Reply to G. Harutyunyan and co-workers:

G. Harutyunyan and co-workers, in their reply to our correspondence, introduce the fascinating concept of “biochemical shunt” to help explain some of the gas exchange abnormalities reported in patients with early coronavirus disease 2019 (COVID-19). In brief, they assert the plausibility that the oxyhaemoglobin dissociation curve (ODC), which may be normal in the arterial and venous blood, could be altered (i.e. reduced oxygen affinity) in the pulmonary blood flowing through diseased alveolar capillaries. It is not easy for us to understand which COVID-19-related factors, or metabolites, might alter the ODC specifically in the pulmonary circulation, and to what extent they involve the lung parenchyma (partially or totally, where and why). Let us suppose, for example, that the biochemical shunt occurs in the whole parenchyma (nearly fully ventilated in early COVID-19). Let us assume that these COVID-19 patients are treated with an inspiratory oxygen fraction of 40% and they are able to maintain an arterial carbon dioxide tension (PaCO2) of 40 mmHg. The lung capillary oxygen tension (PO2), in equilibrium with alveolar PO2 (PAO2), will be around 235 mmHg (at a respiratory quotient of 0.8). Even assuming a dramatic right shift of the ODC (as may occur with a pH 7.0, a carbon dioxide tension (PCO2) of 40 mmHg, and 2,3-diphosphoglycerate of 1.6 mM, i.e. double the normal concentration), with a capillary PO2 of 235 mmHg, the haemoglobin oxygen saturation would be 99.5% [1], 99.8% [2] or 98.7% [3], depending on which equation is used. It is even more difficult to accept the biochemical shunt if the alteration to the ODC occurs only, as an example, in 50% of the lung parenchyma.

We have also some problems in conceptualising the discussion of G. Harutyunyan and co-workers about the PaCO2–end-tidal carbon dioxide tension (PETCO2) gap. Shunt or, more correctly, the venous admixture, does affect the alveolar–arterial PCO2 (PACO2–PaCO2 gap), while the PETCO2–PACO2 gap is a function of the alveolar dead space. Therefore, in the ideal gas exchanger, the PETCO2/PaCO2 ratio is an indicator of the overall gas exchange efficiency in the lung, which includes both shunt and dead space fractions [4]. A ratio of 1 would indicate the “perfect” gas exchanger, i.e. no shunt and no dead space. This is the physiological background of the paper from Lazzari et al. [5].

Finally, if we set aside the Riley's approach, more commonly used for the definition of shunt and dead space, and we refer to a continuous distribution of ventilation and perfusion and their mismatch, it is worth remembering that the ventilation–perfusion mismatch affects both oxygen and carbon dioxide exchange, which must always be considered together [6]. We remain, however, interested to learn about these local metabolic or endothelial factors that affect the ODC selectively in the alveolar capillaries, but not in the systemic blood, and their quantitative contribution to the gas exchange abnormalities seen in COVID-19.