Abstract
Background
Pneumothorax can cause distressing breathlessness, however the effect of the accumulated air in the pleural space and its association with diaphragmatic function and symptoms of breathlessness is not well understood. Bendopnoea is an evolving clinical symptom that has been demonstrated as clinically useful in some heart and lung conditions. Whether bendopnoea is present in patients with pneumothorax, and its potential clinical usefulness has not yet been investigated. The PASE study is a pilot study to explore the incidence and clinical relevance of bendopnoea in patients with pneumothorax and may provide better understanding of pneumothorax related dyspnoea.
Methods
PASE is a prospective study. Eligible patients are assessed at baseline (pre air drainage/lung reinflation) and in patients whose pneumothorax resolves once the lung has re‐expanded (post conservative management or air drainage procedure). Outcome measures include the incidence of bendopnoea, correlation of the associated symptoms (pain and breathlessness) to the severity of bendopnoea and the size of pneumothorax; and correlation with clinical outcome (i.e., response to air drainage/lung reinflation). The study will recruit 50 participants.
Discussion
This is the first study to explore bendopnoea in patients with pneumothorax. The presence and significance of bendopnoea in relation to clinical and physiological parameters in patients with pneumothorax requires investigation. The findings of this study may further current understanding of dyspnoea related pneumothorax.
Trial Registration
Name of the registry: Australia New Zealand Clinical Trial Registry
Trial registration number : ACTRN12623001109695p.
URL of the trial registry record for this trial : https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386631&isReview=true
Date of registration : Registered on 24 October 2023.
Funding of the trial : This study has not received grant support. The study is sponsored by the Institute for Respiratory Health, a not‐for‐profit organisation.
Name and contact information for the trial sponsor : Mr Bi Lam; Finance manager. Level 2, 6 Verdun Street, Nedlands, WA 6009.
Role of sponsor : The funder is not involved in the planning of the study, gathering, analysing, and interpreting the data, or in preparing the manuscript.
Protocol version : 1.
Keywords: bendopnoea, dyspnoea, pneumothorax
This is the protocol for the PASE study. The PASE study is a pilot study to explore the incidence and clinical relevance of bendopnoea in patients with pneumothorax and may provide better understanding of pneumothorax related dyspnoea.
INTRODUCTION
Pneumothorax occurs when air leaks from the lung and accumulates between the chest wall and the lung, resulting in partial lung collapse. The build‐up of air may impair diaphragm function. The mechanism of breathlessness in pneumothorax is unclear, and symptoms can vary between patients. Some patients present with minimal or absent symptoms, whilst others experience distressing breathlessness and pain. Sometimes tubes may need to be inserted between the ribs to drain the collected air and help the lung reinflate, and occasionally surgery is required to stop the leak.
Currently, the effect of the accumulated air in the pleural space and its association with diaphragmatic function and symptoms of breathlessness is not well understood. Bendopnoea (breathlessness when bending forward) is an evolving clinical symptom that has been demonstrated as clinically useful in some heart and lung conditions. Whether bendopnoea is present in patients with pneumothorax, and its potential clinical usefulness has not yet been investigated.
The PASE study is a pilot study to explore the incidence and clinical relevance of bendopnoea in patients with pneumothorax and may provide better understanding of breathlessness in pneumothorax.
Background and rationale
Pneumothorax is a condition characterized by the presence of air in the pleural space between the lung and chest wall. 1 This abnormal accumulation of air can cause partial or complete collapse of the lung, and the patient can experience breathlessness and chest pain. 2 , 3
Pneumothorax can be classified as spontaneous or traumatic (including from medical procedures). Bendopnoea is a simple and safe bedside test that requires patients to bend forward and report symptoms of breathlessness. It does not require the use of any equipment or specific resources and can be completed within 60 s, therefore the test can be easily replicated during routine assessments in all settings.
