Real-time Effort Driven VENTilator Management

Study Overview
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Brief Summary
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This study is a Phase II controlled clinical trial that will obtain comprehensive, serial assessments of respiratory muscle strength and architecture to understand the evolution of ventilator-induced respiratory muscle weakness in critically ill children, and test whether a novel computer-based approach (Real-time Effort Driven ventilator management (REDvent)) can preserve respiratory muscle strength and reduce time on MV. REDvent offers systematic recommendations to reduce controlled ventilation during the acute phase of MV, and uses real-time measures from esophageal manometry to adjust supported ventilator pressures such that patient effort of breathing remains in a normal range during the ventilator weaning phase. This phase II clinical trial is expected to enroll 276 children with pulmonary parenchymal disease, anticipated to be ventilated > 48 hrs. Patients will be randomized to REDvent-acute vs. usual care for the acute phase of MV (interval from intubation to first spontaneous breathing trial (SBT)). Patients in either group who fail their first Spontaneous Breathing Trial (SBT), will also be randomized to REDvent-weaning vs. usual care for the weaning phase of MV (interval from first SBT to passing SBT). The primary clinical outcome is length of weaning (time from first SBT until successful passage of an SBT or extubation (whichever comes first)). Mechanistic outcomes surround multi-modal serial measures of respiratory muscle capacity (PiMax), load (resistance, compliance), effort (esophageal manometry), and architecture (ultrasound) throughout the course of MV. Upon completion, this study will provide important information on the pathogenesis and timing of respiratory muscle weakness during MV in children and whether this weakness can be mitigated by promoting more normal patient effort during MV via the use of REDvent. This will form the basis for a larger, Phase III multi-center study, powered for key clinical outcomes such as 28-day Ventilator Free Days.

Detailed Description
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Study Aims: SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the duration of weaning from MV (Primary outcome). SA2: To determine if changes to direct measures of respiratory muscle strength, load, effort, and architecture throughout the duration of MV are related to weaning outcomes. SA3: To determine if patient effort of breathing during both acute and weaning phases of MV is independently associated with the development of respiratory muscle weakness. Study Design: Single-center randomized controlled trial (138 children per arm) using REDvent (intervention arm) as compared with usual care ventilator management including a standardized daily SBT (control arm). Acute phase randomization will occur upon study enrollment, and patients who fail the first SBT will undergo a weaning phase randomization. The investigators will obtain serial measurements of respiratory system capacity, load, effort of breathing, and diaphragm architecture throughout the course of MV. Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT). Intervention Arm (REDvent-acute): Patients will be managed with pressure control plus pressure support ventilation using a computerized decision support tool that will recommend changes to ventilator settings approximately every 4 hr (with or without a new blood gas). If the patient is spontaneously breathing, it will incorporate real-time measures of effort of breathing (esophageal manometry) to keep it in a target range. Control Arm (Control-acute): Ventilator management will be per usual care until the patient meets weaning criteria and passes the oxygenation test. Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Intervention Arm (REDvent-weaning): Patients will be managed in a pressure support/CPAP mode of ventilation with assessments or changes to the level of pressure support every 4 hours, targeting maintaining effort of breathing (esophageal manometry) in a normal range. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT. Control Arm (Control-weaning): Ventilator management will be per usual care. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT. Analysis Plan and Sample Size Justification: Aim 1: The primary outcome is weaning duration. Sample size has been determined to adequately power 3 separate comparative analyses: (a) REDvent-acute versus Acute Phase control (b) REDvent-weaning phase versus Weaning Phase control (c) REDvent both phases versus control both phases. Power is based on 2 planned methods for analysis: cox proportional hazard ratios for multivariable analysis and univariate analysis with an independent t-test using log transformation (as needed) to account for the expected distribution of weaning duration. For all three of the planned comparisons above, with the proposed sample size the investigators would be adequately powered (>0.8) to detect a difference in weaning duration of ≥ 1 day, or a hazard ratio of ≥ 1.4 between groups. The secondary outcomes are ventilator free days and extubation failure. Directly comparing control only patients to REDvent only patients, with an expected standard deviation for VFDs between 5 to 9 days, the investigators will be able to detect a 2-day change in VFDs between groups with a power between 0.35 and 0.82. Re-intubation rates are expected to be 10%, allowing the investigators to confirm that REDvent is not inferior to usual care in regards to re-intubation with a non-inferiority margin of 0.10 with a power of 0.8 and alpha of 0.05. Aim 2: The primary outcome of this aim is weaning duration. For respiratory muscle strength the investigators will compare the first measured aPiMax (after resolution of the acute phase, before the first SBT), the trajectory and value of the daily aPiMax during the weaning phase prior to extubation, the lowest and highest measured aPiMax, and aPiMax on the day of extubation against weaning duration. For analysis, aPiMax will be dichotomized at 30 cmH2O, and weaning duration will be compared between patients with aPiMax > 30 versus ≤ 30 cmH2O using a t-test with or without log-transformation, or Mann-Whitney U test, depending on the distribution. From preliminary data, it is anticipated at least 35% of patients (n=84) will have aPiMax ≤ 30 cmH2O. Based on a similar power analysis as presented above, this would allow the investigators to determine whether low aPiMax is associated with a ≥ 1-day increase in weaning duration, with an alpha of 0.05 and power of 0.8. The investigators will perform identical analysis for ePiMax. Diaphragm Thickness analysis will compound daily ultrasound measures to detect the relative change in diaphragm thickness from study day 1 until passage of an SBT. The investigators will compare the change in thickness after resolution of the acute phase (on the day of the first SBT) against weaning duration, in a similar manner as proposed above for aPiMax. In addition to weaning duration, the investigators will also examine whether the respiratory measures taken just prior to or during each SBT are associated with the patient passing the SBT. For example with aPiMax and ePiMax, the investigators will examine if there is a dose response relationship between PiMax measured just before the SBT and the rate of passage of the subsequent SBT. Aim 3: The primary outcome of this aim is aPiMax < 30 cmH2O.The analysis will focus on determining whether the degree of patient effort of breathing is independently associated with the development of respiratory muscle weakness. For the acute phase, the investigators will generate a time-weighted average PRP during the acute phase and graph it against aPiMax at the first SBT. They will subsequently dichotomize aPiMax at the first SBT and compare mean time weighted average PRP in the acute phase between aPiMax groups (> 30 vs. ≤ 30 cmH2O). For the weaning phase, the investigators will graph the changes in aPiMax throughout the weaning phase (from first failed SBT until successful SBT) against time-weighted average PRP, with the anticipation that low PRP will be associated with either further reductions in aPiMax, or no improvement, while PRP in the physiologic range of 150-400 will be associated with improvement in aPiMax. The investigators will subsequently dichotomize aPiMax (at 30 cm H2O) at the time of successful passage of an SBT and compare time-weighted average PRP in the weaning phase between aPiMax groups. Subsequently, the investigators will build a multivariable logistic regression model on the outcome of aPiMax ≤ 30 cmH2O to determine if time-weighted PRP in the acute phase, weaning phase or both have an independent association with preserving aPiMax, after controlling for confounding variables.

