64 AJTCCM VOL. 29 NO. 2 2023
ORIGINAL RESEARCH: BRIEF REPORT
e initial wave of the COVID ‑19 pandemic will be remembered
for the unprecedented burden of patients admitted to intensive
care units (ICUs) with refractory hypoxaemic respiratory failure.[1]
Studies in severe acute respiratory distress syndrome (ARDS) with
refractory hypoxaemia suggest that inhaled nitric oxide (iNO) can
be added to ventilatory strategies as a potential bridge to clinical
improvement.[2,3] It is well described that iNO improves pulmonary
ventilation‑perfusion matching by dilating vessels in ventilated parts
of the lungs, thereby improving ventilation and reducing pulmonary
hypertension. Potential anti‑inammatory, antiviral and antioxidative
effects have also been reported.[4,5] Given the pathophysiology of
refractory hypoxaemia in severe COVID ‑19, iNO remains a potential
management strategy despite its role in COVID ‑19 remaining unclear
and under investigation.[6]
We report our experience in a tertiary respiratory ICU with the use of
iNO in 10 mechanically ventilated patients with refractory hypoxaemia
to temporarily improve oxygenation while waiting for clinical recovery.
Refractory hypoxaemia was dened as an arterial oxygen pressure
(PaO2)/fraction of inspired oxygen (FiO2) (P/F) ratio <100 despite
an increased FiO2, prone positioning, the application of high positive
end‑expiratory pressure of ≥10 cmH2O or the use of airway pressure
release ventilation. A large proportion of our cohort had received
neuromuscular blockade and was on vasoactive support, or had
been at some point during their ICU stay. Extracorporeal membrane
oxygenation was not available at our institution during this time. Our
cohort included one patient with conrmed pulmonary embolism and
myocarditis, one patient with global myocardial ischaemia, and one
patient who was in peri‑arrest at the time of iNO administration. All
the patients had internal jugular central venous lines in situ, with the
catheter tip conrmed at the cavoatrial junction.
e iNO mixture was introduced into the inspiratory limb of the
ventilator tubing at a concentration of 15 ‑ 20 ppm. Arterial and central
venous blood was sampled immediately before iNO initiation and
aer one and a half hours of iNO therapy, with all other infusions and
e eect of inhaled nitric oxide on shunt fraction in mechanically
ventilated patients with COVID ‑19 pneumonia
A G P van Zyl,1 MB ChB, DA (SA), FCA (SA), MMed (Anaesthesiol); B W Allwood, 2 MB BCh, DCH (SA), DA (SA), FCP (SA), MPH, Cert
Pulm (SA) PhD; C F N Koegelenberg,2 MBChB, MMed (Int), FCP (SA), FRCP (UK), Cert Pulm (SA), PhD; U Lalla,1 FCP (SA), Cert Crit
Care (SA); F Retief,3 FCA (SA)
1 Department of Anaesthesiology and Critical Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
2 Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic
Hospital, Cape Town, South Africa
3 Department of Anaesthesiology and Critical Care, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Corresponding author: A G P van Zyl (agpvanzyl@gmail.com)
Studies in patients with severe acute respiratory distress syndrome (ARDS) with refractory hypoxaemia suggest that inhaled nitric oxide
(iNO) can be added to ventilatory strategies as a potential bridge to clinical improvement. However, the potential role of iNO as a management
strategy in severe COVID‑19 pneumonia remains unclear. e authors describe their clinical ndings of using iNO for severe COVID‑19
pneumonia in 10 patients with refractory hypoxaemia in a tertiary respiratory intensive care unit. e results showed an improvement in
shunt fraction, P/F ratio, PaO2 and arterial oxygen saturation but the improvements did not translate into a mortality benet. is report
adds to the current body of literature indicating that the correct indications, timing, dose and duration of iNO therapy and how to harness
its pleiotropic eects still remain to be elucidated.
Keywords. Acute respiratory dieases syndrome, COVID‑19, inhaled nitric oxide.
