The primary objective of this trial is to evaluate the short-term efficacy of nasal negative pressure oscillatory airway clearance delivered via a novel bronchial drainage device, compared with OPEP, in hospitalized patients experiencing acute exacerbations of bronchiectasis. Efficacy will be assessed by comparing sputum clearance and other airway clearance–related outcomes between interventions.

Secondary objectives are to assess the safety, tolerability and feasibility of nasal negative pressure oscillatory airway clearance in the acute hospital setting, as well as patient acceptance of the intervention. In addition, the study aims to explore the effects of NNPO on pulmonary function during hospitalization.

This prospective, multicenter, randomized, crossover, non-inferiority trial aims to evaluate the efficacy of a novel airway clearance technique, nasal negative pressure oscillatory (NNPO) therapy, in hospitalized patients. The protocol is developed and reported in accordance with the SPIRIT 2025 guidelines (15). To minimize inter-individual variability in sputum production and airway clearance capacity, a self-controlled crossover design is employed, with each participant receiving both interventions and serving as their own control. NNPO therapy is compared with conventional airway clearance using oscillatory positive expiratory pressure (OPEP).

The study is conducted over a continuous 4-day intervention period. Participants receive one intervention on Days 1 and 3 and the alternate intervention on Days 2 and 4. Two treatment sequences are predefined: Sequence A, in which NNPO is administered on Day 1 followed by OPEP on Day 2, and Sequence B, in which OPEP is administered on Day 1 followed by NNPO on Day 2. The same intervention sequence is repeated on Days 3 and 4 to enhance the reliability of treatment comparisons. Allocation to Sequence A or Sequence B is performed using a computer-generated randomization schedule (Figure 1).

The primary objective of the trial is to determine whether NNPO therapy, as a short-term intervention, is non-inferior to conventional OPEP therapy with respect to sputum clearance.

Randomization was performed using a computer-generated random sequence, which assigned participants to one of two intervention sequences (NNPO first or OPEP first) in a 1:1 ratio. Allocation was concealed using sealed, opaque envelopes prepared by an independent researcher not involved in participant recruitment, intervention delivery, or outcome assessment. Due to the nature of the interventions, participants and treating physiotherapists were not blinded. However, outcome assessors and data analysts were blinded to treatment allocation throughout the study.

A formal washout period will not be incorporated in this study because hospitalized patients with acute exacerbation of bronchiectasis may experience rapid changes in airway secretion burden and clinical status over a short period. In addition, suspending airway clearance during a washout period would be unethical, as secretion clearance is necessary in this patient population, making a prolonged washout period impractical. However, to minimize potential carryover effects, each intervention will be performed on a separate day.

The trial will be conducted across four tertiary teaching hospitals in China. The China–Japan Friendship Hospital in Beijing will serve as the coordinating center, with participating sites including the First Affiliated Hospital of Nanchang University (Nanchang), Shandong Provincial Hospital Affiliated to Shandong First Medical University (Jinan), and The First People’s Hospital of Yunnan Provincial (Kunming). All participating centers have established respiratory rehabilitation teams and experience in airway clearance interventions. Prior to study initiation, investigators at all sites will receive unified training on the study protocol to ensure consistency and standardization of trial procedures.

Participants eligible for inclusion are adults aged 18–75 years with radiologically confirmed bronchiectasis on high-resolution computed tomography, hospitalized for acute exacerbation (defined as worsening of ≥3 key symptoms for ≥48 h requiring treatment change), and able to provide written informed consent. Participants are excluded if they have severe cardiovascular disease (e.g., decompensated heart failure, unstable arrhythmia), recent massive hemoptysis (>100 mL in a single episode or >300 mL within 24 h), severe tympanic membrane pathology or recent otologic surgery, or cognitive/psychiatric conditions impairing understanding or cooperation.

Allocated interventions may be withdrawal under the following circumstances: serious adverse events or clinically significant deterioration related to the intervention; development of contraindicating conditions (e.g., hemoptysis, acute cardiorespiratory instability, severe intolerance); participant request for withdrawal; or inability to safely continue as judged by the investigator. In such cases, participants will continue to receive standard medical care according to routine practice (Table 1).

NNPO therapy was delivered using a nasal device that generated oscillatory negative pressure airflow in enhanced mode (flow rate: 2600 mL·min⁻¹ ± 500 mL·min⁻¹; pressure range: 320–900 Pa; sinusoidal waveform at 50 Hz). During NNPO therapy, participants wore a nasal interface and performed repeated standardized breathing maneuvers consisting of a slow deep inspiration, a 2–3-s end-inspiratory breath hold, followed by a slow expiration while receiving oscillatory negative pressure airflow via the nasal route.

