HFNC and NIV for COVID-19 Complicated by Respiratory Failure

A novel coronavirus, subsequently named by the World Health Organization (WHO) as severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged as the cause of atypical
pneumonia linked to a seafood market in Wuhan, China in Dec 2019. Since then, SARS-CoV-2
related-disease (named COVID-19 by the WHO), has spread internationally to the scale of a
global pandemic. Although most patients present with mild respiratory symptoms, some have
severe pneumonia and a small proportion may become critically ill. Severe COVID-19 disease
often progresses to acute hypoxemic respiratory failure requiring high fractional
concentration of inspired oxygen (FiO2) and consideration for non-invasive ventilation (NIV)
strategies.

High-flow nasal cannula (HFNC) has emerged as a non-invasive strategy improving oxygenation
and carbon dioxide clearance by, in comparisons to other NIV strategies, better matching
patients' inspiratory demands by delivering up to 60 L/min of gas flow and FiO2 up to 1.0. A
systematic review found low certainty evidence suggesting benefit of HFNC in reducing the
need for invasive mechanical ventilation (IMV) or escalation of oxygen therapy compared to
conventional oxygen therapy (COT), and moderate certainty evidence suggesting no large
difference in mortality. HFNC may reduce the need for IMV and associated complications such
as ventilator-associated pneumonias, and alleviate the strain on healthcare systems during
the COVID-19 pandemic.

COVID-19 spreads predominantly through respiratory droplets and fomites. There is concern,
however, that airborne transmission may occur during respiratory procedures that generate
aerosols. Airborne transmission involves smaller particles, typically <5μm in diameter, which
may remain suspended in the air for extended periods of time, transmitted over distances
greater than 1m, and inhaled into the lower airways. Reduction of respiratory particles to <5
µm involves evaporation of larger droplets and their contained organisms, and rehydration
after deposition into the airway; therefore, airborne transmission is organism-specific, and
requires the organism to survive a process of desiccation and aerosolization in sufficient
numbers to cause infection. SARS-CoV2 has been shown to survive in air for 3 hrs after
deliberate aerolization.

The Surviving Sepsis Campaign (SSC) COVID-19 guidelines provide a weak recommendation for the
preferential use of HFNC over other NIV strategies in patients refractory to COT for type 1
respiratory failure.10 The use of high flow rates raises concerns that HFNC may cause
aerosolization of infectious particles. Using a human patient simulator and smoke particles
as markers visualized by a laser light sheet, HFNC with humidification may disperse exhaled
air up to 172mm upward and 620mm laterally when the nasal cannula is clipped on properly and
loosely respectively. Using the same methodology, NIV via the old generation oronasal masks
could disperse exhaled air diffusely but there is limited exhaled air dispersion through the
new generation masks with better design of the exhalation ports. In contrast, exhaled air
dispersion from conventional nasal cannula delivering oxygen at 5L/min without humidification
may disperse exhaled air to 1m towards the end of the bed.

Due to lack of field data on the use of these respiratory therapies in patients with COVID-19
complicated by respiratory failure, the role of fine particle aerosols in transmission of
viral infection during application of HFNC and NIV is unknown. Because of uncertainty around
the potential for aerosolization, the WHO has recommended that HFNC, NIV, including bubble
CPAP, should be used with airborne precautions until further evaluation of safety can be
completed. To alleviate concern by the healthcare workers in delivering these respiratory
therapies to patients with COVID-19 complicated by respiratory failure, it is important to
conduct a field test using viral samplers in patients with COVID-19 who require these
therapies for respiratory failure.

Aims and objectives This study aims to detect whether SARS-2 virus can be detected in small
particles in the hospital isolation rooms in patients who receive a) HFNC up to 60L/min, b)
NIV via oronasal masks and c) conventional nasal cannula.

