2.1 Study design
This is a multicentre, assessor-blinded, four-arm RCT conducted at five academic and tertiary general hospitals in China, including Fujian Medical University Shengli Clinical College, the First Hospital of Nanping City of Affiliated Fujian Medical University, Putian College Affiliated Hospital, the First Hospital of Longyan City of Affiliated Fujian Medical University, Ningde Hospital affiliated with Ningde Normal College. These five centres are located in Fujian Province's central, eastern, western, southern, and northern regions, respectively. Medical centre enrolment criteria are more than 15 beds in each ICU, and more than 500 ICU patients admitted to each ICU per year. Finally, 10 ICUs from five participating hospitals were enrolled, including medical, respiratory, surgical, and comprehensive ICUs. This trial is funded by the Fujian Provincial Department of Science and Technology beginning in January 2022, with the trial duration expected to be three years.
2.2 Participants
2.2.1 Inclusion criteria:
(1) 18 years ≤ age ≤ 80 years;
(2) ICU stay ≥ 48h;
(3) APACHEII ≥ 8 points;
(4) Patients were awake and able to cooperate with five standardized questions ≥ 3 points[28];
(5) Patients could walk independently two weeks before transfer to ICU;
(6) Patients or proxies signed written informed consent.
2.2.2 Exclusion criteria:
(1) Not suitable for early activity or rehabilitation exercises: acute phase of myocardial infarction, ruptured thoracic aortic aneurysm, obstructive hypertrophic cardiomyopathy, uncontrolled lethal arrhythmia, pulmonary embolism, acute phase of asthma, severe pulmonary hypertension, myasthenia gravis, Guillain-Barré syndrome, spinal cord injury, unstable fracture, recent deep vein thrombosis (DVT) or venous thromboembolism (VTE), active uncontrolled bleeding, restriction of activity during hospitalisation due to medical condition and other factors;
(2) Acute phase of brain injury and its possible long-term physical dysfunction and impaired consciousness; cognitive dysfunction or mental impairment;
(3) Contraindication to enteral nutrition or the need for prolonged fasting;
(4) Inability to achieve muscle strength level 3 during ICU hospitalisation;
(5) During femoral arterial cannulation.
2.2.3 Withdrawal criteria:
(1) Voluntary withdrawal from the study during the intervention;
(2) Acute complications making the continuation of the intervention impossible or necessitating termination of the intervention due to changes in condition, death, etc.;
(3) Received intervention for less than one week;
(4) Lost visit.
2.2.4 Participant recruitment and consent
Daily eligibility checks are conducted in the study site ICUs by skilled researchers to ascertain eligibility. Patients who fit any exclusion criteria will promptly be excluded, and those who are not will be checked every day to determine whether they satisfy any inclusion criteria. Once the study subjects meet the above criteria, the investigator meets with the legal proxies to go over the trial and ensure that they grasp study consent, and ask for their informed consent. For those who do, randomisation groups will be generated within 24 hours for individuals who meet all inclusion, and no exclusion, criteria. Figure 1 shows the planned flow of patients through the study.
2.2.5 Randomisation
A coordinator, who is not involved in site enrollment and is unaware of the site codes' mapping, will generate random numbers using a random number generator (https://www.random.org/). The coordinator will prepare a randomization list consisting of several sets of numbers, where numbers 1, 2, 3, and 4 represent resistance training alone, HMB supplementation, combined resistance training and HMB, and usual care, respectively. These random numbers will be placed in sequentially coded, sealed, and opaque envelopes. Similarly, each center will prepare a set of envelopes.Once a patient is enrolled in the study, the investigator will open the envelope with the smallest item number in the relevant stratification group. This means that each patient will be randomized in a 1:1:1:1 ratio to receive either (1) resistance training alone, (2) HMB supplementation, (3) combined resistance training and HMB, or (4) usual care.
2.2.6 Blinding
Due to the inherent characteristics of resistance training and HMB, blinding this study from patients, families, or ICU clinicians is not feasible. To minimise bias, outcome assessments are being conducted by blinded assessors and statisticians.
