- Email: [email protected]
Seven-day intensive preoperative rehabilitation for elderly patients with lung cancer: a randomized controlled trial
Accepted Manuscript Seven-Day Intensive Preoperative Rehabilitation for Elderly Patients with Lung Cancer: A Randomized Controlled Trial Yutian Lai, MD, Jian Huang, MD, Mei Yang, MD, Jianhua Su, PhD, Jing Liu, PhD, Guowei Che, MD PII:
S0022-4804(16)30416-4
DOI:
10.1016/j.jss.2016.09.033
Reference:
YJSRE 14001
To appear in:
Journal of Surgical Research
Received Date: 22 June 2016 Revised Date:
4 September 2016
Accepted Date: 21 September 2016
Please cite this article as: Lai Y, Huang J, Yang M, Su J, Liu J, Che G, Seven-Day Intensive Preoperative Rehabilitation for Elderly Patients with Lung Cancer: A Randomized Controlled Trial, Journal of Surgical Research (2016), doi: 10.1016/j.jss.2016.09.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT Title Page
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Title: Seven-Day Intensive Preoperative Rehabilitation for Elderly Patients with Lung Cancer: A Randomized Controlled Trial
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Running title: Modified pulmonary rehabilitation for elderly patients with lung cancer
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Authors: Yutian Lai (MD)
1,*
, Jian Huang (MD)
(PhD) 3, Guowei Che (MD) 1,
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1,*,ψ
, Mei Yang (MD) 1, Jianhua Su (PhD) 2, Jing Liu
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1
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China
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2
Rehabilitation Department, West China Hospital, Sichuan University, Chengdu 610041, P.R. China
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3
West China School of Public Health, Sichuan University, Chengdu 610041, P.R. China
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*
These authors contributed to the work equally and should be regarded as co-first authors.
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Corresponding authors.
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Conflict of interest statement
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Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu 610041, P.R.
The authors have no conflicts of interest to disclose. Funding
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This study was supported by the Foundation of Science and Technology Support Plan, Department of
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Sichuan Province (2014SZ0148 and 2015SZ0158).
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Corresponding author:
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1: Guowei Che, E-mail: [email protected]
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2: Jian Huang, E-mail: [email protected]
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Tel. & Fax number: +86-2885422494
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Address: No. 37 Guoxue Road, Wuhou Area, Chengdu, P.R. China
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Author contributions Yutian Lai, Jian Huang and Guowei Che made substantial contributions to the conception and
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design of the work; Yutian Lai and Jian Huang drafted the work and revised it critically for important
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intellectual content; Jing Liu contributed to the acquisition, analysis and interpretation of the data; and
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Jianhua Su and Mei Yang contributed rehabilitation technology assistance and guidance.
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Abstract
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Background As a newly developed treatment, preoperative pulmonary rehabilitation (PR) has been studied in
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depth. However, few studies have assessed the relationship between advanced age and a shorter-term
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intensive pattern of preoperative PR in patients with lung cancer (LC), and especially those patients
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waiting for therapeutic LC surgeries. This study investigated short-term preoperative PR combined with
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inspiratory muscle training (IMT) and aerobic endurance training in elderly patients scheduled to
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undergo LC lobectomy.
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Methods
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A prospective randomized controlled trial with a total of 60 subjects aged ≥70 was conducted. The
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intervention group (PR group) was treated for one week with systematic and highly intensive
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preoperative PR training before lobectomy, and the control group (NPR group) was treated with
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conventional preoperative respiratory management. We analyzed the 6-min walking distance (6-MWD),
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the peak expiratory flow (PEF), and quality-of-life scores before and after the rehabilitation regimen as
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well as the incidence of postoperative pulmonary complications (PPCs).
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Results
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In total, 30 patients (PR group) completely executed the 7-day intensive preoperative PR, and 30
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patients (NPR group) served as the control group. The two groups were comparable at baseline. During
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the preoperative PR, a significantly longer 6-MWD (increase: 28.6±18.2 vs. 9.4±27.0 m;
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between-groups difference: 19.2 m, P=0.029) and an increased PEF (increase: 26.2±22.5 vs. 8.2±10.3
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L/min; between-groups difference: 18.0 L/min, P<0.001) were noted in the PR group compared with the
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NPR group. After LC surgery, the mean postoperative length of stay (6.9±4.4 vs. 10.7±6.4 days,
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P=0.010) and total hospital stay (16.0±4.5 vs. 19.7±6.5 days, P=0.012) were significantly reduced in the
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PR group. Thirty-day PPCs were noted in 4 (13.3%) patients in the PR group and 11 (36.7%) patients in
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the NPR group, with a significant difference between the two groups (P=0.037).
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Conclusions For elderly LC patients scheduled to undergo surgery in China, a 7-day intensive pattern of
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preoperative PR combined with IMT and aerobic endurance training may be a feasible rehabilitation
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strategy with positive physical and psychological effects.
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Key Words: elderly, preoperative pulmonary rehabilitation, lung cancer.
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Introduction
Malignant tumors are the most health- and life-threatening disease in humans, and lung cancer (LC) ranks first among all tumors in China in terms of its morbidity rate [1, 2]. Surgical resection remains the
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optimal treatment for resectable LC, particularly for pre-malignant and early lesions [3]. However, the
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postoperative pulmonary complication (PPC) rate remains high, which has an adverse effect on surgical
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outcomes.
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Among LC patients, the elderly are at high risk of PPCs due to poor lung fitness, cardiopulmonary
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intolerance and more comorbidities compared with younger individuals. Further clinical trials are
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needed to confirm the safety and efficacy of preventive and therapeutic approaches (including
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pulmonary rehabilitation (PR) programs) in the elderly. To improve postoperative outcomes, there has
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been growing interest in the role of preoperative PR over the past decade. Our previous clinical
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experiments demonstrated that systematic, highly intensive rehabilitation could be an effective
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treatment, providing positive physical and psychological effects on surgical patients [4-6].
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Based on this finding, we hypothesized that systemic, intensive preoperative rehabilitation may
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play an impactful role in improving cardiopulmonary intolerance and subsequently reducing the PPC
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rate. This pattern may perhaps be a feasible and practical treatment for elderly patients. Thus, in this
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study, a prospective randomized trial was conducted to evaluate the effects of a modified combined PR
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program that integrates respiratory exercise and physical rehabilitation within a short period before LC
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lobectomy in patients ≥70 years of age.
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Materials and Methods
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Study subjects and grouping
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A prospective randomized controlled trial (RCT) with a total of 127 subjects was conducted in the
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Department of Thoracic Surgery, West China Hospital, between June 2015 and March 2016. During the
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study, patients were screened according to the inclusion/exclusion criteria (Table 1) and were randomly
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allocated into the PR or control (non-pulmonary rehabilitation, NPR) group (Figure 1).
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Inclusion/exclusion criteria:
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All included patients had a definite diagnosis of primary non-small-cell LC (NSCLC) based on
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preoperative pathological examination and preoperative imageological examinations according to
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NSCLC diagnosis and treatment guidelines, had no surgical contraindication to and were willing to
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undergo video-assisted thoracic surgery (VATS) or traditional thoracotomy (open) lobectomy, and
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agreed to receive preoperative PR.
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Patients with contraindications or risk factors for adverse events, such as a history of myocardial
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infarction, cerebrovascular accident (<1 year), unstable angina pectoris, aneurysm, hemoptysis (<90
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days), severe arrhythmia or musculoskeletal or mental disorders, were excluded. In addition, patients
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with SpO2 <90% during the 6-min walking test; with an absence of NSCLC, as confirmed by
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postoperative pathological examination; or with sub-lobar resection or pneumonectomy were also
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excluded.
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Preoperative PR program The program was primarily a physical intervention focusing on exercise endurance training and
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inspiratory muscle training (IMT). All participants were assessed, and data were recorded by a
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physiotherapist who was blinded to the grouping and the study purpose.
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The preoperative PR procedure was as follows:
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On the first day, the 6-min walking distance (6-MWD) test and the pulmonary function test (PFT)
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were performed to assess the patients’ initial cardiopulmonary function. The 6-MWD test was
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performed as suggested by the American Thoracic Society Pulmonary Function Standards Committee.
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Health-related quality of life (HRQoL) was evaluated in both groups and recorded using a chart based
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on EORTC QLQ-C30 & LC13_CN (version 3), both of which have a score scale ranging from 0 to 100.
