Impact of non-steroidal anti-inflammatory drugs exposure on persistent cough after pulmonary resection in a Chinese tertiary hospital: a prospective cohort study protocol

Abstract

Introduction

Previous studies have pointed out that persistent cough is a common complication after pulmonary resection and its occurrence is closely related to inflammatory response. However, there are no clinical studies to date that directly verify that the use of non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the incidence of persistent cough after pulmonary resection (CAP). In view of this, this study aimed to explore and confirm whether exposure to NSAIDs can effectively reduce the incidence of CAP through a prospective cohort study.

Methods and analysis

We will conduct a single-centre, prospective cohort comparative study to investigate the impact of NSAIDs use on persistent cough after video-assisted thoracoscopic (VATS) lung resection surgery. The study will include all patients without preoperative cough symptoms who are scheduled for VATS lung resection. These patients will be divided into exposed and non-exposed groups according to whether they used NSAIDs after surgery. The primary outcome measures of this study are the incidence of CAP and the association between NSAIDs exposure and the incidence of CAP in patients undergoing VATS lung resection, while the secondary outcome parameter was set as severity of cough.

Ethics and dissemination

This research was approved by the Ethics Committee of the 920th Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army (2024-041-01). The study findings will be published in peer-reviewed journals and presented at professional conferences.

Trial registration number

NCT06476249.

Correspondence to Dr Wen-Ke Cai; [email protected] ; Dr Xin Zhang; [email protected] ; Dr Gong-Hao He; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• The prospective design enhances reliability and reduces recall bias.

• The sample size was relatively large, which gives us sufficient power to explore the relationship between non-steroidal anti-inflammatory drugs (NSAIDs) exposure and cough after pulmonary resection (CAP).

• We use propensity score matching to minimise confounding bias and the e-value to assess the impact of unmeasured confounding.

• It is a single-centre study, which may limit the generalisability of our findings.

• We cannot directly assess the causality between the exposure of NSAIDs and the incidence of CAP.

Introduction

Persistent cough after pulmonary resection (CAP) is a prevalent postoperative complication, affecting approximately 24.4% to 55% of patients.^1–3 This condition not only prolongs recovery but also significantly affects the psychological well-being and overall quality of life of patients.^{4 5} Despite its prevalence, effective targeted therapeutic options for CAP remain scarce.

Previous evidence suggests that CAP may be associated with the stimulation of pulmonary C fibres and local inflammatory responses.^6–8 The bronchopulmonary C fibres, part of the vagus nerve system, are particularly sensitive to chemical stimuli, including prostaglandins.^9–12 In the comprehensive management of postoperative patients, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used due to their capabilities of exerting antipyretic, analgesic and anti-inflammatory effects through inhibiting the synthesis of prostaglandins.^{13 14}

Based on these findings, we hypothesise that the NSAIDs might mitigate the incidence or severity of CAP by reducing inflammation and stimulation of pulmonary C fibres. To investigate this hypothesis, we have designed a prospective cohort study, which, to our knowledge, is the first clinical investigation specifically exploring the relationship between NSAIDs use and CAP. The findings from this study are anticipated to provide valuable clinical evidence that could inform management strategies for CAP and ultimately enhance patient outcomes.

Methods and analysis

Study design

This study is a prospective cohort study planned to include patients with solitary pulmonary nodules diagnosed by CT and who have undergone video-assisted thoracoscopic (VATS) lung resection surgery. After enrolment, the patients were divided into the exposed group and the non-exposed group based on whether they used NSAIDs. Exposure to NSAIDs primarily stems from postoperative analgesia. According to the Enhanced Recovery After Surgery (ERAS) guidelines, NSAIDs alone or in combination with acetaminophen should be the preferred analgesic regimen for postoperative pain management.¹⁵ In actual clinical practice, the final medication plan is determined through collaborative discussion between the patient’s attending physician (independent of the research team) and the patient and family members, with the attending physician providing detailed explanations of the analgesic regimen.

