Abstract
BACKGROUND: High-flow nasal cannula (HFNC) is increasingly used for the management of respiratory failure. Settings include 
, total gas flow, and temperature target. Resulting absolute humidity (AH) at the nasal cannula may affect clinical tolerance, and optimal settings with respect to hygrometry remain poorly documented.
METHODS: A bench study was designed to assess AH delivered by 4 HFNC devices (Optiflow, Airvo 2, Precision Flow, and Hydrate) according to flow, ambient temperature, and other available settings. Clinical tolerance of different levels of hygrometry (20, 30, and 40 mg H2O/L) was evaluated in 15 healthy volunteers.
RESULTS: With 
set at 1.0, normal ambient temperature, and settings made accordingly to the manufacturers’ recommendations, mean ± SD AH was 42.2 ± 3.1, 39.5 ± 1.8, 35.7 ± 2.0, and 32.9 ± 2.7 mg H2O/L for the Airvo 2, Optiflow, Hydrate, and Precision Flow, respectively, (P < .001). AH dropped from −3.5 to −10.7 mg H2O/L (P <. 001) with high ambient temperature, except for the Precision Flow. Increasing flow did not significantly affect AH except for the Precision Flow (from 36.4 ± 1.6 to 29.8 ± 0.2 mg H2O/L at 10 and 40 L/min, respectively, [P < .001]). The lowest AH was encountered with the Optiflow set with noninvasive ventilation (NIV) mode, without compensation algorithm, and at high ambient temperature (14.2 ± 1.5 mg H2O/L). In studied subjects, AH significantly affected breathing comfort, reduced from 7.0 ± 1.0 to 3.0 ± 2.0 at 40 and 20 mg H2O/L, respectively, (P < .001). Comfort was similar at 30 and 40 mg H2O/L.
CONCLUSIONS: When used according to manufacturer’s recommendations and at normal ambient temperature, all the HFNC devices evaluated achieved satisfactory hygrometric output with respect to breathing comfort evaluated in healthy subjects (≥ 30 mg H2O/L). Substantial differences exist between devices, and optimal knowledge of their working principles is required as inappropriate usage may dramatically alter efficacy and clinical tolerance.
Introduction
High-flow nasal cannula (HFNC) devices have been developed and introduced in the market over the past decade.1,2 They deliver flows up to 60 L/min, and 
can be adjusted from 0.21 to nearly 1.0. Several large-scaled, randomized, controlled trials comparing HFNC to conventional oxygen therapy in patients with various etiologies of acute hypoxemic respiratory failure have reported conflicting results in terms of respiratory complications or survival.3-6 However, HFNC is frequently used in the management of acute hypoxemic respiratory failure.7-9
The use of high flows allows better control of delivered 
,10 but beyond this, many physiological and clinical benefits have been suggested.11,12 HFNC devices have repeatedly been reported to improve comfort,3,13-15 decrease breathing frequency3,6,16-19 and respiratory effort20-23 in comparison with conventional oxygen therapy. Thus, these benefits have promoted the widespread use of this therapy.
Of note, besides the well-described detrimental effects of dry and cold gas inhalation on airway mucosa,24,25 the use of high flows has been shown to markedly affect patient breathing comfort.26 Actually, the clinical tolerance of such flows during HFNC is allowed by the delivery of heated and humidified gas, significantly reducing mouth and throat dryness.13,26 There is, nevertheless, a paucity of data available in the literature regarding hygrometric performances of HFNC devices, even though this aspect is likely to play a major role in patient tolerance and thus in the treatment success.
We, therefore, designed this study to evaluate the impact of different hygrometric levels on the comfort of breathing in healthy volunteers and to assess the hygrometric performances of several available HFNC devices under various conditions.
QUICK LOOK
Current Knowledge
The clinical tolerance of high-flow nasal cannula (HFNC) has been repeatedly suggested to be related to adequate warming and humidification of respiratory gases, but the technical performances of available devices and clinical tolerance of different levels of hygrometry remain poorly documented. Consequently, clinical recommendations in terms of hygrometric output for HFNC are lacking.
