Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation: The PROMIZING Study

Study Overview
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Brief Summary
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For adult patients with acute respiratory failure requiring invasive mechanical ventilation, does a ventilation strategy using proportional assist ventilation with load-adjustable gain factors (PAV+) result in a shorter duration of time spent on mechanical ventilation than a ventilation strategy using pressure support ventilation (PSV)?

Detailed Description
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Patients with acute respiratory failure require mechanical ventilation to help them breathe until they recover from their acute illness. Although mechanical ventilation is necessary to sustain life in such situations, it can induce weakness of the respiratory muscles which may lead to prolonged dependence on the ventilator. Prolonged dependence on mechanical ventilation is associated with increased mortality, morbidity and costs to the healthcare system. Thus, a main goal of assisted mechanical ventilation is to reduce the patient's respiratory distress while maintaining some respiratory muscle activity. To attain this goal, the amount of ventilator assistance should theoretically be adjusted to target normal or reasonable levels of respiratory effort. Modes of Mechanical Ventilation: Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mode of mechanical ventilation which delivers assistance to breathe in proportion to the patient's effort. The proportional assistance, called the gain, can be adjusted by the clinician to maintain the patient's respiratory effort or workload within a reasonable range. This is the only mode of ventilation which allows for measurement and targeting of a specific range of respiratory muscle activity by the patient. Pressure support ventilation (PSV) is a mode of ventilation which is considered the current standard of care for assisting breathing of patients during the recovery phase of acute respiratory failure. Several studies have shown short term advantages of PAV over PSV, including improved patient-ventilator synchronization, improved adaptability to changes in patient effort, and improved sleep quality. Goal of this Randomized Controlled Trial: To demonstrate that for patients with acute respiratory failure, ventilation with PAV+, being more physiological, will result in a shorter duration of time spent on mechanical ventilation than ventilation with PSV.

Official Title
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Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation: The PROMIZING Study

Conditions
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Critically Ill, Acute Respiratory Failure

Intervention / Treatment
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* Other: PSV ventilation strategy
* Other: PAV+ ventilation strategy


