivariable logistic regression analysis determined the association between delay per minute of the time from call to first EA in both pre- or in- hospital settings and outcomes.

Results: Of the 16,452 patients, 9344 were eligible for our analyses. In univariable analysis, the delay in EA was associated with decreased favorable neurological outcomes only when the initial rhythm was a Non-shockable rhythm. In multivariable analyses, delay in EA was associated with decreased ROSC (adjusted odds ratio [OR] for one minute delay, 0.97; 95% confidence interval [CI], 0.96-0.98) and 1-month survival (adjusted OR, 0.95; 95% CI, 0.92-0.97) when the initial rhythm was a non-shockable rhythm, whereas during a shockable rhythm, delay in EA was not associated with decreased ROSC and 1-month survival.

Conclusions: While assessing the effectiveness of epinephrine for OHCA, we should consider the time-limited ef- fects of epinephrine. Additionally, consideration of early EA based on the pathophysiology is needed.

(C) 2018

Introduction

Out-of-hospital cardiac arrest (OHCA) is an increasing Public health problem in most countries. Approximately, 300,000, 280,000, and 100,000 OHCAs occur annually in the USA [1], Europe [2], and Japan [3], respectively. Epinephrine administration (EA) was recommended for all OHCAs before 1974 [4] and is still recommended in the 2015

* Corresponding author at: Department of Emergency Medicine and Critical Care, Tokyo Bay Urayasu Ichikawa Medical Center, 3-4-32, Todaijima, Urayasu-city, Chiba, Japan.

E-mail address: [email protected] (Y. Homma).

guidelines [5-7]. Unlike the confirmed usefulness of Early defibrillation and uninterrupted chest compressions [8], the effectiveness of EA for fa- vorable neurological outcomes in OHCA has been controversial [9-11]. Recently, much attention has been paid to the time-dependent asso- ciation between EA and outcomes in OHCA, and studies have shown that early EA was associated with the increased return of spontaneous circulation (ROSC) after arrival at the hospital. However, survival till dis- charge and neurological outcomes remained controversial [12-17]. Nev- ertheless, the following knowledge gaps have not been adequately examined: (i) actual EA time for in-hospital settings and (ii) classifica- tion into initial rhythms. The SOS-KANTO 2012 study [18] distinctly

https://doi.org/10.1016/j.ajem.2018.05.037

0735-6757/(C) 2018

differs from previous studies because it includes in-hospital care in ad- dition to the Utstein data. Accordingly, we deduced that we could fill these knowledge gaps using data from the SOS-KANTO 2012 study.

This study assessed the association between the timing of first EA, in both pre- and in-hospital settings, and neurological outcomes following OHCA with initial shockable and Non-shockable rhythms, using data from the SOS-KANTO 2012 study.

Methods

Study design

This was a post-hoc analysis of the SOS-KANTO 2012 study, which is a multicenter prospective cohort study, that registered 16,452 OHCA pa- tients from eastern Japan [18]. This study included patients from 67 emergency hospitals between January 2012 and March 2013 with the support of the Kanto Regional Group of the Japanese Association for Acute Medicine. This study was approved by the relevant institutional review boards of all 67 institutions, which waived the requirement for informed patient consent to ensure participant anonymity, as stipulated in the Japanese government guidelines. This study also followed STROBE statement in reporting observational studies [19]. All cardiac ar- rest patients, who were transported to the participant hospitals by Emergency Medical Service (EMS) providers, were included [18].

Study setting and population

In Japan, the fire departments of each municipality provide EMS. The Fire and Disaster Management Agency of Japan supervises the nation- wide EMS system [12,20,21]. Each region has its own medical direction teams, which comprise fire agencies, local medical associations, local government, and emergency hospitals. The protocol for cardiopulmo- nary resuscitation (CPR) of each medical direction team is essentially uniformed and it is based on the Japan Resuscitation Council guidelines, which were adopted by the regional medical direction councils [5]. In general, an ambulance crew includes three EMS staff members, and usually, one of them is an emergency lifesaving technician (ELST). ELSTs are permitted to insert a peripheral intravenous line and adminis- trate the Ringer lactate solution. EA by certified ELSTs in the field has been allowed since April 2006 [21]. According to online direct medical direction, medical direction teams permit them to administer epineph- rine to patients aged N8 years with Pulseless electrical activity , ventricular fibrillation or pulseless ventricular tachycardia rhythms after defibrillation, or witnessed asystole [22]. Therefore, the first dose of epinephrine for OHCA patients is administered either by ELSTs in prehospital settings except for non-witnessed asystole, or emergency physicians after arrival at hospitals.

The present study included consecutive patients aged >=18 years who experienced OHCA, which was confirmed by the EMS providers on site; received CPR from EMS providers; were administered epinephrine in pre- or in-hospital settings; and were subsequently transported to the participating institutions. Exclusion criteria were as follows: (i) cases in which the call to first EA time was b0 or N60 min, because these cases were obviously regarded as input errors or abnormal pre- or in- hospital settings [23]; or (ii) patients with missing or unknown data of the call to first EA time and initial rhythm.

Study protocol

The EMS providers collected the prehospital information, including the Utstein style details [24]. The physicians collected the in-hospital in- formation using patient forms. In particular, we focused on the time from call to first EA, which is defined as the time from EMS call to first EA in pre- or in-hospital settings [12]. If the patient was first adminis- tered epinephrine by ELSTs, it was defined as a prehospital setting; however, if ELSTs could not administer epinephrine before arriving at

the hospital and emergency physicians first administered the epineph- rine, it was defined as an in-hospital setting.

