Noninvasive respiratory support for acute respiratory failure—high flow nasal cannula oxygen or non-invasive ventilation?

Noninvasive respiratory support for acute respiratory failure—high flow nasal cannula oxygen or non-invasive ventilation?

Gerard F. Curley1,2,3, John G. Laffy1,2,3, Haibo Zhang1,2,3, Arthur S. Slutsky3,4

1Department of Anesthesia, St Michael’s Hospital, and The Critical Illness and Injury Research Centre, Keenan Research Centre for Biomedical Science of St Michael’s Hospital, Toronto, Ontario, Canada; 2Department of Anesthesia, 3Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada; 4Department of Medicine, St Michael’s Hospital, and The Critical Illness and Injury Research Centre, Keenan Research Centre for Biomedical Science of St Michael’s Hospital, Toronto, Ontario, Canada

Correspondence to: Arthur S. Slutsky. Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada. Email:

Submitted Jun 30, 2015. Accepted for publication Jul 09, 2015.

doi: 10.3978/j.issn.2072-1439.2015.07.18

For patients with acute respiratory failure there may be advantages to the avoidance of invasive mechanical ventilation, i.e., ventilation via endotracheal intubation. Indeed, soon after the introduction of invasive mechanical ventilation many complications of positive pressure ventilation were identified (1,2). Some are directly related to the intubation procedure, such as cardiac arrest following endotracheal intubation, and laryngeal or tracheal injury leading to long-term sequelae. Others are related to the fact that the endotracheal tube adversely affects pulmonary host defenses (e.g., cough, mucociliary transport) setting the stage for ventilator-associated pneumonia, that carries its own risk of morbidity and mortality (3). Invasive mechanical ventilation generally requires sedation, which itself is often a cause of prolonged weaning and prolonged mechanical ventilation.

These major safety considerations prompted the development of non-invasive methods for delivering respiratory support without the need for intubation. Convincing evidence that non-invasive ventilation (NIV) diminishes the risk of infectious complications has been obtained from randomized controlled trials and Meta-analyses, as well as from large cohort studies and case-control studies, which have demonstrated substantial decreases in all categories of nosocomial infection (3-7). With NIV, sedation is usually not required or, if necessary, it is administered at low doses (6). By averting airway intubation, non-invasive methods of respiratory support leaves the upper airway intact, preserves airway defenses, and allows patients to eat, vocalize normally, and clear secretions more effectively.

Strengthening the rationale for the use of non-invasive respiratory support is evidence that has accumulated over the past decade that NIV lowers morbidity and mortality rates of selected patients with acute respiratory failure and may shorten hospital length of stay (8), thus reducing costs. NIV is now considered the ventilatory mode of choice in acute respiratory failure due to chronic obstructive pulmonary disease (COPD) exacerbations (9-11), acute cardiogenic pulmonary edema (12,13), and hypoxemic failure in immunocompromised patients (6,14), and for facilitating extubation in patients with COPD who fail spontaneous breathing trials (15). NIV use in these conditions is underpinned by a sound physiologic rationale—in COPD, NIV can address several of the major abnormalities in respiratory mechanics, allowing the patient to generate larger tidal volumes with less effort; in cardiogenic pulmonary edema, NIV decreases left ventricular afterload, and reduces left and right ventricular preload. By contrast, the beneficial effects of NIV remain unclear in patients with de novo acute hypoxemic respiratory failure, that is, non-hypercapnic patients having acute respiratory failure in the absence of a cardiac origin or underlying chronic pulmonary disease. NIV is more likely to fail in hypoxemic patients (16), and NIV failure could be associated with increased mortality (17). In unselected patients admitted to ICUs for acute hypoxemic respiratory failure, the rate of intubation is particularly high, reaching 60% (17,18), and their in-ICU mortality after intubation may exceed 60% (17,18). Thus, NIV may improve outcome of patients who succeed in NIV by avoiding intubation, but may worsen outcome by delaying intubation in those having failed NIV.

Over the past 2 decades, systems to deliver heated and humidified oxygen at high flows through nasal cannulae have been developed as an alternative to standard oxygen delivery systems and NIV. Not withstanding the success of NIV for certain indications, high-flow nasal cannula (HFNC) oxygen delivery has been gaining attention as an alternative means of respiratory support from several clinical research groups and has been proposed as a supportive therapy in critically ill patients with acute respiratory failure (19), including post-operative respiratory failure (20), during bronchoscopy (21), or to prevent severe desaturation during intubation of patients with mild-to-moderate hypoxemia (22). The apparatus comprises an air/oxygen blender, an active heated humidifier, a single heated circuit, and a nasal cannula. At the air/oxygen blender, the inspiratory fraction of oxygen (FiO2) is set from 0.21 to 1.0 at a flow of up to 60 L/min. The gas is heated and humidified with the active humidifier and delivered through the heated circuit.

