Ventilation/perfusion mismatch is not the sole reason for hypoxaemia in early stage COVID-19 patients

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 (Vʹ_A/Qʹ) mismatch.

According to the laws of physics, increasing fractional concentration of oxygen in inspired gas (F_IO2) can increase arterial blood oxygen saturation (S_aO2) in case of Vʹ_A/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 S_aO2 by a positive feedback mechanism (binding of oxygen to Hb facilitates binding of new oxygen molecules). These biochemical processes may improve the S_aO2 in patients with decreased Hb–O₂ affinity in alveolar capillaries without any Vʹ_A/Qʹ mismatch. Therefore, in cases of “happy” hypoxia or silent hypoxaemia, an exaggerated increase in S_aO2 with minimal hyperoxia may take place due to the allosteric effects of oxygen rather than Vʹ_A/Qʹ maldistribution. Also, a high level of oxygen dependency is commonly seen in all stages of COVID-19 with frequent use of high F_IO2 without of development of atelectasis in the hypoventilated areas of the lungs, which also can't be explained by the Vʹ_A/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 Vʹ_A/Qʹ ratio will result in a higher alveolar (P_ACO2) and arterial carbon dioxide tension (P_aCO2), but won't change the P_aCO2 and end-tidal carbon dioxide tension (P_ETCO2) gap [2]. Also, due to the low resistance to diffusion of CO₂, P_aCO2–P_ETCO2 gap is maintained unchanged in cases when patients have oxygen diffusion limitations [3].

Surprisingly, COVID-19 patients may achieve a high P_aCO2–P_ETCO2 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 P_aCO2–P_ETCO2 gap for supine position of 20.6 mmHg and 14.9 mmHg for prone position. Busana et al. [6] reported a P_aCO2–P_ETCO2 gap of 15 mmHg in COVID-19 patients who need a high F_IO2 to maintain S_aO2. In critically ill COVID-19 patients, as presented by Chen et al. [7], the P_aCO2–P_ETCO2 gap is reached at very high levels of 33 mmHg (18–40 mmHg).

So, considering excessively high levels of the P_aCO2–P_ETCO2 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 Vʹ_A/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 F_IO2, 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 P_aCO2–P_ETCO2 gap without any true shunt or dead space.