The pathophysiology of ‘happy’ hypoxemia in COVID-19

The novel coronavirus disease 2019 (COVID-19) pandemic is a global crisis, challenging healthcare systems worldwide. Many patients present with a remarkable disconnect in rest between profound hypoxemia yet without proportional signs of respiratory distress (i.e. happy hypoxemia) and rapid deterioration can occur. This particular clinical presentation in COVID-19 patients contrasts with the experience of physicians usually treating critically ill patients in respiratory failure and ensuring timely referral to the intensive care unit can, therefore, be challenging. A thorough understanding of the pathophysiological determinants of respiratory drive and hypoxemia may promote a more complete comprehension of a patient’s clinical presentation and management. Preserved oxygen saturation despite low partial pressure of oxygen in arterial blood samples occur, due to leftward shift of the oxyhemoglobin dissociation curve induced by hypoxemia-driven hyperventilation as well as possible direct viral interactions with hemoglobin. Ventilation-perfusion mismatch, ranging from shunts to alveolar dead space ventilation, is the central hallmark and offers various therapeutic targets.

Electrolyte Disorders

The regulation of acid–base balance in the body underlies the importance of pH in a variety of cellular and subcellular biological functions; for example, regulation of protein synthesis and intermediate carbohydrate metabolism are pH-sensitive processes. Clinically, this is apparent by the failure to grow normally in an acidemic environment and explains an increase in anaerobic glycolysis in alkalemia, due to an increase in a rate-limiting step of glycolysis phosphofructokinase-l. pH is important in numerous transport functions across membranes, such as increasing acid extrusion from cells when cellular pH drops. In general, cellular pH is lower than extracellular pH related to the electronegativity within cellular structures. The delivery of oxygen to tissues such as the brain and skeletal muscle is very much dependent on extracellular pH via the shift in the oxyhemoglobin dissociation curve.

Sickle Cell Anemia as a Disease of Oxygen Transport: Possible Implications for the Prevention of Sickle Cell Crises.

Abstract 4617 Introduction The formation of deoxy-sickle hemoglobin polymers is the key triggering event for the pathophysiological manifestations of Sickle Cell Anemia (SCA). The formation of deoxy-sickle hemoglobin polymers is directly related to the degree of oxygen desaturation (Sa02) which is a known component of SCA [Prior studies have demonstrated SaO2's in the 78 – 90% range]. This decrease in Sa02 in SCA results from the marked shift to the right of the oxyhemoglobin dissociation curve that commonly occurs in SCA. Prior attempts to have this corrected have focused directly on the right shifted curve itself, rather than the underlying physiologic reasons for the shift. A right-shifted curve results in a decreased affinity between oxygen and hemoglobin which at bottom is a defense mechanism to improve oxygen delivery to the tissues in the presence of anemia. Our hypothesis is that a modest increase in cardiac output under certain conditions of hemoglobin concentration [Hb], oxygen consumption [VO2], cardiac output [Q], and oxygen tension at 50% saturation [P50] (while breathing room air) can decrease the extent of a rightward shift of the oxyhemoglobin dissociation curve (ie. resulting in a decreased torr value for the P50). Since a decrease in the P50 will result in an increase in the SaO2 which is directly related to the degree of polymer formation, an increase in Q can potentially decrease the deoxy-sickle hemoglobin polymer fraction. Methods The approach and theoretical data presented below is based on the method of oxygen transport calculations (J. Surg Research 2009;155; 201-209) and the quantitative relationship between deoxy-sickle hemoglobin and SaO2 as determined by magnetic double resonance spectroscopy (Proc. Natl Acad Sci 1980: 77; 5487-5491). Results The theoretical data below are cardiac outputs (L/min/m2) at various hemoglobin concentrations and P50 levels as shown below for a VO2 fixed at 150 ml/min/m2 and a mixed venous PO2 [PvO2] fixed at 40 torr and an FiO2 of 0.21 (room air) Discussion The elevated P50's remain an inviting target for future therapeutic modalities in sickle cell disease. The theoretical oxygen transport data presented support the concept that elevation of the cardiac output could potentially decrease the rightward shift of the oxyhemoglobin dissociation curve. This should result in a decrease of the deoxy-sickle hemoglobin polymer fraction leading, potentially, to a decreased incidence of sickle cell crises. For a given increase in Q, a higher P50, a lower Hb, and a lower VO2 (data not shown) will result in a greater decrease in P50. Based on the above data the ideal range of oxygen transport parameters where a modest increase in Q (approximately 0.5 L/min/m2) would be most effective, would be for P50's from 42 to 50 torr with a Hb range of 7 – 9 gms.%. It remains unknown the degree to which the increase in P50 in Sickle Cell Anemia is responsive to increased tissue oxygen delivery. This is a question that potentially can be answered in the experimental laboratory. Disclosures: No relevant conflicts of interest to declare.