2.3 Study intervention
2.3.1 Develop resistance training intervention
The hierarchical resistance training intervention protocol used in this study was developed by the investigators through a systematic literature search and revised by Delphi expert consultation— see Table 1 and Figure 2. The intervention protocol included three physical function levels—supine, sitting, and standing position—each level containing seven to eight actions, such as chest pressing, elbow flexion, rowing, ankle dorsiflexion, ankle plantarflexion, knee extension, and hip flexion, as well as bridge exercises and abdominal breathing, to stimulate the muscle groups in the upper body, lower body, and core muscle, training movements examples are shown in Supplementary Figure 1. This was done in accordance with the clinical guidelines[29] and consensus of experts[30] in the early rehabilitation of critically ill patients. The frequency (F) of the resistance training intervention will be performed five times per week by trained charge nurses or physiotherapists. The training intensity(I) will gradually be augmented through progressive overload, and the Rating of Perceived Exertion (Borg’s 6-20, 6-reflecting minimal exertion to 20-reflecting maximal exertion) will be employed. The duration time (T) will last 20-30min each day, including warming, exercise, and cooldown. The intervention will continue from randomisation until hospital discharge in supervised training by site-trained researchers, including patients both in ICU and those undergoing general hospitalisation. The type (T) of intervention will involve resistance against body weight or elastic bands. TheraBand elastic bands (The Hygenic Corporation, Akron, OH, U.S.) with lower rank two colour-coded levels of resistance (yellow and red) will be used in the rehabilitation intervention. The resistance of the elastic bands at 50% and 200% elongation are as follows: yellow = 0.83/1.69 kg, red = 1.10/2.26 kg.
2.3.2 HMB intervention description
HMB is provided in addition to usual care to target total energy delivery of 20-25kcal/kg per day in the acute phase, 25-30kcal/kg per day in the stable phase, and target total protein delivery of 1.2-2g/kg per day[31]. The nutritional supplement applied in this study was Keirou (Entenogene, Guangzhou), which per 10g contains 8.32g of maltodextrin, 1.5g of HMBCa, 0.1g of a sweet orange powder, and 0.08g of sucralose, providing 34kcal of energy, and no protein. A total of 10g of supplement (containing 1.5g HMB) dissolved in 100ml of warm water, is administered orally or through tube feeding twice a day by nurses. HMB should be initiated when the patient is on enteral nutrition and should be suspended in case of intolerance to enteral nutrition.
2.3.3 Standard ICU co-interventions for all patients
Routine rehabilitation training and nutritional management of ICU patients are used, conducted by the supervising physician and charge nurse. Routine nutritional and rehabilitation measures for ICU patients followed the medical group treatment protocol, and no additional intervention will be imposed by investigators.
Rehabilitation training: According to the best evidence summary of early activities for patients with ICU-AW[32], early rehabilitation is carried out in conjunction with clinical practice, 20-30 min per day, with routine rehabilitation training modalities decided by the medical team. The rehabilitation training modalities received by ICU patients will be accurately recorded.
① Rehabilitation for patients who cannot actively cooperate includes passive joint activities in bed, assisted functional activities, passive sitting in bed, etc.;
② Rehabilitation contents for patients who can cooperate and perform partial rehabilitation activities focus on bedside sitting, bedside activities, bed-chair transfer, bicycle-assisted training, etc.;
③ Rehabilitation contents for patients who can move focus on active bedside activities, dynamic standing, assisted walking and a higher level of muscular endurance training
④ Patients with drainage tubes can gradually transition to choosing appropriate times each day for bed release, sitting, standing, trunk control, mobility activities, endurance training, and appropriate physical therapy.
Nutritional management: Following the American College of Critical Care Medicine Guidelines for the Implementation and Evaluation of Nutritional Support Therapy in Adult Critically Ill Patients, the energy goal for ICU patients is 20-25 kcal/kg/d in the acute phase and 25-30 kcal/kg/d in the stable phase, with a protein goal of 1.2-2 g/kg/d[31].
2.4 Outcomes measurements
According to the Core Outcome Set (COS) of rehabilitation-related outcome indicators for ICU patients[33] and the Core Outcome Measurement Set (COMS)[34], based on the previous studies[35-37] using the International Classification of Functioning, Disability and Health (ICF) theoretical framework[38] to construct the rehabilitation-related outcome indicators for ICU patients, outcomes measurements in this study were divided into four categories, that is, physical function and structure impairment, activity limitation, participation limitation, and quality of life, in addition to characteristics, mortality, and daily assessment. The arrangement of time and personnel for data collection is shown in table 2.
