Trial design
This study will be a single-center randomized controlled trial in which 160 stroke patients are randomly divided into study and control groups. The study will be conducted at Shanghai Xuhui Central Hospital between March1 2018 and March 31 2021. The study will recruit eligible subjects from the inpatient and outpatient departments of rehabilitation medicine of Shanghai Xuhui district central hospital in Shanghai. All patients enrolled in the study group and the control group will be allocated in a 1:1 ratio. LQG combined with conventional rehabilitation will be completed by patients in the study group, while traditional core stability training combined with conventional rehabilitation will be completed by patients in the control group. TIS (Trunk impairment scale) will be used as the main evaluation index. The secondary evaluation index will include the Fugl-Meyer Assessment, Maximum Phonation Time, Dynamic and Static Balance Testing (Tecnobody PK-254, Italy), The thickness of diaphragm, Diaphragm Mobile degrees, Modified Barthel index and Berg Balance Scale. All assessments will be conducted at baseline, 2 weeks at the end of the rehabilitation course. The flow chart of study protocol is shown in Figure 1. The research proposal has been designed according to the recommendation of SPIRIT. (Fig 2 and Additional File 1)
Primary and secondary outcomes of the study
In this study, "Trunk impairment scale" will be selected as the main observation index. At the same time, the clinical effect will be divided into three grades: Complete response (CR), Partial response (PR), No response (NR) to evaluate the curative effect before and after treatment. And this observation index will be defined as ranked data.
The secondary outcome measurements will include other relevant evaluation indicators such as FMA, Berg, ADL, MPT, dynamic and static balance function, the diaphragm thickness and the muscle mobility of the diaphragm. The data obtained from these indicators will be measurement data.
Primary outcome measurement procedures
Experienced physicians will assess the primary measures before and after treatment for 2 weeks. The TIS scale will be used to measure the main results (Table 1).
A main investigator will evaluate trunk postural control in the entry and exit stages. Trunk postural control will be conducted according to the Spanish Version of Trunk Impairment Scale 2.0. This scale consists of 3 sub-scales: The subscale of the first item is "static sitting balance" (score range 0-7) to assess the ability of the patient to maintain a sitting balance by landing on their feet and crossing their legs. The patient should cross the leg on the affected side. The second sub-scale will evaluate the dynamic sitting balance (score range 0-10) and assess the lateral flexion of the trunk, starting from the upper and lower trunk. The third sub-scale will evaluate the coordination (score range 0-6) and tests the ability to independently rotate the shoulder girdle and pelvic girdle. The total scores will range from 0 to 23, with a higher score denoting a better performance [19].
We will calculate the evaluation of efficacy before and after the intervention. The criteria will be:
CR: TIS total score increased ≥7 points after treatment;
PR: 3 points ≤TIS total score increased ≤ 6 points;
NR: the total TIS score after treatment was ≤2 points or worse.
Table 1.Specific measurement of trunk posture control levels carried out by TIS
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Baseline
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2 weeks
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Trunk posture control measurement
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Evaluation date
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Signature of therapist
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Secondary outcome measurement procedures
The secondary outcome measurements will include other relevant evaluation indicators such as FMA, Berg, ADL, MPT, dynamic and static balance function, the diaphragm thickness and the muscle mobility of the diaphragm (Table 2). Experienced physicians will evaluate the secondary outcomes at baseline and 2 weeks after treatment.
The simplified Fugl-Meyer scale will be used for the assessment of motor function and is often used in clinical rehabilitation, because it is reliable and effective [20,21]. The scale has a total score of 100, which is divided into motor function evaluation of the upper and lower limbs, among which the upper limb score is 56and the lower limb score is 44. Each item has a 3-point rating, and a higher score indicates better motor function. The classification of its dysfunction is as follows: <50: severe dyskinesia, 50-84: significant dyspraxia, 85-95: moderate dyskinesia, 96-99: mild dyskinesia,100: normal.
