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Inhaled Nitric Oxide Explored for COVID-19 Oxygenation

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MAY 13, 2020 — The successful treatment of a patient with pulmonary arterial hypertension who contracted COVID-19 with self-administered inhaled nitrous oxide from a tankless device at home has caught the imagination of researchers investigating treatments for other patients.

It is not clear whether the team was treating the COVID or “some manifestation of her pulmonary hypertension exacerbation,” said Roham Zamanian, MD, a pulmonologist at Stanford Health in Palo Alto, California.

This is why a clinical trial is needed, he told Medscape Medical News.

“In this case, the COVID-19 respiratory infection led to a pulmonary hypertension exacerbation,” he explained. And the 34-year-old woman, who is also a physician, had demonstrated a response to nitric oxide before contracting the COVID-19 virus.

Zamanian and his colleagues describe the case in a letter published online in the American Journal of Respiratory and Critical Care. It will be discussed at the upcoming American Thoracic Society 2020 International Conference.

COVID-19 was confirmed in the patient, who had stable vasoreactive idiopathic pulmonary arterial hypertension, after she returned from a trip to Egypt. She did not want to travel the 350 miles from her home to the hospital for treatment, potentially infecting others, unless it was absolutely necessary.

“We had to make sure we were doing the right thing treating her at home, and we had to do it quickly,” Zamanian said. The patient was put on a remote routine — with vital monitoring in place — that included 6-minute walk tests twice daily and video conferencing. She also completed the EmPHasis-10 questionnaire, which is used to assess the status of patients with pulmonary hypertension.

The care team filed an Emergency Investigational New Drug application for the off-label at-home use of the tankless inhaled nitric oxide system (GENOSYL DS, VERO Biotech), which was approved by the US Food and Drug Administration. The system has so far been approved only for the treatment of newborns with persistent pulmonary hypertension.

Off-label inhaled nitric oxide has never been used in an outpatient setting. “That’s where this case is unique,” Zamanian explained.


“This case was very specific. We knew she was vasoreactive, and she knew how to use the device,” he said. “And we know nitric oxide is a quick-acting medication when it works, showing results in minutes, if not seconds.”

Within 24 hours of approval, the tankless system arrived at her home.

The patient’s therapy consisted of nitric oxide at a dose of 20 ppm plus supplemental oxygen delivered by nasal cannula at a dose of 2 L/min for 12 to 14 hours a day. After symptomatic improvement, a stepwise reduction in nitric oxide was implemented from day 13 to 17, with the dose dropping to 10 ppm, 5 ppm, and then 0 ppm.

“We quickly knew she was responding and feeling better. Without the medication, she would very likely have needed to be hospitalized,” Zamanian said.

“The real novelty of this case is demonstrating use in an outpatient system,” he pointed out. “My perspective is that this particular case was very specific, in a person who had been formally evaluated and known to be responsive to this treatment.”

The team is now preparing to launch a clinical trial of inhaled nitric oxide in COVID-19 patients without pulmonary hypertension, Zamanian reported.

Treating Other Patients

Nitric oxide could be useful for patients who come in with pulmonary hypertension, but “we have to test and figure that out. It could also be that patients with other underlying lung diseases could be helped with nitric oxide as well,” Zamanian said.

To treat on an outpatient basis, “we would need to make sure patients have established and reliable communications with an investigator or physician.” In addition, a protocol will have to be established that outlines how to administer the nitric oxide treatment and how to connect the nasal cannula.

“We envision patients being prescribed a certain dose and then working with either their healthcare provider or respiratory therapist to follow the standards we set,” he explained.

Although it is not a cure, nitric oxide could improve oxygenation for COIVD-19 patients in respiratory distress who have a component of abnormal pulmonary vascular function “largely driven” by ventilation perfusion — or V/Q — mismatch, he explained.


It is widely known that the gas, because it is a selective pulmonary vasodilator, can be used as rescue therapy in patients with refractory hypoxemia due to acute respiratory distress syndrome (ARDS).

“There is justification for studying it in both pulmonary hypertension and nonpulmonary hypertension patients,” Zamanian added. “The idea is that there is a component of pulmonary function and constriction with COVID-19 that may be at play here, which is not typical of regular ARDS.”

Several Trials Underway

In early April, an investigation into the use of high-dose nitric oxide therapy for the treatment of patients infected with SARS-CoV-2 who suffer lung complications was approved by the Therapeutic Products Directorate of Health Canada.

The NONTM — Inhaled Gaseous Nitric Oxide Antimicrobial Treatment of Difficult Bacterial and Viral Lung (COVID-19) Infections — trial will test the use of Thiolanox, a high-concentration, 5000 ppm nitric oxide canister (Mallinckrodt Pharmaceuticals) administered with the INODD delivery device (Novoteris), at Vancouver Coastal Health Authority facilities. The open-label safety study will look at whether nitric oxide can reduce the bacterial load in the lungs of adults and adolescents.

Last week, two randomized multicenter clinical trials — also focused on the potential therapeutic benefits of nitric oxide in patients with COVID-19 in a hospital setting — were launched by teams at the Massachusetts General Hospital in Boston.

The NoCovid trial will look at nitric oxide for mild to moderate COVID-19 in 240 patients treated with a noninvasive CPAP system or a non-rebreathing mask system.

The NOSARSCOVID trial will look at the use of the INOmax (Mallinckrodt) nitric oxide inhalation system in 200 COVID-19 patients with severe acute respiratory syndrome.

“Data suggest that inhaled nitric oxide may have an important role in helping patients with acute respiratory distress syndrome (ARDS) to achieve normal oxygen levels in the blood,” Lorenzo Berra, MD, from Massachusetts General Hospital, said in a news release from Mallinckrodt announcing NOSARSCOVID.

“The trial we are conducting will help us gain critical insights into the potential effectiveness of INOmax in treating ARDS in critically ill COVID-19 patients,” Berra explains.

INOmax has already been used to treat COVID-19 patients in more than 170 hospitals in the United States, according to the news release.


Still, for COVID-19 treatment, “it’s still all hypothetical, as it hasn’t been proven,” said Alex Stenzler, founder and president of Novoteris.

We’ve demonstrated that we are able to get more oxygen to the blood and that there are some pro- and anti-inflammatory properties, “but there’s no randomized evidence, and the numbers are small,” he told Medscape Medical News.

And if there is a response or benefit, “we won’t know the reason for that benefit — if it’s anti-inflammatory, antiviral, or a vascular effect,” he pointed out.

“Nitric oxide is one of the most important signaling molecules in the human body. Our own body uses it to kill organisms and cells, heal wounds,” he explained, but “we’re a long way off from knowing” whether it can help ARDS patients.

COVID-19 Ventilation Clinical Practice Guidelines, issued by the European Society of Intensive Care Medicine and the Society of Critical Care, warn that “in patients with ARDS who are on mechanical ventilation, routine use of inhaled nitric oxide is not recommended,” as reported by Medscape.

Antimicrobial, Antiviral Properties

Previous studies of nitric oxide have shown that it has antiviral and antimicrobial properties.

Nitric oxide was shown to reduce H1N1 in vitro in Madin-Darby canine kidney (MDCK) epithelial cells in a 2013 study conducted by Chris Miller, PhD, from the University of British Columbia in Vancouver, and colleagues. Miller is currently involved in the NONTM trial.

This could be an added benefit of treatment. “Nitric oxide has been shown to have antiviral properties,” Zamanian said. “We need to investigate it further to see how it can help us avoid negative outcomes.”

Medscape Medical News


American Thoracic Society (ATS) 2020 International Conference.

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