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Predictors of favorable and poor prognosis in unwitnessed out-of-hospital cardiac arrest with a non-shockable initial rhythm
International Journal of Cardiology 176 (2014) 910–915
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Predictors of favorable and poor prognosis in unwitnessed out-of-hospital cardiac arrest with a non-shockable initial rhythm Tatsuma Fukuda ⁎, Takehiro Matsubara, Kent Doi, Naoko Fukuda-Ohashi, Naoki Yahagi Department of Emergency and Critical Care Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
a r t i c l e
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Article history: Received 17 May 2014 Received in revised form 5 August 2014 Accepted 9 August 2014 Available online 17 August 2014 Keywords: Out-of-hospital cardiac arrest Medical futility Prognosis
a b s t r a c t Background: Unwitnessed OHCA patients with non-shockable initial rhythms account for nearly half of all OHCA patients, and their prognosis is extremely poor. To date, no studies have focused on these patients. This study aimed to investigating the predictors of favorable and poor prognosis in these patients. Methods: We conducted a nationwide, population-based, observational study of data from the All Japan Utstein Registry, which included 121,081 adult OHCA patients subjected to resuscitation attempts from January 1, 2010 to December 31, 2010. The primary endpoint was favorable neurological outcome one month after OHCA. Results: Of the eligible 120,721 patients, 68,024 (56.3%) were unwitnessed OHCA patients with nonshockable initial rhythms. A younger age (18–64 years: as a reference; 65–84 years: OR 0.68, 95% CI 0.54–0.87, p = 0.0019; ≥ 85 years: OR 0.46, 95% CI 0.33–0.63, p b 0.0001), conversion to shockable rhythm (OR 2.14, 95% CI 1.43–3.13, p = 0.0003), and pre-hospital ROSC (OR 94.85, 95% CI 75.71–119.35, p b 0.0001) were independently associated with a favorable neurological outcome. Favorable neurological outcome rate was 28.8% in unwitnessed OHCA patients with non-shockable initial rhythms with all three favorable predictors, and 0.18% in patients without any of the three predictors (OR 230.34, 95% CI 127.37–402.96, P b 0.0001). Conclusions: It may be worthwhile to provide maximum lifesaving medical resources for patients with all of the favorable predictors (b65 years, conversion to shockable rhythm, and pre-hospital ROSC); however, continued resuscitation efforts for patients without these predictors should likely be restrained. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Out-of-hospital cardiac arrest (OHCA), a condition with one of the poorest prognoses, is experienced by 125,000, 275,000, and 375,000 individuals annually in Japan, Europe, and the USA, respectively [1–4]. Although the rate of survival after OHCA has increased along with advances in care throughout the “chain of survival,” it remains low [5,6]. The prognosis is especially poor in cases of unwitnessed OHCA with non-shockable initial rhythms [2,7,8]. In fact, a lack of witnesses and a non-shockable rhythm are the main criteria in the pre-hospital termination of resuscitation (TOR) rule [9–14]. Unwitnessed OHCA patients with non-shockable initial rhythms account for nearly half of all OHCA patients, and their prognosis is extremely poor [1,2,7,8]; therefore,
Abbreviations: OHCA, out-of-hospital cardiac arrest; TOR, termination of resuscitation; FDMA, Fire and Disaster Management Agency; EMS, emergency medical service; AED, automated external defibrillator; CPR, cardiopulmonary resuscitation; AHA, American Heart Association; ILCOR, International Liaison Committee on Resuscitation; ROSC, return of spontaneous circulation; CPC, Glasgow–Pittsburgh cerebral performance category; ANOVA, analysis of variance; OR, odds ratio; CI, confidence interval; SD, standard deviation; ADL, activity of daily living. ⁎ Corresponding author. Tel.: +81 3 3815 5411; fax: +81 3 3814 6446. E-mail address: [email protected] (T. Fukuda).
http://dx.doi.org/10.1016/j.ijcard.2014.08.057 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
these patients are considered suitable candidates for TOR. On the other hand, it is extremely important to identify the factors that contribute to a favorable prognosis in such cases because there are a limited number of patients who will be discharged with a favorable outcome in these many cases. To date, no studies have focused on a large sample of unwitnessed OHCA patients with non-shockable initial rhythms. This study aimed to investigating the predictors of both favorable and poor prognosis in unwitnessed OHCA patients with nonshockable initial rhythms. 2. Methods 2.1. Study design and participants We conducted a population-based cohort study of data from the All-Japan Utstein Registry of the Fire and Disaster Management Agency (FDMA), a prospective, nationwide, population-based registry system of all OHCA patients maintained via Utstein-style data collection [15]. All adults aged ≥18 years who suffered from OHCA and for whom resuscitation was attempted by emergency medical service (EMS) personnel with subsequent transport to emergency hospitals from January 1 to December 31, 2010 were enrolled in this study. Patients whose data and information regarding the onset time, call receipt time, hospital arrival time, airway management status, or the public access automated external defibrillator (AED) usage status were missing or unknown were excluded from the analysis.
T. Fukuda et al. / International Journal of Cardiology 176 (2014) 910–915 This study was conducted in accordance with the amended Declaration of Helsinki. The FDMA and the Institutional Review Board of The University of Tokyo approved this study with a waiver of informed consent because of the anonymous nature of the data.
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All statistical analyses were performed using JMP Pro 10.0.2 software (SAS institute Inc., Cary, NC, USA). All tests were two-tailed, and P values of b 0.05 were considered statistically significant.
2.2. Study setting Japan comprises an area of approximately 378,000 km2 with 47 prefectures, and the population of Japan in 2010 was approximately 128 million, with approximately 107 million people aged ≥18 years [16]. The EMS system in Japan has been described previously [2,17–19]. In 2010, EMSs were provided by municipal governments via 802 fire stations with dispatch centers [20]. An ambulance team usually comprises three EMS personnel, including at least one professionally trained emergency lifesaving technician. Some emergency lifesaving technicians are authorized to secure infusion lines, administer epinephrine, perform endotracheal intubation and defibrillation, and lead cardiopulmonary resuscitation (CPR). CPR is performed in conformity with the Japanese CPR guidelines, which are based on the guidelines stipulated by the American Heart Association (AHA) and the International Liaison Committee on Resuscitation (ILCOR) [21–23]. EMS personnel are not allowed to terminate resuscitation out of hospital except in specific situations such as decapitation, rigor mortis, livor mortis, or decomposition; advance directives, living wills, or do-not-attempt-resuscitation orders are not generally accepted in Japan [21,24]. Therefore, nearly all OHCA patients treated by EMS personnel are transported to an emergency hospital [25]. 2.3. Data collection and quality control The data were collected prospectively using Utstein-style templates and included information regarding the sex, age, bystander witness status, bystander CPR status, etiology of arrest, initial cardiac rhythm, public-access AED usage, defibrillation by EMS, presence of an emergency lifesaving technician or physician in the ambulance, administration of epinephrine, and type of airway management. The definitions of terms related to OHCA care such as cardiac arrest, bystander CPR, or etiology of arrest conformed to those in the ILCOR statement [15]. A series of EMS times, including the call receipt, vehicle arrival at the scene, contact with the patient, initiation of CPR, departure from the scene, and hospital arrival, were also recorded according to the clock used by each EMS system. The outcome data included the return of spontaneous circulation (ROSC) prior to hospital arrival, 1-month survival, and neurological status at one month after OHCA. The 1month follow-up data were collected by the EMS personnel in charge of each patient with OHCA. The EMS queried the medical control director at the hospital and received a written response, including reconfirmation of the etiology of the arrest. If the patient was not at the hospital, the EMS personnel conducted a follow-up investigation. The data forms were completed by the EMS personnel in charge of the patients, and the data were integrated into the Utstein registry system on the FDMA database server. FDMA logically evaluated the data using the computer system and returned the data forms to the respective fire stations for reconfirmation unless the data were complete. 2.4. Study endpoints The primary endpoint was a favorable neurological outcome at 1 month after OHCA, defined a priori as a Glasgow–Pittsburgh cerebral performance score category (CPC) of 1 or 2 (good performance or moderate disability, respectively). A CPC of 3, 4, or 5 (severe disability, vegetative state, or death, respectively) was regarded as an unfavorable neurological outcome [15]. The secondary endpoint was the 1-month survival. 2.5. Statistical analysis The total sample size in this nationwide, population-based study was determined according to the number of patients registered in the All-Japan Utstein Registry database in 2010. Continuous and categorical variables were assessed using an analysis of variance (ANOVA) and χ 2 test, respectively. A multivariate logistic regression analysis was performed to examine the contribution of each predictor to one-month survival and a favorable neurological outcome. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated after adjusting for potential confounding factors such as sex, age (18–64, 65–84, ≥ 85 years), bystander CPR status, etiology of arrest, conversion to shockable rhythm, epinephrine administration, advanced airway management, time from call to hospital arrival (b15, 15–29, ≥ 30 min), and pre-hospital ROSC. Despite having a non-shockable initial rhythm, patients for whom more than one defibrillation was performed prior to arrival at the hospital were regarded as patients with conversion to shockable rhythm. We divided the patients into the following four groups based on the multivariate logistic regression analysis results: (Group A) patients who were b65 years of age, converted to shockable rhythm, and had pre-hospital ROSC; (Group B) patients who did not qualify for Group A but had pre-hospital ROSC; (Group C) patients who were below the age of 65 or converted to shockable rhythm but did not qualify for Group A or B; and (Group D) patients who did not qualify for Group A, B, or C. We compared the outcomes between the four groups. The ORs and 95% CIs for favorable outcomes were calculated for each group versus group D, which served as the reference group.
