Prone and Oscillation Pediatric Clinical Trial

Although acute respiratory distress syndrome is a life-threatening and frequent
problem experienced by thousands of children each year, little evidence
supports best ventilation practices during their critical illness. For over 25
years, pediatric critical care clinicians have debated the risk-benefit ratio
of supine versus prone positioning and conventional mechanical ventilation
(CMV) versus high-frequency oscillatory ventilation (HFOV).This debate has been
recently fueled by the completion of the Pediatric Acute Lung Injury Consensus
Conference Group (PALICC) guidelines noting the lack of high quality evidence
and the publication of three definitive adult-based studies with acute
respiratory distress syndrome (ARDS); specifically, one positive prone
positioning trial and two adult ARDS HFOV clinical trials -- one neutral and
one likely harmful.5-7 Without pediatric-specific data, the debate of how best
to care for children with severe Pediatric Acute Respiratory Distress Syndrome
(PARDS) will continue and prevent progress in the field.
Unique maturational differences prevent data generated in adults to be directly
applied to children. There are important differences in lung growth and
development, immune response and surfactant homeostasis. The scientific premise
supporting the potential benefits of prone positioning and HFOV are
well-grounded. Prone positioning augments ventilation (V) and perfusion (Q)
matching along the gravitational axis. Improved V/Q matching reduces the need
for potentially toxic levels of delivered oxygen and mean airway pressure. HFOV
is a mode of ventilation that takes advantage of hysteresis, maintaining the
lung open throughout the respiratory cycle, and aims to prevent the injurious
effects of volutrauma, atelectrauma and
potentially biotrauma that has been linked to multiple organ dysfunction
syndrome (MODS).It is unknown whether prone positioning and/or HFOV provides a
benefit in children with severe PARDS as compared to supine positioning and/or
a CMV strategy that delivers small tidal volumes.

The purpose of PROSpect (PRone and OScillation PEdiatric Clinical Trial) is to
provide evidence to support best ventilation practices in critically ill
children with severe PARDS defined per PALICC guidelines. We propose a
two-by-two factorial, response-adaptive, randomized controlled clinical trial
of supine/prone positioning and CMV/HFOV. Approximately 50 pediatric intensive
care units (PICUs), about 2/3 U.S. and 1/3 international, with at least 5 years
of experience with prone positioning and HFOV that can provide back-up
extracorporeal membrane oxygenation (ECMO) support, will participate. Eligible
patients with severe PARDS will be randomized within 48 hours of meeting
eligibility criteria and within 4 days of endotracheal intubation to one of
four groups: supine/CMV, prone/CMV, supine/HFOV or prone/HFOV. Subjects who
fail their assigned positional and/or ventilation therapy for either persistent
hypoxemia or hypercapnia may receive a 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 have powered
this study to detect a clinically
meaningful 2-day improvement in VFD. Up to 1,000 patients will be randomized,
stratified by age group (<1; 1-7; 8-17 years) and direct/indirect lung injury.
Adaptive randomization will first occur after 400 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.
PROSpect may close enrollment early for efficacy or futility based on
pre-specified stopping rules. Subjects will be monitored for safety and
followed until hospital discharge or hospital Day 90, whichever occurs
first. Data will be analyzed per intention-to-treat for the primary analyses
and per-protocol received for primary, secondary and exploratory analyses.

Specific Aims: In children with severe PARDS:
1. To compare the effects of prone positioning with supine positioning on
ventilator-free days.
2. To compare the effects of HFOV with CMV on ventilator-free days.
Hypothesis: Children with severe PARDS treated with prone positioning or HFOV
will
demonstrate more VFD.

Secondary: To compare the impact of these interventions on nonpulmonary organ
failure-free
days.
Hypothesis: Children with severe PARDS treated with prone positioning or HFOV
will
demonstrate more nonpulmonary organ failure-free days.

Exploratory: To explore the interaction effects of prone positioning with HFOV
on VFD and
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.

2 x 2 factorial randomized controlled adaptive design trial

Patients are randomized to one of four groups:
CMV + supine positioning
CMV + prone positioning
HFOV + supine positioning
HFOV + prone positioning

The burden is minimal as patients are deeply sedated and/or paralysed and
subjected to an intervention that is not uncommon in the intensive care unit.
The risk is moderate-to-high, as the study population includes children with
severe PARDS and there are inherent risks with both prone positioning and HFOV.
However, these risks of these interventions are comparable when a patient would
not bein the trial.