a b s t r a c t

Background: Earlier administration of intravenous recombinant tissue-type plasminogen activator (rtPA) and Mechanical thrombectomy (MT) improves the Neurological prognosis of patients with acute ischemic stroke . We introduced a new protocol that includes head and chest computed tomography and magnetic resonance imaging (MRI)/ magnetic resonance angiography (MRA) for all patients, which is quite different from previously evaluated protocols. This study aimed to examine whether this protocol could contribute to the prompt therapeutic intervention of AIS.

Methods: This is a retrospective observational study analyzing patients with AIS who were transported to our hospital by ambulance between January 2015 and November 2021. An AIS initial treatment protocol was intro- duced in April 2020, under which, CT and MRI/MRA imaging were performed in all patients, and the indication for rtPA and MT were determined. The participants were divided into those who were treated before and after the protocol introduction (Conventional treatment and protocol groups, respectively). The time from hospital arrival to the start of rtPA administration (Door-to-needle time: DNT) and the time from hospital arrival to the start of endovascular treatment (door-to-puncture time: DPT) were compared between the groups.

Result: A total of 121 patients were analyzed, wherein 63 patients received rtPA (18 in the conventional treat- ment group and 45 in the protocol group) and 98 patients received MT (32 in the conventional treatment group and 66 in the protocol group). The median DNT was 97.0 (IQR 49.0-138.0) min vs. 56.5 (IQR 41.0-72.0) min (p < 0.001) for the conventional treatment and the protocol groups, respectively. The median DPT was

129.0 (IQR 62.0-196.0) min vs. 55.0 (IQR 40.5-69.5) min (p < 0.001), respectively. Moreover, DNT was achieved within 60 min in 5.6% vs. 69.9% (p < 0.001) and DPT within 90 min in 25.0% vs. 85.7% (p < 0.001), respectively. Conclusion: The introduction of a protocol, including CT/MRI imaging, significantly shortened DNT and DPT.

(C) 2022

1. Introduction

Approximately 5.5 million people worldwide and 120,000 people in Japan die from stroke annually [1]. As the world’s population continue

Abbreviation: AHA, American Heart Association; AIS, Acute ischemic stroke ; ASA, American Stroke Association; ASPECTS, Alberta Stroke Program Early Computed Tomography Score; CSC, comprehensive stroke center; CT, computed tomography; DNT, door-to-needle time; DPT, door-to-puncture time; DWI, diffusion-weighted images; DWI-FLAIR, diffusion-weighted image and fluid-attenuated inversion recovery; IQR, inter- quartile range; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; MT, mechanical thrombectomy; NIHSS, National Institutes of Health Stroke Scale; PT-INR, prothrombin time-international normalized ratio; rtPA, recombinant tissue-type plasmin- ogen activator.

* Corresponding author.

E-mail addresses: [email protected] (S. Kanou), [email protected] (S. Nakahara), [email protected] (Y. Miki).

to age, the number of patients with stroke is projected to increase in the future; thus, higher quality stroke treatment is required. Previous studies have shown the effectiveness of the intravenous administration of recombinant tissue-type plasminogen activator (rtPA) [2] and me- chanical thrombectomy (MT) [3] to improve neurological prognosis. Furthermore, these treatments are the standard of care according to the American Heart Association (AHA)/American Stroke Association guidelines [4].

Diagnosis and initiation of treatments as soon as possible after the arrival of patients at the hospital are important to obtain good out- comes. The AHA guidelines recommend that rtPA administration should be initiated within 60 min and MT should be initiated within 90 min after hospital arrival [5]. Thus, an acute stroke team that includes physi- cians, nurses, and radiologists must be established, and specific proto- cols must be introduced [4]. Studies that examined the effectiveness of

https://doi.org/10.1016/j.ajem.2022.09.011

0735-6757/(C) 2022

protocol implementation reported that the clarification of the roles of each profession; standardization of procedures, including history tak- ing, examination, computed tomography (CT) imaging, and treatment, and simulation training significantly reduced the time from hospital ar- rival to treatment and increased the rate of rtPA use [6-8]. However, these protocols are all based on CT imaging. In contrast, Goyal et al. [9] reported a protocol that includes magnetic resonance imaging (MRI), but only for cases that are difficult to diagnose with CT.

