Development and Feasibility of the Early Rehabilitation Program on Postoperative Enhanced Recovery Following Minimally Invasive Esophagectomy: A Prospective Randomized Controlled Trial

Background: Perioperative rehabilitation management is essential to enhanced recovery after surgery. Few reports, however, focused on quantitative, detailed early activity plans for patients after esophagectomy. Aim: The purpose of this research was to estimate the effect of the Early Rehabilitation Program (ERP) on the recovery of bowel function and physical function for patients undergoing esophagectomy. Method: In this single-blind, 2-arm, parallel-group, randomized pilot clinical trial, patients were selected from June 2019 to February 2020 and assigned to the intervention group (IG) or the control group(CG) randomly. The participants in IG received an ERP strategy during the perioperative period, and the CG received routine care. The recovery of bowel and physical function, readiness for hospital discharge (RHD) and postoperative hospital stay were evaluated on the day of discharge. Results: 215 cases were enrolled and randomized to the CG (n=108) or IG (n=107). There was no signicant difference between the two groups in terms of demographic and clinical characteristics and baseline physical function. After the ERP intervention, the IG group presented a signicantly shorter time to rst atus (P<0.001) and to rst bowel movement postoperative (P=0.024), and a better physical function recovery (P (cid:0) 0.001), compared with the CG group. The analysis also showed that participants in the IG have higher scores of RHD and shorter length of postoperative stay than the CG (P (cid:0) 0.05). Conclusion: The ndings suggest that the ERP can improve bowel and physical function recovery, ameliorate patients' RHD, and shorten postoperative hospital stay for patients undergoing MIE.


Background
Esophageal cancer (EC) is the seventh most common cancer and the sixth most common cause of death overall on the global burden of cancer worldwide. [1] In China, the latest epidemiological survey showed that around 145,700 new cases and 188,100 deaths of EC occurred in 2015, which were higher than the average level of worldwide. [2] Surgery is still the standard treatment for resectable EC, which is comprised of esophagectomy with radical lymphadenectomy. Esophagectomy is also a major and complex surgery with unacceptable morbidity and mortality rates. A global review of high-volume hospitals performing esophagectomy showed overall morbidity of 59% and 30-day mortality of 2.4%. [3] Many new strategies and technologies attempted to reduce complications and promote fast recovery, such as minimally invasive esophagectomy (MIE) and the concept of enhanced recovery after surgery (ERAS). ERAS was described rst in 1997 by Henrik Kehlet, which is a multimodal pathway integrating evidence-based protocols into clinical practice, and has been widely applied to reduce the surgical stress response, postoperative medical complications, hospital stay and improve recovery after major surgery.

Research Design
In this single-blind, 2-arm, parallel-group, randomized pilot clinical trial, patients with EC undergoing surgery were selected using convenience sampling and divided into intervention group (IG) and control group (CG) randomly by lottery. Researchers involving in the formulation and implementation of intervention programs were informed about the allocated intervention. However, research assessors, data management staff and all patients were blinded to the intervention. Furthermore, research subjects would be placed into different wards in order to avoid mutual contamination between patients. All participants in this study received written, and oral information and written informed consent was obtained from patients or their family prior to the trial. In addition, the principles of the Helsinki Declaration have been respected.
This study was approved by the Ethics Committee of the local Medical Ethics Committee(2014xjs4), and the protocol registered in the ClinicalTrials.gov (registration number: NCT01998230).

Participants
The study performed between June 2019 and February 2020 at the Department of Thoracic Surgery of Henan Cancer hospital in China. All patients with EC who had received surgery recruited by the following conditions. Eligibility criteria: histologically proven EC and selected for McKeown MIE, age ≤ 75 years, volunteer to this research and be informed consent. Exclusion criteria included previous severe lung, brain and heart organic diseases, bone and joint disorders, emergency surgery, serious postoperative complications such as anastomotic leakage, inability to perform language communication or text understanding.