The modified Barthel index (MBI) scale will be used to evaluate the quality of daily life. The scale is divided into 10 items and evaluated on the basis of patients' functional status. The 10 items are bathing, grooming, defecation, eating, entering and leaving the toilet, transferring, walking on flat ground, going up and down stairs, etc. The total score is 100 points. The classification of its dysfunction is as follows: 100 points: self-care, 61-99: mild dysfunction, 41-60: moderate dysfunction, ≤40: severe dysfunction. The lower the MBI score, the more independent the patients are and the worse their daily living ability [22].
The Berg Balance Scale (BBS), which is widely regarded as an effective measure of balance in stroke patients and healthy older adults, will be used to evaluate balance function. The BBS scale consists of 14 items, each of which is graded on a scale of 5. The classification of its dysfunction is as follows:0-20 points, poor balance function, patients need to use a wheelchair;21-40 points, have a certain balance ability, the patient can walk under the assistance;41-56 points, with good balance function, the patient can walk independently. A score less than 40 points indicates the risk of falling [23].
Maximum phonation time (MPT)will be used to measure the length of time a simple vowel is emitted after deep breathing. The measurement requirements of MPT are as follows: 1) the longer the pronunciation time is, the better; 2) breathing evenly; 3) even breathing loudness; and 4) pitch within the correct frequency range. At the same time, the relatively longer MPT value will be taken as the final evaluation result. For instance, According to the reference standard of Chinese MPT [24]: 16-40 males, 95%[24.4,25.2];16-40 females, 95%[16.3,16.9].The assessment results must meet the above requirements, namely the tone and volume of the pronunciation should be kept at a comfortable level [25].
Static stability and dynamic balance testing will be measured by the Prokin proprioception evaluation and training system (PK254P, Tecnobody Srl, Italy). Static stability testing will proceed as follows [26]: Standard seat position; 1) the balance plate is arranged on the platform, the height of the foot platform adjusted, contact with the ground and curtsying subjects sit under 90°-100°; 2) adjustment of the seat of the subject and position the femur large rotor on the balance plate A3-A5 axis; 3) adjustment of the feet-shoulder width of subjects; 4) chest rise, eyes to the front; and 5) subjects arms crossed, elbow, shoulder proneness of 45° hung up. The standard standing position: 1) Symmetrical on the A1-A5 axis and subjects will be close to each other; 2) the medial border of the feet will be 10 cm apart and the highest point of the bilateral arch located on the A3-A5 axis. The static balance test has 6 observation indices as follows: 1) the displacement difference of the x and y axis; 2) the standard deviation of fore and after, left and right directions; 3) the average motion speed before and after, left and right; 4) the motion length; 5) COP area; and 6) the area ratio and length ratio under the test of the motion area and Romberg.
Dynamic balance testing will occur as follows [27]: 1) The two feet standing apart with inclined plates; entry of general data of patients, selection and evaluation module, adjustment of the resistance buffer system as recommended by the “8” (a total of 10 files, if the file number is high the more resistance, set to “8”. The tester will be required to wear a chest position sensor, which will be located about the two nipples and connected to the midpoint of the sternum. The dynamic balance test has 4 observational indices thus: 1) Trunk Stability Index (TSI), front and rear, left and right, circumference; 2) Average Trajectory Error (ATE); 3) Test Execution Time (TTE); 4) Average Weight Force Difference (AWFD, kg).
