key: cord-0718327-sswi5j8i
authors: Reynolds, Alexandra S.; Lee, Alison G.; Renz, Joshua; DeSantis, Katherine; Liang, John; Powell, Charles A.; Ventetuolo, Corey E.; Poor, Hooman D.
title: Reply to Chiang and Gupta and to Swenson et al.
date: 2021-02-01
journal: Am J Respir Crit Care Med
DOI: 10.1164/rccm.202010-3974le
sha: c1de161ec435d4e7032d718b71443d11719ce18b
doc_id: 718327
cord_uid: sswi5j8i

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Reply to Chiang and Gupta and to Swenson et al.

We appreciate the continued interest in our research letter (1) and hope our findings lead to new avenues of investigation to clarify the mechanisms of hypoxemia and respiratory failure in this complex and devastating disease.

Chiang and colleagues suggest that transpulmonary bubble transit (TPBT) in coronavirus disease (COVID-19) respiratory failure could result not only from pulmonary vascular dilatations and pulmonary arteriovenous malformations but also from intussusceptive and sprouting angiogenesis as described by Ackermann and colleagues (2) . In this autopsy series of seven patients with COVID-19 respiratory failure, Ackermann and colleagues showed that the extent of intussusceptive angiogenesis correlated with hospitalization duration that ranged from 3 to 9 days. In our study, the hospitalization duration at the time of performing the contrast-enhanced transcranial Doppler (TCD) was significantly longer (median duration, 24 d; interquartile range, 13-35 d), which would provide adequate time for the development of such vascular lesions. Notably, of those participants with detected microbubbles (n = 15), we find a trend toward increasing number of microbubbles with increasing duration of hospitalization at the time of performing the TCD (r = 0.47, P = 0.11; Figure 1 ). Chiang and colleagues posit that pulmonary vasodilation may not only precede but also serve as a stimulus for intussusceptive angiogenesis. If this progression of vascular derangements holds true in COVID-19 respiratory failure, it will be important to identify patients that exhibit abnormal pulmonary vasodilation earlier in the course of disease to design clinical trials of therapeutics that specifically target the pulmonary vasculature.

Swenson and colleagues suggest that patent foramen ovale (PFO) could contribute to microbubble detection in our study. Given that the reported prevalence of PFO in patients with acute respiratory distress syndrome (ARDS) is between 14 and 19% (3-5) and that we detected microbubbles in 83% of the patients in our study, we believe the contribution of PFO to the microbubble detection in our study is minimal. We agree that it would have been useful to perform the contrast-enhanced TCD in patients with equally severe non-COVID-19 ARDS as a control group. However, Boissier and colleagues performed contrast-enhanced transesophageal echocardiography, a technique that is equally sensitive to contrast-enhanced TCD, on 216 patients with classical ARDS who were also ruled out for the presence of PFO ( . This strategy was associated with improvement of respiratory mechanics (decrease of driving pressure, increase of respiratory system compliance) and oxygenation through reduction of atelectasis. Interestingly, this was not accompanied by impairment in right and left ventricular functions. Moreover, a very similar swine model confirmed these results. Besides these findings, we are surprised that some important points of respiratory mechanics in morbidly obese patients are not discussed. First, complete airway closure is a very frequent phenomena in those patients (up to 65% for class III obesity) (2). It can be easily identified as the inflection point on the initial portion of a low-flow inflation pressure-volume when volume started to increase. The lack of consideration of complete airway pressure (by using a PEEP lower than the opening airway pressure) induces an overestimation of driving pressure, respiratory system, and lung elastances (2) . Second, the association of low VT and supine position in obesity may induce consequent expiratory airflow limitation, which can be easily visualized and measured as intrinsic PEEP (3) . Therefore, if intrinsic PEEP is not considered, it could mislead correct values of expiratory transpulmonary pressure (total PEEP minus 

Ventilationperfusion distributions in the adult respiratory distress syndrome

Pulmonary vascular dilatation detected by automated transcranial doppler in COVID-19 pneumonia

Pulmonary vascular dilatation detected by automated transcranial doppler in COVID-19 pneumonia

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19

Echocardiographic detection of transpulmonary bubble transit during acute respiratory distress syndrome

Prevalence and prognosis of shunting across patent foramen ovale during acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS)-associated acute cor pulmonale and patent foramen ovale: a multicenter noninvasive hemodynamic study

Author disclosures are available with the text of this letter at www.atsjournals.org.