Interventions
Patients in the CG received usual nursing measures after McKeown MIE, which included conventional postoperative feeding, pain management, safe and comfortable environment, wound care, diet guidance, medication care, psychological counseling, regular postoperative rehabilitation exercises etc. The pulmonary rehabilitation and physical exercise conducted by nurses according to the routine of postoperative care.
Participants in the IG received the ERP based on King's TGA and usual care. According to the treatment characteristics of patients during the perioperative period, the program designed into two main parts: prerehabilitation before surgery and fast rehabilitation after surgery, which includes six stages in total. The intervention implementation process was as follows: (1) Forming a research team The members of the ERP team included two thoracic surgeons, four nurses, one rehabilitation therapist, and respiratory therapist, and was led by a nursing manager.
(2) Comprehensive evaluation When patients are admitted to the hospital, the research team should conduct a comprehensive examination for patients. The assessment includes: 1)disease conditions; 2) cardiopulmonary function, including cardiac ultrasound, lung function, hematological indicators, etc; 3) disease cognition, including psychological status, relationship with family, perception of disease, awareness of self-disease management, social support system, etc.

(3) Formulating program
This was a nurse-led ERP, which was guided by King's TGA during the formulating process. Therefore, before the program is formulating, researchers need to explain the concept of ERAS and the signi cance of early activities to patients, and discuss pre and post-operative rehabilitation types and target amount together. The individualized practical rehabilitation target list formed with the joint participation of patients and researchers, including short-term and long-term activities. Team discussion was necessary before the program began to implement. The theoretical framework of this study carried out according to Fig. 1. Finally, the rehabilitation activity plan would be presented in tables and in stages, including the training items, content, methods, frequency, and target quantity for each stage, the sample table was shown in Table 1. (4)Intervention safeguards: To ensure the effective implementation of the intervention program, we have made the following efforts: 1) A safe environment for activities: such as temperature and humidity, clean and dry ground, auxiliary equipment, and mobile monitors if necessary; 2) Adequate analgesia management: Painlessness is the prerequisite for early postoperative activities. Multimodal analgesia and individualized analgesia programs ought to use to control the patient's pain to less than 3 points (Visual analogue scoring); 3) Extubation as soon as possible: After evaluation by the research team, the urinary tube and gastric tube were generally removed on the POD 1 to facilitate activities. 4) Recording activities: A recording table of perioperative rehabilitation activities had established, so that researchers could record the times and amount of patient's daily activities, and note patient's daily activities on the bedside visual board; 5) Encouragement and adjustment: Positive encouragement should be given when the target is completed. Adjustment and update of the rehabilitation plan would be conducted based on cause analysis and solution searching by researcher and patient, when the goal is not achieved. (5)Precautions: The guidance and supervision of medical staff were essential when patients begin to perform stair climbing training or get out of bed to ensure the safety. Rehabilitation activities should stop immediately, when patients suffered from arrhythmia, chest tightness, suffocation and other discomforts, and the next rehabilitation plan would decide after the evaluation and treatment by a professional doctor.

Outcomes and Sample Size
At baseline, all patients underwent a preoperative assessment on the day of admission, including sociodemographic data, medical history and comorbidities, and physical function. Subsequently, the ERP or usual nursing measures implemented until patient discharge. Research outcomes measured on the day of discharge, which usually was on the 7-9th day postoperative.
The primary endpoints were bowel function recovery (measured as the time to rst atus and bowel movement postoperative) and physical function (measured by the timed up and go test and frailty score) in both the groups. In the Timed up and go test (TUGT), time will be recorded for participants to rise from a chair, walk 3 meters, and turn around, walk back to the chair and sit down [18] . Take the test twice, and the average value used as a research result. The frailty score was developed by Fried and colleagues [19] , whose criteria comprise ve components: exhaustion, unintentional weight loss, slowness, weak muscle strength, and low physical activity. For the ve frailty criteria, 1 score would be given if the criterion was met. The total scores ranges between 0 and 5, and participants would be classi ed as robustness states (0 score), pre-frailty (1 or 2 scores), or frailty (3 or more scores) [20] .
The secondary endpoints were readiness for hospital discharge (RHD) and postoperative hospital stay in both groups. The RHD questionnaire was developed by Weiss et al in 2006 [21] and has been translated and revised into Chinese version by Taiwanese scholars [22] . This scale consists 12 items and 3 dimensions, covering physical status, adaptive ability, and expected support. The score range of each item is from 0 to 10. The overall Cronbach's α coe cient of the scale was 0.89 [22] , con rming its validity.
The sample size was calculated based on the primary outcome-the time to rst atus after surgery.
Previously published results [23] showed that the mean values of time to rst atus in the IG and CG were 2.6 days and 3.4 days, and the standard deviation was 1.7 days. Group sample sizes of 72 and 72 achieve 80.08% power to reject the null hypothesis of equal means when the population mean difference is µ1 -µ2 = 3.4-2.6 = 0.8, with a standard deviation for both groups of 1.7 and with a signi cance level (alpha) of 0.05, using a two-sided two-sample equal-variance t-test by PASS 15.0 software. Allowing for 20% attrition, we increased the sample size to 180 patients (90 participants per group) at baseline.