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A high score on these disease-specific HRQoL instruments used for oncology patients reflects either a
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good state of function or a high intensity of symptoms [7].
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Daily activities included IMT (performed in the ward) and aerobic endurance training (performed
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in the rehabilitation training center), as follows: 1). Abdominal breathing training: The diaphragm
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muscles were strengthened through this exercise (twice per day at 15 to 20 min each). The patients
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slowly inhaled to their maximum lung capacity through their nose, held their breath for a short period,
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and then exhaled slowly through their lips with their abdominal muscles tightened. 2). Expiration
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exercise: A simple respiratory training device (Voldyne 5000, Sherwood Medical Supplies, St. Louis,
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MO, USA) was used for this training. The patients were guided to exhale calmly at the beginning, to
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then deeply inhale through the suction nozzle of the training device, and to finally exhale slowly after
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holding their breath for several seconds. The training pattern was performed 3 times per day for 20 min
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each. 3). Aerobic endurance training: The NuStep device (NuStep, Inc. Ann Arbor, MI) was used in the
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rehabilitation training center for this purpose. The patients adjusted the resistance gear range according
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to their own speed and power at first and then increased the resistance range progressively. During the
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training, the procedure was stopped if the patients had any obvious discomfort, such as shortness of
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breath, dyspnea or exhaustion. The patients were allowed to rest until their condition could withstand
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subsequent training. This pattern lasted 30 min daily.
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At the end of the 7-day PR, the 6-MWD test, PFT and EORTC QLQ-C30 & LC13_CN (version 3)
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were performed again to complete the program. In addition, the NPR group underwent the same
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assessments before the surgery.
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Outcome measures
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Thirty-day PPCs were identified and recorded based on the medical records, and the data collection
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was blinded for the purpose of the study design. We used the Clavien-Dindo complication classification
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system to classify the PPCs into five grades, and the PPCs were ultimately defined as Clavien-Dindo
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grade II to grade V. The EORTC QLQ-C30 and EORTC LC13_CN were used to assess patient
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symptoms and HRQoL. Additional data collected included the 6-MWD and peak expiratory flow (PEF).
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Data analysis
The primary endpoint of the study was reduction of the PPC rate. The type I error rate (α) was set
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as 5%, with 80% statistical power. We expected to produce a 30% difference in the PPC rate. The
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calculation was based on unpublished study data (n=176), which revealed an 8.5% PPC rate in the PR
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group. With a one-sided alternative, we needed to include 30 patients in each group.
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All continuous variables are presented as the mean ± standard deviation (SD); non-normally
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distributed data, as the median and range; and binary variables, as a proportion. Among continuous
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variables, discrete variables were analyzed using the chi-square test or Fisher’s exact test. All results
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were considered significant at P<0.05. Statistical analyses were performed using SPSS software V.21.0.
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Results
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Study population and characteristics
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A total of 127 patients were screened for participation, and 67 were excluded from the study.
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During the PR, 38 patients did not meet the inclusion criteria, 22 refused to participate in the regimen,
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and 7 quit for various reasons. Therefore, 60 patients were ultimately included in the study. The two
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groups were comparable in terms of demographic and surgical characteristics and baseline outcome
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variables. All differences between the groups were non-significant (Table 2).
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Safety considerations and adverse events
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During the study, 4 patients in the PR group suspended the training because they could not endure
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the highly intensive regimen, 1 perceived a lack of benefit, and 1 suffered from knee pain. According to
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the intention-to-treat principle, we included those who did not complete the regimen in the final
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analysis.
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Endpoint outcomes
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The mean postoperative length of stay (6.9±4.4 vs. 10.7±6.4 days, P=0.010) and total in-hospital
stay (16.0±4.5 vs. 19.7±6.5 days, P=0.012) were significantly reduced in the PR group (Table 2).
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The increased 6-MWD (increase: 28.6±18.2 vs. 9.4±27.0 m; between-groups difference: 19.2 m,
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P=0.029) and PEF (increase: 26.2±22.5 vs. 8.2±10.3 L/min; between-groups difference: 18.0 L/min
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P<0.001) in the PR group were significantly different compared with the parameters in the NPR group.
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However, no differences in other PFT indexes, including forced vital capacity (FVC; between-groups
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difference: -0.01 L; P=0.795), forced expiratory volume in one second (FEV1; between-groups
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difference: -0.02 L; P=0.146), and diffusion capacity of the lung for carbon monoxide (Dlco;
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between-groups difference: -0.28 mL/min/mmHg; P=0.452), were observed between the groups (Table
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3).
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Regarding QoL assessment, no difference was observed between the groups in terms of global
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QoL (between-groups difference: -0.5; P=0.785), physical function (between-groups difference: -0.67;
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P=0.691), emotional function (between-groups difference: -2.2; P=0.206) or the dyspnea score
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(between-groups difference: 0.37; P=0.808) (Table 3).
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Data on PPCs occurring in 30 days were available for all participants and were classified using the
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Clavien-Dindo complication classification system. We included grades II to V to calculate PPC rates for
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grade I PPCs that had limited clinical significance. A total of 4 patients (13.3%) in the PR group and 11
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patients (36.7%) in the NPR group developed PPCs, with a significant difference noted between the two
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groups (P=0.037). Pneumonia was the main postoperative pulmonary complication (18.3%, 11/60)
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(Table 4).
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Discussion
This prospective randomized study depicted the effect of short-term preoperative PR in elderly LC
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patients. The main intervention treatment in this study was a modified preoperative PR program
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combined with IMT and aerobic endurance training. Inspiratory training has a long history of research,
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especially among patients with chronic obstructive pulmonary disease (COPD), asthma, or poor lung
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function. This training has been proven effective for improving inspiratory muscle strength and
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endurance, functional exercise capacity, dyspnea symptoms and QoL [8-11], and a randomized study
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published in JAMA demonstrated that two weeks of preoperative IMT could reduce the incidence of
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PPCs following thoracic surgery [12]. Enhanced inspiratory muscle strength is thought to be a
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determinant of functional capacity after thoracic surgery [13]. Moreover, with regard to aerobic
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endurance training, despite being a multifactorial determinant, a recent study showed that this parameter
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could represent disease severity and clinically relevant exercise tolerance in pediatric pulmonary arterial
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hypertension [14] to preserve the ejection fraction in patients with heart failure [15]. Another study
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demonstrated that quadriceps strength could be successfully improved, as confirmed by pathology, by
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conventional early postoperative PR [16]. In summary, the reasons above provide reliable support for
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our use of IMT and aerobic endurance as interventions in the preoperative rehabilitation setting. We
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hypothesized that shorter-term intensive treatment with IMT in combination with aerobic endurance
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training in elderly patients could be a better strategy than conventional care.
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Regarding the duration of preoperative PR, a few studies have investigated the correlation with
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efficiency and duration. Frésard et al. reported that the acceptable duration for significantly improving
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respiratory muscle strength and the recovery of pulmonary function was 3 to 15 days [17, 18].
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Meanwhile, Yasuo et al. reported a duration of two weeks [18], and Benzo et al. concluded that a
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four-week duration was optimal [8]. In China, one week is the maximum time period that may be
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acceptable before an operation, as a longer duration may reduce patient compliance. Before further
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analyzing this notion, it is important to note that this social phenomenon may be due to two aspects.
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First, a deficiency in adequate community health care and public health consciousness may be present,
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which is most clearly observed in patients from struggling economic areas. Deficiencies in basic-level
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hospitals and the primary care system make it infeasible and impracticable for patients to undergo
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rehabilitation either at home or in community hospitals. Additionally, LC patients generally spend 7 to
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10 days preparing for surgery, including completing the diagnostic process and finishing surgery-related
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examinations, because of the inadequate equipment and technical skills at basic institutions. Second,
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this effect may be mainly due to economics and currently misunderstood problems in medical ethics,
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seriously exacerbating psychological resistance to spending 7 days or more in completing a
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rehabilitation plan, although this is not yet an official viewpoint. Thus, in our study, based on our
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previous experience, we set duration of 7 days for intensive PR for all PR-group patients. This duration
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may allow achievement of effective PR and may also balance the contradictions of patient compliance
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and patient economic support.