What This Paper Contributes to Our Knowledge
Common HFNC devices can deliver adequate inspiratory humidity during optimal conditions, but substantial under-humidification may occur with high ambient temperature, high flows, and low target temperature. Our data suggest delivering a minimum humidity target around 30 mg H2O/L during HFNC therapy.
Methods
Clinical Study
Subjects.
The ethics review board of the Institut Universitaire de Cardiologie et de Pneumologie de Québec approved the study protocol (# 21115), and all subjects gave their written informed consent prior to enrollment. Eligibility was assessed by a medical questionnaire confirming the absence of any significant respiratory disease, rhinitis, or chronic medication.
Protocol.
Subjects underwent 3 sessions of HFNC performed under 3 randomized hygrometric conditions: 20, 30, and 40 mg H2O/L of absolute humidity (AH). During every session, the flow was set at 40 L/min, and the 
was set at 0.21. Ambient temperature in the laboratory was set at 21°C. The target values of AH of inspired gases were achieved with the use of specific settings on the MR730 heater humidifier (Fisher & Paykel Healthcare, Auckland, New Zealand) and controlled before each evaluation by psychrometric measurements (Supplemental Fig. 2) (see the supplementary materials at http://www.rcjournal.com).27,28 Each session lasted for 10 min, with a 5-min wash-out period in between. Subjects were blinded for the tested condition.
Measurements.
At the end of each session, subjects were asked to evaluate their breathing comfort on a 10-cm visual analog scale, ranging from 0 (extremely uncomfortable) to 10 (extremely comfortable). Subjects were also asked on a 4-point scale to score their nasal dryness (from 0 = no dryness to 3 = severe dryness) and the presence of nasal droplets (from 0 = no droplets to 3 = numerous droplets).
Bench Study
We tested 4 devices with different working principles: Optiflow and Airvo 2 (Fisher & Paykel Healthcare, Auckland, New Zealand), Precision Flow (Vapotherm, Stevensville, Maryland), and Hydrate Omni (Hydrate, Midlothian, Virginia) (Supplemental Fig. 1). All these devices increase water content in inspiratory gases but through different technologies described in the online supplement (see the supplementary materials at http://www.rcjournal.com).
Protocol.
HFNC devices were successively evaluated with a randomized sequence of 4 different flows (10, 20, 30, and 40 L/min for Optiflow, Precision Flow, and Hydrate; and 15, 20, 30, and 40 L/min for Airvo 2). Highest flows were also evaluated when available (ie, 50 L/min with Airvo 2 and 60 L/min for Optiflow). During each condition, 
was set to the highest value available (
max, ie, approximately 100%). An evaluation of the effects of different 
with the Optiflow and Airvo 2 is provided in the online supplement. As ambient air temperature can markedly affect hygrometric performances of heated-wire humidifiers,29 we performed all measurements under normal (22–24°C) and high ambient temperatures (28–30°C). The target temperature on the devices was set at 37°C or “invasive” mode, as recommended by manufacturers for HFNC usage. Conditions evaluated are summarized in Table 1.
Devices and Conditions Evaluated During the Protocol
All devices evaluated propose adjustable temperature that can be modified by 1°C increments (Precision Flow, Hydrate) or be driven by “pre-settings” regulating the temperature at the outlet of the humidification chamber (“invasive” and “noninvasive ventilation” [“NIV”] modes with the Optiflow and 37°C, 34°C, and 31°C with the Airvo 2). We, therefore, performed additional measurements to evaluate these pre-settings with the Optiflow and Airvo 2 with both normal and high ambient temperatures. We also performed measurements with the Optiflow with and without compensation algorithm activated.29 Measurements of the humidity of medical oxygen with and without cold humidification were also performed at 10 L/min with standard oxygen circuits to be used as comparison values.
Measurements.
Hygrometric measurements were performed after 2 h of steady state using the psychrometric method on which additional information is provided in the online supplement.27,28 Measurements were taken on the distal part of the circuit, that is, just before the nasal cannula (Supplemental Fig. 2) (see the supplementary materials at http://www.rcjournal.com). For each condition, 3 measurements were obtained on separate days, and results are given as mean ± SD.