Official Title
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Identifying and Preventing Ventilator Induced Diaphragm Dysfunction in Children

Conditions
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Ventilation Therapy; Complications, Diaphragm Disease, Pediatric Respiratory Diseases

Intervention / Treatment
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* Other: Computerized Ventilator Protocol
* Diagnostic Test: Esophageal Manometry
* Diagnostic Test: Respiratory Inductance Plethysmography (RIP)
* Diagnostic Test: Diaphragm Ultrasound
* Diagnostic Test: Maximal Inspiratory Pressure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children > 1 month (>44 weeks CGA) and ≤ 18 years of age AND Supported on mechanical ventilation with pulmonary parenchymal disease (i.e., pneumonia, bronchiolitis, Pediatric Acute Respiratory Distress Syndrome (PARDS)) with Oxygen Saturation Index (OSI) ≥ 5 or Oxygenation Index (OI) ≥) AND Who are within 48 hours of initiation of invasive mechanical ventilation (allow for up to 72 hours for those transferred from another institution) Exclusion Criteria: Contraindications to use of an esophageal catheter (i.e. severe mucosal bleeding, nasal encephalocele, transphenoidal surgery) OR Contraindications to use of RIP bands (i.e. omphalocele, chest immobilizer or cast) OR Conditions precluding diaphragm ultrasound measurement (i.e. abdominal wall defects, pregnancy) OR Conditions on enrollment that preclude conventional methods of weaning (i.e., status asthmaticus, severe lower airway obstruction, critical airway, intracranial hypertension, Extra Corporeal Life Support (ECLS), intubation for UAO, DNR, severe chronic respiratory failure, spinal cord injury above lumbar region, cyanotic heart disease (unrepaired or palliated)) OR Primary Attending physician refuses (will be cleared with primary attending before approaching the patient).