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PPCs are the major evaluation index for assessing the effect of PR in the short or long term. With
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the rapid development of surgical technology, medical apparatuses and instruments, and antibiotics
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since the 1970s and given that thoracoscopic procedures are associated with a lower risk of PPCs
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compared with open thoracotomy, it is surprising that the rates and types of PPCs associated with lung
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surgery have remained high [5]. However, intensive PR may reduce the incidence of PPCs [16, 21].
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This effect is mainly attributed to the fact that PPCs vary widely across studies and have no
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standardized global classification [22]. Fortunately, a recent meta-analysis demonstrated that
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preoperative exercise-based PR can reduce the incidence of postoperative complications [4], which is
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thought to be a mixed outcome based on physical and psychological evidence. For instance, in our study,
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we found that an intensive physical intervention could improve exercise tolerance with correct guidance
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[16]. Additionally, the increasing intensity of our modified PR program could build more
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self-confidence in patients following surgical stress. Moreover, the incidence of PPCs in the PR group
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was reduced compared with that in the NPR group, and a significant difference was noted between the
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two groups; these findings indicate that the comprehensive short-term rehabilitation regimen could be
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an effective and feasible rehabilitation strategy for surgical patients with LC, and particularly elderly
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patients, given their poor lung fitness, cardiopulmonary intolerance and increased comorbidities.
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During the preoperative PR process, we observed differences in the 6-WMD and PEF between the groups. As an index, the 6-MWD exhibits a close correlation with peak oxygen consumption (peak VO2)
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and serves as an excellent prediction of reduced peak VO2 [22]. Another study summarized this index
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as reflecting the disease severity and clinically relevant exercise tolerance [14]. Another indicator, PEF,
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is an index used as a measurement of huff strength [24]. Huff is considered a more effective method
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compared with cough in improving the clearance ability of endotracheal hypersecretion [25], and both
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of these processes are necessary defenses against respiratory tract infection that aid in reducing the
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incidence of complications. The enhancement of the PEF and 6-MWD reflect the improvement of
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exercise tolerance and the clearance ability of endotracheal hypersecretion in the intervention group,
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and these findings might have indicated that a reduced PPC rate would occur. Interestingly, the overall
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length of stay and the postoperative length of stay were significantly reduced in the PR group compared
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with the NPR group. The potential reasons for this finding may include fewer PPCs and better
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postoperative recovery in the intervention group, which led to a shorter postoperative hospital stay.
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This study also has certain limitations that cannot be disclaimed or ignored. First, all the
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participants in this study were enrolled via a single regional medical center in southwest China, so the
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sample was just a small part of the related population that was surgically treated in our department. This
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limitation might have led to type II statistical error for the patient cohort baseline characteristics, though
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in the study, the groups were comparable in in terms of baseline characteristics. However, the
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center-specific bias included in this study design is undeniable. In addition, racial differences and
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regional disparities, and especially differences in the incidence of PPCs among groups, nations and
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races, were not considered in the study, which may have partly influenced the study’s accuracy. Second,
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in the process of the patient selection, we excluded several patients for various reasons. For example,
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patients who refused to participate were not included, which may have inevitably confounded the results
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and limited the generalizability of the conclusions. We also set an age of ≥70 years as an inclusion
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criterion, and several of the enrolled individuals exhibited certain risk factors, such as COPD, a
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smoking history, and critical PFT values. These confounders made it more difficult to perform a
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subgroup analysis. Third, pulmonary function before and after PR is controversial, and a study
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published in JAMA showed that short-term preoperative PR could improve pulmonary function in
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patients who underwent coronary artery bypass graft surgery [26]; however, no difference regarding
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PFT results, except PEF, was observed in our study.
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Conclusions
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Our study showed that the combined preoperative PR program played a positive physical role in
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improving the PEF and 6-MWD in elderly surgical patients with LC while significantly reducing the
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postoperative length of stay. We thus consider the 7-day intensive pattern of preoperative PR to be a
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feasible rehabilitation strategy for elderly LC patients in China.
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Ethics Statement and Informed Consent This exploratory randomized study was approved by the West China Hospital of Sichuan
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University Clinical Trials and Biomedical Ethics Committee and the Chinese Ethics Committee of
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Registering Clinical Trials (UIN Number: ChiCTR-IOR-16008109). All patients signed informed
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consent forms before the information could be obtained.
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Acknowledgments
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The authors thank all the personal trainers and physiotherapists for their work during the study
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process; Dr. Hongxia Zhou for patient recruitment; and the nurses Dan Ma, Zhihua Xu and Juan Chen
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for nursing care support. We also thank all the participants for their kind participation and cooperation.
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Funding/Support
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This study was funded by two project grants (No. 2014SZ0148 and No. 2015SZ0158) from the Foundation of Science and Technology Support Plan, Department of Sichuan Province, China.
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Conflict of Interest Statement
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References
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1.
Oncol. 2012; 23: x320–x327. 2.
Zheng RS, Zeng HM, Zhang SW. lung cancer incidence and mortality in China, 2010. Thorac
RI PT
288 289
Vansteenkiste J, Dooms C, Mascaux C, et al. Screening and early detection of lung cancer. Ann
Cancer. 2014; 5: 330–336.
290 3.
Onugha OI, Lee JM. Surgical Treatment of Lung Cancer. Cancer Treat Res. 2016; 170: 77-104
292
4.
Sebio Garcia R, Yáñez Brage MI, Giménez Moolhuyzen E, et al., Functional and postoperative
SC
291
outcomes after preoperative exercise training in patients with lung cancer: a systematic review and
294
meta-analysis. Interact Cardiovasc Thorac Surg. 2016; pii: ivw152.
295
5.
M AN U
293
Gao K, Yu PM, Su JH, et al. Cardiopulmonary exercise testing screening and preoperative pulmonary rehabilitation reduce postoperative complications and improve fast-track recovery after
297
lung cancer surgery: A study for 342 cases. Thorac Cancer. 2015; 6: 443-9.
298
6.
TE D
296
Arbane G, Tropman D, Jackson D, et al. Evaluation of an early exercise intervention after thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength
300
and exercise tolerance: randomised controlled trial. Lung Cancer. 2011; 71: 229-34. 7.
health-related quality of life scores from the EORTC QLQ-C30 in lung cancer patients
302
participating in randomized controlled trials. Support Care Cancer. 2011; 19: 1753-60.
303 304
8.
307
Benzo R, Wigle D, Novotny P, et al. Preoperative pulmonary rehabilitation before lung cancer
resection: results from two randomized studies. Lung Cancer. 2011; 74: 441-5.
305 306
Maringwa JT, Quinten C, King M, et al. Minimal important differences for interpreting
AC C
301
EP
299
9.
Crandall K, Maguire R, Campbell A, et al. Exercise intervention for patients surgically treated for Non-Small Cell Lung Cancer (NSCLC): a systematic review. Surg Oncol. 2014; 23: 17-30.
Page 16
ACCEPTED MANUSCRIPT 308
10. Yamana I, Takeno S, Hashimoto T, et al. Randomized Controlled Study to Evaluate the Efficacy of
309
a Preoperative Respiratory Rehabilitation Program to Prevent Postoperative Pulmonary
310
Complications after Esophagectomy. Dig Surg. 2015; 32: 331-337. 11. Stefanelli F, Meoli I, Cobuccio R, et al. High-intensity training and cardiopulmonary exercise
312
testing in patients with chronic obstructive pulmonary disease and non-small-cell lung cancer
313
undergoing lobectomy. Eur J Cardiothorac Surg. 2013; 44: e260-5.
RI PT
311
12. Hulzebos EH, Helders PJ, Favié NJ, et al. Preoperative Intensive Inspiratory Muscle Training to
315
Prevent Postoperative Pulmonary Complications in High-Risk patients Undergoing CABG Surgery.
316
JAMA. 2006; 296: 1851-7.
M AN U
SC
314
13. Stein R, Maia CP, Silveira AD, et al. Inspiratory muscle strength as a determinant of functional
318
capacity early after coronary artery bypass graft surgery. Arch Phys Med Rehabil. 2009; 90:
319
1685-91.
TE D
317
14. Douwes JM, Hegeman AK, van der Krieke MB, et al. Six-minute walking distance and decrease in
321
oxygen saturation during the six-minute walk test in pediatric pulmonary arterial hypertension. Int
322
J Cardiol. 2016; 202: 34-9.
