Oxyhemoglobin Dissociation Curve in COVID-19 Patients

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Original Article / Özgün Araştırma
Received/Geliş Ta rihi: 18.05.2021
Accepted/Ka bul Ta ri hi: 20.02.2023
Ad dress for Cor res pon den ce/Ya zış ma Ad re si: Lect. Hilal Üstündağ MD, Erzincan Binali Yıldırım
University Faculty of Medicine, Department of Physiology, Erzincan, Turkey
Phone: +90 541 969 98 47 E-mail: hurcar@gmail.com
ORCID ID: orcid.org/0000-0003-3140-0755
COVID-19 Hastalarında Oksihemoglobin Disosiasyon Eğrisi
Hilal Üstündağ1, Cuma Mertoğlu2, Mehmet Tahir Huyut3
1Erzincan Binali Yıldırım University Faculty of Medicine, Department of Physiology, Erzincan, Turkey
2İnönü University Faculty of Medicine, Department of Biochemistry, Malatya, Turkey
3Erzincan Binali Yıldırım University Faculty of Medicine, Department of Biostatistics, Erzincan, Turkey
Abstract
Objective: Coronavirus disease-2019 (COVID-19) is a disease that can progress with hypoxemia and severe respiratory distress
in some patients. The oxyhemoglobin dissociation curve (ODC) is critical to understanding the effects of O2 exchange. This study
aimed to evaluate the relationship between the ODC and oxygen-carrying capacity of hemoglobin (Hb) in COVID-19 patients.
Materials and Methods: In the study, ODCs were created by examining the data obtained from the arterial blood gas analyses of 686
intensive care unit (ICU) and non-ICU COVID-19 patients retrospectively.
Results: It was concluded that patients with COVID-19 and other respiratory distress patients had a slight right-leaning trend in the
ODC compared with the standard curve. The P50 value of the ICU group was higher than the other groups (mean: 30.74 mmHg,
n=131, p=0.047). While the percentage of oxyhemoglobin (mean: 65.44% vs 69.81%, p=0.015), the amount of glucose (mean: 163.39
mg/dL vs 195.36 mg/dL, p=0.002) and pH (median: 7.38 vs 7.41, p=0.007) in the non-ICU group was higher compared with the
control group, the carboxyhemoglobin percentage (mean: 1.66% vs 1.13%, p=0.000), PCO2 (42.02 mmHg vs 39.44 mmHg, p=0.015),
potassium (mean: 4.33 mmol/L vs 4.04, p=0.026), and sodium (mean: 138.10 mmol/L vs 135.80 mmol/L, p=0.000) were lower. The
methemoglobin percentage of the ICU group was lower (p=0.000) than the other groups.
Conclusion: The ODC of COVID-19 and other respiratory distress patients shifts slightly to the right, indicating that patients have
partial respiratory difficulties.
Keywords: COVID-19, hematological parameters, oxygen affinity, SARS-CoV-2
Öz
Amaç: Koronavirüs hastalığı-2019 (COVID-19), hipoksemi ve bazı hastalarda ciddi derecede solunum sıkıntısı ile seyredebilen bir
hastalıktır. Oksihemoglobin disosiasyon eğrisi (ODC), O2 değişiminin etkilerini anlamak için çok önemlidir. Bu çalışmanın amacı;
COVID-19 hastalarında ODC ve hemoglobin (Hb) arasındaki oksijen taşıma kapasitesi ilişkisini değerlendirmektir.
Gereç ve Yöntemler: Çalışmada, yoğun bakım ünitesi (YBÜ) COVID-19, yoğun bakım dışı (non-YBÜ) COVID-19 ve COVID-19 olmayan
diğer solunum sıkıntılı toplam 686 hastanın arter kan gazından elde edilen veriler retrospektif olarak incelenerek oksihemoglobin
eğrileri oluşturuldu.
Bulgular: COVID-19 tanılı ve diğer solunum sıkıntılı hastaların ODC’lerinin standart eğriye göre hafif sağa eğilim gösterdiği belirlendi.
