Baseline interview
Upon patient recruitment and allocation to groups, a one-on-one baseline interview and evaluation will be conducted to (1) record patients’ comprehensive medical history; (2) assess patients’ nutritional states; (3) assess patients’ functional capacity during the 6-minute walk test (6MWT); (4) conduct a pulmonary function test (Spirodoc portable pulmonary function meter, Medical International Research S.r.l., 09000261972), during which the forced expiratory volume in one second (FEV1, L), FEV1%, forced vital capacity (FVC, L), FVC%, FEV1/FVC, peak expiratory flow (PEF, L/s), and PEF% will be recorded; (5) record laboratory results, if applicable, including the levels of alanine transaminase (ALT), creatine (CR), c-reactive protein (CRP), albumin (Alb), glucose (Glu), and myocardial enzymes; (6) evaluate the patients’ baseline quality of life and mental state using standard tools [hospital anxiety and depression scale (HADS), World Health Organization disability assessment schedule II (WHODAS 2.0) score, postoperative quality of recovery score − 15 (QoR-15)]; (7) explain in detail the prehabilitation plan for both groups; (8) encourage patients to choose a preferred way to be followed up, such as by telephone, short text messages or WeChat messaging.
Interventions
Aside from the prehabilitation strategies, all patients enrolled will receive conventional perioperative recommendations, including those based on preoperative anesthesia assessments, drug treatment recommendations for chronic diseases, and recommendations to quit smoking and practice abstinence. The patients will also be provided information on anesthesia and surgical processes, according to each individual’s needs.
We will encourage the patients in both groups to choose their preferred types of exercise and form individual-specific prehabilitation plans. A prehabilitation instruction brochure will be distributed to patients along with a daily self-evaluation prehabilitation journal, where they can record their adherence to the prehabilitation plans. Standardized short message interviews will be sent to patients twice a week in the manner chosen by the patients to optimize adherence and promote timely feedback. The patients will receive intraoperative and perioperative care according to standard practice in terms of the surgical procedures, anesthesia and analgesia management and nursing care.
The patients will be encouraged to reach out to our researchers if there are injuries or discomforts during the follow-up period. Since intervention is based on moderate exercise and nutrition supplement, and exercise plan is individualized to consider participants’ capacity and preference, harm of the intervention is considered minimal. However, if patients experience injuries or discomforts due to the exercises or whey protein supplement, the intervention will be discontinued and we plan to offer appropriate medical and financial support. At any point of the study period, if patients request to stop or pause with the intervention, the intervention will be discontinued.
Multimodal prehabilitation strategy features
For the multimodal group, we will implement the following prehabilitation strategy:
1) A 30-minute aerobic exercise session will be performed at least 3 times a week; it will be divided into a 5-minute warm-up (including ankle extensor lifts and static quadriceps contraction) and a 25-minute aerobic exercise in the form of jogging, power walking or cycling, depending on the patients’ individual choice. We will encourage patients to tailor their exercise intensity to the Borg rating of perceived exertion (RPE) scale [17] shown by Table 1., and target heart rate (HR), increasing or decreasing the intensity according to the level of exertion throughout the prehabilitation period. We will recommend that patients achieve moderate to high levels of exertion, as indicated by 13–16 points on the Borg RPE scale and a target HR of (220-age-resting HR) ×70%+resting HR. The methods of using the Borg RPE scale and target HR to adjust the exercise intensity will be explained at the baseline interview, and both methods will be illustrated in the brochure we give the patients. We will also provide each patient with a pulse oximeter (Jiangsu Yuyue Medical Equipment & Supply Co., Ltd., 20172201070) to help monitor HR. For patients who choose an outdoor activity as their aerobic exercise training method, we will stress the importance of safety and advise them to avoid exercising outdoors on days with poor air quality index values (> 100).
