Discussion
The present study showed that oxygen saturation measured by pulse oximetry underestimated the arterial oxygen saturation obtained from ABG analysis in non-critically ill patients who were hospitalized due to COVID-19. Increased fibrinogen and ferritin level, decreased lymphocyte count were independently associated with large SpO2-SaO2 difference (>4%). Bland-Altman analysis comparing SpO2 with SaO2 within the total study group demonstrated the negative bias of 4.02% with limits of agreement of -9.22 % to 1.17 %. The bias became significantly higher in patients with higher ferritin, fibrinogen, and lower lymphocyte count.
Hypoxemia is one of the hallmarks of severe COVID-19. Patients hospitalized in hospital wards due to severe disease should be monitored closely for vital signs, including oxygen saturation to detect any worsening or respiratory failure 11,12. ABG analyses remain the gold standard for measurement of oxygen saturation, but it is invasive and painful therefore inconvenient for frequent monitorization. Pulse oximeters are widely used as standard medical instrument for noninvasively monitoring arterial oxygen saturation (SpO2). Previous studies suggested that pulse oximetry is an accurate method to assess SaO2 in most adult patients in the clinical setting. However, studies indicated clinically meaningful differences between SpO2 and SaO2 in some clinical conditions such as sepsis, septic shock, hyperbilirubinemia, anemia, and hypovolemia4,13,14. Guidelines recommend using a pulse oximeter rather than invasive ABG for the monitoring of COVID-19 patients, unless there is a suspicion of carbon dioxide retention15,16.
Wilson-Baig and colleagues reported 17 patients with COVID‐19 pneumonia under critical care suggesting that SpO2 is underestimating SaO2 by a mean difference of 5.3% with 95% limits of agreement. They explained their findings with possible different spectral properties of high ferritin, d‐dimer or other proteins at 660 nm and 940 nm; arteriolar dilatation and microvascular complications secondary to tissue hypoxia in patients with COVID‐196. Recently, Philip et al. reported another study evaluating the accuracy of pulse oximeter for stepping down from critical care in patients with COVID-19. In this study, it was reported that pulse oximetry has a slightly suboptimal level of agreement with SaO2 measurement (bias of 0.4% with limits of agreement of −4.3 % to 5.2 %). The authors expressed potential causes of differences in their study including skin color of patients, the allowable time between SpO2 and SaO2measurement of up to 15 minutes, the peripheral vasoconstriction due to hypothermia or vasopressor use. However the authors emphasized that their study aimed to determine the limits of agreement of the pulse oximeter, so the possible factors that caused suboptimal measurement were not evaluated in the study17. In both studies on the reliability of pulse oximetry in COVID-19, the laboratory findings of the patients were not evaluated.
To our current knowledge, hyperinflammation and coagulopathy are responsible for disease severity on the pathogenesis of COVID-19. SARS-CoV-2 lead systemic inflammation and diffuse microvascular thrombosis by triggering a unique endothelial response; endothelial exocytosis, which simultaneously activates 2 parallel pathways. Also, inflammatory cytokines releasing from endothelium, are the major mediators involved in coagulation activation18. Consistently, patients with moderate to severe COVID-19 often have hypercoagulable state, suggesting widespread thrombosis and fibrinolysis, as well as elevated levels of D-dimer and fibrinogen19,20. Fibrinogen is a macromolecular plasma protein that causes increase in blood viscosity or stasis, especially in microvascular structures by causing erythrocytes to form large aggregates, called rouleaux 21,22. D-dimer is a degradation product of fibrin, reflecting the coagulation system’s turnover and previous data showed D-dimer might be used as a marker of microcirculatory failure 23. Besides coagulation markers, ferritin, CRP, IL-6 levels are used as biomarkers of inflammation, and the increased levels of these biomarkers predict disease severity in COVID-19 24. Decreased lymphocyte count is also associated with COVID-19 severity and a predictor of hyperinflammation 25. As a result of these mechanisms and published studies, increased ferritin, CRP, fibrinogen, D-dimer levels and decreased lymphocyte count are known to be clinical predictors of disease severity26-28.
Based on the previous data and results of our study, we hypothesize that, causing microvascular damage and perfusion impairment related inflammation and hypercoagulation may be the cause of large measurement difference of SpO2 and SaO2 in patients with COVID-19. This difference may tend to be greater in the presence of ferritin, fibrinogen, D-dimer elevation and lymphopenia, which indicate increased severity of inflammation and hypercoagulability. Also, as Wilson-Baig et al. emphasized, different spectral properties of these serum proteins might have caused errors in the measurement of the oximeter 6. Further physiological studies are required to support this view.
Another point to mention, our study group (N=117) showed negative bias on difference between SpO2 and SaO2. In only 10 patients (8.54%), SpO2 levels were measured higher than SaO2 with mean difference 1.1±0.7%. Studies of pulse oximeter accuracy in different patient groups have shown mixed results; while some studies have found that SpO2 has overestimated SaO2, others have found the opposite9,29-31. Similar to our research, both two previous studies evaluating pulse oximetry in COVID-19 revealed that SpO2 underestimated the SaO2 level6,17. This situation may also cause clinically inconsistent hypoxemia in a group of COVID-19 patients, which has also been described as silent hypoxemia. We think pulse oximetry may not be sufficient to assess actual oxygen saturation in hospitalized COVID-19 patients, especially with increased inflammatory and coagulation biomarkers.
To the best of our knowledge, this is the first study to compare SpO2 and SaO2 in non-critically ill COVID-19 patients. As distinct from two previous studies with COVID patients in intensive care 9,24, the present study included a higher number of patients and additionally the SpO2-SaO2 difference was evaluated with the laboratory parameters.
Our study has some limitations. First, this study conducted retrospectively and we evaluated the blood pressure and body temperature on a daily record of patients’ file, but real-time data was lacking. The other limitation was, we measured patients SpO2 via same pulse oximeter type, and we do not know whether the results would differ if we used another model pulse oximeter. On the other hand, the pulse oximeters in our wards were approved by Food and Drug Administration (FDA) and European Conformity (CE). The third limitation of the study was that it did not have a control group with non-COVID to compare results.
To conclude, pulse oximetry may not be sufficient to assess actual oxygen saturation in hospitalized COVID-19 patients. Therefore, especially in patients with high ferritin and fibrinogen levels and low lymphocyte count low SpO2 measurements may be confirmed by ABG. Further studies are needed to assess discrepancies of SpO2 and SaO2 in COVID-19.
Conflict of interest: Authors declared no conflict of interest