FLORALI: High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure

Frat. NEJM 2015; first published on line on May 17th 2015 doi: 10.1056/NEJMoa1503326

Clinical Question

• In patients with acute hypoxaemic respiratory failure, does high-flow oxygen through nasal cannula, compared with standard oxygen delivered through a facemask or non-invasive positive-pressure ventilation, prevent intubation?

Design

• Multicenter, open-label trial
• Randomisation was performed in permuted blocks of six, with stratification according to centre and whether there was any patient history of cardiac insufficiency
• Patients were randomly assigned within 3 hours of validation of inclusion criteria into one of the three groups in a 1:1:1 ratio using a web-based tool
• Power calculation based on the assumption that 60% of patients treated with standard face mask oxygen would require intubation. 300 patients would then provide 80% power to show an absolute difference of 20% in the primary outcome between standard face mask oxygen group and the other two groups

Setting

• 23 French ICUs
• February 2011 – April 2013

Population

• Inclusion: 18 years of age or older; met all 4 of the following criteria
  • RR > 25 breaths per minute; PaO2/FiO2 < 300mmHg whilst the patient was breathing oxygen at a flow rate of ≥ 10 litres per minute for at least 15 minutes; PaCO2 < 45 mmHg; absence of a clinical history of underlying chronic respiratory failure
  • FiO₂ was measured by a portable oxygen analyser that was introduced in the non-rebreather face mask
• Exclusion: PaCO2  ≥ 45 mmHg; exacerbation of asthma or chronic respiratory failure; cardiogenic pulmonary oedema; severe neutropenia; haemodynamic instability; use of vasopressors; GCS <12; contraindication to noninvasive ventilation; urgent need for intubation; do-not-intubate decision
• 310 patients
  • Pneumonia was the cause of hypoxaemia in 82% of cases

Interventions:

• High-flow-oxygen group (also known as ‘high flow nasal cannula’ or ‘HFNC’)
  • Via nasal cannula (Optiflow)
  • Gas flow rate of 50 l/min at FiO2 initially of 1.0 and adjusted to maintain SpO₂ of ≥ 92%
  • Applied for at least 2 calendar days

OR

• Noninvasive ventilation group
  • Pressure-support level was adjusted with the aim of obtaining an expired tidal volume of 7-10mls/kg of predicted body weight
  • Initial PEEP between 2-10 cmH₂0
  • FiO₂ or PEEP level, or both was adjusted to maintain SpO₂ of ≥ 92%
  • Continued for 8 hours per day (sessions of at least one hour) for at least 2 calendar days. Between sessions, oxygen was delivered via high-flow oxygen (HFNC)

OR

Outcome

• Primary outcome: Proportion of patients who required endotracheal intubation within 28 days after randomisation:
  • High-Flow oxygen: 40 patients (38%)
  • Non-invasive ventilation: 55 patients (50%)
  • Standard oxygen: 44 patients (47%)
  • p = 0.18
    • High-flow vs Standard: ARR 9.07% (-4.6% to 22.74%); NNT 12
    • High-flow vs NIV: ARR 12.26% (-0.87% to 25.40%); NNT 9
    • Standard vs NIV: ARR 3.19% (-10.56% to 16.94%); NNT 32

• Secondary outcome (high flow vs non-invasive vs standard)
  • ICU mortality (%)
    • 11% vs 25% vs 19% p = 0.047
  • 90 day mortality (%)
    • 12% vs 28% vs 23% p = 0.02
      • High-flow vs Standard: ARR 11.14% (95% CI 0.55% to 21.74%); NNT 9 (95% CI 4.6 to 183.5)
      • High-flow vs NIV: ARR 15.92% (95% CI 5.45% to 26.39%); NNT 7 (95% CI 3.8 to 18.4)
      • Standard vs NIV: ARR 4.78% (95% CI -7.22% to 16.78%); NNT 21 (95% CI cannot be easily represented as they cross infinity – i.e. not statistically significant and cross null hypothesis)
  • Ventilator free days up to 28 days: mean days (SD)
    • 24 (+/- 8) vs 19 (+/-12) vs 22 (+/-10) p = 0.002
  • Duration of ICU stay
    • No statistical difference

• Other outcomes (high flow vs non-invasive vs standard)
  • Respiratory discomfort and dyspnoea score after 1 hour of treatment
    • Improved with high-flow oxygen group compared with other two strategies
  • Complications
    • No statistical difference between groups
    • Time to intubation was similar between groups
  • Post hoc analysis of patients with PaO2/FiO2 < 200mmHg
    • Intubation at day 28: n(%)
      • 29 (34.9%) vs 47 (58%) vs 39 (52.7%) p = 0.009
    • Ventilator free days up to 28 days: mean days (SD)
      • 24 (+/-8) vs 18 (+/-12) vs 21 (+/-10) p = <0.001
    • ICU Mortality: n(%)
      • 10 (12%) vs 23 (28.4%) vs 16 (21.6%) p = 0.03
    • Mortality at 90 days: n(%)
      • 11 (13.2%) vs 26 (32.1) vs 20 (27%) p = 0.01

Authors’ Conclusions

• In patients with acute hypoxaemic respiratory failure and without hypercapnia, treatment with high-flow nasal oxygen, standard face mask oxygen, or non-invasive ventilation did not result in a significantly different intubation rates. There was a significant difference in favour of high-flow nasal oxygen in 90 day mortality

Strengths

• A useful pragmatic trial that addresses an important clinical question
• The co-ordinating centre and all investigators remained unaware of the study group outcomes until the data were locked

Weaknesses

• A simpler study design may have been to compare high-flow oxygen to non-rebreather facemask or non-invasive ventilation
• 25% of the patients in the non-invasive group received this treatment for less than 4 hours each day (IQR 4-12 on day 1; IQR 4-13 on day 2). 50% received this treatment for 8 hours or less. 75% spent the majority of the 24 hour period on facemask standard oxygen. There is a subsequently a large crossover effect with the standard facemask group
• The name of the study is misleading (FLORALI = High FLow Nasal Oxygen in the Resuscitation of patients with Acute Lung Injury). This study is not an investigation of Acute Lung Injury (e.g. 21% of subjects had unilateral infiltrates, thus not meeting the definition of ALI). The most recent definition of ARDS also no longer recognises ALI
• Most patients had pneumonia (82%). The results of this study are not generalisable to all patients with hypoxaemic respiratory failure