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Background. e recent pandemic has seen unprecedented demand for respiratory support of patients with COVID‑19 pneumonia,
stretching services and clinicians. Yet despite the global numbers of patients treated, guidance is not clear on the correct choice of modality
or the timing of escalation of therapy for an individual patient.
is narrative review assesses the available literature on the best use of dierent modalities of respiratory support for an individual patient,
and discusses benets and risks of each, coupled with practical advice to improve outcomes.
On current data, in an ideal context, it appears that as disease severity worsens, conventional oxygen therapy is not sucient alone. In more
severe disease, i.e. PaO2/FiO2 ratios below approximately 200, helmet‑CPAP (continuous positive airway pressure) (although not widely
available) may be superior to high‑ow nasal cannula (HFNC) therapy or facemask non‑invasive ventilation (NIV)/CPAP, and that facemask
NIV/CPAP may be superior to HFNC, but with noted important complications, including risk of pneumothoraces.
In an ideal context, invasive mechanical ventilation should not be delayed where indicated and available. Vitally, the choice of respiratory
support should not be prescriptive but contextualised to each setting, as supply and demand of resources vary markedly between institutions.
Over time, institutions should develop clear policies to guide clinicians before demand exceeds supply, and should frequently review best
practice as evidence matures.
Keywords. COVID‑19; mechanical ventilation; high‑ow nasal cannula; continuous positive airway pressure; non‑invasive ventilation.
Afr J Thoracic Crit Care Med 2022;28(3):119‑128. https://doi.org/10.7196/AJTCCM.2022.v28i3.241
1. Introduction
Respiratory support for the spectrum of patients with hypoxic
COVID‑19 pneumonia has included: oxygen delivered via facemask
or nasal cannula (or both simultaneously – so‑called ‘double‑
barrel oxygen’); high‑flow nasal cannula (HFNC); continuous
positive airway pressure (CPAP); non‑invasive ventilation (NIV);
and invasive mechanical ventilation (IMV). Despite widespread
use of each modality, definitive and evidence‑based guidelines
informing when each is best utilised are varied and inconsistent.[1]
Each modality has unique benefits and drawbacks, and decisions
regarding selection of therapy for any individual COVID‑19
patient, as well as when to escalate therapy, have largely been based
on clinical experience, expert opinion, pre‑COVID‑19 literature,
and gradually emerging evidence from the COVID‑19 pandemic.
In particular, the optimal timing of intubation and invasive
mechanical ventilation remains a key, yet inadequately addressed,
question for clinicians.[2]
The COVID‑19 pandemic has placed unprecedented demands
on global critical care services, resulting in the use of HFNC, NIV
and CPAP outside an intensive care or high‑care setting, posing
novel challenges to healthcare staff and with potential risks to
patients.[3] The challenges involved in providing appropriate
ventilatory support to patients are further amplified in Africa
by a lack of resources including critical care beds, equipment,
trained intensivists, and the world’s lowest vaccination rates.[4,5]
Given these difficulties, guidance on the optimal use of limited
resources, such as HFNC and NIV/CPAP, is important. However,
it is impossible to provide blanket guidance on the use of such
modalities without careful consideration of the context in which
they are required.
e optimal management of the patient with COVID‑19 pneumonia:
HFNC, NIV/CPAP or mechanical ventilation?
A G B Broadhurst,1 MB ChB, Dip HIV Man; C Botha,1 MB ChB; G Calligaro,2 BSc Hons, MB BCh, Dip PEC (SA), MMed (Int), FCP (SA),
Cert Pulm (SA); C Lee,3 MB BCh, FCP (SA), Cert Crit Care (SA) Phys; U Lalla,1 MB ChB, FCP (SA), MMed (Int), Cert Crit Care (SA) Phys;
C F N Koegelenberg,1 MB ChB, MMed (Int), FCP (SA), FRCP (UK), Cert Pulm (SA), PhD; P D Gopalan,4 MB ChB, FCA (SA), Cert Crit
Care (SA), PhD; I A Joubert,5 MB BCh, DA (SA), FCA (SA), Cert Crit Care (SA); G A Richards,6 MB BCh, PhD, FCP (SA), FRCP, MASSAf;
BWAllwood,1 MB BCh, DCH (SA), DA (SA), FCP (SA), MPH, Cert Pulm (SA), PhD
1 Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
2 Division of Pulmonology, Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa
3 Discipline of Internal Medicine, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Grey’s Hospital,
Pietermaritzburg, South Africa
4 Discipline of Anaesthesiology and Critical Care, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
5 Department of Anaesthesia and Peri-operative Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
6 Department of Internal Medicine, Charlotte Maxeke Johannesburg Academic Hospital, and Faculty of Health Sciences, University of the Witwatersrand,
Johannesburg, South Africa
Corresponding author: A Broadhurst (alistairbroadhurst@gmail.com)
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The purpose of this narrative review is to assist clinicians with
best‑practice decisions in the respiratory support of critically ill
patients with COVID‑19 pneumonia, by summarising the available
evidence and comparing the use of the different modalities of
ventilation, namely conventional HFNC, NIV/CPAP and IMV.
Evidence is supplemented by expert opinion from the authors
where knowledge gaps remain and, importantly, taking into account
the large variability in resources between institutions, regions and
nations, as well as demand for those resources during COVID‑19
waves. Thus, while providing guidance for best practice, the review
concludes with the importance of contextualisation in decision
making.
