Evidence mounts supporting inhaled nitric oxide as COVID-19 treatment
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Research exploring inhaled nitric oxide’s potential to treat COVID-19 is underway.
Nitric oxide works mechanistically as “a naturally produced molecule that is critical to the immune response against pathogens and infections," according to a press release from Bellerophon Therapeutics.
“We’ve used this gas for 20-plus years to treat acute respiratory syndrome and heart issues, Keith Scott, MD, MSc, FCCM, principal investigator of a clinical trial that recently started at Louisiana State University Health Shreveport, told Healio Primary Care. “We have good familiarity with it, we know how to use it and we can anticipate what its benefits will be.”
Lou Ignarro, PhD, who was awarded the Nobel Prize for nitric oxide research, said in an interview that inhaled nitric oxide was used to treat a limited number of patients during the 2003 SARS outbreak.
Compared with ventilation, “inhaled nitric oxide dilates or widens arteries to allow more blood to flow through the lungs,” Ignarro said. “It also relaxes the trachea and bronchioles, allowing more air to come in.”
Roger Alvarez, DO, MPH, assistant professor of pulmonology at the University of Miami’s Miller School of Medicine, told Healio Primary Care that he and his colleagues successfully treated 24 of 25 patients with COVID-19 using INOpulse (Bellerophon Therapeutics).
“INOpulse is a portable inhaled nitric oxide device with a small cartridge with three channels,” said Alvarez, who also a Bellerophon Therapeutics investigator. “One carries the patient’s oxygen, one carries nitric oxide and one appropriately adjusts the dose based on the patient’s breathing pattern.”
The FDA recently granted INOpulse emergency expanded access for the treatment of patients with COVID-19. The agency also recently accepted Bellerophon Therapeutics’ investigational new drug application to initiate a phase 3 study of INOpulse, according to a company press release. Meanwhile, the company said it will make INOpulse available to as many patients as possible.
Roham T. Zamanian, MD, associate professor of pulmonology and critical care at Stanford University School of Medicine, and colleagues recently described successfully treating COVID-19 with inhaled nitric oxide in an American Journal of Respiratory and Critical Care Medicine case report.
They filed an emergency investigational new drug application with the FDA for the gas after diagnosing a 34-year-old woman with concomitant idiopathic pulmonary arterial hypertension and COVID-19. After the FDA accepted the application, the woman started inhaled nitric oxide therapy at a dose of 20 parts per million plus two liters per minute of supplemental oxygen. She was gradually weaned off the inhaled nitric oxide until she recovered.
Zamanian and colleagues said that the case “is the first to our knowledge of outpatient telehealth management of an idiopathic pulmonary arterial hypertension patient with COVID-19 disease.”
Adverse events associated with inhaled nitric oxide include blood oxygenation reductions or buildups of nitric acid. However, these events occurred because the treatment was incorrectly administered, a member of a research team in Massachusetts told an NPR member station.
Alvarez’s research team is also exploring the hypothesis that inhaled nitric oxide has antiviral characteristics.
“There are some data that it causes that effect,” he said.
Scott said that he is testing the same theory.
“I started looking at inhaled nitric oxide and said, ‘Hey, this looks like it has antiviral activity,’” he explained. “It seemed like a natural thing to study.”
Sandra L. Kane-Gill, PharmD, MS, FCCM, an executive committee member of the Society of Critical Care Medicine, said that investigating the antiviral properties of nitric oxide is an “interesting idea,” but she noted that there are no human data to support the claim.
“The connection was only ever identified in animal models,” she said.
Should it be used?
The NIH and the Surviving Sepsis Campaign both make strong recommendations against the routine use of nitric oxide, Kevin C. Wilson, MD, a professor of medicine at the Boston University School of Medicine, said in an interview.
“Those recommendations are based upon indirect evidence from patients with acute respiratory distress syndrome, in whom nitric oxide transiently improves oxygenation but does not improve mortality, and it may cause acute kidney injury,” he said.“However, research on nitric oxide is reasonable because hypoxemic respiratory failure in COVID-19 may differ from traditional acute respiratory distress syndrome. Such research should be undertaken with caution.”
Scott, who will collaborate with the research team in Massachusetts and in other projects, said an interim analysis showed “there are no real side effects,” and so research can continue. Approximately 450 patients are enrolled in these trials, according to clinicaltrials.gov.
“More people will be using inhaled nitric oxide to treat COVID-19 when these data get out,” he said. – by Janel Miller
References: Clinicaltrials.gov. Nitric oxide gas inhalation therapy for mild/moderate COVID-19 (NoCovid). https://clinicaltrials.gov/ct2/show/NCT04305457. Accessed May 5, 2020.
Clinicaltrials.gov. Nitric oxide gas inhalation in severe acute respiratory syndrome in COVID-19. https://clinicaltrials.gov/ct2/show/NCT04290871. Accessed May 5. 2020.
Moran B. Can inhaling nitric oxide treat — or prevent — COVID-19? MGH wants to find out. WBUR. https://www.wbur.org/commonhealth/2020/04/10/nitric-oxide-gas-mass-general-coronavirus-tests. Accessed May 5, 2020.
Zamanian RT, et al. Am J Respir Crit Care Med. 2020;doi:10.1164/rccm.202004-0937LE.
Disclosures: Alvarez reports research support from Bellerophon Therapeutics. Ignarro reports a professional relationship with one of the Massachusetts clinical trial researchers. Scott reports no relevant financial disclosures. Kane-Gill is treasurer of the Society for Critical Care Medicine. Wilson is chief of guidelines and documents at the American Thoracic Society.
Perspective
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Taha Qazi, MD
Currently, there have been limited case studies and case series in COVID-19 patients who have been treated with nitric oxide. Nitric oxide use has side effects and in rare situations, adverse events related to its use. Thus, its use in an unmonitored and unrestricted setting should probably not be undertaken. There are clinical trials where nitric oxide therapy is being placed in COVID-19 patients. These trials are ongoing and will attempt to assess whether or not nitric oxide will have therapeutic benefits for patients with COVID-19.
I have used agents to increase a patient’s body production of nitric oxide in patients with pulmonary hypertension. We do know there are some benefits in these patients. In one of the case reports described in the article, a patient with pulmonary hypertension developed COVID-19. In this select patient, the use of the agent resulted in improvement in daily activity.
There is also unpublished data from the University of Miami where the group is using nitric oxide in 24 patients and they have seen nitric oxide as beneficial. Once again, this is in a monitored setting with physicians who have experience providing and monitoring the use of nitric oxide. A continued concern is the unrestricted use in an unmonitored setting that may expose patients to significant side effects that may be problematic.
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