2. Work in Progress!
Please note that this slide deck was created as a study recruitment tool and should not be used without permission from Dr. Martha Curley.
These slides reflect our thinking as of June 13, 2017 and will likely change as we continue to refine the study protocol.

3. Investigative Team Multiple Principal Investigators
Ira M Cheifetz, MD FCCM FAARC (Duke)
Martin. C.J. Kneyber, MD PhD FCCM (Holland)
Martha A.Q. Curley, PhD RN FAAN (PENN/Boston)
DCC: David Wypij PhD (Boston)
Jason Connors PHD (Berry & Associates)
AU/NZ lead: Simon Erickson, MD (Perth)
Asia lead: Jan Hau Lee, MD (Singapore)

4. Advisory Committee
Dr. Brian Kavanagh (University of Toronto, The Hospital for Sick Children)
Dr. Michael Matthay (University of California San Francisco) and
Dr. Peter C. Rimensberger (University Hospital of Geneva, Switzerland)

5. Rationale Prone positioning HFOV Negative pediatric prone trial
PF ratio <300 and mandated HFOV with OI of 15
Positive adult-based PROSEVA trial
HFOV
Two negative adult-based clinical trials: OSCAR and OSCILLATE
No pediatric data

6. PROSpect
Purpose: To provide the field of pediatric critical care evidence to support best ventilation practices in critically ill children with severe PARDS.

7. Specific Aims
SA 1: To compare the effects of prone positioning with supine positioning on ventilator-free days. SA 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 VFDs.

8. Specific Aims
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 VFDs and to 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 HRQL.

9. Primary Outcome
Ventilator-free days where non-survivors receive zero VFDs
Superiority would be declared if VFDs were 2 days superior, a value that represents a clinically meaningful value (balanced with similar adverse events).

10. Pre-specified adverse events
Prone positioning: unplanned extubation, vascular line/invasive tube removal, plugging/obstruction of the endotracheal tube with secretions and/or blood, main-stem bronchus intubation, transient hemodynamic instability or cardiac dysrhythmias, hypercarbia (unresponsive to ventilation protocols), clinically significant agitation facial and eyelid edema, pressure ulcers and corneal abrasions
Ventilation protocols: hemodynamic instability, airleak, cardiac dysrhythmias related to increased mPaw, mucous plugging/airway obstruction, clinically significant agitation and pressure ulcers

11. Inclusion Criteria Patients will be screened daily
Consecutive pediatric patients
Age: ≥ 2 weeks of age (≥ 42 weeks post gestational age) and < 18 years of age
Intubated and mechanically ventilated for < 4 days
Severe PARDS per PALICC guidelines for < 48 hours
chest imaging consistent with acute pulmonary parenchymal disease, and
2 consecutive arterial blood gases (separated by 4H during which time the clinical team is working to recruit lung volume and optimize the patient’s hemodynamic per PALICC guidelines) demonstrating OI ≥ 16 or an OSI ≥ 12.3

12. Exclusion Criteria Status asthmaticus Perinatal related lung disease
Obstructive airway disease
bronchiolitis or disease states characterized by either: hypercapnia with FiO2 < 0.30, and/or evidence of increased resistance visible on the flow – time scalar, and/or presence of intrinsic PEEP
Chronic MV (including noninvasive) or O2 dependent on admission
Neuromuscular respiratory failure
Intracranial bleeding
Facial surgery or trauma
Unstable fractures
Acute abdominal process,
BMI >40 kg/m2
PP, HFOV, ECMO with current illness
DNR
Pregnancy
Perinatal related lung disease
CHD or congenital/acquired diaphragm paralysis
Respiratory failure secondary to cardiac failure or fluid overload
Cyanotic heart disease
Cardiomyopathy
Unilateral lung disease
Primary pulmonary hypertension
Post HSCT
Bronchiolitis obliterans
Post Lung Transplant
Critical airway or anatomical obstruction of the lower airway

13. Center Participation
Recruiting PICUs worldwide that are experienced in both prone positioning and HFOV, can enroll a minimum of 6 subjects/year, and have the capacity to provide ECMO support for pediatric pulmonary patients. 
All US sites must engage in a reliance agreement with the PENN IRB.  International sites will maintain local human subject’s review.
All case report forms to be completed in English. 
All sites must be capable of enrolling at least one subject in our first year of funding.  

14. Design Supine Prone CMV CMV & Supine CMV & Prone HFOV HFOV & Supine
2x2 factorial, response-adaptive, randomized controlled clinical trial of supine/prone positioning and CMV/HFOV
Consecutive subjects with severe PARDS will be randomized to one of four groups
Randomization stratified by age group(<1; 1-8; 8+) and direct/indirect lung injury
Supine
Prone
CMV
CMV & Supine
CMV & Prone
HFOV
HFOV & Supine
HFOV & Prone

15. Adaptive Randomization
If any group demonstrates inferiority (inferior by 6+ days) at a planned interim analysis, randomization will be adapted to eliminate that arm and increase allocation to non-inferior arms (after consideration of age and illness strata)

16. Design Patients will managed per assigned cell until failure declared:
Failed ventilation strategy: 4-hour pattern of either:
Persistent hypoxia (SaO2 < 85%) with FiO2 1.0 and
CMV: max PEEP per grid
HFOV: MAP > 35 cm H2O
Persistent hypoventilation (pH <7.15) + per mode and
CMV: PIP > 32 cm H2O and a RR that does not cause intrinsic PEEP
HFOV: max power/amplitude at a frequency < 9 Hz
Failed Positioning Strategy (Supine or Prone) – as above
May consider reciprocal therapy (per bedside team discretion) while considering ECMO cannulation.

17. Protocol Highlights All groups
Post enrollment, administer NMB for 24 hours, then as clinically indicated
Aline and SpO2, time-based capnography is required and volumetric capnography optional when supported with CMV
Daily Test for Patient Readiness for Extubation (ERT)
Positioning
Supine positioning: reposition Q2H 
Prone positioning: 16H per day until pattern of improving lung function consistent with resolving PARDS and the subject is close to meeting criteria to be tested for extubation readiness; specifically, spontaneous breathing and OI < 8 in the supine position for at least 4 hours after the end of the last prone session.

18. Protocol Highlights Ventilation
CMV per PALICC guidelines -- includes lung recruitment maneuver to determine optimal PEEP
HFOV: SensorMedics 3100 A/B
No HFOV until volume resuscitated
HFOV based on physiologic principles of gas delivery and the available literature.
To optimize the high-frequency approach, high rates (> 8 Hz) will be used knowing that increased amplitudes will be required for adequate ventilation.
Given the known attenuation of pressure amplitude across the endotracheal tube and along the natural airways, pressure amplitude and tidal volume delivery will remain within typical parameters for HFOV at the alveolar level.

19. Co-Interventions Fluids, sedation, skin care guidelines
Monitor iNO and steroid use

20. Start/End of Study Start of assisted breathing
Followed until hospital discharge or hospital Day 90
1,3,6,12 month telephone based interview

21. Timeline Letter of Commitment – April 15, 2017
NIH submission – June 13, 2017
NIH review – Oct/Nov 2017
NIH Council (funding decision) – Jan 2018

22. Thank you!
PROSpect-network.org