The thickness of the diaphragm will be measured by ultrasound (Tdi): Subjects will take the supine position and breathe autonomously. It is worth noting that in order to avoid measurement error, we uniformly selected the right side of patients for measurement. All phrenic ultrasound examinations in this study were performed by the same doctor with formal ultrasound training. Therefore,A linear high frequency probe will be positioned on the right axillary front and the probe set perpendicular to the chest wall between ribs 8 and 9. If the diaphragm is not visible in this position the probe may be moved up to the 7th and 8th intercostals. The image of the phrenic junction consists of 3 layers of connective tissue, namely the bilateral hyperechoic area (pleura, peritoneum) and the intermediate mixed type echo area (composed of the anechoic diaphragm tissue and its internal hyperechoic fascia). The 3 layers are parallel during respiration. A moving cursor will be used to measure the thickness of the diaphragm at the end of quiet breathing (functional residual air position, TdiFRC), and the thickness of the diaphragm at the end of maximum inspiration (forced lung capacity, TdiVC), respectively. The values of 3 respiratory cycles will be measured and averaged. The change of diaphragm thickness from the end of quiet exhalation to the end of maximum inspiration will be calculated as: TF= (TdiFVC - TdiFRC) / TdiFRC[28].
Ultrasonic measurement of phrenic muscle mobility (D/M): degree of diaphragm mobility measurement will be the displacement distance of the diaphragm dome FRC and TLC, with subjects lying at a 45° angle. A convex transducer (3.5 MHz) will be placed in the medial line of the right axilla at the costal margin of the thorax and the fixed finger positioned towards the skull. For each image of the m-mode record, we will determine the vertical distance between the point corresponding to the starting maximum inspiration and the point corresponding to the maximum diaphragm displacement [29].
Table 2.Comprehensive evaluation of trunk posture control disorders after stroke using FMA, Berg, ADL, MPT, dynamic and static balance function, diaphragm thickness and the muscle mobility of the diaphragm
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Baseline
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2 weeks
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Fugl-Meyer assessment
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Berg balance scale
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Barthel index
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Static balance testing
1) displacement difference of the x and y axes;
2) standard deviation of fore and after, left and right directions;
3) average motion speed before and after, left and right;
4) motion length;
5) COP area
6) area ratio and length ratio under the test of the motion area and Romberg.
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Dynamic balance testing
1) trunk stability index (front and rear, left and right, circumference);
2) average trajectory error (ATE);
3) test execution time (TTE);
4) average weight force difference (kg) )
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Maximum phonation time (s)
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Diaphragm thickness
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Muscle mobility of diaphragm
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Adverse event collection procedure during the trial
Adverse events and procedures during the trial will be reported, processed and recorded in a timely manner. This study will complete a two-week clinical intervention to identify the reasons responsible for adverse events and to ensure that patient safety, health, and their rights are maintained. Serious adverse events will be submitted to the principal investigator within 24 hours. The clinical trial office and ethics committee of Shanghai Xuhui District Central Hospital will jointly put forward reasonable suggestions.
Trial setting
The rehabilitation department of Shanghai Xuhui District Central Hospital will carry out this study. Physical therapists will provide comprehensive rehabilitation for all patients including exercise therapy, occupational therapy, speech therapy and traditional rehabilitation.
Inclusion criteria
The criteria for inclusion of subjects in the study will be: (1) met the diagnostic criteria of cerebral infraction or cerebral hemorrhage; (2) with TCM diagnostic criteria of stroke; (3) the first onset of stroke, with trunk postural control disorder; (4) a trunk impairment scale evaluation score between 6 and 17, and a sitting balance > 2 levels; (5) between 40 and 80 years old; (6) course of disease 2 weeks to 6 months; (7) good physical strength, can withstand 45 minutes of training; (8) at least one side movement function of a normal limb or at least Brunnstrom ≥ 4 levels; (10) patients with stable vital signs; (11) agreed to sign an informed consent document.
Exclusion criteria
Exclusion criteria for potential subjects in this study will be: (1) consciousness disorder, severe cognitive dysfunction and hemianopia; (2) at the same time with dysarthria, aphasia; (3) physical training can not be tolerated for 45 minutes; (4) with heart, brain, kidney and other organs in acute diseases; (5) serious mental disorders; (6) modified mini-mental state examination ≤ 23.