2. High-flow nasal cannula oxygen
therapy (HFNC)
HFNC had not been widely adopted as a means of respiratory
support prior to the COVID‑19 pandemic. It is an oxygen‑delivery
method capable of supplying high inspired partial pressures of
warmed and humidified oxygen. The device consists of a flow
generator which provides gas flow rates of up to 60L/min, an
air‑oxygen blender that can vary the inspired oxygen fraction
(FiO2) ranging from 21% to 100% irrespective of flow rate, and
a humidifier that saturates the gas mixture. Certain devices lack
an air‑oxygen blender and the inspired oxygen fraction is set
manually by the adjustment of a separate oxygen flowmeter. The
disadvantage of this is that when flow is altered, the inspired
fraction of oxygen is changed.
Humidification temperatures can range from 31°C ‑ 37°C and
are adjusted to patient comfort. To minimise condensation, the
heated humidified gas flows through insulated and heated tubing
and is delivered to the patient via a soft and pliable nasal interface,
offering advantage over conventional nasal cannulae, or venturi
and reservoir mask systems. HFNC has an added advantage of
allowing the patient to talk, eat and drink during treatment.
The main physiological effect of HFNC in improving
oxygenation is due to the very high flow rates of gas delivered.
These flow rates better match the inspiratory demands of patients
in respiratory failure. In conventional oxygen interfaces (e.g.
venturi masks), the FiO2 is reduced by entrainment of room air
at the mouth, proportional to the patient’s minute ventilation
and peak inspiratory flow (PIF) – both of which are increased in
respiratory distress.[6‑8] HFNC delivers a flow which far exceeds
the patient’s minute ventilation and PIF, thus offsetting room
air entrainment, and delivering a reliable FiO2. A separate but
related mechanism is that HFNC washes out the nasopharyngeal
dead space. This purges the CO2 (and nitrogen if high FiO2) from
exhaled breath in the upper airways, reducing rebreathing and
thereby increasing both the alveolar partial pressure of oxygen and
the fraction of minute ventilation participating in gas exchange.[9]
Lastly, the high flow rates increase positive end‑expiratory pressure
(PEEP), which can decrease the work of breathing, and improve
oxygenation. However, this effect is likely to be modest at best, with
the increase in PEEP estimated to be only ~1 cmH2O of PEEP for
every 10 L/min of high‑flow delivered, with changes through the
respiratory cycle, and is reduced with open mouth‑breathing.[10]
2.1. HFNC compared with conventional oxygen
therapy (COT)
e term COT includes oxygen delivered via reservoir facemask,
venturi mask (40% FiO2) and nasal cannula.
At face value, HFNC has many benets over COT, yet there is
surprisingly little evidence for its use in respiratory failure in adults,
particularly prior to the COVID‑19 pandemic.[11] e initial preference
for HFNC in many parts of the world was based on indirect data
from patients with non‑COVID‑19 causes of hypoxaemic respiratory
failure which, on balance, favoured HFNC compared with CPAP, as
well as studies that suggested a high failure rate of CPAP in patients
with Middle East respiratory syndrome (MERS).[12]
The effectiveness of HFNC in a resource‑limited setting was
established by Calligaro etal.[13] during the rst wave of COVID‑19,
and included 293 consecutive patients with COVID‑19‑related severe
respiratory failure. e median (IQR) arterial oxygen partial pressure
to fraction inspired oxygen ratio (PaO2/FiO2) was 68. Of these, 47% of
patients were successfully weaned from HFNC. e median duration
of HFNC was 6 days in those successfully treated v. 2 days in those
who failed (p<0.001). A higher ratio of oxygen saturation/FiO2 to
respiratory rate within 6 h (ROX‑6 score) aer HFNC commencement
was associated with success. One limitation to this study was that there
was no control group.
It may be expected that, in COVID‑19 pneumonia, HFNC would
have better outcomes compared with COT, given the reduced work
of breathing and improved mechanisms of oxygenation discussed
above. However, the data for denitive conclusions are not yet mature.
Equally, in resource‑divergent contexts, one must consider if these
modalities are an ‘end in themselves’ (i.e. are an indication of what is
available) or a ‘bridge’ to more invasive support.
A recent, predominantly pre‑COVID‑19 Cochrane review that
included 31 studies (22 parallel‑group and nine cross‑over designs)
with 5 136 patients, concluded that HFNC in general may lead to less
treatment failure when compared with COT, but probably makes little
or no dierence to treatment failure when compared with CPAP or
nasal intermittent positive pressure ventilation (NIPPV) in hypoxic
respiratory failure.[14] However, the authors rated the evidence to be
of low or very low certainty. Another meta‑analysis that included 25
randomised clinical trials (3 804 participants), concluded that HFNC
was associated with a reduced need for intubation compared with
COT (risk ratio 0.76).[15]
In patients with severe COVID‑19 pneumonia, a retrospective
report from France found reduced rates of intubation and mechanical
ventilation with HFNC compared with other modalities. e mean
PaO2/FiO2 ratio was 126 (97 ‑ 195) in the patients who received HFNC
and 130 (86 ‑ 189) in those who did not.[16] In contrast, the authors
of the recently concluded RECOVERY‑respiratory support (RS) trial
concluded that ‘HFNC provided no benet compared with COT’ in
the primary outcome of intubation or death within 30 days.[17] It should
be noted that the mean PaO2/FiO2 was 135 for patients treated with
COT and 139 for those oered HFNC (much higher than in the study
by Calligaro etal.[13]). Moreover, the median time to intubation was
one day for both groups, suggesting that the investigators opted for an
‘early intubation’ strategy, which signicantly limits the interpretation
of the results for contexts where escalation to invasive mechanical
ventilation is not feasible.