Table 1. Borg RPE scale
|
Score
|
Level of exertion
|
|
6
|
No exertion at all
|
|
7
|
Extremely light
|
|
8
|
Minimal recognition of effort
|
|
9
|
Very light (equivalent to walking at your own pace for several minutes)
|
|
10
|
Could just start to beware of breathing
|
|
11
|
Fairly light (conversation is easy and feel like you could keep the pace for a long time)
|
|
12
|
Light
|
|
13
|
Somewhat hard, but still feel able to continue
|
|
14
|
You could hear your breathing clearly but not struggling
|
|
15
|
Hard (You could talk but not in full sentences)
|
|
16
|
Heavy
|
|
17
|
Very hard. You could continue but would be pushing yourself to feel very fatigued
|
|
18
|
You could not talk because of the heavy panting
|
|
19
|
Extremely hard
|
|
20
|
Maximal exertion
|
2) Guided resistance exercise will be performed at least twice a week. At the baseline interview, a research staff qualified in performing physical therapy training and evaluations will initially evaluate the physical status of the patients and then explain and demonstrate the resistance exercises. We will provide each patient in the multimodal group with two pulling straps of different elasticities. Resistance training will be performed with either strap, depending on the patient’s individual strength limits. Most patients will start training with the less elastic strap and advance to the more elastic strap once they feel that training with the less elastic strap requires too little effort. We will assign 4 pre-set resistance postures for the training sessions, involving 4 major muscle groups (upper and lower limbs, chest and core muscles). The complete resistance training session will include 3 sets of exercises with an interval of 2 minutes between each set. Each set will include 10–12 repetitions of the 4 resistance postures. At the end of each complete session, the patients will be asked to evaluate their perceived exertion by using the Borg RPE scale. The target score will be 13–16. The number of repetitions performed within each set and the strap selection should be adjusted on an individual basis throughout the prehabilitation period according to the Borg RPE scores.
3) Breathing exercises will be performed at least 3 times per day, with each session lasting more than 10 minutes. We will introduce three types of exercises: (1) guided effective coughing (sit up and lean slightly forward, inhale fully then cough out in a short and forceful manner while engaging core muscles), (2) blowing up a small balloon in one breath and blowing it up slowly for more than 5 seconds, (3) breathing training with the Tri-Ball Respiratory Exerciser (Leventon S.A., Barcelona, Spain) that we will distribute. All three types of breathing exercises will be demonstrated at the baseline interview and explained in the brochure. The patients will be allowed choose to conduct one or more types of breathing exercises in one session.
4) Regarding nutritional advice and whey protein supplementation, patients’ nutritional status and dietary habits will be evaluated at baseline by a research staff member trained in nutriology. Nutritional advice predetermined by our nutritionists will be given to modulate the patient’s eating habits, mainly aiming at reducing fat-rich diets and increasing high-quality protein uptake. Patients with malnutrition will be advised to increase their calorie uptake. We will also provide patients in the multimodal group with whey protein powder (Inerish; Sino-American Medical Institute Inc, San Diego, CA) as a protein supplement and advise them to take it daily (20 g/day for males and 15 g/day for females). If patients plan on performing exercises that day, we will advise that the whey protein powder is taken within 1 h postexercise, promoting muscle synthesis.
5) Psychological therapy will include listening to soothing music, broadcasts or other relaxing activities of the patients’ choice before sleep. We will provide each patient in the multimodal group with a simple music player with prerecorded relaxing, classical music tracks and encourage patients to use it if they prefer this type of relaxation method. We will also encourage patients to choose their preferred methods of relaxation, including listening to audiobooks, meditating, watching relaxing television shows, etc.
Aerobic prehabilitation strategy features
The aerobic group will receive the same instructions regarding the individualized home-based aerobic exercise program as the multimodal group will, but they will not receive advice regarding the other aspects of their behaviors. These patients will also be advised to record their daily exercises in a prehabilitation journal and will receive the same follow-up interviews twice a week.
Outcomes
The primary outcome will be the perioperative 6MWD (baseline, 1 day presurgery and 30 days postsurgery). The 6MWT will be conducted following the guidelines of the American Thoracic Society (ATS) [18]. The research staff members who will be involved in performing the 6MWT will all be trained before administering this test. We will conduct the 6MWT indoors in a 30-meter-long corridor in PUMCH. We will ensure that supplies needed for safety issues are readily available whenever the 6MWT is performed, including oxygen, sublingual nitroglycerine, aspirin, and albuterol. All the staff members who will be involved have been previously certified in cardiopulmonary resuscitation. The 6MWT will be conducted in a standard manner. From the 10-minute rest period before the test to all the verbal instructions provided to the patients before and during the test, all procedures will be performed in accordance with the standard ATS guidelines.
We will record patients’ sex, age, height, weight, medications before the test, and whether they need oxygen supplementation during the test. We will measure blood pressure, HR, oxygen saturation, and the Borg RPE score before and after the test. We will note the number of laps and calculate the 6MWD.
