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