In patients with pneumothoraxes, the level of breathlessness varies amongst patients and the precise mechanism of breathlessness in pneumothorax remains unknown. In contrast, breathlessness in patients with pleural effusion is now linked with diaphragmatic dysfunction due to presence of pleural fluid. Whether that holds true for pleural air in pneumothorax is also unknown. Bendopnoea is emerging as a clinically useful symptom related to patient outcomes in many cardiorespiratory diseases, however, it has not yet been explored in pleural disorders. Our literature review showed that bendopnoea is a clinical biomarker in patients with advanced heart failure (HF) 4 , 5 and in those with pulmonary arterial hypertension (PAH) 6 that is associated with prognosis, 4 , 5 functional capacity, 6 haemodynamic characteristics 6 and right ventricular function. 6
The incidence of bendopnoea has not yet been reported in patients with pneumothorax (Aim 1), including the correlation of bendopnoea with pain, breathlessness, size of pneumothorax and respiratory physiological parameters (Aim 2). In the context of pneumothorax, the clinical usefulness of bendopnoea as a predictor of outcome is yet to be explored.
Objective
The PASE study will explore the incidence of breathlessness on bending forward (bendopnoea) in patients with pneumothorax and whether this is associated with symptoms, size of pneumothorax, physiological parameters and the clinical outcome.
We hypothesise that bendopnoea:
is prevalent in individuals with pneumothorax and
-
is a useful clinical marker:
that is associated with severity of breathlessness,
that reflects the size and types of pneumothoraxes, and
that correlates with clinical outcome (i.e., response to drainage/lung reinflation).
Study Aims and Outcomes: In a prospectively recruited unbiased/unselected cross‐sectional cohort of patients with pneumothorax, this study will explore the:
incidence of bendopnoea,
correlation with associated symptoms (pain and breathlessness), physiological parameters (e.g., oxygen saturations) to the severity of bendopnoea and the size of pneumothorax; and correlation with clinical outcome (i.e., response to drainage/lung reinflation).
The above will be performed in all patients with a new diagnosis of pneumothorax at baseline, and in patients whose pneumothorax resolves once the lung has re‐expanded (post conservative management or air drainage procedure).
Trial design
PASE is a prospective study.
METHODS
Participant screening, selection, and recruitment
The site principal investigator (PI) will screen patients with pneumothorax appropriate to be included in the study. Potential participants will be approached about the study and provided with the participant information and consent form to read and given time to ask questions to the study team. They will also be given time to discuss the study with family and carers, if needed. Eligible participants will be offered entry and enrolled after providing informed consent. The site principal investigator will be aware of their dual role as the patients' primary physician and as a clinical researcher and where this patient dependency can be a potential conflict. All participants will receive standard care for their conditions as per their treating clinicians. Enrolment and screening logs will be maintained.
Study setting
This study will enrol 50 consecutive eligible patients with pneumothorax from the pleural service of Australian centres.
Eligibility criteria
Eligibility criteria includes in‐ and out‐patients referred to the enrolment centres for assessment of a new diagnosis of unilateral spontaneous (primary or secondary) pneumothorax or iatrogenic pneumothorax.
Exclusion criteria
Exclusion criteria includes pneumothorax with a concurrent pleural effusion >1 cm in size, haemodynamic instability (defined as systolic blood pressure of <90 mmHg, heart rate in beats per minute greater than or equal to systolic blood pressure in mmHg, respiratory rate of >30 breaths per minute, and SpO2 of <90% on room air), age < 18 years, mechanical limitations in bending forward (e.g., spinal conditions or large abdominal mass), pregnancy/lactation and inability to consent or comply with protocol.
Participant withdrawal criteria
Participants can withdraw at any time from the study and do not need to provide a reason. We will retain all participant data up until the time of withdrawal as outlined in the Participant Information and Consent Form. There may be reasons for the site PI to decide to withdraw a participant from the study. This could be due to inability to comply with the study protocol such as attending study visits or for other compliance issues. A participant may also be withdrawn in their best interests. In all cases, the study withdrawal form will be completed and a copy submitted to the lead site. Withdrawn participants will not be replaced. If considered clinically necessary, withdrawn participants will be asked to return to clinic for safety follow‐up appointment(s).