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In a recent randomised controlled trial (RCT) of 199 patients who
were randomly assigned HFNC or COT (median PaO2/FiO2 ratios 104
and 105, respectively) for COVID‑19, HFNC signicantly reduced the
need for IMV (HR 0.62; 95% condence interval (CI) 0.39 ‑ 0.96) as
well as reducing the time to clinical recovery.[18] us, it is possible that
the benet of HFNC over COT may be maximal in patients with more
severe disease and lower PaO2/FiO2 ratios.
e choice between HFNC and COT is context specic and needs
to be carefully considered, with many questions remaining. It remains
probable that HFNC is a better modality than COT where escalation
to mechanical ventilation is not possible, and for patients with more
severe acute respiratory distress syndrome (ARDS) (e.g. PaO2/FiO2
ratios <150). It is not known if the same holds true in settings where
invasive ventilation is readily available, or for less severe ARDS (e.g.
PaO2/FiO2 ratios >200). Further, the modality in which COT is
administered should be considered, and HFNC may have less benet
over reservoir facemask oxygen than venturi mask and nasal cannula
oxygen therapy. ese questions remain unanswered.
Additionally, concerns have been raised about prolonged HFNC
delaying invasive ventilation, when indicated and available. HFNC
has been anecdotally observed to result in signicant atelectasis when
prolonged over a number of days. is is probably due to a combination
of factors including: inadequate PEEP, washout of nitrogen splinting of
alveoli with high FiO2, reduced lung compliance resulting in smaller
tidal volumes at high respiratory rates, and patient immobility. is
progression to atelectasis in severe COVID‑19 pneumonia may
theoretically make delayed invasive ventilation less successful.
2.2. Tips and tricks for HFNC
HFNC should ideally be initiated in an awake and co‑operative patient
once the saturation drops below 92% despite receiving oxygen.[13]
HFNC is not an appropriate modality for patients with a rising arterial
partial pressure of carbon dioxide (PaCO2), nor with an altered mental
state, nor very high work of breathing.[13]
HFNC can be administered by non‑ICU specialists in non‑
critical care environments without the use of invasive monitoring or
intensive patient‑to‑nurse ratios.[13,19] is has important implications
for resource‑constrained settings where access to intensive care for
patients with severe COVID‑19 pneumonia is limited. e minimum
monitoring requirement for HFNC is pulse oximetry. Ideally, and if
available, patients should be cohorted in high‑care areas or COVID‑19
wards, with the hope that economies of scale and increased access
to HFNC‑trained sta may reduce costs and improve outcomes. e
degree to which HFNC can be scaled up is highly dependent on local
oxygen capacity, the delivery infrastructure within hospitals, and the
robustness of the oxygen supply chain.
HFNC can also be combined with awake self‑proning, which itself
has been shown to improve oxygenation and reduce the need for
intubation in COVID‑19 pneumonia.[20] HFNC should be initiated
at a ow rate of 45 ‑ 60 L/min, with titration of the FiO2 to maintain
adequate oxygenation. e nasal interface should be an appropriate
size for the patient and adjusted to ensure a proper t. Common
complications that can cause rapid desaturation, and even death, are
tube kinking and interface malpositioning. Malpositioning, or so‑
called interface disconnections, occur when the nasal interface either
dislodges from the patient’s nose or if the interface occludes against the
side of the nasal cavity, thus obstructing the ow of oxygen. Patients
should be instructed to keep their mouths closed as far as possible
in order to maximise the benecial eects of HFNC including PEEP,
dead space washout, and decreasing room air entrainment.
e addition of facemask oxygen to patients on HFNC (all PaO2/
FiO2 <98) improved oxygen saturation by a mean of 5.1% (95% CI
3 ‑ 7.2%) in a small study of 18 patients. e mechanism for this is
not entirely understood; however, the authors hypothesised that a
facemask may limit the entrainment of room air, especially when the
patient breathes with their mouth open.[21] While this is encouraging,
especially in countries where escalation of care beyond HFNC may
be limited, one caution should be exercised: where poor nurse:patient
ratios exist, the facemask may obscure possible disconnections of the
HFNC interface.
Patients should be reassessed regularly aer HFNC initiation to
determine the need for escalation of respiratory support; the oxygen
saturation/FiO2 divided by respiratory rate (ROX score) is a useful
tool for the early prediction of treatment outcome.[13,22,23] e timing
of intubation remains a dicult decision which relies on a composite
clinical assessment of respiratory eort, patient exhaustion, rising
arterial partial pressure of carbon dioxide (PaCO2) or altered
mental state. e ROX score and ROX score trends are objective
measures that utilise easily measured respiratory parameters and
can potentially reassure the clinician about the safety of continuing
with HFNC. Sudden deterioration in a patient’s condition should
precipitate rapid reassessment of the equipment and interfaces, as
patients frequently have limited physiological reserve. e electricity
supply should be checked, as many devices do not contain an in‑
built back‑up power supply. Additionally, humidier irrigation uid
should be checked regularly, as a lack of humidication can cause
airway desiccation and decrease tolerance of the device.
