Study: Overt and occult hypoxemia in patients hospitalized with novel coronavirus disease 2019. Image Credit: Dmitry Naumov / Shutterstock

Overt and occult hypoxemia in patients hospitalized with COVID-19

In a recent study posted to the medRxiv* preprint server, researchers assessed whether non-invasive estimation of the ratio of arterial oxygen partial pressure (PaO2) to the fractional inspired oxygen (Fi O2), that is, the P/F ratio could measure overt and occult hypoxemia in patients with coronavirus disease 2019 (COVID-19).

Study: Overt and occult hypoxemia in patients hospitalized with novel coronavirus disease 2019† Image Credit: Dmitry Naumov / Shutterstock

Modeling the risk of adverse COVID-19 outcomes has been an area of ​​intense research. Hypoxemia markers can serve as robust predictors of adverse disease outcomes as progressive hypoxemia reflects the clinical worsening of COVID-19. Oxygen saturation (SpO2) using pulse oximetry and the oxygen flow rate are the most common markers of hypoxemia.

Most studies have SpO. used2 in their models without oxygen supplementation; however, the National Early Warning Score (NEWS) models include oxygen supplementation regardless of flow rate. Therefore, the resulting scores do not always reflect the severity of hypoxemia. Nevertheless, these factors do not limit the P/F ratio.

The authors previously described a non-invasive estimation of P/F ratios (ePFR) of oxygen dissociation curves for a cohort of non-intubated hospital patients. They believed that the P/F ratios of these models could be a valid surrogate for overt hypoxemia. Importantly, pulse oximetry measurements showed racial bias resulting in ‘occult hypoxemia’, namely undiagnosed arterial desaturation at three times the rate in black patients compared to white patients. Therefore, the authors speculate that studying ePFR distributions by race could reveal occult hypoxemia.

About the study

In the current study, researchers identified a cohort of adults with hospital encounters for acute COVID-19 at the University of Virginia (UVA) Medical Center and two hospitals affiliated with Emory University. UVA medical center serves a rural and white population, and Emory locations serve the urban and primarily black population. There were 1,172 hospital visits at the UVA due to COVID-19, and the latest cohort at the UVA included 1,100 hospital visits between March 2020 and February 2021.

As of December 2021, there were more than 12,700 hospital encounters at Emory locations, and a third (4,219) of those were randomly sampled. The team asked the data warehouse to provide 1) baseline risk predictors such as age, race, sex, weight, height, and Charlson comorbidity index (CCI), 2) all components of ePFR, sequential organ failure assessment (SOFA) score, NEWS, and SpO2/FiO2 (S/F) ratio, and 3) time of admission/transfer to intensive care unit (ICU) or death.

The primary outcome of the study was clinical worsening, that is, ICU transfer or hospital death. Adjusted odds ratios (AOR) were calculated to determine the association of ePFR with clinical deterioration. The increase in AUROC (Area under Receiver Operating Characteristics Curves) was measured when ePFR was added to a baseline risk model.

They also measured (for comparison) the increase in AUROC with the addition of SpO2, S/F ratio, NEWS, SOFA and oxygen flow rate to the same baseline model. Race was used as a proxy for skin color and racial differences (non-black versus black) in the empirical cumulative distribution functions (ECDFs) were estimated using the two-sample Kolmogorov-Smirnov test.

Evaluation of the construct validity of operational markers of hypoxemia in hypothetical clinical scenarios.  Construct validity of a marker of hypoxemia is the extent to which that marker accurately reflects the clinical construct of hypoxemia.

Evaluation of the construct validity of operational markers of hypoxemia in hypothetical clinical scenarios. Construct validity of a marker of hypoxemia is the extent to which that marker accurately reflects the clinical construct of hypoxemia. This figure examines the construct validity of five operational markers of hypoxemia (rows) in common clinical scenarios (columns). In each scenario (column), two records of a patient’s oxygenation are compared (record A on the left, record B on the right). The first row titled “clinical insight” describes a clinically sensible conclusion that a clinician might make by comparing the two records. For example, in scenario 2, a clinician is likely to conclude that the two records do not represent a meaningful change in the severity of hypoxemic respiratory failure (row 1, column 2). Instead, Record B (SpO2 of 91% on 2 lpm of oxygen) may simply reflect the fact that a physician started supplemental oxygen in response to record A (SpO2 of 85% on room air). Each of the following rows describes the conclusion based solely on comparing a particular marker of hypoxemia. For example, if only SpO . compare2 in scenario 2 (row 2, column 2) the conclusion would be that record A reflects significantly more severe hypoxemia than record B (SpO2 of 85% v/s 91%). Given the varying range of each marker, we used the following cut-off values ​​to determine a “significantly more/less hypoxemia”: any difference ≥ 1 for NEWS (range 0 to 5), any difference ≥ 2 for SpO2 (range 85 to 100) and supplemental oxygen flow (range 0 to 15 LPM), and any difference ≥ 50 for S/F ratio (range 85 – 476) and P/F ratio (range 50 – 632). A cell is shaded green when there is a match between the marker of hypoxemia and clinical acumen; and it is shaded in red if there is disagreement. This figure illustrates the advantages of estimated P/F ratios over other markers – it is the only marker that agrees with clinical judgment in all scenarios. We were unable to envision a scenario where the P/F ratio would be inferior to other markers. (RA = Room air; LPM = liters per minute)


Clinical deterioration was recorded in 177 patients (17%) at the UVA medical center and 791 (19%) at Emory sites. Overt hypoxemia independently predicted primary outcome within 24 hours with an AOR of 0.99 for UVA subjects and 0.995 for Emory subjects. Adding ePFR to baseline risk models caused model discrimination with AUROC of 0.76 for UVA and 0.71 for Emory. This was better than SpO . to add2 or oxygen flow rate to baseline, but similar to adding the S/F ratio.

In addition, ePFR outperformed the NEWS models on UVA and Emory sites. The authors observed that the ECDFs were shifted to the right in black subjects compared to non-black subjects. This meant that black patients apparently had better oxygenation with a greater SpO2, ePFR and S/F ratios than non-black patients. Still, worse outcomes were evident in black patients for comparable oxygenation levels.

When clinical deterioration was modeled for UVA patients using race, SpO2, and other baseline predictors, they found that race was not a significant predictor. However, race was significantly a strong predictor when SpO2 was replaced by S/F ratio or ePFR in that model. Similarly, race was a significant predictor for Emory data when the primary outcome was modeled by S/F ratio or ePFR than by SpO2


The study found that the P/F ratio had significant predictive validity for COVID-19 outcomes. They also noted that pathological hypoxemia could be hidden in black patients. The ePFR-based model outperformed complex models such as Sepsis-3 and NEWS in predicting clinical decline.

For comparable oxygenation levels, black subjects had an increased risk of adverse outcomes than non-black subjects. This was indicative of the occult hypoxemia phenomenon that leads clinicians to have a lower FiO. to use2 settings due to a falsely reassuring reading of SpO2 and therefore lead to poorer (COVID-19) outcomes.

In conclusion, the P/F ratios accurately predicted the severity of overt hypoxemia, and ePFR would allow real-world statistical modeling of racial disparities in outcomes attributable to occult hypoxemia from pulse oximetry measurements.

*Important announcement

medRxiv publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, that should guide clinical practice/health-related behavior or be treated as established information.

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