Study design and setting
In this study, patients will be randomly divided into two groups. Intervention group: Acupuncture combined with oral medication. Control group: Western medicine treatment plan. Patients who meet the inclusion and exclusion conditions first complete informed consent, are randomly divided into groups, and are randomly stratified according to the clinical treatment period of the "Plan". For specific stratification factors and reasons, see "Sample Estimation" of the statistical analysis plan. The intervention time was 12 weeks. The treatment was observed for 7 days, followed up for 28 days, and the evaluators will be evaluated blindly. During the observation period, patients who meet the criteria of the "Removal of Isolation and Discharge from the Plan" or those who have died and actively withdrew will be suspended from observation. After the observation period, patients who do not meet the "Resolution" of the Isolation and Discharge from the Hospital will still be hospitalized for standard treatment. In addition, we will implement a clinical surveillance system to ensure research quality.The trial work plan is summarized in Fig. 2.
Inclusion/exclusion criteria
We aim to recruit patients with PSCI who feel down in the dumps despite standard medical therapy.Patient inclusion criteria：(1) A clear history of ischemic stroke or hemorrhagic stroke was confirmed by CT/MRI examination of the head; (2) Memory and/or cognitive and executive function impairments. Cognitive dysfunction has been determined after Mini Mental State Evaluation (MMSE) score; (3) Age will be limited to between 40-75 years of age, regardless of gender; (4) Stable condition, clear awareness , No aphasia, can take drugs orally; (5) No severe comorbidities, no major depression; (6) Agree and sign the patient's informed consent.
Exclusion criteria:(1) Computer computed tomography (CT) or magnetic resonance imaging (MRI) shows that in addition to the responsible lesion, there are other lesions unrelated to the lesion or severe brain atrophy or white matter porosity; (2) with sensory Aphasia or motor aphasia that affects speech communication; (3) People with a previous history of mental retardation; (4) Patients with previous mental illness and/or with epilepsy; (5) Unstable vital signs, diabetes, blood Patients with disease or tumor; (6) Patients who have been taking sedatives for a long time; (7) People with a history of allergies to drugs and food; (8) People who have been identified with a cognitive impairment before a stroke.
Control group
Patients in the control group will receive conventional drug treatment, specifically, given donazepam hydrochloride tablets 5 mg orally once a night. If there are no adverse reactions, take 3 consecutive months. And they will be given symptomatic supportive treatments such as improving circulation, anti-free radicals, anti-platelet aggregation, lipid-lowering, and blood pressure. In addition, all patients underwent routine rehabilitation exercises after stroke.
Intervention group
In the intervention group, acupuncture will be added to the control group. We will select Baihui, Shenting, Sishencong, Neiguan and Waiguan as the main acupuncture points. After the doctor cleans his hands, he disinfects with an ethanol cotton ball. Wipe outward with a medical ethanol cotton ball or iodophor from the center of the patient's acupuncture site. We will use acupuncture needles with a size of 0.25 mm×40 mm. Acupuncture physicians start treatment with acupuncture on the inside, outside and outside points. The order of acupuncture at acupoints is left internal pass, right internal pass, left external pass, and right external pass. The needle point is inserted into the acupuncture point vertically downward, and the needle insertion speed should be fast. After the needle point penetrates the cortex, slowly insert the needle inward, the depth is about 15mm, until the Qi is obtained. The needle method mainly adopts the gentle lifting method, that is, after getting Qi, the patient does not aggravate the pain level as a standard, and the lifting method is used to puncture slowly. Secondly, acupuncture the Baihui acupoint on the head, keep the needle tip at an angle of 20 ° with the plane of the scalp, and quickly pierce the needle tip into the scalp. After penetrating the cortex, the needle points back into the needle along the vein, and the needle is inserted about 15mm. Until the Qi is obtained, the needle method is still used to gently lift. Finally, acupuncture Sishencong, pick up the local skin at the acupuncture point, and quickly pierce the needle tip to gain anger. At the same time, with the method of air-conduction, the patient closed his eyes, closed his lips lightly, snorted, and breathed slowly until the acupuncture needle will be pulled out. The indwelling time of acupuncture needles in each acupuncture point is 30 minutes. After pulling out the acupuncture needle, sterilize the cotton ball and press the area for 30s without bleeding. The above treatment will be performed once a day, followed by a rest day after 6 consecutive days of treatment for a total of 12 weeks.