An overlooked aspect of patient monitoring is the eect that
ethnicity has on pulse oximeter readings. A recent article highlighted
that in the crucial SpO2 bracket of 85 ‑ 89%, pulse oximeters record
the SpO2 of black patients as 3.9% higher than the true value. is
is in comparison with white patients, where the pulse oximeter
overestimates the true SpO2 to a lesser degree (the pulse oximeter
reading is 2.4% higher than the true SpO2 on average). Using a
mixed‑eects linear model, in comparison with white patients, pulse
oximetry overestimated the true SpO2 in black patients by 1.8%.
us, using SpO2 monitoring alone, the severity of hypoxia in black
patients may be underestimated in comparison with white patients.[24]
There has been concern that HFNC may increase bio‑aerosol
dispersion in the environment owing to the high gas ow, with the
potential for nosocomial transmission to other patients and healthcare
workers. However, this risk seems to be considerably overstated.[25,26]
Dispersion studies have shown that, compared with oxygen therapy
with a mask, the utilisation of HFNC does not increase either
dispersion or microbiological contamination into the environment.
is is particularly so as the patient can wear a surgical mask over the
HFNC to reduce aerosol transmission during coughing or sneezing,
which represents an additional benet.
3. NIV/CPAP (including helmet CPAP)
In clinical medicine, the terms NIV and CPAP are often used
(incorrectly) interchangeably. For the purposes of this review, NIV
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is dened as the application of bi‑level positive pressure and CPAP
is dened as the application of a single level of positive pressure
throughout the respiratory cycle. ese modalities may be delivered
via a facemask or helmet apparatus (CPAP only).
3.1. Benets and risks
Although evidence for the ecacy of NIV and CPAP in COVID‑19
is limited,[27‑30] it may be considered in the management of
acute respiratory failure. eir benets are well documented in
patients with chronic obstructive pulmonary disease (COPD)
and cardiogenic pulmonary oedema.[31] However, they have been
associated with a failure rate exceeding 70% in viral pneumonias
in general[32] and, before COVID‑19, a higher mortality rate was
reported in ARDS patients with a PaO2/FiO2 ratio <150 mmHg
compared with IMV.[33]
A lack of randomised controlled trials on the use of NIV/CPAP
in COVID‑19 has resulted in signicant variations in international
guidelines[34] and clinical practice,[35] reecting existing uncertainty
of benefits and harm, and a variety of factors influencing use,
including availability of critical care beds[35] and the theoretical risk
of nosocomial infections.
The potential to avert intubation[18,27,36] and the considerable
morbidity and mortality associated with IMV[37,38] makes NIV/
CPAP appealing modalities in COVID‑19. Additionally, NIV/CPAP
has emerged as feasible modalities outside the ICU. In a systematic
review and meta‑analysis of 17 studies and 3 377 patients with
COVID‑19 outside an ICU setting, 26% (21 ‑ 30%) failed NIV and
required intubation, with an overall mortality of 36% (30 ‑ 41%).[3]
e converse argument remains that modied care outside a critical
care unit may be detrimental. Without appropriate monitoring and
nursing care, inadvertent disconnection from the ventilator circuit
in the agitated patient, device intolerance, suboptimal delivery
of nutrition, and delayed recognition of clinical deterioration are
substantial risks.
Of concern, patients with COVID‑19 who have failed NIV and
require intubation have a higher risk of mortality.[3,27,39] Benets related
to the avoidance of IMV must be balanced with the risk of NIV/CPAP
failure and potentially worse outcomes that follow. In a retrospective
cohort of 61 patients, Avdeev etal.[28] reported a mortality rate of 88%
in the 28% of patients who failed NIV and required IMV, as compared
with the 72% where NIV was deemed successful, although probable
confounding limits interpretation. Delayed intubation and patient
self‑inflicted lung injury (P‑SILI) are postulated to contribute to
these adverse outcomes. Elevated respiratory drive, high tidal volume
and increased uctuations in pleural pressure during spontaneous
breathing may exacerbate lung injury[3,40,41] and a higher incidence
of pneumomediastinum has been reported.[17] Extrapolated from
IMV, measures to mitigate P‑SILI in NIV currently being considered
include limitation of tidal volume,[42] application of PEEP[43] and a
reduction of spontaneous eort.[40] However, to date, no ventilatory
NIV strategy has been identied that might limit the risk and improve
patient outcomes.[40]
If available, helmet CPAP is a preferred option over facemask
NIV, having the benets of improved patient comfort and tolerance,
the ability to deliver higher levels of PEEP than facemask NIV and
HFNC,[44] and decreased aerosol dispersion.[45] Interestingly, a single‑
centre RCT of 83 patients which compared facemask NIV with helmet
CPAP (median PaO2/FiO2ratio of 144 in the facemask NIV group, 118
in the helmet CPAP group) showed that helmet CPAP reduced the
need for intubation (61% v. 18%) and decreased mortality[46] compared
with facemask NIV, despite lower PaO2/FiO2 ratios. Moreover, helmet
CPAP negates the need for a ventilator and may be connected to an
oxygen system in a ward, which may be particularly desirable in a
pandemic setting.
Although helmet CPAP is not available in many places, a single‑
centre, pre‑COVID‑19 study from Canada suggests that helmet CPAP
is more cost‑eective than facemask CPAP.[47] It remains to be seen if
this benet may be extrapolated to other contexts.
