This is a single-center, parallel-arms, clinical randomized controlled trial (RCT). The protocol was registered with the China Clinical Trial Registry (item number: ChiCTR2000029994) and the trial protocol was approved by the Ethics Committee of Huangshi Hospital of Traditional Chinese Medicine (item number: HSZYYJ-2020-003-01).A total of 120 patients will be recruited from the Huangshi hospital of Traditional Chinese Medicine in Hubei Provence. Written informed consent will be provided by all patients at the time of recruitment. Patients with severe pneumonia symptom will be recruit who have an equal chance of being allocated randomly to guideline therapy or guideline therapy plus TCMR. Due to the limitations of intervention methods, only the outcome assessors and statisticians are blinded. The assessor will perform evaluation and analysis of outcome at three points (before treatment, 7th day during hospitalization and the discharge day). Data management and statistics will be conducted in the Rehabilitation Medical College of Shanghai University of Traditional Chinese Medicine (SUTCM). The study design is illustrated in the flow chart in Figure.1 and the study schedule is presented in Figure.2 Additional file 1 shows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist.
Patients with severe COVID-19 will be recruited, which should meet the diagnostic criteria of "Diagnostic and treatment protocol for Novel Coronavirus Pneumonia (The Fifth Trial Version)" issued by the National Health Commission of China on February 8, 202019. The participants are from Department of Infectious Diseases in Huangshi Hospital of Traditional Chinese Medicine. The recruitment advertisements will be placed on the inpatient, network, WeChat and Weibo official platforms to achieve the potential participants.
Patients can only be recruited if they meet each of the following conditions (1) Meet the severity patient with COVID-19 critical diagnosis criteria20; (2) The age of patients is between 20 and 80, and is not limited to male or female; (3)The patient's condition is basically stable, conscious and cooperative in examination;(4)Volunteer to join the trial and sign the "informed consent”;(5)Promise not to perform other exercise program.
Those who meet one of the following conditions will be removed.(1)The patient is complicated by other serious underlying diseases, such as chronic obstructive pulmonary disease, obstructive pulmonary disease, coronary heart disease, and hypertension;(2)Serious mental illness;(3) Cognitive dysfunction, unable to understand the trial process and rehabilitation content;(4) Patients with severe bone and joint diseases (such as spinal arthritis, severe osteoporosis, periarthritis, etc.) affecting limb function and movement;(4)Patients have respiratory failure and require mechanical ventilation or shock or combined organ failure requiring Intensive Care Unit (ICU)monitoring and treatment.（5）Pregnant or lactating women; (6)Participate in other forms of exercise during the trial.
Drop out and suspension criteria
During the intervention period, patients have the right to withdraw whatever the reason and time under the protection of Declaration of Helsinki21. As long as any of the following conditions are met, it will withdraw. (1)Patients with poor compliance who did not follow treatment as required;(2) Those who had serious adverse reactions during the trial or the condition deteriorated further, with respiratory failure, multiple organ failure, shock, etc.;(3)Case data are incomplete and affect the judgement of curative effect;(4)Patients withdraws by himself;(4) Participants in other rehabilitation program during the trial;(5) Researchers do not consider the participants appropriate to continue participating in this researcher.
All recruited patients in the two arms with severe syndrome should be treated routinely along with the official medical plan22.On the basis of the guideline therapy, the test group required a standardized TCMR program consisting of acupressure therapy and Liuzijue Qigong exercise. Both of them are performed twice a day at 10 am and 4 pm respectively. Each time, acupressure is performed first, and then Liuzijue Qigong exercises will continue. 20 minutes for each treatment, for a total of 40 minutes will be need. The TCMR program is ongoing during the patient's stay until the patient is discharged. They should reach a consensus in advance on the acupuncture points, pressure levels and duration. Liuzijue Qigong was demonstrated live by the therapists on the first day until the patient was able to operate it skillfully. Patients will be provided with paper and video versions of exercises to facilitate subsequent practice. Therapists performing rehabilitation therapy are required 10 years of clinical experience in acupressure and qigong therapy, which should undergo rigorous clinical trial training before conducting trials. Until pass the exam can they performed the intervention. Daily treatments are required to be recorded, and regular researchers will review completion.
The health authorities in China draft the conventional treatment plan for patients with severe condition which are described below.(1)Patients should ensure adequate rest time, and medical staff need to closely monitor vital signs, oxygen saturation, etc.;(2) Additionally, it is necessary to monitor blood routine, urine routine, C-reactive protein, biochemical indicators, blood coagulation function, arterial blood gas analysis, chest imaging, etc. according to the changes of the condition;(3)Timely effective oxygen therapy measures should be taken especially severe patients should receive nasal cannula or mask to inhale oxygen, and promptly evaluate whether respiratory distress and / or hypoxemia is relieved;(4)Doctors should use antiviral drugs and combined with antibiotics if necessary;(5)To maintain the stability of the internal environment, they should strengthen supportive treatment to ensure sufficient heat and pay attention to water and electrolyte balance; (6) Also, early Chinese medicine can be used to relieve the syndromes.