Initial electrocardiogram (ECG) rhythms were classified into two groups as follows: shockable rhythms comprised ventricular fibrillation and pulseless ventricular tachycardia, whereas non-shockable rhythms included asystole and PEA. Etiology of cardiac arrest was determined by the physicians caring for the patients. Patients were diagnosed with car- diac arrest due to (presumed) cardiac etiology unless an obvious non- cardiac etiology was observed (i.e., cerebrovascular disease, respiratory disease, severe trauma, drowning, asphyxiation, and drug overdose) [3].

Measures

The multivariable models adjusted for gender, age, ADL just before OHCA (independent/non-independent), bystander witnesses (yes/no), bystander CPR (yes/no), call to EMS contact time (minutes), total amount of administered epinephrine (mg), etiology of cardiac arrest (cardiac etiology/non-cardiac etiology), and initial rhythms (shockable rhythms/non-shockable rhythms, using when analyzed in overall pa- tients), with consideration of multicollinearity that defined as variance inflation factor b10. These covariates were selected based on the clinical plausibility and a priori knowledge [13,16]. Further, we adjusted for within-institution clustering using a generalized estimating equation to adjust institutional variability [3]. We collected the data of call to first EA time as both continuous and categorical variables, which were equally partitioned into quarters of the call to first EA time.

Outcomes

The primary result included 1-month favorable neurological out- comes. The secondary result included 1-month survival and ROSC. The neurological status was defined using the cerebral performance cate- gory (CPC) scores. A favorable neurological outcome was defined as a CPC score of 1 (good performance) or 2 (moderate disability). A poor neurological outcome was defined as a CPC score of 3 (severe disability), 4 (vegetative state), or 5 (death) [25]. One-month neurological status was collected by researchers of each participating institution. When the patients were admitted to the hospitals, they collected the informa- tion from inpatient records. When the patients were discharged or transferred to other hospitals for rehabilitation, they collected the infor- mation by telephone follow-up [26].

Data analysis

Continuous values are expressed as mean with standard deviation or median with interquartile range (IQR), and categorical values are expressed as number (%). Patients’ characteristics and outcomes were evaluated using the chi-square test for binary variables and the t-test, ANOVA for continuous variables, as appropriate. Multivariable logistic regression analysis was performed to investigate the association be- tween delay per min in call to first EA time (as defined above) and out- comes. Call to first EA time was analyzed as a continuous variable, and the initial rhythms were classified into shockable rhythms and non- shockable rhythms for analysis. Adjusted odds ratios (ORs) for a 1- min delay in call to first EA time and the 95% confidence intervals (CIs) were calculated for each outcome. In sensitivity analysis, to assess the linearity of the association between the timing of first EA and outcomes, we used another model in the multivariable analysis, with the timing of first EA assessed as four categorical variables (by interquartile).

All statistical analyses were performed using the IBM Statistical Package for the Social Sciences version 22.0 (IBM, Corp, Armonk, NY, USA).

Fig. 1. Patient selection. OHCA, Out-of-hospital cardiac arrest; ROSC, Return of spontaneous circulation; EMS, Emergency Medical Service; CPR, Cardiopulmonary resuscitation.

Results

Characteristics of study population

Of the 16,452 patients who experienced OHCA during the study pe- riod, 9344 were eligible for our analyses (Fig. 1); among these, 8626 (92.3%) had non-shockable rhythms and 718 (7.7%) had shockable rhythms. Table 1 shows the baseline characteristics of the eligible pa- tients, with first EA time as a categorical variable that equally partitioned into quarters of the call to first EA time. Among the study population, 1923 (20.7%) had ROSC, 235 (2.5%) survived for 1 month, and 80 (0.9%) had favorable CPC after 1 month. Univariate analysis showed that gender, age, witness, bystander CPR, call to EMS contact time, total amount of administered epinephrine, and etiology of cardiac arrest were significantly associated with the first EA time in overall pa- tients; age, witness, bystander CPR, call to EMS contact time, total amount of administered epinephrine, and etiology of cardiac arrest were signifi- cantly associated with the first EA time in cases of non-shockable rhythm; and the call to EMS contact time and etiology of cardiac arrest was signif- icantly associated with the first EA time in cases of shockable rhythm. The number of patients in whom epinephrine was administered in pre- hospital settings was 2634 (28.2%) in overall, 2313 (26.8%) in non- shockable rhythm, and 321 (44.7%) in shockable rhythm.

Fig. 2 shows the histogram between the number of patients and call to first EA time. The median (IQR) of call to first EA time was 35 (27-43) min, and the minimum and maximum values of call to first EA time were 8 and 60 min. Some previous studies have divided the call to first EA time at the 10-min timepoint [14]; however, our data contained only 17 patients who were administered epinephrine at <=10 min. Hence, we equally partitioned the first EA time into quarters of the call to first EA time: 1-15 min, 16-30 min, 31-45 min, and 46-60 min.

Main results

Table 2 shows the univariable and multivariable analysis for out- comes by type of initial rhythm using the call to first EA time as a contin- uous variable. There was no multicollinearity among the adopted variables in these models. We could not investigate the neurological outcomes by multivariable analysis because of limited numbers of tar- get events. In the univariable analysis, delay in EA was associated with decreased neurological outcome in overall patients and in patient with non-shockable rhythm. However, there was no significant association between the call to first EA time and good neurological outcomes in pa- tients with shockable rhythm. In the multivariable analysis, after adjusting for age, gender, independent ADL, witness, bystander CPR, call to EMS contact time, total amount of administered epinephrine, car- diac etiology, and within-institution clustering using a generalized esti- mating equation, if the epinephrine was administered at a later stage, the chance of ROSC and 1-month survival was decreased only when the initial rhythm was a non-shockable rhythm; whereas, delay in EA was not associated with the decreased both ROSC and 1-month survival when the initial rhythm was a shockable rhythm.