4. Outcome benets of NIV/CPAP
ere are copious pre‑COVID‑19 data supporting the use of NIV/
CPAP in patients with acute exacerbations of COPD and acute
cardiogenic pulmonary oedema.[48,49] However, data defining the
benet of NIV/CPAP in patients with acute respiratory failure due to
other causes have historically been less clear.[50]
A network meta‑analysis[15] was conducted which consisted of 25
pre‑COVID‑19 studies comparing helmet CPAP, facemask NIV and
HFNC with COT. Intubation rates were signicantly lower in the three
non‑invasive groups compared with COT (helmet CPAP: RR 0.26,
95% CI 0.14 ‑ 0.46; facemask NIV: RR 0.76, 95% CI 0.62 ‑ 0.90; HFNC,
RR 0.76, 95% CI 0.55 ‑ 0.99). When compared with HFNC, helmet
CPAP was associated with a signicantly decreased risk of intubation
(RR 0.35, 95% CI 0.18 ‑ 0.66) while facemask NIV was not (RR 1.01,
95% CI 0.74 ‑ 1.38). In comparison with COT, the risk of death was
lower in the helmet CPAP and facemask NIV groups (helmet CPAP:
RR 0.40, 95% CI 0.24 ‑ 0.6; facemask NIV: RR 0.83, 95% CI 0.68 ‑
0.99) but was not signicantly dierent for the HFNC group (RR 0.87,
95% CI 0.62 ‑ 1.15). Importantly, the mortality benet in the facemask
NIV group was not signicant in patients with severe disease (mean
PaO2:FiO2 <200 mmHg). COPD and congestive cardiac failure were
excluded from the analysis, implying these were the most likely groups
to benet from NIV/CPAP. However, the heterogeneity of the patient
groups in the included studies was an important limitation in this
meta‑analysis.
In the setting of COVID‑19, data do not consistently demonstrate
superior outcomes of one or other of NIV/CPAP and HFNC v.
COT.[16,29,36,51‑53]
Helmet CPAP has further been compared with HFNC in a
randomised trial from Italy of 109 COVID‑19 infected patients with
moderate or severe acute hypoxaemic respiratory failure. Patients
receiving helmet CPAP experienced lower rates of intubation (30%
v. 51%) as well as more days free of invasive mechanical ventilation
(28 v. 25 days).[36]
e RECOVERY‑RS Trial[17] is the largest clinical trial to date to
compare CPAP, HFNC and COT in patients with moderate or severe
COVID‑19. The CPAP group had a reduced composite outcome
risk of endotracheal intubation or death within 30 days (OR 0.72,
95% CI 0.53 ‑ 0.96, p=0.03). However, the CPAP group experienced
a higher rate of adverse events such as haemodynamic instability,
pneumothorax and pneumomediastinum.
Although there is a lack of robust data to inform the choice of the
best non‑invasive modality, current evidence suggests that helmet
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CPAP may have an advantage over facemask NIV/CPAP,[15] while
either facemask or helmet NIV/CPAP may hold benet over HFNC.[17]
However, more data are needed both to conrm this evidence, as
well as to determine which modality is best for which level of disease
severity. For example, do patients with lower PaO2/FiO2 ratios (<150)
or higher work of breathing do better on NIV/CPAP compared with
HFNC, or vice versa?
When to initiate NIV/CPAP
Clinical trials and published guidelines have varied in the criteria used
to initiate NIV/CPAP.[17,29,36,54] Similar to HFNC, ongoing hypoxaemia
(SpO2<94% at sea level) while on COT (10 ‑ 15 L/min) and respiratory
fatigue (RR>30/min, accessory muscle use, hypercapnia) should be
used as indicators for initiating NIV/CPAP. Once a trial of NIV/CPAP
is considered, it should be commenced as soon as possible and closely
monitored for worsening respiratory fatigue. As inspiratory eort
has been associated with the development of P‑SILI,[32,55] it should be
considered in patient monitoring.
In terms of evaluating for NIV/CPAP failure, the ROX score utilises
respiratory rate as a surrogate for respiratory eort, but does not fully
account for respiratory muscle exertion. An alternative monitoring
tool is the HACOR score (a composite score of heart rate, acidosis,
consciousness, oxygenation and respiratory rate)[56] which has been
shown to predict NIV/CPAP failure accurately. However, this score
has the same limitation as the ROX score in terms of not considering
respiratory eort (only rate), and has not been shown to be better than
PaO2/FiO2 ratio in predicting NIV/CPAP failure.[57]
Who is the ideal candidate for NIV/CPAP?
With current data available, there is no ‘ideal’ candidate for NIV/CPAP.
In addition to hypoxaemia, patients with a high work of breathing are
most likely to derive benet from NIV/CPAP,[15] but this should be
balanced against a patient’s tolerance for the modality.
Evidence supports the use of NIV/CPAP in acute exacerbation
of COPD and cardiogenic pulmonary oedema,[32,48,49] and these
conditions are incorporated into clinical algorithms for COVID‑19,[50]
with logic suggesting that NIV/CPAP may be the preferred modality.
Who should not be placed on NIV/CPAP?
Patients who have an emergent need for endotracheal intubation
should not be placed on NIV/CPAP, e.g. owing to imminent cardiac
or respiratory arrest. Other relative contra‑indications to NIV/
CPAP include: diminished level of consciousness; patients who are
unable to co‑operate; those with compromised upper airways owing
to obstructions; inability to clear secretions; and patients with non‑
respiratory organ failure (e.g. severe encephalopathy, severe upper
gastrointestinal bleeding, haemodynamic instability, or unstable
cardiac arrhythmias).[34,58]
4.1. Tips and tricks for NIV/CPAP
A variety of interfaces through which NIV/CPAP is delivered are
available, each with its own benets and pitfalls. Careful selection
for proper fit, optimal seal and patient tolerance is essential for
success, and is an essential part of therapy initiation. Patients should
be ‘coached’ through initiation of NIV/CPAP and, to avoid feelings
of claustrophobia, patients can be asked to self‑apply (i.e. hold) the
facemask, before the head straps are attached. Additionally, initiation
at lower levels of pressure is advised, with gradual escalation over the
following few hours.[59] Regular pressure care of the nasal bridge is
needed in patients receiving prolonged NIV/CPAP.