324 325
15. Zotter-Tufaro C, Mascherbauer J, Duca F, et al. Prognostic Significance and Determinants of the
AC C
323
EP
320
6-Min Walk Test in Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2015; 3: 459-66.
326
16. Arbane G, Tropman D, Jackson D, et al. Evaluation of an early exercise intervention after
327
thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength
328
and exercise tolerance: randomised controlled trial. Lung Cancer. 2011; 71: 229-34.
329
17. Shiono, S, Abiko M, and Sato T. Postoperative complications in elderly patients after lung cancer
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surgery. Interact Cardiovasc Thorac Surg. 2013; 16: 819-23. 18. Sekine Y, Chiyo M, Iwata T, et al. Perioperative rehabilitation and physiotherapy for lung cancer
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patients with chronic obstructive pulmonary disease. Jpn J Thorac Cardiovasc Surg. 2005; 53:
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237-43.
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factors among city, township and rural area adults in China. BMJ Open. 2015; 5: e008417.
20. Cederholm T, Bosaeus I, Barazzoni R, et al. Diagnostic criteria for malnutrition—An ESPEN Consensus Statement. Clin Nutr. 2015; 34: 335-40.
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19. Zou Y, Zhang R, Zhou B, et al. A comparison study on the prevalence of obesity and its associated
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21. Pehlivan E, Turna A, Gurses A, et al. The Effects of Preoperative Short-term Intense Physical
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Therapy in Lung Cancer Patients: A Randomized Controlled Trial. Ann Thorac Cardiovasc Surg.
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2011; 17: 461-468.
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22. Dindo D, Demartines N, Clavien PA, et al. Classification of surgical complications: a new proposal
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with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240: 205-13. 23. Kehmeier ES, Sommer MH, Galonska A, et al. Diagnostic value of the six-minute walk test
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(6MWT) in grown-up congenital heart disease (GUCH): Comparison with clinical status and
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functional exercise capacity. Int J Cardiol. 2016; 203: 90-7.
347 348 349
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24. Hasani A, Pavia D, Agnew JE, et al. Regional mucus transport following unproductive cough and forced expiration technique in patients with airways obstruction. Chest. 1994; 105: 1420-5.
25. Ishida H, Kobara K, Osaka H, et al. Correlation between Peak Expiratory Flow and Abdominal Muscle Thickness. J Phys Ther Sci. 2014; 26: 1791-3.
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26. Hulzebos EH, Helders PJ, Favié NJ, et al. Preoperative Intensive Inspiratory Muscle Training to
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Prevent Postoperative Pulmonary Complications in High-Risk Patients Undergoing CABG Surgery.
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JAMA. 2006; 296:1851-7.
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Figure Legend
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Figure 1: Eligibility and allocation of the study population
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Table 1
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Inclusion and exclusion criteria Inclusion Age ≥70 Primary NSCLC Underwent LC lobectomy Exclusion SpO2 <90% during the 6-min walking test No NSCLC Did not receive surgery High risk of adverse events Myocardial infarction or cerebrovascular accident within one year Unstable angina pectoris Aneurysm Musculoskeletal or mental disorder
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P-value
72.5±3.4
71.6±1.9
0.228
16 (53.3) 2.1±0.5 69.8±16.9 3.0±0.7 22.3±4.2 77.6± 25.0 2 (6.7) 6 (20.0) 5 (16.7) 3 (10.0)
18 (60.0) 2.0±0.6 62.7±18.8 3.0±0.7 21.7±3.9 72.3±16.4 3 (10.0) 5 (16.7) 4 (13.3) 2 (6.7)
0.602 0.380 0.127 0.981 0.579 0.339 1.000 0.739 1.000 1.000 0.240
16 (53.3) 10 (33.3) 3 (10.0) 1 (3.3)
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NPR group
18 (60.0) 10 (33.3) 2 (6.7) 0 (0)
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Age, mean ± SD Gender Male FEV1, L ppoFEV1% FVC, L Dlco, mL/min/mmHg ppoDlco% ASA score >3 Current smoking status COPD BMI >30 Clinical stage Stage I Stage II Stage III Stage IV Surgical approach VATS Open Average duration of in-hospital stay, days Preoperative, days Postoperative, days
PR group
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20 (66.7) 10 (33.3) 19.7±6.5 9.0±1.6 10.7±6.4
0.781 0.012 1.000 0.010
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The data are presented as the mean ± SD, median (range) or n (%). COPD: chronic obstructive pulmonary disease, defined as FEV1/FVC <70% and FEV1 <80% of predicted; BMI: body mass index; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; Dlco: diffusion capacity of the lung for carbon monoxide; ppoFEV1%: postoperative predicted FEV1%; ppoDLCO%: postoperative predicted DLCO%; VATS: video-assisted thoracic surgery.
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21 (70.0) 9 (30.0) 16.0±4.5 9.0±1.1 6.9±4.4
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Table 3: Between-groups differences between baseline and post-intervention for 6-MWD, PFT and QoL
Outcome variable
PR group (n=30)
NPR group (n=30)
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Between-groups difference
After the exercise
Before the exercise
After the exercise
Difference (95% CI)
P-value
6-MWD, m
431.7±102.8
460.3±93.6
434.5.4±86.2
443.9±88.4
19.2 (2.1 to 36.3)
0.029
PFT FEV1, L FVC, L Dlco, mL/min/mmHg PEF, L/min QoL evaluation
2.1±0.5 3.0±0.7 22.3±4.2 351.7±132.3
2.2±0.5 3.1±0.6 22.9±4.8 377.8±130.5
2.0±0.6 3.0±0.7 21.7±3.9 372.0±101.2
2.0±0.6 3.1±0.7 22.0±3.7 380.1±102.8
-0.02 (-0.06 to 0.01) -0.01 (-0.11 to 0.08) -0.28 (-1.0 to 0.46 ) 18.0 (8.9 to 27.1)
0.146 0.795 0.452 <0.001
Global QoL*
69.7±13.9
71.3±13.6
69.7 ±12.7
69.8±12.1
-0.5 (-4.6 to 3.5)
0.785
Physical function*
88.9±6.4
89.4±6.3
88.5±7.1
88.0±7.6
-0.67 (-4.0 to 2.7)
0.691
Emotional function*
86.6±9.5
90.2±7.4
83.8±10.6
86.7±8.9
-2.2 (-5.7 to 1.3)
0.206
Dyspnea score
12.2± 17.9
7.3±14.0
8.7±14.8
11.3±17.3
0.37 (-2.7 to 3.4)
0.808
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The data are presented as the mean ± SD. *Higher scores indicate better functioning (scaled from 0 to 100). †Lower scores indicate less dyspnea (scaled from 0 to 100). FEV1: forced expiratory volume in one second; FVC: forced vital capacity; Dlco: diffusion capacity of the lung for carbon monoxide; PEF: peak expiratory flow; 6-MWD: 6-min walking distance; QoL: quality of life.
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Before the exercise
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Complication grade
n=30
11 (36.7) 16 (53.3) 12 (40.0) 8 (26.7)
New rise in C-reactive protein or WBC count Positive blood cultures Atelectasis Pleural effusion Grade II Pneumonia Mechanical ventilation <48 h
7 (23.3)
9 (30.0)
4 (13.3) 6 (20.0) 4 (13.3) 4 (13.3) 4 (13.3) 2 (6.7)
Pleural effusion needing tube Atelectasis needing toilet bronchoscopy Grade III
1 (3.3) 2 (6.7) 2 (6.7)
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2 (6.7) 1 (3.3 4 (13.3)
1 (3.3) 2 (6.7) 1 (3.3)
0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
1 (3.3) 1 (3.3) 1 (3.3) 1 (3.3) 1 (3.3)
0 (0.0) 0 (0.0)
1 (3.3) 1 (3.3)
*PPCs were defined as grades II to V. ICU: intensive care unit; ARDS: adult respiratory distress syndrome.
