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In the early days of the pandemic in New York City, physicians were having serious debates about whether COVID-19 patients developed typical acute respiratory distress syndrome (ARDS), or if they were suffering from a different phenomenon entirely.

The main discrepancy was that patients with severe hypoxemia often had well preserved lung compliance; their lungs weren't "stiff," as is seen in typical ARDS.

Now, a team at Mount Sinai Hospital thinks they may have an explanation for that disconnect -- and it was a completely serendipitous finding, according to Alexandra Reynolds, MD, and Hooman Poor, MD, who published their findings in a letter in the .

Reynolds, a neurointensivist, wondered whether her COVID-19 patients were having frequent strokes, given rising concerns about clotting being a significant feature of the disease. So she used transcranial Doppler ultrasound to assess blood flow in the brain. A robotic version of enabled the researchers to attach the scanner and leave the patient room for analysis, which was helpful during COVID quarantine, she said.

"I was expecting to see microemboli given the reports of clotting, but I saw zero emboli in the patients I scanned," Reynolds told 麻豆传媒.

That led her to do a "bubble study," in which saline is agitated to include air bubbles that are then injected and can be detected by the Doppler. It's usually done to detect patent foramen ovale (PFO), as bubbles injected into a vein would cross from the right side of the heart to the left side if there was indeed a hole.

Normally, those bubbles are ultimately filtered by the lungs: they pass from the right side of the heart into the lung vasculature. There, they would be too large to pass through normal capillaries and would be filtered out, Poor said.

But nine of 11 COVID ICU patients Reynolds initially assessed had a positive bubble study, she told 麻豆传媒.

"Is it possible these bubbles were all going through the lungs?" she wondered. "I didn't know what to make of it, so I called up Hooman, a pulmonary vasculature specialist ... and he said, 'This is amazing.'"

The transit of the bubbles suggested vasodilation of the lung capillaries, Poor said. That could mean that blood may be flowing too fast through those capillaries to absorb enough oxygen.

Poor drew on his knowledge of hepatopulmonary syndrome for the hypothesis. In that condition, patients with chronic liver disease have hypoxemia as a result of vasodilation in the lungs. Though the underlying mechanism isn't clear, it's thought to be due to the accumulation of some substance that the liver normally clears. These patients "have dilation of blood vessels in the lungs, and they also have positive bubble studies," he said.

Reynolds and Poor then conducted a study of 18 additional ICU patients, and found that 15 had microbubbles that transited all the way to the brain.

While they didn't do echocardiograms to see if PFO was to blame, Poor said it's not likely given that the condition only has a prevalence of about 20% in the general population.

Their study also showed that the number of microbubbles was inversely correlated with P/F ratio, a measure of inhaled oxygen to blood oxygen, so those with the most bubbles had the lowest oxygen levels. Additionally, the number of microbubbles was inversely correlated to lung compliance, so more bubbles were associated with stiffer lungs.

Poor said the findings may unify previously reported research that COVID "ARDS" involved two different phenotypes: type L characterized by normal lung compliance in the presence of hypoxemia, and type H resembling a more typical ARDS profile of worse lung compliance.

Poor said their study suggests that there aren't really two separate phenotypes, but rather that pulmonary vasodilation may worsen in parallel with the diffuse alveolar damage typically seen in ARDS.

"This points to vasodilation [of the pulmonary capillaries] being a major mechanism of hypoxemia in these patients," Poor said. "I think this is the happy medium, where this is the mechanism by which those puzzling aspects can be explained."

As with hepatopulmonary syndrome, it's not clear what exactly is causing the vasodilation in the lungs of patients with COVID-19, Poor said. It could be due to inflammation in the lungs, or the disease may be causing some vasodilatory substance to circulate through the body.

Further studies are needed, Poor and Reynolds said, before any recommendations can be made about treating vasodilation to improve outcomes for COVID-19 patients. They are now working on a larger, multicenter trial with Brown University and the University of Tennessee.

Erik Swenson, MD, a pulmonary and critical care specialist at the University of Washington in Seattle, who was not involved in the research, agreed that further study is needed. Most importantly, a control group of patients with ARDS with equivalent hypoxemia should be examined, he said.

"Perhaps ARDS patients have the same findings that then makes this phenomenon not unique or relevant to the hypoxemia of COVID-19," Swenson told 麻豆传媒.

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