To the Editor:
Some patients with coronavirus disease (COVID-19) pneumonia demonstrate severe hypoxemia despite having near normal lung compliance, a combination not commonly seen in typical acute respiratory distress syndrome (ARDS) (1) . The disconnect between gas exchange and lung mechanics in COVID-19 pneumonia has raised the question of whether the mechanisms of hypoxemia in COVID-19 pneumonia differ from those in classical ARDS. Dual-energy computed tomographic imaging has demonstrated pulmonary vessel dilatation (2) and autopsies have shown pulmonary capillary deformation (3) in patients with COVID-19 pneumonia.
Contrast-enhanced transcranial Doppler (TCD) of the bilateral middle cerebral arteries after the injection of agitated saline is an ultrasound technique, similar to transthoracic or transesophageal echocardiography, that can be performed to detect microbubbles and diagnose intracardiac or intrapulmonary shunt ( Figure 1 ) (4, 5) . TCD is more sensitive than transthoracic echocardiography in detecting right-to-left shunt, (6) and it is less invasive than transesophageal echocardiography. We performed a cross-sectional pilot study of TCD (Lucid Robotic System; NovaSignal Corp) in all mechanically ventilated patients with severe COVID-19 pneumonia from two COVID-19 ICUs who were not undergoing continuous renal replacement therapy or extracorporeal membrane oxygenation (N = 18). This study was approved by the Mount Sinai Institutional Review Board (approval 20-03660). Agitated saline was injected through either a peripheral intravenous line in the upper extremity or a central line in the internal jugular vein. The system software automatically counted the number of microbubbles detected over 20 seconds; as a quality control measure, we manually counted and confirmed the number of microbubbles and were blinded to the patients' clinical condition and Pa O 2 :FI O 2 ratio. Sixty-one percent (n = 11) of patients were men. Patients had a median age of 59 years (interquartile range, 54-68 years), with a Pa O 2 :FI O 2 ratio of 127 mm Hg (interquartile range, 94-173 mm Hg). Lung compliance was measured in 16 patients and was low (median 22 ml/cm H 2 O; interquartile range 15-34 ml/cm H 2 O). None of the patients had a known history of chronic liver disease or preexisting intracardiac shunt. Contrastenhanced TCD detected a median of 8 microbubbles (interquartile range, 1-22; range 0-300). Three major findings from contrastenhanced TCD were observed. First, 15 of 18 (83%) patients had detectable microbubbles (see Figure 1 for representative images). Second, the Pa O 2 :FI O 2 ratio was inversely correlated with the number of microbubbles (Pearson's r = 20.55; P = 0.02) ( Figure 2A) . Third, the number of microbubbles was inversely correlated to lung compliance (Pearson's r = 20.61; P = 0.01) ( Figure 2B) . These data suggest that pulmonary vasodilatations may explain the disproportionate hypoxemia in some patients with COVID-19 pneumonia and, somewhat surprisingly, track with poor lung compliance (1). Our detection of transpulmonary bubbles may be analogous to hepatopulmonary syndrome, a pulmonary vascular disorder of chronic liver disease characterized by pulmonary vascular dilatations with increased blood flow to affected lung units, which results in ventilation-perfusion mismatch and hypoxemia (4). The normal lung filters microbubbles from the injection of agitated saline as the bubble diameter is larger (smallest bubble approximately 24 mm in diameter [5] ) than the normal pulmonary capillary (,15 mm in diameter [7] ). In hepatopulmonary syndrome, and similar to what we observed in this pilot study, the presence and degree of transpulmonary bubble transit correlate with the degree of hypoxemia (8) . Although we cannot rule out intracardiac shunt as a cause of observed microbubbles, we note that the prevalence of transpulmonary bubbles seen in our study is markedly higher than the prevalence of patent foramen ovales seen in the general population (9) . In a prior study of 265 patients with ARDS receiving mechanical ventilation, only 42 patients (16%) were found to have patent foramen ovale as assessed by contrast transesophageal echocardiography (10) .
