Introduction Introduction • Mechanical ventilation can perpetuate lung Mechanical ventilation can perpetuate lung

injuryinjury• Repetitive overstretching or collapse of lung Repetitive overstretching or collapse of lung

units can generate local and systemic units can generate local and systemic inflammation, multiorgan failure and death inflammation, multiorgan failure and death

• Clinical trials support the use:Clinical trials support the use: - Smaller tidal volumes (6 ml/kg)- Smaller tidal volumes (6 ml/kg) - Higher levels of PEEP - Higher levels of PEEP

High-frequency oscillatory ventilation High-frequency oscillatory ventilation (HFOV) (HFOV) - - Deliver small tidal volumes (1 to 2 ml/kg)Deliver small tidal volumes (1 to 2 ml/kg) - High rates (3 to 15 breaths/sec)- High rates (3 to 15 breaths/sec)

•Randomized trials suggest that HFOV improve Randomized trials suggest that HFOV improve oxygenation and survival oxygenation and survival •These trials were limited by small sample sizes These trials were limited by small sample sizes and outdated ventilation strategies for the and outdated ventilation strategies for the control groupcontrol groupThey compared HFOV with a conventional ventilation in patients with new-onset, moderate-

to-severe ARDS

MethodsMethods

• Multicenter randomized trialMulticenter randomized trial• We enrolled patients at the 27 centers in We enrolled patients at the 27 centers in

Canada, United States, Saudi Arabia, Chile, Canada, United States, Saudi Arabia, Chile, and India from July 2009 through August 2012 and India from July 2009 through August 2012

• The trial protocol was approved by the The trial protocol was approved by the research ethics board at each participating siteresearch ethics board at each participating site

• For HFOV, we used the Sensor Medics 3100B For HFOV, we used the Sensor Medics 3100B High-Frequency Oscillatory Ventilator High-Frequency Oscillatory Ventilator

PatientsPatients Patients were eligible for inclusion: Patients were eligible for inclusion:

•If they had onset of pulmonary symptoms If they had onset of pulmonary symptoms within the previous 2 weekswithin the previous 2 weeks•Tracheal intubationTracheal intubation•Hypoxemia (Pao2/Fio2 ≤200, Fio2 ≥0.5)Hypoxemia (Pao2/Fio2 ≤200, Fio2 ≥0.5)•Bilateral air-space opacities on chest Bilateral air-space opacities on chest radiographyradiography

Patients excludedPatients excluded

• Hypoxemia related to Hypoxemia related to left atrial hypertensionleft atrial hypertension

• Suspected vasculitic Suspected vasculitic pulmonary pulmonary hemorrhagehemorrhage

• Neuromuscular Neuromuscular disordersdisorders

• Severe chronic Severe chronic respiratory diseaserespiratory disease

• Expected 6-month Expected 6-month mortality exceeding mortality exceeding 50%50%

• Risk for intracranial Risk for intracranial hypertensionhypertension

• < 16 years or > 85 < 16 years or > 85 years years

• Weight was less than Weight was less than 35 kg 35 kg

After enrollment, standardized ventilator After enrollment, standardized ventilator settings was:settings was:

After 30 minutesAfter 30 minutes

Pressure control mode:Pressure control mode:- Vt 6 ml/kg- Vt 6 ml/kg

- Fio2: 0.60 with PEEP 10 cm H2O or - Fio2: 0.60 with PEEP 10 cm H2O or higherhigher

If the Pao2/Fio2 remained at 200 or If the Pao2/Fio2 remained at 200 or lower, patients underwent lower, patients underwent

randomizationrandomization

Eligible patients were randomly assigned in a Eligible patients were randomly assigned in a 1:1 ratio to the HFOV group or to the 1:1 ratio to the HFOV group or to the

conventional-ventilation groupconventional-ventilation group

HFOV ProtocolHFOV Protocol

Control Ventilation ProtocolControl Ventilation Protocol

• Vt: 6 ml/kg, plateau Paw: 35 cm H2O or less, Vt: 6 ml/kg, plateau Paw: 35 cm H2O or less, and high levels of PEEPand high levels of PEEP

• After an initial recruitment maneuver (same for After an initial recruitment maneuver (same for the HFOV group)the HFOV group)

• Used pressure-control mode with PEEP: 20 cm Used pressure-control mode with PEEP: 20 cm H2OH2O

• For patients receiving pressure support with For patients receiving pressure support with PEEP: 10 cm H2O or less and an Fio2 of 0.4 or PEEP: 10 cm H2O or less and an Fio2 of 0.4 or less, there were no limits on Vt or Pawless, there were no limits on Vt or Paw

