Reply to Jounieaux et al.: On Happy Hypoxia and on Sadly Ignored "Acute Vascular Distress Syndrome" in Patients with COVID-19.

From the Authors:

We thank Dr. Jounieaux and colleagues for their comments on our Perspective (1).

They raise several points and are especially emphatic about the importance of intrapulmonary shunt in the pathophysiology of coronavirus disease (COVID-19). Observing hypoxemia in a patient with a viral respiratory tract infection—whether associated with florid or feeble infiltrates—is not a surprise. We did not discuss the mechanisms of hypoxemia in our Perspective because one of us had addressed this topic in a recent editorial (2).

The focus of our Perspective was the lack of dyspnea in patients with profound hypoxemia (such as a PaO of 37 mm Hg in our patient M.D.) (1). In their 2002 study, Jounieaux and colleagues (3) reported that a PaCO of between 29.3 mm Hg and 34.1 mm Hg ablated the ventilatory response to hypoxia. In reality, the threshold is higher; response to hypoxia is absent at PaCO of 39 mm Hg (4). Thus, a patient with a PaO of 37 mm Hg (equivalent to an oxygen saturation of 71%) would not be expected to complain of dyspnea if PaCO were 39 mm Hg (or lower) (1).

Jounieaux and colleagues aver that we deem problems with pulse oximetry to be the major explanation for happy hypoxia. We never said that. Physicians recognize that pulse oximetry is remarkably accurate for saturations of 85–100%, but many are not aware that pulse oximetry commonly displays falsely low readings—by 10% or more—at saturations of less than 80% (1). Given that pulse oximetry is the first tool used to evaluate patients with suspected hypoxemia, this inbuilt tendency to exaggerate the severity of hypoxemia is one factor that may have perplexed some physicians evaluating patients with COVID-19. If a pulse oximeter is displaying a low saturation, it is important to obtain an arterial blood gas measurement whenever possible.

In referring to Figure 1 in our Perspective (a plot of the ventilatory response to hypoxia), Jounieaux and colleagues claim that low levels of PaO will induce e of >20 L/min. This will happen at a Po2 of ∼51 mm Hg in a normocapnic person (1). If PaCO is less than 40 mm Hg, e will remain unchanged despite profound hypoxia (4).

Jounieaux and colleagues assert that e of >20 L/min instigates accessory muscle recruitment. In a classic study, Campbell demonstrated that sternomastoid activity (during carbon dioxide rebreathing) did not commence until e reached 41–105 L/min (5).

COVID-19 has raised many challenges—political, sociological, biological, and clinical—but coinage of a new label (acute vascular distress syndrome) is unlikely to solve these problems. Although intrapulmonary shunt contributes to hypoxia in some patients with COVID-19, shunt does not determine how the respiratory centers respond to hypoxia and whether a patient complains of dyspnea.

Our Perspective was written to provide understanding to physicians (quoted in newspaper articles) who express bewilderment as to the mechanism of happy hypoxia in patients with COVID-19 (1). We listed several likely contributors, including physiological variables that impact operations of the respiratory control system, fever in producing a rightward shift in the oxygen dissociation curve, unreliability of pulse oximetry at saturations below 80%, and varying interpretations (among clinicians) as to what the word hypoxemia means (1).

We are concerned that befuddled or ruffled physicians might take actions that negatively impact patient care, such as inserting an endotracheal tube (for mechanical ventilation) in patients not exhibiting an increase in work of breathing and who display oxygen saturations that are low but far from being a threat to life (1, 6). We are hopeful that clinical decisions based on a scientific understanding of biological processes operating beneath a patient’s skin result in more rational care and are less likely to cause harm.