Hypoxemia in ARDS is predominantly caused by right-to-left shunt, in which systemic venous blood flows to lung regions with collapsed and/or flooded alveoli and does not get oxygenated as it passes through the lung (11) . Transpulmonary bubble transit has been detected in 26% of patients with classical ARDS, although neither their presence nor their severity correlates with oxygenation (10), implying that pulmonary vascular dilatations are not a major mechanism of hypoxemia in typical ARDS. In order for transpulmonary bubble transit to occur, pulmonary vascular dilatations or pulmonary arteriovenous malformations must be present; a lack of hypoxic vasoconstriction is not sufficient. Although these observations are preliminary, the correlation seen here between the degree of transpulmonary bubble transit and Pa O 2 :FI O 2 ratio suggests that pulmonary vascular dilatation may be a significant cause of hypoxemia in patients with COVID-19 respiratory failure. Interestingly, patients with worse lung compliance demonstrated more microbubbles, which suggests that pulmonary vascular dilatation may worsen in parallel with the typical diffuse alveolar damage of ARDS.
Our understanding of the pathophysiology of hypoxemic respiratory in COVID-19 is limited. Although a larger, confirmatory study is needed, these data, in conjunction with recent radiographic and autopsy findings, seem to implicate pulmonary vascular dilatation as a cause of hypoxemia in patients with COVID-19 pneumonia. n Author disclosures are available with the text of this letter at www.atsjournals.org. 
To the Editor:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease (COVID-19) pandemic. In severe de novo acute hypoxemic respiratory failure, high-flow nasal cannula (HFNC) oxygen improves oxygenation and reduces _ VE and work of breathing (1, 2) . In addition, the technique has demonstrated clinical benefits in such patients (3, 4) .
To test the hypothesis that HFNC reduces intubation rate and mortality in patients with COVID-19 admitted to the ICU for acute respiratory failure, we designed this retrospective study that compares patients who received HFNC to those who did not in a cohort of 379 critically ill patients.
All consecutive patients with acute respiratory failure and laboratory-confirmed SARS-CoV-2 infection admitted to one of the four participating dedicated COVID-19 ICUs in Paris, France, between February 21 and April 24, 2020, were enrolled. Acute respiratory failure was defined as respiratory rate >25, bilateral pulmonary infiltrates on chest X-ray or computed tomography scan, and need for standard oxygen >3 L/min 21 to maintain peripheral arterial oxygen saturation >92%. Laboratory confirmation of SARS-CoV-2 was defined as a positive result of realtime RT-PCR assay of nasal and pharyngeal swabs (5) . The study was approved by the ethics committee of the French Intensive Care Society (n. 20-23), which waived the need for informed consent from individual patients because of the retrospective nature of this chart review. Data were abstracted from the medical charts and electronic reports by attending intensivists at each hospital. FI O 2 was calculated as 0.211 (oxygen flow [L/min 21 ] 3 0.03) in patients receiving standard oxygen and was actual FI O 2 in those receiving HFNC. In the four participating units, HFNC targeted a flow >50 L/min, which could be reduced in case of poor tolerance. Need for invasive mechanical ventilation and mortality 28 days after ICU admission were recorded. Continuous variables were described as median (interquartile range) and were compared between groups using the nonparametric Wilcoxon rank-sum test. Categorical variables were described as frequency (percentages) and were compared between groups using Fisher's exact test. Mortality was assessed using survival analysis; Kaplan-Meier graphs were used to express the probability of death from inclusion to Day 28, and comparisons were performed using the log-rank test. We used a competing risks model to account for the risk of invasive mechanical ventilation while taking into account discharge alive and death as time-dependent competing risks. Comparisons were performed using the Gray test. Risk of death was assessed using Cox model including variables at ICU admission, such as oxygenation modality.
In a sensitivity analysis, a propensity score (PS)-matched analysis was performed according to factors associated with receiving HFNC. On the basis of a conditional backward model, the following variables were selected for inclusion into the PS model: immunosuppression, ICU admission within 7 days from symptom onset, vasopressors, and acute kidney injury. A case-matching procedure was performed on 1:1 ratio without replacement and according to the nearest neighbor method. The adequacy of the matching procedure was assessed by plotting PS across groups and assessing differences across groups using standardized mean difference. Univariate analysis and then double adjustment by Cox model were performed on relevant variables associated with outcome and those poorly matched.
Statistical analyses were performed with R statistical software, version 3.4.4 (available online at http://www.r-project.org/), and 