Theoretically, HFNC has a number of advantages over other respiratory support systems, including conventional nasal cannula, face masks, or NIV. First, because gas is generally warmed to 37 °C and completely humidified in HFNC circuits, mucociliary function remain intact and patients report minimal discomfort (23). This is often in contrast to the delivery of low flow oxygen which is generally not humidified, leading to patient complaints such as dry nose, dry throat, and nasal pain (24,25). Insufficient heating and humidification leads to poor tolerance to oxygen therapy. Second, with HFNC the flow demands of patients are better met, maintaining the inspired FiO2 relatively constant (26). HFNC generates a higher flow rate compared to other oxygen delivery systems, exceeding the patient’s peak inspiratory flow rate in most cases. For example, during hypopharyngeal oxygraphy studies (26), during nose breathing at rest, above a flow rate of 30 L/min using HFNC the measured FiO2 was close to the delivered FiO2. Using conventional devices, oxygen flow is usually <15 L/min. However, the inspiratory flow of patients with respiratory failure varies widely in a range from 30 to more than 100 L/min. The difference between patient inspiratory flow and delivered flow is large, leading to entrainment of room air with the delivered gas, thus resulting in variable and lower than expected FiO2 (27). Third, although delivered through an open system, high flow overcomes resistance against expiratory flow and creates positive nasopharyngeal pressure (28). While the pressure is relatively low compared with closed systems, it is considered adequate to increase lung volume or recruit collapsed alveoli (29,30). A further advantage of HFNC is the wash out of carbon dioxide in anatomical dead space. Breathing frequency is lower with HFNC, while PaCO2 and tidal volume remain relatively constant indicating that dead space is reduced (19,31,32). These results suggest effective carbon dioxide washout with HFNC. Finally, another major difference between NIV and HFNC is the interface. While interfaces for NIV increase anatomical dead space, those for HFNC actually decrease dead space.

Until now, only anecdotal case reports, case series and some preliminary controlled trials have provided an evidence base to guide the use of HFNC in adults with respiratory failure. The recently published FLORALI (high flow oxygen therapy for resuscitation of patients with acute lung injury) study (33), provides much needed randomized controlled trial data on the types and severities of hypoxemic respiratory failure that are most likely to benefit from HFNC. This multicenter 310 patient trial was designed to assess the rate of endotracheal intubation and other clinical outcomes among three groups: high-flow oxygen (heated and humidified air/oxygen mixture at a gas flow rate of 50 L/min applied via large-bore binasal prongs), standard oxygen therapy, and noninvasive ventilation for patients with acute, nonhypercapnic, hypoxemic respiratory failure [ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2:FiO2), ≤300 mmHg]. The trial excluded patients with a history of chronic respiratory disease, including COPD, as well as patients with cardiogenic pulmonary edema, severe neutropenia and hypercapnic patients (PaCO2 >45 mmHg), as NIV has already demonstrated a reduction in the intubation rate and mortality in these patients.

The primary outcome, the rate of endotracheal intubation, did not differ significantly among the groups (high flow 38% vs. standard 47% and NIV 50%) (P=0.18). However, in a post hoc adjusted analysis that included the 238 patients with severe initial hypoxemia (PaO2:FiO2, ≤200 mmHg), the intubation rate was significantly lower among patients who received high-flow oxygen than among patients in the other two groups (P=0.009).

In the entire cohort of 310 patients, the high-flow oxygen significantly increased the number of ventilator-free days and also reduced 90-day mortality, compared with standard oxygen therapy (P=0.046) or NIV (P=0.006). As compared with the other strategies, high-flow oxygen was associated with less respiratory discomfort and a reduction in dyspnea, as measured by validated assessments of patient comfort. Because there was a lower respiratory rate than was observed with the other strategies at the same partial pressure of arterial carbon dioxide, it appears that the system for delivering high-flow oxygen through a nasal cannula also decreased the pulmonary dead space.

What conclusions can we draw from this study? The safety and efficacy of HFNC in non-hypercapnic respiratory failure appears to be superior to NIV or conventional facemask oxygen. However, the study does have some limitations including population itself, the use of NIV therein, the relatively small sample size, and the failure of the study to meet its primary endpoint. Just over 3/4 of the patients in each group had pneumonia, while the same proportion of patients had bilateral infiltrates on chest radiograph, thus fulfilling the criteria for acute respiratory distress syndrome (ARDS). The use of NIV in this patient population is open to question.

