The FLARE Four
- The perceived discordance between severity of hypoxemia and both the extent of radiographic disease and level of clinical distress in COVID-19 has led many to propose novel mechanisms of hypoxemia
- In patients with acute respiratory distress syndrome (ARDS), shunt is usually thought of as the major mechanism of hypoxemia, but it has been established that ventilation–perfusion mismatch can also be an important contributor
- There is no unique failure of hypoxic pulmonary vasoconstriction in COVID-19; its efficacy varies between individuals and also depends on the extent of pulmonary involvement, amount of supplemental oxygen and ventilation strategy
- The possibility of pulmonary vascular pathology, including thrombosis, in patients with severe ARDS is well-documented, and the contribution of thrombosis to hypoxemia in ARDS was established well before the advent of COVID-19
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Severe COVID-19 typically presents with severe hypoxemia and, often, acute respiratory distress syndrome (ARDS). The perceived discordance between the severity of hypoxemia and both the extent of radiographic disease and level of clinical distress has led many to propose that novel mechanisms must underlie the hypoxemia.
In a fast literature update posted on May 19, 2020, Corey Hardin, MD, PhD, physician in the Division of Pulmonary and Critical Care Medicine, and Kathryn Hibbert, MD, director of the Medical ICU and physician in the Division of Pulmonary and Critical Care Medicine, with advisory review by Dr. Andy Luks of the University of Washington, conclude that nothing in the available literature suggests a novel mechanism of hypoxemia in COVID-19.
Hypoxemia with Mild Chest Imaging Results
Shunt in ARDS is often seen in the setting of alveolar collapse/filling, leading to substantial opacities on chest imaging. COVID-19 patients are reported to be hypoxemic in the absence of significant consolidation on chest imaging, leading some to postulate that the hypoxemia must be due to a novel mechanism.
This ignores the known contribution of ventilation–perfusion (V/Q) mismatch to hypoxemia in ARDS. Patients with mild imaging abnormalities and significant calculated shunt fractions may have V/Q mismatch as the dominant source of their hypoxemia, with little to no true pulmonary shunt. (Dr. Hardin and Dr. Hibbert review the fundamental mechanisms of hypoxemia in a companion fast literature update posted on May 18, 2020.)
No Failure of Homeostasis
Some further argue that since the area of impaired ventilation is apparently small, COVID-19 must represent a unique failure of normal homeostatic mechanisms of the lung. Chief among these is a complex response called hypoxic pulmonary vasoconstriction (HPV). Normally HPV diverts blood away from a poorly ventilated region, preserving V/Q matching throughout most of the lung.
However, the degree of effectiveness of HPV in a given patient is unpredictable. In addition to genetically determined interindividual variations, the degree of lung opacification, the use of supplemental oxygen and ventilator parameters can affect its efficacy. Perfusion of poorly ventilated lung regions is therefore not unexpected or unique to COVID-19.
Thrombosis Already Linked to Hypoxemia
The observation of pulmonary vascular involvement in COVID-19 respiratory failure has led to much speculation about unique mechanisms of thrombosis, such as SARS-CoV-2 binding to endothelial cells.
Yet the possibility of pulmonary vascular pathology, including thrombosis, in severe ARDS is a well-documented phenomenon. In addition, the contribution of thrombosis to hypoxemia in ARDS patients was established well before COVID-19, in a paper published in 1987. Hypoxemia results from a variation of ventilation–perfusion (V/Q) mismatch and an increase in the number of lung units where perfusion greatly exceeds ventilation.
The published observations on hypoxemia in association with COVID-19 are fully consistent with what was already known about the general mechanisms of hypoxemia, ARDS and the limits of hypoxic pulmonary vasoconstriction. Extraordinary claims, in addition to requiring extraordinary evidence, should at minimum be prompted by a novel observation. There is neither an unexplained observation nor evidence of any kind to suggest the fundamental mechanism of hypoxemia in COVID-19 has never been seen before.
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