Subjects and indications of respiratory therapy:

This is a field test to be performed at the Prince of Wales hospital ward 12C single bed
isolation room with 12 air changes per hr on patients (n=5 for each category of respiratory
therapy) with confirmed COVID-19 who require treatment for respiratory failure with a) HFNC
up to 60L/min, b) NIV via oronasal masks and c) conventional nasal cannula up to 5L/min of
oxygen. Five patients in each treatment category will be recruited as the majority (80%) of
confirmed cases in HK have been mild without respiratory failure. For example, among the 974
cases as of 10 April 2020, 23 and 25 patients respectively have ever required supplemental
oxygen at least 3L/min on the isolation wards and ICU support (for IMV, ECMO or shock).
Different respiratory therapy will be decided by the physician on duty for patients with
different degree of respiratory failure. In general, conventional nasal cannula is used for
mild respiratory failure while HFNC is required to those who remain hypoxic. NIV is usually
applied for those with type 2 respiratory failure. In adults with COVID-19, the SSC
Guidelines suggest starting supplemental oxygen if the peripheral oxygen saturation (SPO2) is
< 92% (weak recommendation, low quality evidence), and recommend starting supplemental oxygen
if SpO2 is < 90% (strong recommendation, moderate quality evidence) to achieve SpO2 not
higher than 96%. For adults with COVID-19 and acute hypoxemic respiratory failure despite
COT, the SSC guidelines suggest using HFNC over NIV (weak recommendation, low quality
evidence). In adults with COVID-19 and acute hypoxemic respiratory failure, if HFNC is not
available and there is no urgent indication for endotracheal intubation, the SSC guidelines
suggest a trial of NIV with close monitoring and short-interval assessment for worsening of
respiratory failure (weak recommendation, very low quality evidence).

Respiratory therapy: COT with nasal cannula 1-5L/min of oxygen will be used to maintain SpO2
around 95% for patients with type 1 respiratory failure. If this is not achievable despite
5L/min of oxygen, HFNC at 50-60L/min with humidification at 37C (Airvo 2, Fisher & Paykel,
Auckland, New Zealand) will be applied while NIV (Respironics V60) via oronasal mask
(Quattro, ResMed) will be reserved for patients with type 2 respiratory failure.

Air samplings:

On each air sampling period while the patient is on respiratory support, we would position 3
stationary devices in the isolation room (one next to each side of the bed and another at the
end of the bed) of the patient with confirmed COVID-19 infection, and sample the air for four
hours continuously. The National Institute for Occupational Safety and Health (NIOSH) device
consists of a three-stage cyclone air samplers set at height 1.5m and 1.0m, which represent
the mouth heights of a standing and sitting adult respectively and a meter that records
temperature and relative humidity (at height 1.3m) every four minutes. The NIOSH samplers are
located around the sampling bed ('Centre'), on the side of the sampling bed ('Side'), or
relocated during the period of the sampling. The NIOSH samplers are placed in the range of
0.5-1m (when placed next to the sampling bed) to 2-2.5m from the patient's head when placed
at the end of the bed.

Air is collected at 3.5L/minute into three size fractions: >4μm (collected in a 15ml tube),
1-4μm (1.5ml tube) and <1μm (by a polytetrafluoroethylene (PTFE) membrane filter with 3.0μm
pore size). For five sampling runs, an extra air sampler (set at height 0.8m) unconnected to
a pump will be added to the device as a negative control. After each collection, the 15ml and
1.5ml tubes are detached and 1 ml of viral transport medium (VTM) are added. The filter is
removed and immersed in 1mL of VTM inside a 5ml tube. All the tubes are then transported to
the laboratory at 4°C, vortexed, and the VTM is aliquoted and stored at -80°C for subsequent
laboratory analysis by reverse-transcriptase-polymerase-chain-reaction (RT-PCR). New sampling
tubes and filters are used and the samplers and other equipment are disinfected between uses.
The tripod, air tubing, sound-proof box and the meter are disinfected with Med-Clean (M&W
International Ltd., Hong Kong), the NIOSH air samplers with 1% Virkon and 2% Citranox
(Alconox Inc, NY, USA), and the filter cassettes are autoclaved.

Viral loads:

Viral loads will be measured from the patient's upper respiratory tract (nasopharyngeal
flocked swab and throat swab) on admission and serially second daily during hospitalization
by means of quantitative RT-PCR assay with primers and probes targeting the N and Orf1b genes
of SARS-CoV-2.

Data processing and analysis:

Statistical analysis: Dependent variables are identified as the nasopharyngeal flocked swab
and throat swab viral load (log10 copies/mL) and detection of viral RNA from one or more
participant air samples (positive) vs. all negative air samples. The Wilcoxon-Mann-Whitney,
Kruskal Wallis tests and Spearman correlation are used to assess the presence of
statistically significant correlations or distributions between independent variables and the
upper respiratory tract swab viral load, while the Wilcoxon-Mann-Whitney and Fisher's exact
tests are used for air samples. Statistical analysis was performed using SAS University
Edition (SAS Institute, Cary, NC, USA).