Skip to content

High-dose Inhaled Nitric Oxide Safe, Effective for Non-Intubated COVID-19 Patients

Key findings

  • This study investigated the effectiveness and safety of inhaling 160 ppm nitric oxide (NO) gas twice daily for 30 minutes in 29 spontaneously breathing, non-intubated hospitalized patients with mild to moderate COVID-19-induced pneumonia
  • NO inhalation was associated with acute reduction of respiratory rate in tachypneic patients, and with an acute improvement in oxygenation in patients who were hypoxemic before beginning an NO treatment
  • The reduction in respiratory rate was sustained throughout hospitalization and until the time of discharge
  • No high levels of methemoglobin, other adverse events or any device failure occurred during NO inhalation and there were no signs of rebound pulmonary hypertension or cases of acute kidney injury
  • Use of inhaled NO was not associated with readmission after hospital discharge

In November 2020, Massachusetts General Hospital researchers reported the benefits of high-dose inhaled nitric oxide (NO) as a rescue therapy for five non-intubated adults critically ill with COVID-19. Their paper, covering a study period from March 18 to May 20, 2020, was published in Critical Care Explorations.

Subsequently, a randomized trial was initiated. The steering committee stopped it early because of the marked reduction of COVID-19–related hospital admissions, but the researchers observed favorable results of treatment.

Lorenzo Berra, MD, anesthesiologist in the Department of Anesthesia, Critical Care and Pain Medicine and medical director for Respiratory Care at Massachusetts General Hospital, and Bijan Safaee Fakhr, MD, research fellow in the Department of Anesthesia, Critical Care and Pain Medicine, and colleagues detail the findings in Nitric Oxide.

Study Methods

Adult inpatients with mild or moderate COVID-19 were eligible for the trial unless they were on long-term oxygen therapy or high-flow nasal cannula therapy at screening. The prespecified sample size was 240 but enrollment was halted in July 2020.

Between March and June 2020, 29 patients received 160 ppm of inhaled NO gas for 30 minutes twice daily. The researchers used a custom-built face mask apparatus, illustrated in the article, and presented in detail by the same group in a paper published by Stefano Gianni, MD, et al. on Nitric Oxide.

The therapy ended after 14 days, a negative SARS-CoV-2 test, no respiratory symptoms for three consecutive days or at hospital discharge. The 29 patients collectively received 217 treatments (median number per patient, 6; range, 1–27).


  • The ratio of SpO2(%) to FiO2(%) in patients with hypoxemia before each treatment session—improved by an average of 49 during treatment and by 22 after treatment
  • Respiratory rate (RR) in patients with tachypnea at baseline—improved by an average of two breaths/minute during treatment and remained reduced by two breaths per minute after treatment
  • RR at 48 hours after the start of therapy—improved by an average of three breaths per minute
  • RR during the first four days of treatment—improved by one breath per minute per day (from a median of 20 breaths per minute)


The reaction between oxyhemoglobin and NO generates methemoglobin, which is unable to bind to oxygen. Methemoglobin levels were monitored continuously during NO treatment and 5% was preestablished as the highest permittable level. The maximum level measured during treatment was 4.7%, and levels rapidly decreased over five minutes in all patients after NO was discontinued.

During and after NO therapy, there were no:

  • Device or system failures, although three patients discontinued treatment because of discomfort from the face mask
  • Hypotensive or hypoxemic episodes
  • Clinical or echocardiographic signs of rebound pulmonary hypertension (14 patients underwent echocardiography)
  • Cases of acute kidney injury during hospitalization


One patient required intubation and mechanical ventilation due to the progression of pulmonary disease. No in-hospital deaths occurred. The median length of stay/recovery time was six days (IQR, 4–8 days).

None of the patients who received NO required hospital readmission due to COVID-19 reactivation. For comparison, the researchers matched 33 other COVID-19 patients admitted to Mass General on age, gender and disease severity, and observed that six (19%) were readmitted within 28 days.

Applying the Data

These findings confirm previous observations from same group (Wiegand, Critical Care Exploration; Safaee Fakhr, Obstetrics & Gynecology), suggesting that the delivery of high-dose inhaled NO is safe for spontaneously breathing patients admitted with COVID-19. The reduction in respiratory rate may indicate a lasting effect from multiple NO treatments beyond selective pulmonary vasodilation and improved ventilation/perfusion matching during treatment.

Learn more about the Department of Anesthesia, Critical Care and Pain Medicine

View all COVID-19 research

Related topics


Massachusetts General Hospital physicians have identified two phenotypes of acute respiratory distress syndrome (ARDS) associated with COVID-19 that are distinct in biochemical profiles and short-term mortality despite minimal differences in respiratory dynamics.


Michael Dougan, MD, PhD, of the Division of Gastroenterology, was an investigator in the BLAZE-1 trial that led to the emergency authorization of bamlanivimab plus etesevimab for treatment of adolescents and adults with mild or moderate COVID-19 who are at high risk of progression to severe disease.