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The novel coronavirus disease 2019 (COVID-19) pandemic is a global crisis, challenging healthcare systems worldwide. Many patients present with a remarkable disconnect in rest between profound hypoxemia yet without proportional signs of respiratory distress (i.e. happy hypoxemia) and rapid deterioration can occur. This particular clinical presentation in COVID-19 patients contrasts with the experience of physicians usually treating critically ill patients in respiratory failure and ensuring timely referral to the intensive care unit can, therefore, be challenging. A thorough understanding of the pathophysiological determinants of respiratory drive and hypoxemia may promote a more complete comprehension of a patient’s clinical presentation and management. Preserved oxygen saturation despite low partial pressure of oxygen in arterial blood samples occur, due to leftward shift of the oxyhemoglobin dissociation curve induced by hypoxemia-driven hyperventilation as well as possible direct viral interactions with hemoglobin. Ventilation-perfusion mismatch, ranging from shunts to alveolar dead space ventilation, is the central hallmark and offers various therapeutic targets. Full text:
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R E V I E W Open Access
The pathophysiology of happyhypoxemia
in COVID-19
Sebastiaan Dhont
, Eric Derom
, Eva Van Braeckel
, Pieter Depuydt
and Bart N. Lambrecht
The novel coronavirus disease 2019 (COVID-19) pandemic is a global crisis, challenging healthcare systems worldwide. Many
patients present with a remarkable disconnect in rest between profound hypoxemia yet without proportional signs of
respiratory distress (i.e. happy hypoxemia) and rapid deterioration can occur. This particular clinical presentation in COVID-19
patients contrasts with the experience of physicians usually treating critically ill patients in respiratory failure and ensuring
timely referral to the intensive care unit can, therefore, be challenging. A thorough understanding of the pathophysiological
determinants of respiratory drive and hypoxemia may promote a more complete comprehension of a patientsclinical
presentation and management. Preserved oxygen saturation despite low partial pressure of oxygen in arterial blood samples
occur, due to leftward shift of the oxyhemoglobin dissociation curve induced by hypoxemia-driven hyperventilation as well
as possible direct viral interactions with hemoglobin. Ventilation-perfusion mismatch, ranging from shunts to alveolar dead
space ventilation, is the central hallmark and offers various therapeutic targets.
Keywords: COVID-19, SARS-CoV-2, Respiratory failure, Hypoxemia, Dyspnea, Gas exchange
Take home message
This review describes the pathophysiological abnormal-
ities in COVID-19 that might explain the disconnect be-
tween the severity of hypoxemia and the relatively mild
respiratory discomfort reported by the patients.
In early December 2019, the first cases of a pneumonia
of unknown origin were identified in Wuhan, the capital
of Hubei province in China. The pathogen responsible
for coronavirus disease 2019 (COVID-19) has been iden-
tified as a novel member of the enveloped RNA betacor-
onavirus family and named severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), due to similar-
ities with SARS-CoV and Middle East Respiratory Syn-
drome (MERS) viruses. Although much is known about
the epidemiology and the clinical characteristics of
COVID-19, little is known about its impact on lung
pathophysiology. COVID-19 has a wide spectrum of
clinical severity, data classifies cases as mild (81%), se-
vere (14%), or critical (5%) [13]. Many patients present
with pronounced arterial hypoxemia yet without propor-
tional signs of respiratory distress, they not even
verbalize a sense of dyspnea [48]. This phenomenon is
referred as silent or happyhypoxemia. Tobin et al. re-
cently presented three cases of happy hypoxemia with
ranging between 36 and 45 mmHg in the absence
of increased alveolar ventilation (P
ranging between
34 and 41 mmHg) [5]. In patients with COVID-19, the
severity of hypoxemia is independently associated with
in-hospital mortality and can be an important predictor
that the patient is at risk of requiring admission to the
intensive care unit (ICU) [9,10]. Since correct recogni-
tion of hypoxemia has such an impact on prognosis and
timely treatment decisions, we here offer an overview of
the pathophysiological abnormalities in COVID-19 that
might explain the disconnect between hypoxemia and
patient sensation of dyspnea.
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* Correspondence:
Department of Internal Medicine and Paediatrics, Ghent University, Corneel
Heymanslaan 10, 9000 Ghent, Belgium
Full list of author information is available at the end of the article
Dhont et al. Respiratory Research (2020) 21:198
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Dyspnea as a sensation
Breathing is centrally controlled by the respiratory cen-
ter in the medulla oblongata and pons regions of the
brainstem (see Fig. 1) that control the respiratory drive
to match respiration to the metabolic demands of the
body [11,12]. The main input affecting the respiratory
drive is derived from chemical feedback among periph-
eral and central chemoreceptors. The center is, however,
also influenced by higher brain cortex, hypothalamic in-
tegrative nociception, feedback from mechanostretch re-
ceptors in muscle and lung, and metabolic rate. The
output of the respiratory center can be divided into
rhythm- (e.g. respiratory rate) and pattern generating
(e.g. depth of breathing effort) signals, and these outputs
may be controlled independently [11,13,14]. Dyspnea is
generally defined as a sensation of uncomfortable, diffi-
cult, or laboredbreathing and occurs, in general, when
the demand for ventilation is out of proportion to the
patients ability to respond. It should be distinguished
from tachypnea (rapid breathing) or hyperpnea (in-
creased ventilation). Dyspnea grading relates to whether
this feeling occurs in rest or upon exercise. This semi-
quantitative approach of scoring is best exemplified by
the frequently used modified Medical Research Council
(MRC) dyspnea scale, which categorizes dyspnea from
grade 0 (dyspnea only with strenuous exercise) to grade
4 (too dyspneic to leave house or breathless when dress-
ing) in relation to subjects of the same age [15,16].
