Background: Nasal High Flow (NHF) therapy delivers flows of heated humidified gases up to 60 LPM (litres per minute) via a nasal cannula. Particles of oral/nasal fluid released by patients undergoing NHF therapy may pose a cross-infection risk, which is a potential concern for treating COVID-19 patients. Methods: Liquid particles within the exhaled breath of healthy participants were measured with two protocols: (
Nasal high flow (NHF) has been increasingly used as an intervention for type 1 respiratory failure. Appropriate use of NHF has been shown to reduce intubation rates, which carries a risk of infection transmission for both patients [[
Concerns have been raised about a potential risk of NHF spreading infection by generating aerosols and droplets when used to support patients with acute respiratory infections. NHF therapy is classed by some countries as an aerosol generating procedure (AGP). A systematic review of AGP and risk of transmission of acute respiratory infections (ARI) to healthcare workers (HCW) reported that more invasive respiratory procedures such as tracheal intubation, tracheotomy and manual ventilation were a significant risk factors for SARS transmission [[
Some countries or healthcare systems have guidance against using NHF for patients with COVID-19 infection, while others are using NHF as a first line therapy. Interestingly, there does not appear any substantive evidence of NHF causing large dispersions of infectious aerosols and infecting heathcare workers. In fact, the low number of relevant dispersion studies and lack of understanding of infection transmission has been highlighted in three recent publications [[
This paper compares the release of particles of oral/nasal fluids during quiet resting breathing, snorting, voluntary coughing and voluntary sneezing, both in the absence of respiratory therapy and when receiving NHF at 30 and 60 LPM (litres per minute). Two techniques are used to determine volumes of oral/nasal fluid released: high speed optical video microscopy and air sampling with a chemical marker instilled into the nose and mouth. It is our hope that this data will inform evidence-based decisions about using NHF, particularly for patients with ARI.
Ethical approval was obtained from the Upper South B Regional Ethics Committee, Ministry of Health, New Zealand URB/09/12/064 and the University of Canterbury Human Ethics Committee (refs. 2009/173 and HEC 2017/105). Written, informed consent was obtained from all subjects.
In the terminology commonly accepted in healthcare, aerosols are suspensions of small particles, including droplet nuclei, with an aerodynamic diameter of 10 μm or less. Droplets are particles with an aerodynamic diameter of > 10 μm. Airborne transmission in a healthcare setting refers to transmission by aerosols of < 10 μm [[
Six healthy volunteers participated: three females aged 20 to 27 years, and three males aged 26 to 59 years. Participants wore a medium size Optiflow
Participants sat with their chin and forehead on a rest. A region of approximately 40 × 30 mm directly below the participants' nostrils was imaged with a high-speed camera (Motion Pro X3
Graph: Fig 1 Imaging layout.
Videos were analyzed using a Java-based image processing program (Image J, National Institutes of Health, Bethesda, MD, USA) for particle frequency, diameter and velocity. The number of particles were recorded in bins with diameter of 0–50, 50–100, 100–150, 200–500, 500–1000, 1000–2000 and 2000–5000 μm. The smallest detectable particle occupies one pixel i.e. has a diameter of 33.0 μm.
The six experimental conditions, each conducted in triplicate on each nostril, were:
- Quiet breathing (at rest) with no therapy, with 30LPM NHF, and with 60LPM NHF.
- Voluntary snort (mouth-closed maximum effort nasal exhale) with no therapy, with 30LPM NHF, and with 60LPM NHF.
Ten healthy volunteers (aged 23–48, 1 female and 9 male) participated. Participants sat in a chair with a headrest. Each participant carried out the sequence of actions described in Table 1. The order of the no-therapy and 60 LPM therapy actions was randomized. Participants acclimatized to the 60 LPM therapy for a few minutes before beginning the NHF tests. Where NHF was used, an Optiflow
Graph
Table 1 Actions for chemical marker test.
Action Therapy repeats Sampling distance Duration Quiet breathing No therapy 2–3 1–2 at 100 mm; 1 at 500 mm 7 mins Voluntary snort (mouth closed, expel air through nose with maximum effort) No therapy 1 500 mm 30 sec Voluntary cough (mouth open) No therapy 1 500 mm 30 sec Voluntary sneeze (allow mouth to open) No therapy 1 500 mm 30 sec Quiet resting breathing 60 LPM 2–3 1–2 at 100 mm; 1 at 500 mm 7 mins Voluntary snort (mouth closed, expel air through nose with maximum effort) 60 LPM 1 500 mm 30 sec Voluntary cough (mouth open) 60 LPM 1 500 mm 30 sec Voluntary sneeze (allow mouth to open) 60 LPM 1 500 mm 30 sec
Air was sampled at a distance of either 100 mm or 500 mm from the participant's nose, using 125 mm diameter qualitative filter paper (Whatman plc, Little Chalfont, Bucks, UK, product number 1005–125) supported on an acrylic grille through which air was drawn at 2.2–18.1 LPM with a vacuum pump. The air flow rate was measured with a TSI 4040 meter (TSI Inc. Shoreview, MN, USA). This sampling system was placed to intercept the maximum exhaled nasal velocity, determined for each test after the participant found a position they could maintain comfortably for the duration. The filter papers were stored in Petri dishes (used as delivered in clean sterile packaging) and frozen for later analysis. A clean grille was used after each block of quiet breathing tests, and after each snort, cough or sneeze.