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5 (16.7) 5 (16.7) 6 (20.0) 8 (26.7) 7 (23.3) 1 (3.3)
1 (3.3) 1 (3.3) 0 (0.0)
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Grade V Death
P-value 0.037 0.796
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4 (13.3) 15 (50.0) 10 (33.3) 9 (30.0)
Chylothorax Grade IV Return to ICU Pulmonary embolism ARDS or respiratory failure
385
n=30
PPC rate* Grade I New-onset purulent sputum Fever >38°C, no focus outside the lungs
Empyema Mechanical ventilation >48 h Bronchopleural fistula
382 383 384
NPR group
0.197
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0.389
1.000
1.000
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S0022-4804(16)30416-4
DOI:
10.1016/j.jss.2016.09.033
Reference:
YJSRE 14001
To appear in:
Journal of Surgical Research
Received Date: 22 June 2016 Revised Date:
4 September 2016
Accepted Date: 21 September 2016
Please cite this article as: Lai Y, Huang J, Yang M, Su J, Liu J, Che G, Seven-Day Intensive Preoperative Rehabilitation for Elderly Patients with Lung Cancer: A Randomized Controlled Trial, Journal of Surgical Research (2016), doi: 10.1016/j.jss.2016.09.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Seven-Day Intensive Preoperative Rehabilitation for Elderly Patients with Lung Cancer: A Randomized Controlled Trial
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Running title: Modified pulmonary rehabilitation for elderly patients with lung cancer
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Authors: Yutian Lai (MD)
1,*
, Jian Huang (MD)
(PhD) 3, Guowei Che (MD) 1,
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1,*,ψ
, Mei Yang (MD) 1, Jianhua Su (PhD) 2, Jing Liu
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1
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China
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2
Rehabilitation Department, West China Hospital, Sichuan University, Chengdu 610041, P.R. China
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3
West China School of Public Health, Sichuan University, Chengdu 610041, P.R. China
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*
These authors contributed to the work equally and should be regarded as co-first authors.
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ψ
Corresponding authors.
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Conflict of interest statement
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Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu 610041, P.R.
The authors have no conflicts of interest to disclose. Funding
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This study was supported by the Foundation of Science and Technology Support Plan, Department of
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Sichuan Province (2014SZ0148 and 2015SZ0158).
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Corresponding author:
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1: Guowei Che, E-mail: [email protected]
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2: Jian Huang, E-mail: [email protected]
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Tel. & Fax number: +86-2885422494
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Address: No. 37 Guoxue Road, Wuhou Area, Chengdu, P.R. China
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Author contributions Yutian Lai, Jian Huang and Guowei Che made substantial contributions to the conception and
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design of the work; Yutian Lai and Jian Huang drafted the work and revised it critically for important
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intellectual content; Jing Liu contributed to the acquisition, analysis and interpretation of the data; and
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Jianhua Su and Mei Yang contributed rehabilitation technology assistance and guidance.
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Abstract
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Background As a newly developed treatment, preoperative pulmonary rehabilitation (PR) has been studied in
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depth. However, few studies have assessed the relationship between advanced age and a shorter-term
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intensive pattern of preoperative PR in patients with lung cancer (LC), and especially those patients
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waiting for therapeutic LC surgeries. This study investigated short-term preoperative PR combined with
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inspiratory muscle training (IMT) and aerobic endurance training in elderly patients scheduled to
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undergo LC lobectomy.
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Methods
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A prospective randomized controlled trial with a total of 60 subjects aged ≥70 was conducted. The
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intervention group (PR group) was treated for one week with systematic and highly intensive
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preoperative PR training before lobectomy, and the control group (NPR group) was treated with
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conventional preoperative respiratory management. We analyzed the 6-min walking distance (6-MWD),
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the peak expiratory flow (PEF), and quality-of-life scores before and after the rehabilitation regimen as
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well as the incidence of postoperative pulmonary complications (PPCs).
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Results
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In total, 30 patients (PR group) completely executed the 7-day intensive preoperative PR, and 30
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patients (NPR group) served as the control group. The two groups were comparable at baseline. During
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the preoperative PR, a significantly longer 6-MWD (increase: 28.6±18.2 vs. 9.4±27.0 m;
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between-groups difference: 19.2 m, P=0.029) and an increased PEF (increase: 26.2±22.5 vs. 8.2±10.3
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L/min; between-groups difference: 18.0 L/min, P<0.001) were noted in the PR group compared with the
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NPR group. After LC surgery, the mean postoperative length of stay (6.9±4.4 vs. 10.7±6.4 days,
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P=0.010) and total hospital stay (16.0±4.5 vs. 19.7±6.5 days, P=0.012) were significantly reduced in the
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PR group. Thirty-day PPCs were noted in 4 (13.3%) patients in the PR group and 11 (36.7%) patients in
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the NPR group, with a significant difference between the two groups (P=0.037).
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Conclusions For elderly LC patients scheduled to undergo surgery in China, a 7-day intensive pattern of
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preoperative PR combined with IMT and aerobic endurance training may be a feasible rehabilitation
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strategy with positive physical and psychological effects.
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Key Words: elderly, preoperative pulmonary rehabilitation, lung cancer.
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Introduction
Malignant tumors are the most health- and life-threatening disease in humans, and lung cancer (LC) ranks first among all tumors in China in terms of its morbidity rate [1, 2]. Surgical resection remains the
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optimal treatment for resectable LC, particularly for pre-malignant and early lesions [3]. However, the
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postoperative pulmonary complication (PPC) rate remains high, which has an adverse effect on surgical
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outcomes.
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Among LC patients, the elderly are at high risk of PPCs due to poor lung fitness, cardiopulmonary
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intolerance and more comorbidities compared with younger individuals. Further clinical trials are
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needed to confirm the safety and efficacy of preventive and therapeutic approaches (including
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pulmonary rehabilitation (PR) programs) in the elderly. To improve postoperative outcomes, there has
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been growing interest in the role of preoperative PR over the past decade. Our previous clinical
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experiments demonstrated that systematic, highly intensive rehabilitation could be an effective
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treatment, providing positive physical and psychological effects on surgical patients [4-6].
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Based on this finding, we hypothesized that systemic, intensive preoperative rehabilitation may
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play an impactful role in improving cardiopulmonary intolerance and subsequently reducing the PPC
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rate. This pattern may perhaps be a feasible and practical treatment for elderly patients. Thus, in this
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study, a prospective randomized trial was conducted to evaluate the effects of a modified combined PR
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program that integrates respiratory exercise and physical rehabilitation within a short period before LC
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lobectomy in patients ≥70 years of age.
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Materials and Methods
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Study subjects and grouping
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A prospective randomized controlled trial (RCT) with a total of 127 subjects was conducted in the
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Department of Thoracic Surgery, West China Hospital, between June 2015 and March 2016. During the
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study, patients were screened according to the inclusion/exclusion criteria (Table 1) and were randomly
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allocated into the PR or control (non-pulmonary rehabilitation, NPR) group (Figure 1).
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Inclusion/exclusion criteria:
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All included patients had a definite diagnosis of primary non-small-cell LC (NSCLC) based on
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preoperative pathological examination and preoperative imageological examinations according to
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NSCLC diagnosis and treatment guidelines, had no surgical contraindication to and were willing to
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undergo video-assisted thoracic surgery (VATS) or traditional thoracotomy (open) lobectomy, and
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agreed to receive preoperative PR.
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Patients with contraindications or risk factors for adverse events, such as a history of myocardial
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infarction, cerebrovascular accident (<1 year), unstable angina pectoris, aneurysm, hemoptysis (<90
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days), severe arrhythmia or musculoskeletal or mental disorders, were excluded. In addition, patients
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with SpO2 <90% during the 6-min walking test; with an absence of NSCLC, as confirmed by
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postoperative pathological examination; or with sub-lobar resection or pneumonectomy were also
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excluded.
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Preoperative PR program The program was primarily a physical intervention focusing on exercise endurance training and
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inspiratory muscle training (IMT). All participants were assessed, and data were recorded by a
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physiotherapist who was blinded to the grouping and the study purpose.
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The preoperative PR procedure was as follows:
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On the first day, the 6-min walking distance (6-MWD) test and the pulmonary function test (PFT)
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were performed to assess the patients’ initial cardiopulmonary function. The 6-MWD test was
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performed as suggested by the American Thoracic Society Pulmonary Function Standards Committee.
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Health-related quality of life (HRQoL) was evaluated in both groups and recorded using a chart based
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on EORTC QLQ-C30 & LC13_CN (version 3), both of which have a score scale ranging from 0 to 100.
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A high score on these disease-specific HRQoL instruments used for oncology patients reflects either a
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good state of function or a high intensity of symptoms [7].
