A Randomized Controlled Study of Muscle Training Exercise Based Pulmonary Rehabilitation on Activity of Daily Living in Patients with Coronavirus Disease 2019

Zhiling Zhao Beijing Chaoyang Hospital Feng Wang Beijing Chaoyang Hospital Xue Wang Beijing Chaoyang Hospital Xiunan Li Beijing Chaoyang Hospital Yi Ren Beijing Chaoyang Hospital Fen Wang Wuhan Union Hospital Shi Liu Wuhan Union Hospital Dandan Chang Capital Medical University Xinglu Zhang Beijing Chaoyang Hospital Yong Lu Beijing Chaoyang Hospital Ziren Tang (  tangziren1970@163.com ) Beijing Chaoyang Hospital Jianchu Zhang Wuhan Union Hospital


Introduction
Coronavirus disease 2019 (COVID-19), a highly infectious respiratory disease, has become the world's leading health problem and caused major public concerns 1 . Since the outbreak of a novel coronavirus epidemic resulting in COVID-19 on December of 2019, a total number of 7,553,182 patients has been con rmed in more than 200 countries until Jun. 13 th . 2 And it is expected to rise even higher as reports from health authorities. However, there is no evidence for effective treatment or intervention for COVID-19 currently.
COVID-19 leads to respiratory dysfunction and muscle weakness, 3 and patients may suffer from respiratory failure. 4,5 Physical and psychological problems of patients have been concerned, especially in recovery stage, so physical therapy has been proposed for patients with COVID-19. Pulmonary rehabilitation is an important intervention for chronic respiratory disease. It was expected that the pulmonary rehabilitation could relieve symptoms and improve functional performance of patients with COVID-19 in recovery stage.
To our knowledge, there are few researches on pulmonary rehabilitation of patients with COVID-19. In this study, we proposed a prospective, randomized controlled trial, aiming at exploring the effectiveness and safety of pulmonary rehabilitation based on muscle training exercise for adult COVID-19 patients. Considering the clinical characteristics of COVID-19 and the conditions of the isolation ward, we designed a set of special pulmonary rehabilitation based on the exercise program widely adopted in clinical practice, including Zheng's supine rehabilitation exercises. 6 Methods Study design and participants The study was a prospective, randomized controlled trial. Patients were enrolled from Union Hospital, Tongji medical college, Huazhong university of science and technology (Wuhan, Hubei Province of China) between February 7 th , and March 31 st , 2020. Pulmonary rehabilitation program was taken place in department of respirotary and critical care medicine, in a medical college a liated teaching hospital. This study was approved by the Institutional Review Board of Wuhan Union Hospital (project approval number 2020-0127), and participants provided written informed consent.
Randomisation was conducted at the trial centre and the participants were randomly allocated to either the pulmonary rehabilitation exercise group or the control group at a ratio of 1:1. Pulmonary rehabilitation exercise group assignments were generated using Statistical Product and Service Solutions (SPSS) 25.0 software (IBM Corp., Armonk, NY, USA) and communicated using sealed opaque envelopes.
Eligible patients were those who were diagnosed as COVID-19 and were admitted to the hospital during the study. Inclusion criteria including:(1) patients aged from 18 to 70 years; (2) patients whose percutaneous oxygen saturation (SpO2) > 90% while the patients breathed ambient air or had oxygen support. (3) patients who were consciousness and could follow instructions. (4) patients whose disease onset > 2 weeks and had been hospitalized > 72 hours.
Criteria of discharge: (1) Normal temperature > 3 days; (2) Respiratory symptoms improved signi cantly; (3) Pulmonary imaging showed that acute exudative lesions were absorbed obviously; (4) The 2019 nCov nucleic acid test of sputum, nasopharynx swab or other respiratory samples was negative twice(sampling time should have an interval of at least 24hours).