3. Results A total of 123,095 OHCA patients were documented during the study period. Of the 121,081 adult OHCA patients subjected to resuscitation attempts, the following were excluded: 6 with an unknown time of onset, call receipt, or hospital arrival; 317 with an unknown airway management status; and 37 with an unknown public access AED usage status (Fig. 1). Of the remaining 120,721 patients, 68,024 (56.3%; 95% CI, 56.1–56.6%) were unwitnessed OHCA patients with non-shockable initial rhythms, 44,218 (36.6%; 95% CI, 36.4–36.9%) were witnessed OHCA patients with non-shockable initial rhythms, 2266 (1.9%; 95% CI, 1.8–2.0%) were unwitnessed OHCA with shockable initial rhythms, and 6213 (5.1%; 95% CI, 5.0–5.3%) were witnessed OHCA patients with shockable initial rhythms. Table 1 lists the baseline demographic characteristics and outcomes for the adult OHCA patients in each group according to the witness status and initial cardiac rhythm. The overall mean age was 74.1 years, and the proportion of male patients was 57.5%. Compared to the patients with shockable initial rhythms, patients with non-shockable initial rhythms were older, and the proportions of male and cardiac etiology were lower. Regarding pre-hospital care, there was a tendency to administer epinephrine primarily to patients with shockable initial rhythms, whereas advanced airway management was implemented primarily in unwitnessed patients. The prognoses were more favorable for patients with shockable initial rhythms and for witnessed patients, and the 1-month survival and favorable neurological outcome rates were approximately 15-fold and 35-fold higher, respectively, in patients with witnessed OHCA and shockable initial rhythms relative to those with unwitnessed OHCA and non-shockable initial rhythms. Table 2 lists the results of a multivariate logistic regression analysis for favorable outcomes in unwitnessed OHCA with a non-shockable initial rhythm. A younger age, conversion to shockable rhythm, and pre-hospital ROSC were independently associated with an improved outcome. In contrast, pre-hospital epinephrine administration and advanced airway management implementation were associated with a poor outcome. Cardiac etiology was associated with a poor 1-month survival and, conversely, a favorable neurological outcome. Table 3 lists the outcomes in each of the four groups according to the factors of age, conversion to shockable rhythm, and pre-hospital ROSC. Pre-hospital ROSC achievement (Groups A and B) correlated closely with a favorable prognosis. Even without pre-hospital ROSC, the prognosis was significantly favorable if patients were either b65 years of age or converted to a shockable rhythm (Group C) when compared with patients aged N 65 years who did not convert to a shockable rhythm (Group D). In patients who were b65 years of age, converted to a shockable rhythm, and achieved pre-hospital ROSC (Group A), the 1-month survival rate was 40.9% and the favorable neurological outcome rate was 28.8%; compared with patients lacking all of these predictors (Group D), the OR for 1-month survival was 75.70 (95% CI, 45.41–124.16; P b 0.0001) and the OR for a favorable neurological outcome was 230.34 (95% CI, 127.37–402.96; P b 0.0001).
4. Discussion In this large, nationwide, population-based cohort study of patients with OHCA, we identified the factors that affected both favorable and poor prognoses in unwitnessed OHCA patients with non-shockable initial rhythms. The prognosis of patients with all favorable predictors (Group A), specifically an age b 65 years, conversion to a shockable rhythm, and achievement of pre-hospital ROSC, was extremely favorable, whereas
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T. Fukuda et al. / International Journal of Cardiology 176 (2014) 910–915
123,095 OHCA in Japan from January 1, 2010 to December 31, 2010
1,784 Excluded (Age < 18 years)
230 Excluded (No resuscitation attempted)
121,081 Adult OHCA with resuscitation attempted
360 Excluded 6 Time related to occurrence, call receipt, or hospital arrival unknown 317 Airway management status unknown 37 Usage of public access AED unknown
120,721 Eligible for analysis
68,024 Unwitnessed with non-shockable initial rhythm
44,218 Witnessed with non-shockable initial rhythm
2,266 Unwitnessed with shockable initial rhythm
6,213 Witnessed with shockable initial rhythm
Fig. 1. Study profile. Abbreviations: OHCA, Out-of-hospital cardiac arrest; AED, Automated external defibrillator.
the prognosis of patients without any of these predictors (Group D) was extremely poor. Research targeting witnessed OHCA with a shockable initial rhythm has increased because many previous studies found the prognosis of unwitnessed OHCA with a non-shockable initial rhythm to be poor [2, 7,8]; however, no large-scale studies have focused on unwitnessed OHCA with a non-shockable initial rhythm. Therefore, the significance of this study is very high. In the future, the findings of this study might facilitate the selection of treatment strategies based on a more detailed prognostic prediction for unwitnessed OHCA with a non-shockable initial rhythm. In other words, among unwitnessed OHCA patients with a non-shockable initial rhythm, maximum efforts should be made to resuscitate those with all favorable predictors (Group A, b65 years of age with a conversion to shockable rhythm and pre-hospital ROSC) by providing as many medical resources as possible. In contrast, continued efforts to resuscitate patients without any of these predictors (Group D) should be restrained. In this study, the 1-month survival rate of Group A was 40.9% (95% CI, 29.9–53.0%), and the favorable neurological outcome rate for this group was 28.8% (95% CI, 19.3–40.6%). These are incredible values that exceeded the prognosis of all witnessed OHCA patients with shockable initial rhythms (1-month survival, 30.2%; favorable neurological outcome, 21.3%). Because the percentage of Group A was very low among unwitnessed OHCA patients with non-shockable initial rhythms, the provision of maximum medical resources to these patients will likely be acceptable. On the other hand, the 1-month survival rate of Group D was 0.91% (95% CI, 0.83–0.99%) and the favorable neurological outcome rate was 0.18% (95% CI, 0.14–0.22%). Despite the 95% CI, less than 1% of these patients were expected to have a favorable prognosis, and it is very likely that the treatments provided to these patients will be medically futile [26,27]. In our previous study, which incorporated another type of nationwide administrative database in Japan [25], we assessed the relationship between the OHCA patient outcome and post-hospital arrival costs. According to that study, 75.4% of OHCA patients died on the day of
arrival and 92.4% patients died prior to discharge, with post-arrival medical expenses of USD 1624/patient and USD 2220/patient, respectively. Based on these findings, throughout Japan, the post-hospital arrival medical expenses alone have been estimated at approximately 153 million dollars/year for OHCA patients who die on the day of arrival and approximately 256 million dollars/year for OHCA patients who die prior to discharge. Given the current reality of post-hospital arrival medical expenses incurred by OHCA patients who have almost no hope of being saved, the ability to determine the usefulness or futility of continued resuscitation efforts using the information available upon hospital arrival is extremely important. In this study, any of the items used as prognostic predictors, including age b 65 years, conversion to shockable rhythm, and pre-hospital ROSC, were considered information collected upon hospital arrival. Using this information, if the incurred post-hospital arrival medical expenses for 73.0% of unwitnessed OHCA with a nonshockable initial rhythm (41.1% of total OHCA) could be reduced, this would make a significant impact. In this study, age b 65 years, conversion to shockable rhythm, and pre-hospital ROSC were used as prognostic predictors for unwitnessed OHCA patients with non-shockable initial rhythms; however, the results of a multivariate logistic regression analysis (Table 2) suggested that cardiac etiology, epinephrine administration, and advanced airway management could be additional prognostic factors. However, a cardiac etiology cannot always be confirmed upon hospital arrival, and as a cardiac etiology is beneficial with respect to a favorable neurological outcome (OR, 1.27; 95% CI, 1.01–1.60; P = 0.0368) but unfavorable with respect to 1-month survival (OR, 0.84; 95% CI, 0.74–0.95; P = 0.0051), this factor has not been used as a prognostic predictor in this study. Regarding the information collected upon hospital arrival, epinephrine administration or advanced airway management may be useful predictors of poor prognosis (Table 2). Previous studies have also indicated the possibility that pre-hospital epinephrine administration and advanced airway management may worsen the prognosis of OHCA [18,19,28–30]; therefore, the inclusion of these factors might yield a more accurate prognostic prediction. Nevertheless, the paradoxical
T. Fukuda et al. / International Journal of Cardiology 176 (2014) 910–915
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Table 1 Baseline demographic characteristics and outcomes for adult OHCA patients in each group according to witness status and initial cardiac rhythm.