The pathophysiologic rationale for NIV use in pneumonia and ARDS is less sound. Unlike exacerbations of COPD, hypoxemic respiratory failure is frequently not associated with frank ventilatory failure, at least in the initial phase. NIV does not address the key pathophysiologic abnormalities of the disease, and in fact a beneficial effect on gas exchange and dyspnea may mask disease deterioration. This could lead to life threatening respiratory failure in case NIV is subsequently interrupted. Therefore, there is likely a severity window for delivering NIV as a preventive support beyond which its use may contribute to harm (34).

Robust large randomized controlled trials of NIV for acute respiratory failure (non-COPD, non-hypercapnic) are relatively scarce, and because of the heterogeneity of causes, studies fail to show that all patient subgroups with hypoxemic respiratory failure benefit equally from NIV. For example, acute pneumonia has long been considered a risk factor for NIV failure (35). A trial evaluating NIV use in heterogeneous respiratory failure showed very poor outcome in the group of patients with pneumonia, with all such patients requiring intubation (36). Another study evaluated NIV use in patients with hypoxemic respiratory failure and identified community acquired pneumonia as a subcategory with a high NIV failure rate (50% intubation rate) (35). A randomized trial showed benefit of NIV in patients with severe community acquired pneumonia, but only in the subgroup with underlying COPD (37). Other studies (7,38), with more rigorous patient selection (such as no alteration in the state of consciousness, absence of organ dysfunction, abundant secretions, cardiac arrhythmias or ischemia) have shown some benefit in patients with acute respiratory failure (including pneumonia) treated with NIV. However, large observational studies describing the use of NIV in pneumonia have often shown high rates of failure (17,35).

Observational studies and subgroup analysis of randomized controlled trials have also identified ARDS as a strong predictor of NIV failure (35,39,40). A multicenter survey (41) evaluated NIV as first-line therapy in early ARDS patients and found that a higher severity score and a PaO2:FiO2 less than or equal to 175 mmHg 1 hour after initiation of NPPV were independently associated with NIV failure. This survey showed that, with NIV use, intubation was avoided in no more than 50% of patients, even in experienced centers. The recent Berlin definition of ARDS suggested that NIV may be indicated only in mild ARDS, and not in severe and moderate ARDS, but also emphasized that the role of NIV in ARDS has to be further evaluated (42). NIV failure in ARDS patients is highly predictable in case of shock, metabolic acidosis, high severity scores of illness, and a greater degree of hypoxemia (40).

Moreover, many patients with ARDS may not be favorable candidates for NIV due to the need to deliver lung protective ventilation. During NIV, high transpulmonary pressure swings and large tidal volumes may be generated, which could lead to the development of ventilator-induced lung injury (VILI) and contribute to the poor outcome observed in intubated patients who fail NIV. Most patients with hypoxemic ARF have a high respiratory drive, and it has been shown experimentally that the increased drive caused by a severe metabolic acidosis may cause lung injury (43). In the study by Frat et al., NIV pressure support levels of 8±3 cm of water, and a PEEP of 5±1 of water resulted in a tidal volume of 9.2±3 mL/kg.

In the FLORALI study (33), it is interesting to note that there were numerically more ICU deaths in the NIV group (27 vs. 12 in the HFNC group and 18 in the standard oxygen group). The unadjusted hazard ratio for ICU death in the three groups was significant only in the NIV vs. HFNC group (HR: 2.55, 95% CI, 1.21-5.35). At 90 days, both the standard oxygen group and the NIV group had increased risk of death, but for the standard oxygen group the confidence interval almost crosses unity (HR: 2.01, 95 CI, 1.01-3.99 for standard oxygen vs. HFNC, HR: 2.5, 95 CI, 1.31-4.78 for NIV vs. HFNC). Importantly, the authors provide some information on why those patients died. Eighteen patients died from refractory shock in the NIV group, vs. six in the HFNC group and twelve in the standard oxygen group. Three died from cardiac arrest in the NIV group, vs. one in each of the other two groups. While the authors state, and the data indicates, that there was no significant difference among the groups in terms of the time until intubation (median 27 hrs in both HFNC and NIV groups vs. 15hrs in standard oxygen groups) or the reasons for intubation, it is clear that NIV can mask deterioration in patients with respiratory failure, while HFNC may simply be a more effective treatment in this patient population. At the very least, this data highlights the importance of careful patient selection for NIV in acute respiratory failure resulting from pneumonia and ARDS.