Stability of oxyhemoglobin affinity in patients with obstructive sleep apnea-hypopnea syndrome without daytime hypoxemia

A decrease in hemoglobin affinity for oxygen is considered an adaptive mechanism against tissue hypoxia. Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by recurrent episodes of apnea and hypopnea resulting in arterial oxygen desaturations during sleep. Maillard et al. ( 10 ) observed a right shift of the oxyhemoglobin dissociation curve (ODC) and an increase in 2,3-diphosphoglycerate (2,3-DPG) concentration ([2,3-DPG]) in 15 patients with severe OSAHS, but some had slight daytime arterial hypoxemia while breathing room air. The aim of our study was to measure the ODC and 2,3-DPG concentrations in a group of subjects normoxemic during daytime referred to our sleep laboratory for suspicion of snoring or OSAHS. The patients were recruited during a period of 6 mo. All arterial and venous blood samples were taken early in the morning within 1 h of awakening following a full-night polysomnography. ODC and 2,3-DPG were analyzed in 88 patients: 56 OSAHS (oxygen desaturation index: 27.5 ± 24.5) and 32 non-OSAHS. We found a significant correlation between the P50 and 2,3-DPG levels in the 88 patients: r = 0.502, P < 0.001. We observed no difference between OSAHS and non-OSAHS for the P50 and for [2,3-DPG]. There was no correlation between the severity of OSAHS and either P50 or [2,3-DPG]. Finally, there was no change in these parameters measured at baseline, after 3 days and after 1 mo of treatment by nasal continuous positive airway pressure in 7 patients with OSAHS. We conclude that patients with OSAHS who are normoxemic during daytime have comparable oxyhemoglobin affinity than nonapneic subjects.

Validation of Oxygen Saturation Monitoring in Neonates

•Background Pulse oximetry is commonly used to monitor oxygenation in neonates, but cannot detect variations in hemoglobin. Venous and arterial oxygen saturations are rarely monitored. Few data are available to validate measurements of oxygen saturation in neonates (venous, arterial, or pulse oximetric). •Purpose To validate oxygen saturation displayed on clinical monitors against analyses (with correction for fetal hemoglobin) of blood samples from neonates and to present the oxyhemoglobin dissociation curve for neonates. •Method Seventy-eight neonates, 25 to 38 weeks’ gestational age, had 660 arterial and 111 venous blood samples collected for analysis. •Results The mean difference between oxygen saturation and oxyhemoglobin level was 3% (SD 1.0) in arterial blood and 3% (SD 1.1) in venous blood. The mean difference between arterial oxygen saturation displayed on the monitor and oxyhemoglobin in arterial blood samples was 2% (SD 2.0); between venous oxygen saturation displayed on the monitor and oxyhemoglobin in venous blood samples it was 3% (SD 2.1) and between oxygen saturation as determined by pulse oximetry and oxyhemoglobin in arterial blood samples it was 2.5% (SD 3.1). At a Pao2 of 50 to 75 mm Hg on the oxyhemoglobin dissociation curve, oxyhemoglobin in arterial blood samples was from 92% to 95%; oxygen saturation was from 95% to 98% in arterial blood samples, from 94% to 97% on the monitor, and from 95% to 97% according to pulse oximetry. •Conclusions The safety limits for pulse oximeters are higher and narrower in neonates (95%–97%) than in adults, and clinical guidelines for neonates may require modification.