How and why do patients present with silent hypoxaemia?
Hypoxaemia is often associated with dyspnoea, but the mechanisms underpinning the sensation of dyspnoea are complex and not completely understood. Factors that can contribute to dyspnoea include changes to the respiratory muscles, CO2 receptors and lung stretch receptors as well as a discord between central output and amount of airflow.22
The causes of silent hypoxaemia and underlying pathophysiological mechanisms are not clearly understood. There are limited data describing this phenomenon; however, it is thought to stem from initial insult to the lungs caused by the direct effect of the SARS-CoV-2 virus and/or secondary immune system-mediated inflammation.7 The lung insult results in alveolar epithelial and capillary endothelial damage, interstitial oedema and alveolar fluid filling, which are typical features of ARDS.
Silent hypoxaemia from COVID-19 is thought to be due to an atypical form of ARDS because autopsy findings have demonstrated typical pathological features of ARDS.23,24 However, pathophysiological differences exist between ARDS that is associated with COVID-19 and ARDS from other causes, such as the presence of more vascular abnormalities in COVID-19 lung injury.7,25 The vascular abnormalities include micro- and macro-thrombosis, vascular dilation and aberrant angiogenesis, which have also been found in other organs in patients with COVID-19.22,26,27 This supports the notion that COVID-19 is part of a systemic vascular pathological process.25
Various theories have been proposed to explain the underlying mechanisms causing silent hypoxaemia in COVID-19. These reflect changes that may occur in the lung parenchyma, blood vessels and neural centres of ventilation control, although the evidence to support them is conflicting. Due to the lack of data in this novel disease, some of this evidence is based on the pathophysiological mechanisms that are known to occur in ARDS due to other causes.7
In non-COVID-19 ARDS, pathological changes result in the lungs becoming more stiff (i.e. lung compliance is reduced). In contrast, the pathological lung changes observed in COVID-19 related ARDS may result in normal or minimally reduced lung compliance.9,28-30 This is somewhat surprising, given the changes of focal and/or bilateral peripheral ground glass opacification and/or consolidation shown on chest imaging in these patients.14 Minimal changes to lung compliance in these patients may mean there is a smaller increase in work of breathing or respiratory drive required to achieve appropriate oxygenation.9,28-32 Additionally, in non-COVID-19 ARDS gas exchange abnormalities can occur as a result of ventilation-perfusion (V-Q) mismatch typically due to fluid filled alveoli or nonventilated areas of lung still being perfused (i.e. shunting). In patients with COVID-19, gas exchange abnormalities may be predominantly due to V-Q mismatch from vascular mediated injury, rather than from injury to the lung parenchyma.7,11 Consequently, lung compliance may not necessarily be affected. However, these theories have not been substantiated because a wide range of changes in lung compliance occur in both COVID-19 and non-COVID-19 related ARDS.7