YBÜ grubunun P50 değeri, diğer gruplara kıyasla daha yüksekti (ortalama: 30,74 mmHg, n=131, p=0,047). Kontrole kıyasla non-
YBÜ grubunun; oksihemoglobin yüzdesi (ortalama: %65,44 vs %69,81, p=0,015), PO2’ı (46,98 mmHg vs 48,98 mmHg, p=0,001),
glikoz miktarı (ortalama: 163,39 mg/dL vs 195,36 mg/dL, p=0,002) ve pH’sı (medyan: 7,38 vs 7,41, p=0,007) daha yüksek iken
karboksihemoglobin yüzdesi (ortalama: %1,66 vs %1,13, p=0,000), PCO2’ı (42,02 mmHg vs 39,44 mmHg, p=0,015), potasyum
(ortalama: 4,33 mmol/L vs 4,04, p=0,026) ve sodyum (ortalama: 138,10 mmol/L vs 135,80 mmol/L, p=0,000) seviyesi daha düşüktü.
YBÜ grubunun methemoglobin yüzdesi ise diğer gruplara kıyasla daha düşüktü (p=0,000).
Sonuç: COVID-19 ve diğer solunum sıkıntılı hastaların ODC’si hafif sağa kaymaktadır, bu sonuç hastaların kısmen solunum güçlüğü
çektiğini göstermektedir.
Anahtar Kelimeler: COVID-19, hematolojik parametreler, oksijen afinitesi, SARS-CoV-2
Oxyhemoglobin Dissociation Curve in COVID-19 Patients
Meandros Med Dent J 2023;24(1):58-64
doi:10.4274/meandros.galenos.2023.87049

Üstündağ et al. COVID-19 and Oxyhemoglobin Dissociation Curve 59
Introduction
Coronaviruses form a large family of viruses that
can cause diseases in humans and animals (1). The
coronavirus disease-2019 (COVID-19) pandemic, from
severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), emerged in 2019 and spread globally. It’s
primarily transmitted through droplets and contact with
mucous membranes after exposure to infected surfaces
(2). COVID-19 symptoms are nonspecific and can’t
be reliably distinguished from other viral respiratory
infections. Initial patients had fever (98%), cough (76%),
fatigue/myalgia (44%), sputum (28%), headache (8%),
hemoptysis (5%), diarrhea (3%), and half reported
shortness of breath (2).
SARS-CoV-2’s damage mechanism to cells, tissues,
and organs is unclear. COVID-19 patients exhibit severe
atypical respiratory distress with hypoxemia, preceding
other symptoms like radiological changes and dyspnea (3).
Hypoxemia is critical in COVID-19, causing organ failure
and death (4). The virus enters cells via ACE2 receptors,
found in alveolar epithelial and vascular endothelial cells,
triggering a strong immune response and widespread
endothelial dysfunction (5).
Hemoglobin (Hb) is a heterotetramer with two alpha and
two beta chains, an iron ion, and a porphyrin ring, essential
for oxygen transport in vertebrates. About 97% of oxygen
is transported from lungs to tissues by Hb in erythrocytes,
while 3% dissolves in plasma and blood cells. Oxygen binds
to Hb at high partial pressure (PO2) in lungs and releases
at low PO2 in tissues due to consumption (6,7) Hb tetramer
structure changes impact oxygen affinity and tissue
oxygenation. Oxygen affinity relates to PO2 and can be read
from the oxyhemoglobin dissociation curve (ODC), with P50
representing 50% Hb oxygen saturation. Hb’s molecular
cooperation results in ODC’s sigmoid shape. ODC shifts left
or right in clinical situations. A right shift decreases oxygen
affinity, improving tissue oxygenation; a left shift does the
opposite. Decreased affinity raises P50, increasing tissue
oxygenation. Factors like 2,3-DPG, pH, and temperature
affect Hbs oxygen affinity (6-8).
With COVID-19 affecting over 22 million globally, theories
explore the pathophysiology. One suggests that SARS-
CoV-2 proteins interact with human Hb, facilitating iron
removal, leading to functional Hb loss and iron accumulation
(9).
