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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
15
APRV ventilation mode, spontaneous-contributed minute-ventilation proportion maintained at 10%-30%. 30-minute stabilization before outcome measurement.
APRV ventilation mode, spontaneous-contributed minute-ventilation proportion maintained at 31%-50%. 30-minute stabilization before outcome measurement.
APRV ventilation mode, spontaneous breathing fully suppressed by deep sedation (RASS-4 to -5). 30-minute stabilization before outcome measurement.
Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China
Ventilation-perfusion mismatch percentage (Mismatch%)
Ventilation-perfusion mismatch percentage (Mismatch%), calculated as the sum of dead-space percentage and shunt percentage measured by electrical impedance tomography (EIT). A composite index reflecting overall ventilation-perfusion mismatch, assessed at baseline and under three APRV experimental conditions. Unit: %
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Match percentage(match%)
Match percentage derived from electrical impedance tomography (EIT). Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Pendelluft amplitude
Pendelluft amplitude derived from electrical impedance tomography (EIT). Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Dead-space percentage
Dead-space percentage derived from electrical impedance tomography (EIT), assessed at baseline and under three APRV experimental conditions. Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Shunt percentage
Intrapulmonary shunt percentage derived from electrical impedance tomography (EIT), assessed at baseline and under three APRV experimental conditions. Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Global inhomogeneity index (GI)
Global inhomogeneity index (GI) derived from electrical impedance tomography (EIT). Unit: unitless.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period
Center of ventilation (CoV)
Center of ventilation (CoV) derived from electrical impedance tomography (EIT), assessed at baseline and under three APRV experimental conditions. Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Tidal recruitment-derecruitment
Tidal recruitment-derecruitment (Tidal R/D) derived from electrical impedance tomography (EIT), assessed at baseline and under three APRV experimental conditions. Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Ventilation distribution
Regional ventilation distribution derived from electrical impedance tomography (EIT), assessed at baseline and under three APRV experimental conditions. Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Perfusion distribution
Regional pulmonary perfusion distribution derived from electrical impedance tomography (EIT), assessed at baseline and under three APRV experimental conditions. Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Peak airway pressure (Ppeak)
Airway peak pressure (Ppeak) measured by mechanical ventilator, assessed at baseline and under three APRV experimental conditions. Unit: cmH₂O
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Plateau pressure (Pplat)
Airway plateau pressure (Pplat) obtained from end-inspiratory hold maneuver, assessed at baseline and under three APRV experimental conditions. Unit: cmH₂O.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Driving pressure (ΔP)
Driving pressure (ΔP) derived from mechanical ventilator measurements. Unit: cmH₂O.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Static respiratory system compliance (Cstat)
Static respiratory system compliance (Cstat), assessed at baseline and under three APRV experimental conditions. Unit: mL/cmH₂O.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
End-inspiratory esophageal pressure (PesI)
End-inspiratory esophageal pressure (PesI) measured by esophageal manometry, assessed at baseline and under three APRV experimental conditions. Unit: cmH₂O.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
End-expiratory esophageal pressure (PesE)
End-expiratory esophageal pressure (PesE) measured by esophageal manometry, assessed at baseline and under three APRV experimental conditions. Unit: cmH₂O
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Esophageal pressure swing (ΔPes)
Esophageal pressure swing (ΔPes) measured by esophageal manometry, assessed at baseline and under three APRV experimental conditions. Unit: cmH₂O.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
End-inspiratory transpulmonary pressure (PtpI)
End-inspiratory transpulmonary pressure (PtpI) derived from airway and esophageal pressure measurements. Unit: cmH₂O.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Transpulmonary driving pressure (ΔPtp)
Transpulmonary driving pressure (ΔPtp) derived from airway and esophageal pressure measurements. Unit: cmH₂O.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
End-expiratory transpulmonary pressure (PtpE)
End-expiratory transpulmonary pressure (PtpE) derived from airway and esophageal pressure, assessed at baseline and under three APRV experimental conditions. Unit: cmH₂O.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Esophageal pressure-time product per minute (PTPes/min)
Esophageal pressure-time product per minute (PTPes/min) read directly from the ventilator interface. Unit: cmH₂O·s/min.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Dynamic transpulmonary driving pressure (ΔPL,dyn)
Dynamic transpulmonary driving pressure (ΔPL,dyn) obtained from ventilator measurements; only measured in the presence of spontaneous breathing effort. Unit: cmH₂O.