Statistical analysis
Descriptive statistics can be used for demographic and clinical characteristics at baseline. Continuous variables were presented as Means ± SD and compared using the unpaired t test. Categorical or ranked variables were presented as frequency (%), and analyzed with the χ2. P < 0.05 was considered statistically signi cant. The statistical analysis performed using SAS 9.4 (SAS Institute Inc., Kerry, USA).

Results
Participant demographics and clinical characteristics 327 potential participants were recruited, of whom 250 (76.45%) patients were included, and randomized into two groups randomly to receive the intervention of usual care or ERP strategy. During the research, 35 patients were excluded, and 215 patients were included in the nal analyses (IG, n = 107; CG, n = 108). The detailed selection process of the participants was as shown in Fig. 2  The primary outcomes about bowel function recovery and physical function recovery were outlined in Tables 3 and 4 respectively. As shown in Table 3  The ERP strategy was even more effective than usual care in improving physical function recovery as measured by the TUGT (s) and Frailty score. As summarized in Table 4, before the intervention (the day of admission), no signi cant differences in baseline physical function between the two groups were observed (P 0.05). After the ERP intervention (the day of discharge), the mean (SD) time of TUGT (s) was 13.22 (4.05) in IG and 16.13 (5.42) in CG, the mean (SD) score of Frailty was 2.16 (0.75) in the IG and 3.22 (1.10) in CG, which showed physical function recovery in IG was signi cantly better than CG (P 0.001).
After the ERP intervention, except the dimension of expected support, the total scores of RHD (P 0.001), physical status (P 0.001) and adaptive ability (P = 0.001) were signi cantly higher in IG than that in the CG, as showed in Table 5. Likewise, compared with the CG, patients in the IG presented a signi cantly shorter in the time of postoperative stay (9.083.48d vs. 12.144.05, respectively, t=-5.94, P < 0.001).

