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High-Frequency Oscillation: State of The Evidence

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  1. High-Frequency Oscillation:State of The Evidence Niall D. Ferguson, MD, FRCPC, MSc Director, Critical Care Medicine University Health Network & Mount Sinai Hospital Associate Professor of Medicine & Physiology Interdepartmental Division of Critical Care Medicine University of Toronto

  2. Disclosures • CareFusion, USA (equipment loan) • Cardinal Health, Canada (equipment service)

  3. Slutsky & Tremblay AJRCCM 1998

  4. ARDS Network • High Stretch • VT: 11.8 • PPLAT: 32-34 • RR: 18 • VMIN: 13 • PEEP: 8 • Mortality 40% • Low Stretch • VT: 6.2 ml/kg • PPLAT: 25 cm H2O • RR: 29 • VMIN: 13 L/min • PEEP: 9 cm H2O • Mortality 31%* *p=0.005 N Engl J Med 2000 342:1301-8

  5. Can We Reduce VILI Further?

  6. HFO vs. Injurious CV in Animals

  7. HFO vs. ‘protective’ CV in animals

  8. p=0.057 30 d p=0.078 90 d Outcomes 30 Day Mortality HFOV: 37% CMV: 52% Absolute Risk Reduction: 15% Relative Risk Reduction: 29% p=0.102 HFOV in adults with ARDS appears safe and may improve outcome – more study is needed

  9. HFO

  10. OSCILLATE Trial Niall D. Ferguson, MD, FRCPC, MSc Maureen O. Meade, MD, FRCPC, MSc For the OSCILLATE Investigators and The Canadian Critical Care Trials Group

  11. Research Question • For critically ill adults with ARDS, does the early application of high frequency oscillation reduce hospital mortality compared to a high-PEEP, low tidal volume ventilation strategy that incorporates HFO exclusively as ‘rescue’ therapy?

  12. Study Design • International, multicentre randomized clinical trial • Pilot randomized trial • 2007-2008 • N = 94 • Acceptability, feasibility • Current randomized trial • 2009-2012 • analysis includes 94 pilot study patients

  13. Population Target: 1200 adults with moderate-severe ARDS • Acute respiratory failure • PaO2/FiO2<200 • Bilateral airspace disease on CXR • Not attributed primarily to circulatory overload • Standardized ventilator settings • Vt 6 mL/kg PBW • PEEP > 10 cm H2O • FiO2> 0.60

  14. Control GroupHigh PEEP, Low VT Ventilation • Based on the Lung Open Ventilation Study (JAMA ’08) • Recruitment manoeuvre: 40 cm H2O x 40 seconds • Initialsettings • FiO2 1.0 • PEEP 20 cm H2O • Pressure control mode • VT6 ml/kg PBW • PPLAT≤ 35 cm H2O

  15. Volume-Pressure Curve Volume HFO Upper Infection Point Lower Inflection Point Pressure

  16. High Frequency Oscillatory Ventilation • Recruitment manoeuvre: 40 cm H2O x 40 seconds • Initial settings • FiO2 1.0 • mPAW30 cm H2O • Bias flow 40 L/min • P = 90 cm H2O • f determined by baseline pH… pH 7.10 = 3.5 Hz pH 7.10-7.19 = 4 Hz pH 7.20-7.35 = 5 Hz pH >7.35 = 6 Hz

  17. Oxygenation Protocols Control FiO2 0.3 0.4 0.4 0.4 0.4 0.4 0.5 0.5 0.6 0.7 0.8 0.8 0.9 1.0 PEEP 5-10 10 12 14 16 18 18 20 20 20 20 22 22 22-24 HFO FiO2 0.4 0.4 0.4 0.4 0.5 0.6 0.6 0.6 0.7 0.8 0.9 1.0 1.0 mPAW 20-24 26 28 30 30 30 32 34 34 34 34 34 36-38 88% < SpO2< 93% 55 mm Hg < PaO2< 80 mmHg

  18. Patient Safety • Volume status assessment prior to initiation • Rx hypotension • with an increase in PEEP/mPAW • with stable PEEP/mPAW • Rx lung over-distention • option to reduce PEEP/mPAW • option to omit recruitment maneuvers • Contraindications to recruitment maneuvers • Criteria for instituting ‘rescue’ therapy • 24-hour help line

  19. Interim Analyses PILOT STUDY ANALYSIS • N = 94 • No stopping rules CONVENTIONAL INTERIM ANALYSIS • N = 800 • O’Brien-Fleming method; 2-sided test, p = 0.01 SAFETY REVIEWS • N = 300, 500, 700 • physiologic changes with study initiation • vasopressors, NMBAs, barotrauma • detailed criteria for requesting mortality data • 1-sided O’Brien-Fleming method; p = 0.00001, 0.0001, 0.0064

  20. Patients • July 2007 through August 2012 (1 year hiatus) • Began in 12 pilot centers - expanded to total 39 centers • Canada; United States; Saudi Arabia; Chile; India • (Mexico; UK; Australia; France) • The Steering Committee terminated the trial on recommendation from the DMC on August 29, 2012 • Following the 500-patient safety analysis • 548 of planned 1200 patients randomized

  21. Baseline Characteristics

  22. Baseline Characteristics

  23. Transition on to Protocol

  24. Ventilation Parameters

  25. Ventilation Groups • HFO Group • 270/275 (98%) patients received HFO • Median 3 (2-8) days of HFO • 222 (81%) moved to conventional ventilation • Median 5 (2-7) days of conventional • Control Group • All patients received conventional ventilation • 34 (12.5%) converted to HFO after 2 (1-4) days • Median 7 (5-15) days of HFO

  26. Main Results

  27. Survival Curve

  28. All Subgroups

  29. Cointerventions

  30. Midazolam doses in week 1 HFOV 199 (100-382) vs. Control 141 (68-240) mg/day; P<0.001

  31. Opioid doses in week 1 HFOV 2980 (1258-4800) vs. Control 2400 (1140-4430) μg/day; P=0.06

  32. Discussion • Early application of HFOV associated with harm compared with a high PEEP, low VT strategy allowing HFOV only for severe refractory hypoxemia • HFOV patients received higher mPaw, more sedatives, more NMBAs, more vasoactive drugs • Subgroup analysis suggest that this finding is robust across severity and experience of groups • Studies that stop early often overestimate effects • No benefit of HFOV • Possibly because we used a more effective control strategy • Harm with HFOV? • Chance • Higher mPaw leading to hemodynamic compromise • Hemodynamic effects of increased sedatives • Possible increased barotrauma and VILI

  33. Discussion • HFOV strategy chosen based on preclinical data and pilot physiological data • Resulted in relatively high mPaw • Other HFOV strategies using lower mPaw may have different effects • Implications for care • Results raise serious concerns about use of early HFOV for adults with moderate-severe ARDS • Even for those with refractory hypoxemia, results increase uncertainty about possible benefits of HFOV

  34. Conclusions • HFOV as used in the OSCILLATE trial does not improve survival and is likely harmful compared with a high PEEP, low tidal volume conventional strategy allowing HFOV only as rescue therapy

  35. 30-Day Mortality: HFO 41.7% vs. 41.1% Hospital Mortality: HFO 50.1% vs. 48.4%

  36. n.ferguson@utoronto.ca November 10-13, 2013 Sheraton Centre Hotel, Toronto