Although MRI and magnetic resonance angiography (MRA) usually require a longer time than CT, they would be quite useful in diagnosing acute ischemic stroke (AIS) and determining the indications for treat- ment if they did not substantially delay the start of acute treatment [10]. Moreover, MRI has a higher inter-rater agreement rate than CT in diagnosing AIS and determining the indications for treatment because of the following: diffusion-weighted images (DWI) can clearly detect AIS at earlier stages than CT; the DWI can provide information in order for the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) to estimate ischemic core volume; and MRA can deter- mine the occluded sites of blood vessels. In addition, diffusion-weighted image and fluid-attenuated inversion recovery (DWI-FLAIR) mismatch would provide useful information regarding the indications of rtPA and MT, particularly for those with unknown onset time (e.g., patients with impaired consciousness, aphasia, and wake-up stroke) and those arriving at the hospital after the standard time interval for treatment (e.g., rtPA should be administered within 4.5 h of the onset) [1,11,12].

Although analysis software is recommended to quantify the size of the ischemic core and hypoperfusion zone for MT indications, particu- larly for those with unknown AIS onset time [11], it is not widely used in Japan. In contrast, MRI is available in most hospitals which provide acute care for AIS. With such resources, a protocol which uses MRI in all cases would be relevant.

Given the benefits of MRI/MRA imaging, we developed a protocol in which both CT and MRI/MRA are performed on all patients and their effects evaluated. This protocol aimed to achieve the guideline- recommended time to treatment, while simultaneously allowing CT to exclude severe diseases other than AIS and MRI/MRA to confirm the diagnosis of AIS and determine the indication for treatment. To our knowledge, the effectiveness of a protocol using both CT and MRI/ MRA in all patients has not been reported. Thus, in this study, we exam- ined whether our AIS initial care protocol could sufficiently shorten the time between hospital arrival and definitive treatment for AIS.

1. Methods
   1. Design

This retrospective observational study was conducted at a tertiary care hospital in the central region of Japan, wherein the time taken to start treatment before and after the protocol was introduced were compared. The study was approved by the ethics committee of the hospital (approval number: R03-27). The need for informed consent was waived because of this study’s retrospective nature.

• 1. Study settings

The medical facilities in Japan designated for emergency treatment are classified into primary, secondary, and tertiary level facilities accord- ing to the severity of the patients they can accept. The municipal fire departments run emergency medical services and transport patients to the hospital by ambulance. Ambulance crews select appropriate medical facilities depending on the severity of the patient’s condition and in accordance with the standards established for the medical care delivery system in the area.

Our hospital is located at the center of the main island of Japan. It is the only tertiary care facility in the medical district, which has a popula- tion of approximately 450,000 and an area of 1200 km². The facility has

564 beds and accepts severely ill or injured patients, as well as patients with mild to moderate illnesses equivalent to primary and secondary emergencies. It has seven emergency physicians who oversee emer- gency cases and two neurosurgeons who oversee the treatment of patients with stroke.

In this district, those who meet two of the following three criteria among patients with suspected stroke are more likely to have severe stroke (major vessel occlusion) and be transported to a tertiary care facility: (1) Japan Coma Scale II-10 (arousable by being spoken to) or higher (worse) or evident aphasia; (2) conjugate eye deviation; and

(3) paralysis of the upper limbs, including incomplete paralysis. These criteria were developed at our hospital based on previous studies [12-14]. There are no criteria related to last known well time and age. Cases with suspected stroke, such as those with monoplegia, dys- rhythmia, or numbness symptoms, that do not meet the above criteria are sent to the nearest secondary level emergency hospital (there are four such hospitals including ours in the medical district). The rtPA administration for AIS is based on the guidelines of the Japan Stroke Society [15], and MT is performed based on the guidelines of the Japan Stroke Society, Japan Neurosurgical society, and Japanese Society for NeuroEndovascular therapy [11].

