The HFNC is very versatile and user friendly. It can be used in a low-monitoring environment, with almost no knowledge of mechanical ventilation. However, most patients treated with the HFNC are extremely hypoxemic, which raises important questions regarding whether it should be used in such conditions. Regardless of this controversy, several potential clinical uses for the HFNC have emerged in recent years. Among these are included the respiratory support of patients with acute hypoxemic respiratory failure or respiratory distress syndrome (ARDS), with respiratory compromise induced by heart failure and with respiratory compromise post-extubation. In this review, we also address the HFNC as an adjunct during airway instrumentation, for immune compromised patients, and as a means of reducing suffering at the end of life.
ARDS and Acute Hypoxemic Respiratory Failure
In 2012, Rello et al. described a series of patients with severe hypoxemia as a result of H1N1 pneumonitis (O
2Sat < 92% on more than 9 l/min of oxygen via face mask). Among the patients receiving oxygen therapy via a HFNC, almost half (9/20) never required intubation and non-responders were obvious within 6 h of initiating HFNC therapy. Importantly, despite the high flows being used, none of the treating medical and nursing staff were infected with the viral disease [
14].
Frat et al. randomized 310 patients with acute respiratory failure (PaO
2/FiO
2 < 300) in 23 medical centers to treatment with either a face mask, NIPPV or HFNC. There was no difference in the intubation rate between the groups but patients treated with the HFNC had more ventilator-free days (if intubated) and better survival rates even after adjustment for simplified acute physiology score II (SAPS II) and a history of cardiac insufficiency [
15]. This paper was subject to several criticisms: that the trial was not powered to detect a difference in mortality [
16], that an excessive number of patients were excluded (only 313 of the 2506 screened patients were randomized) [
17], that treatment with NIV was suboptimal [
18], that there was significant treatment overlap between the groups [
18] and finally that the fragility index was low (i.e., it would take only 5 events to change the significance of the results) [
16]. Frat et al. emphasized the advantage of the homogeneity of their study groups in their response to comments regarding patient exclusion, noted that five more deaths would represent almost 40% of the patients who died and stated that the treatment provided with NIV (median 8 h daily for the first two days) was hardly suboptimal and that the fact that the NIV group received HFNC support between NIV sessions only strengthens the argument for the benefit of HFNC [
19].
Three meta-analyses have studied the literature comparing HFNC to conventional oxygen therapy and NIV in patients with acute hypoxemic respiratory failure. These are presented in Table
1. To summarize, mortality remains unaffected but the HFNC seems to be better tolerated than conventional oxygen therapy by the patients. Although there seems to be a signal suggesting that the HFNC may reduce intubation rate this issue remains controversial; one of the papers suggested this finding may be specific to high-risk patients (as defined by APACHE II or SAPS II scores) [
20], whereas another included a trial sequential analysis which demonstrated that more studies on the topic are required [
21].
Table 1
Meta-analyses of the use of high-flow nasal cannulas (HFNCs) in hypoxemic respiratory failure
| Adults with PaO2/FiO2 ≤ 300 mmHg OR SpO2 < 92% on 10–12 l/min O2 | 18 | 3881 | NIV or conventional oxygen therapy | Lower compared to conventional oxygen therapy but similar to NIV | Similar | Lower RR with HFNC compared to both conventional oxygen therapy and NIV. PaO2/FiO2 better than with conventional oxygen therapy. No difference in ICU LOS. No effect on PaCO2 or pH |
| Adults with acute hypoxemic respiratory failure (PaO2/FiO2 ≤ 300) | 6 | 1892 | NIV or conventional oxygen therapy | Lower compared to conventional oxygen therapy in high-risk patients, but similar to NIV | Similar | |
| Adults with respiratory failure | 9 | 2507 | Conventional oxygen therapy | Similar | Similar | Better tolerance of HFNC |
Hypoxemia Induced by Severe Heart Failure
Roca et al. studied 10 patients with New York Heart Association (NYHA) class III heart failure during treatment with HFNC (baseline, 20 l/min, 40 l/min and post-treatment). The degree of inferior vena cava (IVC) collapse decreased in proportion to the gas flow provided, returning to baseline after treatment discontinuation (median 37, 28, 21 and 39% respectively). At the same time, respiratory rates nearly halved. The researchers concluded that the HFNC reduces preload reduction and thus may benefit patients with heart failure [
22]. This study was criticized later by Esquinas and Papakados who noted that IVC collapsibility may be affected by multiple factors that had not been controlled for by the investigators (e.g., airway leaks, peak inspiratory and expiratory pressures, respiratory breathing patterns, airway resistance and flow characteristics) and that preload reduction should have also affected the pulmonary artery pressure and right and/or left ventricular ejection fraction, all of which remained unaffected, making the assumption regarding mechanism void [
23].
