key: cord-0718958-5hjdz351 authors: Woyke, Simon; Rauch, Simon; Ströhle, Mathias; Gatterer, Hannes title: Modulation of Hb-O2 affinity to improve hypoxemia in COVID-19 patients date: 2020-04-28 journal: Clin Nutr DOI: 10.1016/j.clnu.2020.04.036 sha: a915ff8efa7fed5b4dd0c50e91fcbeb5fc075593 doc_id: 718958 cord_uid: 5hjdz351 Summary 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. The oxygen dissociation curve (ODC) describes the dependency of the oxygen saturation on the oxygen partial pressure (PO 2 ) [1] . With its sigmoid shape, the curve is subjected to right or left shifts, thereby changing hemoglobin-O 2 affinity. An increase in the partial pressure of carbon dioxide (PCO 2 ), in 2,3-diphosphoglycerate (2,3 DPG) and in temperature as well as a decrease in pH lead to a rightshift 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 (SaO 2 ) and consequently arterial oxygen content (CaO 2 ). With a PO 2 of 60 mmHg, for instance, SaO 2 may be around 81% [1] at a pH of 7.27 (corresponding to a PCO 2 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 PCO 2 of 40 mmHg [3] . Assuming a hemoglobin concentration of 12 g/dl, this corresponds to an increase in CaO 2 from 13.0 to 14.5 ml/dl. Further assuming a cardiac output of 6 l/min, the delivery of oxygen (DO 2 ) increases from 780 to 870 ml/min. This increase in DO 2 by augmenting CaO 2 is equivalent to a DO 2 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 SpO 2 may even widen with lower PO 2 , due to the shape of the ODC, or changes in body temperature, leading to an even greater effect on DO 2 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 noninvasive 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 PCO 2 and increased body temperature is a shift of the ODC to the right, worsening hypoxemia. In these patients, the PO 2 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 SpO 2 . 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 (PO 2 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 (FiO 2 : 5%), 5-HMF increased hemoglobin affinity, preserved systemic O 2 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 SaO 2 , 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 Ca 2þ 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 a-ketoglutaric acid increased SpO 2 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 SaO 2 , 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 O 2 unloading, leading to an unchanged cellular oxygen supply despite an increased DO 2 . Even though comparability might be questioned, recent data on hypoxic exercise show that a high O 2 -affinity and hence enhanced oxygen uptake in the lungs, outweighed deficits in peripheral O 2 unloading [2, 18] . Additionally, it was reported previously that in hypoxic conditions O 2 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. Oxygen transport by hemoglobin With haemoglobin as with politics -should we shift right or left? Red blood cell function in hypoxia at altitude and exercise Haemodynamic response during low-dose dobutamine infusion in patients with chronic systolic heart failure: comparison of echocardiographic and invasive measurements Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Covid-19 does not lead to a "typical" acute respiratory distress syndrome Management of critically ill adults with COVID-19 Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19) Guidelines on the management of acute respiratory distress syndrome Increased hemoglobin O2 affinity protects during acute hypoxia Cardiovascular parameters in a swine model of normobaric hypoxia treated with 5-Hydroxymethyl-2-Furfural (5-HMF) Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca(2þ) currents A phase 1, first-in-man, doseeresponse study of Aes-103 (5-HMF), an anti-sickling, allosteric modifier of hemoglobin oxygen affinity in healthy normal volunteers Effects of 5-hydroxymethyl-2-furfural on the volume and membrane permeability of red blood cells from patients with sickle cell disease 5-Hydroxymethylfurfural and alpha-ketoglutaric acid supplementation increases oxygen saturation during prolonged exercise in normobaric hypoxia The impact of preoperative micronutrient supplementation in lung surgery. A prospective randomized trial of oral supplementation of combined alphaketoglutaric acid and 5-hydroxymethylfurfural Toxicology and risk assessment of 5-Hydroxymethylfurfural in food Influence of high affinity haemoglobin on the response to normoxic and hypoxic exercise Limitations to oxygen transport and utilization during sprint exercise in humans: evidence for a functional reserve in muscle O2 diffusing capacity None.