Participation Criteria
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Eligibility Criteria
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A staged enrolment process will be used to identify patients eligible to be enrolled and randomized in the study. At each stage of the enrolment process, a patient must meet inclusion criteria and not meet exclusion criteria in order to pass. To progress to the next stage, patients must continue to pass criteria from the prior stages. After enrolment, there are also specific tests to perform (with pass/fail criteria) to determine eligibility to be randomized. A. SCREENING INCLUSION CRITERIA: A1. Age 18 years or older A2. Intubated and receiving any mode of invasive mechanical ventilation ≥ 24 hours A. SCREENING EXCLUSION CRITERIA: A3. Anticipating withdrawal of life support and/or shift to palliation as the goal of care A4. Severe central neurologic disorder (eg. Hemorrhage, stroke, tumour) causing elevated intracranial pressure, or impaired control of breathing, or requiring specific ventilator adjustments (i.e. To attain specific CO2 target) or requiring neurosurgical intervention A5. Known or suspected severe or progressive neuromuscular disorder likely to result in prolonged or chronic ventilator dependence (eg. Guillain-Barré syndrome, Myasthenia Gravis, ALS, MS, high spinal cord injury, kyphoscoliosis or other restrictive disorder) (Note that obesity hypoventilation syndrome that may be managed with nocturnal non-invasive ventilation is NOT an exclusion under A5) A6. Severe COPD: Baseline daytime hypercapnea (pCO2> 50 mmHg) OR GOLD 4 airflow limitation (FEV1<30% predicted) OR MRC class 4 symptoms (I am too breathless to leave the house OR I am breathless when dressing) A7. Broncho-pleural fistula A8. Tracheostomy present at ICU admission for the purpose of chronic or prolonged mechanical ventilation (>21 days). (Note that a patient who was endotracheally intubated for acute respiratory failure and received a tracheostomy during their ICU admission, prior to enrolment, is not excluded under A8). A9. Current enrolment in a confounding study, as assessed by the steering committee A10. Previous randomization in the PROMIZING Study A11. Severe, end-stage, irreversible respiratory or cardiac disease (e.g. interstitial lung disease, pulmonary fibrosis, cardiomyopathy, valvulopathy) likely to result in prolonged or chronic ventilator dependence /unlikely to wean from mechanical ventilation [Note: patients who are candidates for intervention to treat the underlying respiratory/cardiac disease (e.g. lung transplant, heart transplant, cardiac surgery) may be re-evaluated once intervention is complete and they no longer meet criteria A11.] B. ENROLMENT INCLUSION CRITERIA: B1. Ability or potential ability to trigger ventilator breaths (i.e. not receiving neuromuscular blockade). B2. On Assist/Control volume-cycled ventilation: Technically satisfactory plateau pressure ≤ 30 cm H2O (see Operations Manual) OR On Assist/Control pressure-controlled ventilation or similar mode: Pressure control plus PEEP ≤ 30 cm H2O OR On Pressure Support ventilation: Pressure support plus PEEP ≤ 30 cm H2O OR On Proportional Assist ventilation: PAV gain <85% B3. PaO2 ≥ 60 mmHg or SpO2 ≥ 90% on FiO2 ≤ 0.60 and PEEP ≤ 15 cm H2O B4. Metabolic disorders corrected: pH ≥7.32 B5. Stable hemodynamic status: stable or decreasing doses of vasopressors for ≥6 hours B6. Anticipate ongoing need for ventilation >24 hours B. ENROLMENT EXCLUSION CRITERIA: B7. Extubated B8. Died B9. Patient has met enrolment inclusion criteria B1-B5 AND has tolerated pressure support of 0-20 cm H2O or proportional assist ventilation of 0-85% for ≥24 consecutive hours (including time on CPAP, t-piece, or tracheostomy mask). (Note (1): that it is acceptable to include a patient who has been tried on pressure support or proportional assist ventilation but has required pressures >20 cmH2O or assistance >85% or has required return to A/C ventilation within the 24 hour time window; Note (2): B9 does not apply to patients on ECMO.) B10. Patient transferred to a non-participating centre B. ENROLMENT DEFERRAL CRITERIA: B11. Plan to extubate/discontinue mechanical ventilation within <24 hours (Reassess within 24 hours) B12. Patient currently on ECMO (Reassess patient once off ECMO) C9: Plan for surgery or complex procedure that will require full ventilation to be done prior to attempting extubation (e.g. Procedure requiring neuromuscular blockade and/or heavy sedation, such that patient would be apneic, or not be able to trigger ventilator) (Reassess after surgery/procedure complete) C. PRESSURE SUPPORT TRIAL INCLUSION CRITEIRA: C2. Upon review of Screening and Enrolment criteria (A and B), the patient still passes. C3. Treating physician has provided verbal consent to proceed with standardized tests and randomization if eligibility criteria are met. C. PRESSURE SUPPORT TRIAL DEFERRAL CRITERIA: C6. High dose vasopressor requirements (i.e. epinephrine or norepinephrine >0.5 ug/kg/min or equivalent) OR patient requiring an increase in dose of vasopressor within 6 hrs C7. Active cardiac ischemia (dynamic ST changes on monitor or ECG within 6 hours) C8. Unstable arrhythmias (HR>140 or <50) with clinical signs of low cardiac output or or SBP<80 mmHg C10. Receiving a strict lung protective ventilation strategy for ARDS (eg. Order on chart to keep Vt ≤6 mL/kg PBW) C. PRESSURE SUPPORT TRIAL EXCLUSION CRITERIA: • C12. Treating physician has declined consent D. WEANING CRITERIA: D1. SpO2≥ 90% on FiO2 ≤0.40 and PEEP ≤8 cmH2O D2. pH ≥7.32 D3. Vasopressor requirements no higher