Statistical Analysis
The clinical part of the trial consisted of subjects on HFNC randomized to 3 hygrometric conditions. A general linear mixed model using a multinomial distribution and a cumulative link function was defined to analyze their nasal dryness, nasal droplets, and their breathing comfort. The first part of the bench study was designed to evaluate 4 HFNC devices with a randomized sequence of 2 room air temperature conditions. After a room air condition was assigned to the device, the 4 different flows were applied in random order. The split-plot statistical model was performed to analyze as a crossover design for the device, and temperature was used, and flows were nested into a condition [or “trial”] using room air. Using this statistical approach, interaction factors were significant. To simplify the statistical analyses, each device was analyzed separately. This approach allowed us to analyze all the flows for Airvo 2 and Optiflow devices. The second part of the trial compared the effects of switching on and off the compensation algorithm for the Optiflow device. Crossover for flows and algorithm factors was nested within an algorithm status. Separate split-plot analyses were performed for the intubation and NIV modes, respectively. The third part of the trial was to analyze the Airvo 2 device at the different preset temperatures. Air room condition and flows were analyzed as crossed factors. The normality hypothesis was verified using the Shapiro-Wilk test using residuals from the statistical model. The results were considered significant when P value was below the 5% threshold. All these statistical analyses were carried out using SAS v9.4 (SAS Institute, Cary, North Carolina).
Results
Clinical Study
Fifteen subjects (age 33 ± 8 y, 9 males) participated in the study. Breathing comfort was significantly lower at 20 mg H2O/L compared to 30 and 40 mg H2O/L, respectively, 3.0 ± 2.0 versus 7.0 ± 2.0 versus 7.0 ± 1.0 (P < .001) (Fig. 1). Nasal dryness sensation was more pronounced at 20 mg H2O/L compared to 30 and 40 mg H2O/L, respectively, 1.9 ± 1.1 versus 0.5 ± 0.8 versus 0.2 ± 0.4 (P = .004) (Supplemental Fig. 3) (see the supplementary materials at http://www.rcjournal.com). The presence of nasal droplets increased with hygrometric level delivered, from 0.4 ± 0.6 to 0.5 ± 0.8 and 0.8 ± 0.8 at 20, 30, and 40 mg H2O/L, respectively, (P = .25) (Supplemental Fig. 4) (see the supplementary materials at http://www.rcjournal.com). All but one subject stated that they preferred when flow was delivered at 30 or 40 mg H2O/L (respectively, 6 and 8 subjects).
Breathing comfort of healthy subjects according to the hygrometry of HFNC. *P ≥ .001 in comparison with 20 mg H2O/L. Each line represents the breathing comfort evaluated on a 10-cm visual analog scale after 10 min of HFNC set at 40 L/min with varying humidity levels for each subject (blind for the conditions). Mean breathing comfort is represented by the bold line.
Bench Study
In total, we performed 366 hygrometric measurements, evaluating 122 different conditions of HFNC delivery that can be summarized as follows.
Conventional oxygen therapy with wall medical oxygen set at 10 L/min delivers hygrometric levels of 2.3 ± 0.3 mg H2O/L and 15.9 ± 0.5 mg H2O/L when administered without and with cold humidification systems, respectively. All flows combined, the highest level of hygrometry was found with the Airvo 2 set at 37°C with normal ambient temperature (41.5 ± 3.1 mg H2O/L); and the lowest was found with the Optiflow set in “NIV” mode, with the compensation algorithm switched off with high ambient temperature (14.2 ± 1.5 mg H2O/L).
Impact of device on delivered humidity.
With flows ranging from 10–15 to 40 L/min (available for all devices), normal ambient temperature (22–24°C) and settings made accordingly to the manufacturers’ recommendations (ie, target temperature set at 37°C or “invasive” mode, compensation algorithm activated when available), all the devices evaluated delivered hygrometric levels close to or above 30 mg H2O/L. On average, the hygrometry was higher with the Airvo 2 in comparison with the Optiflow, the Hydrate, and the Precision Flow (42.2 ± 3.1, 39.5 ± 1.8, 35.7 ± 2.0, and 32.9 ± 2.7 mg H2O/L, respectively, P < .001). With high ambient air temperature (28–30°C), the Optiflow provided the highest humidity, followed by the Precision Flow, the Hydrate, and the Airvo 2 (35.9 ± 2.0, 34.5 ± 3.2, 32.2 ± 0.5, and 31.4 ± 3.0 mg H2O/L, respectively, P <.001) (Fig. 2).
