The goal of this clinical trial is to learn the formation and recovery rate of methemoglobin (MetHb) in severely sick patients with pneumonia who receive high doses of inhaled nitric oxide (iNO) therapy at 250 parts per million (ppm), not exceeding 300 ppm. Meanwhile, the benefits of the therapy to treat severely sick patients with pneumonia will be explored. Patients who are 18 years or older, newly diagnosed with pneumonia, and severely sick with requirement of a breathing machine could be included. The main questions it aims to answer are:

How does methemoglobin change through the iNO treatment? Does iNO therapy increase the number of patients recovering from pneumonia? Researchers will compare iNO treatment to placebo, which means using the same device as the treatment group without delivering the study drug.

Participants will:

• Receive iNO treatment starting at 250 ppm, not exceeding 300 ppm, 40 min, every 6 hours, from day 1 to day 5
• Be followed up for 60 days

This study is designed as a pilot, double-blinded, randomized controlled trial to investigate levels of methemoglobin in the treatment group versus the control group and efficacy of high dose inhaled NO among critically ill patients with pneumonia. We will enroll 34 adult patients with newly diagnosed pneumonia and invasive mechanical ventilation who are admitted to the ICUs at Massachusetts General Hospital.

After enrollment, participants will be randomized in 1:1 ratio to intervention group or control group. Baseline characteristics will be collected.

During treatment period, patients allocated to the intervention group will receive high dose inhaled NO starting at 250 ppm (not exceeding 300 ppm), 40min, 4 times daily, for 5 days. The control group will receive sham intervention. Both groups will receive standard therapy.

During follow-up period, we will follow participants for a total duration of 60 days. Methemoglobin kinetic levels and efficacy outcomes will be collected.

Inclusion Criteria:

• 18 years or older
• Intubated and mechanically ventilated
• Within 72h of diagnosis of community- or hospital-acquired pneumonia
• Written informed consent obtained from patients or legally authorized representatives

Exclusion Criteria:

• Baseline methemoglobin 3% or higher
• Genetic diseases including glucose-6-phosphate dehydrogenase deficiency, cytochrome b5 reductase deficiency, sickle cell disease
• Oxygen saturation < 88% on 100% inspired fraction of oxygen
• Anemia with hemoglobin < 7.0 g/dl
• Acute cardiogenic shock requiring inotropic or mechanical support with an ejection fraction less than 20%
• Receiving inhaled NO therapy or decision to initiate inhaled NO therapy within 24 hours post randomization
• A decision to do-not-resuscitate (DNR)
• Enrollment in another experimental antimicrobial treatment protocol
• Patients for whom follow-up is expected to be impossible

All IPD that underlie results in a publication

Beginning 1 year after publication with no end date

A proposal that describes planned analyses must be submitted to the principal investigator via email. Data sharing agreement should be reached, documented and signed.