Discussion
Esophagectomy has identi ed as a particularly complex surgical procedure due to documented high levels of perioperative morbidity and mortality [24] . Advances in perioperative management concepts and medical technology had been proposed to reduce surgical risk and perioperative morbidity and mortality, thus improving surgical short-and long-term outcomes. [25][26][27] According to the components of ERAS guidelines, early and structured mobilization is an essential factor to accelerate recovery, and there is a strong relationship between physical activity and quality of life generally [28] . Ambulate early not only prevents complications associated with bed rest and maintain muscle function, but also empowers patients to play an active role in their rehabilitation from surgery. [7] Therefore, an early and goal-directed mobilization plan should formulate by the involvement of the chest physiotherapist for EC patients on each day of perioperative.
Cardiopulmonary tness and physical functioning are key determinants of tness for major thoracic surgery. [29] One strength of our study is preoperative rehabilitation, which was involved in ERP intervention for esophageal cancer after surgery and included stair climbing training and inspiratory muscle training by a tapered ow resistive inspiratory loading handheld device. "Pre-rehabilitation before the operation can accelerate recovery after operation", this is the philosophy of our team in the implementation of ERAS. Previous research showed that preoperative moderate intensity activity was associated with a lower risk of postoperative complications following oesophagectomy and therefore may have therapeutic potential. [30] One scoping review [31] provided an overview of the available evidence of possible bene cial effects of preoperative exercise therapy in surgery, which showed that the preoperative exercise programs could increase in exercise capacity and physical tness, preserve pulmonary function, reduce the incidence of postoperative complications, and decrease the length of hospital stay. Although, some studies [7] suggested that the preoperative rehabilitation program requires at least 4 weeks, there is limited data for esophagectomy about the general consensus or clear practical guidance currently regarding exercise methods and exercise time norms.
This randomized clinical trial provided evidence that ERP, involving pre-rehabilitation and early postoperative activity, was effective in promoting recovery of bowel function and physical function in patients undergoing esophagectomy. TUGT test is a common method to observe patient's balance motor function and daily activities, and is an important index to evaluate patient's prognosis. [32] Although the physical tness of EC patients was affected to a certain extent due to the operation, analysis of this study showed that the time of TUGT in the IG (13.224.05) was signi cantly shorter than the CG (16.135.42) when discharged after the intervention of ERP. The frailty scores was range from 1 to 4, there were signi cant statistical differences between the two groups. Something worth noting is that 32.09% of patients are in a frailty state (three or more scores) and 56.28% are in a pre-frailty state (one or two scores) after esophagectomy, which should require adequate attention from medical staffs.
RHD is a self-perception of patients about whether they are ready to be discharged, it is related to medical satisfaction and safety after discharge closely. Studies [33,34] have shown that the higher RHD, the stronger ability to cope with health challenges after discharge. In this study, the RHD of patients after esophagectomy was at a medium level. Given that physical recovery is closely related to the patient's self-feeling and self-care ability in life when discharged from hospital, the improvement of RHD from patients was hypothesized as a potential secondary bene t of this program. Furthermore, ERP strategy was bene cial to enhance the level of RHD as well as shorten the postoperative hospital stay.
Surprisingly, in this subanalysis, the ndings showed that the postoperative hospital stay was approximately 3 days shorter in the ERP group (9.083.48d) than the usual care group (12.144.05d). One systematic review from 26 studies showed that early enteral nutrition could promote intestinal function recovery and shorten the time of postoperative hospital stay for patients undergoing gastrointestinal surgery. [35] This reduced postoperative hospital stay was likely the result of the early atus and bowel movement after surgery, which will shorten the fasting time of patients, and achieve the purpose of early oral intake, nutrition improvement, and fast postoperative recovery.
Maximizing the patient's subjective initiative in disease management during the perioperative rehabilitation process is very important. The King's TGA emphasizes effective communication and interaction between health professionals and patients, which is consistent with the classi cation systems suggested by the North American Nursing Diagnoses Association (NANDA). [16] This research used this theory as a framework to develop a detailed rehabilitation plan and set short-term and long-term goals together with patients. For example, on the rst day after surgery, we encourage patients to engage in bedside activities following by "5-3-1 methods" with a de nite short-term goal, 1-2 times in the morning and 3-4 times in the afternoon. Besides, a professional multidisciplinary team was established to make individual, evidence-based and stepwise adaptation of the rehabilitation program according to patients' actual status, physical e cacy and clinical symptoms.

Limitations
Some limitations also should be mentioned in our research. First, due to the limited preoperative time, the time of preoperative rehabilitation in this study is relatively short (approximately 7-10 days), which may not be able to fully offer the possibility for improving tness. Therefore, novel strategies such as maximizing physical function during short-term training, or using the occasion of neoadjuvant to exercise before surgery, need to be explored. Second, the sample size and variation were limited because the objects came from a single center. Future studies should recruit participants from multi-centers to achieve a larger sample size and more variation, and further verify the effectiveness of the ERP. Third, in this study research staff were aware of the interventions and randomization results. Despite all efforts to maintain blinding, we could not implement a double-blind method owing to the nature of the interventional research. These circumstances may have led to the overestimation of the effect of the ERP.
Fourth, due to the limitations of research conditions, we could not evaluate patients' electrophysiological indicators to re ect the improvement of physical function, which is an important research eld of rehabilitation medicine.

Conclusions
In conclusion, the present study showed that the ERP, which was a nurse-led, contained six staged procedure, and guided by King's TGA, was practical and feasible in accelerating bowel and physical function recovery for EC patients after MIE. Besides, in the context of ERAS, the ERP can also improve patient's RHD and shorten the postoperative hospital stay, which may enhance patient's medical experience and hospital operation e ciency. Clinical nurses play a key role in patient's perioperative recovery, the results of this research motivate nurses to formulate quantitative, detailed and individualized early activity plans for patients combining nursing theory with clinical practice.

Declarations
All authors disclose no con icts of interest.