High-dose inhaled nitric oxide improves oxygenation in COVID-19 pneumonia

Key takeaways:

• Arterial oxygenation in critically ill adults with COVID-19 pneumonia improved with high-dose inhaled nitric oxide.
• Plasma and sputum viral loads went down over time with this treatment.

Adults on mechanical ventilation for COVID-19 pneumonia showed improvements in oxygenation with high-dose inhaled nitric oxide, according to results published in American Journal of Respiratory and Critical Care Medicine.

Lorenzo Berra

“Our current trial challenges the conventional understanding of nitric oxide, which was previously primarily seen as a rescue therapy for refractory hypoxemia in respiratory failure,” Lorenzo Berra, MD, medical director of respiratory care at Massachusetts General Hospital and the Reginald Jenney Associate Professor of Anesthesia at Harvard Medical School, told Healio.

In a phase 2, multicenter, single-blind, randomized, controlled, parallel-arm clinical trial, Berra and colleagues assessed 193 adults (median age, 62 years; 33.7% women; 51.8% white) with COVID-19 pneumonia placed on mechanical ventilation to find out whether arterial oxygenation (PaO₂/FiO₂) improves with high-dose inhaled nitric oxide (n = 94) vs. usual care (n = 99) at 48 hours. The patients in the treatment group received 80 parts per million (ppm) of nitric oxide for 48 hours, which was then decreased to 40 ppm until severe hypoxemia resolved.

Researchers also compared time to reach a PaO₂/FiO₂ greater than 300 mmHg for at least 24 hours, the number of patients who reached this milestone by day 28, and mortality both on day 28 and day 90 between the two treatment groups.

At baseline, the treatment group had lower PaO₂/FiO₂ than the usual care group (177 mmHg vs. 195 mmHg).

At the 48-hour mark, researchers found greater improvement in PaO₂/FiO₂ among those receiving inhaled nitric oxide vs. those receiving usual care (mean change, 28.3 mmHg vs. –1.4 mmHg).

It took slightly longer for the inhaled nitric oxide group to reach a PaO₂/FiO₂ greater than 300 mmHg that was sustained for 24 hours compared with the usual care group (mean, 8.7 days vs. 8.4 days); however, more patients from the treatment group achieved this arterial oxygenation level on day 28 (27.7% vs. 17.2%).

According to researchers, receiving high-dose inhaled nitric oxide corresponded with a 98.1% probability for achieving a PaO₂/FiO₂ greater than 300 mmHg (RR = 2.03; 95% credible interval [CrI], 1.11-3.86).

Rates of all-cause mortality were similar between patients in the inhaled nitric oxide group and patients in the usual care group at both day 28 (28.7% vs. 27.3%) and day 90 (34% vs. 32.3%). Researchers also did not find any significant differences in mechanical ventilation duration.

Further, patients who received nitric oxide therapy did not experience any serious adverse events, according to researchers.

Of the total cohort, researchers collected plasma and sputum from 17 patients in the nitric oxide group and 20 patients in the usual care group to compare median viral loads between the two groups.

Although researchers found comparable median viral loads of both plasma and sputum taken after randomization between the two groups, those receiving inhaled nitric oxide had a greater reduction in plasma viral load (change per unit time = –0.21; 95% CrI, –0.25 to –0.17; group differences = –0.3; 95% CrI, –1 to 0.42) and sputum viral load (change per unit time = –0.13; 95% CrI, –0.16 to –0.11; group differences = 0.29; 95% CrI, –0.87 to 1.44) over time vs. those receiving usual care.

“We were genuinely taken aback by the study’s findings, particularly in regard to the rate of viral load reduction observed in patients who were randomly assigned to receive nitric oxide gas,” Berra told Healio.

In addition to these findings, researchers observed that those receiving inhaled nitric oxide had fewer neurological signs and symptoms at 90 days than those receiving usual care (4.2% vs. 17.2%), as well as fewer sensory symptoms (0% vs. 14.1%).

“Surprisingly, our results suggest that nitric oxide therapy could be more beneficial when administered at high dose during the early stages of COVID-19 (and, possibly, respiratory infectious diseases),” Berra told Healio. “This discovery is particularly significant because nitric oxide is a known endogenous molecule with broad antimicrobial spectrum.”

Reference:

• Clinical trial reveals benefits of inhaled nitric oxide for patients with respiratory failure due to COVID-19 pneumonia. https://www.massgeneral.org/news/press-release/nitric-oxide-covid-pneumonia. Published Oct. 6, 2023. Accessed Oct. 18, 2023.