key: cord-1009598-p1kynpqz
authors: Vogel, Dominik J.; Formenti, Federico; Retter, Andrew J.; Vasques, Francesco; Camporota, Luigi
title: A left shift in the oxyhaemoglobin dissociation curve in patients with severe coronavirus disease 2019 (COVID‐19)
date: 2020-10-10
journal: Br J Haematol
DOI: 10.1111/bjh.17128
sha: 6767144531ef92e1fbd6b550a35b5e447147a145
doc_id: 1009598
cord_uid: p1kynpqz

Critically ill patients with coronavirus disease 2019 (COVID‐19) present with hypoxaemia and are mechanically ventilated to support gas exchange. We performed a retrospective, observational study of blood gas analyses (n = 3518) obtained from patients with COVID‐19 to investigate changes in haemoglobin oxygen (Hb–O(2)) affinity. Calculated oxygen tension at half‐saturation (p(50)) was on average (±SD) 3·3 (3·13) mmHg lower than the normal p(50) value (23·4 vs. 26·7 mmHg; P < 0·0001). Compared to an unmatched historic control of patients with other causes of severe respiratory failure, patients with COVID‐19 had a significantly higher Hb–O(2) affinity (mean [SD] p(50) 23·4 [3·13] vs. 24·6 [5.4] mmHg; P < 0·0001). We hypothesise that, due to the long disease process, acclimatisation to hypoxaemia could play a role.

Keywords: haemoglobin, oxygen affinity, infection.

Coronavirus disease 2019 is characterised by hypoxaemia that can precede radiological changes or other clinical symptoms including dyspnoea. 1 Given that the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has a vascular tropism, 2 the physiological manifestation of the altered pulmonary perfusion, hypoxaemia is to a degree disproportionate to the severity of parenchymal lung disease. In addition, direct (midbrain 3 ) or indirect (via metabolism of angiotensin II on the carotid bodies 4 ) viral actions can affect respiratory drive and response to hypoxaemia. The duration of the disease is generally more prolonged compared to acute respiratory distress syndrome (ARDS) from other aetiologies. 1 As reported by Daniel et al. 5 in this Journal, haemoglobin (Hb) oxygen (O 2 ) affinity in 14 patients with COVID-19 was not different from 11 control participants, when affinity was measured in vitro with a Hemox analyser, with a standardised pH (7Á4) and temperature. These oxygen tensions at half-saturation (p 50 ) values were obtained directly from the blood gas analyser, without adjustments for physiological changes in CO 2 or pH in vivo, which could be important in COVID-19. We hypothesised that in vivo Hb-O 2 affinity could be affected by other factors in COVID-19.

To assess alterations in in vivo Hb-O 2 affinity, we performed a retrospective, observational analysis of all arterial and venous blood gases (n = 3518) obtained from all intubated and ventilated patients (n = 43) with severe COVID-19 in one intensive care unit (ICU), at Guy's and St Thomas' Hospital (London, UK) between 15 April and 15 May 2020. Institutional approval was gained from the local audit committee (project reference: 11013). The need for individual informed consent was waived for this retrospective analysis of data collected prospectively for routine care, with no breach of privacy or anonymity. The study qualified as a service evaluation as defined by the UK NHS Health Research Authority (NHS HRA) and therefore did not require review by a research ethics committee.

Measured values of partial pressure of oxygen (pO 2 ) and oxygen saturation (SO 2 ) were compared to the standard oxyhaemoglobin dissociation curve (ODC) for normal Hb-O 2 affinity. 6 The p 50 values were calculated using the Hill equation (Eq.) 7, 8 (after correcting for pH, temperature and base excess 9 ; Hill Eq. 1, see below) and derived from Roche blood short report First published online 10 October 2020 doi: 10.1111/bjh.17128 gas analyser (Cobas system, F. Hoffmann-La Roche Ltd; 10 Roche Eq. 2, see below), and compared to the normal value (for pH 7Á4, 37Á0°C and pCO 2 40 mmHg) of 26Á7 mmHg respectively. [11] [12] [13] Results were compared to a historic, unmatched control cohort with an overall total of 15 945 arterial and venous blood gas samples obtained from 828 critically ill patients with acute respiratory failure (pneumonia/pneumonitis, or secondary ARDS, but presumed COVID-19 negative, as these samples were obtained in 2017 and earlier). The one-sample t-test was used for comparison between actual means (Eq. 1 and Eq. 2, see below) and normal value. The two-tailed, unpaired t-test was used for comparison between means of COVID-19 and control samples. Statistical analysis was performed using Prism (GraphPad Software Inc., La Jolla, CA, USA).

We calculated the p 50 using two methods:

A total of 3518 blood gas analyses of 43 patients [34 (79%) male; mean (range) age 53 (26-77) years] were obtained (Table I ). Figure S1 presents pO 2 and SO 2 values. Figure 1 shows the distribution of p 50 values derived by the Hill equation (Eq. 1). Compared to the standard p 50 value of 26Á7 mmHg, Eq. 1 presented a difference of 3Á3 mmHg [mean p 50 23Á4 mmHg, 99% confidence interval (CI) 23Á23-23Á50; P < 0Á0001] and Eq. 2 a difference of 1Á9 mmHg (mean p 50 24Á8 mmHg, 99% CI 24Á68-25Á00; P < 0Á0001). Table I shows the comparison to the control group data. Data on intra-and inter-subject variability, as well as data on temporal trends is shown in the supplement.