Data collection
Baseline data of all patients were collected, including demographic (age and sex, height, weight, body mass index), general condition, symptoms, comorbidities, vital signs (body temperature, heart rate, respiratory rate, and blood pressure), laboratory tests (blood routine test, arterial blood gas analysis (ABG)), chest computed tomography scan, Barthel activities of daily living (ADL) scores 7 and manual muscle test (MMT). Medical and respiratory support, complications, and outcomes were also analysesed. Vital signs, rating of perceived exertion scale (RPE) 8 and SpO 2 were recorded prior to and after physical rehabilitation exercise. Data of symptoms, MMT and arterial blood gas analysis were recorded before discharge. Data of ADL was recorded after 7days of after exercise and before discharge and SpO 2 was recorded after 3days and 7days of after exercise and before discharge.

Assessment Measures
Barthel ADL was modi ed in 1988 to a 20 point scale that measures in increments of 1 point, which was from 0 fully dependent to 20(fully independent). The nal score could be multiplied by 5 to obtain a 100 point score, and it was proposed that scores of 0-20 indicating "total" dependency, 21-60 indicating "severe" dependency, 61-90 indicating "moderate" dependency, and 91-99 indicating "slight" dependency. The Barthel ADL assessment comprised: feeding, grooming, bathing, dressing, toilet use, presence of fecal incontinence, presence of urinary incontinence, transfers (e.g. moving from wheelchair to bed), walking on an even surface (or propelling a wheelchair if unable to walk), and ascending and descending stairs. It was already widely used as the measurement of daily living activities and had become a standard measure of physical disability in clinical practice 7 .
RPE scale was a 15-point scale, ranging from 6 to 20 (corresponds to an approximate heart rate between 60 and 200), designed to estimate how heavy and strenuous the work is perceived 8 .
Scoring of the manual muscle testing(MMT): Grade 0: no contraction of the tibialis anterior. Grade 1: visible contraction of the tibialis anterior,Grade 2: active movement with gravity eliminated. Grade 3: active movement against gravity. Grade 4: active movement against gravity and moderate resistance. Grade 5: normal response (against gravity with full resistance).

Intervention
Respiratory support and medication treatment was applied to each patient, which was consistent with the guide for the prevention and treatment of coronavirus disease 2019 9 .Each patient received supportive treatment. The pulmonary rehabilitation program based on muscle training exercise, including bedside exercises for patients who were able to stand, and in-bed exercises for those patients who were bedridden. Procedures of excise training are detailed further in e-Appendix 1.Patients who were able to stand, took step 1 to step 6 program, which respiratory muscle, torso and limb movements were designed in different positions. For those patients who were bedridden, took step 1 to step 3 program, movement of upper and lower limbs and the change of body position were implemented to all.
Breathing rehabilitation would take 15 minutes each time, twice a day. Patients who took inbed or bedside exercise depended on the decision of doctor. Patients who had a RR<28, HR<100, and lower lim MMT>4 would preferred bedside exercise.
Whether patients performed muscle training exercise and pulmonary rehabilitation under O 2 therapy decided by SpO 2 during exercise. In the course of rehabilitation, patients followed original respiratory support, and adjust the level of respiratory support according to the change of SpO 2 , making ensure that SpO 2 > 88% could be maintained in the course of rehabilitation.
It should be terminated if SpO 2 could not be maintained above 88%. The program was performed by two respiratory therapists in intervention group, and supervised by a physician. Each patients took at least seven days of pulmonary rehabilitation program based on muscle training exercise. In control group, no special exercise training were guided by docters.
In the process of muscle training exercises, once one of the following situations occured, the patient should immediately stop exercising: 10 (1) Borg scale > 3 (10 points in total); (2) one of the symptoms: chest tightness, dyspnea, dizziness, headache, unclear vision, palpitation, sweating, inability to maintain balance, pain (chest pain, strong headache or strong abdominal pain) or fatigue; (3) other situations which clinicians judged that were unsuitable continuing pulmonary rehabilitation: heart rate < 40 or > 130 beats/min; mean blood pressure < 65mmHg or > 110mmhg, or more than 20% change from baseline; respiratory rate: > 40 times/min or < 5 times / min; SpO 2 ≤ 88% or decrease > 4%; new arrhythmia; new myocardial ischemia or unstable angina.