Background measurements (7 min duration) were run before and after each participant. No riboflavin was detected in any of these, indicating the room ventilation was adequate to prevent contamination between tests.
For quantitative analysis, the samples were brought to room temperature and riboflavin was extracted from the filter paper using 3.5 ml of Milli-Q water (Merck Millipore, Burlington, MA, USA) with 5 minutes of gentle agitation. 1.5 mL of the supernatant was drawn off and expelled through a 0.45 μm filter into HPLC vials. These were analyzed with a Dionex UHPLC Focused (Thermo Fisher Scientific, Waltham, MA, USA) fitted with an autosampler, Ultimate
A six-point external standard calibration curve (0, 50, 100, 200, 400, 800 and 1000 ng/mL) of 95% purity riboflavin 5' monophosphate (Sigma Aldrich, F8399) was used for the quantification of samples and the calibration standards were analyzed prior to starting the sample sequence. Milli-Q blanks were analyzed after the calibration standards and after every 14 samples to ensure there was no carry-over from the previous runs. A 100 ng/mL check standard was run after every sample sequence to confirm the validity of the calibration curve. Calibration standards and samples were analyzed in duplicate aliquots. Chromeleon (c) Dionex (Version 7.2.7.10369) software was used for peak fitting and calibration.
The concentration of oral/nasal fluid emitted by the participant and collected by the sampling system was calculated using the concentration of the riboflavin, the air flow rate through the filter paper, the duration of the test, and the volume of Milli-Q water used to extract the riboflavin.
The duplicate aliquots agreed within 4% except for two instances in which four overlapping peaks were fitted at the riboflavin retention time.
The detection limit for riboflavin, estimated based on the signal to noise ratio in the chromatogram (S/N = 3) was 2.75 ng/mL. The concentration of oral/nasal fluid in air required to meet this detection limit is given in Table 2.
Graph
Table 2 Detection limits of oral/nasal fluid.
Air flow rate (LPM) Test duration (min) Detection limit (μL oral/nasal fluid per m3 air) 2.5 0.5 3.6 18.1 0.5 0.5 2.3 7 0.28 12.7 7 0.05
(
When snorting, five out of six participants produced visible particles in all conditions. An example image is shown in Fig 2. The particles ranged in diameter from the smallest detectable size of 33 μm to 5000 μm (5mm) in diameter. Interpersonal variation was large. One (female) participant produced no detectable particles with NHF at 60LPM.
Graph: Fig 2 Particles during snort, no therapy (left) and snort, 60 LPM NHF (right).From top to bottom on the right of each image is a silhouette of a participant's nose, lips (left image) or nasal cannula (right image) and chin.
The number of particles detected (mean, minimum and maximum), are given in Table 3 and Fig 3 as a function of size. The depth of focus limits the accuracy of the size measurement. Data are shown only for the four experimental conditions in which particles were present. The values are averaged over three repeats on each the left and right nostril. There was no significant difference between left and right nostrils so the data are combined for presentation here, as well as over the three replications.
Graph: Fig 3 Number of particles (averaged over both nostrils and all participants).Error bars are 1 standard deviation.
Graph
Table 3 Summary of average particle numbers across six participants and for the four conditions for which particles were detected by imaging.
Particle dia. (μm) Quiet breathing, 60 LPM Snort, no therapy Snort, 30 LPM Snort, 60 LPM Mean Min Max Mean Min Max Mean Min Max Mean Min Max 50 0.8 0.0 2.5 5.0 0.0 18.3 3.0 0.0 10.5 3.4 0.0 9.9 100 2.5 0.0 10.0 14.7 0.0 46.7 9.7 0.0 38.3 11.9 0.0 34.1 150 2.5 0.0 10.2 28.9 0.5 121.0 14.7 0.0 59.2 18.4 1.2 62.9 200 2.6 0.0 10.3 26.4 1.7 101.0 11.6 0.0 39.3 16.0 1.4 50.7 500 5.9 0.0 21.0 72.9 2.7 276.8 30.4 0.0 119.3 45.9 6.3 136.3 1000 0.6 0.0 2.7 24.0 1.0 78.8 9.6 0.0 28.5 10.2 1.7 24.6 2000 0.1 0.0 0.3 6.1 0.3 19.7 1.3 0.0 3.5 0.8 0.0 3.2 5000 0.1 0.0 0.5 0.6 0.0 2.5 0.0 0.0 0.0 0.0 0.0 0.1
Fig 3 shows that with quiet breathing, no particles were recorded with unsupported breathing or 30 LPM NHF (detection limit for single particles 33 μm). Particles were detected from 2 of 6 participants at 60 LPM quiet breathing at approximately 10% of the rate caused by unsupported vigorous breathing. Quiet and vigorous breathing gave very different particle numbers (p < 0.001). Unsupported vigorous breathing released the greatest numbers of particles. Vigorous breathing with NHF at 60 LPM released half the number of particles compared to vigorous breathing without NHF. For vigorous breathing, the type of therapy has no significant effect (p = 0.3135).