n Sex (male) Age (y), mean (SD) 1) 18≤, b65 2) 65≤, b85 3) 85≤ Witnessed Bystander CPR Cardiac etiology Shockable initial rhythm Defibrillated over one time Physician present in ambulance Epinephrine administration Advanced airway management Time from call to hospital arrival (min), mean (SD) 1) b15 2) 15≤, b30 3) 30≤ Pre-hospital ROSC 1-month survival Favorable neurological outcome
Total
Unwitnessed and nonshockable initial rhythm
Witnessed and nonshockable initial rhythm
Unwitnessed and shockable initial rhythm
Witnessed and shockable initial rhythm
P
120,721 69,416 (57.5) 74.1 (16.0) 27,969 (23.2) 58,998 (48.9) 33,754 (28.0) 50,431 (41.8) 51,422 (42.6) 67,515 (55.9) 8479 (7.0) 13,194 (10.9) 3689 (3.1) 14,221 (11.8) 49,585 (41.1) 33.5 (13.8) 1266 (1.1) 51,445 (42.6) 68,010 (56.3) 10,142 (8.4) 6914 (5.7) 3509 (2.9)
68,024 37,573 (55.2)
44,218 25,347 (57.3)
2266 1667 (73.6)
6213 4829 (77.7)
b0.0001
74.2 (16.2)
75.2 (15.5)
68.3 (15.0)
66.1 (15.3)
b0.0001
15,357 (22.6)
9090 (20.6)
833 (36.8)
2689 (43.3)
33,215 (48.8)
21,758 (49.2)
1134 (50.0)
2891 (46.5)
19,452 (28.6)
13,370 (30.2)
299 (13.2)
633 (10.2)
0 (0.0)
44,218 (100.0)
0 (0.0)
6213 (100.0)
b0.0001
30,452 (44.8)
16,960 (38.4)
1034 (45.6)
2976 (47.9)
b0.0001
37,835 (55.6)
22,342 (50.5)
1883 (83.1)
5455 (87.8)
b0.0001
0 (0.0)
0 (0.0)
2266 (100.0)
6213 (100.0)
b0.0001
2260 (3.3)
2873 (6.5)
2133 (94.1)
5928 (95.4)
b0.0001
1373 (2.0)
1871 (4.2)
107 (4.7)
338 (5.4)
b0.0001
5388 (7.9)
7063 (16.0)
486 (21.5)
1284 (20.7)
b0.0001
2823 (41.5)
17,918 (40.5)
996 (44.0)
2440 (39.3)
b0.0001
32.8 (12.8)
34.6 (14.8)
32.8 (15.2)
33.8 (15.5)
b0.0001
695 (1.0)
446 (1.0)
46 (2.0)
79 (1.3)
30,330 (44.6)
17,400 (39.4)
1040 (45.9)
2675 (43.1)
36,999 (54.4)
26,372 (59.6)
1180 (52.1)
3459 (55.7)
2085 (3.1)
5624 (12.7)
417 (18.4)
2016 (32.5)
b0.0001
1260 (1.9)
3404 (7.7)
376 (16.6)
1874 (30.2)
b0.0001
396 (0.6)
1575 (3.6)
213 (9.4)
1325 (21.3)
b0.0001
The data are expressed as the number (%) of patients or the mean (SD) unless otherwise indicated. All baseline characteristics and outcomes between the four groups were statistically significant at a P value of b 0.05. Abbreviations: OHCA, out-of-hospital cardiac arrest; SD, standard deviation; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation.
treatment strategy of ceasing resuscitation efforts upon hospital arrival for patients who had received assertive pre-hospital intervention may be generally difficult to accept, and therefore these components have also been excluded from the prognostic predictors in this study.
The findings of this study might help to determine treatment strategies for unwitnessed OHCA patients with non-shockable initial rhythms, many of whom may potentially not benefit from resuscitation. The findings might also contribute significantly to the implementation
Table 2 Contributing factors to favorable outcomes in unwitnessed OHCA with non-shockable initial rhythms. 1-month survival Adjusted OR (95% CI) Male Age 1) 18≤, b65 2) 65≤, b85 3) 85≤ Bystander CPR Cardiac etiology Conversion to shockable rhythm Epinephrine administration Advanced airway management Call to hospital arrival 1) b15 2) 15≤, b30 3) 30≤ Pre-hospital ROSC
Favorable neurological outcome P
Adjusted OR (95% CI)
P
0.97 (0.85–1.09)
0.59
1.05 (0.84–1.31)
0.68
Reference 0.81 (0.70–0.93) 0.63 (0.53–0.75) 1.08 (0.96–1.22) 0.84 (0.74–0.95) 1.91 (1.48–2.43) 0.48 (0.39–0.59) 0.86 (0.76–0.98)
0 b0.0001 0.2 0.01 b0.0001 b0.0001 0.03
Reference 0.68 (0.54–0.87) 0.46 (0.33–0.63) 1.10 (0.89–1.36) 1.27 (1.01–1.60) 2.14 (1.43–3.13) 0.15 (0.09–0.25) 0.38 (0.29–0.50)
0 b0.0001 0.39 0.04 0 b0.0001 b0.0001
Reference 0.79 (0.48–1.40) 0.51 (0.31–0.90) 44.81 (39.13–51.34)
0.41 0.02 b0.0001
Reference 1.17 (0.45–4.06) 0.97 (0.37–3.35) 94.85 (75.71–119.35)
0.77 0.95 b0.0001
Abbreviations: OHCA, out-of-hospital cardiac arrest; OR, odds ratio; CI, confidence interval; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation
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Table 3 Outcomes in each of the four groups (Groups A–D). 1-month survival n, (%) Total [n = 68,024 (100.0%)] Group A [n = 66 (0.1%)] Group B [n = 2.019 (3.0%)] Group C [n = 16,281 (23.9%)] Group D [n = 49,658 (73.0%)]
n = 1260 (1.9%) 27 (40.9) 557 (27.6) 226 (1.4) 450 (0.9)
Favorable neurological outcome OR (95% CI), P value
n, (%)
OR (95% CI), P value
75.70 (45.51–124.16), P b 0.0001 41.66 (36.42–47.68), P b 0.0001 1.54 (1.31–1.81), P b 0.0001 Reference
n = 396 (0.6%) 19 (28.8) 245 (12.1) 45 (0.3) 87 (0.2)
230.34 (127.37–402.96), P b 0.0001 78.69 (61.60–101.45), P b 0.0001 1.58 (1.09–2.25), P = 0.0156 Reference
We divided the patients into the following four groups based on the multivariate logistic regression analysis results: (Group A) patients who were b65 years of age, converted to shockable rhythm, and had pre-hospital ROSC; (Group B) patients who did not qualify for Group A but had pre-hospital ROSC; (Group C) patients who were below the age of 65 or converted to shockable rhythm but did not qualify for Group A or B; and (Group D) patients who did not qualify for Group A, B, or C. Abbreviations: OR, odds ratio; CI, confidence interval; ROSC, return of spontaneous circulation.
of treatment based on prognostic predictions even in cardiopulmonary resuscitation. Because the prognostic predictors of age b65 years, conversion to shockable rhythm, and pre-hospital ROSC in this study only included information collected prior to hospital arrival, in countries such as Japan where pre-hospital termination of resuscitation is a complicated issue, these factors might help to determine treatment strategies immediately after hospital arrival. Additionally, this information could prove extremely useful, as it can be obtained in the absence of special techniques.
