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
Impaired pulmonary vascular regulation and vasoplegia (i.e. the absence of hypoxic pulmonary vasoconstriction) is another possible mechanism contributing to silent hypoxaemia.9 Computed tomographic perfusion imaging has shown vascular engorgement and increased perfusion to areas of diseased lung in patients with COVID-19.33 Although this does not provide clear evidence for impairment in hypoxic pulmonary vasoconstriction, it suggests that there may be dysregulation in pulmonary perfusion. Direct effects of the virus on the microvascular endothelial cells may also impair the signals that usually occur in response to hypoxia.34
The SARS-CoV-2 virus can also have direct effects on chemoreceptors involved with neural signalling and ventilation control.35,36 This may lead to impairment of central and peripheral oxygen sensing systems and subsequent loss of dyspnoea sensation.
The postulated mechanisms for direct effects of the virus on the pulmonary vasculature and peripheral and central chemoreceptors may be related to expression of angiotensin-converting enzyme-2 (ACE-2) in these structures, as the SARS-CoV-2 virus has an affinity to bind to the ACE-2 receptor on human cells.2,37 There are very limited data to confirm these theories and further research is required to increase our understanding of silent hypoxaemia in COVID-19.
Management of silent hypoxaemia
The management of silent hypoxaemia rests on recognition and early intervention. With the ability to monitor patient oxygen saturation remotely via pulse oximeter, early detection is feasible, and many outpatient programs provide patients with equipment for self-monitoring.38 Patients with silent hypoxaemia are at risk of rapid deterioration, development of respiratory failure and increased risk of death, therefore early initiation of respiratory support is paramount. Subsequent management of respiratory failure involves support with supplemental oxygen and appropriate noninvasive or invasive ventilation. Concurrent medical management of COVID-19 may incorporate medications such as immunomodulatory therapies, including dexamethasone and tocilizumab, and antiviral agents such as remdesivir.39 Ventilatory techniques, including self-initiated prone positioning in nonventilated patients are widely used, with at least a trend towards benefit being shown in the setting of a randomised controlled trial.40,41
Few clinicians in current practice have had to manage the volume and extent of respiratory failure that COVID-19 has brought about. Even in Australia, which has been relatively protected, the pandemic has stretched resources, including those of intensive care and respiratory medicine. Silent hypoxaemia may be unique to COVID-19 or may represent effects of acute viral pneumonia that have only now achieved widespread recognition. Recognition of this phenomenon in patients with COVID-19 who are in the community is challenging because patients do not report dyspnoea and are not in respiratory distress. The degree of hypoxaemia is out of proportion to their symptoms, or lack thereof, and the use of a simple tool such as a pulse oximeter is an easy way to identify hypoxaemia. An understanding of the possible physiological mechanisms – respiratory, vascular and neurological – will help clinicians detect this condition early, anticipate deterioration, institute therapies and lead to better outcomes and longer-term recovery for patients.
The sheer magnitude of the SARS-CoV-2 pandemic has thrown many aspects of viral disease into sharp relief, ranging from public health measures to innovative developments in intensive care medicine. Silent hypoxaemia, which is crucial to detect and rewarding to treat, may represent just such a phenomenon. RMT