Procedures in Both GroupsProcedures in Both Groups• Patients with hypoxemia (Fio2 of 0.9 or Patients with hypoxemia (Fio2 of 0.9 or

greater), clinicians could institute prone greater), clinicians could institute prone positioning or NO positioning or NO

Statistical AnalysisStatistical Analysis

• We summarized data using means with We summarized data using means with standard deviations, medians, interquartile standard deviations, medians, interquartile ranges, proportionsranges, proportions

• Normally distributed data were compared with Normally distributed data were compared with the use of Student’s t-testthe use of Student’s t-test

• Non normally distributed data with the use of Non normally distributed data with the use of Wilcoxon rank-sum testWilcoxon rank-sum test

• Proportions with the use of Mantel–Haenszel Proportions with the use of Mantel–Haenszel chi-square testchi-square test

Statistical AnalysisStatistical Analysis

• Primary outcome was in-hospital mortalityPrimary outcome was in-hospital mortality• We used logistic regression to adjust the We used logistic regression to adjust the

treatment effect for baseline variables: treatment effect for baseline variables: - Age - Age - APACHE II- APACHE II - Presence or absence of sepsis- Presence or absence of sepsis - Duration of hospitalization before - Duration of hospitalization before

randomization randomization

ResultsResults

Early Termination of the TrialEarly Termination of the Trial

•After the 500-patient analysis, the steering After the 500-patient analysis, the steering committee terminated the trialcommittee terminated the trial•At the time of termination 548 patients had At the time of termination 548 patients had undergone randomization: undergone randomization: - 275 to the HFOV group- 275 to the HFOV group - 273 to the control-ventilation group - 273 to the control-ventilation group

Cardiorespiratory ResultsCardiorespiratory Results

• On day 1, On day 1, mPawmPaw in HFOV group: 31±2.6 cm in HFOV group: 31±2.6 cm H2O, H2O, FrequencyFrequency: 5.5±1.0 Hz: 5.5±1.0 Hz

• Control group underwent ventilation with:Control group underwent ventilation with: VtVt: 6.1±1.3 ml/kg,: 6.1±1.3 ml/kg, PEEP PEEP: 18±3.2, : 18±3.2, PpltPplt: 32±5.7 : 32±5.7

cm H20cm H20• The mean Fio2 in the control group was The mean Fio2 in the control group was

similar to HFOV groupsimilar to HFOV group• Fluid balance was higher in the HFOV groupFluid balance was higher in the HFOV group

DiscussionDiscussion

• Early application of HFOV in patients with Early application of HFOV in patients with moderate to severe ARDS was associated with moderate to severe ARDS was associated with higher mortality than CV higher mortality than CV

• HFOV was associated with higher mPaw, HFOV was associated with higher mPaw, greater use of sedatives, neuromuscular greater use of sedatives, neuromuscular blockers, and vasoactive drugsblockers, and vasoactive drugs

Reasons to end studyReasons to end study

• Increased mortality with HFOV in three Increased mortality with HFOV in three consecutive analysesconsecutive analyses

• Increased need for vasoactive drugs in the Increased need for vasoactive drugs in the HFOV group suggested a mechanism of HFOV group suggested a mechanism of harmharm

• Put patients at risk with little likelihood of Put patients at risk with little likelihood of benefitbenefit

Plausible mechanisms that may Plausible mechanisms that may contribute to increased mortality with contribute to increased mortality with HFOVHFOV

• Higher mPaw may result in hemodynamic Higher mPaw may result in hemodynamic compromise compromise

• Decreasing venous return or directly affecting Decreasing venous return or directly affecting right ventricular function right ventricular function

• Increased use of vasodilating sedative agentsIncreased use of vasodilating sedative agents• Possibility of increased barotrauma Possibility of increased barotrauma

It is possible that an HFOV protocol that uses It is possible that an HFOV protocol that uses lower mean airway pressures, a different lower mean airway pressures, a different

ratio of inspiratory-to-expiratory time, or a ratio of inspiratory-to-expiratory time, or a lower oscillatory frequency might have led lower oscillatory frequency might have led

to different resultsto different results

Conclusions Conclusions

In adults with moderate-to-severe ARDS, In adults with moderate-to-severe ARDS, early application of HFOV, as compared with early application of HFOV, as compared with

a ventilation strategy of low tidal volume a ventilation strategy of low tidal volume and high positive end-expiratory pressure, and high positive end-expiratory pressure,

does not reduce, and may increase, in-does not reduce, and may increase, in-hospital mortalityhospital mortality

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