HIGH-FREQUENCY OSCILLATION:STATE OF THE EVIDENCE

Niall D. Ferguson, MD, FRCPC, MScDirector, Critical Care Medicine

University Health Network & Mount Sinai Hospital

Associate Professor of Medicine & PhysiologyInterdepartmental Division of Critical Care Medicine

University of Toronto

Disclosures

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

Slutsky & Tremblay AJRCCM 1998

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

Can We Reduce VILI Further?

HFO vs. Injurious CV in Animals

HFO vs. ‘protective’ CV in animals

Outcomes

30 Day Mortality

HFOV: 37%CMV: 52%

Absolute Risk Reduction: 15%Relative Risk Reduction: 29%

p=0.102

p=0.057 30 d

p=0.078 90 d

HFOV in adults with ARDS appears safe and may improve outcome – more study is needed

HFO

OSCILLATE TRIALNiall D. Ferguson, MD, FRCPC, MSc

Maureen O. Meade, MD, FRCPC, MSc

For the OSCILLATE Investigators and

The Canadian Critical Care Trials Group

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?

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

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

Control GroupHigh PEEP, Low VT Ventilation• Based on the Lung Open Ventilation Study (JAMA ’08)

• Recruitment manoeuvre: 40 cm H2O x 40 seconds

• Initial settings• FiO2 1.0• PEEP 20 cm H2O• Pressure control mode• VT 6 ml/kg PBW • PPLAT ≤ 35 cm H2O

Volume-Pressure Curve

HFOVolume

Pressure

Lower Inflection

Point

Upper Infection

Point

High Frequency Oscillatory Ventilation

• Recruitment manoeuvre: 40 cm H2O x 40 seconds • Initial settings

• FiO2 1.0• mPAW 30 cm H2O• Bias flow 40 L/min• P = 90 cm H2O• f determined by baseline pH…

pH 7.10 = 3.5 HzpH 7.10-7.19 = 4 HzpH 7.20-7.35 = 5 HzpH >7.35 = 6 Hz

Oxygenation Protocols

ControlFiO2 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 1.0PEEP 5-10 10 12 14 16 18 18 20 20 20 20 22 22 22-24

HFOFiO2 0.4 0.4 0.4 0.4 0.5 0.6 0.6 0.6 0.7 0.8 0.9 1.0 1.0mPAW 20-24 26 28 30 30 30 32 34 34 34 34 34 36-38

88% < SpO2 < 93% 55 mm Hg < PaO2 < 80 mmHg

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

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

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

Baseline Characteristics

Baseline Characteristics

Transition on to Protocol

Ventilation Parameters Day 1

HFOV Control

Delta P 87 (7.8)

Frequency 5.5 (1)

mPaw 31 (2.6) 24 (4)

VT 6.1 (1.3)

PEEP 18 (3.2)

PPLAT 32 (5.7)

FIO2 0.62 (0.19) 0.64 (0.20)

PaO2 84 (38) 94 (52)

PaCO2 46 (15) 52 (17)

Fluid Balance

2897 (3124)

2410 (2901)

Day 1 Day 3 Day 7

HFOV Control HFOV Control HFOV Control

Delta P 87 (7.8) 85 (9.5) 87 (7.3)

Frequency 5.5 (1) 6.8 (2) 6.8 (2)

mPaw 31 (2.6) 24 (4) 26 (6.8) 20 (6.4) 21 (8.9) 18 (7.1)

VT 6.1 (1.3) 6.6 (1.8) 7.0 (1.8)

PEEP 18 (3.2) 13 (4.5) 12 (4.6)

PPLAT 32 (5.7) 27 (8.1) 24 (8.7)

FIO2 0.62 (0.19) 0.64 (0.20) 0.50 (0.16) 0.45 (0.14) 0.45 (0.16) 0.42 (0.16)

PaO2 84 (38) 94 (52) 78 (21) 73 (18) 76 (26) 75 (23)

PaCO2 46 (15) 52 (17) 51 (15) 46 (11) 50 (17) 47 (15)

Fluid Balance

2897 (3124)

2410 (2901)

1519 (2430)

1147 (2486)

-87 (2072)

-215 (2298)

Day 1 Day 3

HFOV Control HFOV Control

Delta P 87 (7.8) 85 (9.5)

Frequency 5.5 (1) 6.8 (2)

mPaw 31 (2.6) 24 (4) 26 (6.8) 20 (6.4)

VT 6.1 (1.3) 6.6 (1.8)

PEEP 18 (3.2) 13 (4.5)

PPLAT 32 (5.7) 27 (8.1)

FIO2 0.62 (0.19) 0.64 (0.20) 0.50 (0.16) 0.45 (0.14)

PaO2 84 (38) 94 (52) 78 (21) 73 (18)

PaCO2 46 (15) 52 (17) 51 (15) 46 (11)

Fluid Balance

2897 (3124)

2410 (2901)

1519 (2430)

1147 (2486)

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

Main Results

Survival Curve

All Subgroups

Cointerventions

Midazolam doses in week 1

HFOV 199 (100-382) vs. Control 141 (68-240) mg/day; P<0.001

Opioid doses in week 1

HFOV 2980 (1258-4800) vs. Control 2400 (1140-4430) μg/day; P=0.06

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

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

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

30-Day Mortality:HFO 41.7% vs. 41.1%

Hospital Mortality:HFO 50.1% vs. 48.4%

n.ferguson@utoronto.ca

November 10-13, 2013Sheraton Centre Hotel, Toronto