Effect of preoperative inspiratory muscle training combined with education course on postoperative pulmonary complications in high-risk patients with lung cancer after video-assisted thoracoscopic surgery: a randomized controlled trial

Abstract

Aims

Surgery provides the best chance of survival for early-stage non-small cell lung cancer patients, resulting in a large number of patients requiring surgical resection each year. Preoperative inspiratory muscle training (IMT) is recognized as an important component of the preoperative management of lung cancer, although there is limited evidence for the delivery of a home-based IMT combined with preoperative education. We developed a programme combining short-term home-based IMT and preoperative physiotherapy education ("the programme") for lung patients with lung cancer. This study aims to evaluate the effectiveness of the programme in reducing postoperative pulmonary complications (PPCs) after video-assisted thoracoscopic surgery (VATs) compared to standard care.

Methods

This randomized controlled clinical trial (RCT) called for 114 participants at a tertiary hospital to be randomized 1:1 to the control group (CG) and the intervention group (IG). All subjects in both groups received routine perioperative rehabilitation intervention and health education manual. Participants in the IG received a detailed education course plus at least seven-day inspiratory muscle training programme before VATs. Outcome assessments were obtained in person at baseline (T0), the day before surgery (T1) and hospital discharge (T2). Primary outcome measure was PPCs using the Melbourne Group Score (MGS) obtained at discharge. Secondary outcomes were health-related quality of life, maximal inspiratory pressure (MIP), Forced expiratory volume in the first second (FEV1), 6-min walk distance (6MWD), length of hospital stay (LOS), anxiety and depression levels, and hospital costs. SPSS 26.0 statistical analysis software was used for analysis, and bilateral tests were used according to statistical tests. When P < 0.05, the difference was considered statistically significant.

Results

In accordance with the protocol, we performed interim unblinding after 50 % of the patients had been enrolled. At the interim analysis, the conditional power was calculated as 0.035 (futility index: 0.965; Supplementary 1), indicating this study should be stopped because there is little chance of achieving statistical significance. No safety concerns were identified. A total of 56 cases (27 cases in the IG and 29 cases in the CG) were finally included from March 2023 to March 2024. The incidence of PPCs between the two groups was not statistically significant (CG = 2/29, IG = 3/27, adjust RR was1.90 (0.29–12.82). One-week preoperative training programme increased MIP, but the results were not sufficient to make a significant difference (P = 0.208). Other secondary outcome measures were also assessed, but no significant between-group differences were found.

Conclusion

Preoperative education combined with one-week IMT has no significant clinical significance in reducing the incidence of postoperative pulmonary complications in lung cancer patients after VATs. Longer preoperative inspiratory muscle interventions or in combination with other exercise modalities need to be explored. A follow-up randomized controlled trial can be carried out after appropriate adjustments to the existing intervention and evaluation protocols.

Trial registration

This trial was registered on the Chinese Clinical Trial Registry website in January 9, 2023 with code ChiCTR2300067464. URL of registry: https://www.chictr.org.cn/

1. Introduction

Lung cancer remains the most common cancer type and the leading cause of cancer death in China [1,2]. In 2022, there will be approximately 4,820,000 new cancer cases and 3,210,000 cancer deaths in China [3]. Compared to the western countries, the number of lung cancer cases in China will continue to increase in the future due to the aging population. With the development of screening methods and minimally invasive surgery, a greater proportion of people can be diagnosed and treated earlier. Nearly 85 % of new lung cancer cases are non–small-cell lung cancer, and surgical resection is the preferred treatment for stages I-IIIA [4], offering the greatest chance for survival [5]. Despite this, the incidence of postoperative pulmonary complications (PPCs) of lung cancer surgery is rather high, ranging from 15.8 to 31.7 % [6], which is significantly higher than that of other types of surgery [[7], [8], [9]]. Studies have confirmed that PPCs can increase the 90-day mortality of postoperative patients to 24.4 %, while this data is only 1.2 % in patients without PPCs [10]. In addition, PPCs can also increase the length of hospital stay by an average of 13–17 days [[11], [12], [13]], resulting in increased medical costs [14].