Study population and recruitment
The study will recruit 160 patients aged 40-80 years who have been diagnosed with cerebral apoplexy in the rehabilitation department ward of Xuhui District Central Hospital in Shanghai from March 2018 to March 2021.
First, Before the start of the study, doctors in the inpatient department of rehabilitation medicine should be informed of the criteria of potential study patients that need to be included in the study, as well as the purpose of the study, and then they should be referred to the researchers of the study. Second, the principal investigator will briefly introduce the inclusion and exclusion criteria for this study and provide the researchers with possible inclusion information, as well as the potential risks and advantages. Third, If the patient are interested in the study, the primary researchers will further provide more detailed information and answer any questions raised. If the patient agrees to participate in the study, the patient or family members will sign the informed consent to guarantee the patient's privacy. Finally, after the patients and their families have signed the informed consent form, the main researchers will include subjects that met the requirements according to the TIS scale.
Randomization and Blinding
Randomization
CW generated the allocation sequence; CW and LY will enroll the participants; YZ will assign participants to the interventions. In this study, a statistician who was not involved in the study used the SPSS 20.0 software to generate a table of random Numbers. patients were randomly divided into two groups at a 1:1 ratio. One group was the study group and the other group was the control group. A table of random Numbers will be placed in a sequentially labeled opaque envelope. The distribution order is then kept by a research assistant who is not involved in recruitment, intervention, outcome evaluation or statistical analysis. After the subjects have met the study criteria, The research assistant will notify the appropriate therapist to intervene and will notify the subject by telephone of the assignment (study group or control group).
Blinding
Patients will be randomly assigned through random coding generated by SPSS to ensure that the evaluator is blind. Only the major researchers will know the order of the random assignments. Outcome assessors will be blinded, that is, the outcome assessors and care providers will be different doctors. The outcome assessors and care providers shall not exchange information in the implementation of the experiments, and the outcome assessors shall not ask the subject for the intervention. In this study, only the assessors will be blinded, so it does not involve unblinding.
Intervention
The LQG (study group) or core stability training (control group) followed by conventional rehabilitation training (30 minutes each) will be completed in 2 weeks 5 times in a quiet room, 10 m2 room with a back-ground noise of ≤ 30 dBA. Experienced physiotherapists will be responsible for completing the training and ensuring that the training process is conducted strictly in accordance with the research program. First, the patient should adjust to a sitting and independent standing position. Then, they should breathe smoothly through their nose, complete the upper body movements, and slowly exhale through the mouth. Meanwhile, It's worth nothing that this research will not have a negative effect or side effects on patients, but in the process of study if a patient’s condition worsens, the damage caused by treatment or evaluation shall be borne by national health insurance. And all patients will receive comprehensive rehabilitation provided by physiotherapists in the Department of Rehabilitation Medicine, Shanghai Xuhui Central Hospital, including exercise therapy, occupational therapy, daily life ability training, and traditional physical factor therapy. The intensity and frequency of comprehensive rehabilitation programs received by the two groups of patients will be the same.
Control group
Patients in the control group will receive traditional core stability training and conventional rehabilitation therapies. Routine rehabilitation training will include drafting training, passive joint movement, walking between parallel bars, occupational therapy, etc. At the same time, core stability training will include abdominal training in the supine position, double bridge movements, single bridge movements, balance ball half bridge movements and forward and backward movement of the sitting pelvis, The patient will be sat on a Bobath ball and use the Bobath handshake to control the flexion, extension, lateral flexion and rotation of the torso. Before the training begins, the therapist will inform the patient of the brief action instructions. For patients with poor respiratory control, manipulation will be adopted to stimulate their abdominal muscle group contraction, and necessary manipulation should be undertaken according to the different limb functions of the patients. The duration of conventional rehabilitation training will be 5 times a week, 30 minutes per session, lasting for 2 weeks. The traditional core stability training will last for 15 minutes five times a week for 2 weeks. All of the control group interventions for traditional core stabilization training will be performed separately by three experienced therapists (MY, LGL and NWD).