We performed a sensitivity analysis by substituting the call to first EA time as four categorical variables (by interquartile) instead of a con- tinuous variable. In this model, even the ORs in the model for 1-month survival in non-shockable rhythm was not significant, we considered that the decreasing ORs by the interquartile meant the adjusted associ- ation of call to first EA time with outcomes persisted (Appendix 1).

Discussion

Here we showed that delay in EA was associated with decreased ROSC and 1-month survival when the initial rhythm was a non- shockable rhythm. In contrast, delay in EA was not associated with de- creased ROSC and 1-month survival when the initial rhythm was a shockable rhythm. The association between time to first EA and favor- able neurological outcomes was unclear for any initial rhythm. We ad- justed for potential confounding factors that were well-known independent risk factors. Furthermore, we investigated the relation be- tween call to first EA time as a continuous variable in pre- or in-hospital settings and outcomes.

In prehospital settings, some studies have reported prospective ob- servational propensity analysis using the Japanese national registry data [20,23,27,28]. They showed that EA in prehospital settings was as- sociated with increased ROSC, especially in cases of initial non- shockable rhythms [20] and was unassociated [27] or associated with decreased Favorable neurological outcomes [20,23,28]. Two randomized controlled trials reported that the patients in the EA group with an ini- tial non-shockable rhythm were likely to achieve ROSC [9,29,30]; how- ever, they were not likely to be discharged with favorable neurological outcomes [29,30], and patients in the EA group with Initial shockable rhythm were likely [9] or not likely to achieve ROSC and less likely to be discharged with favorable neurological outcomes [29,30]. Two meta-analyses investigated the association between EA before arrival to the hospital and outcomes for OHCA [31,32]. Both meta-analyses showed that EA before arrival to the hospital was associated with a sig- nificantly increased ROSC; however, it was not associated with hospital admission and survival to discharge [31], and it increased poor neuro- logic outcome at the time of discharge [32]. Unfortunately, in these studies, the call to first EA time was not known. The place of administer- ing EA or the person administering it does not matter, but the time does. Two large observational studies reported that early EA (defined as within 10 min) was associated with increased favorable neurologic sur- vival [12,13]. Alternatively, some recent studies have reported that early EA was associated with increased ROSC, but not with favorable neuro- logical outcomes [14,15]. It was reported that the delay in first EA wors- ened the neurological outcomes even in the limited patients who achieved ROSC, after adjusting for hospital interventions [33]. When

Table 1

Baseline characteristics of eligible patients with first epinephrine administration time as four categorical variables, stratified by interquartiles of the total number of included patients for each epinephrine administration time.

Overall Call to first EA? time (min) p

First quarter

Second quarter

Third quarter

Fourth quarter

valueb

1-15 min

16-30 min

31-45 min

46-60 min

Overall, n 9344

257

3059

4323

1705

Gender, male (% [95%CI])

5670 (60.7

158 (61.5

1920 (62.8

2607 (60.3

985 (57.8

0.008

[59.7-61.7])

[55.2-67.5])

[61.0-64.5])

[58.8-61.8])

[55.4-60.1])

Age (mean, 95%CI [SD])

71.2 (70.8-71.5

71.9 (69.6-74.1

71.9 (71.3-72.5

70.9 (70.4-71.4

70.6 (69.9-71.4

0.008

[16.5])

[16.4])

[15.9])

[16.8])

[16.5])

Independent ADLa (% [95%CI])

5679 (74.8

168 (73.0

1899 (76.6

2565 (74.0

1047 (73.7

0.09

[73.8-75.7])

[66.8-78.7])

[74.9-78.2])

[72.5-75.5])

[71.4-76.0])

Witness (% [95%CI])

4502 (48.2

127 (49.4

1695 (55.4

1923 (44.5

757 (44.4

b0.001

[47.2-49.2])

[43.1-55.7])

[53.6-57.2])

[43.1-46.0])

[42.0-46.8])

Bystander CPRa (% [95%CI])

3477 (37.3

124 (48.4

1264 (41.4

1576 (36.6

513 (30.2

b0.001

Call to EMSa contact time, min (mean, 95%CI [SD])

[36.3-38.3])

9.3 (9.3-9.4 [3.7])

[42.2-54.7])

6.8 (6.5-7.0 [1.8])

[39.7-43.2])

8.2 (8.1-8.4 [3.0])

[35.1-38.0])

9.2 (9.1-9.3 [3.3])

[28.0-32.4])

11.7 (11.5-11.9

b0.001

[4.6])

Total amount of administered epinephrine, mg (mean,

4.3 (4.2-4.3 [2.8])

6.1 (5.6-6.6 [3.5])

4.7 (4.6-4.8 [3.0])

4.2 (4.1-4.2 [2.7])

3.8 (3.6-3.9 [2.4])

b0.001

95%CI [SD])

Cardiac etiology (% [95%CI])

4564 (50.2

144 (58.5

1524 (51.5

2029 (48.2

867 (51.9

b0.001

[49.2-51.3])

[52.1-64.8])

[49.7-53.3])

[46.7-49.7])

[49.4-54.3])

Non-shockable rhythm, n 8626

219

2735

4046

1626

Gender, male (% [95%CI])

5090 (59.0

126 (57.5

1653 (60.4

2391 (59.1

920 (56.6

0.09

[58.0-60.0])

[50.7-64.2])

[58.6-62.3])

[57.6-60.6])

[54.1-59.0])

Age (mean, 95%CI [SD])