Primary outcomes
The selection of outcomes will be evaluated by Mini Mental State Examination Scale (MMSE). This scale will be conducted by two trained assessors who performed a combined MMSE examination of the patient, using conversation and observation. After the MMSE test has been over, the two raters independently scored and took the average of the two as the final score. According to the international agreement MMSE score, The scale includes the following 7 aspects: time-oriented force, place-oriented force, immediate memory, attention and computing power, delayed memory, language, and spatial perception. A total of 30 items, each answer is worth 1 point, the answer is wrong or do not know the answer 0 points, the total scale of the scale is 0-30 points. The test results are closely related to cultural level. Scoring reference: scores 27-30: normal; scores <27 can be considered cognitive impairment; scores 21-26 are mild cognitive dysfunction; scores 10-20 are moderate cognitive dysfunction ; A score of 0-9 is considered severe cognitive impairment.The primary and secondary outcome measures are shown in Table 1.
Secondary outcomes
For the secondary outcomes, we will use the Montreal Cognitive Assessment Scale (MOCA). It is an assessment tool for rapid screening of cognitive abnormalities. It includes 11 inspection items in 8 cognitive areas including attention and concentration, executive function, memory, language, visual structure skills, abstract thinking, computing and orientation. The total score is 30 points and ≥ 26 points are normal. It has high sensitivity, covers important cognitive areas, and has a short test time, which is suitable for clinical application. However, it is also affected by education level, differences in cultural background, the examiner's skills and experience in using MoCA, the environment of the examination and the emotional and mental state of the testee will all affect the score, and for mild cognitive function Obstacles are more sensitive. As education level is considered to be the most independent factor affecting the MOCA score. In order to correct the bias caused by education level, the total score is increased by 1 point for subjects with less than 12 years of education. For subjects with 4-9 years of education, the total score is increased by 2 points, and for those with 10-12 years of education, the score is increased by 1 point. This can better correct the bias caused by low education levels.
Instruments and definitions
The MMSE compiled by Foistein and others in 1975 is one of the most influential and widely used screening scales at home and abroad. The scientific and rationality of this scale in predicting the progress of cognitive function in stroke patients has been fully confirmed. MMSE is a screening scale that mainly evaluates cognitive areas such as orientation, instantaneous memory, calculated attention, delayed recall, ability to understand and use, and language function. This scale is generally used for preliminary screening tests for cognitive function. In clinical practice, the MMSE scale is simple, time-saving and easy to operate. The scale has high sensitivity and specificity for detecting dementia, and has good validity and reliability. However, it also has the disadvantages of rough scores and incomplete evaluation. Because the education level of patients will affect their assessment results, false positive results may be clinically obtained. Other studies have shown that the MMSE scale scoring method is too simple and leads to poor sensitivity. The sensitivity for screening for mild cognitive impairment (MCI) is only 1% -9%, and there is a "ceiling effect". Therefore, other scales need to be further improved and supplemented.
The Montreal Cognitive Assessment Scale (MoCA) was developed by Canadian Nasreddine and others based on clinical experience and with reference to MMSE (Concise Mental State Examination) cognitive items and scores. The Montreal Cognitive Assessment Scale adds assessments of functions such as executive function, visual spatial function, fluency of words, digital forward and backward. As early as 2006, MOCA has been recommended by international organizations as a 5-minute rapid screening PSCI scale. In 2007, the "Expert Consensus of Vascular Cognitive Impairment in China" listed it as the preferred test scale. In the same year, the 3rd Canadian Consensus Diagnosis and Treatment Conference and the Cardiovascular Society Consensus Conference also recommended MOCA for MCI testing. Where MMSE cannot detect cognitive impairment, MOCA can be an effective and simple screening tool. In addition, the patient's early MOCA score can predict the risk of cognitive impairment and risk in the future, and has certain predictive validity. It has certain guiding value for clinical judgment of patients' cognitive prognosis.