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Daily activities included IMT (performed in the ward) and aerobic endurance training (performed
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in the rehabilitation training center), as follows: 1). Abdominal breathing training: The diaphragm
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muscles were strengthened through this exercise (twice per day at 15 to 20 min each). The patients
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slowly inhaled to their maximum lung capacity through their nose, held their breath for a short period,
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and then exhaled slowly through their lips with their abdominal muscles tightened. 2). Expiration
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exercise: A simple respiratory training device (Voldyne 5000, Sherwood Medical Supplies, St. Louis,
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MO, USA) was used for this training. The patients were guided to exhale calmly at the beginning, to
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then deeply inhale through the suction nozzle of the training device, and to finally exhale slowly after
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holding their breath for several seconds. The training pattern was performed 3 times per day for 20 min
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each. 3). Aerobic endurance training: The NuStep device (NuStep, Inc. Ann Arbor, MI) was used in the
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rehabilitation training center for this purpose. The patients adjusted the resistance gear range according
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to their own speed and power at first and then increased the resistance range progressively. During the
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training, the procedure was stopped if the patients had any obvious discomfort, such as shortness of
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breath, dyspnea or exhaustion. The patients were allowed to rest until their condition could withstand
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subsequent training. This pattern lasted 30 min daily.
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At the end of the 7-day PR, the 6-MWD test, PFT and EORTC QLQ-C30 & LC13_CN (version 3)
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were performed again to complete the program. In addition, the NPR group underwent the same
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assessments before the surgery.
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Outcome measures
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Thirty-day PPCs were identified and recorded based on the medical records, and the data collection
131
was blinded for the purpose of the study design. We used the Clavien-Dindo complication classification
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system to classify the PPCs into five grades, and the PPCs were ultimately defined as Clavien-Dindo
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grade II to grade V. The EORTC QLQ-C30 and EORTC LC13_CN were used to assess patient
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symptoms and HRQoL. Additional data collected included the 6-MWD and peak expiratory flow (PEF).
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Data analysis
The primary endpoint of the study was reduction of the PPC rate. The type I error rate (α) was set
138
as 5%, with 80% statistical power. We expected to produce a 30% difference in the PPC rate. The
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calculation was based on unpublished study data (n=176), which revealed an 8.5% PPC rate in the PR
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group. With a one-sided alternative, we needed to include 30 patients in each group.
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All continuous variables are presented as the mean ± standard deviation (SD); non-normally
142
distributed data, as the median and range; and binary variables, as a proportion. Among continuous
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variables, discrete variables were analyzed using the chi-square test or Fisher’s exact test. All results
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were considered significant at P<0.05. Statistical analyses were performed using SPSS software V.21.0.
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Results
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Study population and characteristics
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A total of 127 patients were screened for participation, and 67 were excluded from the study.
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During the PR, 38 patients did not meet the inclusion criteria, 22 refused to participate in the regimen,
150
and 7 quit for various reasons. Therefore, 60 patients were ultimately included in the study. The two
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groups were comparable in terms of demographic and surgical characteristics and baseline outcome
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variables. All differences between the groups were non-significant (Table 2).
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Safety considerations and adverse events
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During the study, 4 patients in the PR group suspended the training because they could not endure
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the highly intensive regimen, 1 perceived a lack of benefit, and 1 suffered from knee pain. According to
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the intention-to-treat principle, we included those who did not complete the regimen in the final
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analysis.
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Endpoint outcomes
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The mean postoperative length of stay (6.9±4.4 vs. 10.7±6.4 days, P=0.010) and total in-hospital
stay (16.0±4.5 vs. 19.7±6.5 days, P=0.012) were significantly reduced in the PR group (Table 2).
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The increased 6-MWD (increase: 28.6±18.2 vs. 9.4±27.0 m; between-groups difference: 19.2 m,
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P=0.029) and PEF (increase: 26.2±22.5 vs. 8.2±10.3 L/min; between-groups difference: 18.0 L/min
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P<0.001) in the PR group were significantly different compared with the parameters in the NPR group.
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However, no differences in other PFT indexes, including forced vital capacity (FVC; between-groups
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difference: -0.01 L; P=0.795), forced expiratory volume in one second (FEV1; between-groups
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difference: -0.02 L; P=0.146), and diffusion capacity of the lung for carbon monoxide (Dlco;
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between-groups difference: -0.28 mL/min/mmHg; P=0.452), were observed between the groups (Table
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3).
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Regarding QoL assessment, no difference was observed between the groups in terms of global
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QoL (between-groups difference: -0.5; P=0.785), physical function (between-groups difference: -0.67;
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P=0.691), emotional function (between-groups difference: -2.2; P=0.206) or the dyspnea score
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(between-groups difference: 0.37; P=0.808) (Table 3).
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Data on PPCs occurring in 30 days were available for all participants and were classified using the
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Clavien-Dindo complication classification system. We included grades II to V to calculate PPC rates for
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grade I PPCs that had limited clinical significance. A total of 4 patients (13.3%) in the PR group and 11
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patients (36.7%) in the NPR group developed PPCs, with a significant difference noted between the two
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groups (P=0.037). Pneumonia was the main postoperative pulmonary complication (18.3%, 11/60)
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(Table 4).
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Discussion
This prospective randomized study depicted the effect of short-term preoperative PR in elderly LC
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patients. The main intervention treatment in this study was a modified preoperative PR program
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combined with IMT and aerobic endurance training. Inspiratory training has a long history of research,
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especially among patients with chronic obstructive pulmonary disease (COPD), asthma, or poor lung
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function. This training has been proven effective for improving inspiratory muscle strength and
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endurance, functional exercise capacity, dyspnea symptoms and QoL [8-11], and a randomized study
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published in JAMA demonstrated that two weeks of preoperative IMT could reduce the incidence of
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PPCs following thoracic surgery [12]. Enhanced inspiratory muscle strength is thought to be a
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determinant of functional capacity after thoracic surgery [13]. Moreover, with regard to aerobic
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endurance training, despite being a multifactorial determinant, a recent study showed that this parameter
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could represent disease severity and clinically relevant exercise tolerance in pediatric pulmonary arterial
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hypertension [14] to preserve the ejection fraction in patients with heart failure [15]. Another study
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demonstrated that quadriceps strength could be successfully improved, as confirmed by pathology, by
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conventional early postoperative PR [16]. In summary, the reasons above provide reliable support for
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our use of IMT and aerobic endurance as interventions in the preoperative rehabilitation setting. We
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hypothesized that shorter-term intensive treatment with IMT in combination with aerobic endurance
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training in elderly patients could be a better strategy than conventional care.
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Regarding the duration of preoperative PR, a few studies have investigated the correlation with
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efficiency and duration. Frésard et al. reported that the acceptable duration for significantly improving
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respiratory muscle strength and the recovery of pulmonary function was 3 to 15 days [17, 18].
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Meanwhile, Yasuo et al. reported a duration of two weeks [18], and Benzo et al. concluded that a
202
four-week duration was optimal [8]. In China, one week is the maximum time period that may be
203
acceptable before an operation, as a longer duration may reduce patient compliance. Before further
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analyzing this notion, it is important to note that this social phenomenon may be due to two aspects.
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First, a deficiency in adequate community health care and public health consciousness may be present,
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which is most clearly observed in patients from struggling economic areas. Deficiencies in basic-level
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hospitals and the primary care system make it infeasible and impracticable for patients to undergo
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rehabilitation either at home or in community hospitals. Additionally, LC patients generally spend 7 to
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10 days preparing for surgery, including completing the diagnostic process and finishing surgery-related
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examinations, because of the inadequate equipment and technical skills at basic institutions. Second,
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this effect may be mainly due to economics and currently misunderstood problems in medical ethics,
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seriously exacerbating psychological resistance to spending 7 days or more in completing a
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rehabilitation plan, although this is not yet an official viewpoint. Thus, in our study, based on our
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previous experience, we set duration of 7 days for intensive PR for all PR-group patients. This duration
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may allow achievement of effective PR and may also balance the contradictions of patient compliance
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and patient economic support.
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PPCs are the major evaluation index for assessing the effect of PR in the short or long term. With
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the rapid development of surgical technology, medical apparatuses and instruments, and antibiotics
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since the 1970s and given that thoracoscopic procedures are associated with a lower risk of PPCs
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compared with open thoracotomy, it is surprising that the rates and types of PPCs associated with lung
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surgery have remained high [5]. However, intensive PR may reduce the incidence of PPCs [16, 21].