71.7 (71.3-72.0

72.7 (70.3-75.2

72.6 (72.0-73.2

71.3 (70.8-71.9

71.0 (70.2-71.8

0.001

[16.5])

[16.7])

[15.8])

[16.9])

[16.3])

Independent ADLa (% [95%CI])

5162 (73.5

195 (70.3

1665 (74.8

2373 (73.2

987 (72.9

0.34

[72.5-74.6])

[63.3-76.6])

[72.9-76.6])

[71.6-74.7])

[70.4-75.2])

Witness (% [95%CI])

3967 (46.0

97 (44.3

1453 (53.1

1721 (42.6

696 (42.8

b0.001

[45.0-47.1])

[37.6-51.1])

[51.2-55.0])

[41.1-44.1])

[40.4-45.3])

Bystander CPRa (% [95%CI])

3165 (36.8

112 (51.4

1116 (40.9

1455 (36.1

482 (29.7

b0.001

Call to EMSa contact time, min (mean, 95%CI [SD])

[35.8-37.8])

9.4 (9.3-9.4 [3.7])

[44.5-58.2])

7.0 (6.7-7.3 [1.8])

[39.1-42.8])

8.1 (8.0-8.2 [2.8])

[34.6-37.6])

9.3 (9.2-9.4 [3.3])

[27.5-32.0])

11.7 (11.5-11.9

b0.001

[4.6])

Total amount of administered epinephrine, mg (mean,

4.2 (4.2-4.3 [2.7])

6.2 (5.7-6.7 [3.4])

4.6 (4.5-4.8 [2.9])

4.1 (4.0-4.2 [2.6])

3.7 (3.6-3.8 [2.4])

b0.001

95%CI [SD])

Cardiac etiology (% [95%CI])

3954 (47.2

107 (51.4

1242 (47.0

1803 (45.8

802 (50.3

0.01

[46.1-48.2])

[44.4-58.4])

[45.1-48.9])

[44.2-47.3])

[47.8-52.8])

Shockable rhythm, n 718

38

324

277

79

Gender, male (% [95%CI])

580 (80.8

32 (84.2

267 (82.4

216 (78.0

65 (82.3

0.50

[77.7-83.6])

[68.7-94.0])

[77.8-86.4])

[72.6-82.7])

[72.1-90.0])

Age (mean, 95%CI [SD])

64.7 (63.5-65.8

66.4 (61.1-71.6

65.7 (63.9-67.5

64.2 (62.5-66.0

62.2 (58.5-65.9

0.23

[14.9])

[13.5])

[15.1])

[14.3])

[16.5])

Independent ADLa (% [95%CI])

517 (89.9

31 (88.6

234 (92.5

192 (86.9

60 (90.9

0.24

[87.2-92.3])

[73.3-96.8])

[88.5-95.4])

[81.7-91.0])

[81.3-96.6])

Witness (% [95%CI])

535 (74.5

30 (78.9

242 (74.7

202 (72.9

61 (77.2

0.78

[71.2-77.7])

[62.7-90.4])

[69.6-79.3])

[67.3-78.1])

[66.4-85.9])

Bystander CPRa (% [95%CI])

316 (43.6

12 (31.6

148 (45.8

121 (43.8

31 (39.2

0.32

Call to EMSa contact time, min (mean, 95%CI [SD])

[39.9-47.3])

8.9 (8.6-9.2 [3.9])

[17.5-48.7])

5.6 (5.0-6.1 [1.4])

[40.3-51.4])

8.7 (8.1-9.2 [4.5])

[37.9-49.9])

8.9 (8.5-9.2 [3.2])

[28.4-50.9])

11.0 (10.1-11.8

b0.001

[3.7])

Total amount of administered epinephrine, mg (mean,

5.0 (4.8-5.3 [3.4])

5.6 (4.1-7.1 [3.8])

5.3 (4.9-5.7 [3.2])

4.9 (4.4-5.3 [3.8])

4.5 (4.0-5.1 [2.5])

0.25

95%CI [SD])

Cardiac etiology (% [95%CI])

610 (86.8

37 (97.4

282 (89.5

272 (83.1

65 (83.3

0.02

[84.0-89.2])

[86.2-99.9])

[85.6-92.7])

[78.1-87.3])

[73.2-90.8])

a EA, epinephrine administration; CI, confidence intervals; SD, standard deviation; ADL, activities of daily living; CPR, cardio pulmonary resuscitation; EMS, emergency medical service.

b Analyzed using the chi-square test and the ANOVA.

the first EA time was analyzed as a continuous variable, early EA was as- sociated with increased survival to hospital discharge and it was rapidly decreased with the increasing EA time delays [16,17]. The first EA time had no significant effect on the favorable neurological outcome [16], or was associated with the favorable neurological outcomes [17]. However, these studies investigated the association between first EA time and outcomes without classified into initial rhythms and without adjusting factors after hospitalization. When OHCA pa- tients were limited with initial non-shockable rhythm, one large study showed that each minute from EMS arrival to EA was associ- ated with decreasing in odds of survival to discharge [34]. Our results of patients with initial non-shockable rhythm were very similar with this study. However, this study excluded patients with initial

shockable rhythm, and did not include patients administered first epinephrine after arrival at hospital. To the best of our knowledge, our study is the first study to evaluate the association between the call to first EA time and outcomes for OHCA combined both pre- and in-hospital settings.