• 1. Operation of AIS initial Treatment protocols

The emergency physician and neurosurgeons jointly developed an original protocol and began its operation in April 2020 (Table 1). Its fea- tures include: the roles of all emergency medicine personnel are clearly defined; all personnel start their roles simultaneously upon activation; all patients go through unenhanced head and chest CT and MRI/MRA; CT/MRI protocols are in place; and the patients are directly transported

Table 1

Acute ischemic Stroke protocol.

• • • Upon receiving a call from emergency medical services
      • Prepare the rtPA set and weight measuring stretcher
      • Call neurosurgeons (first report) (by emergency physician)
    • Upon patient arrival at the emergency department
      • Secure two intravenous routes
      • Perform blood tests (blood count, biochemical, coagulation, infection, and blood type) including PT-INR (this takes 30 min)
      • Perform blood gas analysis to check creatinine and glucose levels
      • Perform electrocardiography
      • Measure weight
      • Assess NIHSS (by junior residents)
      • Fill out “rtPA checklist” to check for contraindications or cautious administration
    • Transfer patient to CT scan room
      • Exclude cerebral hemorrhage and acute aortic dissection (by emergency physician)
      • Call neurosurgeons (second report) (by emergency physician)
      • Administer Edaravone (skipped if creatinine >1.5 mg/dL)
      • Call in radiologic technicians and nurses on call (by nurse)
    • Transfer patient to MRI room
      • Obtain informed consent form relatives for rtPA and MT (by emergency physician)
      • Determine the treatment plan based on neuroimaging (by neurosurgeons)
    • Transfer patient to angiography room or emergency department
      • Initiate rtPA (by junior resident) and MT (by neurosurgeon) in angiogra- phy room
      • Initiate rtPA in the emergency department

rtPA: Recombinant tissue-type plasminogen activator. NIHSS: National Institutes of Health Stroke Scale.

MT: Mechanical thrombectomy.

PT-INR: Prothrombin time-international normalized ratio. CT: Computed tomography.

MRI: Magnetic resonance imaging.

to angiography from the MRI room. This allows for treatment to begin in a Short period of time.

If a request was received by the emergency physician from the emergency medical services team for the transportation of a patient with suspected AIS who met the above criteria, the clinician activated the protocol. For less severe cases of suspected stroke, emergency phy- sicians had the discretion to activate the protocol after examining the patient, even if they did not meet the criteria, if they had symptoms such as paralysis and aphasia and had a short time interval from symp- tom onset to hospital arrival.

Prior to the arrival of the patient, nurses from the emergency medi- cal center prepared a stretcher for weighing and rtPA administration, and the neurosurgeons were requested by the emergency physicians to stand by. The emergency physicians confirmed the roles and instructed the nurses, residents, as well as the radiological technologists to secure CT and MRI scan rooms and an angiography room.

Upon the patient’s arrival at the hospital, their history, including time of symptom onset and discovery, past history, and medications were taken. The patient’s venous route was also secured in the emergency department. Furthermore, a blood sample was taken to check their blood glucose, renal function, and prothrombin time- international normalized ratio (PT-INR). An electrocardiogram was also taken, and the patient’s weight was measured to calculate rtPA dosage. In Japan, PT-INR measurement, wherein the results could be obtained in 30 min, is required to determine the indication for rtPA ac- cording to the guidelines [15]. Furthermore, we measured the National Institutes of Health Stroke Scale , and the contraindications to rtPA were checked using a checklist (Appendix 1).

After completing these evaluations, imaging studies were performed, following the protocol. First, non-enhanced CT exams of the head and chest were performed in all patients to rule out hemorrhagic stroke and exclude thoracic aortic dissection. If the CT exams are negative, patients were transferred to the MRI laboratory for head MRI + MRA. To minimize the imaging time, the MRI protocol only requires the following images: DWI, FLAIR (DWI-FLAIR mismatch is used to estimate time of onset), T2*-weighted images, and MRA. During neuroimaging, written informed consent was obtained from the family for rtPA by the emergency physicians and MT as needed, and the images were reviewed by the neu- rologists to determine the treatment plan. The patient, when MT was in- dicated according to the guidelines (Appendix 2), was transferred directly from the MRI scan room to the angiography room, where rtPA and MT were performed simultaneously. When MT was not indicated, the patient was transferred back to the emergency department to receive rtPA ad- ministration. Prior to the introduction of the protocol, following the 2015 Japanese Society for Neuroendovascular Therapy guidelines [16], rtPA and MT were performed sequentially: rtPA was administered in the emergency department, and the patients were moved to the angiog- raphy room to receive MT if rtPA was ineffective.

