Shenoy et al. BMC Medicine(2020) 18:260
https://doi.org/10.1186/s12916-020-01735-2

CORRESPONDENCE

Open AccessConsiderations for target oxygen saturationin COVID-19 patients: are we undershooting?
Niraj Shenoy1* , Rebecca Luchtel1 and Perminder Gulani2

Abstract
Background: The current target oxygen saturation range for patients with COVID-19 recommended by the
National Institutes of Health is 92–96%.
Main body: This article critically examines the evidence guiding current target oxygen saturation recommendation
for COVID-19 patients, and raises important concerns in the extrapolation of data from the two studies stated to be
guiding the recommendation. Next, it examines the influence of hypoxia on upregulation of ACE2 (target receptor
for SARS-CoV-2 entry) expression, with supporting transcriptomic analysis of a publicly available gene expression
profile dataset of human renal proximal tubular epithelial cells cultured in normoxic or hypoxic conditions. Finally, it
discusses potential implications of specific clinical observations and considerations in COVID-19 patients on target
oxygen saturation, such as diffuse systemic endothelitis and microthrombi playing an important pathogenic role in
the wide range of systemic manifestations, exacerbation of hypoxic pulmonary vasoconstriction in the setting of
pulmonary vascular endothelitis/microthrombi, the phenomenon of “silent hypoxemia” with some patients
presenting to the hospital with severe hypoxemia disproportional to symptoms, and overburdened health systems
and public health resources in many parts of the world with adverse implications on outpatient monitoring andearly institution of oxygen supplementation.
Conclusions: The above factors and analyses, put together, call for an urgent exploration and re-evaluation oftarget oxygen saturation in COVID-19 patients, both in the inpatient and outpatient settings. Until data from suchtrials become available, where possible, it may be prudent to target an oxygen saturation at least at the upper endof the recommended 92–96% range in COVID-19 patients both in the inpatient and outpatient settings (in patientsthat are normoxemic at pre-COVID baseline). Home pulse oximetry, tele-monitoring, and earlier institution ofoxygen supplementation for hypoxemic COVID-19 outpatients could be beneficial, where public health resources
allow for their implementation.
Keywords: SARS-CoV-2, COVID-19, Hypoxemia, Hypoxia, ACE2

* Correspondence: niraj.shenoy@einsteinmed.org
1
Department of Medicine (Oncology), Albert Einstein College of Medicine,Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA
Full list of author information is available at the end of the article© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

Shenoy et al. BMC Medicine(2020) 18:260

BackgroundThe current target oxygen saturation range for patientswith COVID-19 recommended by the NIH is 92–96%.
“The use of supplemental oxygen in adults with COVID19 has not been studied, but indirect evidence fromother critical illnesses suggests the optimal oxygen target
is an SpO2 between 92% and 96%” (https://www.covid1
9treatmentguidelines.nih.gov/critical-care/oxygenationand-ventilation/). The indirect evidence refers to the following two studies:– A meta-analysis of 25 RCTs (randomized controlled
trials) in 16,037 acutely ill patients [1], which concluded that liberal oxygenation (median 96%, range
94–99%) was associated with increased mortality(relative risk 1·21, 95% CI 1·03–1·43) when compared with conservative oxygenation.
– The LOCO-2 trial [2] where ARDS (acute respiratory distress syndrome) patients were randomized toconservative (target partial pressure of arterial oxygen [PaO2], 55 to 70 mmHg; oxygen saturation as
measured by pulse oximetry [SpO2], 88–92%) vs liberal (target PaO2, 90 to 105 mmHg; SpO2, ≥ 96%)
oxygen arms. The trial was stopped early due to increased deaths in the conservative arm. At day 90,
44.4% of patients in the conservative-oxygen groupand 30.4% of patients in the liberal-oxygen group
had died (difference, 14.0 percentage points; 95% CI,
0.7 to 27.2).

Main bodyHere, we examine the above two studies guiding current
target oxygen saturation recommendations for COVID19; discuss, with supporting transcriptomic analyses, theinfluence of hypoxia on ACE2 (angiotensin converting
enzyme-2, target receptor for SARS-CoV-2 entry) expression; reflect on relevant clinical observations andconsiderations in COVID-19 patients; and propose a reevaluation of target oxygen saturation in these patients—both in the inpatient and outpatient settings.
Critical analysis of studies guiding current target oxygen
saturation recommendation

First, a closer look at the two studies on which thecurrent recommendations are based:
The 2018 meta-analysis was not specific to ARDS (oreven hypoxemia). RCTs in non-hypoxemic stroke patients exploring supplemental oxygen vs room air were
included in the analysis, with supplemental oxygen being
grouped in the overall “liberal oxygenation” arm androom-air oxygenation in non-hypoxemic patientsgrouped under the overall “conservative oxygenation”
arm. Non-hypoxemic stroke patients receiving room air,i.e., “conservative oxygenation,” had a lower death rate.