While assessing the effectiveness of the timing of EA for OHCA, we should consider the time-limited effects of epinephrine and the patho- physiology of OHCA. Prehospital EA delays hospital arrival [23]. It causes delayed in-hospital care, such as the administration of Antiarrhythmic drugs, percutaneous coronary intervention, and target temperature management (TTM). Alternatively, early EA might result in a chance of early ROSC and early in-hospital care for Post-cardiac arrest syndrome especially when the initial rhythm is non-shockable. Some studies have

Fig. 2. Histogram for the number of patients by call to first epinephrine administration time. EA, Epinephrine administration.

shown that early EA is associated with increased favorable neurological outcomes in limited situations [22,35].

Limitations

Our study has some inherent limitations. First, it represents only the Kanto region, which may affect the generalizability of the find- ings; however, the overall survival rates and patients’ characteristics were similar to the findings of the Japanese population-based re- ports that used prehospital data [36]. Second, we excluded 4227 pa- tients because of outlier or missing or unknown data. This number consisted nearly 1/4 of the study group. These might cause selection bias. ROSC in these excluded patients was worse than study patients; however, 1-month survival and 1-month neurological outcome were better than study patients (Appendix 2). Third, the median time from the call to first EA time was longer than that reported in other studies [37]. This might worsen the effectiveness of epinephrine in OHCA. In Japan, medical direction teams permit ELSTs to administer epinephrine under the online direct medical direction [22], and they have to obtain patient’s family consent, prepare intravenous equip- ment on site and establish an intravenous line before EA. These might affect delaying EA. Furthermore, our study includes the data of the call to first EA time for not only pre-hospital but also in- hospital settings. This system also might be responsible for extend- ing the time from call to first EA. However, our study demonstrated that early EA increased the chance of ROSC, even extending the time from call to first EA. The association between early EA and

neurological outcomes might not have been demonstrated because of the extension of the time from call to first EA. Fourth, there would be still the residual confounders on our results and we could not perform time dependent matching because of the limited study sample size. Finally, we could not compare the effect of epinephrine in this study; however, patients who responded to initial defibrilla- tion shock and who did not need epinephrine for ROSC will have a better prognosis than those who do not respond to initial defibrilla- tion and therefore who need epinephrine for ROSC [38]. This prob- lem makes it difficult to investigate the effect of epinephrine in OHCA and may denigrate it. Accordingly, we included only patients who were administered epinephrine to investigate the effectiveness of the timing of EA for OHCA limitedly and after excluding the above problem.

Conclusions

We conclude from our results that delay in EA can decrease the chance of ROSC and 1-month survival only when the initial rhythm was a non-shockable rhythm; however, we cannot demonstrate the association between early EA and neurological outcomes. The effect of early EA on neurological outcomes needs to be examined accord- ing to the pathophysiology (e.g., initially shockable rhythm vs. non- shockable rhythm) and time-effectiveness. We should consider a flexible protocol for early EA such as changing the priority and adding time restriction by initial rhythm.

Conflict of interest

All authors report no conflict of interest.

Financial support

No grant or other financial support.

Presentation

I presented this study at AHA ReSS 2015, Orlando, FL, USA.

Acknowledgments

This study was supported by Japanese Association for Acute Med- icine of Kanto. The funder had no role in the execution of this study or interpretation of the results. All members that participated in the current study are members of Japanese Association for Acute Medicine of Kanto. The members of the steering council and partici- pating institutions of SOS-KANTO 2012 Study Group are listed in the Appendix 3.

Table 2

Multivariable analysis for outcomes stratified by type of initial rhythm.

OR (95%CIa) for one minute delay

Overall

Non-shockable rhythm

Shockable rhythm

ROSCa

unadjusted

adjustedb

0.97 (0.96-0.97)

0.97 (0.96-0.98)

0.97 (0.97-0.98)

0.97 (0.96-0.98)

0.98 (0.96-0.99)

0.99 (0.98-1.02)

1-month survival

unadjusted adjustedb

1-month CPCa 1 or 2

0.94 (0.93-0.96)

0.98 (0.95-0.99)

0.93 (0.92-0.95)

0.95 (0.92-0.97)

0.99 (0.97-1.01)

1.02 (0.99-1.04)

unadjusted

0.96 (0.94-0.98)

0.96 (0.93-0.99)

0.99 (0.96-1.01)

adjustedb

a EA, epinephrine administration; ROSC, return of spontaneous circulation; CPC, cerebral performance category; CI, confidence interval.

b Adjusted for age, gender, independent ADL, witness, bystander CPR, initial rhythms (using when analyzed in overall patients), call to EMS contact time, total amount of administered epinephrine, cardiac etiology and within-institution clustering using a generalized estimating equation.

Appendix 1. Sensitivity analysis performed by substituting call to first epinephrine administration time as four categorical variables by interquartiles of the total number of included patients for each EA time

Call to first EAa time (min) OR (95%CIa) using first quarter as referenceb

First quarter

Second quarter

Third quarter

Fourth quarter

1-15 min

16-30 min

31-45 min

46-60 min

ROSCa

Overall

Unadjusted

Adjustedb

Reference

Reference

0.87 (0.66-1.15)

0.77 (0.51-1.17)

0.55 (0.42-0.73)

0.55 (0.36-0.84)

0.38 (0.28-0.51)

0.38 (0.25-0.60)

Non-shockable rhythm

Unadjusted

Adjustedb

Reference

Reference

0.90 (0.66-1.23)

0.71 (0.44-1.13)

0.58 (0.42-0.79)

0.48 (0.03-0.76)

0.41 (0.29-0.57)

0.32 (0.20-0.52)

Shockable rhythm

Unadjusted

Adjustedb

Reference

Reference

0.92 (0.47-1.81)

1.04 (0.41-2.63)

0.76 (0.38-1.51)

1.21 (0.48-3.05)

0.51 (0.23-1.13)

0,85 (0.29-2.47)