Various sensory, pain and emotional stimuli affect the
sensation of breathing via the cerebral cortex and hypo-
thalamus [17,18]. The abnormal sense of muscle effort
is another contributor to dyspnea. Conscious awareness
of the activation of respiratory muscles is absent in
healthy breathing. However, when the respiratory mus-
cles are fatigued or weakened due to altered lung me-
chanics (e.g. decreased thoracic compliance), breathing
may be perceived as a substantial effort [12]. Dyspnea
can also be caused by input from the mechanoreceptors
in the respiratory tract and the chest wall. Stimulation of
vagal irritant receptors (e.g. bronchoconstriction, breath-
ing through an external resistance) appears to intensify
dyspnea [12,19,20]. The contribution of metabolic rate
in modulating sense of dyspnea in critically ill patients
remains unclear, despite its well-established role during
exercise [11,21]. The best-known determinants of the
respiratory drive are the central and peripheral chemore-
ceptors. Changes in partial gas pressure of dissolved car-
bon dioxide in the blood (PaCO
) seem the most
important component, causing shifts in pH at the level
of both the peripheral and central chemoreceptors [11,
12,22]. At steady state, the arterial PaCO
is determined
by the following equation:
Fig. 1 Main inputs affecting respiratory center (RCC)
Dhont et al. Respiratory Research (2020) 21:198 Page 2 of 9
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K constant (863 mmHg)
Rate of CO
minute ventilation
dead space
Vt tidal volume
The normal response to hypercapnia (caused by increased
, hypoventilation or increased VCO
) is an increase in
respiratory drive and minute volume ventilation [23].
Hypoxemia itself rather plays a limited role in the sensation
of breathlessness experienced by patients with
cardiopulmonary disease on the opposite of hypercapnia that
creates per se dyspnea [12,24,25]. In healthy subjects, the
respiratory drive shifts minimally in mild hypoxemia (PaO
6065 mmHg), such as resulting from stays at high altitude
or experimental hypoxic chambers [11,26]. Many patients
with dyspnea are not hypoxemic, while those who are,
usually experience only a slight improvement in symptoms
after hypoxemia is corrected with supplemental oxygen
therapy [12]. When arterial P
drops below 40 mmHg,
dyspnea often occurs [12]. Of note, the normal response to
hypoxemia is a rise in minute ventilation, primarily by
increasing tidal volume and respiratory rate. Increased
respiratory rate (tachypnea) and tidal volume (hyperpnea) -
signs of impending hypoxemic respiratory failure [11,27].
Furthermore, PaCO
serves as one of the fundamental
regulators of cerebral blood flow. Hyperventilation causes
decreased PaCO2 which subsequently leads to arterial
vasoconstriction thus lowering cerebral blood flow and
intracranial pressure. In contrary, increase in PaCO
leads to
increased intracranial pressure ultimately leading to
deteriorating level of consciousness, altered brainstem
reflexes, and altered postural and motor responses [28,29].
At the bedside, a profound understanding of the
pathophysiological determinants of respiratory drive and
hypoxemia may promote a more complete comprehension
of a COVID-19 of a patients clinical presentation and timely
management [11].
Happy hypoxemia in COVID-19
The disconnect between the severity of hypoxemia and
the relatively mild respiratory discomfort reported by the
COVID-19 patients contrasts with the experience of phy-
sicians usually treating critically ill patients in respiratory
failure [30]. Guan reported dyspnea in only 18.7% of 1099
hospitalized COVID-19 patients, despite low PaO2/FiO2
ratios, abnormal CT scans (86%) and common require-
ment for supplemental oxygen (41%) [31]. Happy or silent
hypoxemia is not exclusively seen in COVID-19, but may
also occur in patients with atelectasis, intrapulmonary
shunt (i.e. arterio-venous malformations) or right-to-left
intracardiac shunt. The adequacy of gas exchange is pri-
marily determined by the balance between pulmonary
ventilation and capillary blood flow, referred as ventila-
tion/perfusion (V/Q) matching [32]. In the initial phase of
COVID-19, several mechanisms contribute to the devel-
opment of arterial hypoxemia (see Fig. 2), without a con-
comitant increase in work of breathing. Rapid clinical
deterioration may occur.
Changes in oxyhemoglobin dissociation curve
Oxygen saturation measured by pulse oximetry
) is often used to detect hypoxemia. However,
should be interpreted with caution in COVID-
19. The sigmoid shaped oxyhemoglobin dissociation
curve seems to shift to the left, due to induced re-
spiratory alkalosis (drop in PaCO
) because of
hypoxemia-driven tachypnea and hyperpnea. During
hypocapnic periods, the affinity of hemoglobin for
oxygen and thus oxygen saturation increases for a
given degree of PaO
, explaining why SpO
can be
well-preserved in the face of a profoundly low PaO
[3335]. This finding is also seen in high altitude
hypoxemia, in which hypocapnia significantly shifts
the oxygen-hemoglobin dissociation curve and im-
proves blood oxygen saturation [36]. The alveolar gas
equation also predicts that hyperventilation and the
resulting drop in the alveolar partial pressure of
carbon dioxide leads to an increase in the alveolar
partial pressure of oxygen and ultimately lead to an
increase in SpO
There might also be a biological explanation for the
leftward shift of the curve in COVID-19. Liu et al. put
forward hypotheses about direct viral interaction with
the heme group of hemoglobin. According to this the-
ory, heme serum levels are increasing in COVID-19
along with harmful iron ions (Fe
) causing inflamma-
tion and cell death (ferroptosis). This leads to the pro-
duction of large amounts of serum ferritin to bind these
free irons in order to reduce tissue damage [37]. In con-
clusion, SpO
should be interpreted in the light of the
presence of hyperventilation (tachypnea, low P
and, if possible, P
via arterial puncture. Measuring
the alveolar to arterial oxygen (P(A-a)O
gradient (150
mmHg - PaCO2/0.8 - P
at sea level) and relating this
value to age and supplemental oxygen (age/4 + 4 + 50
0.21) in mmHg) can be insightful. This can be
performed rapidly on a smartphone app [38]. The P(A-
gradient is increased either by V/Q mismatch or by
intrapulmonary shunting. Hypoxemia due to V/Q
Dhont et al. Respiratory Research (2020) 21:198 Page 3 of 9
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mismatch can be easily corrected by supplemental oxy-
gen therapy whereas pulmonary shunts have a poor re-
sponse to oxygen therapy [39].