It may be an important strategy to reduce PPCs after major surgery, especially those respiratory muscles and chest wall injuries were involved. In the normal situation, multimodal intervention programs along with a longer intervention time will yield better results [15,16]. But the clinical situation is that there is not always time for a traditional cardiopulmonary rehabilitation program before surgery [17], since in China lung cancer patients often receive surgical treatment in a very timely manner after diagnosis [18]. The lack of access to facility-based exercise programs is also a barrier to routine participation. Preoperative breathing exercise targeting the respiratory system has been proved to reduce length of stay(LOS), PPCs, and pneumonia and potentially improved 6MWD in patients undergoing surgical lung cancer resection [[19], [20], [21], [22], [23]]. Notably, inspiratory muscle training (IMT) is not bound by location constraints and is readily implementable and it was an important home-based rehabilitation strategy during COVID-19 [24,25]. So far, IMT has been reported to have positive effect among patients with COPD, asthma, or reduced lung function [[26], [27], [28]], and has been proven effective in improving dyspnea, functional exercise capacity and life quality when provided alone [26]. Therefore, it is particularly important to study a prerehabilitation program that can reduce PPCs after lung cancer surgery in a short period of time, and a short-term preoperative home-based exercise intervention is more feasible before lung cancer resection [29].

Preoperative education enables patients to master more operation-related information. Patients who have taken the preoperative education course perform better in terms of expectations, pain, and preparedness [30]. Study shows that 30 min of preoperative health education plus patient-led breathing training during the six weeks before surgery reduced PPCs by nearly half. Moreover, it is cost-effective in the economic analysis of postoperative health [31,32]. In addition, patients with more risk factors derive more benefit from pulmonary rehabilitation [33,34], selecting high-risk patients for targeted intervention can optimize the use of medical resources [35].

There was a lack of randomized controlled studies on preoperative education and short-term home-based preoperative IMT for patients after VATs in China. Therefore, this study accurately selected high-risk patients, combined with preoperative education and short-term preoperative training, explored the impact on postoperative PPCs, length of stay and other indicators of patients after VATs. We hypothesize that the combined intervention one week before the surgery will reduce the incidence of PPCs in patients after the surgery.

2. Methods

2.1. Study design and participants

The trial was a single-center, evaluator blind, randomized placebo-controlled trial conducted at a tertiary hospital between March 1st and March 31st, 2024. in Fuzhou, Fujian, China. The experiment has been approved by the ethics committee of the hospital (Approval No.: MRCTA, ECFAH of MFU [2021]569). The trial was registered on the Chinese Clinical Trial Registry website (ChiCTR2300067464, January 9, 2023), URL of registry: https://Xwww.chictr.org.cn/. According to the study protocol, we conducted a mid-term unblinding of the study and found there was no significant difference in the primary outcome measures, hence we ended the enrollment of patients early. Full details of the rationale, design, protocol and interventions of the trial have been published elsewhere [36]. We confirm that all research was performed in accordance with relevant guidelines and regulations.

2.1.1. Inclusion criteria

Eligible patients included: 1) Over 18 years of age, 2) Non-small cell lung cancer diagnosed by imaging, 3) Planned to have video-assisted thoracic surgery (VATs), requiring an overnight hospital stay, 4) Patients with any of the risk factors for PPCs, including age ≥70 years, BMI≥30 kg/m², heavy smoking history (smoking index ≥400 years/smoking cessation ≤2 weeks before surgery), 1-s rate ≤70 %, and secondary lung surgery, 5) Having time ≥7 days prior to surgery, 6) General anesthesia is required during the operation, 7) Sign informed consent and participate voluntarily.