In another study of the same issue (i.e., whether the HFNC generates a continuous positive airway pressure [CPAP] effect), five female and five male healthy volunteers were connected to a HFNC at flows ranging between 0 and 60 l/min. The pressure generated inside the pharynx (measured using a catheter) showed that an increase in flow of 10 l/min produced a 0.8 cmH
2O increase in expiratory pressures. Additional factors increasing this pressure were mouth closure (2 cmH
2O), female sex (0.6 cmH
2O), and greater height (0.5 cmH
2O per every 10 cm) [
6].
Post-extubation Respiratory Compromise
The rate of failed extubation is very variable but may range up 20% or more [
24,
25] and the ideal treatment for prevention of reintubation has yet to be determined. Whether HFNC is beneficial post-extubation has been studied in patients after cardiothoracic surgery, abdominal surgery and in general ICU patients at both high- and low-risk for reintubation.
Stéphan et al. randomized high-risk patients from six medical centers who developed hypoxemia after cardiothoracic surgery to either HFNC (
n = 414) or NIV (
n = 416). Patients were included only if they had failed a spontaneous breathing trial or extubation previously, or had other risk factors for failed extubation (body mass index [BMI] > 30 or left ventricular ejection fraction [LVEF] < 40%). The authors concluded that the HFNC is a valid treatment option in this selective population after finding that the HFNC was non-inferior to NIV in terms of treatment failure, reintubation rate, time to treatment failure and mortality and that this treatment caused less pressure sores and skin breakdown and decreased respiratory rates [
26]. A meta-analysis comparing HFNC with conventional oxygen therapy via face mask in the same patient population, adults extubated after cardiac surgery, found only two studies [
27,
28] appropriate for inclusion (overall 495 patients). The HFNC was associated with less “escalation of therapy” (e.g., the need to increase HFNC flow, crossover to NIV) but the eventual reintubation rate was similar [
29].
In the OPERA (Optiflow® to prevent Post-Extubation hypoxemia after Abdominal surgery) trial, Futier et al. randomized patients after abdominal surgery in three medical centers to preemptive application of either HFNC (
n = 108) or conventional oxygen therapy via face mask (
n = 112). No significant differences were found in patient outcomes [
30]. Maggiore et al. randomized general ICU patients at risk of hypoxemia (PaO
2/FiO
2 < 300 immediately before extubation) to preemptive use of either the HFNC (
n = 53) or a Venturi mask (
n = 52). Patients treated with the HFNC had higher PaO
2/FiO
2 ratios and less interface displacement. They also desaturated less, underwent fewer reintubations and required less ventilator support. Contrary to Futier et al. these authors concluded that the HFNC should have a role in pre-emptive post-extubation management [
31].
These inconclusive results drove others to try to determine which patients would benefit from a HFNC after extubation. Patients from seven sites were classified as either high- or low-risk for reintubation. Elderly patients (> 65 years old) and those with a high burden of disease (APACHE II score > 12 points on extubation day, or > 1 comorbidity), risk factors for failed extubation (BMI > 30, heart failure as the primary indication for mechanical ventilation, moderate to severe chronic obstructive pulmonary disease [COPD]) or respiratory issues potentially affecting weaning (airway patency problems, inadequate management of secretions, difficult/prolonged weaning, mechanical ventilation > 7 days) were defined as high risk. The high-risk patients were randomized to either NIV (
n = 314) or HFNC (
n = 290). The low-risk patients were randomized to either conventional oxygen therapy (
n = 263) or HFNC (
n = 264). The high-risk group demonstrated non-inferiority of the HFNC compared to NIV regarding reintubation rate and mortality. Only patient comfort was improved with the HFNC [
32]. The low-risk group demonstrated a lower rate of reintubation within 72 h with the HFNC, mainly attributable to a decrease in respiratory problems. The number needed to treat in this group was calculated as 1 per 14 (95% confidence interval 8.14) [
33].