5. Limitations Our study featured several limitations. First, the optimal age cut-off value for a favorable outcome is unclear. In this study, age was divided into three categories: adults (≥18 years), elderly (65–85 years), and oldest-elderly (≥85 years), and the prognosis was found to be better in the younger age group; however, the optimum cut-off value was not determined. Moreover, depending upon the initial activity of daily living (ADL) or underlying comorbidities, the prognosis might vary significantly even among patients of the same age. Given the possible existence of some confounding factors in the relationship between age and prognosis, in future studies, it might be necessary to collect information and perform analyses while considering these factors to more accurately predict prognosis. Second, the conversion to shockable rhythm was not directly verified. In this study, regardless of the initial non-shockable initial rhythm status, patients who were subjected to more than one defibrillation before hospital arrival were considered to have a conversion to shockable rhythm. For this reason, it is possible that in reality, even patients who do not convert to shockable rhythm, including those who are defibrillated because of malfunction of the AED or misdiagnosis by the EMS, are regarded as patients with conversion to shockable rhythm. To examine the validity of the study findings, it will be necessary to directly verify the conversion of shockable rhythm and evaluate the collected data. Third, the prognostic predictors of this study are not equally helpful in cases of patients for whom the time interval between the call receipt and hospital arrival was short. In this study, the time from call to hospital arrival was approximately 33 min; only 1% patients arrived in b15 min. It appears that the prognostic predictors of conversion to shockable rhythm and pre-hospital ROSC can only be used if a particular length of time has passed before hospital arrival, and therefore it might be necessary to investigate other prognostic predictors in patients with a short time interval between call receipt and hospital arrival. Moreover, the minimum time interval between the call receipt and hospital arrival at which the prognostic predictors identified in this study can be available will need to be investigated in the future.
Fourth, the findings of this study might only indicate association and not causality. In Japan, nearly all OHCA patients receive medical attention. The Utstein Registry data used in this study included nearly all types of OHCA, and this study was conducted under the assumption that the same resuscitation efforts were attempted in all registered patients. However, it is possible that the same resuscitation efforts may not have been made in all OHCA patients. It is possible that many EMS personnel and clinicians are aware of prognostic predictors, such as age b 65 years, conversion to shockable rhythm, and pre-hospital ROSC, that could be considered individual factors with an influence on prognosis. This awareness might affect the viewpoint of the pre-hospital or in-hospital health care providers. In other words, these providers might make assertive resuscitation efforts for patients with these predictors while avoiding sufficient intervention for patients without these factors. As such, the findings of this study might merely illustrate this phenomenon. To minimize such interference with causal relationships, it is necessary to perform resuscitation for OHCA patients while blinding information that might influence the viewpoint of the health care provider; however, it may be impossible to do so in actual practice. Finally, as with all epidemiological studies, data integrity, validity, and ascertainment bias are potential limitations. The use of a uniform data record based on the Utstein-style guidelines for reporting cardiac arrest, the large sample size, and the population-based design were intended to minimize these potential sources of bias.
6. Conclusions We identified the factors that affected both favorable and poor prognoses in a large, nationwide, population-based cohort study of unwitnessed OHCA patients with non-shockable initial rhythms. Although it may be worthwhile to provide maximum lifesaving medical resources for patients with all of the favorable predictors (age b65 years, conversion to shockable rhythm, and pre-hospital ROSC), continued resuscitation efforts for patients without these predictors should likely be restrained.
Contributors T Fukuda, as the principal investigator, participated in the study conception, design and completion; data collection, management, and analysis; interpretation of results; and revision of the manuscript, and he contributed to the final report. T Matsubara, K Doi, N Fukuda-Ohashi, and N Yahagi participated in the study conception, the data collection and management, and the interpretation of results. T Fukuda performed the statistical analysis. All authors approved the final version. T Fukuda takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
T. Fukuda et al. / International Journal of Cardiology 176 (2014) 910–915
Role of the funding sources We received no funding for this study. There were no sponsors who played a role in the data analysis, the data interpretation, or the composition of the report. The FDMA collected and managed the data but played no role in the design or performance of the study. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit the manuscript for publication. Conflict of interest We declare that we have no conflicts of interest. Submission declaration This manuscript has not been published previously, and it is not under consideration for publication elsewhere. Its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was conducted. If accepted, it will not be published elsewhere, including electronically in the same form, in English, or in any other language, without the written consent of the copyrightholder. Acknowledgments We thank all of the EMS personnel and the participating physicians in Japan, as well as the FDMA and the Institute for Fire Safety and Disaster Preparedness of Japan, for their generous cooperation in establishing and maintaining the Utstein database. References [1] Hasegawa K, Tsugawa Y, Camargo Jr CA, Hiraide A, Brown DF. Regional variability in survival outcomes of out-of-hospital cardiac arrest: The All-Japan Utstein Registry. Resuscitation 2013;84:1099–107. [2] Fukuda T, Ohashi N, Doi K, et al. Impact of seasonal temperature environment on the neurological prognosis of out-of-hospital cardiac arrest: a nationwide, populationbased cohort study. J Crit Care 2014;29:840–7. [3] Atwood C, Eisenberg MS, Herlitz J, Rea TD. Incidence of EMS-treated out-of-hospital cardiac arrest in Europe. Resuscitation 2005;67:75–80. [4] Roger VL, Go AS, Lloyd-Jones DM. et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics — 2012 update: a report from the American Heart Association. Circulation 2012;125:e2-220. [5] Rea TD, Eisenberg MS, Becker LJ, Murray JA, Hearne T. Temporal trends in sudden cardiac arrest: a 25-year emergency medical services perspective. Circulation 2003;107:2780–5. [6] Herlitz J, Bång A, Gunnarsson J, et al. Factors associated with survival to hospital discharge among patients hospitalized alive after out of hospital cardiac arrest: change in outcome over 20 years in the community of Göteberg, Sweden. Heart 2003;89: 25–30. [7] McNally B, Robb R, Mehta M, et al. Out-oh-hospital cardiac arrest surveillance — Cardiac Arrest Registry to Enhance Survival (CARES), United States, October 1, 2005–December 31, 2010. MMWR Surveill Summ 2011;60:1–19. [8] Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-ofhospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2010;3:63–81.
