Study design and ethics statement
This was a single-blinded, randomized controlled efficacy trial with 2 parallel groups and intention-to-treat analysis. The study protocol has been registered at Chinese Clinical Trial Registry (ChiCTR2000033166) and approved by the medical ethics committee of West China Hospital of Sichuan University (#19-667). All patients were informed of the procedure, the use of their data and images for research. They understood the purposes and provided written informed consent according to the 1964 Declaration of Helsinki prior to their participation.
Participant recruitment
From May 2020 to August 2020, we prospectively enrolled all adult individuals with a diagnosed SCI below T3 and above L2 at least 1 month. Participants were recruited from inpatients in 3 units of Rehabilitation center, West China Hospital, Sichuan University. None of them had EAW training experience before. In addition, the eligible individuals met the following inclusion criteria: (1) American spinal injuries association impairment scale [25] (ASIA) classified with A, B or C, (2) the height was between 1.50 meters and 1.85 meters and (3) stopped smoking for over 6 months. Individuals were excluded if: (1) spasticity of any the lower extremity muscles scored over 2 according to the Modified Ashworth Scale [26], (2) with unstable fracture, (3) diagnosed with severe osteoporosis (bone mineral density t-score < -3.5), (4) with any respiratory or other neurological diseases.
Randomization and Blinding
The individuals were randomly divided into the EAW group or conventional group by simple randomization method, using computer-generated simple random tables. The sequences were preserved using closed envelop method by one researcher who did not participant in the trainings and assessments (H.C.H). PFT and LEMS assessment of individuals pre- and post-training were performed by the same two clinical researchers (X.Y. and Y.O) who were blinded and did not know whether the individual was in EAW or conventional group. 6MWT was performed by two researchers who participated in EAW training (H.C and C.P.D) and conventional training (H.Y.Z). Clinical data was recorded after averaging.
Interventions
The AIDER (AssItive DEvice for paRalyzed patient) powered robotic exoskeleton was used for the EAW training. All subjects were individually fitted to the robotic exoskeleton according to pelvic width, thigh length, and shank length. EAW training program was conducted consecutive 4 days a week, 16 training sessions in total. Every training session lasted 50 to 60 minutes containing interval rest as needed by standing, leaning on the wall, or sitting while wearing the device. Training session included sitting, standing, walking, climbing stairs and slope with maximal assistance-walking mode (Fig. 1) and reaching 40-60% maximal heart rate (HR, HRmax=220 - age) that is checked with the values of a heart rate sensor (Polar H10, POLAR® China).
For the conventional group, the rehabilitation program included strength training using dumbbell between 5 kg and 20 kg, aerobic exercise, such as walking training with brace as well as static and dynamic balance training in sitting or standing position. The conventional rehabilitation training had the same intensity, duration, and frequency as EAW training (40-60% HRmax, 50-60 min/session, 4 days/week, 4 weeks). Medications and rehabilitation nursing were ordered based on the medical condition.
Measures
Outcome measures were collected and analyzed at the baseline and end of 16-session intervention period.
Primary outcome
PFT was completed with a computerized spirometer (Vyntus™ SPIRO PC Spirometer, Vyaire Medical Inc., Mettawa, US) based on the standardized procedures as the American Thoracic Society [27] described. To determine PF parameters, participants performed PFT seating in the wheelchair and were forbidden to disclose their intervention assignment to the assessor. The PFT was performed with the participants wearing a nose clip. If the participant coughed or made a mistake, the numerical values were not recorded. Three repeated maneuvers were performed, separated by a five-minute rest and the best result was recorded automatically. The PFT consisted of the assessments of FVC, FEV1, FEF25/50/75, PEF, and MVV.
FVC refers to the total capacity of air that can be blown out by maxima forced expiration following maximal inspiration. FEV1 refers to the capacity of air that is blown out for a single second. FEF25/50/75 means forced expiratory flow at 25%, 50% and 75% of the FVC. PEF reflects the intensity of respiratory muscles. MVV refers to the maximum volume of air, a subject can breathe over a specified period [28].
Secondary outcomes
The 6MWT (6-minute walk test) was performed in door that is aimed to determine walking ability. Additionally, it can manifest cardiorespiratory endurance through evaluating the walking distance in accordance with the guidelines of the American Thoracic Society [29]. At the beginning and end of the test, clinical researchers recorded the participant’s HR, and peripheral oxygen saturation (SpO2). In additional, the level of effort at the end of the test was reported by the rate of perceived exertion (RPE) based on the Borg scale [30]. Participants ambulated using their preferred stability aid (either crutches or walker). Individuals in EAW group were allowed to wear the exoskeleton, while those in conventional group using the knee-ankle-foot orthoses if they had one. The outcome of distance will be recorded as 0 and others be recorded according to the facts, if the individuals cannot walk. Moreover, lower extremity motor score [31] and ASIA scores were reported to demonstrate the recovery of muscle strength and neurological level.
Data Analysis
The statisticians (X.N.X and J.D) were blinded to the program and completed analyses utilized SPSS version 25 (SPSS Inc, Chicago, Illinois). The Shapiro-Wilk test was used to determine if data were normally distributed. These were recorded as means±standard deviations (SDs), others were described as median and inter quartile range (IQR) where necessary. The mean values (Δ) of post-intervention minus pre-intervention were recorded. Independent Student t-test was used to compare continuous data related to clinical features between two groups. Paired Test Student t-test was used to compare varies between pre- and post-intervention. Furthermore, the Fisher’s exact and Pearson’s Chi-square tests were used if the data were categorical variables. Wilcoxon rank-sum test and Mann–Whitney U test were used if the data was not normally distributed. Pearson correlation test was performed to discuss the relation between the distance of 6MWT and changes of PF parameters. In all statistical tests, p< 0.05 was defined as significant.