Inhaled nitric oxide therapy in acute bronchiolitis: A multicenter randomized clinical trial

Aviv Goldbart, Inbal Golan-Tripto, Giora Pillar, Galit Livnat-Levanon, Ori Efrati, Ronen Spiegel, Ronit Lubetzky, Moran Lavie, Lior Carmon, Abdi Ghaffari, Amit Nahum, Aviv Goldbart, Inbal Golan-Tripto, Giora Pillar, Galit Livnat-Levanon, Ori Efrati, Ronen Spiegel, Ronit Lubetzky, Moran Lavie, Lior Carmon, Abdi Ghaffari, Amit Nahum

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).

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
A flow diagram of patient enrollment, exclusion, and outcome analysis. Out of 73 patients that were assessed for the research, we ended with 2 equal groups of 34 pt. that received either iNO or oxygen.
Figure 2
Figure 2
Methemoglobin and nitrogen dioxide levels. Pooled MetHb (panel A) and inspired NO2 (panel B) data from the start and end of all treatments (343 total inhalations) are shown in Box-Whisker plots. The dotted lines indicate the study safety threshold limits of 7% for MetHb and 5 ppm for NO2. Box-Whisker plot: boxes display 25th to 75th percentile, middle line represents the median, and whiskers extend to minimum and maximum values. (Panel C) shows mean ± SD of daily MetHb levels at baseline, start (pre-) and end (post-) of each NO inhalation, and at discharge.
Figure 3
Figure 3
Mean efficacy outcomes show overall improvements in iNO group compared to the control. Mean ± SD for length of stay (LOS, panel A), time to SpO2 ≥92% (panel B), and time to clinical score ≤5 (panel C) were analyzed in PP population as described in methods. The value at top of each plot provides the difference between the means.

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