Outcomes
The following parameters will be assessed using a range of validated tools for all patients.
At baseline (pre drainage/lung reinflation) and,
In patients whose pneumothorax resolves once the lung has re‐expanded (post conservative management or air drainage procedure).
Bendopnoea is assessed
- In a qualitative manner (as modified from Baeza‐Trinidad et al. 7 ) with the following question:
- “Since the onset of your symptoms, how has shortness of breath when bending forward impacted your day‐to‐day activities?
- Not at all: I did not feel breathless bending forward.
- Mildly: I felt slightly breathless bending forward, but could still perform activities like tying shoelaces.
- Moderately: I felt very breathless bending forward and had to stop activities like tying shoelaces.
- Severely: I felt too breathless to bend forward.
- After the lung has re‐expanded, the question will be phrased: ‘Compared to the first assessment/since the procedure, how does shortness of breath when bending forward impact your day‐to‐day activities?’
- With objective testing, as per published studies 6 , 7 , 8 :
- Patient sitting in a chair is instructed to bend forward at the waist and aim to touch his/her ankles and maintain this position for up to 60 s. Patient will inform the investigator as soon as breathlessness occurs, and the time of onset of bendopnoea recorded.
- Bendopnoea is recorded as:
- Time to breathlessness, and
- Present or absent during the test.
Degree of breathlessness and impairment on functional activities
Breathlessness will be measured using a 100 mm visual analogue scale (VAS) anchored by ‘no shortness of breath at all’ and ‘maximum shortness of breath’. 9 VAS scores have been used previously to measure breathlessness in this population. 10 The mean of the VAS scores measured by two independent researchers will be documented.
The impact of breathlessness on function
Pain will be measured using a 100 mm visual analogue scale (VAS) anchored by ‘no pain’ and ‘worst pain’. 11 The mean of the VAS scores measured by two independent researchers will be documented.
Patient characteristics
Breathlessness can be a result of concurrent illnesses (e.g., heart failure, COPD etc.) and intrathoracic (e.g., pulmonary emboli) or extrathoracic factors (e.g., muscle wasting) which will be captured from case notes. Height, weight and body mass index will be recorded. Cardio‐pulmonary status (respiratory and heart rates, blood pressure and oxygen saturation) and the aetiology of the pneumothorax will be recorded.
Pneumothorax characteristics
The size of the pneumothorax will be measured on standard erect PA inspiration chest radiographs (CXR) with the Light Index 1 and Collins Method. 12 The Light Index measures the average diameter of the lung and the hemithorax, cubing these diameters, and finding the rations 1 whereas the Collins Method calculates the ‘sum of interpleural distances’ which estimates the pneumothorax size. 12
Participant timeline
Participation flow is demonstrated in Figure 1 and time burden to patients in shown in Table 1.
FIGURE 1.
Study flowchart; trial entry, trial treatment and post procedure care.
TABLE 1.
Patient time burden.
| Procedure | Duration (mins) | Visit 1 (day 0) | Visit 2 (once lung has re‐expanded) |
|---|---|---|---|
| Informed consent | 10 | x | |
| Baseline observations | 5 | x | |
| VAS score breathlessness | 1 | x | x |
| VAS score pain | 1 | x | x |
| Bendopnoea tests | 5 | x | x |
Sample size
This study will aim to recruit 50 participants with spontaneous (primary and secondary) pneumothorax and iatrogenic pneumothorax over 24‐months. This number is achievable in the proposed timeframe and accounts for those who decline to take part in the study.
Recruitment
The study will enrol participants for a period of 24 months. This is based on the number of potentially suitable participants seen in the recruiting centre (~1–2 week).