Time frame: At the end of each 30-minute APRV experimental condition (after stabilization)
Inspiratory muscle pressure (Pmus)
Inspiratory muscle pressure (Pmus) obtained from ventilator measurements; only measured in the presence of spontaneous breathing effort. Unit: cmH₂O
Time frame: At the end of each 30-minute APRV experimental condition (after stabilization)
End-expiratory occlusion pressure (ΔPocc)
End-expiratory occlusion pressure (ΔPocc) obtained from ventilator measurements; only measured in the presence of spontaneous breathing effort. Unit: cmH₂O
Time frame: At the end of each 30-minute APRV experimental condition (after stabilization)
Airway occlusion pressure (P0.1)
Airway occlusion pressure (P0.1) obtained from ventilator measurements; only measured in the presence of spontaneous breathing effort. Unit: cmH₂O
Time frame: At the end of each 30-minute APRV experimental condition (after stabilization)
Muscular pressure index (PMI)
Muscular pressure index (PMI) obtained from ventilator measurements; only measured in the presence of spontaneous breathing effort. Unit: cmH₂O
Time frame: At the end of each 30-minute APRV experimental condition (after stabilization)
Negative inspiratory force (NIF)
Negative inspiratory force (NIF) obtained from ventilator measurements; only measured in the presence of spontaneous breathing effort. Unit: cmH₂O
Time frame: At the end of each 30-minute APRV experimental condition (after stabilization)
Heart rate
Heart rate from continuous bedside monitoring, assessed at baseline and under three APRV experimental conditions. Unit: beats per minute.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Mean arterial pressure (MAP)
Mean arterial pressure (MAP) measured via invasive arterial catheter, assessed at baseline and under three APRV experimental conditions. Unit: mmHg.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Vasopressor dosage (μg/kg/min)
Dosage of vasoactive medications, assessed at baseline and under three APRV experimental conditions. Unit: μg/kg/min
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Central venous pressure (CVP)
Central venous pressure (CVP), assessed at baseline and under three APRV experimental conditions. Unit: mmHg.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Right-ventricular fractional area change
Right-ventricular fractional area change measured by transthoracic echocardiography, assessed at baseline and under three APRV experimental conditions. Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Velocity-time-integral (VTI)
Velocity-time-integral (VTI) measured by transthoracic echocardiography, assessed at baseline and under three APRV experimental conditions. Unit: cm.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Tricuspid annular plane systolic excursion (TAPSE)
Tricuspid annular plane systolic excursion (TAPSE) measured by transthoracic echocardiography, assessed at baseline and under three APRV experimental conditions. Unit: mm.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Cardiac output (CO)
Cardiac output (CO) calculated from velocity-time integral (VTI) measured by transthoracic echocardiography, assessed at baseline and under three APRV experimental conditions. Unit: L/min.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Stroke volume (SV)
Stroke volume (SV) calculated from velocity-time-integral (VTI) measured by transthoracic echocardiography, assessed at baseline and under three APRV experimental conditions. Unit: mL.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Diaphragm displacement
Diaphragm displacement measured by bedside diaphragm ultrasound, assessed in two out of the three APRV experimental conditions only when spontaneous breathing was present. Unit: mm.
Time frame: At the end of 30-minute APRV experimental conditions with spontaneous breathing effort (after stabilization)
Diaphragm thickening fraction
Diaphragm thickening fraction measured by bedside diaphragm ultrasound, assessed in two out of the three APRV experimental conditions only when spontaneous breathing was present. Unit: %.
Time frame: At the end of 30-minute APRV experimental conditions with spontaneous breathing effort (after stabilization)
Lung 12-zone ultrasound score
Lung ultrasound score based on 12-zone lung ultrasound assessment, assessed at baseline and under three APRV experimental conditions. Unit: unitless.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Overdistension (OD) pixel count
Pixel count of lung overdistension (OD), exported directly from electrical impedance tomography (EIT) software basic module, averaged over complete respiratory cycles within selected time interval, measured at baseline (prior to intervention, after stabilization) and at the end of each 30-minute APRV experimental condition (after stabilization). Unit: pixels.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Overdistension (OD) proportion
Proportion of lung overdistension (OD) relative to total lung-region pixels, exported directly from electrical impedance tomography (EIT) software basic module, averaged over complete respiratory cycles within selected time interval, measured at baseline (prior to intervention, after stabilization) and at the end of each 30-minute APRV experimental condition (after stabilization). Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Recruitment (CR) pixel count
Pixel count of lung recruitment (CR), exported directly from electrical impedance tomography (EIT) software basic module, averaged over complete respiratory cycles within selected time interval, measured at baseline (prior to intervention, after stabilization) and at the end of each 30-minute APRV experimental condition (after stabilization). Unit: pixels.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Recruitment (CR) proportion
Proportion of lung recruitment (CR) relative to total lung-region pixels, exported directly from electrical impedance tomography (EIT) software basic module, averaged over complete respiratory cycles within selected time interval, measured at baseline (prior to intervention, after stabilization) and at the end of each 30-minute APRV experimental condition (after stabilization). Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Atelectasis (AT) pixel count
Pixel count of lung atelectasis (AT), exported directly from electrical impedance tomography (EIT) software basic module, averaged over complete respiratory cycles within selected time interval, measured at baseline (prior to intervention, after stabilization) and at the end of each 30-minute APRV experimental condition (after stabilization). Unit: pixels.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
Atelectasis (AT) proportion
Proportion of lung atelectasis (AT) relative to total lung-region pixels, exported directly from electrical impedance tomography (EIT) software basic module, averaged over complete respiratory cycles within selected time interval, measured at baseline (prior to intervention, after stabilization) and at the end of each 30-minute APRV experimental condition (after stabilization). Unit: %.
Time frame: Baseline and at the end of each 30-minute experimental condition during the study intervention period.
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