Page 2 of 6

Similarly, RCTs of supplemental oxygen vs room air inlargely normoxemic patients with myocardial infarction
were also included in the analyses. Extrapolating thesedata to patients with ARDS raises significant concerns of
relevance. Next, one of the RCTs included in the metaanalysis, the Oxygen-ICU Randomized Clinical Trial in
critically ill patients [3], had a significant influence on
the final analysis with a death rate of 80/243 vs 58/235
in liberal vs conservative oxygenation. In that study,
however, “conservative oxygenation” was defined as an
SpO2 of 94–98% or PaO2 between 70 and 100 mmHg,
whereas conventional/liberal oxygenation was defined asan SpO2 of 97–100%, allowing PaO2 values up to 150
mmHg [3]. Therefore, what was considered “conservative” in that study had overlapping saturation ranges
with the definition of “liberal” in the overall analysis. In
addition, patients in the “liberal” arm in that study wereallowed very high non-physiologic PaO2 levels.
Prior to the LOCO-2 trial, the National Heart, Lung,
and Blood Institute ARDS Clinical Trials Network recommended a target PaO2 between 55 and 80 mmHg
(SpO2 88–95%). In fact, the LOCO-2 trial was conductedwith the hypothesis that the lower limits of that range(PaO2 between 55 and 70 mmHg) would improve outcomes in comparison with target PaO2 between 90 and
105 mmHg. The opposite was true (adjusted hazard ratio
for 90-day mortality of 1.62; 95% CI 1.02 to 2.56), andthe trial was stopped early. Five mesenteric ischemic
events were reported in the conservative-oxygen group.
Put together, RCT data in ARDS patients evaluatingtarget SpO2 ≥ 96% (with a target upper PaO2 limit of
105 mmHg) vs target SpO2 92–95% are lacking. RCT
data in ARDS has demonstrated that SpO2 ≥ 96% is significantly better than SpO2 88–92%. Basing oxygen saturation recommendations in ARDS patients, in part, on
the 2018 meta-analysis, raises important concerns as detailed above.
ACE2 and hypoxia

Second, the role of ACE2 in SARS-CoV-2 pathogenesis
and progression as a target receptor for viral entry as
well as the influence of hypoxia on ACE2 expression
merits particular consideration. ACE2 is a negative regulator of the angiotensin system and a counter-regulatory enzyme of ACE. While ACE coverts angiotensin I toangiotensin II, ACE2 degrades angiotensin II to angiotensin-(1-7). ACE2 expression and its catalytic product angiotensin-(1-7) have been shown to be protective against
lung injury and ARDS by opposing the proliferative,
hypertrophic, and fibrotic effects of angiotensin II [4–10].
SARS-CoV-2, by targeting (using as an entry receptor)
the very protein that is protective against the above deleterious effects, poses unique challenges. The binding affinity of SARS-CoV-2 Spike protein to ACE2 receptor

Shenoy et al. BMC Medicine(2020) 18:260

has been reported to be 10–20 times higher than thatwith SARS-CoV Spike protein [11], likely playing a keyrole in the markedly enhanced virulence. ACE2 knockout mice had significantly lower lung injury scores and
SARS-CoV Spike RNA from SARS-CoV infection compared to wild type [12].
In humans, ACE2 is expressed abundantly on the surface of lung alveolar epithelial cells and enterocytes. It isalso expressed in arterial and venous endothelial cells aswell as arterial smooth muscle cells within multiple organs(lung, stomach, intestines, kidney, brain, bone marrow,spleen, etc.) [13]. This widespread expression of ACE2,
and its high affinity with the SARS-CoV-2 Spike protein,possibly accounts for the range of severe clinical manifestations apart from ARDS, including acute renal failure andencephalopathy, with the pathogenic mechanism being
diffuse endothelitis and microthrombi [14–16].
Intriguingly, pulmonary artery smooth muscle cells(PASMC) in rats have been shown to increase the expression of ACE2 with hypoxia, both at the transcript
and protein levels [17]. In the experiment, the cells wereincubated at 3% oxygen concentration for 0, 6, 12, 24,
and 48 h. The normalized ACE2 transcript reached amaximum of 3-fold at the 12-h timepoint, and the normalized ACE2 protein expression reached a maximumof 2-fold at the 24-h timepoint, both with high statisticalsignificance (Fig. 1C, 1D of ref. [17]). Similar effect ofhypoxia on upregulation of ACE2 expression, both at
the transcript and protein levels, has also been demonstrated in human pulmonary artery smooth muscle cells(Fig. 1A-E of ref. [18]).

