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Abstract
Objective To compare the neurological outcomes of out-of-hospital cardiac arrest due to anaphylaxis (OHCA-A) and cardiac causes (OHCA-C).
Design Retrospective observational study.
Setting Japanese nationwide dataset from 2012 to 2021.
Participants In total, 153 890 patients were included in this study, of which 331 had OHCA-A and 153 559 had OHCA-C.
Outcome measures The primary outcome was a favourable neurological outcome 1 month after cardiac arrest. The secondary outcome was survival at 1 month.
Results Patients with OHCA-A had a significantly higher favourable neurological outcome rate (24.2% vs 11.7%, p<0.001) and higher survival rate at 1 month (33.2% vs 16.1%, p<0.001) than patients with OHCA-C. Multivariable logistic regression analysis revealed that OHCA-A was associated with higher odds of favourable neurological outcomes (adjusted OR (adj OR): 1.86; 95% CI 1.34 to 2.59) and survival at 1 month (adj OR: 2.43; 95% CI 1.78 to 3.31). Similarly, the propensity score-matched cohort showed favourable neurological outcomes in patients with OHCA-A (OR: 2.91; 95% CI 1.83 to 4.65).
Conclusion Compared with OHCA-C, OHCA-A is associated with favourable neurological outcomes and warrants more aggressive resuscitation efforts.
- Out-of-Hospital Cardiac Arrest
- Cardiopulmonary Resuscitation
- Emergency Service, Hospital
Data availability statement
Data may be obtained from a third party and are not publicly available. The data that support the findings of this study were obtained with permission from the Fire and Disaster Management Agency in Japan. Restrictions apply to the availability of these data.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This retrospective observational study was based on a nationwide population-based registry of out-of-hospital cardiac arrest (OHCA) in Japan.
We conducted logistic regression analysis and propensity score-based sensitivity analysis to compare the neurological outcomes of OHCA due to anaphylaxis and cardiac causes.
The data lack background information on the patients and treatment after arrival at the hospital.
The data are limited to Japan, thus the generalisability to other countries is not clear.
Introduction
Out-of-hospital cardiac arrests (OHCAs) are categorised into cardiac causes (OHCA-C) and non-cardiac causes.1 Compared with OHCA-C, OHCAs due to non-cardiac causes have been found to have lower survival rates owing to the lower occurrence of ventricular fibrillation/tachycardia.2 Due to this, OHCA-C are attracting greater attention.3 However, not all OHCAs due to non-cardiac causes have a uniformly poor prognosis. Ota et al reported that OHCAs due to anaphylaxis (OHCA-A) have more favourable outcomes than OHCAs due to other non-cardiac causes.4
The Ministry of Health, Labour and Welfare in Japan reported that the number of deaths from anaphylaxis, generally, remains flat, with approximately 60 deaths per year. Despite the introduction of epinephrine autoinjector prescriptions in 2013, the number of prescriptions has not changed dramatically and anaphylaxis remains an important problem in Japan.5 This is consistent with global trends; Turner et al reported an increasing trend in annual anaphylaxis cases and a stagnating trend in the rate of fatal anaphylaxis.6 Even though anaphylaxis is still an important problem worldwide, there are only limited data regarding the neurological outcomes of OHCA-A and a comparison of OHCA-A and OHCA-C has not been reported. In this study, we focused on comparing the neurological outcomes of OHCA-C and OHCA-A.
Methods
Study design and participants
This retrospective observational study was based on data from the All-Japan Utstein Registry, a nationwide population-based registry of patients with OHCA. The data included all patients with OHCA treated by emergency medical services (EMS) in Japan.
Japanese prehospital setting
In Japan, an ambulance is called, the call is connected to a command centre and background information is gathered. Thereafter, EMS personnel from the closest fire station are requested to attend. There is usually no physician in an ambulance. After arriving and assessing the situation, EMS personnel request a hospital for acceptance. For patients with cardiac arrest, all EMS personnel are permitted to perform chest compression, bag–valve–mask ventilation, electrical defibrillation and airway management using a supraglottic device. Certified EMS personnel can perform intravenous line placement, epinephrine administration and tracheal intubation.