(
Graph: Fig 4 Summary of data from chemical marker test.Black circles are the means, error bars are +/- one standard deviation (due to the logarithmic scale, the negative error bar is obscured by the datapoint marker), and bars show the range from minimum to maximum. White bars are no therapy (NT), grey bars are 60 LPM NHF. The figure of 100 or 500 is the distance in mm. The solid line is the maximum detection limit and the dashed line is the minimum (as detectability depends on air flow rate).
Graph
Table 4 Results of the chemical marker tests expressed as the concentration of oral/nasal fluid in air. Values for each subject are the mean of the duplicate aliquots. Zero values indicate any marker present was below the detection limit. The second quiet breathing, 100 mm distance test was omitted for Participant Four due to time limitations.
μL oral/nasal fluid per cubic metre of air Participant Therapy Dist (mm) 1 2 3 4 5 6 7 8 9 10 Mean s.d. Quiet No 100 0 0 0 0 0 0 0 0 0 0 - - Quiet No 100 0 0 0 Omitted 0 0 0 0 0 0 - - Quiet No 500 0 0 0 0 0 0 0 0 0 0 - - Snort No 500 260 2,843 27.6 11.9 145 30.5 13,786 678 2,419 259 2,046 4,252 Cough No 500 5.13 19.4 38.7 117 24.9 0.00 4,233 1,080 10.1 804 633 1,323 Sneeze No 500 2,507 48.3 0.00 66.2 110 132 3,445 2,379 193 10,219 1,910 3,194 Quiet 60 LPM 100 0.00 0.00 0.00 1.68 6.12 0.00 0.00 0.00 0.00 0.00 0.78 1.95 Quiet 60 LPM 100 0.00 0.00 17.0 Omitted 0.00 0.00 0.00 0.00 0.26 0.00 1.72 5.64 Quiet 60 LPM 500 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 - - Snort 60 LPM 500 13.2 1,424 21.0 21.1 43.2 980 489 86.2 1,541 211 483 608 Cough 60 LPM 500 157 606 37.8 17.5 0.00 106 15,274 3,484 335 382 2,040 4,766 Sneeze 60 LPM 500 1,327 9.71 31.2 26.4 12.8 60.3 2,133 8,739 249 923 1,351 2,695
Only the obvious difference in quiet versus vigorous breathing was significant (p < 0.001). There were no significant differences due to therapy, nor between types of vigorous breathing, nor due to distance (quiet only), nor due to therapy order, and there were no two-way interactions between these factors.
Oral/nasal fluid was not detected in quiet resting breathing without NHF therapy. Oral/nasal fluid was detected 4 times in 29 tests in quiet breathing with NHF therapy. It never exceeded 17 μL per cubic metre of sampled air, and counting only those instances where it was detected, it was at a mean level of 6.3 μL per cubic metre of sampled air. This was 1/200 th of the average level detected in snort, cough or sneeze. It was detected in two cases during quiet breathing where this was the first action the participant did, and in two cases where they completed no-therapy actions first.
With no therapy, oral/nasal fluid was detected in quantities exceeding 633 μL per cubic metre in all snorts, nine out of ten coughs, and nine out of ten sneezes.
With NHF (60 LPM), oral/nasal fluid was detected in quantities exceeding 483 μL per cubic metre in all snorts, 9 out of 10 coughs, and all sneezes.
Snort, cough and sneeze all release the same order of magnitude of oral/nasal fluid. The quantities detected in with-therapy and no-therapy cases are of similar order of magnitude.