Absolute humidity delivered according to device and ambient temperature. Units are expressed as mean ± SD mg H2O/L (absolute humidity). The values presented are averaged from flows ranging from 15–20 L/min to 40 L/min (available for all devices) and were obtained with normal (22–24°C) and high (28–30°C) ambient temperatures, 
set at its maximum, temperature target set at 37°C or “invasive” mode (when available), and compensation algorithm activated (when available).
Impact of ambient temperature on delivered humidity
Modification of ambient temperature (with flows ranging from 10–15 to 40 L/min) significantly modified the hygrometry delivered by the devices. From normal to high ambient temperatures, the hygrometry delivered by the Optiflow, Airvo 2, and Hydrate was reduced by 3.6, 10.7, and 3.5 mg H2O/L, respectively, (P < .001), whereas the hygrometry delivered by the Precision Flow increased by 1.6 mg H2O/L (P = .11) (Fig. 2). The impact of ambient temperature was similar for low flows (−3.9 mg H2O/L for flows ≤ 20 L/min) and high flows (−4.0 mg H2O/L for flows ≥ 30 L/min) (Supplemental Table 1) (see the supplementary materials at http://www.rcjournal.com).
Impact of flow on delivered humidity.
The effect of flow setting differed according to the devices and the conditions evaluated. Results obtained with temperature target at 37°C or “invasive” mode (when available) and compensation algorithm activated (when available) are displayed in Table 2 for normal ambient temperatures (22–24°C) and high ambient temperatures (28–30°C). A summary of the effects of flow on hygrometry merging normal and high ambient temperature is provided in Figure 3.
Hygrometry Delivered With Settings Made According to the Manufacturer’s Recommendations
Effects of flow setting on absolute humidity. Units are expressed as mean ± SD mg H2O/L (absolute humidity). The values presented are averaged from measurements obtained with normal (22–24°C) and high (28–30°C) ambient temperatures, 
set at its maximum, temperature target set at 37°C or “invasive” mode (when available), and compensation algorithm activated (when available).
Combination of different parameters on delivered humidity.
For the Optiflow, the hygrometry delivered at normal ambient temperature was significantly lower with “NIV” mode (31°C at the humidification chamber) in comparison with “invasive” mode (37°C at the humidification chamber) (23.3 ± 2.1 mg H2O/L vs 39.9 ± 1.9 mg H2O/L, respectively, P < .001). The impact of this setting was found with low (≤ 20 L/min) and high (≥ 30 L/min) flows as well as with normal (22–24°C) and high (28–30°C) ambient temperatures (Table 3 and Supplemental Table 2) (see the supplementary materials at http://www.rcjournal.com). The maximum humidity drop was encountered with high flows and normal ambient temperature (reduction of 18.2 mg H2O/L with “NIV” mode compared to “invasive” mode, P <. 001) (Supplemental Table 2) (see the supplementary materials at http://www.rcjournal.com). For the Airvo 2, decreasing temperature setting significantly decreased hygrometry at normal ambient temperature, from 41.5 ± 3.1 mg H2O/L at 37°C to 28.6 ± 2.8 mg H2O/L at 31°C (P < .001) (Table 3). The impact of this setting was found in every tested condition, and the maximum humidity drop was encountered with low flows and normal ambient temperature (reduction of 15.0 mg H2O/L at 31°C compared to 37°C, P < .001) (Supplemental Table 2) (see the supplementary materials at http://www.rcjournal.com).
Hygrometry Delivered According to Target Temperature Setting
With the Optiflow, switching off the compensation algorithm with normal ambient temperature did not significantly modify the hygrometry delivered by the device, both with “invasive” and “NIV” modes. However, with high ambient temperature, switching off the compensation algorithm significantly reduced the hygrometry from 36.0 ± 1.8 mg H2O/L to 33.0 ± 1.5 mg H2O/L with “invasive” mode (reduction of 2.9 mg H2O/L, P = .001) and from 23.8 ± 3.3 mg H2O/L to 14.2 ± 1.5 mg H2O/L with “NIV” mode (reduction of 9.7 mg H2O/L, P < .001) (Supplemental Table 3).
