PROSpect: Prone and Oscillation Pediatric Clinical Trial

Study Overview
=================
Brief Summary
-----------------
Severe pediatric acute respiratory distress syndrome (PARDS) is a life-threatening and frequent problem experienced by thousands of children each year. Little evidence supports current supportive practices during their critical illness. The overall objective of this study is to identify the best positional and/or ventilation practice that leads to improved patient outcomes in these critically ill children. We hypothesize that children with high moderate-severe PARDS treated with either prone positioning or high-frequency oscillatory ventilation (HFOV) will demonstrate more days off the ventilator when compared to children treated with supine positioning or conventional mechanical ventilation (CMV).

Detailed Description
-----------------
PROSpect is a two-by-two factorial, response-adaptive, randomized controlled clinical trial of supine/prone positioning and conventional mechanical ventilation (CMV)/high-frequency oscillatory ventilation (HFOV). About 60 pediatric intensive care units (PICUs), two thirds U.S. and one third international, with at least 5 years of experience with prone positioning and HFOV in the care of pediatric patients with severe Pediatric Acute Respiratory Distress Syndrome (PARDS), that can provide back-up extracorporeal membrane oxygenation (ECMO) support, are participating. Eligible consecutive subjects with high moderate-severe PARDS will be randomized to one of four groups: supine/CMV, prone/CMV, supine/HFOV, prone/HFOV. Subjects who fail their assigned positional and/or ventilation therapy for either persistent hypoxia or hypercapnia may receive the reciprocal therapy while being considered for ECMO cannulation. Our primary outcome is ventilator-free days (VFD) through day 28, where non-survivors receive zero VFD. We hypothesize that children with severe PARDS treated with either prone positioning or HFOV will demonstrate ≥ 2 more VFD. Our secondary outcome is nonpulmonary organ failure-free days. We will also explore the interaction effects of prone positioning with HFOV on VFDs and also investigate the impact of these interventions on 90-day in-hospital mortality and, among survivors, the duration of mechanical ventilation, PICU and hospital length of stay, and the trajectory of post-PICU functional status and health-related quality of life (HRQL). Up to 800 subjects with severe PARDS will be randomized, stratified by age group and direct/indirect lung injury. Adaptive randomization will first occur after 300 patients are randomized and have been followed for 28 days, and every 100 patients thereafter. At these randomization update analyses, new allocation probabilities will be computed based on ongoing intention-to-treat trial results, increasing allocation to well performing arms and decreasing allocation to poorly performing arms. Data will be analyzed per intention-to-treat for the primary analyses and per-protocol received for primary, secondary and exploratory analyses.

Official Title
-----------------
PROSpect: Prone and Oscillation Pediatric Clinical Trial

Conditions
-----------------
Acute Respiratory Distress Syndrome in Children

Intervention / Treatment
-----------------
* Other: Either supine or prone positioning and either CMV or HFOV


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Intubated and mechanically ventilated with high moderate-severe PARDS for <48 hours per PALICC guidelines (chest imaging consistent with acute pulmonary parenchymal disease and OI ≥12 or OSI ≥10). We require two blood gases meeting moderate-severe PARDS criteria (separated by at least 4 ± 2 hours during which time the clinical team is actively working to recruit lung volume and optimize the patient's hemodynamic status per PALICC guidelines; specifically, incremental and decremental PEEP changes to optimize lung volume). A second blood gas is not required for OI ≥16. Exclusion criteria: Perinatal related lung disease Unrepaired congenital diaphragmatic hernia or congenital/acquired diaphragm paralysis Respiratory failure explained by cardiac failure or fluid overload Cyanotic heart disease Cardiomyopathy Unilateral lung disease Primary pulmonary hypertension Intubated for status asthmaticus Obstructive airway disease (e.g., Severe airways disease without parenchymal involvement or disease characterized by hypercapnia with FiO2 <0.30 and/or evidence of increased resistance visible on the flow - time scalar and/or presence of intrinsic PEEP) Active air leak Bronchiolitis obliterans Post hematopoietic stem cell transplant; specifically, patients receiving continuous supplemental oxygen for three or more days prior to intubation; receiving noninvasive ventilation for more than 24 hours prior to intubation; receiving more than one vasoactive medication at time of meeting inclusion criteria; spending more than four days in the PICU prior to intubation; supported on or with immediate plans for renal replacement therapies; with two or more allogeneic transplants; who relapsed after the transplant; or with diffuse alveolar hemorrhage Post lung transplant Home ventilator dependent with baseline Oxygen Saturation Index (OSI) >6 Neuromuscular respiratory failure Critical airway (e.g., post laryngotracheal surgery or new tracheostomy) or anatomical obstruction of the lower airway (e.g., mediastinal mass) Facial surgery or trauma in previous 2 weeks Head trauma (managed with hyperventilation) Intracranial bleeding Unstable spine, femur or pelvic fractures Open abdomen Currently receiving more than 6 consecutive hours of either prone positioning or HFOV Supported on ECMO during the current admission Family/medical team not providing full support (patient treatment considered futile) Previously enrolled in current study Enrolled in any other interventional clinical trial not approved for co-enrollment Known pregnancy

