Hernandez 2

Effect of Post-extubation High-Flow Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation Respiratory Failure in High-Risk Patients
A Randomized Clinical Trial

Hernandez. JAMA 2016;316(15):1565-1574. doi:10.1001/jama.2016.14194

Clinical Question

  • In critically ill patients who are at high risk for re-intubation, is high flow nasal oxygen non-inferior to non-invasive ventilation in reducing re-intubation and post-extubation respiratory failure?


  • Hernandez has previously demonstrated that in low risk patients the risk of re-intubation can be decreased with the use of high-flow nasal oxygen post-exubation
  • Nava and Ferrer reported that in high risk patients, the use of post extubation non-invasive ventilation can reduce re-intubation rates and respiratory failure
  • This trial was designed to determine if high flow nasal oxygen was non-inferior to non-invasive ventilation at reducing re-intubation and post-extubation respiratory failure in high risk patients.


  • Randomised controlled trial
  • Random number generator through telephone call centre
  • Non-inferiority study
  • Non-blinded
  • Investigators excluded from clinical decisions
  • Sample size calculation: 600 patients required to give 80% power to allow a non-inferiority margin of 10% for the high flow group, assuming baseline re-intubaton rate of 20-25% for each therapy and allowing for a patient loss rate of 15%
  • Per-protocol and intention to treat analysis performed for primary outcome


  • 3 Intensive Care Units, Spain
  • Data collected: September 2012-October 2014


  • Inclusion criteria: Received mechanical ventilation for >12 hours and ready for planned extubation with at least 1 of following risk-risk factors for re-intubation:
    • >65 years
    • APACHE II >12 on extubation day
    • BMI >30
    • Inadequate secretions management
    • Difficult or prolonged weaning
    • >1 co-morbidity
    • Heart Failure as primary indication for mechanical ventilation
    • Moderate/severe COPD
    • Airway patency problems
    • Mechanical ventilation > 7 days
  • Exclusion criteria: Do-not-resuscitate orders, tracheostomies, hypercapnia during spontaneous breathing trial, accidental extubation, self extubation
  • 1211 patients met inclusion criteria of whom 604 randomised
  • Comparing baseline characteristics of non-invasive groups vs. high flow nasal group
    • Age: 64.4 vs. 64.6
    • APACHE II (median)
      • On admission: 16 vs. 16
      • At extubation: 10 vs. 11
    • Length of mechanical ventilation before extubation (median): 4 vs. 4 days
    • High-risk factors for re-intubation
      • Age >65 years: 58% vs. 57%
      • Heart failure as primary indication for ventilation: 9.9% vs. 5.5%
      • COPD: 20.7% vs. 17.6%
      • APACHE II >12 on extubation day: 40.8% vs. 45.2%
      • Prolonged mechanical ventilation: 38.2% vs. 34.8%
    • Diagnosis at admission
      • Surgical: 33.4% vs. 43.8%
      • Trauma: 10.5% vs. 6.6%
      • Medical: 59.2% vs. 53.1%
        • Primary respiratory failure: 38.5% vs. 33.8%


  • High-flow nasal oxygen
    • Flow initially set at 10l/min and titrated upwards until experienced discomfort
    • Temp initially set at 37C
    • FiO2 adjusted to target SpO2 >92%
    • Rescue therapy with NIV not allowed


  • Non-invasive ventilation (NIV)
    • Full face-mask NIV (Respironics)
    • PEEP and inspiratory pressure support adjusted to target RR 25/min, SpO2 92% and pH 7.35
    • Sedatives to increase tolerance to NIV were not allowed
    • Total time patients received NIV was 14 hours (IQR 8-23)

Management common to both groups

  • Pre-defined weaning protocol, extubation and re-intubation criteria
  • Aimed to continue high-flow conditioned oxygen therapy or NIV for 24 hours post extubation


  • Primary outcomes: (Comparing NIV with high flow nasal oxygen)
    • Re-intubation within 72 hours – high flow nasal oxygen was non-inferior
      • 19.1% vs. 22.8% (risk difference -3.7%; 95% C.I. -9.1% to infinity)
    • Post extubation respiratory failure – significantly more common in NIV group
      • 39.8% vs. 26.9% (risk difference 12.9%, 95% C.I. 6.6% to infinity)
      • Post extubation respiratory failure defined as any of the following: pH <7.35 with PaCO2 >45mmHg, SpO2 <90% or PaO2 <60mmHg at FiO2 >0.4, Respiratory rate >35, >1 point drop in GCS, agitation, or clinical signs suggestive of respiratory muscle fatigue or increased work of breathing
  • Secondary outcomes: (Comparing NIV with high flow nasal oxygen)
    • Respiratory related re-intubations – no significant difference
      •  15.9%  vs. 16.9% (absolute difference 1; 95% C.I. -4.9 to 6.9)
    • Cause of post-extubation respiratory failure: inability to clear secretions – no significant difference
      • 16.6% vs. 10.3%
    • Median time to re-intubation – no significant difference
      • 21.5 vs. 26.5 hours (absolute difference, -5 hours, 95% C.I. -34 to 24 hours)
    • Median ICU length of stay – significantly shorter in high flow group
      • 4 vs. 3 days, p=0.048
    • Hospital length of stay – significantly shorter in high flow group
      • 26 vs. 23 days, (absolute difference 3, 95% C.I. -6.8 to -0.8)
    • Hospital mortality – no significant difference
      • 17.8% vs. 20.3% (absolute difference -2.5, 95% C.I. -8.8 to 3.8)
    • Adverse events (requiring treatment discontinuation for >=25% of per-protocol time)- significantly greater in NIV group
      • 43% vs. 0%, p<0.001

Authors’ Conclusions

  • In patients that are high-risk for requiring re-intubation the use of high flow nasal oxygen was non-inferior to non-invasive ventilation and may offer some advantages


  • Randomised
  • Multi-centre
  • Standardised protocols for weaning, extubation and re-intubation
  • Registered at clinicaltrials.gov
  • Intention to treat and per-protocol analysis performed


  • Definition of respiratory failure included subjective measurements- combined with the fact that the study was non-blinded this may lead to bias
  • There were two primary outcomes, and only one (risk of re-intubation) had a sample size calculation performed
  • The study protocol did not allow sedatives or helmet NIV to increase NIV tolerance, which may have led to increased treatment failures in the NIV group
  • There was a sudden increase in the number of patients requiring re-intubation in the hours post 24 hours, suggesting that longer treatment periods may be beneficial
  • For the results reported, the 95% C.I. for the primary outcome included an increase in re-intubation rate of 9.1% for the high flow nasal oxygen group, which would still be a clinically significant difference (despite a non-inferiority margin of 10%). A larger trial would be required to determine non-inferiority at a lower threshold

The Bottom Line

  • This randomised controlled trial demonstrated that in patients that are high risk for re-intubation the use of high flow nasal oxygen was non-inferior to non-invasive ventilation
  • The non-inferiority margin was set at 10% which means that clinically significant differences may have not been detected with this study
  • Post-extubation respiratory failure was significantly more common in the NIV group, however “respiratory failure” included subjective measurements – this result should be treated with caution
  • In patients that are high risk for re-intubation I will use non-invasive ventilation, and if this not tolerated then change to high flow nasal oxygen

External Links


Summary author: David Slessor
Summary date: 10th July 2017
Peer-review editor: Segun Olusanya

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