In order to quantitatively assess the severity, pattern of changes and impact of cough on patients’ physiological and social life, the study used various standardised assessment tools: Leicester Cough Questionnaire (LCQ), Cough Symptom Score (CSS), Hull Airway Reflux Questionnaire (HARQ) and Visual Analogue Scale (VAS). The VAS uses a scale spanning from 0 to 100 mm, with 0 mm representing the absence of cough and 100 mm indicating the most extreme cough symptoms. The HARQ stands as a validated assessment tool, having demonstrated its diagnostic accuracy in various studies (online supplemental table S1).¹⁶ The CSS serves as a straightforward yet highly effective instrument for gauging the intensity of cough, featuring two questions that predominantly concentrate on individuals’ subjective evaluations of cough frequency during both daytime and nighttime hours (online supplemental table S2).¹⁷ The LCQ, originally conceived for the purpose of assessing chronic cough, encompasses 19 items that are categorised into three distinct dimensions (online supplemental table S3).¹⁸

The primary purpose of the study is to analyse whether exposure to NSAIDs could reduce the incidence of CAP.

Study registration

This study is registered with the US National Institutes of Health on ClinicalTrials.gov under the identifier NCT06476249. Recruitment for this study is anticipated to begin soon and will be open for a period of up to 3 years.

Study population

Participants in this study will be recruited from the 920th Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army. Eligible patients must be aged between 18 and 70 years and must have undergone the VATS lung resection surgery. The study will exclude individuals based on the following criteria: (1) pre-existing cough conditions: patients with a history of cough prior to surgery, including those with asthma or those taking angiotensin-converting enzyme inhibitors (ACEI). (2) Tumour metastasis: patients with distant metastasis of the tumour. (3) Pregnancy or breastfeeding: female patients who are pregnant or breastfeeding. (4) Other systemic major diseases: patients with significant systemic conditions such as malignant tumours, chronic liver insufficiency or chronic renal insufficiency. (5) Mental illness: patients diagnosed with severe mental health disorders. (6) Follow-up compliance: patients who refuse follow-up or have incomplete clinical information at baseline. (7) Poor compliance: patients with poor adherence to study protocols or those deemed unsuitable for inclusion by the investigator. Moreover, given that previous studies have established mediastinal lymph node dissection (MLND) as a significant risk factor for CAP,¹⁹ we performed a subgroup analysis by stratifying the study population into: MLND group and non-MLND group.

During the participant recruitment phase, the research team will thoroughly explain the study’s purpose, design and all relevant details to potential participants and their families. This approach ensures transparency of information and facilitates a comprehensive understanding of the study. Following this informative process, participants and their families will independently decide whether to consent to participation, thereby upholding the principles of voluntariness and ethical standards in research. All participants who agree to take part in the study will be required to sign an informed consent form and provide necessary demographic and clinical data.

Observation parameters and schedule

Table 1 outlines the key elements of the study follow-up process. Prior to the commencement of the study, all participants or their legal representatives must provide written informed consent. Following consent, each participant is required to complete a two-part baseline questionnaire, available in either paper or electronic format. The first part of the questionnaire collects basic personal information, including age, gender, body mass index (BMI), education level, smoking history and alcohol consumption history. The second part assesses cough symptoms using four standardised tools: the LCQ, the CSS, the HARQ and the VAS. The follow-up plan has been meticulously designed. The initial follow-up is scheduled for the third postoperative day to gather comprehensive data from the LCQ, CSS, HARQ and VAS. Subsequent brief follow-ups are planned for the 7th, 11th and 15th days postsurgery, during which only CSS and VAS data will be collected. During these follow-ups, staff will carefully document the number of medical visits and the use of antitussive medications by the participants. Long-term follow-up will occur at 30, 90 and 180 days post-surgery, during which comprehensive data collection using the LCQ, CSS, HARQ and VAS will be repeated. Additionally, updates will be made to records regarding the participants’ medical treatments and the use of cough-related medications.

Table 1

The key elements of the study follow-up process

Follow-up content	Follow-up time points
	Baseline	3 days	7 days	11 days	15 days	30 days	90 days	180 days
LCQ	■	■				■	■	■
CSS	■	■	■	■	■	■	■	■
HARQ	■	■				■	■	■
VAS	■	■	■	■	■	■	■	■
CT of the chest	■	■				■	■
Number of clinic visits			■	■	■	■	■	■
Cough medication use	■	■	■	■	■	■	■	■

CSS, Cough Symptom Score; CT, computed tomography; HARQ, Hull Airway Reflux Questionnaire; LCQ, Leicester Cough Questionnaire; VAS, Visual Analogue Scale.

