Effect of Spontaneous Breathing in APRV Mode on Respiratory Physiology of ARDS Patients

A Randomized Controlled Trial Of The Effect Of Spontaneous Breathing In APRV Mode On Respiratory Physiology In Patients With Acute Respiratory Distress Syndrome

This is a single-center, prospective, randomized, three-period crossover physiological study in adult patients with moderate-to-severe acute respiratory distress syndrome (ARDS, PaO₂/FiO₂ ≤150 mmHg). Each enrolled subject will receive all three APRV ventilation conditions in random sequence: low-level spontaneous breathing (spontaneous minute-ventilation proportion 10%-30%), high-level spontaneous breathing (31%-50%), and fully suppressed spontaneous breathing as control. A 30-minute wash-out period is set between each condition to restore unified physiological baseline. Primary outcome is ventilation-perfusion mismatch percentage (mismatch%) measured by Electrical Impedance Tomography (EIT). Secondary outcomes include EIT-derived pulmonary parameters, respiratory mechanics, hemodynamics, diaphragmatic function and safety profiles. Only short-term, reversible ventilator and sedation adjustments will be performed; routine clinical management remains unchanged throughout the trial.

Acute respiratory distress syndrome (ARDS) is a life-threatening critical respiratory illness characterized by heterogeneous pulmonary injury and severe ventilation-perfusion mismatch. Airway Pressure Release Ventilation (APRV) permits spontaneous breathing throughout the whole respiratory cycle, which may improve regional ventilation-perfusion matching and hemodynamic status. Nevertheless, excessive spontaneous breathing effort may trigger pendelluft phenomenon, augment regional lung strain and precipitate patient-self-inflicted lung injury (P-SILI). To date, the safe intensity range of spontaneous breathing during APRV for moderate-to-severe ARDS patients has not been well defined.

This single-center, randomized 3-period crossover self-controlled physiological trial enrolls ICU adult patients aged 18-80 years, diagnosed with moderate-to-severe ARDS (PaO₂/FiO₂ ≤ 150 mmHg) within 48-hours of invasive mechanical ventilation. After written informed consent obtained from legal surrogates, subjects will first receive a 60-minute baseline ventilation period following ARDSnet low-tidal-volume pressure-control ventilation strategy under deep sedation without spontaneous breathing. Subsequently, every participant will undergo three APRV intervention states in computer-generated random order: Condition A: APRV with low-intensity spontaneous breathing (spontaneous-contributed minute ventilation 10%-30%); Condition B: APRV with high-intensity spontaneous breathing (31%-50%); Condition C: APRV with fully suppressed spontaneous breathing via deep sedation (RASS -4 to -5). Each intervention maintains target spontaneous-breathing intensity for 30-minute stabilization before data collection. A mandatory 30-minute wash-out phase will be implemented between successive interventions to revert subjects back to baseline pressure-control ventilation and sedation status.

Primary endpoint is the comparison of ventilation-perfusion mismatch percentage (mismatch%, calculated as sum of dead-space fraction and shunt fraction) among three states measured by bedside EIT. Secondary endpoints contain multiple EIT quantitative indices, respiratory mechanics parameters (including esophageal-pressure-derived transpulmonary pressure), hemodynamic and right-ventricular function, diaphragmatic ultrasound indices, arterial blood gas variables. Adverse events related to respiratory, circulatory and operational procedures are closely monitored as safety outcomes.

Planned sample size is 14-16 enrolled participants to achieve 12 evaluable subjects completing all three intervention sequences considering dropout rate. All ventilator and sedation modifications are short-term and reversible; standard clinical therapeutic regimens will not be altered except for study-related procedures. After finishing all three intervention periods, ventilator and sedation settings will be returned to clinical team's discretion. Linear mixed-effect models will be applied for statistical analysis of crossover-design data.

Inclusion Criteria:

• 1. Age ≥18 and ≤80 years old. 2. Diagnosed with moderate-to-severe ARDS according to the 2023 global ARDS definition.

  3. Within 48 hours of invasive mechanical ventilation. After 1-hour low-tidal-volume pressure-controlled ventilation following ARDSnet strategy, arterial blood gas shows PaO₂/FiO₂ ≤ 150 mmHg.

  4. Written informed consent is obtained from the patient or their legal surrogate decision-maker after full explanation of the study by the principal investigator or authorized study physician.

Exclusion Criteria:

• 1. Refractory shock defined as persistent hyperlactatemia and/or prolonged capillary refill time, fluid-resistant, requiring norepinephrine ≥ 0.5 μg/kg/min.

  2. Severe chronic medical conditions severely affecting cardiopulmonary function: severe chronic obstructive pulmonary disease, interstitial lung disease, pulmonary embolism, right-heart failure, pulmonary hypertension, or severe arrhythmia.

  3. Radiologically confirmed bronchopleural fistula, status post lobectomy, or other major thoracic surgery.

  4. Contraindications to electrical impedance tomography (EIT): extensive chest skin injury or infection, implanted cardiac pacemaker or defibrillator, etc.

  5. Contraindications for esophageal manometry placement: esophageal obstruction, perforation, severe esophageal varices, etc.

  6. Diaphragmatic hernia, severe chest wall deformity, or significant pulmonary bullae.

  7. Significant coagulation abnormalities (PT or APTT prolonged ≥2 times upper limit of normal, or INR>2.0) with active bleeding risk.

  8. Severe intracranial hypertension (>20 mmHg), severe traumatic brain injury (GCS ≤8), or neuromuscular disorders.

  9. Pregnant or breastfeeding women. 10. Patients already receiving ECMO therapy. 11. Expected survival time <24 hours judged by attending physician. 12. Body mass index (BMI) >35 kg/m². 13. Previously enrolled in this study or participating in other interventional clinical trials.