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OBJECTIVE: The study was performed to determine the changes in blood methaemoglobin level during the inhalation of nitric oxide. DESIGN: The study was an unblinded dose-response study. PARTICIPANTS: 5 healthy adult volunteers aged 30-36 (4 male and 1 female) were studied on 4 occasions separated by at least one week. INTERVENTION: Nitric oxide was inhaled at inspired concentrations of 32, 64, 128, and 512 volumes per million (vpm) in air. Venous blood samples were taken every 10 min for methaemoglobin determination. Inhalation continued for 3 h (32, 64 and 128 vpm) or until the methaemoglobin exceeded 5% of the total haemoglobin (512 vpm). The methaemoglobin levels were also recorded for 3 h after 512 vpm nitric oxide had been stopped. MEASUREMENTS AND RESULTS: Both the increase in methaemoglobin fraction during nitric oxide inhalation and the decay after ceasing inhalation fitted well with a first order model describing methaemoglobin elimination. The calculated time constants were between 39-91 min. The predicted mean maximum methaemoglobin levels that would be achieved during inhalation of 32, 64, 128, and 512 vpm nitric oxide were 1.04% (0.92-1.16), 1.75% (1.80-1.90%), 3.75% (3.58-4.05), 6.93% (5.70-8.16) respectively (95% confidence interval of estimate in brackets). CONCLUSIONS: In normal individuals inhalation of up to 128 vpm of nitric oxide, greater than any dose used clinically to date, does not result in clinically significant methaemoglobinaemia. Maximum methaemoglobin levels are likely to be reached in 3-5 h after inhalation begins. However, these figures may not apply to critically ill adults and infants. Nitric oxide may have other toxic effects not examined in this study.


Journal article


Intensive Care Med

Publication Date





581 - 584


Administration, Inhalation, Adult, Dose-Response Relationship, Drug, Female, Humans, Male, Methemoglobinemia, Nitric Oxide, Reference Values, Time Factors