Outcomes evaluation
Primary outcome was improvement of ADL following pulmonary rehabilitation before enrollment and before discharge. Intragroup and inter-group comparisons were conducted. Secondary outcome were changes of MMT, ABG and length of hospital staying (LOS). Adverse effects of pulmonary rehabilitation were also analysed during pulmonary rehabilitation program.

Sample Size
Since the COVID-19 was considered as a new disease, there was no reference data for pulmonary rehabilitation. Sample size was calculated based on our pilot study. In the previous work, we carried out pulmonary rehabilitation exercise on 5 patients, and observed their symptom changes and ADL score improvement. Meanwhile, We also referred to data based on community-acquired pneumonia patients, which previously reported by Anderson J and Simone DC. 11 We estimate a 35% improvement in ADL score between the pulmonary rehabilitation group and control group with a two-sided test size of 5% and power of 80%. 27 eligible participants were required per study arm. Considering that about 10% of the enrolled cases might dropped out of the study, we nally set the sample size as 60 cases, with 30 cases in the pulmonary rehabilitation group and 30 cases in the control group. The sample size was determined using SPSS 25.0 software. Statistical analysis SPSS 25.0 software was used for the statistical analysis. Results are expressed as mean±SD forvariables normally distributed and abnormally distributed data were expressed as median (IQR). For primary and secondary outcome, intragroup comparisons of quantitative data were done using the paired Student't t test or Wilkinson rank test for variables which were not normally distributed. Inter-group comparisons were done using unpaired Student's t tests or with Mann-Whitney U test for variables non-normally distributed. Categorical variables were compared using X 2 tests or Fisher test. Correlation analysesbetween two ADL and variables were done by Spearman correlation. P value <0.05 indicated a statistically signi cant difference.

Results
A total of sixty COVID-19 patients were enrolled in this study. Sixty patients were in the nal analysis including 34 males and 26 females. (The ow of participants recruitment in this study was showed in Figure 1).Thirty patients were in pulmonary rehabilitation exercise group and thirty patients were in control group.
There were no signi cant difference of sex between two groups (16 males vs. 18 males, retrospectively, p=0.602).
Participants had a mean age of 54.43±10.57 years. The mean time of starting pulmonary rehabilitation exercise after hospitalization was 12.28±10.31 days and the average time of patients taking physical rehabilitation exercise was 14.39±5.05 days. There were no signi cant differences of symptoms, past history and regular treatment between two group. No statistically signi cant differences of vital signs of patients and arterial blood gas analysis were observed between two groups. (Demographic and parameters of baseline were presented in Table 1, and  (Figure 2). The between-group comparisons of ADL and MMT following physical rehabilitation exercise before discharge were showed in table 2.
Before discharge, we observed no signi cant differences between two groups for MMT assessed by mMRC in pulmonary rehabilitation exercise group and control group (5.00 [5.00, 5.00] vs. 5.00 [5.00, 5.00], respectively). However, both groups increased MMT. Respiratory rate was lower in pulmonary rehabilitation exercise group than control group in statistically signi cance (p=0.005), but there was no signi cant clinical meaning. Although there was no statistical difference of LOS, we observed a trend of shorter hospital staying time in pulmonary rehabilitation exercise group ( There were no signi cant differences in the arterial blood gas analysis between the two groups before enrollment (p>0.05), but there was a signi cant increase in PaO 2 (80.23±6.49 vs. 90.47±7.82, respectively, p<0.001) between the control group and the pulmonary rehabilitation exercise group before discharge( Table 2). Patients in the pulmonary rehabilitation exercise group had more improvement of PaO 2 and SpO 2 than in the control group. SpO 2 signi cantly increased after seven days and before discharge (Figure 3).
In total subjects, the improvement of ADL was signi cantly releted with pulmonary rehabilitation based on muscle training exercise, younger age (r= -0.551, p<0.01), higher PaO 2 (r=0.539, p<0.01). Sex, BMI, smoking, concomitant medical history, and oxygen therapy were not related to ADL in correlation analysis.
Complications ofpulmonary rehabilitation based on muscle training exercise It showed that pulmonary rehabilitation based on muscle training exercise in COVID-19 patients was well tolerated. Data on adverse events related to the intervention was mild, and could relieve after termination of activity. The proportion of participants who had adverse events was 13.3% (4 patients) in the study intervention and none of them quitted the clinical trial. Two participants suffering from dyspnea and palpitation, while one patient with sweating during exercise on the rst day, and symptoms relived after stopping exercise. While in the next day, patients continued exercise with no symptoms reported. One participants who reported lower SpO 2 , higher HR and dyspnea on the third day during the study period, and SpO 2 rose when they had oxygen therapy and continued the physical rehabilitation program. None of these patients had severe complications during the study. In the control group, two patients had deep venous thrombosis and one patient suffered secondary bacterial infection during the observation.