Impact of 
on delivered humidity.
did not significantly affect humidity delivered with Optiflow. On the contrary, with Airvo 2, the mean humidity delivered was 35.9 ± 5.3 mg H2O/L with 
set at 0.21 and 29.4 ± 7.5 mg H2O/L with 
max (P < .001). The effects of different 
with Optiflow and Airvo 2 are detailed in the online supplement and presented in Supplemental Figures 5 to 7 (see the supplementary materials at http://www.rcjournal.com).
Discussion
Our results show that when used according to manufacturer’s recommendations and when ambient temperature is normal all the evaluated HFNC devices achieved satisfactory hygrometric output (≥ 30 mg H2O/L) with respect to breathing comfort evaluated in healthy subjects. In the clinical evaluation in healthy subjects, inspired humidity of 30 and 40 mg H2O/L was equivalent in terms of comfort but much better tolerated in comparison with 20 mg H2O/L.
These data are consistent with previous bench evaluations performed by Chikata et al30 under intermediate room air condition (25.6 ± 0.5°C) in which they found that Airvo 2 and Optiflow provided AH from 35.3 ± 2.0 to 37.6 ± 2.1 mg H2O/L and 33.1 ± 1.5 to 36.2 ± 1.8 mg H2O/L, with flows ranging from 20 to 50 L/min, respectively. Nevertheless, our results underline that substantial differences exist between the devices and that their inner characteristics (principles of operation, algorithms) may yield different behavior for a similar situation. For instance, all evaluated devices reduced their hygrometric performances in the condition of high ambient temperature except the Precision Flow. It can be speculated for this device that high ambient temperature reduced the temperature drop of the water circulating along the circuit, thus promoting better AH in the delivered gases compared to normal ambient temperature. Conversely, the decreased hygrometric output at 28–30°C with other devices might be explained by a downregulation of the heater plate temperature promoted by high ambient temperature, therefore reducing water vapor content in the air flow. From our results, it should be emphasized that following manufacturer’s recommendations provided satisfactory performances in most situations whereas inappropriate usage may dramatically alter devices’ efficacy (with humidity delivered below 15 mg H2O/L), as previously reported for invasive mechanical ventilation29,31 and NIV.32 Several histological studies yielded consistent findings on the detrimental effects of the exposition of airway epithelium to underhumidified gases, increasing airway resistance33 and promoting airway inflammation.34 Models of airway mucosa exposed to levels of hygrometry below 15 mg H2O/L reported mucociliary dysfunction proportional to the duration of exposure.24 On the opposite, clinical data suggest improved mucociliary clearance with the use of HFNC adequately heated and humidified.35,36
Yet, the optimal target of hygrometry of inspiratory gases delivered with HFNC is unclear. Recent guidelines recommend using humidified oxygen for patients who require high-flow oxygen systems for more than 24 h or who report upper airway discomfort due to dryness.37 In the current study, significant and severe discomfort was achieved in healthy subjects within 10 min of usage of HFNC at 20 mg H2O/L, which supports systematic humidification during HFNC.