Causes of hypoxemia in COVID-19
Intrapulmonary shunting
Arterial hypoxemia early in SARS-CoV-2 infection is
primarily caused by V/Q mismatch and thus persistence
of pulmonary arterial blood flow to non-ventilated al-
veoli, reflected by a marked increase in P(A-a)O
ent. The infection leads to a modest local interstitial
edema, particularly located at the interface between lung
structures with different elastic properties, where stress
and strain are concentrated [27]. Due to increased lung
edema (leading to ground-glass opacities and consolida-
tion on chest imaging), loss of surfactant and superim-
posed pressure, alveolar collapse ensues and a
substantial fraction of the cardiac output is perfusing
non-aerated lung tissue, resulting in intrapulmonary
shunting [27]. As previously discussed, tidal volume in-
creases during the disease course leading to rising nega-
tive inspiratory intrathoracic pressure. The latter, in
combination with increased lung permeability due to in-
flammation, will eventually result in progressive edema,
alveolar flooding, and patient self-inflicted lung injury
(P-SILI), as first described by Barach in 1938 [11,40,
41]. Over time, the increased edema will further enhance
lung weight, alveolar collapse, and dependent atelectasis,
resulting in progressively increasing shunt fraction and
further decline of oxygenation which cannot completely
be corrected by increasing F
Loss of lung perfusion regulation
The persistence of high pulmonary blood flow to non-
aerated lung alveoli appears to be caused by the relative
failure of the hypoxic pulmonary vasoconstriction mech-
anism (constriction of small intrapulmonary arteries in re-
sponse to alveolar hypoxia) during SARS-CoV-2 infection,
as recently illustrated by Lang et al. using dual-energy CT
[42,43]. Whether the latter mechanism is only triggered
by the release of endogenous vasodilator prostaglandins,
bradykinin, and cytokines associated with the inflamma-
tory process or also by other yet undefined mechanisms
remains to be investigated [33,44,45]. Vasoplegia also
seems to be influential in the loss of lung perfusion regula-
tion, possibly induced by shear stress on the interfaces
between lung structures, as part of the P-SILI spectrum
[4547]. Further, dysregulation of the renin-angiotensin
system (RAS) contribute to the pathophysiology of
COVID-19 [4852]. Angiotensin-converting enzyme 2
(ACE2) is the principal functional receptor used by SARS-
CoV-2 for cell entry, implying ACE2 internalization [52
54]. ACE2 converts angiotensin II (Ang II) to angiotensin
17(Ang17) and is also important for degrading brady-
kinin. Hence, diminished levels of ACE2 lead to an in-
crease in Ang II, mediating pulmonary vasoconstriction
through agonism at Ang II-receptor, while Ang 17op-
poses the actions of Ang II [50,51,54]. Recently, Liu et al.
revealed that serum Ang II levels were linearly associated
with viral load and lung injury in COVID-19 [55].
Intravascular microthrombi
Endothelial injury is emerging as a central hallmark of
COVID-19 pathogenesis, and the cytopathic virus can
Fig. 2 Mechanisms of hypoxemia in COVID-19
Dhont et al. Respiratory Research (2020) 21:198 Page 4 of 9
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directly infect lung capillary endothelial cells that ex-
press ACE2 [54,56]. Intravascular microthrombi are the
net result of an imbalance between procoagulant and fi-
brinolytic activity in the presence of acute inflammation
and endothelial injury [45,5759]. The pro-coagulant
activity might result from complement system-mediated
activation of clotting, similar to some forms of throm-
botic microangiopathy (TMA), or could be due to inhib-
ition of plasminogen activation and fibrinolysis via
increased activity of plasminogen activator inhibitor
(PAI-1 and -2) which are induced as acute-phase pro-
teins under the influence of IL-6. Diffuse intravascular
coagulation (DIC) is also seen in patients with severe
COVID-19, mediated via endothelial release of tissue
factor and activation of clotting factor VII and XI. Many
patients with COVID-19 develop elevated D-dimers sug-
gesting the formation of blood clots. D-dimer levels on
admission are used to predict in-hospital mortality in
COVID-19, and DIC present much more frequently
(71%) in COVID-19 patients with a dismal prognosis,
versus only 0,6% of survivors [6063]. Autopsy of the
lungs after severe disease showed fibrin deposition, dif-
fuse alveolar damage, vascular wall thickening, and fre-
quently occurring complement-rich microthrombi
occluding lung capillaries and larger thrombi causing
pulmonary artery thrombosis and embolism [6365].
Hypercoagulable state leads to further deterioration in
V/Q mismatch and lung tissue damage. Moreover, co-
agulation is also modulated by activating C-reactive pro-
tein and ensuing complement activation and hepatic
synthesis of fibrinogen as an acute phase protein in
COVID-19 [66].
Impaired diffusion capacity
Lung diffusion capacity (DLCO) can be impaired,
although pure diffusion defects are rarely a cause for
increased P(A-a)O
gradient at rest [67,68]. SARS-CoV-
2 propagates within alveolar type II cells, where a large
number of viral particles will be produced and released,
followed by immune response mediated destruction of
infected cells (virus-linked pyroptosis) [54]. Loss of al-
veolar epithelial cells and a pro-coagulant state cause the
denuded basement membrane to be covered with debris,
consisting of fibrin, dead cells, and complement activa-
tion products, collectively referred to as hyaline mem-
branes [54,69]. With incremental exercise and in the
face of absent hypoxic vasoconstriction in COVID-19, a
hyperdynamic pulmonary circulation might not allow
sufficient time for red blood cells to equilibrate their
oxygen uptake. A diffusion limitation may, therefore,
occur in COVID-19 leading to a raised P(A-a)O
ent and exercise-induced arterial hypoxemia (EIAH)
[68]. Recently, Xiaoneng Mo et al. confirmed a decrease
in DLCO in COVID-19 patients at the time of discharge.
The prevalence of impaired diffusing-capacity was linked
to the severity of disease, respectively 30.4% in mild ill-
ness, 42.4% in pneumonia and 84.2% in severe pneumo-
nia [70]. Long-term studies are needed to address
whether these deficits are persistent as seen in MERS
where 37% of MERS survivors still presented with an im-
pairment of DLCO [39].