Three consecutive breathing maneuvers were performed, followed by 30–40 s of quiet breathing; this sequence constituted one cycle and lasted approximately 3 min.

OPEP therapy was administered using an oscillatory positive expiratory pressure device (PE100, Respiratory Rehabilitation Device, e-Linkcare Meditech Co., Ltd), with expiratory pressure set between 10 and 20 cm H₂O in accordance with manufacturer recommendations. Participants followed the same standardized breathing structure as in the NNPO intervention, including a slow deep inspiration, a 2–3-s end-inspiratory breath hold, and expiration performed through the OPEP device.

The cycle structure, timing, and session organization were identical to those used during NNPO therapy; the only difference between interventions was the expiratory phase, during which expiration was performed through the OPEP device rather than during nasal negative pressure delivery.

Each supervised session consisted of two sets of five cycles. After completion of the first five cycles (approximately 15 min), participants were encouraged to perform huffing and coughing to facilitate airway secretion clearance, followed by a short rest before commencing the second set. The total session duration was approximately 30 min. Huffing was systematically instructed at 15 min after session initiation and again at the end of the session, with additional coughing encouraged as needed (Figure 2).

Device settings were maintained throughout each session and adjusted only to ensure patient comfort and tolerance.

In addition to the supervised intervention sessions, all participants received instruction in general airway clearance techniques without the use of devices as part of routine care. These techniques referred to commonly used non-device strategies, such as appropriate mobilization, breathing control, huffing, and coughing. Participants were not restricted in the frequency or type of self-performed airway clearance techniques outside the supervised intervention sessions.

The primary outcome was sputum wet weight, collected during each treatment session and for up to 30 min after session completion. Sputum was collected into pre-weighed, sealed sterile containers and immediately weighed using a calibrated electronic scale. Collection was performed using a standardized procedure under the supervision of study personnel throughout the airway clearance process. During collection, participants were instructed to avoid swallowing sputum when present and to expectorate it promptly for collection. Study personnel made real-time judgments based on the pattern of expectoration and avoided collecting secretions following throat clearing or intentional saliva generation. For participants with viscous oral secretions that might increase the risk of saliva contamination, mouth rinsing with water was permitted prior to treatment to reduce oral contamination.

Secondary outcomes include: (1) Lung function—FEV₁, FVC, FEV₁/FVC, MEF₇₅, MEF₅₀, MEF₂₅, and MMEF₇₅/₂₅—measured before and 30 min after each daily treatment session. Lung function parameters were assessed using a respiratory rehabilitation device (PE100, e-Linkcare Meditech Co., Ltd.); (2) peripheral oxygen saturation (SpO₂/FiO₂) measured at rest before treatment, during the final minute of each session, and 30 min post-treatment; (3) patient-reported treatment efficacy and comfort assessed using 10-cm visual analogue scales after completion of all treatment days; and (4) the incidence of adverse events during or immediately after each session (Table 2).

The sample size was calculated based on the primary outcome, sputum wet weight, using a non-inferiority design. A non-inferiority margin of 1.5 g was prespecified, as justified above. Variability estimates were obtained from a preliminary pilot study, which indicated a within-subject standard deviation of approximately σ g for wet sputum weight following airway clearance interventions.

Assuming a true mean difference of 0 g between NNPO and OPEP, a one-sided significance level (α) of 0.025, and 80% power, a minimum of 38 participants was required to demonstrate non-inferiority in this crossover study. To allow for potential dropouts or incomplete data, the target sample size was increased to 42 participants.

Limitations include the short intervention period, which precludes assessment of long-term outcomes such as exacerbation recurrence or hospital stay, and the inability to blind participants or therapists. Nonetheless, the use of objective primary outcomes and standardized protocols is expected to minimize bias. Overall, this study will provide high-quality evidence on the short-term efficacy and safety of NNPO and inform evidence-based, individualized airway clearance strategies in hospitalized patients with acute bronchiectasis exacerbations.

In addition, some anticholinergic agents such as ipratropium bromide have been suggested to reduce bronchial secretions (20), which could theoretically influence sputum volume, as well as by the natural clinical course during treatment, in which sputum volume may gradually decrease over time. From an ethical and practical perspective, it was neither feasible nor appropriate to restrict or modify clinically indicated medications in hospitalized patients, and such variability therefore reflects real-world clinical practice. To mitigate the potential bias introduced by these unavoidable factors, this study employed a randomized crossover design, allowing each participant to serve as their own control, focused on sputum expectoration following a single treatment session, and conducted all interventions and assessments at a fixed time each morning. Nevertheless, residual confounding related to concurrent treatments cannot be completely excluded and is acknowledged as a limitation of the study.