To our knowledge this is the first study to compare the optical video-microscopy and chemical marker methods for oral/nasal fluid dispersion in the presence and absence of NHF. It was evident from both measurement modalities that high energy respiratory maneuvers like coughing, sneezing and snorting generated high volumes of particles, either with or without NHF, compared to quiet breathing. Higher expired flow velocities are expected to generate stronger shear forces over the mucosa, generating more airborne particles [[
During vigorous breathing there were fewer particles produced with NHF than without NHF. This was true at both flow rates in the imaging tests, and true when averaged over snort, cough and sneeze in the marker tests. NHF's apparent mitigation of particle generation during vigorous breathing may be explained by particles impacting on the cannula interface. Another possible explanation is that NHF imposes an expiratory flow resistance that increases expiratory time [[
On the points on which they are directly comparable, the results of the two methods agree qualitatively that (
For the oral/nasal fluid collection, it should be noted that with quiet breathing alone there were no detectable levels in the twenty nine measurements, while the addition of 60 LPM NHF increased this to four out of twenty nine tests with detectable volumes. However, these quiet breathing measurements were taken over a seven-minute period and produced 200 to 1000 times lower volumes of oral/nasal fluid than the higher energy respiratory maneuvers of coughing, sneezing and snorting achieved in a 30 second period. Looking at this another way, coughing with no therapy produced 633 μL/m
SARS-CoV-2 RNA has been detected in particles of 0.25–4 μm diameter [[
It has been postulated that a higher clinical acuity Acute Respiratory Distress Syndrome (ARDS) patient will generate more particles due to higher work of breathing, increased closing capacity and altered respiratory tract fluid [[
One study had five healthy participants sit in a chair, gargle 10 ml of food coloring then cough, and measure how far the visible droplets went on paper on the floor. They reported that the discernable particles traveled on average 2.48 m with no therapy and 2.91 m with NHF at 60 LPM [[
This study's findings are in general concordance with these other published studies of particle dispersion with NHF. However there is still a dearth of high quality data regarding aerosol and droplet generation, and this should be resolved to improve the understanding of the possible mechanism of transmission, and to inform evidence based guidelines for health care workers treating patients infected with Covid-19 and related diseases [[
Many clinical interventions and therapies are considered to have the potential to generate aerosols, including standard oxygen therapy, non-invasive ventilation, intubation, nebulisation and NHF therapy. It is important to gain a full understanding of the potential benefits of using any of these therapies in the context of any associated risks. The mechanism of droplet and aerosol virus transmission is also not fully understood. The emerging evidence suggests the generation of numbers of particles increases with the vigor of the respiratory activity.
The potential benefits of using NHF therapy should be weighed against the risks. One of the primary indications for use of NHF is treating type 1 respiratory failure. In a large RCT conducted in 23 ICUs in France and Belgium involving 310 participants, NHF was reported to reduce intubation rates compared to non-rebreather face mask or NIV for a subgroup of those with Acute Hypoxic Respiratory Failure (AHRF) and a PaO2:FIO2 of 200 mm Hg or less, of whom the majority had community acquired pneumonia [[
A systematic review of SARS-related literature conducted to understand the risk of transmission to healthcare workers from aerosol-generating procedures [[
There is speculation that NHF may increase the chances of aerosol generation and COVID-19 transmission. However, there is a lack of evidence to support that NHF is any worse than other low risk respiratory therapy such as oxygen therapy or NIV, and its use may avoid the need for high risk procedures such as intubation.
This study had numerous limitations: the sample size is small, all participants were healthy; there was a narrow age distribution (although previous research indicates no reason to expect different results from other participant in quiet breathing. Tobin et al. [[
60 LPM NHF therapy may cause some small quantity of oral/nasal fluid to be released during quiet breathing, at levels of less than 17 μL per cubic metre of air. The addition of a filter barrier may be indicated.
Vigorous breathing (snort, cough or sneeze) releases 200 to 1000 times more oral/nasal fluid than quiet breathing.
60 LPM NHF does not make the levels of oral/nasal fluid emitted during cough, snort or sneeze greater compared to unsupported breathing.
We do not find evidence for large numbers of particles being dispersed by NHF, compared to cough or sneeze. NHF is a useful therapy for Type 1 Respiratory failure and reducing escalation to high infection risk procedures like intubation.
Vigorous breathing without NHF is the worst-case scenario that should drive infection prevention and control measures. The use of NHF, per se, does not increase the risk of generation of infectious airborne aerosols above the risk of patient-generated aerosols. Adherence to standard contact and droplet precautions are likely to be sufficient when NHF is applied.
S1 Data.
(XLSX)
We wish to thank Kimberly Kovacs-Wilks, Morkel Zaayman, Meike Holzenkaempfer and Amanda Inglis of the School of Physical and Chemical Sciences, University of Canterbury, for their help with the HPLC analysis.
By M. C. Jermy; C. J. T. Spence; R. Kirton; J. F. O'Donnell; N. Kabaliuk; S. Gaw; H. Hockey; Y. Jiang; Z. Zulkhairi Abidin; R. L. Dougherty; P. Rowe; A. S. Mahaliyana; A. Gibbs and S. A. Roberts
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