Exploring Inhaled Nitric Oxide (iNo) As As An Adjuvant COVID-19 Treatment For Pulmonary Issues

Nitric Oxide: Previously published findings from the 2003 SARS-CoV infection suggest the potential role of inhaled nitric oxide (iNO) as a supportive measure for treating infection in patients with pulmonary complications. Treatment with inhaled nitric oxide reversed pulmonary hypertension, improved severe hypoxia, and shortened the length of ventilatory support compared with matched control patients with SARS.  https://academic.oup.com/cid/article/39/10/1531/460542


 
At the moment a phase 2 study of iNO is underway in patients with COVID-19 with the goal of preventing disease progression in those with severe Acute Respiratory Disease Syndrome (ARDS). A phase 3 study (PULSE-CVD19-001) for iNO (INOpulse; Bellerophon Therapeutics) was accepted by the US FDA in mid-March 2020 to evaluate efficacy and safety in patients diagnosed with COVID-19 who require supplemental oxygen before the disease progresses to necessitate mechanical ventilation support. The Society of Critical Care Medicine recommends against the routine use of iNO in patients with COVID-19 pneumonia. Instead, they suggest a trial only in mechanically ventilated patients with severe ARDS and hypoxemia despite other rescue strategies.  The cost of iNO is reported as exceeding US$100/hour. https://www.clinicaltrialsarena.com/news/mallinckrodt-nitric-oxide-covid-19/
and https://www.globenewswire.com/news-release/2020/05/11/2031087/0/en/Bellerophon-Therapeutics-Announces-FDA-Clears-Initiation-of-Phase-3-Study-for-INOpulse-Inhaled-Nitric-Oxide-Therapy-to-Treat-COVID-19.html
 
It is said that 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.
 
Dr Keith Scott, MD, MSc, FCCM, principal investigator of a clinical trial that recently started at Louisiana State University Health Shreveport, told Thailand Medical News, “We’ve used this gas for 20-plus years to treat acute respiratory syndrome and heart issues. We have good familiarity with it, we know how to use it and we can anticipate what its benefits will be.”

Dr 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.
 
He said, “Compared with ventilation, inhaled nitric oxide dilates or widens arteries to allow more blood to flow through the lungs. It also relaxes the trachea and bronchioles, allowing more air to come in.”
 
Assistant Professor of Pulmonology at the University of Miami’s Miller School of Medicine, Dr Roger Alvarez, DO, MPH said that he and his colleagues successfully treated 24 of 25 patients with COVID-19 using INOpulse (Bellerophon Therapeutics ).
 
He explained, “INOpulse is a portable inhaled nitric oxide device with a small cartridge with three channels. One carries the patient’s oxygen, one carries nitric oxide and one appropriately adjusts the dose based on the patient’s breathing pattern.”
 
The US 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.
 
The company said it will make INOpulse available to as many patients as possible.
 
Associate Professor of Pulmonology and critical care at Stanford University School of Medicine, Dr Roham T. Zamanian, MD, and colleagues recently described successfully treating COVID-19 with inhaled nitric oxide in an American Journal of Respiratory and Critical Care Medicine case report. https://www.atsjournals.org/doi/abs/10.1164/rccm.202004-0937LE
 
The researchers filed an emergency investigational new drug application with the US 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.

Dr 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.”
 
To date recorded 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,
 
Interestingly a member of a research team in Massachusetts said that Dr Alvarez’s research team is also exploring the hypothesis that inhaled nitric oxide has antiviral characteristics.
 
Dr 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.
 
However the NIH and the Surviving Sepsis Campaign both make strong recommendations against the routine use of nitric oxide, Dr Kevin C. Wilson, MD, a professor of medicine at the Boston University School of Medicine, “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. 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.”
 
Meanwhile researchers at Massachusetts General Hospital (MGH) are still pursuing more research as to whether inhaling nitric oxide can help treat patients with COVID-19, or even prevent people from getting the disease.
 
MGH is the only hospital in the United States, and one of the few in the world, studying it for the treatment of COVID-19, according to the CDC. (MGH is conducting one of the studies in cooperation with teams in Alabama and Louisiana.)
 
Typically Nitric oxide is a colorless gas, not to be confused with "nitrous oxide," better known as laughing gas, or "nitrogen dioxide," a smoggy brown air pollutant. The human body makes nitric oxide on its own, and uses it as a chemical messenger. Low levels of nitric oxide constrict blood vessels; higher levels dilate them, increasing blood flow. When patients inhale it through a face mask or mechanical ventilator, it can open airways and help them breathe better.
 