In conclusion, a growing body of evidence suggests that HFNC oxygen therapy is an innovative and effective modality for the early treatment of adults with respiratory failure associated with diverse underlying diseases. However, there is no therapy that is efficient in every patient and in every type of acute respiratory failure. The study by Frat et al. (33) has improved our knowledge regarding the right indication for HFNC–conscious, cooperative, non-hypercapnic patients, without chronic respiratory failure. While more randomized studies are needed to confirm the clinical advantages of HFNC over other methods in specific adult populations, HFNC should be considered for the treatment of early acute respiratory failure.




Provenance: This is a Guest Editorial commissioned by the Section Editor Ming Zhong (Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China).

Conflicts of Interest: The authors have no conflicts of interest to declare.


  1. Pingleton SK. Complications of acute respiratory failure. Am Rev Respir Dis 1988;137:1463-93. [PubMed]
  2. Stauffer JL, Olson DE, Petty TL. Complications and consequences of endotracheal intubation and tracheotomy. A prospective study of 150 critically ill adult patients. Am J Med 1981;70:65-76. [PubMed]
  3. Girou E, Brun-Buisson C, Taillé S, et al. Secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema. JAMA 2003;290:2985-91. [PubMed]
  4. Girou E, Schortgen F, Delclaux C, et al. Association of noninvasive ventilation with nosocomial infections and survival in critically ill patients. JAMA 2000;284:2361-7. [PubMed]
  5. Nourdine K, Combes P, Carton MJ, et al. Does noninvasive ventilation reduce the ICU nosocomial infection risk? A prospective clinical survey. Intensive Care Med 1999;25:567-73. [PubMed]
  6. Antonelli M, Conti G, Bufi M, et al. Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation: a randomized trial. JAMA 2000;283:235-41. [PubMed]
  7. Antonelli M, Conti G, Rocco M, et al. A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. N Engl J Med 1998;339:429-35. [PubMed]
  8. Tomii K, Seo R, Tachikawa R, et al. Impact of noninvasive ventilation (NIV) trial for various types of acute respiratory failure in the emergency department; decreased mortality and use of the ICU. Respir Med 2009;103:67-73. [PubMed]
  9. Brochard L, Isabey D, Piquet J, et al. Reversal of acute exacerbations of chronic obstructive lung disease by inspiratory assistance with a face mask. N Engl J Med 1990;323:1523-30. [PubMed]
  10. Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial. Lancet 2000;355:1931-5. [PubMed]
  11. Lightowler JV, Wedzicha JA, Elliott MW, et al. Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ 2003;326:185. [PubMed]
  12. Bersten AD, Holt AW, Vedig AE, et al. Treatment of severe cardiogenic pulmonary edema with continuous positive airway pressure delivered by face mask. N Engl J Med 1991;325:1825-30. [PubMed]
  13. Masip J, Roque M, Sánchez B, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA 2005;294:3124-30. [PubMed]
  14. Hilbert G, Gruson D, Vargas F, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med 2001;344:481-7. [PubMed]
  15. Ferrer M, Esquinas A, Arancibia F, et al. Noninvasive ventilation during persistent weaning failure: a randomized controlled trial. Am J Respir Crit Care Med 2003;168:70-6. [PubMed]
  16. Demoule A, Girou E, Richard JC, et al. Increased use of noninvasive ventilation in French intensive care units. Intensive Care Med 2006;32:1747-55. [PubMed]
  17. Demoule A, Girou E, Richard JC, et al. Benefits and risks of success or failure of noninvasive ventilation. Intensive Care Med 2006;32:1756-65. [PubMed]
  18. Schettino G, Altobelli N, Kacmarek RM. Noninvasive positive-pressure ventilation in acute respiratory failure outside clinical trials: experience at the Massachusetts General Hospital. Crit Care Med 2008;36:441-7. [PubMed]
  19. Sztrymf B, Messika J, Bertrand F, et al. Beneficial effects of humidified high flow nasal oxygen in critical care patients: a prospective pilot study. Intensive Care Med 2011;37:1780-6. [PubMed]
  20. Stéphan F, Barrucand B, Petit P, et al. High-Flow Nasal Oxygen vs Noninvasive Positive Airway Pressure in Hypoxemic Patients After Cardiothoracic Surgery: A Randomized Clinical Trial. JAMA 2015;313:2331-9. [PubMed]
  21. Simon M, Braune S, Frings D, et al. High-flow nasal cannula oxygen versus non-invasive ventilation in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy--a prospective randomised trial. Crit Care 2014;18:712. [PubMed]