Understanding respiration and gas exchange principles is
key for diagnosing and treating respiratory illnesses. Some
diseases stem from poor ventilation, membrane diffusion
disorders, or gas transport issues (6). Arterial blood gas
analysis assesses lung function and oxygenation, providing
crucial information on patient's respiratory and metabolic
status to guide treatment decisions (6,10,11)
The aim of this study was to determine whether there is
a direct interaction between the viral proteins that cause
COVID-19 and Hb that may lead to loss of oxygen carrying
capacity in the oxygen Hb dissociation curve obtained from
the artery blood gas.
Materials and Methods
Study Design
In the study, lab data of patients admitted to Erzincan
Binali Yıldırım University Mengücek Research Hospital’s
intensive care unit (ICU) between May 2020 and February
2021, diagnosed with COVID-19 (polymerase chain reaction
positive for SARS-CoV-2), non-ICU, and non-COVID-19
respiratory distress (control) were retrospectively
examined. The study was approved by the Ethics Committee
for Clinical Research at Erzincan University Faculty of
Medicine (decision no: 05/05, date: 22.03.2020). Patients’
demographic information and arterial blood gas values were
recorded. Arterial blood gas samples were analyzed using
ABL 700 (Radiometer, Copenhagen, Denmark).
Statistical Analysis
Descriptive statistics for patient and control groups’
demographic and laboratory findings were presented.
Quantitative variables were defined by average, median,
interquartile range, and standard deviation; categorical
variables as frequency and percentage. Categorical
variables were analyzed using the χ2 test. Shapiro-Wilk
test checked normality hypothesis for quantitative variables
between groups. Levene test was used to hypothesize
variances’ homogeneity. Parameters meeting parametric
test assumptions were analyzed with one-way ANOVA,
while Kruskal-Wallis analyzed those without. Tukey and
Dunnett post-hoc tests determined significant changes’
sources. Differences between groups were denoted by
symbols, with different symbols signifying significant
differences. Box-Plot charts summarized deterministic
statistical characteristics, distribution, and parameter
differences by groups. SPSS (version 20.0) was used for
data analysis, with a p-value <0.05 considered significant.
Results
The study involved 343 COVID-19 patients and 343 control
patients with different respiratory etiologies without
COVID-19. O2-Hb dissociation curves were generated
using COVID-19 patient data and control group data, then
compared (12). Table 1 shows average ages of ICU, non-ICU,
and control groups as 71.51, 68.79, and 66.00 respectively;
gender distributions were 80 males/51 females, 122
males/90 females, and 209 males/139 females. In ODC
evaluations (Figure 1), non-ICU and control group curves
without COVID-19 were similar; ICU group’s ODC slightly
tilted right, and all groups trended right compared to the
standard curve. ICU group’s P50 value was higher (mean:
30.74 mmHg, n=131, p=0.047). Non-ICU group had higher
oxyhemoglobin percentage (mean: 65.44% vs 69.81%,
p=0.015), PO2 (46.98 mmHg vs. 48.98 mmHg, p=0.001),
glucose (mean: 163.39 mg/dL vs 195.36 mg/dL, p=0.002),

60 Üstündağ et al. COVID-19 and Oxyhemoglobin Dissociation Curve
Table 1. Summary of results from patients with ICU COVID-19, non-ICU COVID-19 and control group without COVID-19
Non-ICU ICU Control p-value
Sex
Male N (%) 122 (57.5) 80 (61.1) 209 (60.9) 0.699
Female N (%) 90 (42.5) 51 (38.9) 134 (39.1)
Parametreler Mean Median SD Min. Max. Mean Median SD Min. Max. Mean Median SD Min. Max.