Dr Libby Hohmann, a physician in the infectious diseases division at Massachusetts General Hospital, calls nitric oxide "a favorite of MGH."
 
Doctors there in 1990 were the first to use the gas to treat a baby born with a serious breathing condition, called persistent pulmonary hypertension of the newborn (PPHN), which was one cause of "blue baby" syndrome. Nitric oxide has since become standard treatment for PPHN, and is also widely used for other respiratory and cardiac problems.
 
Dr Hohmann added, "It has advantageous effects for people with certain kinds of respiratory failure," says and it also appears to have some direct antiviral effects. The inhaled gas only affects the lungs, and the effects are short-lived.’
 
Dr Robert Kacmarek, director of respiratory care at MGH and one of the leaders of the nitric oxide trials there said, "You see an effect within minutes And as soon as you stop it, the effect goes away."
 
Dr Kacmarek says there can be side effects if the gas is not administered properly, like a dip in blood oxygenation, or a buildup of nitric acid that can harm the lungs. But there are rarely any long-term side effects.I is relatively safe.
 
Though doctors and researchers are generally familiar with nitric oxide's respiratory effects, less is known about its potential antiviral effects. There's some evidence that inhaled nitric oxide gas can destroy or inactivate viruses, including anecdotal evidence that it helped patients with SARS  a similar coronavirus during the 2003 epidemic.
 
Dr  Kacmarek. "At the time they used it they weren't sure exactly why it was beneficial. But since then there's been a lot of bench laboratory studies looking at its effect on viruses, bacteria, etc., That's the reason we're doing these studies, because we believe that the combined effect of improving oxygenation because all of these patients have oxygenation problems and the potential antiviral effect of the drug may change the course of the disease in an individual."
 
Medical researchers at MGH have four clinical trials either planned or underway. Right now they are testing severely ill patients who are already on ventilators, to see if the gas can help them get off the ventilators more quickly and ultimately survive. They're also testing patients with mild-to-moderate COVID-19 to see if inhaling nitric oxide can prevent progression of the disease and keep the patient off a ventilator. And they've started an international registry of ICU COVID-19 patients on ventilators, to help consolidate worldwide data.
 
Also in the works, but not yet approved, is a study on whether giving nitric oxide to COVID-19 patients in the ER can stop their disease from getting worse, and keep patients out of the hospital.
 
Importantly, the final study, which is just getting started, will examine whether giving nitric oxide to health care workers who aren't sick, might actually prevent them from getting COVID-19.
 
Dr Paul Sax, clinical director of the division of infectious diseases at Brigham and Women's Hospital, who is not, involved with the MGH studies sadi that it is "an interesting hypothesis."
 
Dr Sax adds, "In the absence of any other proven preventive therapy, it's reasonable to try it as long as people are going in with their eyes open and signed informed consent and understand the risks."
 
The first prevention trial will eventually enroll up to 470 health care professionals working with COVID-19 patients. The workers will inhale nitric oxide at the beginning and end of their shifts, and go about their business as usual in between. (A control group will not receive the drug.) Researchers will check the workers for fever or other COVID-19 symptoms every day.
 
Dr Kacmarek explained "A high percentage of caregivers develop COVID-19. You don't know, after you finish your shift, whether you've been exposed, whether you inhaled any of the virus and we're hoping that this will prevent caregivers from getting the disease."
 
Though there are still no proven drugs for preventing or treating COVID-19, and Kacmarek cautions that people should not try to administer nitric oxide on their own.
 
He warned, "It's really dangerous. It comes in tanks in very high concentrations, and if you breathe those high concentrations, the outcome would not be good."
 
Additional References:
 
Clinicaltrials.gov. Nitric oxide gas inhalation therapy for mild/moderate COVID-19 (NoCovid). https://clinicaltrials.gov/ct2/show/NCT04305457.
 
Clinicaltrials.gov. Nitric oxide gas inhalation in severe acute
espiratory syndrome in COVID-19. https://clinicaltrials.gov/ct2/show/NCT04290871 
 
Zamanian RT, et al. Am J Respir Crit Care Med. 2020;doi:10.1164/rccm.202004-0937LE.
 
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