Afr J Thoracic Crit Care Med 2023;29(2):e279. https://doi.org/10.7196/AJTCCM.2023.v29i2.279
What the study adds
is brief report adds to the body of literature exploring the potential use of inhaled nitric oxide as a management strategy in patients with
severe COVID‑19 pneumonia with refractory hypoxaemia.
What are the implications of the ndings
e ndings of the report shows that there is a benecial role of using inhaled nitric oxide to improve respiratory parameters, but that it
does not translate to a mortality benet. It adds to the investigation of establishing which patients, the duration and at what dose, inhaled
nitric oxide should be used to gain maximum benet for this subgroup of patients.
AJTCCM VOL. 29 NO. 2 2023 65
ORIGINAL RESEARCH: BRIEF REPORT
ventilator settings le unchanged. e shunt fraction was calculated
using the Berggren equation with the central venous saturation used as
a surrogate for the mixed venous saturation.[7]
e patients in our cohort were treated during the rst wave of the
COVID ‑19 pandemic from May to July 2020. We report the eect of
iNO on shunt fraction, response, PaO2 and central venous oxygen
content. Responders to iNO therapy were dened as having a 20%
increase in the P/F ratio.[8]
e results show that in our cohort there was a mean decrease in shunt
fraction of 20%, an increase in PaO2 of 2.2 kPa, an increase in arterial
oxygen saturation (SO2) of 10% and an increase in central venous SO2
of 7%. ere was an average increase in P/F ratio of 19. If patients 2
and 5 (iNO initiated as a salvage measure in a peri‑arrest situation)
are omitted from analysis, the mean decrease in shunt fraction is 25%.
e patient diagnosed with a pulmonary embolism (patient 4)
had the greatest decrease in shunt fraction at 46%. While 4 patients
(patients 1, 3, 7 and 10) had large increases in P/F ratio and PaO2,
all had a decrease in shunt fraction of at least 20%. Six of the 10
patients (60%) were considered responders to iNO therapy. Only 2
patients, patient 2 (peri‑arrest) and patient 5 (peri‑arrest, with global
myocardial ischaemia on inotropic support), demonstrated worsening
of their P/F ratio. No patient survived to ICU discharge.
Our findings are similar to existing reports on the effects of
iNO therapy on oxygenation and P/F ratio. Both ‘no change’ and
a ‘signicant change’ in PaO2 and P/F ratios have been reported at
similar iNO concentrations and durations.[9,10]
Given our study population, namely only patients with refractory
hypoxaemia (as dened above) and a mean P/F ratio of 53.7, for whom
no other therapeutic options were available, the magnitude of the
average improvement in shunt fraction is striking, with the majority
of patients demonstrating >20% improvement in shunt fraction and
PaO2. ese results included two peri‑arrest patients, in whom the
addition of iNO was a salvage attempt to reverse the decline.
e optimal dose, duration and timing of iNO to produce maximal
clinical benet are not known. Similar to previous studies, the positive
change of parameters did not translate to an improvement in mortality.
is may reect both the extremely late application of iNO in the course
of the disease pathology and the amount of iNO therapy we were able
to provide, owing to its high cost. Earlier application of iNO may well
have altered outcomes, given the clinical improvement and documented
pleiotropic and antiviral properties of iNO.[5]
We found no other reports investigating the eect of iNO on shunt
fraction specically. e signicant decrease in shunt fraction in the
patient with pulmonary embolism, and its resultant eect on central
venous and arterial oxygenation, demonstrated how the compounded
pathophysiological effects of both pulmonary embolism and severe
ARDS on shunting were attenuated by iNO.
e patients who deteriorated or failed to improve with iNO were both
peri‑arrest, and the lack of response can be explained by the negligible
eect that an increase in arterial or central venous oxygen content might
have in the presence of a low cardiac output.[11] We postulate that a positive
response would have been seen if isolated right ventricular dysfunction
was present, owing to the eect of iNO on pulmonary vascular resistance
and the subsequent increase in cardiac output.
