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Abstract
BackgroundSubstantial numbers of neonates with hypoxic respiratory failure (HRF) do not immediately respond to inhaled nitric oxide (iNO) and are often labeled as non-responders. This retrospective data analysis assessed time to treatment response in the iNO key registration trial.MethodsTreatment response was defined as a ≥10% increase in partial pressure of arterial oxygen (PaO2) or a ≥10% decrease in oxygenation index (OI) after initiation of study gas without the need for extracorporeal membrane oxygenation (ECMO). The proportion of patients showing a response at 30 min, 1 h, 24 h, and >24 h after iNO or placebo initiation was calculated and stratified by baseline PaO2 and OI.ResultsData from 248 patients (iNO: n = 126; placebo: n = 122) were included; 66 patients receiving iNO showed improvement in oxygenation without needing ECMO versus 38 receiving placebo. Of the 66 iNO responders, 73% responded within ≤30 min, 9% within ≤1 h, 12% within ≤24 h, and 6% after 24 h. Of the 38 patients with improvement in oxygenation without needing ECMO while receiving placebo, 53% showed improvement within ≤30 min, 16% within ≤1 h, 29% within ≤24 h, and 3% after 24 h. Baseline disease severity was not predictive of time to response. Of the 48 patients in the iNO treatment group who were classified as non-responders due to eventual need for ECMO and not included in the analysis of responders, 40 (83%) had an initial improvement in oxygenation during iNO therapy.ConclusionsChanges in PaO2 and OI after iNO initiation appear to be imprecise biomarkers of response to therapy in neonates with HRF. In some patients treated with iNO, it took up to 24 h to achieve improvement in oxygenation without need for ECMO, and a majority of those who eventually required ECMO did show an initial improvement in oxygenation during iNO treatment. Thus, reliable, objective, early criteria for iNO response still need to be established, and initial PaO2/OI responses should be interpreted with caution, particularly when considering discontinuing iNO therapy.
Highlights
Substantial numbers of neonates with hypoxic respiratory failure (HRF) do not immediately respond to inhaled nitric oxide and are often labeled as non-responders
The main outcome of interest for the current post hoc analysis was the time from initiation of the study gas to achievement of treatment response, defined as a ≥10% increase in Partial pressure of arterial oxygen (PaO2) or a ≥10% decrease in oxygenation index (OI) after initiation of the study treatment without the need for extracorporeal membrane oxygenation (ECMO)
While many term and late preterm patients with HRF who responded to inhaled nitric oxide (iNO) treatment did so within 60 min, we found that there were patients who continued to exhibit an oxygenation response after 60 min, no statistical difference was observed in the proportion of patients showing a late response in the iNO group versus the placebo group
Summary
Substantial numbers of neonates with hypoxic respiratory failure (HRF) do not immediately respond to inhaled nitric oxide (iNO) and are often labeled as non-responders. The Clinical Inhaled Nitric Oxide Research Group Investigation (CINRGI) study, the key registration trial of iNO in this patient population, showed that administration of low doses of iNO, initiated at 20 ppm and titrated down to 5 ppm as tolerated, was associated with a significant reduction in the use of ECMO (38% in the iNO group vs 64% in the placebo group; p = 0.001), a significant increase in the mean (SD) ratio of arterial-to-alveolar oxygen tension (0.10 [0.14] vs 0.05 [0.13]; p = 0.02), and a significant reduction in the incidence of chronic lung disease, as defined by the need for supplemental oxygen at 30 days of age (7% vs 20%; p = 0.02) [5]. These findings from the CINRGI trial demonstrated the effectiveness of iNO in this patient population and led to the approval of iNO by the US Food and Drug Administration (FDA) for these patients in 1999
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