Preservation of lung mechanics
The outline presented in the previous paragraphs largely
clarifies the dissociation between the severity of
hypoxemia in COVID-19 and relatively well-preserved
lung mechanics. Gas exchange abnormalities in some
patients with COVID-19 occur earlier than increases in
mechanical loads [41]. During the first days of infection,
there is no increased airway resistance, and there is pre-
sumably no increased anatomical or physiological dead
space ventilation. The breathing effort also remains ra-
ther low because lung compliance is normal in many pa-
tients without pre-existing lung disease. As recently
shown by Gattinoni et al. in a cohort of 16 critically ill
patients, relatively normal values for respiratory system
compliance (50.2 ± 14.3 ml/cmH2O) went hand in hand
with a dramatically increased shunt fraction of 0.50 ±
0.11 [47]. Such a wide discrepancy is highly unusual for
most forms of disorders that lead to acute lung injury
and ARDS [47,71]. Relatively high compliance indicates
a well-preserved lung gas volume and explains in part
the absence of dyspnea early in the course of illness [42,
47,61,72,73]. In contrast, Ziehr et al. described a low
compliance and a uniform presentation consistent with
the Berlin definition for ARDS in a cohort of COVID-19
patients [30,70]. Of note, patients on mechanical venti-
lation have the highest COVID-19 severity and thus
probably the lowest respiratory system compliance. Dys-
pnea itself may have precipitated mechanical ventilation,
and the latter may be a surrogate marker for low com-
pliance in COVID-19 [41]. Understanding of the respira-
tory mechanics found in COVID-19 will continue to
evolve as further research is reported.
Rapid deterioration
Hypoxemia-driven tachypnoea, hyperpnea and altered
oxygenation predict clinical deterioration induced by
either disease severity and/or host response and/or
suboptimal management [35,61]. As the disease
progresses, the more consolidated air spaces do not
inflate as easily at higher transpulmonary pressures. The
volume loss is proportionally greater at higher lung
volumes. This loss of volume reduces total lung
compliance and increases the work of breathing [45].
There is also evidence that the dynamic compliance of
the remaining ventilated lung is reduced in SARS-CoV-2
pneumonia (as seen in pneumococcal pneumonia) most
Dhont et al. Respiratory Research (2020) 21:198 Page 5 of 9
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possibly by a reduction in surfactant activity, further in-
creasing the work of breathing [45]. Physiological dead
space is also increasing due to reduced blood flow
caused by intravascular thrombi. Importantly, the anx-
iety experienced by COVID-19 patients also affects the
cortical feedback to the respiratory centers. Conse-
quently, as the disease progresses, dyspnea becomes in-
creasingly apparent.
Thoughts on management
At the stage that COVID-19 patients are admitted to the
hospital with hypoxemia, viral replication is well under-
way and in addition to giving antiviral medication,
optimization of the V/Q mismatch and reduction of
cytokine storm remain the major therapeutic goals. Re-
garding perfusion, avoiding microthrombi and ongoing
fibrin deposition is one of the therapeutic strategies. It
seems prudent to use thromboprophylaxis in all
COVID-19 patients, particularly in those with high D-
dimers on admission [59,66,74]. Moore et al. recently
suggested the use of tissue plasminogen activator (tPA)
to treat ARDS in COVID-19 [75]. In addition, tackling
the systemic prothrombotic complication using anti-
inflammatory medications (such as anti-IL6R toci-
lizumab or sarilumab, or the anti-IL6 antibody siltuxi-
mab or complement inhibiting strategies) to prevent
macro- and microthrombi represents another potential
approach and several trials are currently verifying this
hypothesis [54]. Effective hypoxic pulmonary vasocon-
striction may be another target to improve the matching
of regional perfusion and ventilation in the lung. There
is an excessive release of inflammatory mediators that
disturbs the balance between nitric oxide (NO),
endothelin, and prostanoids in the pulmonary capillaries
[76], although inhaled NO has consistently failed to
show an improvement in mortality in ARDS [5355,84].
RAS modulation (e.g. angiotensin receptor blockers,
recombinant soluble ACE2, and inhibition of the brady-
kinin system) may have a potential role in restoring lung
perfusion regulation, and trials are ongoing [5052].
Regarding ventilation, supplemental oxygen is the first
step in facilitating oxygenation. In patients with refractory
hypoxemic respiratory failure (increasing shunt fraction),
timely but not premature intubation and invasive
ventilation support may be superior to non-invasive venti-
lation in boosting transpulmonary pressure, opening col-
lapsed alveoli, improving oxygenation, decreasing oxygen
debt, avoiding P-SILI and offering a better chance for the
lungs to heal [61,76,77]. Considering the critical cases,
most patients fulfil the Berlin criteria of ARDS, where
lung-protective ventilation, prone ventilation, effective
sedation and analgesia, and high positive end-expiratory
pressure (PEEP) are key [54,61,70,77]. COVID-19 pa-
tients are exquisitely PEEP sensitive [7880]. Tolerance
for modest permissive hypercapnia minimizes ventilator-
induced lung injury (VILI) [61]. Since prone position re-
cruits the dorsal lung regions and diverts blood flow to
these caudal regions, it may have particular importance in
COVID-19 when used early and in relatively long sessions
[42]. Although further trials are needed to evaluate the im-
pact on disease severity and mortality, several authors
confirmed that awake proning can improve oxygenation
in COVID-19 [8183].
The remarkable dissociation between profound hypoxemic
respiratory failure and a clinically happypatient is frequently
seen and should prompt physicians and health care workers
not only to rely on the patients apparent wellbeing but
closely monitor respiratory rate, signs of hyperventilation,
oxygen saturation and invasive measurements of hypoxemia/
hypocapnia at regular time intervals. Pulse oximetry should
be interpreted with caution, because left-sided shifting of the
oxyhemoglobin dissociation curve. The arterial hypoxemia is
induced by intrapulmonary shunting, dysregulated hypoxic
pulmonary vasoconstriction, impaired lung diffusion, and
formation of intravascular microthrombi. As in the first days
of the disease, the lung mechanics are well-preserved and
there is no increased airway resistance or dead space ventila-
tion. The respiratory center thus does not sense an uncom-
fortable sensation of breathing. However, sudden and rapid
respiratory decompensation may occur, and tachypnea and
hyperpnea might be the most important clinical warning
signs of impending respiratory failure in COVID-19 patients.