This follow-up programme is designed to thoroughly investigate the risk factors and dynamic changes associated with CAP through systematic data collection and analysis.

Sample size

This study employs a cohort design to investigate the incidence of CAP as the primary outcome. Based on documented CAP incidence rates ranging from 24.4% to 55%,^1–3 we selected 24.4% as the incidence rate for the non-exposed group. Assuming an incidence rate of 19% for the exposed group, with a two-sided significance level (α) of 0.05 and 90% statistical power (1-β), and an equal allocation ratio (1:1) between groups, the initial calculated sample size required 358 participants per group. Accounting for a potential 15% loss to follow-up and participant refusal, the final minimum sample size was determined to be 422 subjects in both the exposed group and 422 in the control group. The 920th Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army, a tertiary-A medical institution located in southwest China, performs approximately 500 lung resection surgeries annually. Therefore, this study plans to recruit and include a total of 1000 patients who have undergone VATS lung resection over the next 3 years (2024 to 2027).

In designing this study, we have adhered to principles of scientific rigour and efficiency, striving to obtain accurate and reliable results in an optimised manner. To achieve this, we will allocate sufficient human resources and establish a dedicated research team. This team will ensure that each participant receives thorough and meticulous investigation and follow-up, thereby enhancing the statistical validity and interpretative power of the research findings. Through this meticulously designed research plan, we aim to provide a scientific basis for managing persistent cough in patients undergoing VATS lung resection and to contribute to the optimisation and improvement of clinical practice.

Clinical data collection

The study will include a comprehensive set of variables, encompassing preoperative lung function, nodule size, and both preoperative and postoperative laboratory tests. These tests include blood routine parameters (eg, white blood cell count and neutrophil count), blood biochemistry (eg, C-reactive protein and procalcitonin), liver and kidney function tests, and other relevant measures. Additionally, variables such as the surgical method, surgical site, operation duration, anaesthesia method and duration, lymph node dissection, pathological results, chest tube calibre, number of days of catheterisation and the use of cough medications and NSAIDs will be recorded. Data on the length of hospital stay and the number of outpatient visits due to cough will also be collected.

All data will be obtained through passive collection from the participants’ electronic medical records.

Study outcome measures

The primary outcome measures of this study are the incidence rate of CAP and the association between NSAIDs exposure and the incidence rate of CAP. The CAP is defined as follows: non-productive cough that occurs more than 2 weeks after pulmonary resection with stable chest roentgenogram results, no evidence of postnasal drip syndrome or asthma, and no ACE inhibitor administration.²⁰

The secondary outcomes of this study are as follows: (1) severity of cough: The severity of cough will be assessed using several questionnaires administered to participants in the observation cohort on the 3rd and 30th postoperative days. (2) Trajectory of cough severity: Changes in cough severity will be monitored over time by administering the CSS and VAS on the 3rd, 7th, 11th, 15th, 30th, 90th and 120th days post-surgery. This approach will allow for the evaluation of the trajectory and fluctuations in cough severity. (3) Imaging changes: Changes in lung imaging results will be evaluated to assess any modifications in lung condition post-surgery.

Data analysis

Missing values will be estimated using multiple interpolation methods.²¹ This study aims to rigorously compare differences between patients with persistent cough and those without persistent cough using advanced statistical analyses. For continuous variables that meet the assumptions of normal distribution and homogeneity of variance, an independent t-test will be employed to assess differences between the two groups. For continuous variables that do not adhere to a normal distribution, the Mann–Whitney U test (also known as the Wilcoxon rank-sum test) will be used. For categorical variables, the χ² test will be used to examine differences between the groups.