• 1. Study population

This study included all patients with AIS who were transported by ambulance and underwent rtPA administration or MT at the hospital between January 2015 (time of establishment of the emergency depart- ment at the hospital) and November 2021. All patients underwent head MRI, wherein the diagnosis of AIS had been made even before the intro- duction of the protocol. Patients, who were transferred from other hos- pitals were included unless they had undergone rtPA or MT prior to the transfer. Patients who came to the hospital on their own or developed AIS in the hospital were excluded.

rtPA administration was indicated for patients who did not meet the exclusion criteria of the Japan Stroke Society guidelines (Appendix 1) [15]. Patients who required cautious administration were treated and included in the study after providing sufficient explanation of the benefits and disadvantages to the patients and their proxies. MT was performed in patients who met the indication criteria of the guidelines

of the Japan Stroke Society, Japanese Neurosurgical society, and Japanese Society for Neuroendovascular Therapy (Appendix 2) [11]. Both rtPA and MT were performed when indicated.

Patients who came to the hospital between January 2015 and March 2020 were categorized as the conventional treatment group, and those who came to the hospital between April 2020 and November 2021 as the protocol group. All patients who underwent rtPA or MT in the pro- tocol group were treated under the activated protocol. No patients were excluded due to missing data during the study period.

• 1. Data collection

All the data for this study were extracted from electronic medical re- cords. The onset time, hospital arrival time, rtPA start time, and MT start (puncture) time were available for all AIS cases transported to our hos- pital. The time interval from the arrival of the ambulance team at the hospital to the start of rtPA was defined as the door-to-needle time , while the time to vascular puncture for MT was defined as the door-to-puncture time (DPT). The patients’ demographic data (age and sex), comorbidities, AIS-related scores (NIHSS, ASPECTS), and occluded sites of blood vessels based on MRA were also collected.

• 1. Analysis

Non-normally distributed continuous variables were described using median and interquartile range (IQR), and categorical variables were de- scribed using number and percentage. DNT and DPT before and after the introduction of the protocol (conventional treatment group vs. protocol group) were compared to test the hypothesis, “Operation of the AIS Initial Treatment Protocol shortened DNT and DPT in acute stroke cases.” Cases in which both rtPA and MT were administered were included in both analyses. As standardized effect sizes to indicate the magnitude of the group differences, rank-biserial correlation coefficient (Spearman’s ?) and Cramer’s V were used for median and proportion differences, respec- tively. These indicators express the differences as the strength of associa- tion between variables (group categorization and time intervals): coefficients of 0.2, 0.5, and 0.8 are considered to be minimum, moderate, and strong effects, respectively. The Mann-Whitney test was used for continuous variables, and the ?² test was used for categorical variables in the before-after comparison. Statistical significance was set at p < 0.05. The required sample sizes were calculated using G*Power. We as- sumed ? = 0.05, power (1-?) = 0.8, and the size ratio of the protocol group to the conventional treatment group was 2:1. Based on previous studies, the effect sizes of DNT and DPT were assumed to be 0.7 (mean 90 min, reduced to 60 min after protocol introduction) and 0.6 (mean 100 min, reduced to 60 min after protocol introduction), respectively, and the standard deviation was 50 for both groups. The results were 41 and 21, respectively, for DNT and 56 and 28, respectively, for DPT. Statistical analysis was performed using IBM SPSS Statistics for Win-

dows, version 24 (IBM Corp., Armonk, N.Y., USA).