During COVID‑19, some clinicians have used intermittent NIV/
CPAP to address the basal atelectasis that invariably occurs with
prolonged HFNC and high FiO2. Although there is physiological
rationale for this approach, and reduction in FiO2 has anecdotally
been observed in some patients, the objective eectiveness of this
strategy is not known, and should not delay IMV when available.
NIV/CPAP has an added benet of using less oxygen compared
with HFNC, which may allow safer transfer of patients between
healthcare facilities, or within facilities (e.g. transport for imaging).
As with HFNC, NIV/CPAP does not appear to result in increased
bio‑aerosol dispersion in comparison with COT via nasal prong or
facemask.[60]
5. Invasive mechanical ventilation (IMV)
5.1. Benets and risks
The risks and benefits of ventilation in the setting of COVID‑19
pneumonia are not dissimilar to the risks and benets of ventilation
in critical care in general. Unfortunately, the literature gives neither
evidence of a direct comparison of NIV/CPAP or HFNC to IMV in the
setting of COVID‑19, nor as to the ideal timing to transition to IMV.
For reasons of resource limitation, most institutions have followed
a stepwise increase in respiratory support for hypoxic patients with
COVID‑19 pneumonia: initiating with COT via nasal prongs; increasing
the inspired FiO2 progressively with various facemask devices; and
thereaer either to NIV/CPAP or HFNC; and nally to IMV.
It would be useful if there were prospective randomised trials to
guide clinicians as to the optimal timing for IMV. e point at which
patients are referred for IMV has been driven by availability of sta
and ventilators, and also by various triage mechanisms. ere are some
dierences with respect to the ventilation of patients with COVID‑19
pneumonia that are worth considering. For example, severely hypoxic
patients with COVID‑19 pneumonia frequently require the use of
neuromuscular blockers in combination with prone positioning
and high ventilator pressures, and these have their own specific
considerations, risks and benets. e use of neuromuscular blockers
brings the risk of awareness in the face of inadequate sedation, as well
as an increased risk for the development of both deep vein thrombosis
and pressure sores.[61]
e ventilation of patients in the prone position reduces access to
the airway and central venous lines and carries the risk of accidental
displacement of invasive devices with repetitive changing of position
from supine to prone and back again. While patients ventilated with
COVID‑19 pneumonia are not phenotypically identical from the
perspective of pulmonary mechanics,[62] many patients are exposed
to ventilatory parameters that are far from ideal. Persistently high
FiO2 in combination with high driving and plateau pressures together
with large ventilatory power, tend to make some degree of ventilator‑
induced lung injury (VILI) unavoidable.[63,64]
Every eort should be made to provide non‑injurious ventilation.
In order to achieve this, both permissive hypercapnoea and permissive
hypoxia have been utilised to avoid hypoxia (delivery) and VILI.
Despite the potentially negative consequences of IMV, the
124 AJTCCM VOL. 28 NO. 3 2022
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alternative of patients remaining on non‑invasive support in the face
of poor lung mechanics and inadequate oxygenation is dire. Clinicians
around the world have had to face the terrible situation of providing
palliative care to patients who refuse IMV or where resources and
triage criteria make ventilation not an option. South African data give
a ventilated survival rate of 30.8%.[65]
e ideal point in time at which IMV should be instituted remains
a vexed question. Should all resources be available, and all patients
candidates for IMV (no triage reason for exclusion), it should be
instituted when other means of non‑invasive support fail. e point
at which failure occurs is dicult to identify. It appears that patients
who have had prolonged non‑invasive respiratory support have a
less favourable outcome with IMV compared with patients who are
intubated earlier. For an individual patient, both the current severity
and trajectory of disease need to be repeatedly assessed, and late
intubations avoided.[66] An earlier identied intubation time point
would be ideal, to discriminate early from late intubations. Although
anecdotal, in our experience this point is reached at approximately two
weeks following the need for respiratory support; however, better data
are needed. Patients with incidental COVID‑19 presenting for another
indication (e.g. for trauma) should probably be considered for IMV
using the same criteria for their primary (non‑COVID‑19) condition,
and appear to have a much better outcome.
Ideal candidates for invasive ventilatory support are those who are
younger, have little or no comorbidity and low sequential organ failure
assessment (SOFA) scores. Conversely, those with poorer outcomes
are older, have more comorbidity, higher SOFA scores and require
IMV late in their illness.[67] is should not, however, exclude them
from consideration should resources be available. e requirement
for either vasopressor or renal support around the time of initiation
of ventilation is associated with a poor outcome.
Tips and tricks for IMV
It has been our collective experience that many patients with
COVID‑19 pneumonia deteriorate on IMV despite usual lung
protective ventilation, with escalating oxygen requirement and
declining PaO2/FiO2 ratios. In the absence of ECMO, the following
strategies can be attempted to improve ventilation and outcomes.