2.4.1 Patient characteristics:
A case report form is made to collect information about patient demographics, physiological factors, disease severity, premorbid status, nutrition, therapy, and other variable assessments access the chart review, inquiry proxy, or in-person evaluation at study enrolment and daily throughout the study period, as shown in the table 3.
2.4.2 Physical function and structure impairment:
(1)Body composition: Bioelectrical Impedance Analysis (BIA, NUTRILAB, AKERN, Italy) will be utilised to assess fat-free mass (FFM), appendicular skeletal muscle mass (ASMM), skeletal muscle index (SMI), and phase angle (PhA).
(2)The MRC score will be used to assess the muscle strength of the six major muscle groups of the extremities (bilateral wrist extension, forearm flexion, shoulder abduction, ankle dorsiflexion, knee extension, and thigh flexion). Each group is divided into six levels according to the Oxford muscle strength scale, and the upper and lower extremities of the left and right sides are measured at the same time, with a total score of 0-60. Higher scores represent greater muscle strength. MRC is considered the gold standard for the diagnosis of ICU-AW, and a score <48 can be diagnosed as ICU-AW[39] .
(3)Grip strength: The CAMRY EH101 handheld electronic grasp strength device will be used to measure the voluntary contraction force of the dominant hand's musculature. The participant will be placed in a supine, neutral forearm position[40, 41], elbow flexed 90 degrees, repeated three times, with the maximal value recorded.
(4)Short Physical Performance Battery (SPPB) will be used to assess physical function, comprising a standing balance test, four-meter walking speed and five sit-to-stand tests, each item worth 0-4 points, with a total score of 0-12 points[42].
(5)Fatigue scale-14 (FS-14) will be used to evaluate recent fatigue symptoms and their severity[43], consisting of 14 items with two dimensions (1-8 is physical fatigue and 9-14 is cerebral fatigue), with a total score ranging from 0 to 14, with higher scores indicating greater fatigue; fatigue symptoms are considered present when the total score ≥7.
(6)Mini-Mental State Examination (MMSE), a simple tool for assessing cognitive function. A total of 30 items with 30 points is stratified by education, with illiterate groups ≤ 17 points, primary groups ≤ 20 points, and secondary and above groups ≤ 24 points deemed to have abnormal cognitive function[44].
(7)Hospital Anxiety and Depression Scale (HADS) consists of two subscales, anxiety and depression, with seven items each and 14 items in total, each of which is scored on a 0-3 scale, with a maximum score of 21 for each component of anxiety and depression, with 0-7 being asymptomatic, 8-10 being suspicious for the presence of symptoms, 11-12 being definitely symptomatic, and >15 suggesting severe affective disorder, where a score of ≥8 is considered positive for anxiety or depressive symptoms[45].
(8)Revised Impact of Event Scale (IES-R) is a 22-item instrument that detects post-traumatic stress disorder (PTSD) symptoms [46]. It assesses the severity of avoidance, intrusion, and hyperarousal symptoms, the three categories of PTSD symptoms. The adoption of a threshold score of 33 out of 88 indicates severe psychological impact of a traumatic event.
2.4.3 Activity limitation:
(1) 6-Minute Walk Test(6MWT) To evaluate functional endurance capacity and mobility, participants were directed to walk independently along a 30-meter hospital corridor and cover as much distance as possible within a 6-minute duration. The recorded outcome, denoted in meters, is known as the 6-Minute Walk Distance (6MWD).
(2) The Physical Activity Scale for the Elderly (PASE) [47] will be used to assess the physical activity of ICU survivors after hospital discharge, including the three dimensions of leisure, housework, and occupation, with a total scale score ranging from 0 and 500, and a higher score indicating a higher level of physical activity.
(3) Functional Status Score for the Intensive Care Unit (FSS-ICU)[48], consisting of rolling, supine to sit transfer, sit to stand transfer, sitting on the edge of the bed, and walking. Each item is scored from 0 to 7, with 0 points representing unable to attempt or complete the task due to weakness, with 7 points representing complete independence. The total score is the sum score of all five items ranging from 0 to 35. Higher scores indicate better functional status.