1-month survival

Overall

Unadjusted

Reference

0.56 (0.33-0.93)

0.24 (0.14-0.40)

0.13 (0.07-0.26)

Adjustedb

Reference

3.23 (0.90-11.57)

1.72 (0.48-6.21)

1.45 (0.37-5.69)

Non-shockable rhythm

Unadjusted

Adjustedb

Reference

Reference

0.41 (0.22-0.75)

1.01 (0.23-4.39)

0.16 (0.09-0.31)

0.46 (0.10-2.02)

0.07 (0.03-0.17)

0.23 (0.04-1.16)

Shockable rhythm

1-month CPCa 1,2

Unadjusted Adjustedb

Reference Reference

1.38 (0.51-3.68)

7.19 (0.89-58.33)

0.94 (0.34-2.56)

5.64 (0.69-46.06)

0.97 (0.31-3.07)

8.87 (0.97-81.34)

Overall

Unadjusted

Adjustedb

Reference

Reference

0.57 (0.24-1.35)

1.41 (0.30-6.61)

0.23 (0.09-0.57)

0.84 (0.18-3.99)

0.22 (0.08-0.62)

0.99 (0.18-5.23)

Non-shockable rhythm

Unadjusted

Adjustedb

Reference

Reference

0.39 (0.11-1.37)

0.52 (0.06-4.47)

0.16 (0.04-0.59)

0.15 (0.02-1.40)

0.17 (0.04-0.79)

0.18 (0.02-1.86)

Shockable rhythm

Unadjusted Adjustedb

Reference Reference

1.04 (0.30-3.61)

2.34 (0.28-19.81)

0.68 (0.19-2.47)

2.16 (0.25-18.47)

0.80 (0.18-3.54)

2.76 (0.27-28.54)

a EA, epinephrine administration; ROSC, return of spontaneous circulation; CPC, cerebral performance category; CI, confidence interval.

b Adjusted for age, gender, independent ADL, witness, bystander CPR, initial rhythms (using when analyzed in overall patients), call to EMS contact time, total amount of administered epinephrine, cardiac etiology and within-institution clustering using a generalized estimating equation.

Appendix 2. Outcomes between exclude and include patients

Exclude

Include

p-Valueb

n

4227

9344

ROSCa (% [95%CIa])

805 (19.4 [18.2-20.7])

1923 (20.7 [19.8-21.5])

0.11

1-month survival (% [95%CIa])

143 (3.4 [2.9-4.0])

235 (2.5 [2.2-2.9])

0.003

1-month CPCa 1,2 (% [95%CIa])

77 (1.9 [1.5-2.3])

80 (0.9 [0.7-1.1])

b0.001

a ROSC, return of spontaneous circulation; CPC, cerebral performance category; CI, confidence interval.

b Analyzed using the chi-square test.

Appendix 3. SOS-KANTO 2012 Study Group

SOS-KANTO 2012 Steering Council

Yokohama City University Medical Center, Kanagawa (President, Naoto Morimura MD); Nihon University School of Medicine, Tokyo (Director, Atsushi Sakurai MD); National Cerebral and Cardiovascular Center Hospital, Osaka (Director, Yoshio Tahara MD); Tokyo Women’s Medical university hospital, Tokyo (Arino Yaguchi MD); Nihon University Surugadai Hospital, Tokyo (Ken Nagao MD); Nippon Medical School Hospital, Tokyo (Tagami Takashi MD); Japanese Red Cross Maebashi Hospital, Gunma (Dai Miyazaki MD); National Disaster Medical Center, Tokyo (Tomoko Ogasawara MD); Keio University Hospital, Tokyo (Kei Hayashida MD, Masaru Suzuki MD);Tokai University School of Medicine, Kanagawa (Mari Amino MD); Kimitsu Chuo Hospital, Chiba (Nobuya Kitamura MD); Juntendo University Nerima Hospital,Tokyo (Tomohisa Nomura MD); Tokyo Metropolitan Children’s Medical Centre, Tokyo (Naoki Shimizu MD); Tokyo Metropolitan Bokutoh Hospital, Tokyo (Akiko Akashi MD), National Center of Neurology and Psy- chiatry, Tokyo, Japan (NaohiroYonemoto DPH).

SOS-KANTO 2012 Study Group

Tokai University School of Medicine (Sadaki Inokuchi MD); St. Marianna University School of Medicine, Yokohama Seibu Hospital (Yoshihiro Masui MD); Koto Hospital (Kunihisa Miura MD); Saitama Medical Center Advanced Tertiary medical center (Haruhiko Tsutsumi MD); Kawasaki Mu- nicipal Hospital Emergency and Critical Care Center (Kiyotsugu Takuma MD); Yokohama Municipal Citizen’s Hospital (Ishihara Atsushi MD); Japanese Red Cross Maebashi Hospital (Minoru Nakano MD); Juntendo University Urayasu Hospital (Hiroshi Tanaka MD); Dokkyo Medical Univer- sity Koshigaya Hospital (Keiichi Ikegami MD); Hachioji Medical Center of Tokyo Medical University (Takao Arai MD); Tokyo Women’s Medical Uni- versity Hospital (Arino Yaguchi MD); Kimitsu Chuo Hospital (Nobuya Kitamura MD); Chiba University Graduate School of Medicine (Shigeto Oda MD); Saiseikai Utsunomiya Hospital (Kenji Kobayashi MD); Mito Saiseikai General Hospital (Takayuki Suda MD); Dokkyo Medical University (Kazuyuki Ono MD); Yokohama City University Medical Center (Naoto Morimura MD); National Hospital Organization Yokohama Medical Center (Ryosuke Furuya MD); National Disaster Medical Center (Yuichi Koido MD); Yamanashi Prefectural Central Hospital (Fumiaki Iwase MD); Surugadai Nihon University Hospital (Ken Nagao MD); Yokohama Rosai Hospital (Shigeru Kanesaka MD); Showa General Hospital (Yasusei Okada MD); Nippon

