Abstract
Currently, there are no approved treatments for infants with acute bronchiolitis, the leading cause for hospitalization of infants worldwide, and thus the recommended approach is supportive. Inhaled Nitric oxide (iNO), possesses anti-viral properties, improves oxygenation, and was shown to be safe in infants with respiratory conditions. Hospitalized infants with acute bronchiolitis were therefore recruited to a prospective double-blinded, multi-center, randomized controlled pilot study. They received intermittent high dose iNO (160 ppm) plus oxygen/air for 30 min or oxygen/air alone (control), five times/day, up to 5 days. Sixty-nine infants were enrolled. No difference was observed in frequencies of subjects with at least one Adverse Event (AE) in iNO (44.1%) vs. control (55.9%); neither was Methemoglobin >7% safety threshold. No drug-related serious AEs (SAEs) were reported. Analysis of Per-Protocol population revealed that length of stay (LOS), time to SpO2 ≥92%, and time to mTal clinical score ≤5 improved by 26.7 ± 12.7 (Welch’s t-test p = 0.04), 20.8 ± 8.9 (p = 0.023), and 14.6 ± 9.1 (p = 0.118) hours, respectively, in the iNO group compared to the control. Overall, high dose iNO (160ppm) was safe, well-tolerated, reduced LOS and showed rapid improvement of oxygen saturation, compared to the standard therapy. Further investigation in larger cohorts is warranted to validate these encouraging efficacy outcomes. (Trial registration: NCT03053388)
Highlights
There are no approved treatments for infants with acute bronchiolitis, the leading cause for hospitalization of infants worldwide, and the recommended approach is supportive
Endogenous NO production is an essential part of the innate defense mechanism of the human immune system which becomes up-regulated by inducible NO synthase during various inflammatory conditions including microbial and viral infections 7,8
Per-Protocol population consisted of all ITT subjects who completed the study in accordance with the protocol, received at least 4 inhalations and their length of stay (LOS) was at least 20 hours
Summary
There are no approved treatments for infants with acute bronchiolitis, the leading cause for hospitalization of infants worldwide, and the recommended approach is supportive. Continuous exposure to high-dose NO in humans would result in methemoglobinemia, which could lead to decreased oxygen transport and hypoxemia[23] To overcome this problem, researchers investigated an intermittent iNO regimen (30 min cycles of 160ppm every 3.5 hours) that retained NO’s antimicrobial activity in pre-clinical models 16,24 and demonstrated safety and tolerability in healthy adults. In a pilot double-blind safety study (n = 43), our group was unable to detect a difference in frequency of AEs and tolerability between intermittent high-dose NO (30 min of 160ppm, 5 times/ day) and supportive treatment alone in infants with moderate bronchiolitis. Our previously published results revealed that mean MetHb levels remained well below the 5% safety threshold limit[27] In this multicenter pilot study, we aimed to determine efficacy, in addition to safety and tolerability, of intermittent high-dose iNO therapy in a larger cohort of hospitalized infants with bronchiolitis
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