COVID-19: Coronavirus Disease 2019; SARS-CoV-2: Severe Acute Respiratory
Syndrome Coronavirus 2; MERS: Middle East Respiratory Syndrome;
ICU: Intensive Care Unit; PaCO
: Partial gas pressure of dissolved carbon
dioxide in the blood; PaO
: Partial gas pressure of dissolved oxygen in the
blood; SpO
: Oxygen saturation measured by pulse oximetry; P(A-a)O
gradient: the alveolar to arterial oxygen gradient; VCO2: Rate of CO2
production; VE: Minute ventilation; VD: Dead space; Vt: Tidal volume; V/
Q: Ventilation/Perfusion; F
: Fraction of inspired oxygen; P-SILI: Patient self-
inflicted lung injury; VILI: Ventilator-induced lung injury; RAS: Renin-
angiotensin system; ACE2: Angiotensin-converting enzyme 2;
Ang: Angiotensin; TMA: Thrombotic microangiopathy; PAI: Plasminogen
activator inhibitor; DIC: Diffuse intravascular coagulation; DLCO: Lung
diffusion capacity; NO: Nitric oxide; PEEP: Positive end-expiratory pressure
SD, ED and BNL wrote the manuscript. BNL, EVB, PD and ED read and
corrected were needed. All authors took part in the discussion leading up to
the manuscript. The authors read and approved the final manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
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Competing interests
The authors declare that they have no competing interests.
Author details
Department of Internal Medicine and Paediatrics, Ghent University, Corneel
Heymanslaan 10, 9000 Ghent, Belgium.
Department of Respiratory Medicine,
Ghent University Hospital, Ghent, Belgium.
Department of Intensive Care
Medicine, Ghent University Hospital, Ghent, Belgium.
VIB-UGent Center for
Inflammation Research, Ghent, Belgium.
Received: 4 June 2020 Accepted: 21 July 2020
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... Happy Hypoxia is a condition that has been a topic of discussion a few times ago because it is called a symptom that someone has COVID-19 [1]. Hypoxia is a term used to describe a condition when the oxygen level is insufficient in the body [2]. Usually occurs due to insufficient oxygen concentration in the blood, otherwise known as Hypoxemia [3]. ...
... These conditions will cause an increase in heart rate [4]. Mostly, hypoxemic patients will complain of being breathless [2]. ...
... Hypoxemia is a symptom of various diseases, such as Hypercholesterolemia [5], Asthma [6], GERD [7], Anxiety Disorder [8], and others. If not immediately known, Hypoxemia can cause damage to cells, tissues, and organs such as the brain and even heart failure [2]. So, Hypoxemia is important to know because it is very closely related to health conditions and can be detected by measuring SpO2 levels and heart rate. ...
Full-text available
This study made the digital system to perform screening (early prediction) of Hypoxemia using MAX30102 sensor with the fuzzy value from SpO2 level and heart rate. This research also uses the Internet of Things (IoT) system to gather data from devices to the cloud. Hypoxemia is a lack of oxygen in the blood flowing in the body. Hypoxemia conditions in the body due to lack of oxygen levels in the blood will cause an increased heart rate. Hypoxemia conditions that are not immediately recognized cause damage to cells, tissues, and organs. Hypoxemia is an essential condition because information about oxygen levels in the blood is closely related to health conditions. In this project, researchers built a Hypoxemia early detection system. From the research results, it is found that the accuracy rate of the system to detect hypoxemia is 80%, with 60% sensitivity and 100% specificity. Based on the experiment, this research is able to help screening detection (early prediction) of Hypoxemia.
... While CARDS has a broad similarity with ARDS [3], several clinical and physiopathological patterns raise questions about the relevance of usual therapeutic guidelines [4]. An "Happy hypoxemia", corresponding to a profound decrease in oxygen saturation observed in remarkably non-dyspnoeic patients has been reported repeatedly in COVID-19 patients [5,6]. In addition, while ARDS is associated with a loss of lung compliance, initial CARDS often combines severe hypoxaemia with near-normal lung compliance. ...
... Such late symptoms are coherent with those usually noted lately during classical ARDS evolution. In patients cured from COVID-19, dyspnoea is, interestingly, opposite to the "happy hypoxemia" which disconnects the severity of hypoxemia and the only mild respiratory discomfort reported by the patients [5]. Reversion of the pattern, associating concomitant improvement of haematosis with worsening of dyspnoea could be explained by compromise of the alveolocapillary membrane, as illustrated by altered DLCO, pulmonary function tests and CT abnormalities reported in a growing number of studies [15,33,34]. ...
Full-text available
Background COVID-19-related Acute Respiratory Distress Syndrome (CARDS) is the severe evolution of the Sars-Cov-2 infection leading to an intensive care unit (ICU) stay. Its onset is associated with “long-covid” including persisting respiratory disorders up to one year. Rehabilitation is suggested by most guidelines in the treatment of “long-covid”. As no randomised controlled trial did support its use in “long-covid” we aimed to evaluate the effects of endurance training rehabilitation (ETR) on dyspnoea in “long-covid” following CARDS. Methods In this multicentre, two-arm, parallel, open, assessor-blinded, randomised, controlled trial performed in three French ICU, we enrolled adults previously admitted for CARDS, discharged for at least three months and presenting an mMRC dyspnea scale score > 1. Eligible patients were randomly allocated (1:1) to receive either ETR or standard physiotherapy (SP), both for three months. Outcomes assessors were masked to treatment assignment. Primary outcome was dyspnoea’s evolution, measured by Multidimensional Dyspnea Profile (MDP) at inclusion and after 90 days. Results Between August 7, 2020 and January 26, 2022, 871 COVID-19 patients were screened, of whom 60 were randomly assigned to ETR (n=27) or SP (n=33). Mean MDP score after treatment was significantly lower in the ETR group than in the SP group (26.15 [SD 15.48] vs. 44.76 [SD 19.25]; mean difference -18.61 [95% CI -27.78 to -9.44]; p<0.0001). Conclusion CARDS patients suffering from breathlessness three months after discharge improved their dyspnoea significantly more when treated with ETR for three months rather than with SP.
