FLORALI

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 SpOof ≥ 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

  • Standard Oxygen delivered via non-rebreather facemask 
    • Gas flow rate of ≥10L/min and rate adjusted to maintain SpO2 ≥92%
    • Continued until patient recovered or was intubated

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

The Bottom Line

  • This study demonstrates that high-flow oxygen via nasal cannula is non-inferior to oxygen delivered by a non-rebreather facemask and BiPAP in reducing the subsequent need for intubation.
  • High flow oxygen reduces ICU and 90 day mortality compared with the other strategies. It also subjectively improves dyspnoea and respiratory discomfort at one hour compared with the other oxygen delivery devices.
  • Further studies are required to confirm whether high flow oxygen is beneficial in pulmonary and extra pulmonary causes of hypoxaemia and to determine its efficacy in ARDS.

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