1. Results

Among the acute stroke cases transported by ambulance and treated at our hospital between January 2015 and November 2021, 121 were el- igible for this study: 40 (23 males) in the conventional treatment group and 81 (52 males) in the protocol group (Table 2). The median ages of the patients were 73.0 years (IQR, 59.0-86.0) and 81.0 years (IQR, 66.0-95.0), respectively. Comorbidities were higher in the protocol group for hypertension, hyperlipidemia, and cerebral infarction. The proportion of patients with unknown interval from onset to hospital ar- rival was higher in the protocol group (32.5% in the conventional group and 48.1% in the protocol group). Median pretreatment NIHSS was 20 (IQR, 5-35) and 18 (IQR, 3-33) in the conventional treatment and pro- tocol groups, respectively, and the DWI-ASPECTS were 5 (IQR, 3-6) and 8 (IQR, 4-9), respectively. Non-enhanced CT and MRI + MRA of the

Table 2

Patient characteristics.

Table 3

Comparison of outcomes before and after the introduction of the Target Stroke Protocol.

Before protocol

Protocol (n = 81)

Effect size*

Before protocol

Protocol p value Effect size

(n = 40)

DNT (min), median

97.0

56.5

<0.001 0.654

rtPA, n. (%)	18 (45.0)	45 (56.6)	0.10	(interquartile range)	(79.1-138.0)	(49.3-64.3)
MT, n. (%)	32 (80)	66 (81.5)	0.05	DNT < 60 min, n (%)	1 (5.6)	31 (69.9)	<0.001	0.618
rtPA+MT, n. (%)	9 (22.5)	30 (37.0)	0.15	DPT (min), median	129.0	55.0	<0.001	0.478
Age (years), median (interquartile	73.0	81.0	0.26	(interquartile range)	(62.0-196.0)	(50.0-79.0)
range)	(59.0-86.0)	(66.0-95.0)		DPT < 90 min, n (%)	8 (25.0)	54 (85.7)	<0.001	0.474
Gender (male), n (%) Comorbidities, n (%)	23 (57.5)	52 (64.2)	0.08	mRS at discharge from hospital, median (interquartile range)	4 (3-5)	4 (3-5)	0.58	0.050

DNT: door-to-needle Time. DPT: door-to-puncture Time. mRS: modified Ranking Scale.

Diabetes	6 (14.6)	15 (18.5)	0.04
Hypertension	18 (45.0)	46 (56.8)	0.11
Hyperlipidemia	4 (10.0)	15 (18.5)	0.11
Atrial fibrillation	13 (32.5)	27 (33.3)	0.01
Myocardial infarction/Heart failure	9 (22.5)	19 (23.5)	0.01
Cerebral infarction	2 (5.0)	12 (14.8)	0.14
Current smoking	16 (40.0)	31 (38.3)	0.02
Interval from onset to hospital arrival,			0.25
n (%) Unknown	13 (32.5)	39 (48.1)
0-1 h	20 (50.0)	22 (27.2)
1-2 h	6 (15.0)	13 (16.5)
2-3 h	1 (2.5)	4 (4.9)
3-4 h	0 (0)	2 (2.5)
4-5 h	0 (0)	0 (0)
hr > 6	0 (0)	1 (1.2)
DWI-ASPECTS, median (interquartile range)	5 (3-6)	8 (4-9)	0.34
NIHSS, median (interquartile range)	20 (5-35)	18 (3-33)	0.04
Occluded site where MT was performed, n (%) M1	12 (46.2)	27 (40.1)	0.25
M2	5 (19.2)	19 (28.8)
M3	0 (0)	4 (6.1)
ICA	6 (23.1)	11 (16.7)
BA	2 (7.7)	2 (3.0)
ACA	0 (0)	1 (1.5)
PCA	1 (3.8)	2 (3.0)

*Spearman’s ? and Cramer’s V were used for median differences and proportion

differences, respectively.

1. Discussion

rtPA: recombinant tissue-type plasminogen activator. MT: mechanical thrombectomy.

ASPECTS: Alberta Stroke Program Early CT Score. DWI: Diffusion Weighted Imaging.