2.1.2. Exclusion criteria

We excluded patients when they were 1) undergoing radiotherapy or chemotherapy, 2) Patients with cognitive impairment, 3) Patients with respiratory instability, such as uncontrolled pneumonia, 4) Patients with an Eastern Cooperative Oncology Group (ECOG) score of 3 or 4 at the time of enrollment.

2.2. Randomization and blinding

A statistical analyst, independent of the study process, used the PROC PLAN procedure of the statistical software SAS 9.4 program to generate a random sequence, and the included sequence numbers were randomly assigned to either intervention (information booklet plus preoperative physiotherapy education and home-based IMT) or control (information booklet alone) in a 1:1 ratio. Participants' assignments are hidden in sequentially numbered sealed opaque envelopes.

In this study, the evaluator was single blind, the blind base was set by SPSS software, the blind base file was set passwords, and the statistical analyst was responsible for saving. The blind code is the intervention for the subject (i.e. stating that A or B stands for IG or CG). The blind bottom is kept by researchers who are not involved in the intervention, evaluation, and statistical analysis, and the evaluator is unaware of the intervention received by the subject at all times. Study data are entered into an encrypted database and stored until all patients have completed follow-up and the data is enabled for analysis.

2.3. Intervention and procedures

Participants in the CG received a preoperative pulmonary rehabilitation education manual, they were asked to read the content themselves. The manual includes the location of surgical wounds and the introduction of postoperative indwelling catheters; The principle of pulmonary sputum increases after operation, the importance of postoperative cough and sputum discharge; Active cycle of breathing Techniques (ACBT) training was started immediately after postoperative wakefulness. Get out of bed as early as possible; Postoperative pain management; The importance of postoperative exercise education and early postoperative rehabilitation. Participants were told it was important to read the manual carefully before surgery, but no training instructions were provided.

Participants in IG had additional preoperative education sessions: a detailed explanation of the manual and teaching patients to properly practice abdominal breathing and how to cough effectively. In addition, participants were also asked to perform home-based IMT. At baseline assessment, participants' maximum inspiratory muscle strength was measured using a portable pulmonary function tester Ebreathe-plus S3(XEEX (Xiamen) Medical Instrument Co., LTD.) The therapist supervised the subjects to exercise the inspiratory muscle at home by using the C-type breathing trainer (Henan Zhengbei Medical Equipment Co., LTD.) through WeChat. The intensity was 60 % of the maximum inspiratory muscle strength, and the training frequency was 3 sets a day, 30 times per group, completed within 15 min.

2.4. Data collection

In terms of demographics, the evaluator will record basic data of participants, including the age, BMI, education background, gender, smoking history, occupation, risk factors. Information about the cancer stage, type of surgery and histological type of cancer will be obtained in the hospital medical record system after the surgery.

The primary outcome was the incidence of PPCs assessed by the Melbourne Group Score, a standardized validated diagnostic tool [[37], [38], [39]]. Participants were evaluated by assessors blinded to group allocation each day 11a.m. after surgery until seventh day or discharge, and PPC was diagnosed when four or more of these eight criteria were present during the hospital stay.

Secondary outcomes measured at enrollment (T0), the day before surgery (T1) and hospital discharge(T2) were physical function measured using 6-min walk distance(6MWD), maximum inspiratory pressure (MIP), Forced expiratory volume in the first second (FEV₁), and self-reported health-related quality of life (HRQoL), self-rating anxiety and depression. All these assessments will be conducted by a trained physiotherapist blinded to the allocation. Feasibility of the trial, length of stay and the total cost during the hospitalization will also be recorded.