2.4.4 Participation limitation
The Barthel Index (BI) of activities of daily living (ADL) [49] will be used to measure functional status and dependency. There are 10 categories in total: feeding, bathing, grooming, dressing, bladder control, bowel control, toilet use, chair–bed transfer, mobility, and stair climbing. Scoring ranges from 0 to 100: a score of 100 is defined as being capable of ADL complete self-care.
2.4.5 Quality of life:
36-Item Short Form Health Survey (SF-36)[50], which comprises 36 questions with eight dimensions: Physical Functioning (PF), Physical Functioning (Role-Physical, RP), Body Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Emotional Functioning (RE), Mental Health (MH). The first four dimensions make up the Physical Component Summary (PCS), and the last four dimensions make up the Mental Component Summary (MCS).
2.4.6 Daily assessment
(1)Daily dietary intake: Patient daily dietary intake and gastrointestinal tolerance during hospitalisation will be recorded by the charge nurse or investigator, and the cumulative energy and protein deficit will be calculated using the lower limits recommended by the American College of Critical Care Medicine Guidelines for the Implementation and Evaluation of Nutritional Support Therapy in Critically Ill Adults[31] on target values for energy and protein intake, i.e., a daily target energy intake of 25 kcal/kg and a target protein intake of 1.2 g/kg.
(2)Daily activity: During the patient's ICU stay, the bedside nurse documents the amount of time the patient spends sitting in a bedside chair and walking, when transfer to the general ward is self-reported by the patient or caregiver and recorded by the charge nurse.
(3)CAM-ICU: The Confusion Assessment Method-ICU will be used by a trained bedside nurse to assess delirium at least every 12 hours.
2.5 Study outcomes
2.5.1Primary outcome
The primary outcomes are 6WMD and SPPB at hospital discharge.
2.5.2 Secondary outcomes
The secondary outcomes are body composition, MRC score, grip strength, FS-14, MMSE, HADS, IESR, FSS-ICU, PASE, BI, SF-36, CAM-ICU, and 60-day mortality.
2.6 Statistical analysis
2.6.1 Sample size determination
The study sample size was determined with the PASS software by ANOVA four-group mean F test with Power=0.90, α of 0.05, and Group=4. With 6MWD at hospital discharge as the primary outcome, the mean and standard deviation of the four arms based on the feasibility study were 273.83±133.06, 159.33±105.29, 257.36± 114.33, 157.83±152.64, respectively. A maximum sample size of 30 per arm is needed, considering a 20% missing rate, thus we will enroll 38 patients in each group, totaling 152 patients.
R software will be used to process the data. Statistical tests are all two-sided, and the differences are considered statistically significant when P<0.05. We followed the principles of intention-to-treat analysis (ITT).
2.6.2 General characteristics analysis
Continuous variables will be tested for normality using the KS-test in conjunction with the PP-plot and QQ-plot; those conforming to normal distribution will be described using mean standard deviation, while those not conforming to normal distribution will be described using the median (interquartile spacing); categorical variables will be described statistically using frequency and percentage. Continuous variables obeying normal distribution will be analysed using the ANOVA test, whereas those not obeying normal distribution will be analysed using the Wilcoxon Rank Sum test; categorical variables will be analysed using the chi-square test, Fisher’s exact test, etc. The mean value will be used to fill in missing characteristics values.
2.6.3 Linear Mixed Model
Linear Mixed Model(LMM) will be used to analyse the differences and trends in FFM, ASMM, SMI, and PhA between the four groups at different assessment time points T0, T1w, T2w, and at discharge; GLMM was used to analyse the differences between the four groups at discharge between SPPB and 6WMD, and between SF-36, IESR and PASE at one month post-discharge; GLMM was used to analyse the differences between the four groups in MRC scores, grip strength, and MMSE at T0, transfer out and discharge and the trend of change; LMM was used to compare the differences and change trends in FS-14, HADS, FSS-ICU and IMS scores at T0, transfer out and discharge, and one month post-discharge between the four groups. The differences in the incidence of ICU-AW at each time point between the four groups were analysed using GLMM. The model will use group, time, and between group and time interactions as fixed effect measures to control for the effect of repeated measures of data, and the variable of centre as a random effect measure to control for the effect of population heterogeneity across centres. The regression coefficient β(95CI%) will be calculated for the resistance training group, HMB group, and combined group compared to the control group as a reference to compare the magnitude of the three intervention effects. The GLMM allows for the presence of missing values, thus missing values in the ending indicator section are not treated specifically.