Recruitment manoeuvres
Recruitment manoeuvres in severely hypoxaemic patients may
transiently increase oxygenation but no outcome studies demonstrate
mortality benefit. They may, however, be considered as a rescue
therapy although the step‑wise manoeuvre is not recommended as it
may cause harm.[68,69]
Airway pressure release ventilation (APRV)
Lung elastance is not homogeneous, and application of positive
pressure results in regional over‑ and under‑distention. Early
initiation of APRV may reduce the incidence of ARDS and mortality
and, in a pre‑COVID‑19 comparison with conventional low tidal
volume ventilation, oxygenation, compliance, need for sedation and
vasopressor use, all favoured the APRV.[70‑73]
APRV applies CPAP with time‑cycled releases to a lower pressure,
usually zero, while allowing uninterrupted spontaneous respiration
to occur. Accordingly, there are four settings: pressure high (P high),
pressure low (P low), time high (T high) and time low (T low). T low
is usually 0.35 ‑ 0.8 seconds, depending on lung elastance, and the end
expiratory lung volume that results can be manipulated by changing
the duration of T low and observing the expiratory ow pattern with
the next cycle initiating at between 50 and 75% of the peak expiratory
ow rate. e auto‑PEEP so generated allows slow non‑traumatic
recruitment to occur, despite diering alveolar re‑expansion time
constants.[71‑76] Spontaneous ventilation also frequently allows sedation
or neuromuscular blockade (NMB) to be reduced or avoided.
Avoidance of uid overload
Inflammatory processes are associated with capillary leak and
non‑cardiogenic pulmonary oedema which is exacerbated by uid
overload. is worsens oxygenation and is associated with worse
outcome.[77,78] Fluid overload predicts longer mechanical ventilation,
prolongs ICU and hospital stay, and increases mortality.[79,80]
Careful uid management from the start, consisting of restrictive
uid administration and judicious use of diuretics, may reduce time
on the ventilator and reduce mortality.[81] However, a de‑resuscitation
protocol in patients who have already been uid overloaded also
improves outcome and reduces mortality safely, the one caveat being
that de‑resuscitation should not be too rapid such that intravascular
volume is depleted with subsequent hypoperfusion.[82,83]
Proning
Pre‑COVID‑19, proning had been associated with improved outcome
and gas exchange owing to reduced ventilation perfusion mismatch.[84‑86]
Whereas there are copious data on awake proning with COVID‑19,
there is less on its use in mechanically ventilated patients. Recent
studies have demonstrated that oxygenation improves but the eect
on outcome remains less clear. A recent study utilised data from the
STOP‑COVID study to emulate a hypothetical ‘target trial’ which
analysed observational data to guide practice.[87] Of 2 338 patients
included, 702 (30.0%) were proned and had a lower adjusted risk of
death with a hazard ratio of 0.84 (95% CI 0.73 ‑ 0.97).[88] Another
large study of 1 057 patients, with ARDS of varying severity of whom
61% were proned, assessed mortality based on disease severity
and whether oxygenation improved. Of the proned patients, 78%
responded to proning (dened as an increase in the PaO2/FiO2 ratio
of at least 20mmHg aer proning) and were termed O2‑responders.
O2‑responders, had a mortality rate of 38% compared with non‑O2‑
responders who had a mortality rate of 65% (p=0.039). is study was
limited by the fact that the proned patients had more severe disease
and a higher mortality rate overall in comparison with those who were
not proned.[89] In addition, patients with lower driving pressures had a
greater increase in PaO2/FiO2 ratio aer proning. is study correlated
with the ndings of another study in which response to proning was
independently associated with liberation from IMV at 28 days and this
was proportional to the extent of the response.[90]
As stated, it is dicult to determine if proning is actually associated
with improved outcome. It is possible that response merely predicts
increased likelihood of survival.[91]
Neuromuscular blockade (NMB)
Early reports indicated that NMB, particularly with cis‑atracurium,
may be benecial in patients with severe ARDS and possibly may
AJTCCM VOL. 28 NO. 3 2022 125
REVIEW
function as a rescue therapy.[92] Subsequent studies have not always
supported the concept and benet has not always been observed.[93]
In addition, a meta‑analysis of ve studies did not show survival
benet.[94] NMB is still utilised with refractory hypoxaemia in an
attempt to decrease the metabolic rate and energy expenditure and to
reduce the likelihood of unplanned extubation.
Permissive hypoxaemia
If ECMO is unavailable and there is profound hypoxaemia despite
maximal ventilatory support, permissive hypoxaemia may be
necessary rather than using injurious mechanical ventilation.[95]
Saturations as low as 80% are survivable so long as oxygen delivery
is maintained, as measured by serial measurements of central venous
oxygen saturation, central venous‑to‑arterial partial pressure of
carbon dioxide dierence, or lactate.[96]
Bronchoscopy
Although there is a risk to both operator and assistants, occasional
patients, particularly those who have not had access to physiotherapy,
may develop mucus plugs which may be present without obvious
atelectasis on imaging. Removal of these has been shown to improve
oxygenation.[97]
6. Contextualisation for settings where
resources are limited
It is important to appreciate that the above discussion highlights
the choice of mode of ventilation for an individual patient with
COVID‑19 pneumonia regardless of resources. However, resources
vary considerably between countries, regions and institutions, and
therefore the discussion presented above needs to be contextualised
to the clinician’s own environment. In reality, choice of management
is oen determined not only by best practice guidelines, but also
by resource availability and resource demand. The COVID‑19
pandemic to date has demonstrated that demand for those resources
varies markedly over time as the various waves wax and wane. is
can quickly lead to demand outstripping resource availability, even
in the most well‑resourced environments.