Medical School Tamanagayama Hospital (Kyoko Unemoto MD); Tokyo Women’s Medical University Yachiyo Medical Center (Tomohito Sadahiro MD); Awa Regional Medical Center (Masayuki Iyanaga MD); Todachuo General Hospital (Asaki Muraoka MD); Japanese Red Cross Medical Center (Munehiro Hayashi MD); St. Luke’s International Hospital (Shinichi Ishimatsu MD); Showa University School of Medicine (Yasufumi Miyake MD); Totsuka Kyoritsu Hospital (Hideo Yokokawa MD); St. Marianna University School of Medicine (Yasuaki Koyama MD); National Hospital Organization Mito Medical Center (Asuka Tsuchiya MD); Tokyo Metropolitan Tama Medical Center (Tetsuya Kashiyama MD); Showa University Fujigaoka Hospital (Munetaka Hayashi MD); Gunma University Graduate School of Medicine (Kiyohiro Oshima MD); Saitama Red Cross Hospital (Kazuya Kiyota MD); Tokyo Metropolitan Bokutoh Hospital (Yuichi Hamabe MD); Nippon Medical School Hospital (Hiroyuki Yokota MD); Keio University Hospital (Shingo Hori MD); Chiba emergency medical center (Shin Inaba MD); Teikyo University School of Medicine (Tetsuya Sakamoto MD); Japanese Red Cross Musashino Hospital (Naoshige Harada MD); National Center for Global Health and Medicine Hospital (Akio Kimura MD); Tokyo Metropol- itan Police Hospital (Masayuki Kanai MD); Medical Hospital of Tokyo Medical and Dental University (Yasuhiro Otomo MD); Juntendo University Nerima Hospital (Manabu Sugita MD); Nihon University School of Medicine (Kosaku Kinoshita MD); Toho University Ohashi Medical Center (Takatoshi Sakurai MD); Saiseikai Yokohamashi Tobu Hospital (Mitsuhide Kitano MD); Nippon Medical School Musashikosugi Hospital (Kiyoshi Matsuda MD); Tokyo Rosai Hospital (Kotaro Tanaka MD); Toho University Omori Medical Center (Katsunori Yoshihara MD); Hiratsuka City Hospital (Kikuo Yoh MD); Yokosuka Kyosai Hospital (Junichi Suzuki MD); Saiseikai Yokohamashi Nambu Hospital (Hiroshi Toyoda MD); Nippon Medical School Chiba Hokusoh Hospital (Kunihiro Mashiko MD); Tokyo Metropolitan Children’s Medical Centre (Naoki Shimizu MD); National Medical Cen- ter for Children and Mothers (Takashi Muguruma MD); Chiba Aoba Municipal Hospital (Tadanaga Shimada MD); Kuki General Hospital (Yoshiro Kobe MD); Matsudo City Hospital (Tomohisa Shoko MD); Japanese Red Cross Narita Hospital (Kazuya Nakanishi MD); Tokyo Bay Urayasu/Ichikawa Medical Center (Takashi Shiga MD); NTT Medical Center Tokyo (Takefumi Yamamoto MD); Tokyo Saiseikai Central Hospital (Kazuhiko Sekine MD); Fuji Heavy Industries Health Insurance Society OTA Memorial Hopital (Shinichi Izuka MD). (http://www.jaamkanto.jp/sos_kanto/sos_kanto2012_ contributors.html).

References

  1. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 2008;300 (12):1423-31.
  2. Atwood C, Eisenberg MS, Herlitz J, Rea TD. Incidence of EMS-treated out-of-hospital cardiac arrest in Europe. Resuscitation 2005;67(1):75-80.
  3. Changes in treatments and outcomes among elderly patients with out-of-hospital cardiac arrest between 2002 and 2012: a post hoc analysis of the SOS-KANTO 2002 and 2012. Resuscitation 2015, 97:76-82.
  4. Standards for cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC) 3 Advanced life support, Jama 1974;227(7):852-60.
  5. JRC resuscitation guideline. Chaper2. ALS JRC resuscitation guideline 2015 online version. http://www.japanresuscitationcouncil.org/wp-content/uploads/2016/04/ 0e5445d84c8c2a31aaa17db0a9c67b76.pdf.
  6. Soar J, Nolan JP, Bottiger BW, Perkins GD, Lott C, Carli P, et al. European resuscitation council guidelines for resuscitation 2015: section 3. Adult advanced life support. Re- suscitation 2015;95:100-47.
  7. Link MS, Berkow LC, Kudenchuk PJ, Halperin HR, Hess EP, Moitra VK, et al. Part 7: adult advanced cardiovascular life support: 2015 American Heart Association guide- lines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015;132(18 Suppl 2):S444-64.
  8. Link MS, Atkins DL, Passman RS, Halperin HR, Samson RA, White RD, et al. Part 6: electrical therapies: automated external defibrillators, defibrillation, cardioversion, and pacing: 2010 American Heart Association guidelines for cardiopulmonary resus- citation and emergency cardiovascular care. Circulation 2010;122(18 Suppl 3): S706-19.
  9. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial. Resuscitation 2011;82(9):1138-43.
  10. Callaway CW. Questioning the use of epinephrine to treat cardiac arrest. JAMA 2012;

    307(11):1198-200.

    Perkins GD, Cottrell P, Gates S. Is adrenaline safe and effective as a treatment for out of hospital cardiac arrest? BMJ 2014;348:g2435.