Ages Eligible for Study
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Minimum Age: 30 Days
Maximum 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized Controlled Trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: REDvent-acute<br>Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT). Patients will be managed with pressure control plus pressure support ventilation using a computerized decision support tool that will recommend changes to ventilator settings approximately every 4 hr (with or without a new blood gas). If the patient is spontaneously breathing, it will incorporate real-time measures of effort of breathing (esophageal manometry) to keep it in a target range. | Other: Computerized Ventilator Protocol<br>* Computerized Decision Support System which recommends changes to ventilator settings to promote physiologic levels of patient effort of breathing.<br>Diagnostic Test: Esophageal Manometry<br>* Esophageal Manometry Catheter to measure effort of breathing an transpulmonary pressure<br>Diagnostic Test: Respiratory Inductance Plethysmography (RIP)<br>* RIP bands to measure thoraco-abdominal synchrony during spontaneous breathing trials<br>Diagnostic Test: Diaphragm Ultrasound<br>* Daily measurement of diaphragm thickness and diaphragm contractile activity<br>Diagnostic Test: Maximal Inspiratory Pressure<br>* Prior to Spontaneous breathing trials, measurement of airway and esophageal maximal inspiratory pressure during airway occlusion<br>|
| Placebo Comparator: Control-acute<br>Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT). Ventilator management will be per usual care until the patient meets weaning criteria and passes the oxygenation test. | Diagnostic Test: Esophageal Manometry<br>* Esophageal Manometry Catheter to measure effort of breathing an transpulmonary pressure<br>Diagnostic Test: Respiratory Inductance Plethysmography (RIP)<br>* RIP bands to measure thoraco-abdominal synchrony during spontaneous breathing trials<br>Diagnostic Test: Diaphragm Ultrasound<br>* Daily measurement of diaphragm thickness and diaphragm contractile activity<br>Diagnostic Test: Maximal Inspiratory Pressure<br>* Prior to Spontaneous breathing trials, measurement of airway and esophageal maximal inspiratory pressure during airway occlusion<br>|
| Experimental: REDvent-weaning<br>Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Patients will be managed in a pressure support/CPAP mode of ventilation with assessments or changes to the level of pressure support every 4 hours, targeting maintaining effort of breathing (esophageal manometry) in a normal range. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT. | Other: Computerized Ventilator Protocol<br>* Computerized Decision Support System which recommends changes to ventilator settings to promote physiologic levels of patient effort of breathing.<br>Diagnostic Test: Esophageal Manometry<br>* Esophageal Manometry Catheter to measure effort of breathing an transpulmonary pressure<br>Diagnostic Test: Respiratory Inductance Plethysmography (RIP)<br>* RIP bands to measure thoraco-abdominal synchrony during spontaneous breathing trials<br>Diagnostic Test: Diaphragm Ultrasound<br>* Daily measurement of diaphragm thickness and diaphragm contractile activity<br>Diagnostic Test: Maximal Inspiratory Pressure<br>* Prior to Spontaneous breathing trials, measurement of airway and esophageal maximal inspiratory pressure during airway occlusion<br>|
| Placebo Comparator: Control-weaning<br>Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Ventilator management will be per usual care. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT. | Diagnostic Test: Esophageal Manometry<br>* Esophageal Manometry Catheter to measure effort of breathing an transpulmonary pressure<br>Diagnostic Test: Respiratory Inductance Plethysmography (RIP)<br>* RIP bands to measure thoraco-abdominal synchrony during spontaneous breathing trials<br>Diagnostic Test: Diaphragm Ultrasound<br>* Daily measurement of diaphragm thickness and diaphragm contractile activity<br>Diagnostic Test: Maximal Inspiratory Pressure<br>* Prior to Spontaneous breathing trials, measurement of airway and esophageal maximal inspiratory pressure during airway occlusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Duration of Weaning | Time from first attempted SBT until SBT passage or extubation [whichever comes first] | First 28 days of Mechanical Ventilation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Ventilator Free Days | Days alive and not on mechanical ventilation | 28 and 60 days | 
| Number of Participants with Extubation Failure | re-intubation or use of non invasive ventilation | 7 days after extubation | 
| Number of Participants with Mortality | Death | Through study completion up to maximum of 90 Days | 
| Median Maximal Inspiratory Airway Pressure During Airway Occlusion (aPiMax) | Measured during standardized airway occlusion maneuvers | Each day after passing oxygenation test through extubation up to a maximum of 28 days | 
| Median Maximal Inspiratory Esophageal Pressure During Airway Occlusion (ePiMax) | Measured during standardized airway occlusion maneuvers | Each day after passing oxygenation test through extubation up to a maximum of 28 days | 
| Median Change in diaphragm thickness on Exhalation (Dte) from baseline | From daily ultrasound measurement | Each day from study initiation until extubation up to a maximum of 28 days |