'Silent' Presentation of Hypoxemia and Cardiorespiratory Compensation in COVID-19

Philip E. Bickler, M.D., Ph.D.; John R. Feiner, M.D.; Michael S. Lipnick, M.D.; William McKleroy, M.D.


Anesthesiology. 2021;134(2):262-269. 

In This Article

Abstract and Introduction


The Coronavirus infection disease 2019 (COVID-19) pandemic is bringing unprecedented numbers of patients with significant hypoxemia to medical care. It is critical that clinicians caring for hypoxemic patients recognize two facts: (1) it is common for hypoxemia to exist without dyspnea ("silent hypoxia"); and (2) while patients may initially achieve cardiorespiratory compensation to hypoxemia, this compensation can fail precipitously. The spectrum of variability in human responses to hypoxemia is striking, influenced by differences in respiratory drive (the hypoxic ventilatory response) related to age, medications, coexisting diseases and genetic background. Healthy individuals usually respond to acute hypoxemia with dyspnea, but because of hypoxic suppression of dyspnea (hypoxic ventilatory decline) and hypocarbic suppression of dyspnea, profound hypoxemia can be minimally symptomatic ("silent"), or noticed only during exertion. Cardiovascular compensation for hypoxemia is similarly variable, with the normal responses of tachycardia and increased cardiac output limited by age, genetics, and coexisting disease. Failure to compensate for decreased oxygen transport is signaled by lactic acidosis, bradycardia, and decreased cardiac output. The latter may develop rapidly, and all are indicators of impending tissue injury or death from hypoxemia.

Articles in the popular media[1,2] and even a few in medical journals[3,4] have stated that the symptoms of hypoxemia in COVID-19 are unique, with minimal dyspnea or cognitive depression despite oxygen saturations measured by pulse oximetry of less than 70%. Based on decades of studies with healthy volunteers and controlled, severe hypoxemia at the University of California at San Francisco Hypoxia Research Laboratory and during high-altitude medical research expeditions, it is our experience that while a lack of dyspnea in response to hypoxemia is not typical, it is commonly observed.

There are several reasons that healthcare providers may be surprised by apparently well-tolerated hypoxemia. First, are several fundamentals related to the regulation of breathing and the sensation of dyspnea: the suppression of respiratory drive by the dual effects of reduced carbon dioxide (hypocarbia), as well as by hypoxemia itself (hypoxic ventilatory decline). Simultaneously, even during severe hypoxemia, cognition can be preserved by autoregulation of cerebral blood flow and brain oxygen delivery.

Another broadly held false belief brought into focus by the COVID-19 pandemic is that hypoxia alone causes tissue injury. This is rarely the case; rather, acidosis and damage develop when cardiovascular compensation fails, critically reducing blood flow and oxygen delivery either globally or to particular organs.[5,6] The critical contribution of cardiovascular compensation to clinical outcome is supported not only by a large body of experimental evidence, but also by our own experience as anesthesiologists, intensivists, and scientists studying hypoxia in human subjects.

The purpose of this focused review is to describe human response to severe hypoxemia, focusing not on the pathophysiology of lung injury but on the respiratory system response to hypoxemia. In addition, we summarize current knowledge of the features and limits of human cardiorespiratory response and adaptation to profound hypoxemia and describe some of the critical parameters that can help identify when adaptive compensation is failing.