Delayed hospital arrival has been identified as the most significant prehospital barrier to thrombolysis within 4.5 h or to mechanical thrombectomy within 6 h for acute ischemic stroke (AIS) (1). The problem of treatment delays is global, but the factors causing prolonged prehospital delays may be different due to variations in ethnicity, culture, socioeconomic features, and health care systems (2, 3). Existed findings suggest that bystander's quick response plays a key role in shortening delays when the stroke occurs. The bystander's timely recognition, action, and emotional response are all associated with hospital arrival within the thrombolysis time window (4, 5). Influenced by traditional Chinese culture, a majority of the elderly would live with their descendants, which has been confirmed to happen much more frequently in China (6–8) than in other countries (9–11). Patients, whose symptoms were discovered by family rather than themselves arrived at the hospital earlier than those who do not live with family (8, 12). Therefore, it is necessary to investigate how factors of family members' cognition and behaviors could influence the prehospital delay.

Thrombolysis is a time-dependent therapy and 1.9 million neuronal apoptosis could be avoided in the ischemic area per minute (15). Several factors affect the interval from stroke onset to hospital admission, but the influencing patterns and factors vary greatly across different populations and regions. We conducted this study to explore the factors that caused the prehospital delay and low rate of thrombolysis in AIS patients in China to enable more patients to arrive at the hospital within the time window. This study found that prehospital delay was severe in China, resulting a low thrombolysis rate. Only 15.0% of AIS patients arrived at the hospital within 4.5 h of stroke onset. The data was close to a previous study conducted in Chengdu, China (12), but lower than previous studies conducted in Eastern China and developed countries (8, 12, 16). The median prehospital delay time was 410 min, which was longer than that reported in north Spain (138.5 min) and Switzerland (150 min) (17), but shorter than that reported in the China QUEST (Quality Evaluation of Stroke Care and Treatment) study (15 h) (6). The thrombolysis rate in AIS patients was 5.8%, which was lower than the rates of studies in Jiangsu, China (18), London (12), and Nepal (19). The possible reason for this is that the health and education system lag behind due to its relatively backward economic development in Western China.

In this study, family members' knowledge about stroke and timely behavior was associated with the early arrival after stroke onset. Family members may play a great role in the use of Emergency Medical Service (EMS). There were 286 (16.0%) patients who arrived at the hospital by ambulance, among which 199 decision-makers were family members and 87 were patients themselves. The study in nonurban East Texas (USA) also showed that only 4.3% of 911 callers were AIS patients themselves and 60.1% were family members (20). Family member's discouragement to call 911 was the potential factor for the rarely EMS utilization (21, 22), and the behavior of waiting for family members was also the potential barrier to timely usage of EMS in the 40–74-year-old population (22). Previous studies also suggested that the bystander's prompt recognition, action, and emotional response were all associated with greater use of EMS and less delay (5, 9, 16, 20, 21, 23–26). However, few studies identified who made decisions on seeking medical help at the onset of a stroke (4, 22, 27), and no studies identified the role of cognitive and behavioral factors of the patient's family members in prehospital delay. This study further confirmed and extended the data: 41.5% of AIS patients' symptoms were first noticed by family members and 43.8% of medical help decisions were made by family members, similar to previous reports (4). The study showed that patients (instead of family members) deciding to seek medical services by themselves was independently associated with late arrival, which is similar to the results of a previous study (27). Family members' sufficient knowledge about timely stroke treatment was independently associated with early arrival and high thrombolysis rate, which could possibly result from cultural factors and family members' lack of stroke knowledge. We also found that living with descendants was associated with early arrival. Previous studies have identified that a majority of the elderly live with their descendants in Western and other regions of China (6–8), which is similar to the study in Korea (28) but higher than in other countries (9–11). The elderly often thought that the symptoms might disappear automatically and 24.2% of patients were afraid of troubling people that are not their family members, so living with their descendants was associated with early arrival. Furthermore, those who were over 65 years old were independently associated with late arrival and conservative therapy, which was consistent with previous studies results (6, 8, 14, 18, 29), but contrasted with others (11, 18, 30). Many people, especially the elderly, who suffer from neurological diseases may be less aware of the signs and symptoms of AIS compared to younger patients in Western China, and they were reluctant to seek medical attention unless they were advised to do so (26, 31). Therefore, to decrease the prehospital delay and the morbidity and mortality of AIS patients, public focus on family members is needed. In recent years, Stroke 1-2-0 Program provides a rapid recognition for stroke (32). It is suggested that more attention should be paid to the family members of stroke patients at high risk.