  11. Nakahara S, Tomio J, Nishida M, Morimura N, Ichikawa M, Sakamoto T. Association between timing of epinephrine administration and intact neurologic survival follow- ing out-of-hospital cardiac arrest in Japan: a population-based prospective observa- tional study. Acad Emerg Med 2012;19(7):782-92.
  12. 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(7):1639-45.
  13. Cantrell Jr CL, Hubble MW, Richards ME. Impact of delayed and infrequent adminis- tration of vasopressors on return of spontaneous circulation during out-of-hospital cardiac arrest. Prehosp Emerg Care 2013;17(1):15-22.
  14. Koscik C, Pinawin A, Mcgovern H, Allen D, Media DE, Ferguson T, et al. Rapid epi- nephrine administration improves early outcomes in out-of-hospital cardiac arrest. Resuscitation 2013;84(7):915-20.
  15. Ewy GA, Bobrow BJ, Chikani V, Sanders AB, Otto CW, Spaite DW, et al. The time de- pendent association of adrenaline administration and survival from out-of-hospital cardiac arrest. Resuscitation 2015;96:180-5.
  16. Hubble MW, Tyson C. Impact of early vasopressor administration on neurological out- comes after prolonged out-of-hospital cardiac arrest. Prehosp Disaster Med 2017:1-8.
  17. Group S-KS. Changes in pre- and in-hospital management and outcomes for out-of- hospital cardiac arrest between 2002 and 2012 in Kanto, Japan: the SOS-KANTO 2012 Study. Acute Med Surg 2015;2(4):225-33.
  18. STROBE statement–checklist of items that should be included in reports of observa- tional studies (STROBE initiative), Int J Public Health 2008;53(1):3-4.
  19. Goto Y, Maeda T, Goto Y. Effects of prehospital epinephrine during out-of-hospital cardiac arrest with initial non-shockable rhythm: an observational cohort study. Crit Care 2013;17(5):R188.
  20. Kitamura T, Iwami T, Kawamura T, Nagao K, Tanaka H, Berg RA, et al. Time- dependent effectiveness of chest compression-only and conventional cardiopulmo- nary resuscitation for out-of-hospital cardiac arrest of Cardiac origin. Resuscitation 2011;82(1):3-9.
  21. Tanaka H, Takyu H, Sagisaka R, Ueta H, Shirakawa T, Kinoshi T, et al. Favorable neu- rological outcomes by early epinephrine administration within 19 minutes after EMS call for out-of-hospital cardiac arrest patients. Am J Emerg Med 2016;34(12): 2284-90.
  22. Fukuda T, Ohashi-Fukuda N, Matsubara T, Gunshin M, Kondo Y, Yahagi N. Effect of prehospital epinephrine on out-of-hospital cardiac arrest: a report from the national out-of-hospital cardiac arrest data registry in Japan, 2011-2012. Eur J Clin Pharmacol 2016;72(10):1255-64.
  23. 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(2):960-75.
  24. 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(21):3385-97.
  25. Hayashida K, Suzuki M, Yonemoto N, Hori S, Tamura T, Sakurai A, et al. Early lactate clearance is associated with improved outcomes in patients with postcardiac arrest syndrome: a prospective, Multicenter observational study (SOS-KANTO 2012 study). Crit Care Med 2017;45(6):e559-66.
  26. 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.
  27. 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(11):1161-8.
  28. Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA 2009; 302(20):2222-9.
  29. Olasveengen TM, Wik L, Sunde K, Steen PA. Outcome when adrenaline (epineph- rine) was actually given vs. not given – post hoc analysis of a randomized clinical trial. Resuscitation 2012;83(3):327-32.
  30. Atiksawedparit P, Rattanasiri S, Mcevoy M, Graham CA, Sittichanbuncha Y, Thakkinstian A. Effects of prehospital adrenaline administration on out-of-hospital Cardiac arrest outcomes: a systematic review and meta-analysis. Crit Care 2014;18 (4):463.
  31. Loomba RS, Nijhawan K, Aggarwal S, Arora RR. Increased return of spontaneous circulation at the expense of neurologic outcomes: is prehospital epinephrine for out-of-hospital cardiac arrest really worth it? J Crit Care 2015;30(6): 1376-81.
  32. Dumas F, Bougouin W, Geri G, Lamhaut L, Bougle A, Daviaud F, et al. Is epinephrine during cardiac arrest associated with worse outcomes in resuscitated patients? J Am Coll Cardiol 2014;64(22):2360-7.
  33. Hansen M, Schmicker RH, Newgard CD, Grunau B, Scheuermeyer F, Cheskes S, et al. Time to epinephrine administration and survival from non-shockable out-of- hospital cardiac arrest among children and adults. Circulation 2018;137(19): 2032-40.
  34. Ueta H, Tanaka H, Tanaka S, Sagisaka R, Takyu H. Quick epinephrine administration induces favorable neurological outcomes in out-of-hospital cardiac arrest patients. Am J Emerg Med 2017;35(5):676-80.
  35. Kitamura T, Iwami T, Kawamura T, Nitta M, Nagao K, Nonogi H, et al. Nationwide im- provements in survival from out-of-hospital cardiac arrest in Japan. Circulation 2012;126(24):2834-43.
  36. Rittenberger JC, Bost JE, Menegazzi JJ. Time to give the first medication during resus- citation in out-of-hospital cardiac arrest. Resuscitation 2006;70(2):201-6.
  37. Ewy GA. The time-sensitive role of vasopressors during resuscitation of ventricular

    fibrillation. J Am Coll Cardiol 2014;64(22):2368-70.

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