Ages Eligible for Study
-----------------
Minimum Age: 2 Weeks
Maximum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Two-by-two factorial, response-adaptive, randomized controlled clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supine / CMV<br>Supine positioning and conventional mechanical ventilation | Other: Either supine or prone positioning and either CMV or HFOV<br>* Supine positioning: Subjects randomized to supine positioning will remain supine. Prone positioning: Subjects randomized to prone positioning will be positioned prone ≥16 hours/day for a maximum of 28 days. CMV strategy: Low tidal volume to obtain exhaled Vt of 5-7 ml/kg (ideal body weight), PIP goal limited to ≤ 28 cm H2O and lung recruitment maneuver to identify best PEEP then maintained per PEEP-FiO2 grid. HFOV strategy: Frequency at 8-12 Hz, amplitude (delta-P) 60-90 and mPaw recruitment maneuver.<br>* Other names: High frequency oscillatory ventilation (HFOV);|
| Experimental: Prone / CMV<br>Prone positioning and conventional mechanical ventilation | Other: Either supine or prone positioning and either CMV or HFOV<br>* Supine positioning: Subjects randomized to supine positioning will remain supine. Prone positioning: Subjects randomized to prone positioning will be positioned prone ≥16 hours/day for a maximum of 28 days. CMV strategy: Low tidal volume to obtain exhaled Vt of 5-7 ml/kg (ideal body weight), PIP goal limited to ≤ 28 cm H2O and lung recruitment maneuver to identify best PEEP then maintained per PEEP-FiO2 grid. HFOV strategy: Frequency at 8-12 Hz, amplitude (delta-P) 60-90 and mPaw recruitment maneuver.<br>* Other names: High frequency oscillatory ventilation (HFOV);|
| Experimental: Supine / HVOF<br>Supine positioning and high-frequency oscillatory ventilation | Other: Either supine or prone positioning and either CMV or HFOV<br>* Supine positioning: Subjects randomized to supine positioning will remain supine. Prone positioning: Subjects randomized to prone positioning will be positioned prone ≥16 hours/day for a maximum of 28 days. CMV strategy: Low tidal volume to obtain exhaled Vt of 5-7 ml/kg (ideal body weight), PIP goal limited to ≤ 28 cm H2O and lung recruitment maneuver to identify best PEEP then maintained per PEEP-FiO2 grid. HFOV strategy: Frequency at 8-12 Hz, amplitude (delta-P) 60-90 and mPaw recruitment maneuver.<br>* Other names: High frequency oscillatory ventilation (HFOV);|
| Experimental: Prone / HFOV<br>Prone positioning and high-frequency oscillatory ventilation | Other: Either supine or prone positioning and either CMV or HFOV<br>* Supine positioning: Subjects randomized to supine positioning will remain supine. Prone positioning: Subjects randomized to prone positioning will be positioned prone ≥16 hours/day for a maximum of 28 days. CMV strategy: Low tidal volume to obtain exhaled Vt of 5-7 ml/kg (ideal body weight), PIP goal limited to ≤ 28 cm H2O and lung recruitment maneuver to identify best PEEP then maintained per PEEP-FiO2 grid. HFOV strategy: Frequency at 8-12 Hz, amplitude (delta-P) 60-90 and mPaw recruitment maneuver.<br>* Other names: High frequency oscillatory ventilation (HFOV);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-free Days (VFD) | Our primary research hypothesis is that children with severe PARDS randomized to either prone positioning or HFOV will demonstrate more ventilator-free days. We hypothesize that a superior treatment would improve VFD by at least 2 days, a clinically meaningful difference. VFD is the number of days within 28 days that a patient is alive and free of mechanical ventilation. Improvement in VFD will be considered within the context of patient safety; specifically, patients must also exhibit a similar safety profile. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nonpulmonary organ failure-free days (OFFD) | Our secondary research hypothesis is that children with severe PARDS randomized to either prone positioning or HFOV will demonstrate more more nonpulmonary organ failure-free days. OFFD is the number of days within 28 days that a patient is alive and free of clinically significant non-pulmonary organ failure. Nonpulmonary organ failure-free days will be calculated based on the clinically important nonpulmonary organ systems (neurologic, cardiovascular, renal and hematologic) using nonpulmonary PEdiatric Logistic Organ Dysfunction-2 (PELOD-20 scores. | 28 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pediatric Acute Respiratory Distress Syndrome (PARDS), Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, child, pediatric intensive care unit