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

Critique of:

Background

Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated. Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia.

Methods

Results

The intubation rate (primary outcome) was 38% (40 of 106 patients) in the high-flow–oxygen group, 47% (44 of 94) in the standard group, and 50% (55 of 110) in the noninvasive-ventilation group (P = 0.18 for all comparisons). The number of ventilator-free days at day 28 was significantly higher in the high-flow–oxygen group (24 +/- 8 days, vs. 22 +/- 10 in the standard-oxygen group and 19 +/- 12 in the noninvasive-ventilation group; P = 0.02 for all comparisons). The hazard ratio for death at 90 days was 2.01 (95% confidence interval [CI], 1.01 to 3.99) with standard oxygen versus high-flow oxygen (P = 0.046) and 2.50 (95% CI, 1.31 to 4.78) with noninvasive ventilation versus high-flow oxygen (P = 0.006).

Conclusions

In patients with nonhypercapnic acute hypoxemic respiratory failure, treatment with high-flow oxygen, standard oxygen, or noninvasive ventilation did not result in significantly different intubation rates. There was a significant difference in favor of high-flow oxygen in 90-day mortality.

Abstract adapted from the original provided courtesy of PubMed: A service of the National Library of Medicine and the National Institutes of Health.

Commentary

Acute respiratory failure (ARF) accounts for one-third of intensive care unit (ICU) admission, resulting in a twofold increase in ICU mortality and prolonged ICU length of stay^2,3. ARF requiring endotracheal intubation and mechanical ventilation brings increased risk of mortality and morbidity, yet the optimal time to initiate ventilator support remains unclear. Noninvasive positive-pressure ventilation (NIPPV) reduces the risk of intubation and mortality in patients with hypercarbic ARF from exacerbation of obstructive lung disease⁴ and in patients with cardiogenic pulmonary edema^4,5. NIPPV has not shown consistent benefits in patients with hypoxemic ARF from pneumonia or acute respiratory distress syndrome (ARDS), with some suggestion of worsened outcomes with “de novo” pneumonia^6,7. NIPPV may prevent secretion clearance and is not advisable on patients unable to remove the mask due to aspiration risk^6,7. In such patients, alternative means of non-invasive respiratory support may be desirable.

High-flow nasal cannula (HFNC) oxygen devices deliver up to 40–60L/min at a precise fraction of inspired oxygen (F_iO₂). High flow rates match the patient’s peak inspiratory flow to prevent room air entrainment and improve comfort, while heat and humidification may prevent airway desiccation to improve mucociliary clearance⁸. By flushing carbon dioxide from the airways, HFNC reduces anatomic dead space to increase ventilatory efficiency and reduce work of breathing, in addition to producing minimal levels of positive end-expiratory pressure⁸.

The FLORALI study randomized 310 patients with hypoxemic ARF to nonrebreather face mask, HFNC using the OptiFlow device (Fisher and Paykel Healthcare) or NIPPV with inspiratory pressure titrated to achieve tidal volume 7–10cc/kg¹. The majority of patients had pneumonia and met criteria for ARDS, with bilateral infiltrates and a ratio of P_aO₂ to F_iO₂ (P/F ratio) <=200 on face mask oxygen. The study excluded patients likely to benefit from NIPPV, including those with hypercarbia, exacerbations of obstructive lung disease or cardiogenic pulmonary edema, along with patients likely to be harmed by NIPPV, including those with hemodynamic instability or depressed mental status. There was no significant reduction in the rate of intubation between groups in the main study population (p = 0.18). A post hoc subgroup analysis in patients with a PF ratio <=200 showed a significantly higher risk of intubation with face-mask oxygen (HR 2.07) or NIPPV (HR 2.57) compared to HFNC (p = 0.009). HFNC was associated with lower mortality in the ICU (p = 0.047) and at 90 days (p = 0.02) in both unadjusted and adjusted analyses, with HR’s ranging from 1.85 to 2.60. Patients in the HFNC group had more ventilator-free days and lower dyspnea scores.

Strengths of this study include multi-center, randomized, intention-to-treat design with enrollment from 23 large ICU’s⁹. Patients expected to benefit from NIPPV were systematically excluded. Since rate of intubation was the primary endpoint, a protocol was used to standardize indications for intubation. Study groups were well-matched at baseline and follow-up was complete. The study has a number of limitations that must be considered when applying the results. This was a highly-selected population enriched in patients with ARDS due to pneumonia without obstructive lung disease or heart failure; only 21% of screened patients with hypoxemic ARF were eligible and 12.5% were included. Patients had limited extrapulmonary organ failure, which is a risk factor for HFNC failure in ARDS¹⁰. The study had limited statistical power for the primary endpoint, with an observed intubation rate of 45% compared to an anticipated intubation rate of 60%. Because the study failed to meet its prespecified primary endpoint, the significant results of the post hoc subgroup analysis and the secondary mortality endpoints are hypothesis-generating rather than conclusive. One-fourth of patients in the face mask arm and one-eighth of patients in the HFNC arm crossed over to receive NIPPV; approximately two-thirds of these patients required intubation. It remains unclear why fewer people died in the HFNC arm, although the 7–10cc/kg tidal volume in the NIPPV arm exceeds the recommended 6cc/kg that has been associated with lower mortality in patients with ARDS^11,12. Protocolized intubation criteria may have delayed intubation, as reflected by the occurrence of two deaths during intubation. While the study’s protocolized intubation criteria seem reasonable as part of a research study, the decision to intubate requires considerable judgment and is difficult to fit to a protocol.

The FLORALI study emphasizes that the approach noninvasive respiratory support in ARF should be tailored to both the underlying physiology (hypoxemic versus hypercarbic ARF) and the causative disease process. HFNC may become the preferred noninvasive modality for patients with hypoxemic ARF due to pneumonia or ARDS, while NIPPV will remain preferred for patients with obstructive lung disease or cardiogenic pulmonary edema. Other recent studies of HFNC have shown mixed results depending on the population studied. HFNC failed to show a benefit over NIPPV for pre-oxygenation prior to intubation, although HFNC during intubation did reduce the risk of desaturation during intubation when compared to face mask^13,14. HFNC was inferior to NIPPV for respiratory support during bronchoscopy¹⁵. HFNC performed equally compared to NIPPV for patients developing ARF after cardiothoracic surgery¹⁶. Further studies are needed to guide our use of HFNC for patients with ARF, and several ongoing studies of HFNC are listed on clinicaltrials.gov.

Recommendation

HFNC is safe and can be considered for first line support of patients with severe hypoxemic ARF not requiring immediate intubation, including pneumonia and early ARDS in the absence of hypercarbia, obstructive lung disease or heart failure exacerbation. Careful monitoring in an ICU during HFNC is essential to ensure timely escalation of therapy in the event of HFNC failure. With either HFNC or NIPPV, intubation should be performed before the patient exhausts their physiologic reserves and decompensates.