2.5. Data analysis

Statistical analyses were performed using R statistical software (Version 4.3.2; R Foundation for Statistical Computing) and SPSS (Version 26.0; SPSS Inc., Chicago, IL, USA). The modified intention-to treat (mITT) analysis set was used for the analysis. Participants with major protocol deviations, including failure to meet inclusion criteria or not receiving any study treatment, were excluded from the mITT analysis. Categorical variables were expressed as percentages (%) and analyzed using either the Chi-square test or Fisher's exact test, as appropriate. The normality of continuous variables was assessed using the Shapiro-Wilk test. Normally distributed data were presented as mean ± standard deviation (SD) and compared using Student's t-test. Non-normally distributed data were expressed as median with interquartile range (IQR) and analyzed using the Mann-Whitney U test. Bonferroni correction was used for multiple comparisons. The relative risk (RR) values of interventions and PPCs were evaluated through generalized linear models with Poisson regression. Repeated measures analysis of variance (ANOVA) was employed to examine the significance of MIP between groups, across time points, and for group-time interactions. A p-value <0.05 was considered statistically significant for all analyses.

2.6. Futility analysis

The trial would be stopped for futility if the conditional power calculated using PASS 15.0 software (NCSS Statistical Software, Utah, USA), i.e. the probability that the final analysis will show a significant difference between the two arms given the data that have been obtained at the interim analysis, falls below 0.2 or 0.1.

3. Results

3.1. Demographic and clinical characteristics

The study progressed to the mid-term from March 2023 to March 2024. At the interim analysis, the conditional power was calculated as 0.035 (futility index: 0.965; Supplementary 1), indicating this study should be stopped because there is little chance of achieving statistical significance. Therefore, we did not continue to collect samples, but based our analysis on the available data. A total of 246 potentially eligible subjects were screened during the recruitment period. According to the inclusion and exclusion criteria, 180 subjects were excluded, and 66 eligible subjects were finally recruited (Fig. 1). Patients were divided into control (n = 33) and intervention (n = 33) groups. In follow-up studies, IG dropped out of the six, the CG out of the four, remaining 27 in IG and 29 in CG, these 56 participants completed preoperative and follow-up assessment before discharge. There was no significant statistical difference identified in the demographic data and clinical symptoms characteristics in two groups except BMI (Table 1). Patients in IG have higher BMI (22.8 ± 2.9 vs 25.2 ± 3.6). The most frequently included high-risk factor was ≥70 years (38/56, 67.9 %).

Fig. 1.

Flowchart of the study.

Table 1.

Baseline Characteristics of intervention and control groups.

Variable	Control (n = 29)	Intervention (n = 27)	Z	P
Age, median [IQR]	71.0(65.0–73.0)	72.0 (65.0–73.0)	−0.346	0.730
Gender, No. (%)			2.61	0.106
Male	23 (79.3)	15 (55.6)
Female	6 (20.7)	12 (44.4)
BMI, mean(SD), kg/m2	22.8 ± 2.9	25.2 ± 3.6	2.836	0.006
Smoking history			3.814	0.149
Never	10 (34.5)	13 (48.1)
Quit smoking	8 (27.6)	10 (37.0)
Smoking	11 (37.9)	4 (14.8)
Number of high-risk factors				0.863
one	21 (72.4)	22 (81.5)
two	6 (20.7)	4 (14.8)
three	1 (3.5)	1 (3.7)
four	1 (3.5)	0 (0.0)
Education background			0.663	0.416
Junior high school or below	24 (82.8)	19 (70.4)
Senior high school or above	4 (13.8)	7 (25.9)
Missing	1 (3.4)	1 (3.7)
Employment status				0.659
Currently working	4 (13.8)	3 (11.1)
Not employed/Retired	23 (79.3)	22 (81.5)
Other	2 (6.9)	2 (7.4)
Cancer stage				0.346
Ⅰ	25 (86.2)	19 (70.4)
Ⅱ	0 (0.0)	2 (7.4)
ⅢA	1 (3.5)	0 (0.0)
other	3 (10.4)	6 (22.2)
Type of surgery				0.583
Segmentectomy	21 (72.4)	16 (59.3)
Wedge resection	1 (3.5)	2 (7.4)
Lobectomy	7 (24.1)	8 (29.6)
Segmentectomy + Wedge resection	0 (0.0)	1 (3.7)
Cancer diagnosis				0.825
Adenocarcinoma	21 (72.4)	20 (74.1)
Squamous carcinoma	4 (13.8)	2 (7.4)
Other	4 (13.8)	5 (18.5)