NIHSS: National Institutes of Health Stroke Scale. M1: Horizontal segment of Middle cerebral artery. M2: Insular segment of middle cerebral artery.

M3: Opercular segment of middle cerebral artery. ICA: Internal carotid artery.

BA: Basilar artery.

ACA: Anterior cerebral artery. PCA: posterior cerebral artery.

*Spearman’s ? and Cramer’s V were used for median differences and proportion differ- ences, respectively.

head was performed. Among the 121 patients, 63 were administered with rtPA (18 in the conventional treatment group and 45 in the proto- col group) and 98 with MT (32 in the conventional treatment group and 66 in the protocol group). Furthermore, 39 patients were administered with both rtPA and MT (nine in the conventional treatment group and 30 in the protocol group). The most common occluded site in patients who underwent MT was M1 (horizontal segment of the middle cerebral artery) in both groups (46.2% in the conventional group and 40.1% in the protocol group).

Significant differences with moderate effect sizes were observed in between the protocol and conventional treatment groups in median DNT (56.5 [IQR 41.0-72.0] and 97.0 [IQR 49.0-138.0] min, respectively) (p < 0.001) (Table 3), median DPT (129.0 [IQR 62.0-196.0] and 55.0

[IQR 40.5-69.5] min, respectively) (p < 0.001), proportion of DNT within 60 min (69.9% and 5.6%, respectively) (p < 0.001), and propor- tion of DPT within 90 min (87.5% vs. 25.0%, respectively) (p < 0.01). In contrast, the modified ranking scale at discharge was not significantly different between the two groups (4 [IQR 3-5] and 4 [IQR 3-5], respec- tively) (p = 0.58).

The present protocol shortened the time from presentation to treat- ment in patients with AIS, achieving the AHA recommendations of DNT

< 60 min and DPT < 90 min in many cases despite its seemingly time- consuming imaging strategy (all patients underwent head and chest CT, and head MRI/MRA). In the United States, a median (IQR) DNT of 52 (32- 70) min and DPT of 119 (75- 174) min have been reported at the Comprehensive Stroke Center (CSC), where advancED treatments such as endovascular therapy are available 24 h a day [17]. The present study indicated almost the same DNT and shorter DPT than the United States CSC study despite the differences in treatment strategies.

Factors that delay AIS treatment include delays in imaging, hyper- tension requiring control, delays in triage, fluctuating neurologic symp- toms, and diagnostic uncertainty [10]. Moreover, MRI imaging, a time- consuming examination, prior to treatment initiation is likely to delay treatment. However, the protocol in the present study controlled these factors to successfully minimize the delay, which included prepa- rations starting before patient arrival, immediate systematic evaluation by emergency physicians, involvement of the neurosurgeon at the ear- liest possible stage, standardized procedures from hospital arrival to di- agnosis and treatment, and minimal diagnostic imaging.

In this study, all patients underwent head MRI/MRA, which differs considerably from previous studies, in which decisions were made mainly using CT. Ajmi et al. [18], and Iglesias et al. [19] achieved shorter DNT by transferring patients directly to the CT laboratory immediately after hospital arrival and starting rtPA there (median DNT of 13 min and 34 min, respectively). However, thrombolytic therapy in a CT room is not feasible in Japan as the Japanese guidelines require PT-INR measurement before treatment [15], which takes approximately 30 min. This study took advantage of this waiting time to enhance the diag- nostic system with MRI/MRA. As normal MRI/MRA imaging takes 20-30 min, an MRI/MRA imaging protocol was implemented to minimize the imaging time. Goyal et al. [9] used a hyperacute MRI protocol to achieve a median DNT of 37 min; however, they performed MRI only for cases in which stroke mimics, such as epilepsy and arthritis, could not be ruled out. The present study also differs from previous studies such that the early initiation of MT was also included in the protocol.

