Study design and data source
The present investigation was a nationwide population-based observational study of all adult patients (age ≥18 years) for whom resuscitation had been attempted after an OHCA in Japan between January 1 2007 and December 31 2010. Cardiac arrest was defined as the cessation of cardiac mechanical activities, as confirmed by the absence of signs of circulation . The cause of arrest was presumed to be cardiac unless evidence suggested external causes (trauma, hanging, drowning, drug overdose, or asphyxia), respiratory diseases, cerebrovascular diseases, malignant tumors, or any other non-cardiac cause. The attribution of cause as non-cardiac or cardiac was made by the physicians in charge in collaboration with the EMS personnel. This study was approved by the Ethical Committee of Kanazawa University. According to the informed consent guidelines in Japan , it is unnecessary to have informed consent from each patient to use secondary data such as on this anonymous database. Therefore, the requirement for written informed consent was waived.
EMS system in Japan
Japan has approximately 127 million residents in an area of 378,000 km2, approximately two-thirds of which is uninhabited mountainous terrain [1, 8, 9]. Details about the Japanese EMS system have been described previously [1, 8, 9]. Briefly, municipal governments provide EMS through approximately 800 fire stations with dispatch centers. The Fire and Disaster Management Agency (FDMA) of Japan supervises the nationwide EMS system [1, 8, 9], whereas each local EMS system is operated by the local fire station. Generally, an ambulance crew includes three EMS staff, including at least one emergency life-saving technician (ELST) [1, 9]. ELSTs are allowed to use several resuscitation methods, including use of semi-automated external defibrillators, insertion of a supraglottic airway device (laryngeal mask airway, laryngeal tube, and esophageal-tracheal twin-lumen airway device), insertion of a peripheral intravenous line, and administration of Ringer lactate solution [1, 9]. Since July 2004, only specially trained ELSTs are permitted to insert a tracheal tube, and since April 2006 they have been permitted to administer intravenous epinephrine in the field under the instruction of an online physician [1, 9]. All EMS providers perform CPR according to the Japanese CPR guidelines , based on the 2005 American Heart Association guidelines , since October, 2006. As EMS personnel in Japan are legally prohibited from terminating resuscitation in the field, most OHCA patients receive CPR from EMS providers and are transported to hospitals, except in cases where fatality is certain . Epinephrine use is implemented according to the FDMA resuscitation guidelines for ELSTs [10, 12]. The guidelines allow ELSTs to attempt intravenous access only twice, and each attempt must take no longer than 90 s. The allowed dosage of epinephrine is 1 mg per attempt, and repeated doses may be administered under a physician’s instruction.
Data collection and quality control
The FDMA launched a prospective population-based observational study including all OHCA patients who received EMS in Japan since January 2005 [1, 9]. EMS personnel at each center recorded the data for OHCA patients with the cooperation of the physician in charge, using an Utstein-style template . The data were transferred to their fire stations and were then integrated into the registry system on the FDMA database server. The data were checked for consistency by the computer system and were confirmed by the FDMA. If the data form was incomplete, the FDMA returned it to the respective fire station, and the form was completed . All data were stored in the nationwide database developed by the FDMA for public use. The FDMA provided permission to analyze this database and provided all the anonymous data to our research group. The main items included in the dataset were as follows: sex, age, causes of arrest (presumed cardiac origin or not), bystander witness status, bystander CPR with or without automated external defibrillator use, initial identified cardiac rhythm, bystander category (that is, the presence or absence of a bystander, or whether the bystander was a layperson or EMS personnel), whether epinephrine was administered, whether advanced airway management techniques (including endotracheal tube, laryngeal mask airway, and esophageal-tracheal tube) were used, whether ROSC was attained before arrival at the hospital, time of the emergency call, time of vehicle arrival at the scene, time of ROSC, time of vehicle arrival at the hospital, time of epinephrine administration, 1-month survival, and neurological outcome at 1 month after cardiac arrest. The neurological outcome was defined using the cerebral performance category (CPC) scale as follows: category 1, good cerebral performance; category 2, moderate cerebral disability; category 3, severe cerebral disability; category 4, coma or vegetative state; and category 5, death . The CPC categorization was determined by the physician in charge. The call-to-response time was calculated as the time from the emergency call to the time of vehicle arrival at the scene. The call-to-hospital arrival time was calculated as the time from the emergency call to the time of vehicle arrival at the hospital.
The primary study end point was 1-month favorable neurological outcome (defined as a CPC of 1 or 2) . The secondary end point was survival at 1 month after the OHCA.
Kolmogorov-Smirnov-Lilliefors tests were performed to evaluate the distributions of continuous variables, and we found that all continuous variables were not normally distributed (all P-values <0.01). Therefore, the Wilcoxon and Kruskal-Wallis tests for continuous variables and the chi-square test for categorical variables were performed to compare the characteristics or outcomes between the cohorts. Multivariate logistic regression analysis including 14 variables was performed to assess the factors contributing to 1-month survival and 1-month CPC 1 to 2 for all eligible patients. The 14 selected variables included year, age, sex, arrest witnessed by any layperson, arrest witnessed by EMS personnel, bystander CPR, presumed cause of arrest, initial cardiac rhythm, prehospital shock delivery, advanced airway management, physician-staffed ambulance, call-to-response time, call-to-hospital arrival time, and prehospital epinephrine administration for the model as an independent variable. These models yielded concordance statistics of 0.78 for 1-month survival and 0.84 for 1-month CPC 1 to 2, which indicated good discrimination.
In the multivariate logistic regression analysis of outcomes, we classified the following three continuous variables into three categories according to the IQR of each variable: age (<65 years, 65 to 85 years, >85 years), call-to-response time (<5 minutes, 5 to 9 minutes, >9 minutes), and call-to-hospital arrival time (<24 minutes, 24 to 37 minutes, >37 minutes).
Continuous variables are expressed as means and standard deviations. Categorical variables are expressed as percentages. As an estimate of effect size and variability, we report odds ratios (ORs) with 95% (CIs. All statistical analyses were performed using the JMP statistical package version 10 (SAS Institute Inc., Cary, NC, USA). All tests were two-tailed, and a value of P <0.05 was considered statistically significant.