In conclusion, in post-extubation respiratory failure, the HFNC is consistently better tolerated than NIV. However, although the HFNC seems non-inferior to NIV with regards to intubation and mortality after cardiothoracic surgery and in high-risk ICU patients, its status remains controversial after abdominal surgery. It remains to be elucidated whether these dissimilarities stem from a variable effect on thoraco-abdominal coordination or other causes. In low-risk hypoxemic patients, support with the HFNC seems to prevent intubation to a certain degree compared to conventional oxygen therapy. The specific subgroups of patients that will benefit from this treatment after extubation require further research.
Airway Instrumentation
The HFNC has been studied as an adjunct to airway instrumentation during manipulation of the airway (e.g., bronchoscopy, intubation) in patients with both low and high risk (i.e., hypoxemia, morbid obesity).
Simon et al. randomized hypoxemic patients (PaO
2/FiO
2 < 300) undergoing bronchoscopy in the critical care setting to HFNC or NIV (20 patients per group). The FiO
2 was set initially to 1.0 and then adjusted to achieve SaO
2 of above 90%. The HFNC was set to deliver 50 l/min and NIV was set to a PEEP of 3–10 cmH
2O and a pressure support of 15–20 cmH
2O. The authors found that the HFNC was inferior to NIV for maintenance of oxygenation during bronchoscopy of critical care patients with moderate to severe hypoxemia [
34].
Lucangelo et al. compared delivery of 50% oxygen before and during bronchoscopy using either a HFNC (40 or 60 l/min) or a Venturi mask in stable patients (SaO
2 > 90% while breathing room air) undergoing bronchoscopy. Fifteen patients in each group contributed data at baseline (while breathing room air), at the end of bronchoscopy (during which they had received 50% oxygen using the assigned treatment modality) and 10 min after bronchoscopy (at which time they were receiving 35% oxygen through a Venturi mask). Patients receiving 60 l/min via HFNC maintained higher PaO
2 values, higher arterial-alveolar oxygen tensions and higher PaO
2/FiO
2 ratios both during and after the procedure. In an attempt to explain their findings, the authors measured airway pressures in healthy volunteers; at a flow rate of 60 l/min the median pressure measured was 3.6 cmH
2O whereas at a flow rate of 40 l/min, the median pressure measured was 0 cmH
2O. Although interesting, this finding does not necessarily mean that HFNC at 60 l/min must be used to maintain oxygenation during bronchoscopy in patients with mild respiratory dysfunction as suggested by the authors [
35].
Induction of sedation/anesthesia for intubation requires (ideally) pre-oxygenation followed by administration of medications (sedatives and/or neuromuscular blockers). The resultant apnea provides better conditions for vocal cord visualization [
36] but at the same time may be accompanied by downward spiraling hypoxemia [
37]. Although oxygenating face masks must be removed for intubation, the HFNC may be left in place, theoretically maintaining CPAP and thereby prolonging the non-hypoxemic apnea time. Vourc’h et al. assigned adult patients with respiratory failure (PaO
2/FiO
2 < 300, respiratory rate > 30) in six ICUs to one of two groups during intubation: either 100% FiO
2/60 l/min delivered by HFNC (
n = 63) or 15 l/min O
2 delivered by a face mask (
n = 61). The HFNC was kept in place during intubation whereas the face mask was removed after induction of general anesthesia. Pre-oxygenation parameters, the duration of the intubation procedure and the quality of airway visualization were similar in the two groups. Despite randomization, the two groups had similar “lowest SaO
2s” and mortality rates. The authors therefore concluded that “using HFNC without discontinuation during an apneic period was not more effective than face mask in preventing desaturation regardless of the severity of respiratory distress” [
37].
Jaber et al. randomized hypoxemic patients undergoing intubation in a single ICU (hypoxemia defined as SaO
2 < 90% on 0.5 FiO
2, respiratory rate > 30, PaO
2/FiO
2 < 300 within the four hours before inclusion) to pre-oxygenation with either a combination of NIV and HFNC (
n = 25) or NIV alone (
n = 24). The time from induction to secure airway was 120 and 60 s for the intervention and control groups, respectively (calculated as non significant). The outcome was assessor-blinded. No differences were observed between the groups in intubation-related complications. However, during intubation, peripheral capillary oxygen saturation (SpO
2) remained constant at 100% with combination treatment but decreased to 96% with NIV alone [
38]. Although this difference was statistically significant, its clinical importance is doubtful.