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[9] Morrison LJ, Kierzek G, Dikema DS, et al. Part 3: ethics: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122(18 Suppl. 3):S665–75. [10] National Association of EMS Physicians. Termination of resuscitation in nontraumatic cardiopulmonary arrest. Prehosp Emerg Care 2011;15:542. [11] Morrison LJ, Visentin LM, Kiss A, et al. Validation of a rule for termination of resuscitation in out-of-hospital cardiac arrest. N Engl J Med 2006;355:478–87. [12] Sasson C, Hegg AJ, Macy M, et al. Prehospital termination of resuscitation in cases of refractory out-of-hospital cardiac arrest. JAMA 2008;300:1432–8. [13] Kajino K, Kitamura T, Iwami T, et al. Current termination of resuscitation (TOR) guidelines predict neurologically favorable outcome in Japan. Resuscitation 2013; 84:54–9. [14] Fukuda T, Ohashi N, Matsubara T, et al. Applicability of prehospital termination of resuscitation rule in an area dense with hospitals in Tokyo: a single-center, retrospective, observational study: Is the prehospital TOR rule applicable in Tokyo? Am J Emerg Med 2014;32:144–9. [15] Jacobs I, Nadkarni V, Bahr J, et al. Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Councils of Southern Africa). Circulation 2004; 110:3385–97. [16] Statistical Research and Training Institute. Japan statistical yearbook 2013. Tokyo: Statistics Bureau, Ministry of Internal Affairs and Communications; 2013. [17] Ogawa T, Akahane M, Koike S, Tanabe S, Mizoguchi T, Imamura T. Outcomes of chest compression only CPR versus conventional CPR conducted by lay people in patients with out of hospital cardiopulmonary arrest witnessed by bystanders: nationwide population based observational study. BMJ 2011;342:c7106. [18] Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata T, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012;307:1161–8. [19] Hasegawa K, Hiraide A, Chang Y, Brown DF. Association of prehospital advanced airway management with neurologic outcome and survival in patients with outof-hospital cardiac arrest. JAMA 2012;309:257–66. [20] Fire and Disaster Management Agency. Ministry of Internal Affairs and Communications. First-aid and rescue operations in Japan, 2013 edition. Tokyo: Fire and Disaster Management Agency, Ministry of Internal Affairs and Communications; 2013 [Japanese]. [21] Japan Resuscitation Council. JRC guidelines 2010. Tokyo: Japan Resuscitation Council; 2012. [22] Field JM, Hazinski MF, Sayre MR, et al. Part 1: executive summary: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122(18 Suppl. 3):S640–56. [23] Nolan JP, Hazinski MF, Billi JE, et al. Part 1: executive summary: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Resuscitation 2010;81(Suppl. 1):e1-25. [24] Fukuda T, Ohashi N, Nishida M, et al. Application of cerebral oxygen saturation to prediction of the futility of resuscitation for out-of-hospital cardiopulmonary arrest patients: a single-center, prospective, observational study: can cerebral oxygen saturation predict the futility of CPR? Am J Emerg Med 2014;32:747–51. [25] Fukuda T, Yasunaga H, Horiguchi H, et al. Health care costs related to out-of-hospital cardiopulmonary arrest in Japan. Resuscitation 2013;84:964–9. [26] Schneiderman LJ, Jecker NS, Jonsen AR. Medical futility: its meaning and ethical implications. Ann Intern Med 1990;112:949–54. [27] Gray WA, Capone RJ, Most AS. Unsuccessful emergency medical resuscitation — are continued efforts in the emergency department justified? N Engl J Med 1991;325: 1393–8. [28] Shin SD, Ahn KO, Song KJ, Park CB, Lee EJ. Out-of-hospital airway management and cardiac arrest outcomes: a propensity score matched analysis. Resuscitation 2012; 83:313–9. [29] Wang HE, Yealy DM. Out-of-hospital endotracheal intubation: where are we? Ann Emerg Med 2006;47:532–41. [30] Ong ME, Tan EH, Ng FS, et al. Cardiac Arrest and Resuscitation Epidemiology Study Group. Survival outcomes with the introduction of intravenous epinephrine in the management of out-of-hospital cardiac arrest. Ann Emerg Med 2007;50:635–42.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Predictors of favorable and poor prognosis in unwitnessed out-of-hospital cardiac arrest with a non-shockable initial rhythm Tatsuma Fukuda ⁎, Takehiro Matsubara, Kent Doi, Naoko Fukuda-Ohashi, Naoki Yahagi Department of Emergency and Critical Care Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
a r t i c l e
i n f o
Article history: Received 17 May 2014 Received in revised form 5 August 2014 Accepted 9 August 2014 Available online 17 August 2014 Keywords: Out-of-hospital cardiac arrest Medical futility Prognosis
a b s t r a c t Background: Unwitnessed OHCA patients with non-shockable initial rhythms account for nearly half of all OHCA patients, and their prognosis is extremely poor. To date, no studies have focused on these patients. This study aimed to investigating the predictors of favorable and poor prognosis in these patients. Methods: We conducted a nationwide, population-based, observational study of data from the All Japan Utstein Registry, which included 121,081 adult OHCA patients subjected to resuscitation attempts from January 1, 2010 to December 31, 2010. The primary endpoint was favorable neurological outcome one month after OHCA. Results: Of the eligible 120,721 patients, 68,024 (56.3%) were unwitnessed OHCA patients with nonshockable initial rhythms. A younger age (18–64 years: as a reference; 65–84 years: OR 0.68, 95% CI 0.54–0.87, p = 0.0019; ≥ 85 years: OR 0.46, 95% CI 0.33–0.63, p b 0.0001), conversion to shockable rhythm (OR 2.14, 95% CI 1.43–3.13, p = 0.0003), and pre-hospital ROSC (OR 94.85, 95% CI 75.71–119.35, p b 0.0001) were independently associated with a favorable neurological outcome. Favorable neurological outcome rate was 28.8% in unwitnessed OHCA patients with non-shockable initial rhythms with all three favorable predictors, and 0.18% in patients without any of the three predictors (OR 230.34, 95% CI 127.37–402.96, P b 0.0001). Conclusions: It may be worthwhile to provide maximum lifesaving medical resources for patients with all of the favorable predictors (b65 years, conversion to shockable rhythm, and pre-hospital ROSC); however, continued resuscitation efforts for patients without these predictors should likely be restrained. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Out-of-hospital cardiac arrest (OHCA), a condition with one of the poorest prognoses, is experienced by 125,000, 275,000, and 375,000 individuals annually in Japan, Europe, and the USA, respectively [1–4]. Although the rate of survival after OHCA has increased along with advances in care throughout the “chain of survival,” it remains low [5,6]. The prognosis is especially poor in cases of unwitnessed OHCA with non-shockable initial rhythms [2,7,8]. In fact, a lack of witnesses and a non-shockable rhythm are the main criteria in the pre-hospital termination of resuscitation (TOR) rule [9–14]. Unwitnessed OHCA patients with non-shockable initial rhythms account for nearly half of all OHCA patients, and their prognosis is extremely poor [1,2,7,8]; therefore,
Abbreviations: OHCA, out-of-hospital cardiac arrest; TOR, termination of resuscitation; FDMA, Fire and Disaster Management Agency; EMS, emergency medical service; AED, automated external defibrillator; CPR, cardiopulmonary resuscitation; AHA, American Heart Association; ILCOR, International Liaison Committee on Resuscitation; ROSC, return of spontaneous circulation; CPC, Glasgow–Pittsburgh cerebral performance category; ANOVA, analysis of variance; OR, odds ratio; CI, confidence interval; SD, standard deviation; ADL, activity of daily living. ⁎ Corresponding author. Tel.: +81 3 3815 5411; fax: +81 3 3814 6446. E-mail address: [email protected] (T. Fukuda).
http://dx.doi.org/10.1016/j.ijcard.2014.08.057 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
these patients are considered suitable candidates for TOR. On the other hand, it is extremely important to identify the factors that contribute to a favorable prognosis in such cases because there are a limited number of patients who will be discharged with a favorable outcome in these many cases. To date, no studies have focused on a large sample of unwitnessed OHCA patients with non-shockable initial rhythms. This study aimed to investigating the predictors of both favorable and poor prognosis in unwitnessed OHCA patients with nonshockable initial rhythms. 2. Methods 2.1. Study design and participants We conducted a population-based cohort study of data from the All-Japan Utstein Registry of the Fire and Disaster Management Agency (FDMA), a prospective, nationwide, population-based registry system of all OHCA patients maintained via Utstein-style data collection [15]. All adults aged ≥18 years who suffered from OHCA and for whom resuscitation was attempted by emergency medical service (EMS) personnel with subsequent transport to emergency hospitals from January 1 to December 31, 2010 were enrolled in this study. Patients whose data and information regarding the onset time, call receipt time, hospital arrival time, airway management status, or the public access automated external defibrillator (AED) usage status were missing or unknown were excluded from the analysis.
T. Fukuda et al. / International Journal of Cardiology 176 (2014) 910–915 This study was conducted in accordance with the amended Declaration of Helsinki. The FDMA and the Institutional Review Board of The University of Tokyo approved this study with a waiver of informed consent because of the anonymous nature of the data.
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All statistical analyses were performed using JMP Pro 10.0.2 software (SAS institute Inc., Cary, NC, USA). All tests were two-tailed, and P values of b 0.05 were considered statistically significant.