Page 3 of 6

We therefore sought to determine if the same trend
could also be observed in other human cells, by analyzing transcriptomic datasets deposited in Gene Expression Omnibus (GEO). Indeed, we found that humanrenal proximal tubular epithelial (HK2) cells cultured in
hypoxic conditions for 24 h had an increase in the ACE2transcript (raw p value = 0.0048, adjusted p value <0.05, Fig. 1a) [19]. Furthermore, knockdown of hypoxia inducible factors 1A and 2A (encoded by HIF1A
and EPAS1) in hypoxic HK2 cells reduced ACE2 transcript (Fig. 1b–d) [19], indicating that hypoxiainduced upregulation of ACE2 in these cells is likely
mediated through the hypoxia inducible factors.
Put together, cellular hypoxia, via upregulating the target receptor for viral entry, could potentially further
contribute to an increase in the severity of SARS-CoV-2
clinical manifestations. This is yet to be tested in an
in vivo model or in humans. It may be useful to determine the effect of hypoxemia on soluble ACE2 receptor
levels in COVID-19 patients.
Relevant clinical observations and considerations

Third, a few clinical considerations:Hypoxic pulmonary vasoconstriction is a wellrecognized phenomenon [23, 24]. With clinical observations of several COVID-19 patients having a marked hypoxemia disproportional to the degree of infiltrates,
pulmonary vasculature endothelitis and microthrombi
which were suspected clinically have now been shown to
be a prominent feature of COVID-19 lung pathology [25].
Any component of hypoxic pulmonary vasoconstriction

Fig. 1 a Human renal proximal tubular epithelial (HK2) cells were cultured simultaneously under either normoxic (20% O2) or hypoxic (1% O2)
conditions for 24 h. Hypoxia increased ACE2 expression (b–d). HK2 cells stably expressing shRNA (short hairpin RNA) targeting HIF1A and/or EPAS1
were cultured under hypoxic (1% O2) conditions for 24 h. (b). Under hypoxic conditions, knockdown of EPAS1 and HIF1A, alone and incombination, reduced ACE2 expression (c, d). shRNA knockdown of EPAS1 and HIF1A gene expression was confirmed. Data expressed as mean ±SE, with 3 replicates per group (n = 3) [19]. The gene expression profile of harvested cells was analyzed by microarray. Data were accessed
through the Gene Expression Omnibus, GSE99324, and processed using affy and limma packages [20–22]. [In summary, hypoxia increased
expression of ACE2 transcript in human renal proximal tubular epithelial (HK2) cells. Knockdown of hypoxia inducible factors 1A and 2A (encodedby HIF1A and EPAS1) with shRNA in hypoxic HK2 cells reduced ACE2 transcript, indicating that hypoxia-induced upregulation of ACE2 transcript inthese cells is likely mediated through the hypoxia inducible factors. Hypoxia➔ ↑HIF1A and ↑HIF2A ➔ ↑ACE2] [Abbreviations: HIF1A, hypoxia
inducible factor-1-alpha; EPAS1, endothelial PAS domain-containing protein 1; GEO, Gene Expression Omnibus; shRNA, short hairpin
RNA—artificial RNA molecule with a tight hairpin turn that can be used to silence target gene expression via RNA interference (RNAi)]

Shenoy et al. BMC Medicine(2020) 18:260

and further exacerbation of pulmonary hypertension inthis setting is best avoided. Further to this point, nocturnal
drop in oxygen saturation is a well-known phenomenon[26], is common in patients with primary pulmonary
hypertension [27], and has also been demonstrated in patients with pneumonia and sepsis [28]. Nocturnal hypoxemia could therefore potentially further exacerbate reflex
pulmonary vasoconstriction as well as peripheral tissue
hypoxia in patients with COVID-19 pneumonia. Patientsin regular inpatient wards or at home who maintain an
SpO2 of 92–94% during the day, with or without O2 supplementation, can have nocturnal drops into the 80s, withhigher drops in patients with obstructive sleep apnea—ahighly prevalent morbidity in obese patients.
Next, diffuse systemic endothelitis and microthrombi
play an important pathogenic role in the wide range ofsystemic manifestations (such as acute renal failure, encephalopathy, cardiovascular complications) seen in
COVID-19 patients [14–16, 29], explaining the improved
outcomes associated with systemic anticoagulation [29].
In the presence of these systemic microthrombi, hypoxemia would be expected to result in a higher degree of
peripheral tissue hypoxia/injury. This is another reason
why the optimal oxygen saturation in COVID-19 ARDS
may be higher than that in ARDS of other etiologies.
The phenomenon of “silent hypoxemia” resulting insome COVID-19 patients presenting to the hospital withsevere hypoxemia disproportional to symptoms is now
being increasingly noted [30–32], and albeit not fully
understood at this stage, may be a harbinger for clinicaldeterioration [30], and further supports outpatient monitoring with pulse oximetry and earlier institution of oxygen supplementation.
Lastly, with overburdened health systems around theworld and viral transmission considerations, COVID-19
patients in the outpatient setting (suspected and confirmed) are instructed to come in to the hospital if their
respiratory status deteriorates, most often with no oxygen saturation monitoring at home. While this approach
may be essential in managing burdened health system
resources and caring for the critically sick, it risks a significant delay in oxygen supplementation for patients inthe outpatient setting. With the lack of strikingly effective therapeutic modalities to date, inpatient mortality
numbers and percentages for COVID-19 patients aroundthe world have been staggering [33–37]. (It is of relevance to note here that even in non-COVID-19 pneumonia outpatients, oxygen saturations less than 92% are
known to be associated with major adverse events [38].)
Put together, while the effects of the degree/duration of
hypoxemia in COVID-19 patients have not been comprehensively studied, the concern of its potential adverse effects (above that in pneumonia/ARDS of other etiologies)
is based on the above-detailed specific considerations andPage 4 of 6

