Discussion
Patients who presented to our hospital with COVID-19 related respiratory distress have had varying forms of oxygen supplementation ranging from those with mild distress on nasal cannulas to those with severe acute respiratory distress syndrome (ARDS) on invasive mechanical ventilation. The only variation in the treatment of this patient as opposed to others was oxygen. The patient in this case was never once supplemented with any oxygen for the entire duration of admission. The reason for withholding supplemental oxygen was the relative clinical stability of this patient despite presenting with hypoxemia. Prior to this case, we had observed several patients with similar clinical presentation who were supplemented with oxygen to meet a required high-set oxygen target. Eventually they ended up having prolonged hospital stay with an increased oxygen demand overtime. Long-term exposure to high levels of oxygen can cause lung injury in the absence of mechanical ventilation, but the combination of these two becomes more lethal leading to further lung damage.(5)
During viral respiratory illnesses, ROS are necessary for eradicating viruses, thus aiding immune cells in phagocytoses function and in signal transduction. Excessive oxygenation can cause the amount of ROS to exceed the required redox homeostasis leading to histologically progressive destruction of alveolocapillary membranes causing obstruction of capillaries forming microthrombi and air leaks via already injured alveoli into the surrounding tissues.(6) Eventually prolonged iatrogenic exposure to oxygen in combination with COVID-19 can exacerbate cell apoptosis at the alveolar epithelium level resulting into pulmonary fibrosis over an extended time period.(7)
Lung tissues are protected by overactive immune mediated Adenosine A2A receptor cells. These immune cells play a critical role in the down-regulation of pulmonary inflammation. Uncontrolled pulmonary inflammation occurs when continuous amount of oxygen is administered that weakens the Adenosine A2A receptor mediated anti-inflammatory mechanism, thereby further exacerbating lung damage.(8) A study done on a small population receiving inhaled Adenosine showed promising results in patients with COVID-19 in an attempt to therapeutically compensate for the oxygen-related loss of the endogenous adenosine receptor (A2AR)-mediated cells and reduce the lung destructing inflammatory process.(9)
Most pulmonary and non-pulmonary related studies recommend that no oxygen supplementation is required when oxygen saturation is more than 92%. Oxygen supplementation should start only if oxygen saturation is less than 90%.(10) However no consensus has yet been established on what the oxygenation target should be in hypoxemic respiratory failure patients.(11)
A meta-analysis study published even before the COVID-19 pandemic described that hyperoxia for a duration of more than 12 to 24 hours often led to serious deleterious side-effects. It was also noted that hyperoxia of even shorter durations may be associated with increased morbidity and mortality in ICU patients.(12) The mortality rates of acutely ill adults in multiple clinical syndromes were lower in those who received conservative amount of oxygen as opposed to the liberal batch.(13)
Recent observation proposes no direct evidence of the benefit of providing supplemental oxygen therapy in the absence of hypoxia in COVID-19 patients such as in patients with low oxygen saturations who are perfectly comfortable or rather, “happy hypoxemic.” It may be used to wean patients off ventilatory support but its use on patients whose lungs have adapted to hypoxemia or who do not require invasive therapy may in turn lead to adverse consequences.(2) Overcorrecting hypoxemia may improve it in the short term, but its long term effects can lead to oxygen induced ARDS and ventilator associated lung injury. This data suggests that the lungs have a better chance of recovery from COVID-19 when exposed to less oxygenation and invasive ventilation. Permissive hypoxemia was found to be feasible and had a better patient outcome when focused on oxygen content (CaO2) rather than oxygen saturations (SaO2).(14)
Based on these oxygen studies and our observation of patients, we could postulate that in patients undergoing a cytokine storm due to COVID-19, prolonged and excessive oxygen therapy adds insult in the form of oxygen reactive species, to an already injured lung. We do not know if this is an isolated case among millions or whether depriving this patient of oxygen did indeed work to his benefit. COVID-19 pneumonia no doubt requires some form of oxygen, but the conundrum lies with those presenting with a mild form of respiratory distress, who despite having low saturations have minimal to no discomfort. COVID-19 respiratory distress presents with an unconventional pathogenesis in terms of hypoxemic patients and their progression to ARDS. Oxygen can do both, heal and harm, and in the setting of COVID-19, which is still a new evolving disease, the question isn’t really about whether or not oxygen is required, but rather how much is required.