Abstract
The transformation of alveolar microcirculation to a peripheral circulation type in COVID-19 patients leads to important decreases in haemoglobin–oxygen affinity and provokes biochemical shunt https://bit.ly/3jE53pe
To the Editor:
It was a pleasure reading the work of Gattinoni et al. [1] dedicated to the pathophysiological mechanisms of hypoxaemia observed in coronavirus disease 2019 (COVID-19) patients. The authors recommend treating the hypoxaemia observed in the early stages of COVID-19 based on ventilation/perfusion (VʹA/Qʹ) mismatch.
According to the laws of physics, increasing fractional concentration of oxygen in inspired gas (FIO2) can increase arterial blood oxygen saturation (SaO2) in case of VʹA/Qʹ <1. Also, it should be recognised that oxygen, as an important homotropic allosteric effector, favours the stabilisation of the quaternary R (relaxed) state of haemoglobin (Hb) allowing for an increase in SaO2 by a positive feedback mechanism (binding of oxygen to Hb facilitates binding of new oxygen molecules). These biochemical processes may improve the SaO2 in patients with decreased Hb–O2 affinity in alveolar capillaries without any VʹA/Qʹ mismatch. Therefore, in cases of “happy” hypoxia or silent hypoxaemia, an exaggerated increase in SaO2 with minimal hyperoxia may take place due to the allosteric effects of oxygen rather than VʹA/Qʹ maldistribution. Also, a high level of oxygen dependency is commonly seen in all stages of COVID-19 with frequent use of high FIO2 without of development of atelectasis in the hypoventilated areas of the lungs, which also can't be explained by the VʹA/Qʹ mismatch.
A discussion of CO2 gas exchange mechanisms will further clarify the course of events resulting in hypoxaemia in COVID-19 patients. The remarkable increase in tidal volume in a patient with COVID-19 can be understood from the biochemical point of view: elimination of CO2, which is a strong heterotropic allosteric effector, will result in stabilisation of Hb's R state and assists its complete oxygenation.
As we know, during hypoventilation, the gases are balanced in the alveolar-capillary space. Hence, a decreased VʹA/Qʹ ratio will result in a higher alveolar (PACO2) and arterial carbon dioxide tension (PaCO2), but won't change the PaCO2 and end-tidal carbon dioxide tension (PETCO2) gap [2]. Also, due to the low resistance to diffusion of CO2, PaCO2–PETCO2 gap is maintained unchanged in cases when patients have oxygen diffusion limitations [3].
Surprisingly, COVID-19 patients may achieve a high PaCO2–PETCO2 gap, sometimes exceeding the predicted cut-off values of mortality in non-COVID-19 acute respiratory distress syndrome (ARDS) patients (i.e. 10–15 mmHg) [4]. Observing the data presented by Viola et al. [5] in type L COVID-19 pneumonia patients, we have found a median PaCO2–PETCO2 gap for supine position of 20.6 mmHg and 14.9 mmHg for prone position. Busana et al. [6] reported a PaCO2–PETCO2 gap of 15 mmHg in COVID-19 patients who need a high FIO2 to maintain SaO2. In critically ill COVID-19 patients, as presented by Chen et al. [7], the PaCO2–PETCO2 gap is reached at very high levels of 33 mmHg (18–40 mmHg).
So, considering excessively high levels of the PaCO2–PETCO2 gap in COVID-19 patients, excluding important right-to-left shunt and massive microthrombosis as a possible cause of huge dead space (pulmonary microthrombi were reported in 57% of COVID-19 autopsy cases) [8], one may not conclude that the main cause of hypoxaemia is solely a VʹA/Qʹ mismatch.
We believe that the main cause of hypoxaemia in COVID-19 patients is the decrease in Hb–O2 affinity in the affected alveolar-capillary bed [9] due to the decrease in the Hill coefficient (n), a measure of cooperativity in a binding process. This process usually occurs in non-alveolar capillaries and it is more accentuated in the cerebral microcirculation [10]. Normobaric hyperoxia in apparently healthy tissue leads to a dramatic elevation of brain oxygen partial pressure to levels up to 147±36 mmHg, but an increase in regional cerebral oxygen saturation assessed by near-infrared spectroscopy is negligible (2.8±1.82%) and within the venous blood oxygen saturation range [11]. Thus, it is possible to encounter situations with venous levels of blood oxygen saturation and a coexisting high oxygen tension in the microcirculation.
According to our concept, the transformation of alveolar microcirculation to a type of peripheral circulation in COVID-19 patients leads to important decreases in Hb–O2 affinity. Additional oxygen concentration and/or hyperventilation are required to fully oxygenate the haemoglobin in the affected areas of the lungs through stabilisation of Hb in its R state.
Other measures that may increase Hb's oxygen affinity will also improve the oxygenation values, such as transfusion of red blood cells (decreasing 2,3-diphosphoglycerate concentration with stabilise Hb in the R state), increases in the concentration of carboxyhaemoglobin, 5-hydroxymethylfurfural, etc. [9].
In mild and moderate COVID-19 cases, when the Hill coefficient is 1<n<2.7, an increase in FIO2, elimination of CO2 by hyperventilation, as well as application of dead space washout, will stabilise the R state of Hb. More problems occur when n≤1: the Hb will change its quaternary state from R to T, which has a very low Hb–O2 affinity and the highest buffer capacity (i.e. it contains a high amount of CO2 and protons) [12].
As a result of decreased Hill coefficient, a biochemical shunt will be created: Hb will become much less saturated with oxygen and won't release enough CO2. The blood from the affected capillaries, after mixing with the blood from normal capillaries, will restore the Hb's R state with a subsequent release of CO2 and a significant increase in the PaCO2–PETCO2 gap without any true shunt or dead space.
VʹA/Qʹ mismatch cannot be the only cause of hypoxaemia in COVID-19 patients. For treatment, it is also important to take into account the Hb's oxygen affinity and the presence of the biochemical shunt in the alveolar-capillary bed.
Footnotes
Provenance: Submitted article, peer reviewed.
Conflicts of interest: All authors have nothing to disclose.
- Received December 27, 2021.
- Accepted April 7, 2022.
- Copyright ©The authors 2022
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