'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.

Disclosures

Anesthesiology. 2021;134(2):262-269. 

In This Article

Degree of Hypoxemia and Lung Injury in Hospitalized Patients With COVID-19

The available information about the pathophysiology of COVID-19 pneumonia suggests that while key features of the disease are more pronounced than in other viral pneumonias, the pathophysiology is not unique.

The cardinal reason for hospital admission in COVID-19 positive patients is hypoxemia.[7–9] Although younger patients with no prior history of lung disease can have severe pneumonia and require invasive ventilation, elderly patients are at especially high risk for severe hypoxemia, with mortality rates of 40 to 80% reported in various cohorts.[8,10–12] Preexisting comorbid conditions, including cardiovascular disease, diabetes mellitus, and chronic lung disease, as well as male sex and obesity, also confer higher risk of severe disease and poor outcomes.[8,10–12]

Hypoxemia is a leading predictor of admission to the intensive care unit, mechanical ventilation, and death.[12,13] Arterial blood gas and oxygen saturation (pulse oximetry) data often show severe hypoxemia at time of presentation, with wide alveolar-arterial PO 2 gradients and low PAO 2/FIO 2 ratios. Increased oxygen requirements have been addressed with increased use of noninvasive oxygen therapy (including high flow nasal oxygen), prone positioning, invasive ventilation, and in some cases, extracorporeal membrane oxygen. Hypercarbic respiratory failure has not been a prominent presenting feature in existing reports or in our experience at University of California at San Francisco.

Intrapulmonary shunt and ventilation/perfusion mismatch are the chief gas exchange abnormalities causing hypoxemia in COVID-19, as they are in other viral pneumonias, bacterial pneumonias,[14] and acute respiratory distress syndrome.[15] However, some features of COVID-19 may be more pronounced than in other viral pneumonias, including substantial endothelial damage and micro-/macro-emboli formation.[16] Limitation of diffusion across the alveolar membrane can cause hypoxemia, but while this is seen in humans at high altitude due to low inspired and alveolar PO2,[17] in patients with loss of functional lung units (such as in interstitial lung disease or emphysema), and in some elite athletes at extremely high levels of cardiac output[18] it does not significantly contribute to hypoxemia in ARDS.[15] Unique to shunt physiology is that increased ventilation decreases carbon dioxide more than it increases oxygenation. The reduced carbon dioxide limits respiratory drive and dyspnea (Figure 1).

Figure 1.

Sensation of and response to arterial hypoxemia. (A) Hypoxemia is sensed primarily at the carotid body ("peripheral") chemoreceptors, and the gain of the carotid body response to hypoxia is increased by increasing PaCO2 and decreasing pH. The central chemoreceptors, located on ventral medulla, primarily sense CO2 and pH, but are slowly modulated by hypoxemia. Increased ventilation decreases PaCO2, limiting the increased respiratory drive and subjective dyspnea from hypoxemia. In COVID-19, gas exchange at time of presentation is primarily impaired by shunt and V̇/Q̇ mismatch, which worsens oxygen exchange, while PaCO2is relatively normal or reduced. Subjective sensation of dyspnea in shunt physiology is limited compared to lung pathology involving increased work of breathing due to increased lung water or interstitial thickening.64 (B) The output of central and peripheral ventilatory control centers varies with innate sensitivity to hypoxemia, in the form of the hypoxic ventilatory response, defined as the slope of the increase in minute ventilation during desaturation, which is essentially linear. Different individuals may have a robust or muted hypoxic ventilatory response. (C) Ventilatory response to hypoxemia is time dependent, exhibiting a roll-off or decline (hypoxic ventilatory decline) within 15 to 20 min of hypoxemia. Breathing becomes progressively periodic with worsening oxygenation46. RR, respiratory rate; V̇/Q̇, ventilation/perfusion ratio;VT, tidal volume.

Although intrapulmonary shunt is the dominant presenting gas exchange abnormality in COVID-19, dead space may significantly worsen with progression of ARDS. Hypoxemia that does not resolve with supplemental oxygen clearly indicates that gas exchange impairment has progressed beyond ventilation/perfusion ration (V̇/Q̇) mismatch and includes substantial intrapulmonary shunt. Alveolar filling, a cardinal feature of ARDS, correlates with lung radiographs and impaired gas exchange. Of note, the pathophysiology of ARDS is different from that of high-altitude pulmonary edema, in that COVID-19 involves an inflammation mediated alveolar fluid leak and that of high-altitude pulmonary edema is related to elevated transcapillary pressure.[19]

The mechanisms by which COVID-19 produces ARDS that affects large proportions of lung parenchyma may involve both a reduced innate immune response and an exaggerated inflammatory cytokine response ("cytokine storm").[20] While the novelty of this pattern of immunologic disturbance is debated,[21] the impacts on pulmonary gas exchange do not appear to be unique. The known physiology of viral pneumonia and ARDS involves well characterized disturbances that produce intrapulmonary shunt, ventilation-perfusion mismatch,[22] increased dead space ventilation, and decreased compliance.[23] Profound gas exchange abnormalities persist after initiation of high-flow nasal oxygen or invasive ventilation despite lung protective ventilator protocols, prone positioning, and maximal FIO2.[8,24,25] As with other pneumonias, some patients maintain near normal lung compliance, and others suffer decreased compliance as disease progresses,[26] representing a diversity of pathology.[27] Appropriate management of invasive ventilation in ARDS has been recently reviewed and no strong data exist to support modification of existing ARDS protocols for COVID-19.[28,29] Readers are referred to the frequently updated consensus statements concerning treatment of COVID-19 by the World Health Organization: (https://www.who.int/publications/i/item/clinical-management-of-covid-19; accessed September 24, 2020).

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