... Among the most predominant symptoms are extreme fatigue, shortness of breath, low-grade fever, cough, headache, chest and/or throat pain, muscle and joint pain, palpitations, diarrhea, loss of smell and/or taste, skin rashes, cognitive de cits such as mental fog, myalgias and tingling in the upper and lower extremities [26][27][28][29][30]. Moreover, while less common, low oxygen saturations have been observed [31], and cardiovascular abnormalities such as arrhythmias, a high heart rate, myocarditis, or acute heart failure [32]. It is pertinent to consider that similar symptoms were reported in patients during the SARS-CoV outbreak in 2002, such as chronic fatigue, illness, or depression [33]. ...
Full-text available
Introduction: Long COVID patients have experienced a decline in their quality of life caused, in part but not wholly, by its negative emotional impact. Some of the most prevalent mental symptoms presented by Long COVID patients are anxiety, depression, and sleep disorders. Therefore, the need has arisen to establish the personal experiences of these patients to understand how they are managing in their daily lives while dealing with the condition. Objective: To increase understanding of the emotional well-being of people diagnosed with Long COVID. Methodology: A qualitative design was created and carried out using 35 patients, with 17 subjects being interviewed individually and 18 of them taking part in two focus groups. The participating patients were recruited in November and December 2021 from Primary Health Care (PHC) centers in the city of Zaragoza (Northern Spain) and from the Association of Long COVID Patients in Aragon. The study themes were emotional well-being, social support networks and experience of discrimination. All analyzes were performed iteratively using NVivo software. Results: The Long COVID patients demonstrated a very low state of mind due to their symptoms and limitations that had been persistent for many months in their daily life. Suicidal thoughts were also mentioned by several patients. They referred to anguish and anxiety about the future as well as fear of reinfection or relapse and returning to work. Many of the participants reported that they have sought the help of a mental health professional. Most identified discriminatory situations in health care. Conclusion: It is necessary to continue delving into the impact that Long COVID has had on mental health, and to provide entities with the necessary resources to solve these problems.
... From our data, we could not find any parameters at IRCU admission that help us to recognize the likelihood of worsening. Moreover, remaining longer in the general ward before IRCU transfer could be wrongly categorized as less severe than reliable (concept of silent hypoxia) [17][18][19]. At IRCU admission, these subjects got worse than expected and quickly deteriorated. ...
Full-text available
The intermediate respiratory care units (IRCUs) have a pivotal role managing escalation and de-escalation between the general wards and the intensive care units (ICUs). Since the COVID-19 pandemic began, the early detection of patients that could improve on non-invasive respiratory therapies (NRTs) in IRCUs without invasive approaches is crucial to ensure proper medical management and optimize limiting ICU resources. The aim of this study was to assess factors associated with survival, ICU admission and intubation likelihood in COVID-19 patients admitted to IRCUs. Observational retrospective study in consecutive patients admitted to the IRCU of a tertiary hospital from March 2020 to April 2021. Inclusion criteria: hypoxemic respiratory failure (SpO2 ≤ 94% and/or respiratory rate ≥ 25 rpm with FiO2 > 50% supplementary oxygen) due to acute COVID-19 infection. Demographic, comorbidities, clinical and analytical data, and medical and NRT data were collected at IRCU admission. Multivariate logistic regression models assessed factors associated with survival, ICU admission, and intubation. From 679 patients, 79 patients (12%) had an order to not do intubation. From the remaining 600 (88%), 81% survived, 41% needed ICU admission and 37% required intubation. In the IRCU, 51% required non-invasive ventilation (NIV group) and 49% did not (non-NIV group). Older age and lack of corticosteroid treatment were associated with higher mortality and intubation risk in the scheme, which could be more beneficial in severe forms. Initial NIV does not always mean worse outcomes.
... Authors found that the dissociation between the profound level of hypoxemia and the lack of clinical signs of respiratory distress was first associated with an imbalance between the processes inducing hypoxemia at the beginning of the disease and the initially preserved lung mechanics with no increased airway resistance or dead space ventilation, hence not stimulating the respiratory centers [31]. Yet, the mechanisms underlying oxygenation impairment in COVID-19 patients seem to primarily be the result of a mismatch between lung ventilation and perfusion ratio, which depends on the adequacy of gas exchange [8,11]. ...
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Introduction: Understanding hypoxemia, with and without the clinical signs of acute respiratory failure (ARF) in COVID-19, is key for management. Hence, from a population of critical patients admitted to the emergency department (ED), we aimed to study silent hypoxemia (Phenotype I) in comparison to symptomatic hypoxemia with clinical signs of ARF (Phenotype II). Methods: This multicenter study was conducted between 1 March and 30 April 2020. Adult patients who were presented to the EDs of nine Great-Eastern French hospitals for confirmed severe or critical COVID-19, who were then directly admitted to the intensive care unit (ICU), were retrospectively included. Results: A total of 423 critical COVID-19 patients were included, out of whom 56.1% presented symptomatic hypoxemia with clinical signs of ARF, whereas 43.9% presented silent hypoxemia. Patients with clinical phenotype II were primarily intubated, initially, in the ED (46%, p < 0.001), whereas those with silent hypoxemia (56.5%, p < 0.001) were primarily intubated in the ICU. Initial univariate analysis revealed higher ICU mortality (29.2% versus 18.8%, p < 0.014) and in-hospital mortality (32.5% versus 18.8%, p < 0.002) in phenotype II. However, multivariate analysis showed no significant differences between the two phenotypes regarding mortality and hospital or ICU length of stay. Conclusions: Silent hypoxemia is explained by various mechanisms, most physiological and unspecific to COVID-19. Survival was found to be comparable in both phenotypes, with decreased survival in favor of Phenotype II. However, the spectrum of silent to symptomatic hypoxemia appears to include a continuum of disease progression, which can brutally evolve into fatal ARF.