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This effect is mainly attributed to the fact that PPCs vary widely across studies and have no
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standardized global classification [22]. Fortunately, a recent meta-analysis demonstrated that
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preoperative exercise-based PR can reduce the incidence of postoperative complications [4], which is
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thought to be a mixed outcome based on physical and psychological evidence. For instance, in our study,
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we found that an intensive physical intervention could improve exercise tolerance with correct guidance
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[16]. Additionally, the increasing intensity of our modified PR program could build more
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self-confidence in patients following surgical stress. Moreover, the incidence of PPCs in the PR group
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was reduced compared with that in the NPR group, and a significant difference was noted between the
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two groups; these findings indicate that the comprehensive short-term rehabilitation regimen could be
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an effective and feasible rehabilitation strategy for surgical patients with LC, and particularly elderly
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patients, given their poor lung fitness, cardiopulmonary intolerance and increased comorbidities.
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During the preoperative PR process, we observed differences in the 6-WMD and PEF between the groups. As an index, the 6-MWD exhibits a close correlation with peak oxygen consumption (peak VO2)
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and serves as an excellent prediction of reduced peak VO2 [22]. Another study summarized this index
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as reflecting the disease severity and clinically relevant exercise tolerance [14]. Another indicator, PEF,
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is an index used as a measurement of huff strength [24]. Huff is considered a more effective method
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compared with cough in improving the clearance ability of endotracheal hypersecretion [25], and both
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of these processes are necessary defenses against respiratory tract infection that aid in reducing the
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incidence of complications. The enhancement of the PEF and 6-MWD reflect the improvement of
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exercise tolerance and the clearance ability of endotracheal hypersecretion in the intervention group,
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and these findings might have indicated that a reduced PPC rate would occur. Interestingly, the overall
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length of stay and the postoperative length of stay were significantly reduced in the PR group compared
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with the NPR group. The potential reasons for this finding may include fewer PPCs and better
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postoperative recovery in the intervention group, which led to a shorter postoperative hospital stay.
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This study also has certain limitations that cannot be disclaimed or ignored. First, all the
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participants in this study were enrolled via a single regional medical center in southwest China, so the
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sample was just a small part of the related population that was surgically treated in our department. This
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limitation might have led to type II statistical error for the patient cohort baseline characteristics, though
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in the study, the groups were comparable in in terms of baseline characteristics. However, the
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center-specific bias included in this study design is undeniable. In addition, racial differences and
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regional disparities, and especially differences in the incidence of PPCs among groups, nations and
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races, were not considered in the study, which may have partly influenced the study’s accuracy. Second,
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in the process of the patient selection, we excluded several patients for various reasons. For example,
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patients who refused to participate were not included, which may have inevitably confounded the results
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and limited the generalizability of the conclusions. We also set an age of ≥70 years as an inclusion
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criterion, and several of the enrolled individuals exhibited certain risk factors, such as COPD, a
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smoking history, and critical PFT values. These confounders made it more difficult to perform a
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subgroup analysis. Third, pulmonary function before and after PR is controversial, and a study
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published in JAMA showed that short-term preoperative PR could improve pulmonary function in
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patients who underwent coronary artery bypass graft surgery [26]; however, no difference regarding
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PFT results, except PEF, was observed in our study.
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Conclusions
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Our study showed that the combined preoperative PR program played a positive physical role in
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improving the PEF and 6-MWD in elderly surgical patients with LC while significantly reducing the
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postoperative length of stay. We thus consider the 7-day intensive pattern of preoperative PR to be a
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feasible rehabilitation strategy for elderly LC patients in China.
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Ethics Statement and Informed Consent This exploratory randomized study was approved by the West China Hospital of Sichuan
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University Clinical Trials and Biomedical Ethics Committee and the Chinese Ethics Committee of
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Registering Clinical Trials (UIN Number: ChiCTR-IOR-16008109). All patients signed informed
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consent forms before the information could be obtained.
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Acknowledgments
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The authors thank all the personal trainers and physiotherapists for their work during the study
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process; Dr. Hongxia Zhou for patient recruitment; and the nurses Dan Ma, Zhihua Xu and Juan Chen
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for nursing care support. We also thank all the participants for their kind participation and cooperation.
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Funding/Support
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This study was funded by two project grants (No. 2014SZ0148 and No. 2015SZ0158) from the Foundation of Science and Technology Support Plan, Department of Sichuan Province, China.
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The authors have no conflicts of interest to disclose.
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Conflict of Interest Statement
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References
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1.
Oncol. 2012; 23: x320–x327. 2.
Zheng RS, Zeng HM, Zhang SW. lung cancer incidence and mortality in China, 2010. Thorac
RI PT
288 289
Vansteenkiste J, Dooms C, Mascaux C, et al. Screening and early detection of lung cancer. Ann
Cancer. 2014; 5: 330–336.
290 3.
Onugha OI, Lee JM. Surgical Treatment of Lung Cancer. Cancer Treat Res. 2016; 170: 77-104
292
4.
Sebio Garcia R, Yáñez Brage MI, Giménez Moolhuyzen E, et al., Functional and postoperative
SC
291
outcomes after preoperative exercise training in patients with lung cancer: a systematic review and
294
meta-analysis. Interact Cardiovasc Thorac Surg. 2016; pii: ivw152.
295
5.
M AN U
293
Gao K, Yu PM, Su JH, et al. Cardiopulmonary exercise testing screening and preoperative pulmonary rehabilitation reduce postoperative complications and improve fast-track recovery after
297
lung cancer surgery: A study for 342 cases. Thorac Cancer. 2015; 6: 443-9.
298
6.
TE D
296
Arbane G, Tropman D, Jackson D, et al. Evaluation of an early exercise intervention after thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength
300
and exercise tolerance: randomised controlled trial. Lung Cancer. 2011; 71: 229-34. 7.
health-related quality of life scores from the EORTC QLQ-C30 in lung cancer patients
302
participating in randomized controlled trials. Support Care Cancer. 2011; 19: 1753-60.
303 304
8.
307
Benzo R, Wigle D, Novotny P, et al. Preoperative pulmonary rehabilitation before lung cancer
resection: results from two randomized studies. Lung Cancer. 2011; 74: 441-5.
305 306
Maringwa JT, Quinten C, King M, et al. Minimal important differences for interpreting
AC C
301
EP
299
9.
Crandall K, Maguire R, Campbell A, et al. Exercise intervention for patients surgically treated for Non-Small Cell Lung Cancer (NSCLC): a systematic review. Surg Oncol. 2014; 23: 17-30.
Page 16
ACCEPTED MANUSCRIPT 308
10. Yamana I, Takeno S, Hashimoto T, et al. Randomized Controlled Study to Evaluate the Efficacy of
309
a Preoperative Respiratory Rehabilitation Program to Prevent Postoperative Pulmonary
310
Complications after Esophagectomy. Dig Surg. 2015; 32: 331-337. 11. Stefanelli F, Meoli I, Cobuccio R, et al. High-intensity training and cardiopulmonary exercise
312
testing in patients with chronic obstructive pulmonary disease and non-small-cell lung cancer
313
undergoing lobectomy. Eur J Cardiothorac Surg. 2013; 44: e260-5.
RI PT
311
12. Hulzebos EH, Helders PJ, Favié NJ, et al. Preoperative Intensive Inspiratory Muscle Training to
315
Prevent Postoperative Pulmonary Complications in High-Risk patients Undergoing CABG Surgery.
316
JAMA. 2006; 296: 1851-7.
M AN U
SC
314
13. Stein R, Maia CP, Silveira AD, et al. Inspiratory muscle strength as a determinant of functional
318
capacity early after coronary artery bypass graft surgery. Arch Phys Med Rehabil. 2009; 90:
319
1685-91.
TE D
317
14. Douwes JM, Hegeman AK, van der Krieke MB, et al. Six-minute walking distance and decrease in
321
oxygen saturation during the six-minute walk test in pediatric pulmonary arterial hypertension. Int
322
J Cardiol. 2016; 202: 34-9.
324 325
15. Zotter-Tufaro C, Mascherbauer J, Duca F, et al. Prognostic Significance and Determinants of the
AC C
323
EP
320
6-Min Walk Test in Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2015; 3: 459-66.