Simon et al. also randomized patients with hypoxemic respiratory failure who required intubation to pre-oxygenation with either a HFNC with 50 l/min of 100% oxygen (
n = 20) or a bag-valve-mask with 10 l/min of 100% oxygen (n = 20). In the 1 min of apnea after induction of anesthesia, saturation dropped significantly more in the bag-valve-mask group than with the HFNC [
39]. The authors observed that only patients that had not been pre-treated with HFNC or NIV prior to pre-oxygenation demonstrated an increase in SpO
2. This led them to conclude that pre-oxygenation with a HFNC prior to intubation should be considered only in patients with mild-moderate hypoxemia. In contrast to other authors who have published on this topic, these authors also calculated the power required to detect a 3% difference in SpO
2 between the groups and concluded that their study had been underpowered to detect the difference they had sought.
Obese patients have a particularly low functional residual capacity (FRC), which increases the likelihood and severity of hypoxemia during apnea when compared to other patients [
40]. Heinrich et al. randomized obese patients (BMI > 35) undergoing intubation for bariatric surgery to receive FiO
2 1.0 in one of three modes (11 per group): HFNC (flow 50 l/min), face mask connected to an anesthesia ventilator (flow 12 l/min) and CPAP (7 cmH
2O). PaO
2 increased significantly in all the groups within one minute of initiating pre-oxygenation. However, after five minutes, patients treated with a HFNC had a significantly higher PaO
2 than those treated with a face mask and, after intubation (at 8.5 min), SpO
2 decreased significantly with the face mask and CPAP but not with the HFNC [
40].
To summarize, HFNCs may have a role in decreasing apneic hypoxemia during airway instrumentation but multicenter trials that include a greater number of patients are required to establish this claim.
Immune Compromise
Immune compromised patients have higher mortality rates than those with no immune compromise when intubated for respiratory failure [
41,
42]. Studies have provided conflicting results regarding mortality and intubation rates when NIV (as a modality to prevent intubation) is used in this population [
43]. Coudroy et al. reviewed the files of immune compromised patients with respiratory failure (i.e., tachypnea or respiratory distress and PaO
2/FiO
2 ≤ 300). The patients were treated with either HFNC (
n = 60), NIV alternating with HFNC (
n = 30), or conventional oxygen therapy (25 patients). The rates of both intubation and mortality were higher with NIV than with the HFNC [
43]. Lee et al. retrospectively studied all patients with hematological malignancy treated with HFNC in a single medical center (
n = 45); one third recovered and the rest eventually received invasive mechanical ventilation due to treatment failure. The mortality rate was 62.2%. Patients who needed endotracheal intubation had higher rates of bacterial pneumonia and death than those who required HFNC treatment alone [
44]. Another post-hoc analysis of adult ICU patients admitted with respiratory failure yielded quite the opposite result; the intubation rate among patients treated with HFNC was 80% and the mortality rate was 73% vs. 26.7% in intubated patients. The major reason for HFNC failure was pneumonia [
45]. None of these studies adjusted for variables that may have driven the choice of treatment (e.g., selection of NIV in patients who were a-priori worse or avoidance of intubation due to futility). Thus, the data regarding use of the HFNC in immune compromised patients are not only conflicting but also of poor quality.
End-of-Life Care
In 2004, the expert working group of the scientific committee of the association of palliative medicine proposed that oxygen therapy be prescribed for patients with advanced cancer if it can alleviate the symptom of breathlessness [
46]. Epstein et al. searched the database of a single hospital and identified 183 cancer patients, 55% with a do-not-attempt-resuscitation (DNAR) order, who had been treated with HFNC (median treatment time 3 days): 41% improved, 44% remained stable and 15% deteriorated during therapy. The overall mortality rate was 55% [
47]. In another retrospective cohort of hypoxemic ICU patients with a ‘do-not-intubate’ order (
n = 50), the authors noted a significant increase in oxygenation and a decrease in respiratory rate despite the eventual 60% mortality rate (median treatment time 30 h) [
48]. The justification for palliative therapy with the HFNC includes both ethical considerations (beneficence) and economic considerations (justice). The benefit to be considered is alleviation of suffering. The justice to be considered is the cost of care. Fealy et al. studied ICU patients treated with a HFNC (
n = 35) versus historical controls treated with a high-flow face mask (
n = 48). The device cost per patient was reduced from $32.56 to $17.62 [
49].