Data collection
All patients with OHCA treated by EMS in Japan were recorded by the Internal Affairs and Communications Agency and included in the All-Japan Utstein Registry. These data include information about the patients, transportations, procedures performed by the EMS and outcomes of the patients based on a standardised Utstein-style format. The aetiology of OHCA was determined by the doctor in charge at the hospital to which the patient was transferred based on the history of presenting illness, physical exam, laboratory data and imaging if taken. The neurological outcomes were reported by the hospitals. Then, the whole data was registered by the EMS. The aetiology of cardiac arrest was classified as cardiac or non-cardiac. Cardiac causes were further divided into definitely cardiac and cardiac by the diagnosis of exclusion, and non-cardiac causes were divided into 10 different aetiologies (cerebrovascular, asphyxia, malignancy, poisoning, drowning, motor vehicle accident, hypothermia, anaphylaxis, other external causes and other natural causes).
Patient population
Patients with OHCA-C and OHCA-A in Japan between 2012 and 2021 were included in this study. Patients with definite cardiogenic OHCA were defined as OHCA-C, and patients with exclusionary diagnosed cardiogenic OHCAs were not included. Patients under 18 years of age and over 120 years of age were excluded. In addition, patients with unrealistic transportation times, patients with missing information and patients who did not receive resuscitation were excluded from the study (figure 1).
Patient enrolment. EMS, emergency medical service; OHCA, out-of-hospital cardiac arrest; ROSC, return of spontaneous circulation.
Study outcomes
The primary outcome was the favourable neurological outcome 1 month after cardiac arrest, defined as a category of 1 (good performance) or 2 (moderate disability) on the Glasgow–Pittsburgh Cerebral Performance Scale.7 8 The secondary endpoint was survival at 1 month.
Analyses
The patients were divided into two groups: OHCA-A and OHCA-C. Patients in the OHCA-A group were those with anaphylaxis as the aetiology of the cardiac arrest, and the patients in the OHCA-C group were those with definite cardiac arrest as the aetiology of the cardiac arrest. Logistic regression analysis was performed to assess the neurological outcomes. The dependent variables included in the analysis were age, sex, bystander witness, bystander cardiopulmonary resuscitation, initial rhythm (shockable or not shockable), EMS defibrillation, EMS epinephrine administration, use of an airway device, return of spontaneous circulation (ROSC) before hospital arrival and EMS response time, defined as the time from the ambulance call to the first EMS contact with the patient. EMS response time and age were treated as continuous variables, and others were treated as categorical variables. We conducted a sensitivity analysis using a one-to-four matched cohort with a propensity score (PS) to examine the robustness of our findings. The PS was calculated using a logistic regression model. The independent variable included in the PS calculation was the type of OHCA (anaphylaxis vs cardiac causes), and the dependent variables were age, sex, area (seven areas in Japan) and time (daytime 09:00–16:59 or night-time 17:00–08:59). Stata (V.18.0; Stat Corp, College Station, Texas, USA) was used for statistical analysis, and a two-tailed p value of <0.05 was considered statistically significant.
Results
Comparison of patients with OHCA-A and OHCA-C
A total of 1 262 013 patients with OHCA were reported in the All-Japan Utstein Registry between 1 January 2012 and 31 December 2021. After applying the exclusion criteria, 153 890 patients were included in the final analysis (figure 1). The baseline characteristics of the OHCA-A and OHCA-C groups are shown in table 1. There were significant differences in age, bystander witness, initial cardiac rhythm, defibrillation by EMS, use of an airway device, area, time, EMS response time and prehospital ROSC. Patients with OHCA-A had a higher rate of favourable neurological outcomes (24.2% vs 11.7%, p<0.001) and a higher survival rate at 1 month (33.2% vs 16.1%, p<0.001).
Baseline characteristics of out-of-hospital cardiac arrests due to anaphylaxis and cardiac causes
Multivariable logistic regression analysis showed the OHCA-A group was associated with significantly higher odds of favourable neurological outcomes (adjusted OR (adj OR): 1.86; 95% CI 1.34 to 2.59) (table 2) and survival at 1 month (adj OR: 2.43; 95% CI 1.78 to 3.31) (table 2) than the OHCA-C group.
Multivariable logistic regression analysis of odds ratio for favourable neurological outcome and survival at one month
Sensitivity analysis
In the one-to-four PS-matched cohort, there were 331 patients with OHCA-A and 1324 patients with OHCA-C. The baseline characteristics were well balanced (table 3). Multivariable logistic regression analysis disclosed that OHCA-A has a significantly higher chance to have favourable neurological outcomes (OR: 2.91; 95% CI 1.83 to 4.65) (table 4).