Discussion
To our knowledge, this is the rst randomized control study to evaluate pulmonary rehabilitation in COVID-19 patients, in which we demonstrated that more than one week pulmonary rehabilitation program in COVID-19 could improve patients life activity. Meanwhile, we found a relatively shorter LOS in pulmonary rehabilitation group.
Although pulmonary rehabilitation is a routine therapy in chronic respiratory disease, there is no evidence to support the routine use of patients who are hospitalized for community-acquired pneumonia (CAP). Long before, a randomized clinical trial examined chest physiotherapy in CAP, but failed to demonstrate improvements in fever, LOS, or mortality. 12 A systematic review and meta-analysis of adjunctive therapies for patients hospitalized for CAP showed that clinical trials with pulmonary rehabilitation therapy were few and could not provide evidence of bene ts from routine use. 13 Until recently, studies showed that an integrated program of physical therapy during hospitalization could improve physical and functional performance in patients with pneumonia. 11,14 For patients who have severe pneumonia and stay in bed for a long time, hospitol acquired muscle weakness and muscle atrophy frequently occur. After discharge, the most common complications of patients with acute respiratory distress syndrome are exercise restriction and decline of life quality, which can last for 5 years. 15,16 These patients may have di culties in climbing up stairs, bending down, lowered functional exercise capacity, and other activities di culties in daily life. 15 Functional exercise in pulmonary rehabilitation can effectively reduce muscle atrophy and improve body functions, including muscle strength, endurance and functional activities. 17 As a highly infectious respiratory disease, pulmonary rehabilitation methods should follow the principle of 4S in COVID-19, which is simple, satisfy, safe and save, 6 in order for patients easily to manipulate. Meanwhile, establishment of a safe pulmonary rehabilitation environment to prevent the spread of virus should be concerned. Rehabilitation outcome is closely related to participation initiatives, environmental and personal factors. In clinical practice, there are many reasons for poor compliance, thus,we took appropriate interventions to help patients activily participating before pulmonary rehabilitation.
Zhou L observed that about three to ve percent of common type COVID-19 patients might aggravate to severe type in 7 to 14 days of disease onset. 18 We evaluated time of disease onset to dyspnea and monitor patients SpO 2 , heart rate, respiratory rate, blood pressure and symptoms to decide the initiation time of pulmonary rehabilitation program. Meanwhile, according to the patient's condition, we designed a set of special pulmonary rehabilitation program, including upper and lower limbs exercise, body position training and breathing rehabilitation. As excessive exercise training may lead muscles injury, resulting in excessive fatigue, we estimated the patient's training intensity by symptoms, vital signs, Borg index and RPE scale.
It was found in this trial that the ADL of the patients with COVID-19 in pulmonary rehabilitation group were notably better than those of the patients in control group. Pulmonary rehabilitation is a pattern of combined treatment for patients' exercise capacity, recovery of pulmonary function and psychology. 19 Previous study showed that, pulmonary rehabilitation therapy has positive effects on improvement of patients with chronic obstructive pulmonary disease (COPD) in physical activity in daily life level. 20 Meantime, our study showed that improvement of ADL was related to younger age, higher PaO 2 , and lower mMRC. Since an observation data showed that the younger patients, the greater the probability of functional recover would get. 16 Therefore, elderly patients might need different intensity or form of pulmonary rehabilitation program to achieve similar effects as young patients.
In this research, we found that dyspnea, measured by mMRC, improved in both groups of patients; but there was a signi cant between-group difference, with pulmonary rehabilitation group better improved in mMRC. This may because functional exercise could increase muscle strength, which was also demonstrated in current study. As we know, the improvement in respiratory muscle strength is important for patients' life quality. The therapy is an important part of management of patients with respiratory disease, and physical training plays an active role in improving exercise capacity and dyspnea. 21,22 The COVID-19 has a great in uence on the patients' psychology. In the clinical process, symptoms of the patients are heavier, while the oxygen and the condition are good. So it is not objective to evaluate the patients condition according to symptoms.