Guideline therapy plus TCMR
Conventional treatment as the authorities required is the same as the control group. At the same time, acupressure therapy and Liuzijue Qigong exercise will be carried out as the TCMR program.
(1) Acupressure therapy
The specific acupressure process is as follows. According to channel-collateral theory, the severe case dialectical is Lung qi deficiency pattern whose characterization is weak cough, dyspnea, low voice, and clear watery sputum with other symptoms of qi deficiency. Therefore, acupoints related to the lung viscera were selected including Feishu (T 3), Danzhong (CV 17), Zhongfu (Lu 1)23. Pressing these points can improve lung symptoms23. First the patient takes a sitting or lying position with the therapist on the patient's right side. Pressing and kneading constitute the manipulation of acupressure. The first step is called continuous shiatsu method. The therapist uses the thumb thread press on the selected acupuncture points with moderate force, which is about 10 Newtons（N）tested by a mechanical instrument25. The direction of the pressure should be perpendicular to the skin surface, hold for 3-7 seconds and then relax, but not leave the skin surface. The second step is kneading the acupoint with the thumb. The thumb acts on the skin surface of the acupoint with a slight force pressure (5N), and then performs a small circular sliding movement with the acupoint as the center. The operation is performed 50 times on each acupoint with pressing method and kneading method respectively.
(2) Liuziju Qigong exercise
The Liuzijue Qigong exercise operates as follows: (1) Preparation phase: the patient is standing with the body in a relaxed state, and abdominal breathing or nasal suction is used to relax the abdominal muscles, the diaphragm is contracted together with not breathing for 3 seconds. (2) Practice phase: Keep lips whistle to make the "Xu, he, hu, si, chui, xi" sound lasting 5seconds successively. After each of the 6 pronunciations, return to the ready posture, and then perform the next exercise. The "Xu, he, xi" sound is repeated 6 times, and the "hu, si, chi" sound is repeated 12 times.
All outcome will be managed by researchers masked to the group assignment, which include Modified Dyspnea Scale 26(MDS), Activities of Daily Living (ADL)27, Patient Health Questionnaire-9 (PHQ-9)28 Length of Hospital Stay (LHS), Respiratory symptoms, Liver function test, Renal function test and lung CT. Evaluating outcomes will at three points (before treatment, 7th day during hospitalization and the discharge day). In addition, vital signs, clinical symptoms and related laboratory tests will be monitored daily.
Primary outcome measurements
We will use MDS, ADL as the primary outcome indicators to evaluate the dyspnea symptoms and physical health.
The scale is highly operable and is often used to measure the impact of activities on dyspnea. It is used to grade dyspnea and muscle fatigue on a scale of 0-10 to reflect the gradual increase in symptoms sensitively. Taking shortness of breath as an example, 0 points: None 10 points: the highest level is most serious of breathlessness. We will assess the MDS with a repeated longitudinal analysis.
The ADL is evaluated using BARTHEL index scale to judge the treatment value and prognosis. If its total score is greater than 40, the patient is considered more valuable. It mainly includes 10 daily life behaviors, such as: eating, bathing, dressing, and controlling bowel movements. Each item can be scored 10 points if it can be completed independently. 5 points are needed for partial help. A total score of 100 indicates that you have good daily activities and do not need to depend on others. A score of> 60 was considered good, indicating mild dysfunction and being able to take care of themselves in basic daily life. A score of 60-41 indicates moderate dysfunction, and it is obvious that daily life depends on others. A score <20 is completely disabled, and daily life is completely dependent on others.
Second outcome measurements
PHQ-9 is used to detect and measure depression and severity in medical populations in clinical settings, which has been conducted in a variety of settings using medical populations. It is a questionnaire containing the frequency with 9 negative items happened to patients in the last 2 weeks. If the answer is not at all, get 0 points; once every few days, get 1 point; once more than half a day, get 2 points; every day, 3 points.
The PHQ-9 score was divided into the following categories of increasing severity: 0–4, 5–9, 10–14, 15–19, and 20 or greater.
The length of time patient is in the hospital will be used as an outcome indicator, which will be recorded on the CRFs by the evaluator and the reason for discharge.