The AHA/ASA guidelines state that the effect of performing MRI in all cases of suspected AIS is unknown [4]. In contrast, in a randomized con- trolled trial reported by Hansen et al., [20], MRI scans allowed neurosur- geons to administer rtPA with more confidence than CT scans and recognize relative contraindications to rtPA more frequently. In addi- tion, DWI-FLAIR mismatch was useful information for those with un- known onset time. Our hospital serves an area with many Elderly people, and the time of onset is often unknown, or the witnessed time of onset is inaccurate. With CT-only protocol, patients with indications for treatment may be missed, if the time of onset is unknown. Previous randomized controlled trials used contrast-enhanced CT or contrast-

enhanced MRI and analysis software to determine the indication for treatment [21,22], and these are recommended in the guidelines [11]. However, analysis software is not widely used, especially in Japan. On the other hand, MRI is widely used in Japan, and the method, which uses DWI-FLAIR mismatch, may be an acceptable protocol.

This study included chest and head CT in all patients to rule out ce- rebral hemorrhage and aortic dissection at an early stage. MRI can diag- nose cerebral hemorrhage; however, it is a time-consuming test compared to CT, and aortic dissection cannot be detected by MRI. With- out the CT of the head and chest in all patients, intervention may be de- layed for Serious diseases other than ischemic stroke. As a CT scan can be performed in a short time, an unenhanced CT of the chest in all patients is acceptable to allow for immediate intervention by emergency physi- cians if a serious disease other than AIS is diagnosed.

This study indicated that DPT was shorter than DNT, which means that the reduction of DPT was larger than that of DNT because of the new treatment strategies in the protocol. rtPA and MT were simulta- neously prepared in the angiography room after MRI. However, the start of rtPA administration is often delayed slightly behind the punc- ture for MT because of the complicated preparation of the drug.

CRediT authorship contribution statement

Seiya Kanou: Writing - original draft, Software, Project administra- tion, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Shinji Nakahara: Writing - review & editing, Super- vision, Methodology, Conceptualization. Motohiro Asaki: Writing - review & editing. Masato Takeuchi: Writing - review & editing. Kana Uchida: Writing - review & editing. Nodoka Yamamori: Writing - review & editing. Yujiro Tanaka: Writing - review & editing. Tomoya Yokoyama: Writing - review & editing. Shohei Nakaya: Writing - review & editing. Yasuo Miki: Writing - review & editing.

Declaration of Competing Interest

None.

Appendix 1. Checklist for contraindications or cautious administra- tion of thrombolytic therapy

Nevertheless, this study has several limitations. First, the single-

center, before-and-after design of this study, could not address the influ- ences of changes that occurred simultaneously as the introduction of the protocol such as the changes in treatment strategy or personnel. The MT strategy was changed at the time of the protocol introduction-MT was initiated after confirming the ineffectiveness of rtPA before the introduc- tion of the protocol; however, rtPA and MT should start simultaneously according to the guidelines [15] after the introduction of the protocol. Al- though this change contributed to the shorter DPT, this change alone is unlikely to cause the 70-min time reduction. In addition, this change had no effect on the timing of rtPA administration; thus, a bias toward DNT was unlikely. Although the director of the neurology department was replaced in April 2020, personnel changes had little effect on the re- sults shown in this study because this protocol was a multi-department collaboration, and the treatment was standardized. Second, this was a single-center study, and it is not clear whether similar results would be obtained if the protocol was implemented at other medical facilities. A multicenter study with a control group is needed to yield generalizable results. Third, this study was designed to investigate the process improve- ment in the emergency department. Moreover, its retrospective design did not allow us to evaluate the contribution of the protocol to the im- provement of the patients’ prognoses. Such evaluations require standard- ized prognoses measurements such as the 90-day Modified Rankin scale, which was unavailable in this study. Risk adjustment is also required for age, severity, and comorbidities. Differences in these factors, particularly the different age distributions, may explain the lack of improvement in the modified Rankin Scale at discharge in this study. Therefore, data col- lection in future prospective studies is needed to evaluate prognosis.

1. Conclusions

We introduced a treatment protocol for acute stroke at our hospital and examined its effect on the reduction of the time from hospital arrival to treatment. Although the protocol included relatively time- consuming elements, such as PT-INR, CT, and MRI/MRA, it significantly shortened the time before treatment.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Source(s) of support in the form of equipment, drugs, or grants None.

