Modulation of Hb-O2 affinity to improve hypoxemia in COVID-19 patients.

This opinion paper aims at discussing the potential impact of modulating the Hb-O2 affinity by the nutritional supplement 5-HMF on patients affected by COVID-19. The paper describes the critical role of the oxygen affinity in hypoxemic COVID-19 patients and the potential positive effect of 5-HMF, a compound shown to increase the Hb-O2 affinity.

Introduction and discussion

The oxygen dissociation curve (ODC) describes the dependency of the oxygen saturation on the oxygen partial pressure (PO2) [1]. With its sigmoid shape, the curve is subjected to right or left shifts, thereby changing hemoglobin-O2 affinity. An increase in the partial pressure of carbon dioxide (PCO2), in 2,3-diphosphoglycerate (2,3 DPG) and in temperature as well as a decrease in pH lead to a right-shift of the ODC, decreasing oxygen affinity, and vice versa [1,2]. In hypoxemic conditions, a shift of the ODC can significantly alter arterial oxygen saturation (SaO2) and consequently arterial oxygen content (CaO2). With a PO2 of 60 mmHg, for instance, SaO2 may be around 81% [1] at a pH of 7.27 (corresponding to a PCO2 of 60 mmHg according to Siggaard-Andersen nomogram) and normal body temperature (37 °C), or about 90% at a pH of 7.4, 37 °C body temperature and an PCO2 of 40 mmHg [3]. Assuming a hemoglobin concentration of 12 g/dl, this corresponds to an increase in CaO2 from 13.0 to 14.5 ml/dl. Further assuming a cardiac output of 6 l/min, the delivery of oxygen (DO2) increases from 780 to 870 ml/min. This increase in DO2 by augmenting CaO2 is equivalent to a DO2 increase by rising cardiac output by approximately 0.7 l/min. This approximates the effect of low-to medium-dose Dobutamine, a commonly used inotrope [4]. The difference in SpO2 may even widen with lower PO2, due to the shape of the ODC, or changes in body temperature, leading to an even greater effect on DO2 as outlined before.

Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly emergent coronavirus [5]. The disease is characterized by symptoms of cough and high fever and causes primarily interstitial lung changes and is characterized by a dissociation between relatively well preserved lung mechanics and the severity of hypoxemia [5]. Intrapulmonary ventilation-perfusion mismatch, probably due to impaired hypoxic vasoconstriction, results in hypoxemic respiratory failure [6]. Oxygen administration via face mask or nasal cannula, high-flow-nasal oxygen or non-invasive ventilation are common first-line interventions to improve oxygenation and dyspnea in these patients [5]. In case of persistent hypoxemia or clinical deterioration, endotracheal intubation and invasive ventilation is required. In mechanically ventilated adults with COVID-19, gentle ventilation with low tidal volume is recommended in order not to further damage the lungs [7,8]. Low tidal volume ventilation often results in hypercapnia, which is tolerated to pH levels as low as 7.2 (permissive hypercapnia) [9]. As outlined above, the consequence of the high PCO2 and increased body temperature is a shift of the ODC to the right, worsening hypoxemia. In these patients, the PO2 levels are on the steep part of the ODC, so that a small shift of the ODC may have a large effect on the oxygen affinity and thus on SpO2. The question arises whether shifting the ODC back to the left would improve oxygenation of COVID-19 patients.

5-hydroxymethylfurfural (5-HMF) is an agent able to shift the oxygen dissociation curve to the left. 5-HMF reduces the P50 (PO2 at which 50% of hemoglobin is saturated with oxygen, a parameter indicating the position of the ODC) via allosteric modification of the hemoglobin [10]. Animal studies showed that under severe hypoxia conditions (FiO2: 5%), 5-HMF increased hemoglobin affinity, preserved systemic O2 delivery and partially was able to maintain microvascular oxygenation (i.e., by protecting arteriolar and venular vasodilation and blood flow) [10]. In swine exposed to severe hypoxia, 5-HMF treatment decreased P50, improved SaO2, and mitigated increases in pulmonary artery pressure [11]. Moreover, a recent study indicated that the substance might have cardiac protective properties by inhibiting L-type Ca2+ channels [12]. However, not only in animal and in vitro models beneficial effects were reported. 5-HMF was also found to increase the oxygen affinity in healthy subjects exposed to hypoxia and in sickle cell disease patients [13,14]. Additionally, the combined oral intake of 5-HMF and α-ketoglutaric acid increased SpO2 during cycling exercise at 3500 m in healthy subjects [15]. The oral intake of these 2 substances was also shown to reduce oxidative stress, to increase exercise capacity and to reduce ICU and hospitalization time in patients admitted for lung resection [16]. It is important to mention that these substances are available as nutritional supplements and that no relevance for humans concerning carcinogenic and genotoxic effects have been found for 5-HMF supplementation [17].

This makes 5-HMF a potential therapeutic agent for the treatment of hypoxemic COVID-19 patients. By facilitating oxygen loading and increasing SaO2, breathing exertion might be reduced. This could delay or even prevent invasive ventilation and hence save valuable intensive care capacity in a crisis like this. In ARDS patients undergoing lung protective ventilation with permissive hypercapnia, a left-shift of the ODC induced by 5-HMF might ameliorate oxygenation by counteracting the hypercapnia effect on the oxygen affinity. On the other hand, a left-shift of the ODC might impair peripheral O2 unloading, leading to an unchanged cellular oxygen supply despite an increased DO2. Even though comparability might be questioned, recent data on hypoxic exercise show that a high O2-affinity and hence enhanced oxygen uptake in the lungs, outweighed deficits in peripheral O2 unloading [2,18]. Additionally, it was reported previously that in hypoxic conditions O2 unloading from Hb does not require a right-shift of the ODC [19].

In conclusion, the modulation of hemoglobin-oxygen affinity by 5-HMF might be worth investigating as a potential therapeutic target in hypoxemic respiratory failure, e.g. due to COVID-19.

Conflict of interest

None.