Data obtained in healthy subjects suggested that a humidity of inspiratory gases above 15 mg H2O/L could be recommended for NIV to enhance comfort and tolerance.32 This level may not apply with HFNC as the gas is delivered continuously. Indeed, our data show extremely low tolerance of hygrometric levels of 20 mg H2O/L during HFNC. This finding is in line with data previously reported during oxygen therapy with “intermediate” flows. Chanques et al26 reported in 30 subjects undergoing oxygen therapy with median flow of 7.8 L/min that mouth and throat dryness were significantly lower using a heater humidifier (30.0 ± 1.0 mg H2O/L) instead of a bubble humidifier (16.0 ± 2.0 mg H2O/L). One can expect that the benefits of active humidification during oxygen therapy is even more pronounced with the use of higher flows.13 The flows provided during HFNC are usually set much higher (20 to 60 L/min).2 With such continuous high flows, the function of nasal mucosa in humidifying and warming inspiratory gases can be overwhelmed; and the target of humidity during HFNC probably should reach the physiological level of hygrometry at the trachea, that is, ≥ 30 mg H2O/L,38 as recommended for invasive ventilation.39
From our results, this corresponds to the “invasive” mode for Optiflow and 37°C for Airvo 2, whatever the flow set and whatever the ambient temperature, in line with manufacturer’s recommendations. It is reasonable to state that this temperature setting may apply for the other devices. Lower temperature setting (31 or 34°C) might be proposed for the Airvo 2 with satisfactory hygrometry output in normal conditions (22–24°C). In the Mauri et al study,40 conducted in patients with acute hypoxemic respiratory failure, comfort was significantly better at 31°C compared to 37°C with the Airvo 2. In this situation, with moderate 
(around 40%), the humidity delivered was probably around 30 mg H2O/L for the 31°C setting and 40 mg H2O/L for the 37°C setting. In the present study, 30 and 40 mg H2O/L were both well tolerated in healthy subjects. However, within a short-term exposure, there was a nonsignificant increase in nasal droplets at 40 mg H2O/L, which may explain the reduced tolerance at 37°C in the Mauri study in which participants were exposed to this setting twice as long as in the current study. Along with our results, the study from Mauri et al40 provides valuable insight for setting temperature target at patient’s bedside, suggesting that a compromise between comfort and optimal delivered humidity can be found under normal ambient temperatures within the range of settings proposed in this device (31, 34, and 37°C). This may be even more relevant in the situations of long-term usage such as domiciliary HFNC.41-43
Our study has several limitations. First, our bench was designed to assess the hygrometry delivered by the devices on the basis of continuous unidirectional flow. In the study of Chikata et al,30 the authors reported that when inspiratory flow was higher than HFNC flow the AH measured at the cannula was significantly reduced. This effect can be explained by room air entrainment and dilution of the inspired gases, a phenomenon that has been widely described to explain the limitations of conventional oxygen therapy in providing stable 
44 and consequently the added value of HFNC when set flow matches or overcomes patient’s inspiratory flow.2,11 Second, the clinical part of our study evaluated the tolerance to different hygrometric levels of healthy volunteers, and evaluation in patients may yield different results. However, the major lack of tolerance of 20 mg H2O/L during a 10-min exposure to HFNC in our healthy subjects, along with the histological evidence of its detrimental effects on airway mucosa,24,33,34 suggests similar findings may be found in subjects. Third, we did not address the effects of different interfaces that may affect droplet formation and thus clinical tolerance. Lastly, our study evaluated short duration of exposure to HFNC and, therefore, cannot apply to routine situations in which therapy is usually delivered continuously or in alternance with NIV. In the study of Cuquemelle et al,13 the benefits of active humidification over no humidification on mouth and throat dryness during oxygen therapy increased with longer duration of exposure (up to 24 h), and we can expect that longer duration of exposure in our study would have induced larger effects in terms of comfort.
Conclusions
We demonstrated that most common HFNC devices can deliver adequate inspiratory humidity during optimal conditions but that under-humidification may occur with high ambient temperature, high flows, and low target temperature. We propose to deliver a minimum humidity target around 30 mg H2O/L during HFNC. Adequate humidification is probably the cornerstone of treatment tolerance and comfort during HFNC. Whether this translates into better clinical outcomes deserves further investigation.
ACKNOWLEDGMENTS
The authors would like to thank all participants who accepted being enrolled as healthy subjects in this study.
Footnotes
- Correspondence: François Lellouche MD PhD, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725, Chemin Sainte-Foy, Québec, Canada G1V4G5. E-mail: francois.lellouche{at}criucpq.ulaval.ca
Supplementary material related to this paper is available at http://www.rcjournal.com.
Dr Lellouche presented a version of this paper at the European Society of Intensive Care Medicine Congress, held in Berlin, Germany, in 2015, and at the American Thoracic Society Congress, held in San Francisco, California, in 2016.
Devices and consumables were provided by Fisher & Paykel Healthcare, Vapotherm, and Hydrate, who had no other involvement in the study. The study was supported by the Groupe de Recherche en Santé Respiratoire de l’Université Laval (GESER).
Mr Delorme is a former employee of ResMed SA, which had no involvement in the current study. Dr Lellouche discloses a relationship with Fisher & Paykel Healthcare. The remaining authors have no conflicts to disclose.
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