Contraindications

Time course from illness onset to treatment initiation

• >4.5 h after onset or no DWI/FLAIR mismatch

Past history

• Non-traumatic internal cranial hemorrhage
• Cerebral infarction within 1 month (does not include cases where symptoms have disappeared for a short time)
• Serious head or spinal cord trauma or surgery within 3 months
• Gastrointestinal or urinary tract bleeding within 21 days
• Major surgery or non-head trauma within 14 days

Clinical findings

• Subarachnoid hemorrhage, combination of bleeding (intracranial, digestive tract, urinary tract, retroperitoneum, hemorrhage)
• Abnormal hypertension refractory to treatment
• Severe liver injury, acute pancreatitis, Infective endocarditis

Hematological findings

• Abnormal blood glucose levels
• PT-INR > 1.7, prolonged APTT, direct oral anticoagulant medication

CT/MRI findings

• Widespread early Ischemic changes, Midline shift

Cases requiring cautious administration Age > 81 years old

Treatment can be started >4.5 h after last confirmation of good health and within

4.5 h of detection using DWI/FLAIR mismatch. Past history

• Biopsy, trauma, delivery or Premature MIscarriage within 10 days
• Cerebral infarction >1 month old (especially in patients with diabetes mellitus)
• Protein allergy

Neurological findings

• NIHSS >26
• Rapidly decreasing symptoms
• Convulsions (off-label if there is a high possibility of epilepsy based on history)

Clinical findings

• cerebral aneurysm, intracranial tumor, cerebral arteriovenous malformation, moyamoya disease
• Thoracic aortic aneurysm, gastrointestinal ulcer, diverticulitis, Colitis
• Active tuberculosis
• Diabetic hemorrhagic ophthalmopathy, hemorrhagic eye disease
• Receiving thrombolytic or antithrombotic drugs (especially oral anticoagulants)
• During menstrual period
• Severe renal failure uncontrolled diabetes mellitus

Toyoda K, Koga M, Iguchi Y, Itabashi R, Inoue M, Okada Y, et al. Guidelines for Intrave- nous Thrombolysis (Recombinant Tissue-type Plasminogen Activator), the Third Edition, March 2019: A Guideline from the Japan Stroke Society. Neurol Med Chir 2019;59 (12):449-91. https://doi.org/10.2176/nmc.st.2019-0177.

rtPA: recombinant tissue-type plasminogen activator NIHSS: National Institutes of Health Stroke Scale

Appendix 2. Indications for MT

Within 6 h of onset (Concomitant use of rtPA)

• Occlusion of the main cerebral artery (ICA or MCA M1)
• Pre-onset mRS score of 0 or 1
• ASPECTS of 6 or higher on head CT or MRI-DWI
• NIHSS score of 6 or higher
• 18 years or older

>6 h after onset

• Occlusion of the main cerebral artery (ICA or MCA M1)
• Pre-onset mRS score of 0 or 1
• NIHSS score of 10 or higher
• ASPECTS score of 7 or higher on MRI-DWI
• MT can be started within 16 h of onset

MT may be considered for patients with widespread ischemia with an ASPECTS score of

<6, mild cases with a NIHSS score of <6, acute cerebral artery occlusion in MCA M2 or BA, and cerebral infarction with a pre-onset mRS score of 2 or higher.

Yamagami H, Hayakawa M, Inoue M, Iihara K, Ogasawara K, Toyoda K, et al. Guidelines for Mechanical Thrombectomy in Japan, the Fourth Edition, March 2020: A Guideline from the Japan Stroke Society, the Japan Neurosurgical Society, and the Japanese Society for Neuroendovascular Therapy. Neurol Med Chir 2021;61(3):163-92. https://doi.org/10. 2176/nmc.st.2020-0357.

rtPA: recombinant tissue-type plasminogen activator mRS: modified Rankin Scale

ICA: internal carotid artery

MCA: middle cerebral artery

NIHSS: National Institutes of Health Stroke Scale ASPECTS: Alberta Stroke Program Early CT Score MT: mechanical thrombectomy

BA: basilar artery

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