FLORALI
PubMed • Full text • PDF • ClinicalTrials.gov
Clinical Question
In patients with acute hypoxemic respiratory failure without hypercapnia, does high-flow oxygen therapy decrease intubation and mortality rates compared to noninvasive ventilation or standard oxygen therapy?
Bottom Line
Risk of death was significantly reduced in patients with acute hypoxemic respiratory failure who received high-flow oxygen therapy compared to those receiving noninvasive ventilation or standard oxygen therapy.
Major Points
There are multiple methods of delivering oxygen that aim to minimize intubation rate and mortality, such as nasal cannula, non-rebreather mask, and noninvasive positive-pressure ventilation (NIPPV) methods like BiPAP and CPAP. There is high quality data that NIPPV reduces intubation rate and mortality in COPD exacerbations[1] and cardiogenic pulmonary edema[2], however its benefits in other forms of acute hypoxemic respiratory failure have yet to be clearly demonstrated.
Published in 2015, the FLORALI trial demonstrated the effectiveness of a new method of oxygen delivery called high-flow nasal cannula (HFNC) in a well-defined subset of patients in acute respiratory failure: those with hypoxemia and without hypercapnia. In this randomized controlled trial, high-flow oxygen therapy had a significant improvement in 90-day mortality compared to either noninvasive ventilation or standard oxygen therapy (12% vs. 28% vs. 23%). While there was no significant reduction in intubation rate overall, patients with more severe hypoxemia, PaO2:FiO2 ≤200 mmHg, did experience a significant reduction in intubation rates with high-flow oxygen therapy, which may have driven this mortality benefit.
In contrast with FLORALI, the HIGH (2018) trial did not find a mortality benefit for HFNC versus standard oxygen supplementation among 776 immunocompromised patients.[3] FLORALI was included in a 2020 meta-analysis.[4]
Guidelines
As of October 2024, no guidelines have been published that reflect the results of this trial.
Design
- Multicenter, open label, randomized, controlled trial
- N=310 patients with acute hypoxemic respiratory failure
- High-flow oxygen therapy (n=106)
- Standard oxygen therapy (n=94)
- Noninvasive ventilation (n=110)
- Setting: 23 ICU centers in France and Belgium
- Enrollment: February 2011 to April 2013
- Complete follow-up at 90 days
- Analysis: Intention-to-treat
- Primary outcome: Proportion of patients intubated at day 28
Population
Inclusion Criteria
- RR ≥25 per minute
- PaO2:FiO2 ≤300 mmHg
- PaCO2 ≤45 mmHg
- No clinical history of chronic respiratory failure
Exclusion Criteria
- Cardiogenic pulmonary edema
- Severe neutropenia
- Hemodynamic instability
- Contraindication to NIPPV (eg, low GCS)
- Urgent need for intubation
Baseline Characteristics
Similar in all three groups
- Age: 60 years
- 64% caused by community-acquired pneumonia
- 77% PaO2:FiO2 ≤200 mmHg
- Mean FiO2 0.65
- SAPS II: 25
Interventions
- Randomized to one of three groups:
- High-flow oxygen therapy: Continuous oxygen through heated humidifier and large binasal prongs, with 50L/min flow at 1.0 FiO2, adjusted to goal: SpO2 ≥92%
- Standard oxygen therapy: Continuous nonrebreather face mask, ≥10 L/min, Goal: SpO2 ≥ 92%
- Noninvasive ventilation: Face mask connected to ventilator with pressure support adjusted to 7-10 ml/kg (PBW) and PEEP 2-10 cm H2O, with adjustment of PEEP/FiO2 to maintain SpO2 ≥92%
- Minimum of 2 calendar days on therapy before switch to standard oxygen therapy allowed
- Between noninvasive ventilation sessions, patients received high-flow oxygen
Outcomes
Comparisons are high-flow vs. standard oxygen vs. noninvasive ventilation.
Primary Outcomes
- Proportion of patients intubated at day 28
- 38% vs. 47% vs. 50% (P=0.18)
- Standard oxygen vs. high-flow: OR 1.45 (0.83–2.55)
- Noninvasive ventilation vs. high-flow: OR 1.65 (0.96–2.84)
Secondary Outcomes
- All-cause mortality in the ICU
- 11% vs. 19% vs. 25% (P=0.047)
- Standard oxygen vs. high-flow: OR 1.85 (0.84–4.09)
- Noninvasive ventilation vs. high-flow: OR 2.55 (1.21–5.35)
- All-cause mortality at 90 days
- 12% vs. 23% vs. 28% (P=0.02)
- Standard oxygen vs. high-flow: OR 2.01 (1.01–3.99)
- Noninvasive ventilation vs. high-flow: OR 2.50 (1.31–4.78)
- Number of ventilator-free days at day 28
- 24 vs. 22 vs. 19 days (P=0.02)
Subgroup Analysis
- Patients with PaO2
- FiO2 ≤200 mmHg:
- Intubation rate: 35% vs. 53% vs. 58% (P=0.01)
- Number of ventilator-free days: 24 vs. 22 vs. 18 days (P<0.001)
- Cause of death
- Refractory shock: 46% vs 55% vs 58% (P=0.04)
- Dyspnea
- Marked improvement – 22% vs. 7% vs. 14%
- Slight improvement– 54% vs. 34% vs. 44%
Adverse Events
- No significant difference between groups
- Number of cardiac arrests occurring before intubation: 2 vs. 1 vs. 0
Criticisms
- Since the majority (>80%) of these patients had pneumonia, it may be inaccurate to generalize these results to sepsis and other causes of acute hypoxemic respiratory failure without hypercapnia.
- This study was underpowered to detect or reject more subtle differences (<20%) in intubation rates.
- Patients in the noninvasive ventilation group received high-flow oxygen between treatments, which may not accurately represent the realistic comparison. Further, the two therapies may have an antagonistic relationship when used in combination.
Funding
- Funded by the Programme Hospitalier de Recherche Clinique Interrégional 2010 of the French Ministry of Health. * Equipment donated by Fisher and Paykel Healthcare who played no other role in the study.
Further Reading
- ↑ Brochard L et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995. 333:817-22.
- ↑ Weng CL et al. Meta-analysis: Noninvasive ventilation in acute cardiogenic pulmonary edema. Ann Intern Med 2010. 152:590-600.
- ↑ Azoulay E et al. Effect of High-Flow Nasal Oxygen vs Standard Oxygen on 28-Day Mortality in Immunocompromised Patients With Acute Respiratory Failure: The HIGH Randomized Clinical Trial. JAMA 2018. 320:2099-2107.
- ↑ Ferreyro BL et al. Association of Noninvasive Oxygenation Strategies With All-Cause Mortality in Adults With Acute Hypoxemic Respiratory Failure: A Systematic Review and Meta-analysis. JAMA 2020. 324:57-67.