Saftey
Adverse reaction (AE) refers to the occurrence of harmful reactions unrelated to the purpose of treatment during the process of preventing, diagnosing or treating diseases by applying drugs according to normal usage and dosage. Its specific occurrence condition is to use the medicine in the normal dosage and normal usage, and exclude the reaction caused by the drug abuse, excessive misuse, use of the medicine in accordance with the prescribed method and quality problems. Efficacy indicators reflect the effectiveness of interventions, while adverse events reflect intervention safety. In this study, adverse events refer to "adverse medical events that occur after a patient or subject in a clinical trial receive an intervention, but are not necessarily causally related to the intervention. Adverse events and adverse reactions The concept is different. Adverse reactions are directly related to the intervention, and the scope of adverse events covers adverse reactions.
Sample size justification
According to clinical experience, the effective rate of PSCI in the intervention group was P1 = 0.80. The PSCI effective rate of the control group was P2 = 0.65 [(two-sided type I error rate of 0.05, α = 0.05); (one-sided type I error rate of 0.10, β = 0.10)]. Substituting f (α, β) into the formula is as follows: n1 = n2 = 10.5 × (0.8 × 0.2 + 0.65 × 0.35) ÷ 0.152 = 75.The lost follow-up rate of patients will be controlled at 10%, so an additional 8 cases are added to each group. n1 = n2 = 83, that is, 83 cases will be taken from each of the intervention group and the control group.According to Cohen, this effect size is considered “moderate”.
Data collection and management
The case report form (CRF) is a paper version, and the CRF is a carbonless copy, in duplicate, to be completed by the investigator. The inspector (CRA) shall conduct an on-site inspection of the CRF, and the problems discovered shall be verified and signed by the researcher after verification. After the completed paper version of the CRF is reviewed and signed by the CRA and the main investigator, the first copy is submitted to the data management unit. After the CRF is submitted, a logical data review is performed by the data management team. If there is any doubt about the data, the data administrator will send an "electronic data inquiry" to the CRA and the researcher, and send the inquiry to the researcher through the CRA. The researcher should answer and return as soon as possible. ,confirm. All error content and modification results shall be recorded and kept properly. Paper CRFs should be properly recorded and kept between researchers, CRAs, and data stewards.
Statistical analysis
Statistical analysis will be performed using SPSS 25.0 software for statistical analysis. The normality of the measurement data is tested. The data obeying the normal distribution is Student's t test, which is expressed by mean±standard deviation. The data not obeying the normal distribution is rank sum test. And marginal homogeneity test; count data are expressed by rate and composition ratio, and comparison is performed by chi-square test; repeated measurement data are expressed by mean±standard deviation, intra-group comparison is performed by analysis of variance of repeated measurement data, and inter-group comparison is by multivariate analysis of variance (MANOVA). P≤0.05 indicates that the difference is statistically significant.
Ethics and dissemination
This study has been approved by the Ethics Committee of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine (Reference number DZMEC-KY-2019-26). Independent clinicians and biostatisticians with extensive research experience in clinical trials will serve as the Data and Safety Monitoring Committee. The Ethics Committee of Dongzhimen Hospital Office may perform random audits to ensure that relevant regulations and guidelines are met. Study participation is voluntary and can be discontinued at any time, and deciding not to take part will not affect a patient’s care. Protocol amendments, adverse effects reporting, and annual review will be overseen by the Ethics Committee of Dongzhimen Hospital. The information provided by the patients will only be shared with members of the research team. Every effort will be made to keep patient information confidential.All research-related paper documents will be kept in a locked cabinet. All patient information will be kept strictly confidential.