DATA COLLECTION, MANAGEMENT, AND ANALYSIS
Data collection methods
Data from paper case report forms is being transposed into the study REDCap database. This will be de‐identified data. The dataset will be exported for analysis at the end of the study from REDCap to an Excel spreadsheet for the designated study statistician. Consent to this study is extended so data collected from this study will be used in future related studies. Those wanting access will need to contact the study CPI and provide an outline of the reason that data access is required. If this is deemed legitimate an amendment will need to be made to state that the data is to be made available to the individual and include the institution where the data will be held and archived. Where possible a virtual transfer of data will be made so that the primary dataset remains at the original institution and is managed according to local guidelines.
Data management
All procedures for the handling and analysis of the data will be conducted according to the ICH GCP guidelines and the National Statement on Ethical Conduct in Human Research (2007)—Updated 2018 and in accordance with local policies and procedures.
Data collected will be stored in line with the Australian Code for the Responsible Conduct of Research for clinical trials and local policy guidelines for research data archiving. Access to the final trial dataset will only be available to the research team at the lead site. Audits, if any, are usually carried out by an independent compliance monitoring officer.
Statistical methods
This is a pilot study to determine whether bendopnoea is present in patients with pneumothorax, and whether it correlates with clinical symptoms (pain and breathlessness), the size of the pneumothorax and respiratory physiological parameters. It also aims to determine whether bendopnoea is correlated with clinical outcome (i.e., response to drainage/lung reinflation).
Descriptive statistics of baseline characteristics of patients and measured bendopnoea, pain and breathlessness responses will be provided. The magnitude and direction of the change between the baseline and post‐intervention measurements (e.g., responses in bendopnoea, pain and breathlessness) will be estimated. Statistical modelling will be applied to determine the correlation of bendopnoea to symptoms, the size of the pneumothorax, physiological parameters and clinical outcomes.
MONITORING
Data monitoring
This study will have site monitoring carried out by the lead site. Source data will be scrutinized to ensure the provision of robust data. Data entered in the CRFs that are transcribed from source documents must be consistent with the source documents or the discrepancies must be explained. Any discrepancies should be resolved with the site PI or otherwise documented as File Notes. Procedure deviations and or violations may be determined at this time and will need to be reported according to local procedure/policy. Source documents are filed at the investigator's site.
Harms
Pleural interventional procedures will only be performed as part of standard of care. Standard medical care and any drainage procedures (prophylactic, diagnostic and therapeutic procedures) remains the responsibility of the treating physician of the patient.
Adverse event reporting
All adverse events relating to the trial investigations, serious and non‐serious, will be fully documented on the appropriate CRFs. For each adverse event, the investigator will provide the onset, end, intensity, treatment required, outcome, seriousness and action taken. The investigator will determine the relationship of the experimental procedure to all AEs as defined on the ‘Adverse Event’ CRF. The basis for judging the intensity of the AE as well as the causal relationship between the experimental procedure and the AE is described below.
An Adverse Event (AE) is defined as any untoward medical occurrence, including an exacerbation of a pre‐existing condition. It does not necessarily have to have a causal relationship with treatment. All adverse events relating to the investigations occurring during the course of the clinical trial (i.e., from signing the informed consent until death or the end of the study follow up period, whichever comes first) will be collected and documented by the investigator according to the specific definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the Trial Master File. Cases will also be reported if a causal link between the AE and the trial investigations is suspected but not confirmed. Any event that meets the criteria for a Serious Adverse Event (SAE), as defined below, reported as an SAE.
A Serious Adverse Event (SAE) is defined as any AE that,
results in death
is life‐threatening
results in persistent or significant disability/incapacity
prolongs hospitalization by ≥24 h (i.e., unexpected overnight admission)
is deemed serious for any other reason such that it is thought to jeopardize the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the above SAE definitions.
SAEs are to be reported immediately to the local ethics committee using the Serious Adverse Event Report Form including a documented causal relationship assessment and providing as much detail regarding the SAE as possible.
Auditing
The study investigators/institutions will permit trial‐related monitoring, audits, and regulatory inspections, providing direct access to source data/documents. This may include, but is not limited to, review by external sponsors, Human Research Ethics Committees and institutional Governance review bodies.