The secondary outcomes will include the perioperative pulmonary function test results, including the FEV1, FEV1%, FVC, FVC%, FEV1/FVC, PEF, and PEF% values (baseline, 1 day presurgery and 30 days postsurgery); the perioperative HADS and WHODAS 2.0 (baseline, 1 day presurgery and 30 days postsurgery); post-surgery QoR-15 (3 consecutive days after surgery); prognostic information (mortality and morbidity, length of hospital stay, ICU stay time, duration of chest tube placement duration); and perioperative laboratory results, if applicable, including the levels of ALT, CR, CRP, Alb, Glu and myocardial enzymes (baseline, 1 day presurgery and 30 days postsurgery).
Implementation timeline
The timeline of this study is 6 to 8 weeks; prehabilitation will be implemented for 2 to 4 weeks before surgery, and the follow-up period will include the 4 weeks after surgery. The timeline will differ across individuals, mainly due to the wait time before surgery. Clinical outcome data will be retrieved by practitioners from the inpatient records within one month after surgery. Figure 2 shows the full timeline.
Sample size
In this study, we will calculate the sample size on the basis of a comparison of the measured primary outcome, the 6MWT result, between a small pilot study and a previous multimodal prehabilitation study conducted in our institute [16]. We will assume the average 6WMD in the aerobic prehabilitation group to be 30 m shorter than that in the multimodal group at 30 days postoperatively. The standard deviation (SD) for the 6MWD will be estimated to be 50 meters for both groups. A sample size of 45 patients each in the aerobic group and multimodal prehabilitation group is required to detect a statistically significant difference at a two-sided significance level of 0.05 and statistical power of 90%. To account for patient dropout and missing data, we plan to recruit a total of 50 patients for each group.
Data collection
Upon receiving informed consent, the researchers will collect the patients’ medical history and demographic information at the baseline interview. Baseline laboratory test results will then be retrieved from patients’ electronic medical records: complete blood count (CBC), liver and kidney function test results, electrolyte levels, and coagulation routine test results.
The 6MWD and pulmonary function test will be conducted and recorded by trained researchers at our institution after they provide standardized instructions and demonstrations of the tests. Patient-reported qualitative questionnaires will be administered by and the results will be recorded by trained researchers.
During the prehabilitation period, message interviews will be sent to patients twice a week by our researchers, and feedback on weekly prehabilitation performance will be recorded.
After surgery, designated clinicians will retrieve the surgical approach performed, tumor assessment results, pathology results and postoperative complications from the patients’ electronic records.
All the data will be collected by researchers who have signed a confidential disclosure agreement. Patients’ identity and personal information will not be disclosed without consent.
All data collected will be recorded first in the paper-based case report form (CRF) and then entered into a digital database by an independent investigator. The digital database will be under the supervision by the Data Monitoring Committee (DMC) composed of two experienced doctors of department of anesthesiology, and one statistician of department of medical research center, PUMCH, who are independent from this study. The DMC members will monitor the integrity of the data and patient safety. Upon data entry, the database will be locked by a password. DMC members will make the decision to unblind, conduct an interim analysis or terminate the trial, if they deem it necessary.
Statistical Analysis
Patients’ baseline characteristics will be described by descriptive analysis and compared between groups to detect clinically relevant differences. If evident baseline imbalance exists, the analysis of the primary outcome will be adjusted. For tests conducted perioperatively including 6MWD, pulmonary function test results, HADS and WHODAS 2.0 score, a linear mixed-effects model will be built to analyze the interaction between intervention and time [19]. Other secondary outcomes including the QoR-15 score, LOS, chest tube duration, postoperative complications will be analyzed using χ2 test and the Mann-Whitney U where appropriate. Patients lost to follow-up will be considered as non-adherence. We will perform sensitivity analysis to test if the analyses of the primary outcome will be robust to the missing values. All statistical analyses will be completed in R (R Foundation for Statistical Computing, Vienna, Austria; version 3.5.2).
Dissemination plans
We plan to communicate trial results thoroughly with our multidisciplinary team and encourage conversations with medical providers in other state facilities during annual conference of Chinese Medical Association. These medical providers will in turn disseminate results to the patient community. We will also inform the patient community of the results during pre-surgery evaluation and consults. We are planning to invite researchers from our multidisciplinary team as co-authors in the publication process, and we are not planning to use professional writers. For further dissemination of the results, we will post the study concept and major results on the website of the anesthesiology department of PUMCH. We will be open to provide the whole study protocol as well as patient-level dataset when approached by interested health providers or researchers.