Study group
In addition to receiving conventional rehabilitation training, patients in the study group will be required to complete the LQG treatment. Patients allocated to the study group will be engaged in LQG rehabilitation programs in addition to conventional rehabilitation therapies. The sequence will be routine rehabilitation and then core stability training. Each time, the rehabilitation course will be divided into LQG for 15 minutes and normal rehabilitation training for 30 minutes. The study group will be completed 5 times per week for 2 weeks in a quiet room. For traditional core stabilization training, all study group interventions will be performed separately by three experienced therapists (YY, WC, FH and WQL).
The key points of LQG oral guidance will consist of pronunciation and breathing. For “XU”, pronunciation will be assisted by the teeth. Space will be left between the teeth and the tongue, with the upper and lower teeth parallel. Air will be drawn from the space between the teeth, and between the teeth and the tongue, and the corners of the mouth will be pulled back a little. When exhaling and pronouncing, the "HE" will be pronounced with the aid of the tongue. The upper teeth will be tapped with the sides of the tongue and air exhaled between the tongue and the upper jaw. During the exhalation and pronunciation, the "HU" sound will be assisted by the throat. The sides of the tongue will be bent upwards and the lips forward, forming a circular opening through which the patient will exhale. During the exhalation and pronunciation, the "SI" will be pronounced with the assistance of the teeth. There will be a narrow gap between the upper and lower teeth. The patient will lightly touch their lower teeth with the tip of their tongue and exhale air between their teeth. During the exhalation and pronunciation, the "CHUI" will be pronounced with the assistance of the lips. The tongue and the corner of the mouth will be pulled back as will the lips into the stretched position, making the back teeth parallel and thus exhaling air from the throat between the sides of the tongue and the stretched lips. In the exhalation process, the "XI" will be pronounced with the assistance of the teeth. The lower teeth will touch the tip of the tongue, and the corners of the mouth will be slightly tilted back, the posterior teeth gently closed and air exhaled through the space between the posterior teeth[30-32].
Our training is one-on-one intervention by the therapist. Before training, for the elderly, we will tell each patient that the "emphasis" will be on breathing and pronunciation. In order that the patient should learn correct pronunciation and breathing accuracy, the patient will need to learn gradually to ‘feel’ the key points of strength rather than the absolute power of pronunciation. For example, the patient may complete in a sitting or standing position. Stroke patients should learn to use healthy upper limbs to assist upper limb movement. Or the physiotherapist can stand on the patient's side to assist in the completion of the movement and maintain the normal position of the chest, spine and pelvis, to provide a stable mechanical structure. Meanwhile,Our training is not in the form of group exercises, but in the form of one-on-one therapist intervention.
LQG action points
Stroke patients with postural dysplasia often show different degrees of hemiplegia and postural abnormalities, resulting in the loss of their ability to sit or stand. It is impossible for these patients to complete the Liuzijue key independently and precisely without assistance. Therefore, the therapist will properly guide the completion of the movement and adjust the training position according to the patient's functional state. As the improvement of patients' balance ability increase, the training position will gradually transition from the sitting position to an independent standing position. As the patient's limb function improves, the therapist will gradually reduce the amount of assistance. Both active and auxiliary limb movements are based on bilateral limb opposition. The most important goal is to complete an accurate respiratory guidance program.
Sample- size calculation
We will use the Trunk impairment scale as the main therapeutic index to evaluate trunk posture control, The Preliminary experimental findings has showed that the effective rate was 80% in the study group and 50% in the control group. The effective rates of the study group and the control group were set as 80% and 50%, respectively. Based on this, this study conducted sample estimation through G*power 3.1 software, and adopted rank sum test model to set the rate of 80% in the treatment group and 50% in the control group for bilateral test, and set a=0.05 and power=0.97 (the setting of this value is based on the statistical power after the end of the experiment (power =0.97 after the end of 40 cases). The distribution ratio was matched by 1:1, and the final sample size was 142, with 71 cases in each of the two groups, taking into account the possibility of 12% attrition rate during the test. Therefore, the total number of samples was finally determined to be 160 cases, namely 80 cases in each group.