Clinicians and healthcare planners working in low‑ and middle‑
income countries (LMICs) are not unfamiliar with making triage
decisions, yet the sheer numbers of patients simultaneously requiring
triage decisions has aected the mental health of many healthcare
workers during the COVID‑19 pandemic, given the consequences
of choices made. It is therefore important for institutions to plan
in advance, and decide on: modalities of respiratory support they
will oer, thresholds and criteria for escalation of care, as well as
criteria for withdrawal of therapy. Advanced planning and eective
communication to all staff will reduce the real‑time stress to
frontline workers, who are able to refer back to institutional policies.
Any institutional planning needs to anticipate uctuations between
demand and supply of resources, and update frequently as new
data emerge. Institutional plans should involve medical ethicists
and, where possible, emergency ‘ethics teams’ should be available
during times of peak need to assist with decision making, especially
regarding termination‑of‑care decisions. Unfortunately, this
planning is best done between waves, when most frontline workers
are exhausted, recovering and naturally avoidant of such topics.
When planning for care, a number of technical factors need to be
considered. e potential institutional demand for resources should
be estimated by determining both the population to be served, as
well as whether alternative institutions for patient care are available
in the geographical vicinity. e equipment needed or available to
provide various ventilation options should be assessed. is includes
assessment not only as to what equipment is required, but additionally
whether the sophistication of this equipment is appropriate to the
context of the institution, whether maintenance and sterilisation of the
equipment is feasible, and whether a continual supply of disposables
is secured.
Equally important is consideration of the human resources
required for each modality of respiratory support. In LMICs, there
is a dire shortage of trained and qualied critical care personnel,
such as physicians, nurses and technologists.[98] Of necessity,
during the COVID‑19 pandemic, sta not au fait with equipment
or advanced patient management, were frequently required to
manage patients above their level of expertise, placing them at risk
of disease transmission and long‑term mental health disorders.[99]
Further, where there is lack of knowledge or supervision, minor
technical problems (e.g. interface kinking or disconnection) can
result in unnecessary patient death. To improve outcomes, critical
care physicians need to embrace the continual role of trainer for
inexperienced sta, as well as to monitor, support and audit the care
being provided.
Additionally, one needs to consider the space required for dierent
modalities oered. Where no dedicated ICU or high‑care beds are
available, will the same care be provided in general wards, or will lesser
care be oered? In most contexts, institutions have elected to oer
lower levels of care in general wards, but this need not hold true for
well‑resourced institutions. It is strongly recommended that severely
ill patients be cohorted together as far as possible, e.g. in ‘high‑ow
wards’. One caveat that should be added is that oxygen and power
supply requirements need to be met in those locations, and engineers
need to be consulted.
While a comprehensive review of infection prevention and control
(IPC) pertaining to COVID‑19 pneumonia is outside the scope of this
review, important barriers in the prevention of transmission of SARS‑
CoV‑2 to healthcare workers in LMICs include availability of personal
protective equipment (PPE), lack of both trained medical sta and sta
trained in the usage of PPE, and a limited environmental infrastructure
to allow for isolation and containment of patients with COVID‑19. e
development of IPC guidelines with implementation through proper
IPC training remains a cornerstone in preventing the nosocomial
transmission of SARS‑CoV‑2.[100] Other measures to improve IPC
that are applicable in LMICs include isolating and cohorting patients
if individual isolation is not possible, forming dedicated teams of
healthcare workers who work exclusively with COVID‑19 patients,
and limiting non‑essential visitors to hospitals.[101]
Summary
On the currently available evidence, for the individual patient, in an
ideal context, as COVID‑19 pneumonia severity worsens, it appears
that COT is not as good as other modalities. With increasing severity of
disease (especially PaO2/FiO2 ratios below approximately 200) helmet‑
CPAP may be superior to HFNC or facemask CPAP, and facemask
126 AJTCCM VOL. 28 NO. 3 2022
REVIEW
CPAP may be superior to HFNC, but with the noted complications.
IMV should not be delayed where indicated.
However, these recommendations need to be strongly tempered and
contextualised to the setting where care is being given, and the issues
of supply and demand of human and other resources. Further, the data
are rapidly evolving and these conclusions will most likely need to be
amended as better data emerge.
Declaration. CK, GC, Ul, GAR and BA are members of the AJTCCM
editorial board. is manuscript was not given any priority over other
manuscripts and was subject to the same review process as any other.
Another editor assumed responsibility for overseeing the peer review of
this submission, and the author’s editorial board member status had no
bearing on editorial consideration and a nal decision.
Acknowledgements. Observation of patients is clinical medicine’s most
important teacher. It is to the patients who endured profound suering
during the COVID‑19 pandemic that we owe the rapid rise in knowledge
that has been attained since the pandemic began.We acknowledge too the
healthcare workers who were stretched to the length and breadth of their
abilities in caring for these patients.
Author contributions. AB, CB and BA contributed to conceptualisation
and design. GC and CK contributed to the sections on HFNC. UL and CL
contributed to the sections on NIV. IJ and GR contributed to the sections
on IMV. BA and PDG contributed to the section on contextualisation.
Funding. is research received no funding from any funding agency in
the public, commercial or not‑for‑prot sectors.
Conicts of interest. None.
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Accepted 19 July 2022.
