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.

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