Age 68.79*71.00 14.47 20.00 96.00 71.51*73.00 13.57 20.00 96.00 62.31#66.00 20.07 19.00 102.00 0.000
P50 (mmHg) 29.25#28.79 3.71 21.28 53.74 30.74*29.66 5.86 21.74 74.39 29.38*# 28.52 6.67 20.65 110.98 0.047
Bicarbonate plasma (mEq/L) 24.18 24.25 4.19 10.30 37.70 24.48 23.80 5.84 11.60 51.00 23.66 23.90 4.42 5.30 42.00 0.252
Bilirubin (mg/dL) 1.60 1.45 1.06 0.00 8.00 2.43 1.50 4.04 0.00 33.00 1.57 1.50 0.93 0.10 7.00 0.838
Deoxyhemoglobin (%) 27.67 21.40 20.73 1.20 92.00 28.62 25.70 22.63 0.50 83.20 31.51 28.30 20.63 0.70 94.30 0.107
Glucoce (mg/dL) 195.36*147.50 123.35 40.00 695.00 185.44 158.00*# 104.38 64.00 879.00 163.39#131.00 96.39 55.00 743.00 0.002
HCO3 (mEq/L) 24.46 24.35 3.92 15.50 33.60 23.84 25.05 6.32 7.4 0 43.50 24.00 23.90 3.81 13.20 38.70 0.771
Hematocrit (%) 42.48 41.95 12.41 0.90 82.60 40.35 40.40 11.78 5.50 73.90 42.69 43.00 10.25 10.10 78.60 0.118
Hemoglobin (g/dL) 13.85 13.70 4.10 0.01 27.20 13.06 12.90 3.91 4.00 24.10 13.94 14.10 3.40 3.10 25.70 0.086
Carboxyhemoglobin (%) 1.13#1.00 0.61 -0.30 4.80 1.02#1.00 0.52 -0.30 2.90 1.66*1.30 1.45 -0.40 11.40 0.000
Chlorine (mmol/L) 106.26 106.00 6.85 74.00 136.00 107.35 107.00 9.65 86.00 145.00 106.09 106.00 8.58 2.60 142.00 0.367
Lactate (mmol/L) 2.09 1.80 1.21 0.10 6.90 2.23 1.80 1.52 0.50 9.30 2.07 1.70 1.35 0.00 13.70 0.506
Methemoglobin (%) 1.36*1.30 .45 -1.10 3.30 1.20#1.20 0.49 0.10 3.20 1.42*1.40 0.44 -1.40 4.60 0.000
Oxyhemoglobin (%) 69.81*75.70 20.60 5.70 96.50 69.2 0#* 72.15 22.54 15.40 96.80 65.44#68.10 20.52 4.00 97.1 0 0.015
Oxygen saturation (%) 71.73 78.20 21.16 5.80 98.80 70.76 73.75 23.06 15.60 99.50 67.53 70.90 21.15 4.10 99.30 0.076
Osmalarite (mOsmol/L) 283.36 283.60 11.61 233.50 340.90 286.14 283.65 18.28 243.20 353.50 285.24 285.65 11.70 237.60 359.30 0.147
pH (7.35-7.45) 7.407*7.415 0.079 7.019 7.557 7.3 90#* 7.408 0.101 7.047 7.590 7.384#7.383 0.080 6.819 7.649 0.007
Potassium (mmol/L) 4.04#3.90 1.37 2.30 16.80 4.14#* 4.00 0.86 2.40 7.00 4.33*4.10 1.55 2.40 20.10 0.026
Sodium (mmol/L) 135.80#136.00 5.92 111.00 164.00 137.61#* 137.00 8.11 117.00 171.00 138.10*139.00 5.51 113.00 163.00 0.000
Standard base (±3 mmol/L) 0.12 0.25 5.10 -17.50 18.70 0.17 0.20 6.62 -18.80 22.80 0.03 0.30 5.71 -24.50 36.00 0.970
Total O2 (mEq/L) 13.80#13.80 5.19 2.30 30.10 12.47*12.10 5.40 2.70 25.90 12.71#* 12.80 4.98 0.90 30.50 0.033
pCO2 (mmHg) 39.44*39.00 9.78 12.20 113.00 41.78#* 39.70 12.92 12.70 101.00 42.02#41.90 9.79 5.40 89.30 0.015
pO2 (mmHg) 48.98#* 44.05 24.26 11.00 177.00 56.86#45.80 36.30 16.00 295.00 46.98*40.00 31.08 5.70 281.00 0.001
Ionized calcium (mg/dL) 1.15*1.16 0.12 0.58 1.86 1.10#1.10 0.10 0.82 1.47 1.1 5*1.15 0.12 0.69 1.96 0.000
The values in Table 1 are presented as mean and standard deviation (SD). Differences between groups with the same symbol were not statistically significant, while differences between groups with
different symbols were found to be significant at a p-value of less than 0.05. ICU: Intensive care unit, COVID-19: Coronavirus disease-2019, SD: Standard deviation, min-max: Minimum-maximum

Üstündağ et al. COVID-19 and Oxyhemoglobin Dissociation Curve 61
and pH (median: 7.38 vs 7.41, p=0.007) than the control
group, but lower carboxyhemoglobin percentage (mean:
1.66% vs 1.13%, p=0.000), PCO2 (42.02 mmHg vs 39.44
mmHg, p=0.015), potassium (mean: 4.33 mmol/L vs 4.04,
p=0.026), and sodium (mean: 138.10 mmol/L vs 135.80
mmol/L, p=0.000). ICU group had lower methemoglobin
percentage (p=0.000).