2.2. Study setting Japan comprises an area of approximately 378,000 km2 with 47 prefectures, and the population of Japan in 2010 was approximately 128 million, with approximately 107 million people aged ≥18 years [16]. The EMS system in Japan has been described previously [2,17–19]. In 2010, EMSs were provided by municipal governments via 802 fire stations with dispatch centers [20]. An ambulance team usually comprises three EMS personnel, including at least one professionally trained emergency lifesaving technician. Some emergency lifesaving technicians are authorized to secure infusion lines, administer epinephrine, perform endotracheal intubation and defibrillation, and lead cardiopulmonary resuscitation (CPR). CPR is performed in conformity with the Japanese CPR guidelines, which are based on the guidelines stipulated by the American Heart Association (AHA) and the International Liaison Committee on Resuscitation (ILCOR) [21–23]. EMS personnel are not allowed to terminate resuscitation out of hospital except in specific situations such as decapitation, rigor mortis, livor mortis, or decomposition; advance directives, living wills, or do-not-attempt-resuscitation orders are not generally accepted in Japan [21,24]. Therefore, nearly all OHCA patients treated by EMS personnel are transported to an emergency hospital [25]. 2.3. Data collection and quality control The data were collected prospectively using Utstein-style templates and included information regarding the sex, age, bystander witness status, bystander CPR status, etiology of arrest, initial cardiac rhythm, public-access AED usage, defibrillation by EMS, presence of an emergency lifesaving technician or physician in the ambulance, administration of epinephrine, and type of airway management. The definitions of terms related to OHCA care such as cardiac arrest, bystander CPR, or etiology of arrest conformed to those in the ILCOR statement [15]. A series of EMS times, including the call receipt, vehicle arrival at the scene, contact with the patient, initiation of CPR, departure from the scene, and hospital arrival, were also recorded according to the clock used by each EMS system. The outcome data included the return of spontaneous circulation (ROSC) prior to hospital arrival, 1-month survival, and neurological status at one month after OHCA. The 1month follow-up data were collected by the EMS personnel in charge of each patient with OHCA. The EMS queried the medical control director at the hospital and received a written response, including reconfirmation of the etiology of the arrest. If the patient was not at the hospital, the EMS personnel conducted a follow-up investigation. The data forms were completed by the EMS personnel in charge of the patients, and the data were integrated into the Utstein registry system on the FDMA database server. FDMA logically evaluated the data using the computer system and returned the data forms to the respective fire stations for reconfirmation unless the data were complete. 2.4. Study endpoints The primary endpoint was a favorable neurological outcome at 1 month after OHCA, defined a priori as a Glasgow–Pittsburgh cerebral performance score category (CPC) of 1 or 2 (good performance or moderate disability, respectively). A CPC of 3, 4, or 5 (severe disability, vegetative state, or death, respectively) was regarded as an unfavorable neurological outcome [15]. The secondary endpoint was the 1-month survival. 2.5. Statistical analysis The total sample size in this nationwide, population-based study was determined according to the number of patients registered in the All-Japan Utstein Registry database in 2010. Continuous and categorical variables were assessed using an analysis of variance (ANOVA) and χ 2 test, respectively. A multivariate logistic regression analysis was performed to examine the contribution of each predictor to one-month survival and a favorable neurological outcome. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated after adjusting for potential confounding factors such as sex, age (18–64, 65–84, ≥ 85 years), bystander CPR status, etiology of arrest, conversion to shockable rhythm, epinephrine administration, advanced airway management, time from call to hospital arrival (b15, 15–29, ≥ 30 min), and pre-hospital ROSC. Despite having a non-shockable initial rhythm, patients for whom more than one defibrillation was performed prior to arrival at the hospital were regarded as patients with conversion to shockable rhythm. We divided the patients into the following four groups based on the multivariate logistic regression analysis results: (Group A) patients who were b65 years of age, converted to shockable rhythm, and had pre-hospital ROSC; (Group B) patients who did not qualify for Group A but had pre-hospital ROSC; (Group C) patients who were below the age of 65 or converted to shockable rhythm but did not qualify for Group A or B; and (Group D) patients who did not qualify for Group A, B, or C. We compared the outcomes between the four groups. The ORs and 95% CIs for favorable outcomes were calculated for each group versus group D, which served as the reference group.
3. Results A total of 123,095 OHCA patients were documented during the study period. Of the 121,081 adult OHCA patients subjected to resuscitation attempts, the following were excluded: 6 with an unknown time of onset, call receipt, or hospital arrival; 317 with an unknown airway management status; and 37 with an unknown public access AED usage status (Fig. 1). Of the remaining 120,721 patients, 68,024 (56.3%; 95% CI, 56.1–56.6%) were unwitnessed OHCA patients with non-shockable initial rhythms, 44,218 (36.6%; 95% CI, 36.4–36.9%) were witnessed OHCA patients with non-shockable initial rhythms, 2266 (1.9%; 95% CI, 1.8–2.0%) were unwitnessed OHCA with shockable initial rhythms, and 6213 (5.1%; 95% CI, 5.0–5.3%) were witnessed OHCA patients with shockable initial rhythms. Table 1 lists the baseline demographic characteristics and outcomes for the adult OHCA patients in each group according to the witness status and initial cardiac rhythm. The overall mean age was 74.1 years, and the proportion of male patients was 57.5%. Compared to the patients with shockable initial rhythms, patients with non-shockable initial rhythms were older, and the proportions of male and cardiac etiology were lower. Regarding pre-hospital care, there was a tendency to administer epinephrine primarily to patients with shockable initial rhythms, whereas advanced airway management was implemented primarily in unwitnessed patients. The prognoses were more favorable for patients with shockable initial rhythms and for witnessed patients, and the 1-month survival and favorable neurological outcome rates were approximately 15-fold and 35-fold higher, respectively, in patients with witnessed OHCA and shockable initial rhythms relative to those with unwitnessed OHCA and non-shockable initial rhythms. Table 2 lists the results of a multivariate logistic regression analysis for favorable outcomes in unwitnessed OHCA with a non-shockable initial rhythm. A younger age, conversion to shockable rhythm, and pre-hospital ROSC were independently associated with an improved outcome. In contrast, pre-hospital epinephrine administration and advanced airway management implementation were associated with a poor outcome. Cardiac etiology was associated with a poor 1-month survival and, conversely, a favorable neurological outcome. Table 3 lists the outcomes in each of the four groups according to the factors of age, conversion to shockable rhythm, and pre-hospital ROSC. Pre-hospital ROSC achievement (Groups A and B) correlated closely with a favorable prognosis. Even without pre-hospital ROSC, the prognosis was significantly favorable if patients were either b65 years of age or converted to a shockable rhythm (Group C) when compared with patients aged N 65 years who did not convert to a shockable rhythm (Group D). In patients who were b65 years of age, converted to a shockable rhythm, and achieved pre-hospital ROSC (Group A), the 1-month survival rate was 40.9% and the favorable neurological outcome rate was 28.8%; compared with patients lacking all of these predictors (Group D), the OR for 1-month survival was 75.70 (95% CI, 45.41–124.16; P b 0.0001) and the OR for a favorable neurological outcome was 230.34 (95% CI, 127.37–402.96; P b 0.0001).
4. Discussion In this large, nationwide, population-based cohort study of patients with OHCA, we identified the factors that affected both favorable and poor prognoses in unwitnessed OHCA patients with non-shockable initial rhythms. The prognosis of patients with all favorable predictors (Group A), specifically an age b 65 years, conversion to a shockable rhythm, and achievement of pre-hospital ROSC, was extremely favorable, whereas
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T. Fukuda et al. / International Journal of Cardiology 176 (2014) 910–915
123,095 OHCA in Japan from January 1, 2010 to December 31, 2010
1,784 Excluded (Age < 18 years)
230 Excluded (No resuscitation attempted)
121,081 Adult OHCA with resuscitation attempted
360 Excluded 6 Time related to occurrence, call receipt, or hospital arrival unknown 317 Airway management status unknown 37 Usage of public access AED unknown
120,721 Eligible for analysis
68,024 Unwitnessed with non-shockable initial rhythm
44,218 Witnessed with non-shockable initial rhythm
2,266 Unwitnessed with shockable initial rhythm
6,213 Witnessed with shockable initial rhythm
Fig. 1. Study profile. Abbreviations: OHCA, Out-of-hospital cardiac arrest; AED, Automated external defibrillator.