Conventional treatment assisted by comprehensive pulmonary rehabilitation therapy has positive effects on PaO 2 with COVID-19 pneumonia patients. Therefore, blood gas analysis of the patients with COVID-19 were evaluated in this study, and the results proved that the pulmonary rehabilitation had remarkable improvement in the patients PaO 2 and SaO 2 . It was consistent with the results of the study by Liu W ,et al 23 in patients with severe pneumonia that physical therapy could ameliorate the blood gas indexes. The pulmonary rehabilitation could effectively improve the blood gas indexes of patients with chronic obstructive pulmonary disease in the stable phase, too. 24 These results have proven that the pulmonary rehabilitation had improvement effects on the the exchange capacity of oxygen in patients.
Pulmonary rehabilitation therapy could improve the respiratory function reserve 25 and ameliorate the patients' cardiopulmonary functions. 6 Exercise rehabilitation commenced during acute or critical illness reduced the extent of functional decline and hastens recover. 21 A study conducted by Mundy LM,et al 26 found that early mobilisation could reduce LOS. However, No signi cant difference of LOS was found between groups in our study, though pulmonary rehabilitation group patients exhibited a trend of shorting LOS. This divergence may have occurred because the LOS in the present study depended on several factors, such as negative test of 2019-nCoV RNA-PCR test, absorbtion of chest images, other than only clinical criteria.
There were no severe complications of related to pulmonary rehabilitation group. No patients discontinued the trial. As the patients included in this trial were severe type in recovery stage, adverse events related to pulmonary rehabilitation are few and can be accepted. And the appropriate indication needs further research. In the control group, two patients complicated with DVT. Coagulation dysfunction can occure in patients with COVID-19, and a signi cant proportion of patients with coagulation disorders have DVT, which have been reported in 25% of cases 27 . We speculate that pulmonary rehabilitation exercise might reduce the risk of occurrence of thrombus through the movement of upper and lower limbs and changes of body position. But this needs larger sample clinical research.
Both groups received normal daily care during the hospitalization period, including drug treatment and oxygen therapy adjusted by the medical staff. All patients were discharged, therefore there was no association between mortality and pulmonary rehabilitation program. This was due to that very severe patients with multi-organ dysfuction were not included, which may correspond to prognosis of a low degree of lethality.
The application of pulmonary rehabilitation program could improve ADL and dyspnea in this group of patients, but some limitations have to be taken into consideration. Firstly, because of limitation of the isolation ward, six-minute walk distance and pulmonary function were not conducted. Secondly, the sample of subjects in this research was small, therefore, enrolled with more patients of multicenter, randomized controlled trials, with appropriate follow-up of are needed.

Conclusion
Exercise protocol might speed-up recovery in ADL as compared to the spontaneous recovery as observed in the control.
Pulmonary rehabilitation is feasible, safe and without increasing economic burden. Therefore, more extensive, standardized studies would be necessary to con rm the clinical and functional bene ts of pulmonary rehabilitation in COVID-19 patients.  Table 2. Variable of arterial blood gas analysis between two groups before discharge Study owchart. Flow diagram illustrating the number of participants in each group.

Figure 2
Mean values of ADL before pulmonary rehabilitation (pre), after seven days of exercise (one week) and before discharge (post) the in pulmonary rehabilitation group patients and in control group. * Intra-group analysis following intervention before discharge(p<0.001). # Comparisons of changes in post minus pre intervention between groups showed greater improvement in PR group (p< 0.001).