A majority of the statistically significant factors for the 4.5-h and for 6-h cutoff points were the same. This study demonstrated that patients who lived in non-urban areas and had a driving time from the onset place to the hospital of more than 30 min were independently associated with late arrival, which is similar to the results of previous studies (5, 17). Although the guidelines emphasized the importance of EMS (33), long driving time was still the main barrier to receiving AIS therapy due to the uneven distribution of hospitals and choosing to use private cars instead of using EMS in Western China (18). Patient's whose initial reaction was to call an ambulance, and arrived by ambulance (14, 16), were independently associated with early arrival. Despite previous studies showed that early arrival was not associated with patients' stroke knowledge (34), it is still believed that stroke education, the ability to describe FAST, and recognizing the problem as a stroke may shorten the prehospital delay (17, 28).

Similar to many other studies, the present study suggested that the factors such as severe stroke (12, 35–37), sudden onset symptoms (5, 34), onset at daylight (16, 19), consciousness disturbance (14, 36, 38, 39), weakness (38), and the use of an ambulance (5, 14, 18, 19, 28, 40) were significantly associated with early arrival. In comparison, those who had a prior stroke, a history of hyperlipidemia (18) or atrial fibrillation (5, 6, 18), had blurred vision in one or both eyes (38, 39) or were referred from other hospitals (6, 14, 41) were associated with delayed arrival. Among all the symptoms, only blurred vision was associated with prolonged prehospital delay, whereas weakness and consciousness disturbance could shorten the prehospital delay. Symptoms such as blurred vision, dizziness, and numbness are often believed by many patients to be relieved by lying down and having a rest. Therefore, milder symptoms should also be included in public stroke education for high-risk individuals.

It was also found that the decision time <60 min (40) was an independent predictor of early hospital arrival. During the study period, 180 patients decided to search for medical service within 30 min the symptoms occurred, among which 152 patients arrived at the hospital within 4.5 h while 28 patients did not. Among those who did not, most of them were live in suburban or rural with more than 1 h driving time, 13 patients were referred from other hospitals. A possible explanation for this might be the insufficient stroke knowledge and long distance. Some onset symptoms of a stroke are mild and similar to hypoglycemia, atrial fibrillation, or other diseases so they may visit the private clinic, community hospital or other departments instead of neurology or emergency departments. Previous studies have demonstrated that private clinics or other departments in different hospitals may differ from departments specialized in stroke recognition and treatment, so clinic doctors and community physicians should also be included in the target groups of the stroke (42).

A previous study confirmed that patients at any age could benefit from early thrombolysis (43). However, this study showed that the elderly was less likely to accept thrombolysis, which was similar to the study results in Singapore and the US (44). This may because the patients' family members worried more about the risk of bleeding from thrombolysis due to patients' underlying diseases and weaker systems. In contrast, people who have high monthly income, high education levels, high NIHSS scores were more likely to accept the thrombolysis therapy. For a poor family, the high cost of thrombolysis was the main barrier to accept the therapy (19, 45). In addition, cultural factors and economic status were also possible causes for this.

This study has several limitations. First, subjects' recall bias could occur inevitably, especially for symptom onset that could be accurate to within 10 min, and even within 30 min for some patients. Since reporting errors could go either way, their impact on our results cannot be determined. Second, patients' memory may be hampered by stroke-related cognitive impairment. Third, although every effort was made to ensure that subjects' interviews were conducted as soon as possible after hospitalization, interviews in some cases were delayed for various reasons. Lastly, missing data, including the participation refusal given by 8.1% of patients and the lack of 1.6% patients' information may have also adversely influenced the regression analyses.

This is the first multicenter study to investigate the factors that influence the prehospital delay of thrombolysis for AIS, with a focus on the recognition and behavior of family members associated with prehospital delay in China. First, only 14.98% patients arrived at hospitals in Western China within 4.5 h, 40.52% patients arrived within 6 h after the onset of symptoms, 5.8% patients received thrombolysis. Second, the findings highlight the importance of the family member's recognition and behavior for early arrival. Third, the association between specific symptoms of stroke and prehospital delay were mixed so more studies should be carried out to further evaluate this link.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by Research Ethics Committee of Chengdu Military General Hospital, Chengdu, China. The patients/participants provided their written informed consent to participate in this study.

RW contributed to the study design and original draft writing. ZW contributed to methodology and data curation. JW and CG performed data collection. YZ and LX conducted the statistical analysis. QW provided funding. DY performed supervision. All authors reviewed the draft and approved the final submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.