the prognosis of patients without any of these predictors (Group D) was extremely poor. Research targeting witnessed OHCA with a shockable initial rhythm has increased because many previous studies found the prognosis of unwitnessed OHCA with a non-shockable initial rhythm to be poor [2, 7,8]; however, no large-scale studies have focused on unwitnessed OHCA with a non-shockable initial rhythm. Therefore, the significance of this study is very high. In the future, the findings of this study might facilitate the selection of treatment strategies based on a more detailed prognostic prediction for unwitnessed OHCA with a non-shockable initial rhythm. In other words, among unwitnessed OHCA patients with a non-shockable initial rhythm, maximum efforts should be made to resuscitate those with all favorable predictors (Group A, b65 years of age with a conversion to shockable rhythm and pre-hospital ROSC) by providing as many medical resources as possible. In contrast, continued efforts to resuscitate patients without any of these predictors (Group D) should be restrained. In this study, the 1-month survival rate of Group A was 40.9% (95% CI, 29.9–53.0%), and the favorable neurological outcome rate for this group was 28.8% (95% CI, 19.3–40.6%). These are incredible values that exceeded the prognosis of all witnessed OHCA patients with shockable initial rhythms (1-month survival, 30.2%; favorable neurological outcome, 21.3%). Because the percentage of Group A was very low among unwitnessed OHCA patients with non-shockable initial rhythms, the provision of maximum medical resources to these patients will likely be acceptable. On the other hand, the 1-month survival rate of Group D was 0.91% (95% CI, 0.83–0.99%) and the favorable neurological outcome rate was 0.18% (95% CI, 0.14–0.22%). Despite the 95% CI, less than 1% of these patients were expected to have a favorable prognosis, and it is very likely that the treatments provided to these patients will be medically futile [26,27]. In our previous study, which incorporated another type of nationwide administrative database in Japan [25], we assessed the relationship between the OHCA patient outcome and post-hospital arrival costs. According to that study, 75.4% of OHCA patients died on the day of
arrival and 92.4% patients died prior to discharge, with post-arrival medical expenses of USD 1624/patient and USD 2220/patient, respectively. Based on these findings, throughout Japan, the post-hospital arrival medical expenses alone have been estimated at approximately 153 million dollars/year for OHCA patients who die on the day of arrival and approximately 256 million dollars/year for OHCA patients who die prior to discharge. Given the current reality of post-hospital arrival medical expenses incurred by OHCA patients who have almost no hope of being saved, the ability to determine the usefulness or futility of continued resuscitation efforts using the information available upon hospital arrival is extremely important. In this study, any of the items used as prognostic predictors, including age b 65 years, conversion to shockable rhythm, and pre-hospital ROSC, were considered information collected upon hospital arrival. Using this information, if the incurred post-hospital arrival medical expenses for 73.0% of unwitnessed OHCA with a nonshockable initial rhythm (41.1% of total OHCA) could be reduced, this would make a significant impact. In this study, age b 65 years, conversion to shockable rhythm, and pre-hospital ROSC were used as prognostic predictors for unwitnessed OHCA patients with non-shockable initial rhythms; however, the results of a multivariate logistic regression analysis (Table 2) suggested that cardiac etiology, epinephrine administration, and advanced airway management could be additional prognostic factors. However, a cardiac etiology cannot always be confirmed upon hospital arrival, and as a cardiac etiology is beneficial with respect to a favorable neurological outcome (OR, 1.27; 95% CI, 1.01–1.60; P = 0.0368) but unfavorable with respect to 1-month survival (OR, 0.84; 95% CI, 0.74–0.95; P = 0.0051), this factor has not been used as a prognostic predictor in this study. Regarding the information collected upon hospital arrival, epinephrine administration or advanced airway management may be useful predictors of poor prognosis (Table 2). Previous studies have also indicated the possibility that pre-hospital epinephrine administration and advanced airway management may worsen the prognosis of OHCA [18,19,28–30]; therefore, the inclusion of these factors might yield a more accurate prognostic prediction. Nevertheless, the paradoxical
T. Fukuda et al. / International Journal of Cardiology 176 (2014) 910–915
913
Table 1 Baseline demographic characteristics and outcomes for adult OHCA patients in each group according to witness status and initial cardiac rhythm.
n Sex (male) Age (y), mean (SD) 1) 18≤, b65 2) 65≤, b85 3) 85≤ Witnessed Bystander CPR Cardiac etiology Shockable initial rhythm Defibrillated over one time Physician present in ambulance Epinephrine administration Advanced airway management Time from call to hospital arrival (min), mean (SD) 1) b15 2) 15≤, b30 3) 30≤ Pre-hospital ROSC 1-month survival Favorable neurological outcome
Total
Unwitnessed and nonshockable initial rhythm
Witnessed and nonshockable initial rhythm
Unwitnessed and shockable initial rhythm
Witnessed and shockable initial rhythm
P
120,721 69,416 (57.5) 74.1 (16.0) 27,969 (23.2) 58,998 (48.9) 33,754 (28.0) 50,431 (41.8) 51,422 (42.6) 67,515 (55.9) 8479 (7.0) 13,194 (10.9) 3689 (3.1) 14,221 (11.8) 49,585 (41.1) 33.5 (13.8) 1266 (1.1) 51,445 (42.6) 68,010 (56.3) 10,142 (8.4) 6914 (5.7) 3509 (2.9)
68,024 37,573 (55.2)
44,218 25,347 (57.3)
2266 1667 (73.6)
6213 4829 (77.7)
b0.0001
74.2 (16.2)
75.2 (15.5)
68.3 (15.0)
66.1 (15.3)
b0.0001
15,357 (22.6)
9090 (20.6)
833 (36.8)
2689 (43.3)
33,215 (48.8)
21,758 (49.2)
1134 (50.0)
2891 (46.5)
19,452 (28.6)
13,370 (30.2)
299 (13.2)
633 (10.2)
0 (0.0)
44,218 (100.0)
0 (0.0)
6213 (100.0)
b0.0001
30,452 (44.8)
16,960 (38.4)
1034 (45.6)
2976 (47.9)
b0.0001
37,835 (55.6)
22,342 (50.5)
1883 (83.1)
5455 (87.8)
b0.0001
0 (0.0)
0 (0.0)
2266 (100.0)
6213 (100.0)
b0.0001
2260 (3.3)
2873 (6.5)
2133 (94.1)
5928 (95.4)
b0.0001
1373 (2.0)
1871 (4.2)
107 (4.7)
338 (5.4)
b0.0001
5388 (7.9)
7063 (16.0)
486 (21.5)
1284 (20.7)
b0.0001
2823 (41.5)
17,918 (40.5)
996 (44.0)
2440 (39.3)
b0.0001
32.8 (12.8)
34.6 (14.8)
32.8 (15.2)
33.8 (15.5)
b0.0001
695 (1.0)
446 (1.0)
46 (2.0)
79 (1.3)
30,330 (44.6)
17,400 (39.4)
1040 (45.9)
2675 (43.1)
36,999 (54.4)
26,372 (59.6)
1180 (52.1)
3459 (55.7)
2085 (3.1)
5624 (12.7)
417 (18.4)
2016 (32.5)
b0.0001
1260 (1.9)
3404 (7.7)
376 (16.6)
1874 (30.2)
b0.0001
396 (0.6)
1575 (3.6)
213 (9.4)
1325 (21.3)
b0.0001
The data are expressed as the number (%) of patients or the mean (SD) unless otherwise indicated. All baseline characteristics and outcomes between the four groups were statistically significant at a P value of b 0.05. Abbreviations: OHCA, out-of-hospital cardiac arrest; SD, standard deviation; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation.
treatment strategy of ceasing resuscitation efforts upon hospital arrival for patients who had received assertive pre-hospital intervention may be generally difficult to accept, and therefore these components have also been excluded from the prognostic predictors in this study.