... 17 La alcalosis respiratoria aguda es el trastorno ácido base inicial en los pacientes con COVID-19, dando lugar a un valor de saturación de oxígeno aparentemente normal, pero con hipoxemia. 18 En nuestro estudio pudimos validar este dato ...
Full-text available artículo original Med Int Méx 2022; 38 (2): 281-287. La hipoxemia como factor de riesgo de lesión renal aguda en COVID-19 Resumen OBJETIVO: Demostrar si en los pacientes con COVID-19 la hipoxemia es un factor de riesgo de lesión renal aguda. MATERIALES Y MÉTODOS: Estudio transversal, retrospectivo, descriptivo, analítico, efectuado del 1 de mayo al 30 de septiembre de 2020, en el que se incluyeron pacientes mayores de 18 años ingresados en el servicio de urgencias de un centro médico de atención COVID-19 con los criterios de caso sospechoso de COVID-19 más tomografía de tórax con imágenes sugerentes; se clasificaron por el valor de creatinina sérica (CrS) en grupo 1, sin lesión renal aguda, y grupo 2, con lesión renal aguda. RESULTADOS: Se reclutaron 105 pacientes. El grupo 1 incluyó 32 pacientes (30.5%) y el grupo 2, 73 (69.5%). La mediana de creatinina sérica al ingreso fue de 0.7 y 1.0 mg/ dL en los grupos 1 y 2, respectivamente (p = 0.05). La mediana de PaO 2 /FiO 2 al ingreso en el grupo 1 fue de 90 mmHg y en el grupo 2 de 105 mmHg (p = 0.76) sin encontrar asociación con lesión renal aguda de ingreso; la saturación arterial de oxígeno (SatO 2) igual o mayor del 92% al momento de ingresar al servicio de urgencias mostró una correlación negativa con la aparición de lesión renal aguda (Pearson:-0.537, p = 0.04). CONCLUSIONES: En la fase inicial de la COVID-19, la hipoxemia no es factor desenca-denante de lesión renal aguda; sin embargo, la SatO 2 puede ser un marcador distractor de estabilidad respiratoria, ya que la hipoxemia persistente sería una condicionante más de la lesión renal aguda. Abstract OBJECTIVE: To demonstrate if in patients with COVID-19 hypoxemia is a risk factor of acute kidney injury. MATERIALS AND METHODS: Cross-sectional, retrospective, descriptive, analytical study was done from May 1 st to September 30 th , 2020, including patients over 18 years of age admitted to the emergency service of a COVID-19 care medical center with the criteria of a suspected case of COVID-19 plus chest tomography with suggestive images. They were classified by the serum creatinine (SCr) value: Group 1 (G1) without acute kidney injury and group 2 (G2) with acute kidney injury. RESULTS: One hundred and five patients were recruited. G1 included 32 patients (30.5%) and G2 73 (69.5%). Median SCr at admission was 0.7 and 1.0 mg/dL for G1 and G2, respectively (p = 0.05). The median PaO 2 /FiO 2 at admission for G1 was 90 mmHg and for G2 105 mmHg (p = 0.76) without finding association with admission acute kidney injury; arterial oxygen saturation (SatO 2) equal or higher than 92% to the moment of admission to the emergency department presented a negative correlation for the development of acute kidney injury (Pearson:-0.537, p = 0.04). CONCLUSIONS: In the initial phase of COVID-19, hypoxemia is not a triggering factor for acute kidney injury; however, SatO 2 can be a distracting marker of respiratory stability since persistent hypoxemia would be one more conditioning of acute kidney injury.
High serum ferritin (hyperferritinemia), a reliable hallmark of severe COVID-19 often associates with a moderate decrease in serum iron (hypoferremia) and a moderate increase in serum hepcidin. This suggests that hyperferritinemia in severe COVID-19 is reflective of inflammation rather than iron overload. To test this possibility, the expression status of ferritin heavy chain (FTH1), transferrin receptor 1 (TFRC), hepcidin (HAMP), and ferroportin (SLC40A1) genes and promoter methylation status of FTH and TFRC genes were examined in blood samples obtained from COVID-19 patients showing no, mild or severe symptoms and in healthy-donor monocytes stimulated with SARS-CoV-2-derived peptides. Severe COVID-19 samples showed a significant increase in FTH1 expression and hypomethylation relative to mild or asymptomatic COVID-19 samples. S-peptide treated monocytes also showed a significant increase in FTH1 expression and hypomethylation relative to that in controls; treatment with ECD or NP did not change FTH1 expression nor its methylation status. In silico and in vitro analysis showed a significant increase in the expression of the TET3 demethylase in S peptide-treated monocytes. Findings presented here suggest that S peptide-driven hypomethylation of the FTH1 gene promoter underlies hyperferritinemia in severe COVID-19 disease.
Background: Coronavirus disease 2019 (COVID-19) may result in rapid onset of hypoxemic respiratory failure. This study aimed to characterize the factors and outcomes associated with prolonged hypoxia in patients with COVID-19. Prolonged severe hypoxia (PSH) was defined as hypoxia requiring ≥ 6 L/min of oxygen by nasal cannula or equivalent for more than 10 days. Research design and methods: This study was designed as a single-center retrospective analysis. Multivariable logistic regression was utilized to assess factors associated with PSH. Results: The final sample included 554 patients with 117 (21%) having PSH. Median length of stay of patients with PSH was significantly longer (median IQR: 18 days vs 6 days, p<0.0001). Patients with prolonged severe hypoxia had significantly higher rates of acute venous thromboembolism (p <0.0001) and major bleeding (p<0.004). The presence of cirrhosis (OR 3.32, 95% CI [1.02 to 10.83]) and hypertension (OR 1.99, 95% CI [1.12 to 3.53]) were independently associated with PSH, while outpatient use of anti-platelet agents had an inverse association (OR 0.57, 95% CI [0.36 to 0.91]. Conclusion: PSH is associated with increased length of stay, morbidity, and mortality. Hypertension and liver cirrhosis were significantly associated with higher odds of PSH, while use of anti-platelet therapy had a protective effect.