well-known principles in respiratory/internal medicine. If
maintaining a higher oxygen saturation in hypoxemic
COVID-19 patients in the outpatient setting could have arole in decreasing the severity of disease progression andcomplications, earlier institution of oxygen supplementation at home and tele-monitoring could potentially bebeneficial.

Conclusions
The above considerations, put together, call for an urgent exploration and re-evaluation of target oxygen saturation in COVID-19 patients, both in the inpatient andoutpatient settings. While conducting randomized controlled trials in the inpatient setting exploring a target
SpO2 ≥ 96% (target upper PaO2 limit of 105 mmHg) vstarget SpO2 92–95% would be relatively less complex interms of execution and logistics, the outpatient setting
would require special considerations such as frequenttele-visits and pulse oximetry recordings, home oxygen
supplementation as needed to meet target oxygen saturation, and patient compliance. Until data from such trials become available, it may be prudent to target anoxygen saturation at least at the upper end of the recommended 92–96% range in COVID-19 patients both in
the inpatient and outpatient settings (in patients that arenormoxemic at pre-COVID baseline). Home pulse oximetry, tele-monitoring, and earlier institution of oxygen
supplementation for hypoxemic COVID-19 outpatients
could be beneficial but should be studied systematicallygiven the significant public health resource implications.
Abbreviations
ACE2: Angiotensin converting enzyme-2; ARDS: Acute respiratory distresssyndrome; SpO2: Oxygen saturation; PaO2: Partial pressure of oxygen; SARSCoV-2: Severe acute respiratory syndrome coronavirus 2; COVID19: Coronavirus disease 2019; PASMC: Pulmonary artery smooth muscle cells;
HIF1A: Hypoxia inducible factor-1-alpha; EPAS1: Endothelial PAS domaincontaining protein 1; RCT: Randomized controlled trial; GEO: Gene Expression
Omnibus; shRNA: Short hairpin RNA
Acknowledgements
Not applicable
Authors’ contributions
N.S.: conceptualization (after experience with management of inpatient
COVID-19 patients), manuscript writing, literature review, data acquisition,and overall analysis. R.L.: ACE2 data acquisition. P.G.: manuscript editing (experience with management of critically ill patients with COVID-19). All authors read and approved the final manuscript.
Authors’ information
N.S. is a faculty physician-scientist (Assistant Professor) in the Department ofMedicine (Oncology) at Albert Einstein College of Medicine/Montefiore andis American Board certified in Internal Medicine, Hematology, and Oncology.
R.L. is a faculty scientist (Research Assistant Professor) in the Department ofMedicine (Oncology) at Albert Einstein College of Medicine/Montefiore. P.G.
is a faculty physician (Assistant Professor) in the Department of Medicine(Critical Care Medicine) at Albert Einstein College of Medicine/Jacobi and isAmerican Board certified in Internal Medicine and Critical Care Medicine.

Shenoy et al. BMC Medicine(2020) 18:260

Funding
Dr. Shenoy’s research is supported by the Albert Einstein Cancer Center core
grant (2P30CA013330-47).
Availability of data and materials
Not applicable
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicableCompeting interests
The authors declare no conflict of interest.
Author details
1
Department of Medicine (Oncology), Albert Einstein College of Medicine,Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
2
Department of Medicine (Critical Care Medicine), Albert Einstein College ofMedicine, Jacobi Medical Center, Bronx, NY 10461, USA.
Received: 15 May 2020 Accepted: 6 August 2020

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