The findings of this study might help to determine treatment strategies for unwitnessed OHCA patients with non-shockable initial rhythms, many of whom may potentially not benefit from resuscitation. The findings might also contribute significantly to the implementation
Table 2 Contributing factors to favorable outcomes in unwitnessed OHCA with non-shockable initial rhythms. 1-month survival Adjusted OR (95% CI) Male Age 1) 18≤, b65 2) 65≤, b85 3) 85≤ Bystander CPR Cardiac etiology Conversion to shockable rhythm Epinephrine administration Advanced airway management Call to hospital arrival 1) b15 2) 15≤, b30 3) 30≤ Pre-hospital ROSC
Favorable neurological outcome P
Adjusted OR (95% CI)
P
0.97 (0.85–1.09)
0.59
1.05 (0.84–1.31)
0.68
Reference 0.81 (0.70–0.93) 0.63 (0.53–0.75) 1.08 (0.96–1.22) 0.84 (0.74–0.95) 1.91 (1.48–2.43) 0.48 (0.39–0.59) 0.86 (0.76–0.98)
0 b0.0001 0.2 0.01 b0.0001 b0.0001 0.03
Reference 0.68 (0.54–0.87) 0.46 (0.33–0.63) 1.10 (0.89–1.36) 1.27 (1.01–1.60) 2.14 (1.43–3.13) 0.15 (0.09–0.25) 0.38 (0.29–0.50)
0 b0.0001 0.39 0.04 0 b0.0001 b0.0001
Reference 0.79 (0.48–1.40) 0.51 (0.31–0.90) 44.81 (39.13–51.34)
0.41 0.02 b0.0001
Reference 1.17 (0.45–4.06) 0.97 (0.37–3.35) 94.85 (75.71–119.35)
0.77 0.95 b0.0001
Abbreviations: OHCA, out-of-hospital cardiac arrest; OR, odds ratio; CI, confidence interval; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation
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Table 3 Outcomes in each of the four groups (Groups A–D). 1-month survival n, (%) Total [n = 68,024 (100.0%)] Group A [n = 66 (0.1%)] Group B [n = 2.019 (3.0%)] Group C [n = 16,281 (23.9%)] Group D [n = 49,658 (73.0%)]
n = 1260 (1.9%) 27 (40.9) 557 (27.6) 226 (1.4) 450 (0.9)
Favorable neurological outcome OR (95% CI), P value
n, (%)
OR (95% CI), P value
75.70 (45.51–124.16), P b 0.0001 41.66 (36.42–47.68), P b 0.0001 1.54 (1.31–1.81), P b 0.0001 Reference
n = 396 (0.6%) 19 (28.8) 245 (12.1) 45 (0.3) 87 (0.2)
230.34 (127.37–402.96), P b 0.0001 78.69 (61.60–101.45), P b 0.0001 1.58 (1.09–2.25), P = 0.0156 Reference
We divided the patients into the following four groups based on the multivariate logistic regression analysis results: (Group A) patients who were b65 years of age, converted to shockable rhythm, and had pre-hospital ROSC; (Group B) patients who did not qualify for Group A but had pre-hospital ROSC; (Group C) patients who were below the age of 65 or converted to shockable rhythm but did not qualify for Group A or B; and (Group D) patients who did not qualify for Group A, B, or C. Abbreviations: OR, odds ratio; CI, confidence interval; ROSC, return of spontaneous circulation.
of treatment based on prognostic predictions even in cardiopulmonary resuscitation. Because the prognostic predictors of age b65 years, conversion to shockable rhythm, and pre-hospital ROSC in this study only included information collected prior to hospital arrival, in countries such as Japan where pre-hospital termination of resuscitation is a complicated issue, these factors might help to determine treatment strategies immediately after hospital arrival. Additionally, this information could prove extremely useful, as it can be obtained in the absence of special techniques.
5. Limitations Our study featured several limitations. First, the optimal age cut-off value for a favorable outcome is unclear. In this study, age was divided into three categories: adults (≥18 years), elderly (65–85 years), and oldest-elderly (≥85 years), and the prognosis was found to be better in the younger age group; however, the optimum cut-off value was not determined. Moreover, depending upon the initial activity of daily living (ADL) or underlying comorbidities, the prognosis might vary significantly even among patients of the same age. Given the possible existence of some confounding factors in the relationship between age and prognosis, in future studies, it might be necessary to collect information and perform analyses while considering these factors to more accurately predict prognosis. Second, the conversion to shockable rhythm was not directly verified. In this study, regardless of the initial non-shockable initial rhythm status, patients who were subjected to more than one defibrillation before hospital arrival were considered to have a conversion to shockable rhythm. For this reason, it is possible that in reality, even patients who do not convert to shockable rhythm, including those who are defibrillated because of malfunction of the AED or misdiagnosis by the EMS, are regarded as patients with conversion to shockable rhythm. To examine the validity of the study findings, it will be necessary to directly verify the conversion of shockable rhythm and evaluate the collected data. Third, the prognostic predictors of this study are not equally helpful in cases of patients for whom the time interval between the call receipt and hospital arrival was short. In this study, the time from call to hospital arrival was approximately 33 min; only 1% patients arrived in b15 min. It appears that the prognostic predictors of conversion to shockable rhythm and pre-hospital ROSC can only be used if a particular length of time has passed before hospital arrival, and therefore it might be necessary to investigate other prognostic predictors in patients with a short time interval between call receipt and hospital arrival. Moreover, the minimum time interval between the call receipt and hospital arrival at which the prognostic predictors identified in this study can be available will need to be investigated in the future.
Fourth, the findings of this study might only indicate association and not causality. In Japan, nearly all OHCA patients receive medical attention. The Utstein Registry data used in this study included nearly all types of OHCA, and this study was conducted under the assumption that the same resuscitation efforts were attempted in all registered patients. However, it is possible that the same resuscitation efforts may not have been made in all OHCA patients. It is possible that many EMS personnel and clinicians are aware of prognostic predictors, such as age b 65 years, conversion to shockable rhythm, and pre-hospital ROSC, that could be considered individual factors with an influence on prognosis. This awareness might affect the viewpoint of the pre-hospital or in-hospital health care providers. In other words, these providers might make assertive resuscitation efforts for patients with these predictors while avoiding sufficient intervention for patients without these factors. As such, the findings of this study might merely illustrate this phenomenon. To minimize such interference with causal relationships, it is necessary to perform resuscitation for OHCA patients while blinding information that might influence the viewpoint of the health care provider; however, it may be impossible to do so in actual practice. Finally, as with all epidemiological studies, data integrity, validity, and ascertainment bias are potential limitations. The use of a uniform data record based on the Utstein-style guidelines for reporting cardiac arrest, the large sample size, and the population-based design were intended to minimize these potential sources of bias.
6. Conclusions We identified the factors that affected both favorable and poor prognoses in a large, nationwide, population-based cohort study of unwitnessed OHCA patients with non-shockable initial rhythms. Although it may be worthwhile to provide maximum lifesaving medical resources for patients with all of the favorable predictors (age b65 years, conversion to shockable rhythm, and pre-hospital ROSC), continued resuscitation efforts for patients without these predictors should likely be restrained.
Contributors T Fukuda, as the principal investigator, participated in the study conception, design and completion; data collection, management, and analysis; interpretation of results; and revision of the manuscript, and he contributed to the final report. T Matsubara, K Doi, N Fukuda-Ohashi, and N Yahagi participated in the study conception, the data collection and management, and the interpretation of results. T Fukuda performed the statistical analysis. All authors approved the final version. T Fukuda takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
T. Fukuda et al. / International Journal of Cardiology 176 (2014) 910–915
Role of the funding sources We received no funding for this study. There were no sponsors who played a role in the data analysis, the data interpretation, or the composition of the report. The FDMA collected and managed the data but played no role in the design or performance of the study. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit the manuscript for publication. Conflict of interest We declare that we have no conflicts of interest. Submission declaration This manuscript has not been published previously, and it is not under consideration for publication elsewhere. Its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was conducted. If accepted, it will not be published elsewhere, including electronically in the same form, in English, or in any other language, without the written consent of the copyrightholder. Acknowledgments We thank all of the EMS personnel and the participating physicians in Japan, as well as the FDMA and the Institute for Fire Safety and Disaster Preparedness of Japan, for their generous cooperation in establishing and maintaining the Utstein database. References [1] Hasegawa K, Tsugawa Y, Camargo Jr CA, Hiraide A, Brown DF. Regional variability in survival outcomes of out-of-hospital cardiac arrest: The All-Japan Utstein Registry. Resuscitation 2013;84:1099–107. [2] Fukuda T, Ohashi N, Doi K, et al. Impact of seasonal temperature environment on the neurological prognosis of out-of-hospital cardiac arrest: a nationwide, populationbased cohort study. J Crit Care 2014;29:840–7. [3] Atwood C, Eisenberg MS, Herlitz J, Rea TD. Incidence of EMS-treated out-of-hospital cardiac arrest in Europe. Resuscitation 2005;67:75–80. [4] Roger VL, Go AS, Lloyd-Jones DM. et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics — 2012 update: a report from the American Heart Association. Circulation 2012;125:e2-220. [5] Rea TD, Eisenberg MS, Becker LJ, Murray JA, Hearne T. Temporal trends in sudden cardiac arrest: a 25-year emergency medical services perspective. Circulation 2003;107:2780–5. [6] Herlitz J, Bång A, Gunnarsson J, et al. Factors associated with survival to hospital discharge among patients hospitalized alive after out of hospital cardiac arrest: change in outcome over 20 years in the community of Göteberg, Sweden. Heart 2003;89: 25–30. [7] McNally B, Robb R, Mehta M, et al. Out-oh-hospital cardiac arrest surveillance — Cardiac Arrest Registry to Enhance Survival (CARES), United States, October 1, 2005–December 31, 2010. MMWR Surveill Summ 2011;60:1–19. [8] Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-ofhospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2010;3:63–81.
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