e limitations of our retrospective data analysis should be noted. We
included unstable patients, with a mean P/F ratio of 53, in our cohort,
Table1. Key results from patients receiving inhaled nitric oxide (N=10)
Before Aer Net change
Patient
Shunt
fraction
(%) P/F ratio
PaO2
(kPa)
Arterial
SO2 (%)
Central
venous
SO2 (%)
Shunt
fraction
(%) P/F ratio
PaO2
(kPa)
Arterial
SO2 (%)
Central
venous
SO2 (%)
Shunt
fraction
(%)
P/F ratio
(%)
PaO2
(kPa)
Arterial
SO2 (%)
Central
venous
SO2 (%)
1 46 60 7.2 84 65 25 90 9.7 93 72 21 52 2.5 9 7
2* 35 71 9.5 92 77 40 57 7.6 88 70 –5 –20 –1.9 –4 –7
3 58 59 6.3 73 54 26 91 9.8 92 70 32 56 3.5 18 16
4† 80 51 5.5 79 74 33 71 7.6 92 78 46 38 2.1 13 4
5‡ 79 31 4.2 35 19 73 30 4 39 16 7 –5 –0.2 3 –3
6 24 85 8 92 68 20 100 9.4 94 70 4 18 1.4 1 1
7 31 67 8.5 92 76 8 140 17.8 98 86 23 109 9.3 6 9
8 72 40 5.4 74 64 37 46 6.2 84 56 35 15 0.8 10 –7
9 75 32 4.3 59 45 62 46 6.2 81 70 13 44 1.9 22 25
10 54 38 5.1 73 50 31 57 7.6 90 70 22 49 2.5 17 19
P/F ratio = PaO2/FiO2 ratio; PaO2 = arterial oxygen pressure; FiO2 = fraction of inspired oxygen; SO2 = oxygen saturation.
*Patient clinically deteriorated to peri‑arrest state at time of nitric oxide administration.
†Patient with conrmed pulmonary embolism and myocarditis on inotropic support.
‡Patient in peri‑arrest state with global myocardial ischaemia on inotropic support.
66 AJTCCM VOL. 29 NO. 2 2023
ORIGINAL RESEARCH: BRIEF REPORT
and there were no specic selection criteria for iNO administration
other than refractory hypoxaemia, which had failed all other traditional
ventilation strategies for ARDS. e benet seen in our cohort could
be inuenced by the severity of hypoxaemia of the patients, where the
eect of a positive change would be more evident. e use of central
venous saturation as a surrogate for mixed venous saturation has many
limitations, as mixed venous saturation is the ow‑weighted average of
coronary sinus and superior and inferior vena cava blood.[12] However,
the error when using central venous oxygen content is more pronounced
in patients with sepsis, where inferior vena cava and coronary sinus ow
has a dominating inuence, as well as in low cardiac output states. A
strength of these ndings is that the study population all had the same
disease pathology, namely severe COVID ‑19 pneumonia, which was
not the case in much pre‑COVID ‑19 work with iNO and ARDS.
Despite the severity of disease, iNO therapy for severe ARDS with
refractory hypoxaemia produced a positive change in PaO2, P/F ratio
and shunt fraction. is did not translate to a mortality benet in our
population, probably owing to the limited duration of therapy with iNO
and the severity of illness. is report adds to the body of literature
investigating the correct indications, timing, dose and duration of
iNO therapy and how to harness the other pleiotropic eects of iNO
to decrease mortality in patients with severe ARDS. An intriguing
observation is the potential benet of iNO for dual pathologies such
as pulmonary embolism with severe ARDS, but this requires further
investigation and conrmation.
Declaration. BWA and CFNK are members of the editorial board.
Acknowledgements. None.
Author contributions. Equal contributions.
Funding. None.
Conicts of interest. None.
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Submitted 12 August 2022. Accepted 3 May 2023. Published July 2023.