than norepinephrine 0.1 ug/kg/min or equivalent. In the final stage (E), patients will be considered eligible for randomization if the following criteria are met. E. RANDOMIZATION INCLUSION CRITERIA: C1. Patient/SDM has provided consent OR Plan to obtain deferred consent as Patient incapable and no SDM available to provide consent within the randomization window E1. Upon review of Criteria A, B, and C, the patient still passes and the patient has passed the PST. E2. Does not meet Weaning Criteria OR Fails the ZERO CPAP Trial OR Fails the SBT E. RANDOMIZATION EXCLUSION CRITERIA: B9. Patient has met enrolment inclusion criteria B1-B5 AND has tolerated pressure support of 0-20 cm H2O or proportional assist ventilation of 0-85% ≥24 consecutive hours (including time on CPAP, t-piece, or tracheostomy mask). Note (1): It is acceptable to include a patient who has been tried on pressure support or proportional assist ventilation but has required pressures >20 cmH2O or assistance >85% or has required return to A/C ventilation within the 24 hour time window; Note (2): B9 does not apply to patients while on ECMO C4. Patient/SDM has declined consent C5. Patient incapable and no SDM available to provide consent (not applicable if plan to obtain deferred consent) E3. Passed SBT on t-piece, FiO2 0.40 for 30-120 minutes E4. Approval withdrawn (by physician or patient/SDM)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PSV ventilation strategy<br>The control is the standard of care PSV ventilation strategy, designed to adjust the level of support according to usual clinical parameters. | Other: PSV ventilation strategy<br>* An algorithm for adjusting the level of pressure support according to usual clinical parameters; patients not tolerating PSV will be switched to Assist/Control mode according to predefined criteria<br>|
| Active Comparator: PAV+ ventilation strategy<br>The intervention is a PAV+ ventilation strategy, designed to adjust the level of support (gain) to target a predefined range of respiratory muscle pressure. | Other: PAV+ ventilation strategy<br>* An algorithm for adjusting the level of support (gain) to maintain a predefined range of respiratory muscle pressure; patients not tolerating PAV+ (Puritan Bennett™ 840 or 980 ventilator) will be switched to Assist/Control mode according to predefined criteria<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from randomization to successful liberation from invasive mechanical ventilation. | Successful liberation is defined as removal of the endotracheal tube AND remaining alive with no need for reintubation/reinstitution of invasive mechanical ventilation for 7 days post extubation, or until successful ICU discharge, or until live hospital discharge, whichever comes first. | up to 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-free days at 14, 21 and 28 days post randomization | Ventilator-free days (VFDs) are defined as the number of days alive and free of INVASIVE ventilation post SUCCESSFUL EXTUBATION or post successful termination of invasive mechanical ventilation (MV) from time of randomization to day 21 post randomization. Successful extubation is defined as removal of the endotracheal tube AND remaining alive with no need for reintubation/reinstitution of invasive mechanical ventilation for 7 days post extubation, or until successful ICU discharge, or until live hospital discharge, whichever comes first. | 14, 21 and 28 days post randomization | 
| Time from randomization to live ICU discharge (up to day 90) | Patients will remain in the study and will continue on the assigned ventilation strategy until: successful extubation, successful ICU discharge, live hospital discharge, death, or 90 days post randomization, whichever comes first. | up to 90 days | 
| Time from randomization to live hospital discharge (up to day 90) | Patients will remain in the study and will continue on the assigned ventilation strategy until: successful extubation, successful ICU discharge, live hospital discharge, death, or 90 days post randomization, whichever comes first. | up to 90 days | 
| Mortality | Measured as ICU mortality; hospital mortality; 14, 21, 28, and 90 day mortality | up to 90 days | 
| Weaning Progress | Measured as time from randomization to: first SBT; first successful SBT; first extubation | up to 90 days | 
| Weaning Difficulties | Measured as the number of patients failing first SBT or first extubation attempt and requiring up to 7 days to extubate (difficult weaning group/group 2); failing first SBT or first extubation attempt and requiring more than 7 days to extubate (prolonged weaning group/group 3) | 90 days | 
| Weaning Complications | Measured as the number of patients: requiring non-invasive ventilation post-extubation; ventilated more than 7 days post randomization, ventilated more than 21 days from time of intubation (prolonged MV group); receiving tracheostomy post-randomization, requiring re-intubation (up to 7d after planned extubation) | 90 days | 
| Tolerance of modes | Measured as number of patients ever requiring A/C mode post randomization; number of patient-days requiring A/C mode post randomization | 90 days | 
| Cumulative dose of narcotics (converted to morphine equivalents); benzodiazepines (converted to midazolam equivalents); propofol, and dexmedetomidine | These are measures of sedation | 90 days | 
| Number of patients and number of patient-days receiving any antipsychotic medication | This is a surrogate measure of delirium | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Proportional Assist Ventilation, Pressure Support Ventilation, Weaning