326
16. Arbane G, Tropman D, Jackson D, et al. Evaluation of an early exercise intervention after
327
thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength
328
and exercise tolerance: randomised controlled trial. Lung Cancer. 2011; 71: 229-34.
329
17. Shiono, S, Abiko M, and Sato T. Postoperative complications in elderly patients after lung cancer
Page 17
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surgery. Interact Cardiovasc Thorac Surg. 2013; 16: 819-23. 18. Sekine Y, Chiyo M, Iwata T, et al. Perioperative rehabilitation and physiotherapy for lung cancer
332
patients with chronic obstructive pulmonary disease. Jpn J Thorac Cardiovasc Surg. 2005; 53:
333
237-43.
336 337
factors among city, township and rural area adults in China. BMJ Open. 2015; 5: e008417.
20. Cederholm T, Bosaeus I, Barazzoni R, et al. Diagnostic criteria for malnutrition—An ESPEN Consensus Statement. Clin Nutr. 2015; 34: 335-40.
SC
335
19. Zou Y, Zhang R, Zhou B, et al. A comparison study on the prevalence of obesity and its associated
M AN U
334
RI PT
331
338
21. Pehlivan E, Turna A, Gurses A, et al. The Effects of Preoperative Short-term Intense Physical
339
Therapy in Lung Cancer Patients: A Randomized Controlled Trial. Ann Thorac Cardiovasc Surg.
340
2011; 17: 461-468.
342
22. Dindo D, Demartines N, Clavien PA, et al. Classification of surgical complications: a new proposal
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with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240: 205-13. 23. Kehmeier ES, Sommer MH, Galonska A, et al. Diagnostic value of the six-minute walk test
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(6MWT) in grown-up congenital heart disease (GUCH): Comparison with clinical status and
345
functional exercise capacity. Int J Cardiol. 2016; 203: 90-7.
347 348 349
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24. Hasani A, Pavia D, Agnew JE, et al. Regional mucus transport following unproductive cough and forced expiration technique in patients with airways obstruction. Chest. 1994; 105: 1420-5.
25. Ishida H, Kobara K, Osaka H, et al. Correlation between Peak Expiratory Flow and Abdominal Muscle Thickness. J Phys Ther Sci. 2014; 26: 1791-3.
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26. Hulzebos EH, Helders PJ, Favié NJ, et al. Preoperative Intensive Inspiratory Muscle Training to
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Prevent Postoperative Pulmonary Complications in High-Risk Patients Undergoing CABG Surgery.
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JAMA. 2006; 296:1851-7.
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Figure Legend
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Figure 1: Eligibility and allocation of the study population
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Table 1
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Inclusion and exclusion criteria Inclusion Age ≥70 Primary NSCLC Underwent LC lobectomy Exclusion SpO2 <90% during the 6-min walking test No NSCLC Did not receive surgery High risk of adverse events Myocardial infarction or cerebrovascular accident within one year Unstable angina pectoris Aneurysm Musculoskeletal or mental disorder
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P-value
72.5±3.4
71.6±1.9
0.228
16 (53.3) 2.1±0.5 69.8±16.9 3.0±0.7 22.3±4.2 77.6± 25.0 2 (6.7) 6 (20.0) 5 (16.7) 3 (10.0)
18 (60.0) 2.0±0.6 62.7±18.8 3.0±0.7 21.7±3.9 72.3±16.4 3 (10.0) 5 (16.7) 4 (13.3) 2 (6.7)
0.602 0.380 0.127 0.981 0.579 0.339 1.000 0.739 1.000 1.000 0.240
16 (53.3) 10 (33.3) 3 (10.0) 1 (3.3)
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NPR group
18 (60.0) 10 (33.3) 2 (6.7) 0 (0)
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Age, mean ± SD Gender Male FEV1, L ppoFEV1% FVC, L Dlco, mL/min/mmHg ppoDlco% ASA score >3 Current smoking status COPD BMI >30 Clinical stage Stage I Stage II Stage III Stage IV Surgical approach VATS Open Average duration of in-hospital stay, days Preoperative, days Postoperative, days
PR group
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20 (66.7) 10 (33.3) 19.7±6.5 9.0±1.6 10.7±6.4
0.781 0.012 1.000 0.010
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The data are presented as the mean ± SD, median (range) or n (%). COPD: chronic obstructive pulmonary disease, defined as FEV1/FVC <70% and FEV1 <80% of predicted; BMI: body mass index; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; Dlco: diffusion capacity of the lung for carbon monoxide; ppoFEV1%: postoperative predicted FEV1%; ppoDLCO%: postoperative predicted DLCO%; VATS: video-assisted thoracic surgery.
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21 (70.0) 9 (30.0) 16.0±4.5 9.0±1.1 6.9±4.4
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Table 3: Between-groups differences between baseline and post-intervention for 6-MWD, PFT and QoL
Outcome variable
PR group (n=30)
NPR group (n=30)
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Between-groups difference
After the exercise
Before the exercise
After the exercise
Difference (95% CI)
P-value
6-MWD, m
431.7±102.8
460.3±93.6
434.5.4±86.2
443.9±88.4
19.2 (2.1 to 36.3)
0.029
PFT FEV1, L FVC, L Dlco, mL/min/mmHg PEF, L/min QoL evaluation
2.1±0.5 3.0±0.7 22.3±4.2 351.7±132.3
2.2±0.5 3.1±0.6 22.9±4.8 377.8±130.5
2.0±0.6 3.0±0.7 21.7±3.9 372.0±101.2
2.0±0.6 3.1±0.7 22.0±3.7 380.1±102.8
-0.02 (-0.06 to 0.01) -0.01 (-0.11 to 0.08) -0.28 (-1.0 to 0.46 ) 18.0 (8.9 to 27.1)
0.146 0.795 0.452 <0.001
Global QoL*
69.7±13.9
71.3±13.6
69.7 ±12.7
69.8±12.1
-0.5 (-4.6 to 3.5)
0.785
Physical function*
88.9±6.4
89.4±6.3
88.5±7.1
88.0±7.6
-0.67 (-4.0 to 2.7)
0.691
Emotional function*
86.6±9.5
90.2±7.4
83.8±10.6
86.7±8.9
-2.2 (-5.7 to 1.3)
0.206
Dyspnea score
12.2± 17.9
7.3±14.0
8.7±14.8
11.3±17.3
0.37 (-2.7 to 3.4)
0.808
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The data are presented as the mean ± SD. *Higher scores indicate better functioning (scaled from 0 to 100). †Lower scores indicate less dyspnea (scaled from 0 to 100). FEV1: forced expiratory volume in one second; FVC: forced vital capacity; Dlco: diffusion capacity of the lung for carbon monoxide; PEF: peak expiratory flow; 6-MWD: 6-min walking distance; QoL: quality of life.
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Complication grade
n=30
11 (36.7) 16 (53.3) 12 (40.0) 8 (26.7)
New rise in C-reactive protein or WBC count Positive blood cultures Atelectasis Pleural effusion Grade II Pneumonia Mechanical ventilation <48 h
7 (23.3)
9 (30.0)
4 (13.3) 6 (20.0) 4 (13.3) 4 (13.3) 4 (13.3) 2 (6.7)
Pleural effusion needing tube Atelectasis needing toilet bronchoscopy Grade III
1 (3.3) 2 (6.7) 2 (6.7)
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2 (6.7) 1 (3.3 4 (13.3)
1 (3.3) 2 (6.7) 1 (3.3)
0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
1 (3.3) 1 (3.3) 1 (3.3) 1 (3.3) 1 (3.3)
0 (0.0) 0 (0.0)
1 (3.3) 1 (3.3)
*PPCs were defined as grades II to V. ICU: intensive care unit; ARDS: adult respiratory distress syndrome.
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5 (16.7) 5 (16.7) 6 (20.0) 8 (26.7) 7 (23.3) 1 (3.3)
1 (3.3) 1 (3.3) 0 (0.0)
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Grade V Death
P-value 0.037 0.796
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4 (13.3) 15 (50.0) 10 (33.3) 9 (30.0)
Chylothorax Grade IV Return to ICU Pulmonary embolism ARDS or respiratory failure
385
n=30
PPC rate* Grade I New-onset purulent sputum Fever >38°C, no focus outside the lungs
Empyema Mechanical ventilation >48 h Bronchopleural fistula
382 383 384
NPR group
0.197
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0.389
1.000
1.000
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