  22. Miguel-Montanes R, Hajage D, Messika J, et al. Use of high-flow nasal cannula oxygen therapy to prevent desaturation during tracheal intubation of intensive care patients with mild-to-moderate hypoxemia. Crit Care Med 2015;43:574-83. [PubMed]
  23. Chikata Y, Izawa M, Okuda N, et al. Humidification performance of two high-flow nasal cannula devices: a bench study. Respir Care 2014;59:1186-90. [PubMed]
  24. Chanques G, Constantin JM, Sauter M, et al. Discomfort associated with underhumidified high-flow oxygen therapy in critically ill patients. Intensive Care Med 2009;35:996-1003. [PubMed]
  25. Campbell EJ, Baker MD, Crites-Silver P. Subjective effects of humidification of oxygen for delivery by nasal cannula. A prospective study. Chest 1988;93:289-93. [PubMed]
  26. Ritchie JE, Williams AB, Gerard C, et al. Evaluation of a humidified nasal high-flow oxygen system, using oxygraphy, capnography and measurement of upper airway pressures. Anaesth Intensive Care 2011;39:1103-10. [PubMed]
  27. Bazuaye EA, Stone TN, Corris PA, et al. Variability of inspired oxygen concentration with nasal cannulas. Thorax 1992;47:609-11. [PubMed]
  28. Parke R, McGuinness S, Eccleston M. Nasal high-flow therapy delivers low level positive airway pressure. Br J Anaesth 2009;103:886-90. [PubMed]
  29. Corley A, Caruana LR, Barnett AG, et al. Oxygen delivery through high-flow nasal cannulae increase end-expiratory lung volume and reduce respiratory rate in post-cardiac surgical patients. Br J Anaesth 2011;107:998-1004. [PubMed]
  30. Riera J, Pérez P, Cortés J, et al. Effect of high-flow nasal cannula and body position on end-expiratory lung volume: a cohort study using electrical impedance tomography. Respir Care 2013;58:589-96. [PubMed]
  31. Itagaki T, Okuda N, Tsunano Y, et al. Effect of high-flow nasal cannula on thoraco-abdominal synchrony in adult critically ill patients. Respir Care 2014;59:70-4. [PubMed]
  32. Sztrymf B, Messika J, Mayot T, et al. Impact of high-flow nasal cannula oxygen therapy on intensive care unit patients with acute respiratory failure: a prospective observational study. J Crit Care 2012;27:324.e9-13.
  33. Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med 2015;372:2185-96. [PubMed]
  34. Brochard L, Lefebvre JC, Cordioli RL, et al. Noninvasive ventilation for patients with hypoxemic acute respiratory failure. Semin Respir Crit Care Med 2014;35:492-500. [PubMed]
  35. Antonelli M, Conti G, Moro ML, et al. Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study. Intensive Care Med 2001;27:1718-28. [PubMed]
  36. Honrubia T, García López FJ, Franco N, et al. Noninvasive vs conventional mechanical ventilation in acute respiratory failure: a multicenter, randomized controlled trial. Chest 2005;128:3916-24. [PubMed]
  37. Confalonieri M, Potena A, Carbone G, et al. Acute respiratory failure in patients with severe community-acquired pneumonia. A prospective randomized evaluation of noninvasive ventilation. Am J Respir Crit Care Med 1999;160:1585-91. [PubMed]
  38. Ferrer M, Esquinas A, Leon M, et al. Noninvasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial. Am J Respir Crit Care Med 2003;168:1438-44. [PubMed]
  39. Gristina GR, Antonelli M, Conti G, et al. Noninvasive versus invasive ventilation for acute respiratory failure in patients with hematologic malignancies: a 5-year multicenter observational survey. Crit Care Med 2011;39:2232-9. [PubMed]
  40. Rana S, Jenad H, Gay PC, et al. Failure of non-invasive ventilation in patients with acute lung injury: observational cohort study. Crit Care 2006;10:R79. [PubMed]
  41. Antonelli M, Conti G, Esquinas A, et al. A multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-line intervention for acute respiratory distress syndrome. Crit Care Med 2007;35:18-25. [PubMed]
  42. Ferguson ND, Fan E, Camporota L, Antonelli M, et al. The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med 2012;38:1573-82. [PubMed]
  43. Mascheroni D, Kolobow T, Fumagalli R, et al. Acute respiratory failure following pharmacologically induced hyperventilation: an experimental animal study. Intensive Care Med 1988;15:8-14. [PubMed]
Cite this article as: Curley GF, Laffey JG, Zhang H, Slutsky AS. Noninvasive respiratory support for acute respiratory failure—high flow nasal cannula oxygen or non-invasive ventilation? J Thorac Dis 2015;7(7):1092-1097. doi: 10.3978/j.issn.2072-1439.2015.07.18