Respiratory symptoms include fatigue, cough, expectoration, chest tightness, dyspnea, sore throat, nasal congestion, runny nose, and some other none- specific symptoms. The severity of these symptoms is recorded sequentially as 0-10, with 0 being no and 10 being the most severe. Key factors such as vital signs and blood oxygen saturation should be monitored as well.
Lung CT is the main imaging method for diagnosis of COVID-19. which can directly visualize the lung inflammation of the patients. It can provide intuitive imaging evidence for the changes of condition. The degree of clinical rehabilitation can be assessed based on the absorption of inflammation in the lung CT of the patients.
Liver and renal function test
Relevant laboratory tests should also be monitored, especially liver and kidney function tests. The whole process of biological specimen inspection will be performed in the hospital, and the hospital laboratory will report the processing of biological specimens.
Sample size calculation
The trial takes the MDS as the primary efficacy outcome. Based on previous clinical studies on the effect of MDC after Liuzijue Qigong intervention, a superiority test was used to estimate the sample size (α = 0.05 , β = 0.10 ).In this study, the target sample size will be 120 participants and anticipating on maximum loss to follow up of 20%.
Department of Science and Technology of SUTCM will generate the randomization sequence using a random number generator (IBM, Chicago, IL, USA) and then sequentially number them in an opaque envelope. The researcher in Shanghai will randomize and inform the therapists in Hubei of the treatment assignments by phone. The allocation concealment procedure will not be exposed until the baseline data have been collected completely. Then eligible patients will be randomly divided into a guideline therapy group and a guideline therapy plus TCMR group, with an allocation proportion of 1:1.
Participants and therapists are unable to be blind about group assignments due to the specific intervention, but the therapists will be masked to the evaluation of outcomes. To reduce the risk of bias, evaluators, data managers, and statisticians were unaware of group assignments during the outcome evaluation and data analysis process. And they will be required to do not share study information with each other. The blinding procedure will be operated until the data are locked.
Data collecting and monitoring
Screeners will complete the collection of demographic and baseline characteristics during the patient recruitment phase. The clinical assessor will use the case report forms (CRFs) to record detailed information on clinical symptoms, signs, auxiliary examinations, each scale outcome, and adverse events. A data manager will enter data into the electronic CRFs in real time carefully. All data managers have data analyze competence and receive unified training, who is independent of the research team and is unaware of the group assignment. Researchers should optimize the trial operation to reduce the risk of data loss, and exclude the data if very few data are lost. Electronic database will be closed after data entry is completed. The administer in Science and Technology Department of SUTCM will be responsible for monitoring the data management.
Statistical analysis will be performed by the research in Rehabilitation Medical College of SUTCM. The statistician will be blind to the allocation of groups. SPSS Windows version 24.0 software will be used for data analysis. The level of significance is established at α<0.05 with a two tailed test. Continuous variables will be expressed as mean ± standard deviation, and categorical variables will be expressed as n (%). Demographic baseline information (age, gender, occupation, etc.) will be tested using a chi-square test and an independent t-test. Comparisons of differences within groups will use paired t-tests, and differences between groups will use independent t-tests. If the data does not have a normal distribution, a nonparametric test (Wilcoxon signed rank test or Wilcoxon rank sum test) will be used for the test. Information on adverse events will be collected through CRFs by researchers. In addition, we will perform an intention-to-treat analysis of missing data in the primary and secondary analyses. As the main statistical analysis, the effectiveness of the TCMR program will be tested by calculating the difference in subject scales at each point (baseline, 7th day of hospitalization, discharge). Fisher ’s exact test will be used to compare the drop -out rate for compliance analysis. Adverse events will be listed and analyzed using a chi-square test or Fisher ’s exact test.
During the whole processing of the trail, quality control will be conducted under the surveillance of the steering committee. To ensure the consistency of methods, all the researchers should be trained with the trial methodology and monitoring technique before he participates in the trial. Supervision activities will be divided into online remote monitoring and offline personal inspection every day. As the research progresses, researchers can submit a request to modify the study scheme. But only the steering committee and ethics committee have the authority to modify or correct the protocol if necessary.
Safety evaluation will be conducted throughout the trial. Although TCMR programs are low-risk, the participants are illness with severe pneumonia. When adverse events occur, the researchers should record them in CRFs in detail and analyze whether they are directly related to the rehabilitation program. Regardless of the cause, if the condition suddenly worsens during the trial and accompanied by severe complications or serious adverse reactions, the trial should be terminated immediately. Researchers need to analyze whether the causes of adverse reactions are related to the intervention method, and take prompt medical measures, such as improving the level of monitoring, symptomatic supportive treatment such as: oxygen therapy support, improve ventilation and maintain vital signs normally.