Baseline characteristics of the propensity score-matched patients
Multivariable logistic regression analysis of OR for favourable neurological outcome in the propensity score-matched patients
Discussion
This retrospective observational study using a nationwide cardiac arrest registry in Japan showed that OHCA-A was associated with more favourable neurological outcomes than OHCA-C. This difference was statistically significant even after adjusting for multiple covariates such as age and the presence of witnesses. Sensitivity analysis of a one-to-four matched cohort using PS revealed the same results.
Three studies analysed nationwide OHCA-A registries: one from Korea and two from Japan.4 9 10 The study in Korea revealed that there was no difference in the survival-to-discharge rate between OHCA-A caused by natural and iatrogenic agents. The two Japanese studies analysed nationwide registries from 2013 to 2015 and 2013 to 2019. The former study reported that the neurological outcomes of OHCA-A was better than that of OHCAs with non-cardiac causes. The latter study identified that witnesses, particularly bystanders, were associated with good neurological outcomes, whereas use of an advanced airway device was associated with poor neurological outcomes in patients with OHCA-A. The present study demonstrated an association between favourable neurological outcomes and OHCA-A compared with OHCA-C.
Epinephrine administration plays an important role in the treatment of anaphylaxis.11 However, epinephrine is administered to patients in cardiac arrest regardless of whether there is an aetiology of anaphylaxis. This could contribute to favourable neurological outcomes in patients with OHCA-A. Murasaka et al demonstrated an association between epinephrine administration or airway device use and poor neurological outcomes in patients with OHCA-A.9 This contradictory finding may be because patients with prolonged cardiac arrest tend to receive epinephrine, while patients who achieve ROSC early, generally, do not receive epinephrine. Whether early administration of epinephrine is useful in the management of OHCA-A is unknown.
The significantly favourable neurological outcomes in the OHCA-A group compared with the OHCA-C group suggest that aggressive resuscitation of patients with OHCA-A is required. Additionally, the past studies implied early detection and intervention to patients with OHCA-A is the most important factor for neurological outcome.9 12 Therefore, to further improve the neurological outcome of OHCA-A, we need to promote early diagnosis of anaphylaxis and early intervention for patients with OHCA-A including bystander CPR.
The importance of appropriate management of anaphylaxis remains high as the incidence of anaphylaxis is increasing worldwide.6 Further studies to improve the neurological outcome of patients with OHCA-A are warranted. However, cardiac arrest due to anaphylaxis is relatively rare and a large dataset, such as a nationwide database, is necessary to analyse outcomes. This study used data from a nationwide database and included 331 patients with OHCA-A, making it the largest study of OHCA-A.
Our study had several limitations. First, this was a retrospective observational study in which it was not possible to determine causation. Second, the data lacked information regarding medical history and socioeconomic status. There could be significant differences in baseline characteristics before the OHCAs. In addition, the data did not include information on treatment after hospital arrival, including the use of targeted temperature management and revascularisation of the coronary artery, which could affect the outcomes. The aetiology of OHCA was determined by individual physicians clinically based on the history of presenting illness, physical exam, laboratory data and imaging if taken. However, there was no protocol for diagnosing the aetiology of OHCA. Overdiagnosis or underdiagnosis might occur. In addition, data for patients with OHCAs were collected over a period of 10 years and the possibility of the impact of medical advances cannot be ruled out. This study only included patients with OHCA in Japan; therefore, it is unclear whether these results can be generalised to other areas where the aetiology of anaphylaxis and healthcare systems are different.
Conclusion
OHCA-A is associated with more favourable neurological outcomes than OHCA-C. To improve the neurological outcome of patients with OHCA-A furthermore, improvements in early detection and intervention are necessary. Further studies are warranted to improve the outcomes of patients with OHCA-A.
Data availability statement
Data may be obtained from a third party and are not publicly available. The data that support the findings of this study were obtained with permission from the Fire and Disaster Management Agency in Japan. Restrictions apply to the availability of these data.
Ethics statements
Patient consent for publication
Ethics approval
This study was approved by the ethics committee of the International University of Health and Welfare, Narita Hospital (24-Im-001, 23 April 2024). Informed consent was not required to conduct this study because it was an observational study without intervention, and the data did not include personal identifiable information.
Acknowledgments
We are thankful to all emergency medical services personnel and healthcare workers who treated the patients with out-of-hospital cardiac arrests and volunteered to collect data.
Footnotes
Contributors KHirata was involved in conception and study design, data analysis and/or interpretation and manuscript drafting. TC was involved in conception and study design, data analyses and/or interpretation and manuscript revision for important intellectual content. KHosono and HT were involved in manuscript revision for important intellectual content. SI and TS were involved in supervision of overall content. TS is the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.