ICU and non-ICU patients had similar deoxyhemoglobin, Hb,
hematocrit, total bilirubin, bicarbonate plasma, chlorine,
lactate, and osmolarity levels compared to control patients
(no significant differences, Table 1, Figure 2).
Discussion
The ODC, which connects oxygen saturation (SO2) and
PO2 in blood, is crucial for understanding blood’s oxygen
transport and release (13). P50 measures Hb's oxygen
affinity, determining oxygen release from microcirculation
to tissues. An increased P50 (rightward ODC shift)
indicates reduced Hb-oxygen binding affinity, promoting
oxygen release into tissues (7). Normal Hbs P50 is around
26 mmHg at 40 mmHg PCO2 pressure (14).
In this study, examining arterial blood gas samples, all
groups had higher P50 values compared to the standard.
ICU COVID-19 patients had a higher P50 value than non-ICU
COVID-19 patients (mean: 29.25 mmHg, p=0.047), with a
slight ODC right shift. This suggests ICU COVID-19 patients
require greater tissue oxygenation due to low O2-Hb
affinity. While Severinghaus’s standard curve (12) indicates
systemic arterial blood oxygen saturation separating from
lungs is around 95 mmHg, Figure 1 shows all three groups’
dissociation curves averaging 98 percent systemic arterial
blood oxygen saturation.
Daniel et al. (15) found no difference in Hb-O2 affinity
between 14 COVID-19 patients and 11 controls using
an in vitro Hemox analyzer with standardized pH and
temperature. P50 values were directly obtained from blood
gas analyzers without adjustment for CO2 or pH changes
in COVID-19. They hypothesized that in vivo Hb-O2 affinity
could be affected by other factors in COVID-19. Vogel et
al. (16) conducted a retrospective, observational study of
blood gas analyses (n=3,518) from COVID-19 patients to
investigate changes in Hb-O2 affinity. They reported that
this condition may play a role in adjusting to hypoxemia
due to the lengthy disease process. Compared to patients
with other causes of severe respiratory failure, COVID-19
patients had significantly higher Hb-O2 affinity. Our findings
show higher P50 and lower Hb-O2 affinity in ICU COVID-19
patients. This may result from patients receiving oxygen
support via ventilators, masks, or nasal cannulas. There
are limited ODC-related studies in COVID-19 patients in the
literature.
In critical illnesses, arterial blood gas (ABG) tests are vital
for assessing lung function, diagnosis, and patient follow-
up (17). Our study showed patients’ pH values were within
the normal range, allowing ODC evaluation at normal pH.
All three groups displayed hypoxemia with ICU and non-
ICU groups having higher PO2 values than controls. Oxygen
therapy may have increased arterial blood PO2 in COVID-19
patients, which is a study limitation. No significant
abnormalities were found in partial oxygen pressure
against Hb oxygen saturation. All groups showed a slight
right shift in ODC. Lower PCO2 levels in non-ICU and ICU
groups may be related to respiratory support therapy (18).
Further in vitro and in vivo studies are needed to validate
our hypothesis and understand the ODC mechanism during
COVID-19 infection.