To determine the association between NSAIDs and CAP, we will employ logistic regression analyses. The results will be presented as OR with corresponding 95% CI. This statistical approach will allow us to quantify the strength of association between various factors and the occurrence of CAP. Spearman’s rank correlation coefficient is used to assess the association between two categorical variables. To mitigate potential baseline confounding factors—variables that may influence the outcome but are not the primary focus of our study—we will employ propensity score matching (PSM) analysis. PSM is a statistical technique designed to create a matched sample,²¹ thereby making the distributions of potential confounders as similar as possible between the CAP group and the non-CAP group. Patients will be matched in a 1:1 ratio using a calliper of 0.2 standard deviations (SDs) of the logit of the estimated propensity score. Standardised mean difference (SMD) will be calculated before and after matching to examine whether the PSM reduces the differences in pretreatment covariates between the two groups. A variable can be considered as a balance between groups when its SMD＜0.1.²² In the intended propensity score model, we plan to incorporate several variables, including gender, age, BMI, education level, smoking history, alcohol consumption history, blood routine parameters, blood biochemistry, liver and kidney function tests, other relevant clinical measures, surgical method, surgical site, operation duration, anaesthesia method and duration, pathological results, chest tube calibre and number of days of catheterisation.

To evaluate the potential impact of unmeasured confounding factors, we will conduct sensitivity analysis using the E-value.²³

Through these analyses, we aim to demonstrate that exposure to NSAIDs reduces the incidence of the CAP and at the same time achieve a comprehensive understanding of the risk factors associated with CAP. This research is expected to provide valuable insights into treatment and prevention strategies for clinicians and patients, thereby contributing to improved patient outcomes and enhanced quality of life.

Discussion

Quality control and supervision

Each questionnaire will be evaluated by three reviewers who will assess the completeness and reliability of every section. If a questionnaire is deemed to be of insufficient quality, the reviewer will contact the participant within 3 days to conduct a telephone re-interview to complete and revise the questionnaire. To ensure data quality, data entry will be performed by two independent individuals. Data managers will regularly review the data, periodically selecting participant profiles at random to re-enter and verify for quality control.

Queue maintenance and control of missed visits

Enrolled patients will be scheduled for seven follow-up visits spanning from the third postoperative day to 180 days. If a participant misses a scheduled visit, the assessor will reach out to the participant or their family to conduct the interview by phone and complete the electronic questionnaire. Additionally, the cohort will use an official WeChat account to disseminate postoperative information, important notices and reminders to participants and their families. This account will also be employed to offer support and counselling, which is anticipated to enhance the follow-up rate for the cohort.

Ethics and dissemination

This research was approved by the Ethics Committee of the 920th Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army (2024-041-01). All informed consent forms will be stored in a locked research office, and personal data will be kept in a digital format within the system, without disclosure in any publications or scientific journals. The study findings will be published in peer-reviewed journals and presented at professional conferences.

Except for the use of NSAIDs, there will be no other differences between the two groups throughout the entire treatment process. While the study requires the collection of routine blood test results and chest CT imaging for standard clinical diagnosis and treatment, it does not necessitate additional blood samples or expose participants to extra radiation. Therefore, participants face no additional burden or risk beyond standard medical procedures.

Limitations

This study represents the first prospective cohort investigation to evaluate the association between NSAIDs exposure and the incidence of CAP. The prospective design, with prespecified data collection protocols and direct investigator oversight, minimised recall bias and enhanced the reliability of exposure-outcome assessments. However, several limitations should be acknowledged. First, it is a single-centre study, which may limit the generalisability of our findings. Consequently, future research should prioritise multi-institutional investigations to elucidate the association between NSAIDs exposure and the incidence of CAP across diverse healthcare settings. Second, while the cohort design allowed for rigorous adjustment of confounders, the observational nature precludes definitive causal inferences between NSAIDs use and CAP. Future randomised controlled trials are needed to validate these associations. Third, for the secondary outcome of cough severity assessment, we employed standardised, validated scales. However, their inherent subjectivity due to patient-reported symptom quantification remains a methodological limitation.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Contributors All authors contributed to the manuscript. RZ was responsible for drafting the initial version of the manuscript, laying out the basic structure and content framework. XZ, GHH and WKC initiated the study and contributed equally as co - corresponding authors. The manuscript was refined by XY and TH. BM and ZXN were responsible for screening the cases, while YFZ and XKL handled the signing of informed consent forms and the collection of questionnaires. JY participated in significant revisions of the manuscript. They have all read, refined and approved the final manuscript. WKC is the guarantor.

Funding The project will be funded by the Young and Middle-aged Academic and Technical Leaders Reserve Talent Project of Yunnan Province (No. 202405AC350037).

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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