A combination of Bohr and Haldane effects provide a physiologic explanation for the increase in arterial oxygen saturation when a face mask is added to a high-flow nasal cannula in severely hypoxemic COVID-19 patients

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Dear editor: We read with great interest the article by Dogani et al. on the potential effect of adding an oxygen mask –without supplemental oxygen– to a high-flow nasal cannula on the improvement of oxygenation, in patients with acute hypoxemic respiratory failure due to COVID-19 [1]. We would like to share some comments considering: (a) the improbability that the oxygenation improvement could be related to a real rise in PaO2 by the use of a mask (although neither PaO2 nor pH data were provided), and (b) the lack of a straightforward physiological mechanism for this observation. We think that the explanation for the observed increase in the arterial oxygen saturation (SaO2) reported was due to a left shift on the hemoglobin dissociation curve, solely under the operation of Bohr and Haldane principles [2, 3]. We propose that an improvement in SaO2 with a stable PaO2 came secondary to a rising in arterial pH according to the Bohr effect, or to a displacement of CO2 bound to hemoglobin (the carbamino compound) by an increase on blood oxygenation (Haldane) (Figs. 1 and 2), while keeping the arterial CO2 content relative stable. In fact, final PaCO2 remained unchanged in the eighteen patients of the study. If we assume an increase in alveolar ventilation by a more efficient high-flow nasal cannula performance (concurring with the authors on a significant reduction of ambient air entrainment), plasma alkalinization came forth naturally: alongside with a ventilatory-driven PaCO2 decrease, protonated hemoglobin released H + which increased its affinity for O2 (the Bohr effect), increasing SaO2 consequently. On the CO2 metabolic side, this effect shifted the bicarbonate buffer equilibrium towards CO2 formation from carbonic acid, producing the release of this gas from erythrocytes that resulted in a slight rise in PCO2. Furthermore, as hemoglobin carried more oxygen, amino group-bound CO2 became displaced into its dissolved fraction (Haldane effect), all of which induced an increase in PaCO2 which would match the previous ventilatory PaCO2 decrease. As a final result, a slight or no major change in PaCO2 was observed. Moreover, progressive hypoxemia correction may have produced an adaptive decrease on Open Access


Dear editor:
We read with great interest the article by Dogani et al. on the potential effect of adding an oxygen mask -without supplemental oxygen-to a high-flow nasal cannula on the improvement of oxygenation, in patients with acute hypoxemic respiratory failure due to . We would like to share some comments considering: (a) the improbability that the oxygenation improvement could be related to a real rise in PaO 2 by the use of a mask (although neither PaO 2 nor pH data were provided), and (b) the lack of a straightforward physiological mechanism for this observation. We think that the explanation for the observed increase in the arterial oxygen saturation (SaO 2 ) reported was due to a left shift on the hemoglobin dissociation curve, solely under the operation of Bohr and Haldane principles [2,3].
We propose that an improvement in SaO 2 with a stable PaO 2 came secondary to a rising in arterial pH according to the Bohr effect, or to a displacement of CO 2 bound to hemoglobin (the carbamino compound) by an increase on blood oxygenation (Haldane) (Figs. 1 and 2), while keeping the arterial CO 2 content relative stable. In fact, final PaCO 2 remained unchanged in the eighteen patients of the study.
If we assume an increase in alveolar ventilation by a more efficient high-flow nasal cannula performance (concurring with the authors on a significant reduction of ambient air entrainment), plasma alkalinization came forth naturally: alongside with a ventilatory-driven PaCO 2 decrease, protonated hemoglobin released H + which increased its affinity for O 2 (the Bohr effect), increasing SaO 2 consequently. On the CO 2 metabolic side, this effect shifted the bicarbonate buffer equilibrium towards CO 2 formation from carbonic acid, producing the release of this gas from erythrocytes that resulted in a slight rise in PCO 2 . Furthermore, as hemoglobin carried more oxygen, amino group-bound CO 2 became displaced into its dissolved fraction (Haldane effect), all of which induced an increase in PaCO 2 which would match the previous ventilatory PaCO 2 decrease. As a final result, a slight or no major change in PaCO 2 was observed.
Moreover, progressive hypoxemia correction may have produced an adaptive decrease on

Open Access
This comment refers to the article available online at https:// doi. org/ 10. 1186/ s13054-021-03738-8. We acknowledge that we are presenting a theoretical model attempting to fill the gaps of an objectively documented observation, despite some lacking data. However, the combination of available data with classic physiologic principles provides another explanation for this interesting and clinically relevant phenomenon.

Authors' response letter
Besarta Dogani, Fredrik Månsson, Fredrik Resman, Hannes Hartman, Johan Tham and Gustav Torisson Dear editor, We thank Dr. Born and Dr. Castro for the input on our research letter describing an increased SaO 2 when adding a mask to high-flow nasal cannula (HFNC) in patients with severe COVID-19 [1]. In a well-reasoned argument, Dr. Born and Dr. Castro propose that the increase in SaO 2 may be due to a left shift in the hemoglobin dissociation curve, i.e. an increase in SaO 2 with a stable PaO 2 [5]. To expand the discussion, we would like to provide data regarding PaO 2 and pH, from the arterial blood gases taken at baseline and after 30 min with mask.
In all participants, PaO 2 increased after 30 min, with a mean difference of 3.2 KPa (95% CI 2.2-4.2), equivalent to ~ 24 mmHg (95% CI 16-32), see Fig. 3. This result is in line with the study by Montiel et al., who applied a surgical mask on top of HFNC [6]. In their study, PaO 2 increased in all participants as well, with a mean difference of 20 mmHg (95% CI 13-26). Furthermore, in our study there was a slight decrease in the average pH after 30 min, from 7.480 to 7.471, with a mean difference of − 0.009 (95% CI − 0.018 to − 0.001). Therefore, we consider it unlikely that a left shift in the hemoglobin dissociation curve would fully explain the observed phenomenon.
We hypothesised that the mask could minimise entrainment of room air, especially when mouth-breathing, although we have no data to support this hypothesis. To the best of our knowledge, no studies have measured fiO2 in COVID-19 patients with HFNC. Studies in healthy volunteers suggest that fiO2 may decrease upon

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Ready to submit your research Ready to submit your research ? Choose BMC and benefit from: ? Choose BMC and benefit from: mouth-breathing or when exercise was used to simulate respiratory distress [7]. Whether this applies in COVID-19 is uncertain. It was beyond the scope of our research letter to study the underlying mechanism, and several concurrent processes may contribute. Therefore, we are sincerely grateful for all input in this matter, including that of dr Swenson [8]. Hopefully, further research in oxygen delivery in severe COVID-19 will elucidate this matter.