In our study which also evaluated the glucose, electrolyte,
bicarbonate, bilirubin, Hb and hematocrit levels in the ABG
analysis; had high blood glucose levels (mean: 195.36 mg/
dL, 185.44 mg/dL, 163.39 mg/dL respectively) outside the
normal range were detected in all patients in the ICU, non-
ICU and control groups. This indicates that patients glucose
metabolism is impaired. In the cross-group comparison
of other data, there were similar levels of Hb, hematocrit,
total bilirubin, bicarbonate plasma, chlorine, lactate and
osmolarity.
Most coronavirus non-structural proteins are mainly found
in infected cells, playing a key role in RNA replication (19).
The virus is unlikely to access significant Hb, and there
is no evidence of infiltration into red blood cells (20). Liu
and Li (9) suggest interactions may occur after immune
hemolysis, but some studies report no significant hemolysis
in COVID-19 patients (21-23). Our study’s clinical data
Figure 1. Comparative oxygen dissociation curves to the standard
curve for all groups: the standard curve as described by JW
Severinghaus (black curve), values of oxygenation saturation
plotted versus PaO2 for patients admitted to the intensive care unit
(ICU) with coronavirus disease-2019 (COVID-19) (green curve), and
control patients without COVID-19 (control; red curve)

62 Üstündağ et al. COVID-19 and Oxyhemoglobin Dissociation Curve
Figure 2. Corresponding laboratory values of age, P50, bicarbonate plasma, bilirubin, deoxyhemoglobin, glucose, HCO3, hematocrit,
hemoglobin, carboxyhemoglobin, chlorine, lactate, methemoglobin, oxyhemoglobin, oxygen saturation, osmolarity, pH, potassium, sodium,
standard base, Total O2, pCO2, pO2, and ionized calcium. The importance of the differences between the groups was indicated by the
symbols. While the differences were found to be insignificant between groups with the same symbol, the differences between groups with
different symbols were found to be significant

Üstündağ et al. COVID-19 and Oxyhemoglobin Dissociation Curve 63
doesn’t show significant hemolysis or abnormal Hb-oxygen
decomposition. Similarly, another study evaluating ABG
data of thirty COVID-19 patients found no significant clinical
effect (24). Recent reports show similar mortality rates
and mechanical ventilation needs for COVID-19 as other
respiratory failure forms (3,25). Additionally, there's no
evidence in the literature of significant anemia or excessive
iron load caused by COVID-19 (21-23).
Our study has limitations due to small sample size, single-
center, and retrospective design. The patient population
receiving respiratory support and various medications in
the service and intensive care unit may not fully reflect
the impact of oxygen on Hb in COVID-19. The Control group
was created from other patients with respiratory distress,
limiting statistical significance. Therefore, larger sample
sizes and in vivo and in vitro experimental studies are
required for further verification.
Conclusion
The medical field and the global scientific community are
making rapid strides in comprehending the underlying
mechanisms of COVID-19 to effectively control its spread,
provide proper care for patients, and ultimately discover
definitive treatment options. In our study, which was
carried out in order to contribute to the enlightenment of the
physiological mechanism of the disease, it was concluded
that patients diagnosed with COVID-19 and other respiratory
distress patients were slightly right-leaning in the Hb-O2
dissociation curve and had a higher percentage of oxygen
saturation of arterial blood in all three groups.
Ethics
Ethics Committee Approval: The study was approved by
the Ethics Committee for Clinical Research at Erzincan
University Faculty of Medicine (decision no: 05/05, date:
22.03.2020).
Informed Consent: Retrospective study.
Peer-review: Externally peer-reviewed.
Authorship Contributions
Concept: H.Ü., Design: H.Ü., C.M., Data Collection or
Processing: C.M., M.T.H., Analysis or Interpretation: H.Ü.,
C.M., M.T.H., Literature Search: H.Ü., C.M., M.T.H., Writing:
H.Ü., M.T.H.
Conflict of Interest: No conflict of interest was declared by
the authors.
Financial Disclosure: The authors declared that this study
received no financial support.
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