Confidentiality
Patient privacy and confidentiality will be maintained, as any information that identifies participants will be available only at the enrolment site and only to designated study investigators, all of whom will either have signed a confidentiality agreement or be employees of the hospital.
DISCUSSION
This is the first study to investigate bendopnoea in patients with pneumothorax. The presence and relevance of bendopnoea in the context of pneumothorax requires investigation. The relationship between the presence of bendopnoea at baseline and clinical and physiological parameters will be explored. The post‐assessment of patients whose pneumothorax resolves will provide information on whether the presence of bendopnoea has a correlation with clinical outcome (i.e., response to drainage/lung reinflation). The findings of this study may further current understanding of pneumothorax related dyspnoea.
Trial status at submission
Protocol version: Version 2.00/04.07.2024. Date recruitment began: 16.04.2024. Estimated recruitment completion date: 16.04.2026.
Dissemination policy
Results from this study will be published in peer‐reviewed journals and presented at national and international conferences. Authorship eligibility guidelines will be discussed prior to publication.
AUTHOR CONTRIBUTIONS
Conceptualisation: Bianca M. Iacopetta and Y. C. Gary Lee. Methodology: Bianca M. Iacopetta, Michaela Donaghy, Carolyn J. Peddle‐McIntyre, and Y. C. Gary Lee. Project administration: Ai Ling Tan, Bianca M. Iacopetta, and Chloe Charlesworth. Data collection/enrolment: Bianca M. Iacopetta, Michaela Donaghy, Chloe Charlesworth, Y. C. Gary Lee. Data curation: Bianca M. Iacopetta. Formal analysis: Bianca M. Iacopetta and Y. C. Gary Lee. Resources: Y C Gary Lee. Supervision: Carolyn J. Peddle‐McIntyre and Y. C. Gary Lee. Protocol preparation (original draft): Bianca M. Iacopetta and Y. C. Gary Lee. All authors reviewed and approved final submission.
FUNDING INFORMATION
This study has no funding to declare.
CONFLICT OF INTEREST STATEMENT
Prof Y. C. Gary Lee is an Editorial Board member of Respirology Case Reports and a co‐author of this article. He was excluded from all editorial decision‐making related to the acceptance of this article for publication. The other authors have no conflict of interests to report.
ETHICS STATEMENT
Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee has approved the study (RGS0000006354). Results will be published in peer‐reviewed journals and presented at scientific conferences. Study investigators will ensure that any amendments to the protocol is approved by the ethics committee and signed by any patients subsequently entering into the trial and those currently in the study, if affected by the amendment.
ACKNOWLEDGMENTS
The design of this trial incorporated input and feedback from the Pleural Consumer Reference Group. Open access publishing facilitated by The University of Western Australia, as part of the Wiley ‐ The University of Western Australia agreement via the Council of Australian University Librarians.
Iacopetta BM, Donaghy M, Charlesworth C, Peddle‐McIntyre CJ, Tan AL, Lee YCG. The Pneumothorax And Symptom Evaluation (PASE) study: Bendopnoea in patients with pneumothorax. Respirology Case Reports. 2024;12(8):e01443. 10.1002/rcr2.1443
Associate Editor: Claude Farah
DATA AVAILABILITY STATEMENT
Investigators at the lead site will have access to the final trial dataset. Supporting data including standard operating procedures, details of data management procedures, case report forms, and datasets generated and/or analysed during the current study will be available to the scientific community with as few restrictions as possible, while retaining exclusive use until publications of major outcomes. Data requests from qualified researchers should be made to YCGL (gary.lee@uwa.edu.au).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Investigators at the lead site will have access to the final trial dataset. Supporting data including standard operating procedures, details of data management procedures, case report forms, and datasets generated and/or analysed during the current study will be available to the scientific community with as few restrictions as possible, while retaining exclusive use until publications of major outcomes. Data requests from qualified researchers should be made to YCGL (gary.lee@uwa.edu.au).