Statistical analysis
1) In this study, the main indicators were determined according to the change levels before and after treatment of TIS, which were divided into three levels of complete response, partial response and no response, and expressed by rate or percentage. The chi-squared test will be used to compare differences in efficacy between groups. 2) the overall curative effect evaluation and the curative effect evaluation method will be employed. The calculation formula is: Effective = (excellent + effective) / total cases × 100%. 3) Secondary indicators (such as MPT, MBI, Berg, FMA, diaphragm thickness and mobility, static and dynamic balance ability, etc.) were all continuous data, a paired sample t test is often used for intra-group comparison, while independent sample t test is often used for inter-group comparison of the difference between the two groups after treatment, and a two-sided test will be used and the significance level is set at P ≤ 0.05. 4) to eliminate the influence of the rehabilitation intervention time, stroke type, age and gender on the efficacy and relative size of intervention methods will be considered and the statistical method of stepwise logistic regression model adopted.
ITT is divided into FAS and PP, where FAS refers to the data set obtained after minimal and fair removal of data from all randomized subjects. PP is sometimes referred to as "valid case" and "valid sample" and is a subset of the total analysis set. The subjects had sufficient adherence to the protocol to be able to estimate the effect of the treatment.
The per-protocol (PP) population will include random patients in the intention to treat (ITT) group, but exclude patients who do not meet the inclusion or exclusion criteria. and randomly assigned patients who do not receive the actual treatment [33].
If the statistical results are the same, ITT (intend to treatment) and PP (per-protocol) are reliable indicators. ITT results will be used if statistical evaluations are different between the two methods. As the final observation result (LOCF), the missing data will be processed. The last observation value of the endpoint will regarded as the follow-up evaluation point of missing data, and the last observation reaction will be regarded as the endpoint of the study.
Monitoring
To ensure the quality of RCT, this study will be completed by Shanghai xuhui central hospital. We will upload data through the China clinical trials registry in a timely manner so that the project management team can identify problems, review collected data and control errors. The drug testing center of Shanghai xuhui central hospital will have the opportunity to get the results of the mid-term trial and make a decision on it. A qualified clinical trial specialist will be invited to monitor the RCT.
Trial quality control
The main researcher, CW and YZ, is responsible for making protocol decisions, while LY is responsible for coordination (e.g., collating/collecting data, analyzing, etc ). JY will be responsible for quality control, YN Z and RW W will be responsible for data development and database management, and YZ will be responsible for setting up a quality control committee.
Researcher training
All researchers will receive Good Clinical Practice (GCP) training and have clinical expertise, qualifications and appropriate abilities for then study. Prior to the beginning of the project, all subjects enrolled will receive uniform training. Through program training in clinical research, the clinical research of purpose will be fully understood by all researchers including the plan, indicators and CRF documents. Each subject will be issued a "researcher's manual" as a reference guide.
Data management
This study will be conducted in strict accordance with the phase plan of the trial. After the baseline and 2-week intervention, all data will be recorded into CRF, and then the data in CRF will be uniformly input into Excel by CW and YN Z. We will create a separate folder for storing the data. At the same time, the data will also be transferred to the network disk for backup, so as not to lose data. We also set up a data management team for two people. When there are errors, one person is responsible for finding and correcting the errors, and the other person is responsible for checking the data again.
Ethics
This study has been approved by the ethics committee of the Shanghai Xuhui District Central Hospital (no. 2017040) and strictly followed the principles of the Helsinki declaration and statement. The trial has been registered on the Chinese clinical trial website (ChiCTR1800014864). All participants will fully understand the contents of this agreement and sign the informed consent document. To determine whether the members of the committee find it necessary to change the research plan, we will submit a detailed written application to the ethics committee.