3.2. Primary outcome

PPCs were evaluated during the post-operative hospital stay till discharge and there was no significant difference in the incidence of PPCs between intervention group and the control group (Table 2). The composite of PPCs defined as the development of at least 4 MGS variables during the hospital stay, 2 patients (6.9 %) were positive in CG, while 3 patients (11.1 %) were positive in IG (adjust RR, 1.90 [95 % CI, 0.29–12.82]). Purulent sputum was the most common pulmonary complication in this study, which occurred in 16 patients (55.2 %) in CG compared with 14 patients (51.8 %) in IG (adjust RR, 0.94 [95 % CI, 0.43–2.02]). No significant differences were detected in MGS variables.

Table 2.

Postoperative clinical events and pulmonary complications.

Outcomes	CG(n = 29)	IG(n = 27)	Risk Ratio(95 %CI)	Adjust Risk Ratio(95 % CI)∗
Primary outcome, No. (%)
4 or more positive variables of MGS during the hospital stay	2(6.9)	3(11.1)	1.61(0.27–9.64)	1.90(0.29–12.82)
Chest x-ray atelectasis/infiltration	9(31.0)	8(29.6)	0.92(0.37–2.48)	1.04(0.38–2.88)
Purulent sputum	16(55.2)	14(51.9)	0.94(0.46–1.92)	0.94(0.43–2.02)
Physician diagnosis of pneumonia/chest infection	0(0.0)	1(3.7)	–	–
Temperature >38 °C	0(0.0)	3(11.1)	–	–
Oxygen saturation <90 % on air	3(10.3)	3(11.1)	1.07(0.22–5.32)	0.66(0.11–4.03)
Positive signs on sputum microbiology	5(17.2)	5(18.5)	1.07(0.31–3.71)	1.00(0.26–3.78)
White cell count >11.2 units	6(20.7)	8(29.6)	1.43(0.50–4.12)	1.62(0.52–5.00)
Readmission/prolonged stay ICU	3(10.3)	2(7.4)	0.72(0.12–4.29)	0.73(0.11–4.93)

not be calculated since figure in one group is 0; -adjusted factor is BMI.

Abbreviations: MGS, Melbourne Group Score.

3.3. Secondary outcomes

MIP was measured more than two times using repeated measures ANOVA. There was no interaction between group and time in affecting MIP (P = 0.433). The time effect was statistically significant (P < 0.001), indicating that the MIP of the enrollment period of subjects in the two groups changed with time. But there was no significant difference in MIP between two groups (P = 0.586, Table 3). One-week MIT before surgery increased MIP, but the results were not sufficient to make a significant difference (P = 0.611). There was no significant difference in the 6MWD at discharge day between the two groups (P = 0.898). Other secondary outcomes including HRQoL, SAS, SDS are presented in supplementary materials (Supplementary 2), In these items, no significant differences were observed.

Table 3.

Comparison of MIP and 6MWD between the two groups.

Groups	Control	Intervention	t/F	P
MIP
Baseline	67.41 ± 27.94	61.15 ± 24.84	0.884	0.380
Before surgery	68.41 ± 24.99	66.00 ± 31.35	0.312	0.756
Discharge day	51.68 ± 28.62	43.31 ± 19.47	1.226	0.226
Group	–	–	0.301	0.586
Time	–	–	36.979	<0.001
Group∗time	-	–	0.798	0.433
6MWD	-	–
Baseline	472.38 ± 70.08	478.24 ± 73.02	−0.306	0.760
Discharge day	320.98 ± 80.60	317.35 ± 108.14	0.129	0.898

Abbreviations: MIP, maximum inspiratory pressure; 6MWD, 6-min walk distance.

