The increased hemoglobin oxygen affinity in COVID-19

to the editor: In their review, “The oxygen dissociation curve of blood in COVID-19,” Böning et al. (1) provide an excellent overview of the available literature, put the increased hemoglobin oxygen affinity (2) into the context of anemia, and present new, important hypotheses.

We fully agree that the absence of a right shift requires further scrutiny, and indeed a left shift is unexpected, even more so in anemia. As Böning et al. suggested, the experimental treatment with chloroquine or hydroxychloroquine could affect the dissociation curve and contribute to the lack of shift, especially as these antimalarials were en vogue at the time of our study, although unfortunately later found to have no benefit or even potential harm (3). Our institution, however, did not treat patients with COVID-19 with chloroquine and hydroxychloroquine, thus we can rule out any confounding effects of these drugs on the increased hemoglobin oxygen affinity found in our study (2).

As Böning et al. hypothesize, the formation of methemoglobin (MetHb) could explain the increase of hemoglobin oxygen affinity. To test this hypothesis, we reanalyzed our data of 3,517 blood gas samples of mechanically ventilated, critically ill patients with COVID-19. We found a median MetHb 0.5% (interquartile range 0.4%–0.7%), which is in the range of MetHb% values reported in healthy nonsmokers (0.67 ± 0.33) (4). The range was 0.1%–7.0% where only 30 samples (<1% of obtained samples) had a MetHb of >3%. The highest single value in the population we studied was 7%, clearly smaller than the average of 16.4% reported by Alamdari et al. (5). Additionally, we did not identify a correlation between MetHb and p₅₀ (Pearson’s R² 0.0057). Overall, we conclude that methemoglobinemia was not the cause of the left shift reported in the cohort we investigated.

Finally, the section on treatment options provides an important translational perspective. We think that the impaired hypoxic pulmonary vasoconstriction and dysregulated pulmonary perfusion may be the main mechanism of hypoxemia in early COVID-19. In this sense, we may add pulmonary vasoactive agents with minimal effects on methemoglobin such as milrinone (6) and almitrine (7) to the list of potentially beneficial agents.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

D.J.V. drafted manuscript; D.J.V., F.F., and L.C. edited and revised manuscript; D.J.V., F.F., and L.C. approved final version of manuscript.