When compared to the control group, patients with COVID-19 had a lower pH and higher pCO 2 Hb-O 2 binding is considered co-operative, that is, binding of the first molecule of O 2 to Hb causes an increase in the O 2 affinity of the remaining Hb subunits. According to mathematical modelling, 17 an increase in Hb-O 2 affinity resulting from a p 50 change of −3 mmHg (as seen in our present data using Eq. 1) only slightly increases SO 2 (by 1%) in arterial blood in normoxia [arterial oxygen partial pressure (PaO 2 ) 90 mmHg]. However, in hypoxia (PaO 2 45 mmHg), the increased Hb-O 2 affinity increases arterial SO 2 by~4Á5%. While being at a disadvantage under normoxaemia, humans with a high Hb-O 2 affinity (adolescents from a family with Hb Andrew-Minneapolis, a stable β-chain mutant with whole blood p 50~1 7 mmHg) respond more appropriately to altitude-induced hypoxia. 16 An increased Hb-O 2 affinity results in oxygenation benefits during severe hypoxia and increases survival during acute hypoxia in several animal models. 15, 18 Thus, a high Hb-O 2 affinity may be of particular importance for O 2 loading in hypoxic conditions. 19 There are well described existing strategies of shifting the ODC to the left and increasing SO 2 at a given pO 2 . A fast increase in Hb-O 2 affinity is mediated by a reduction of CO 2 and increase of pH via hyperventilation under environmental hypoxia. This reversible alteration can occur rapidly within seconds to minutes. A slower mechanism is a decrease in 2,3-diphosphoglycerate (DPG) or other organic phosphates. 17 Reduced 2,3-DPG levels were observed in critically ill normoxaemic patients; however, the effect on p 50 was diminished potentially due to acidaemia in this cohort. 20 A hypothetical explanation for our present findings in patients with COVID-19 could be the response to prolonged periods of hypoxia. Patients with COVID-19 often present to hospital after a period lasting on average 15 days, during which patients may suffer from 'happy hypoxia', a term coined for the phenomenon that profoundly low SO 2 levels are found in individuals with relatively little subjective sensation of dyspnoea. 21 It has been hypothesised that SARS-CoV-2 may exert an idiosyncratic effect on the respiratory system via angiotensin-converting-enzyme 2 receptors in the carotid body and the midbrain, and this may lead to attenuation of the perceived dyspnoea. 3, 4, 22 The patients in our present COVID-19 group might have had unrecognised hypoxia for a significant period prior to their hospital admission. Furthermore, even after hospital admission, many patients with COVID-19 remain relatively stable for a few days before they deteriorate and are admitted to the ICU. 1 Thus, when compared to a general critical care population (e.g. patients with ARDS in whom hypoxia has to develop within 7 days, as per the Berlin definition), patients with respiratory failure secondary to COVID-19 may have a much longer time to 'acclimatise' to hypoxaemia. These changes in p 50 continued to be present during the length of the stay in ICU, therefore we suspect a sustained response, which could be explained by reduced 2,3-DPG levels. 23 The mechanisms and the importance of this phenomenon require further studies.

Dominik J. Vogel designed the study, collected the data, analysed the data, interpreted the data and drafted the first version of the manuscript. Federico Formenti interpreted the data. Andrew J. Retter interpreted the data. Francesco Vasques interpreted the data. Luigi Camporota designed the study and interpreted the data. All authors read and approved the final manuscript. 

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

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Blood gas calculator

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Survival at extreme altitude: protective effect of increased hemoglobin-oxygen affinity

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Increased hemoglobin O2 affinity protects during acute hypoxia

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Why COVID-19 silent hypoxemia is baffling to physicians

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The authors declare no competing interests.

Additional supporting information may be found online in the Supporting Information section at the end of the article.Fig S1. SO 2 with respective pO 2 for 3518 blood gas analyses (circles) and the sigmoid fitting line (green line). For comparison standard oxyhaemoglobin dissociation curve is shown (dashed red line). 1 Fig S2. Hill plot showing SO 2 with respective pO 2 for 3518 blood gas analyses (circles) and the sigmoid fitting line (green line). For comparison standard oxyhaemoglobin dissociation curve is shown (dashed red line). 1 Fig S3. Distribution of the mean p 50 calculated for each subject according to the following equation. Fig S4. Distribution of absolute difference between each measurement and the respective individual's mean p 50 calculated with Hill Eq. 1. Fig S5. Delta between each individual measurement from the mean p 50 of that subject plotted over time starting from the first measurement. Fig S6. Distribution of the individual patients' mean p 50 calculated with Eq. 1 and Eq. 2 plotted according to their length of stay during the observation period.Data S1. Supplemental results.