4. Discussion

This study investigated the effects of preoperative IMT combined with education course on PPCs as well as physical function and mental health in high-risk patients underwent VATs. The main results showed no significant reduction in PPCs with the intervention compared to the control group.

The lack of significant reduction in PPCs may be attributed to several factors, including insufficient intervention, suboptimal patient adherence, and the high baseline risk of the study population. Although Fresad et al. reported that an acceptable duration for significantly improving respiratory muscle strength and restoring lung function would be 3–15 days [40,41]. But Kendall [16] also emphasized that more than two weeks of exercise for inspiratory muscle training is needed. Previous study showed preoperative exercise programs could increase functional capacity and prevent pulmonary complications after lung cancer resection [[42], [43], [44]], a seven-day intensive pattern of preoperative PR combined with IMT and aerobic endurance training could lead to positive physical and psychological effects [20], but from our perspective this improvements should be assigned to the comprehensive training methods, especially training that includes aerobic, resistance, and other whole-body exercises.

Furthermore, since participants were not supervised, suboptimal adherence may exist. Participants reported the home-based training, but we couldn't ensure the quality of it. Hence, more use of video calls or app-enabled devices to monitor adherence could be explored in the future, since home-based and technology-supported rehabilitation programmes have been introduced to cardiac field in an attempt to widen access and participation [45,46].

Our findings contrast with those of previous studies that reported a significant reduction in PPCs with preoperative IMT. This discrepancy may also due to differences in patient selection, as our study focused exclusively on high-risk lung cancer patients, who may require more intensive or prolonged interventions to achieve similar benefits since previous research reveals that high-risk patients presented a poorer exercise capacity and a worse self-perceived health status at discharge [47]. It is also possible that we underestimated the benefits of the information manual, such that its benefits alone overwrote the benefits of the inspiratory muscle intervention. Patients who were equipped with information before surgery have a lower incidence of PPCs 30 days after discharge [31], since preoperative cancer education can increase patients' knowledge, reduce anxiety, improve satisfaction and reduce medical costs [48,49].

Another factor is the discrepancy between the diagnostic criteria the PPCs. PPCs is a subjective scale, the results of different items varied significantly among hospitals at the same level, The incidence of PPCs in the CG of our trial is only about 10 %, which is consistent with the literature in the same period [50], but it is quite different from other tertiary hospitals, which is 33.2 % [51]. We attribute this result to the different medical models in different regions in China, resulting in large differences in the assessment of items. The "diagnosis of pneumonia, lower respiratory tract or upper respiratory tract infection, or unspecified chest infection" item is not an objective indicator and is closely related to the doctor's clinical experience, so there may be inconsistent judgments and missed diagnoses. Future multi-center randomized controlled trials need to be explored.

This study has several limitations. First, the relatively short duration of follow-up may preclude a comprehensive assessment of long-term outcomes like 30-day readmission rate in this cohort of lung cancer patients. Second, the single-center design may affect the generalizability of our findings due to potential regional biases in clinical practice and surgery tpyes. Finally, the imprecision in measuring postoperative PPCs might have hindered our ability to detect significant intergroup differences.

Future research should explore the potential benefits of combining IMT with other preoperative interventions to further reduce the risk of PPCs. Moreover, the limitations of our trial underscore the need for long-term, multi-center studies that incorporate more precise assessment tools.

CRediT authorship contribution statement

Ting Lu: Writing – review & editing, Writing – original draft, Investigation, Funding acquisition. Zhixuan Shi: Writing – review & editing, Formal analysis, Data curation. Shuna Huang: Writing – review & editing, Methodology, Formal analysis. Lan Lv: Project administration. Xinyuan Chen: Writing – review & editing, Methodology. Ke Ma: Software, Methodology. Xu Li: Supervision, Data curation. Fancai Lai: Supervision, Data curation. Jun Ni: Supervision, Resources.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Data availability

Data will be made available on request.