OSCILLATE

Published

Ferguson ND, et al. "High-Frequency Oscillation in Early Acute Respiratory Distress Syndrome". The New England Journal of Medicine. 2013. 368(9):795-805.
PubMed • Full text • PDF

Clinical Question

In patients is moderate to severe early ARDS, does high-frequency oscillatory ventilation reduce in-hospital mortality?

Bottom Line

In patients with moderate to severe early ARDS, early high-frequency oscillatory ventilation might increase in-hospital mortality

Major Points

The high mortality rates of ARDS have been improved upon by the ARDSNet trial's (2000) protocol of low V_T (6 mL/kg) and has become standard of care in ICUs. Development of high-frequency oscillatory ventilation (HFOV) was thought to further improve survival through prevention of atelectrauma given its ability to deliver even smaller V_T of 1-2 mL/kg delivered at 3-15 breaths per second. Early trials on HFOV like MOAT (2002) indicated a potential benefit for the therapy, though interpretation of the results was muddled by lack of comparison of HFOV to a modern, low V_T strategy.

The 2013 OSCILLATE trial randomized 548 intubated ICU patients with early moderate-to-severe ARDS to HFOV or a ventilatory mode similar to that used in ARDSNet with a primary outcome of in-hospital mortality. The trial was stopped early because of the interim analysis demonstrating a 12% absolute increase in in-hospital mortality with HFOV (47% vs. 35%, NNH 8). The similar OSCAR trial (2013) published concurrently explored the use of HFOV in all patients with ARDS. It did not demonstrate a mortality benefit.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)

• Recommend against using high-frequency oscillatory ventilation in adults with ARDS from sepsis (strong recommendation, moderate quality of evidence)

Design

• Multicenter, prospective, non-blinded, randomized controlled trial
• N=548 intubated patients with early, moderate-to-severe ARDS
  • HFOV (n=275)
  • Control (n=273)
• Setting: 39 ICUs in 5 countries
• Enrollment: 2009-1012 (stopped early given significant findings)
• Follow-up: Until hospital discharge
• Analysis: Intention-to-treat
• Primary outcome: In-hospital mortality

Population

Inclusion Criteria

• Intubated patients with pulmonary symptoms for ≤2 weeks
• ARDS defined by:
  • Hypoxemia with PaO₂:F_IO₂≤200 when F_IO₂≥0.5
  • Bilateral airspace disease

Exclusion Criteria

• Left atrial hypertension causing hypoxemia
• Pulmonary hemorrhage from vasculitis
• Neuromuscular disorders likely to prolong need for ventilation
• "Severe chronic respiratory disease"
• Expected 6 month mortality from preexisting illness
• At risk for intracranial hypertension
• "Lack of commitment to life support"
• Expected time on ventilator <48 hours
• Age <16 or >85 years
• Weight <35 kg or >1kg/cm of height
• Meeting of eligibility criteria for >72 hours
• Already receiving HFOV
• Physicians declining enrollment

Baseline Characteristics

From the HFOV group.

• Demographics: Age 55 years, female 39%
• APACHE II score: 29
• ARDS risk factors:
  • Sepsis: 47%
  • Pneumonia: 56%
  • Gastric aspiration: 18%
  • Trauma: 4%
  • Other: 26%
• V_T: 7.2 mL/kg
• Plateau pressure: 29 cmH₂O
• PEEP: 13 cmH₂O
• Minute ventilation: 11.3 L/min
• Oxygenation index: 19.6
• PaO₂:F_IO₂: 121 mmHg
• PaCO₂: 46 mmHg
• Arterial pH: 7.32
• Barotrauma: 7%
• Other interventions:
  • Vasopressors: 67%
  • RRT: 11%
  • Glucocorticoids: 34%
  • Neuromuscular blockers: 31%

Interventions

• Patients enrolled and were maintained on pressure-control mode with V_T 6 mL/kg and F_IO₂ of 0.60, and PEEP ≥10 cmH₂O as needed
• If PaO₂:F_IO₂ was ≤200, patients were randomized to one of two groups:
  • HFOV:
    • Recruitment of 40 cmH₂O for 40 seconds
    • Mean airway pressure of 30 cmH₂O with pressure adjusted to maintain a PaO₂ of 55-80 mmHg
    • V_T minimized to keep pH >7.25
    • Reversion to standard ventilation of mean airway pressure was ≤24 cmH₂O for 12 hours or anytime when ≤20 cmH₂O
    • Re-initiation of HFOV if F_IO₂ >0.4 or PEEP >14 cmH₂O for >1 hour in the subsequent 48 hours
  • Control:
    • Recruitment of 40 cmH₂O for 40 seconds
    • Pressure control mode, V_T of 6 mL/kg with plateau pressures ≤35 cmH₂O, and PEEP of 20 cmH₂O with adjustments made per the protocol
    • Patients could be maintained on pressure-support or volume-assist modes
    • Weaning protocol using spontaneous breathing trials
• Both groups could reduce PEEP or mean airway pressure based upon clinical judgement of lung overdistension
• If requiring F_IO₂ ≥0.9, hypoxemia protocols like NO or change in positioning could be instituted
• Any alternative therapy could be started for three groups:
  • Refractory hypoxemia - defined as PaO₂ <60 mmHg for ≥1 hour with F_IO₂ of 1.0 and neuromuscular blockade
  • Refractory barotrauma - defined as persistent pneumothorax or worsening subcutaneous emphysema despite two thoracostomy tubes on the affected side
  • Refractory acidosis - pH ≤7.05 despite neuromuscular blockade
• Medical management was otherwise left to the attending physicians

Outcomes

Presented as HFOV vs. control.

Primary Outcome

In-hospital mortality

47% vs. 35% (RR 1.33; 95% CI 1.09-1.64; P=0.005; NNH=8)

Secondary Outcomes

ICU mortality

45% vs. 31% (RR 1.45; 95% CI 1.17-1.81; P=0.001)

28 day mortality

40% vs 29% (RR 1.41; 95% CI 1.12-1.79; P=0.004)

New barotrauma

18% vs. 13% (RR 1.37; 95% CI 0.91-2.06; P=0.13)

Refractory barotrauma: <1% vs. <1% (NS)

New tracheostomy

22% vs. 25% (RR 0.87; 95% CI 0.64-1.19; P=0.39)

Refractory hypoxemia

7% vs. 14% (RR 0.50; 95% CI 0.29-0.84; P=0.007)

Refractory hypoxemia mortality: 79% vs. 66% (RR 1.20; 95% CI 0.87-1.66; P=0.31)

Refractory acidosis

3% vs. 3% (RR 1.20; 95% CI 0.44-2.85; P=0.82)

Mechanical ventilation duration in survivors

11 days vs. 10 days (NS)

ICU duration in survivors

15 days vs. 14 days (NS)

Hospitalization duration in survivors

30 days vs 25 days (NS)

Criticisms

• The authors identify that the trial was stopped early despite the stopping thresholds not being met and that the high mean airway pressure HFOV protocol may have led to worse outcomes than one with lower pressures
• The sedation strategy in the HFOV group may have led to higher mortality as patients may have been given higher doses of sedative and, subsequently, fluids
• The HFOV may have been initiated too late
• Successful HFOV may take expertise not present at the study centers

Funding

• Canadian Institutes of Health
• King Abdullah International Medical Research Center
• Authors with financial ties to private groups