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Objective: The aim of this study was to assess the outcomes of critically ill patients with COVID-19 in an intensive care unit seen by a care team formed by intensive and nonintensive physicians and treatment guided by processes and protocols linked to the "choosing wisely" concept, comparing them with similar data recently published. Methods: An observational cohort including adult patients with COVID-19 admitted to the intensive care unit of Hospital Independence between August 2020 and August 2021. Inclusion criteria were 18 years of age or older and there were no exclusion criteria. Results: The study included 449 patients, of which 64.1% were referred from the ward, 21.6% from emergency rooms, and 14.2% from another hospital (continuity of attendance). The overall mortality was 48.5%, occurring mainly in the elderly and or those undergoing mechanical ventilation. We did not find any associations between different strata of body mass index and mortality. In the multivariate analysis, the time elapsed between the onset of symptoms and hospital admission, mechanical ventilation, C-reactive protein value at the end of the first week in the intensive care unit, and renal failure were independently associated with mortality. Vaccinated people comprised 8.8% of the sample, with no differences in mortality among the different vaccines, and 13.4% of patients underwent palliative treatment. Conclusions: Patients admitted for acute respiratory syndrome due to SARS-CoV-2 are severe and have a high mortality rate, mainly if submitted to invasive mechanical ventilation. The emergence of acute renal failure marks an especially severe subgroup with increased mortality. Processes and protocols linked to the "choosing-wisely" concept seemed to significantly benefit our intensive care unit since it had a large contingent of nonspecialist physicians.
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Background: COVID-19 Acute Respiratory Distress Syndrome (CARDS) is the major complication of COVID-19. The SARS-CoV-2 outbreaks rapidly saturating ICU beds, forcing the application of non-invasive respiratory support (NIRS) in respiratory intermediate care unit (RICU). Methods: 515 patients were enrolled in our observational prospective study based on CARDS developed in RICU during the three Italian pandemic waves (150, 180 and 185 patients respectively). All selected patients (aged 18-80) were treated with Helmet-Continuous Positive Airway Pressure (H-CPAP). The primary aim of the study is to compare the patients’ clinical characteristics and outcomes (H-CPAP success/failure and survival/death) during the three different pandemic waves. The secondary aim is to evaluate and detect the main predictors of the H-CPAP success and survival/death in patients selected by having CARDS criteria. Results: The worst ratio of arterial partial pressure of oxygen (PaO2) and fraction of inspired oxygen (FiO2) PaO2/FiO2 during H-CPAP stratified the subjects in mild (82-15.9%), moderate (202-39.2%) and severe (231-44.9%) CARDS. H-CPAP success has increased during the three waves (62%, 69% and 77% respectively) and the mortality rate has decreased (28%, 21% and 13%). H-CPAP success/failure and survival/death were related to the ratio PaO2/FiO2 (worst score) in H-CPAP and steroids administration. D-dimer at admission, FiO2 in H-CPAP, and level of PEEP were also associated with H-CPAP success. Conclusions: Our study suggests good clinical outcomes with H-CPAP in CARDS in RICU. CARDS has a biphasic trend confirmed in all the three waves, with a worsening patients’ trend from admission to subsequent days of hospitalization. A widespread use of steroids in our center could play a role in achieving good clinical outcomes. The proper management during hospitalization by pulmonologist in RICU may affect these patients’ trend. We observed a significant improvement of prognosis in the three different waves: patients are found to be progressively slightly less severe.
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Since December 2019, the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) has rapidly spread worldwide, challenging the clinician and focusing the entire globe on critical illness high mortality. This article is protected by copyright. All rights reserved.
Patients with COVID-19 are described as exhibiting oxygen levels incompatible with life without dyspnea. The pairing-dubbed happy hypoxia, but more precisely termed silent hypoxemia-is especially bewildering to physicians and is considered as defying basic biology. This combination has attracted extensive coverage in media but has not been discussed in medical journals. It is possible that coronavirus has an idiosyncratic action on receptors involved in chemosensitivity to oxygen, but well-established pathophysiological mechanisms can account for most, if not all, cases of silent hypoxemia. These mechanisms include how dyspnea and the respiratory centers respond to low levels of oxygen, how prevailing carbon dioxide tensions (PaCO2) blunt the brain's response to hypoxia, effects of disease and age on control of breathing, inaccuracy of pulse oximetry at low oxygen saturations, and temperature-induced shifts in the oxygen dissociation curve. Without knowledge of these mechanisms, physicians caring for hypoxemic patients free of dyspnea are operating in the dark-placing vulnerable COVID-19 patients at considerable risk. In conclusion, features about COVID-19 that physicians find baffling become less strange when viewed in the light of long-established principles of respiratory physiology; an understanding of these mechanisms will enhance patient care if the much-anticipated second wave emerges. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (
Patients infected with the SARS-CoV-2 virus can present with a wide variety of symptoms including being entirely asymptomatic. Despite having no or minimal symptoms, some patients may have markedly reduced pulse oximetry readings. This has been referred to as “silent” or “apathetic” hypoxia (Ottestad et al., 2020 [1]). We present a case of a 72-year-old male with COVID-19 syndrome who presented to the emergency department with minimal symptoms but low peripheral oxygen saturation readings. The patient deteriorated over the following days and eventually died as a result of overwhelming multi-organ system failure. This case highlights the utility of peripheral oxygen measurements in the evaluation of patients with SARS-CoV-2 infection. Self-monitoring of pulse oximetry by patients discharged from the emergency department is a potential way to identify patients needing to return for further evaluation.
Doctors debate how to treat patients with low blood oxygen but without trouble breathing.
This opinion paper aims at discussing the potential impact of modulating the Hb-O2 affinity by the nutritional supplement 5-HMF on patients affected by COVID-19. The paper describes the critical role of the oxygen affinity in hypoxemic COVID-19 patients and the potential positive effect of 5-HMF, a compound shown to increase the Hb-O2 affinity.