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Inhaled nitric oxide for neonates with persistent pulmonary hypertension of the newborn in the CINRGI study: time to treatment response.

ABSTRACT: BACKGROUND: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. This retrospective data analysis assessed time to treatment response in the iNO key registration trial. METHODS:Treatment 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. RESULTS:Data 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. CONCLUSIONS:Changes 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.

SUBMITTER: Nelin LD

PROVIDER: S-EPMC6330425 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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Inhaled nitric oxide for neonates with persistent pulmonary hypertension of the newborn in the CINRGI study: time to treatment response.

Nelin Leif D LD Potenziano Jim L JL

BMC pediatrics 20190112 1

<h4>Background</h4>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. This retrospective data analysis assessed time to treatment response in the iNO key registration trial.<h4>Methods</h4>Treatment response was defined as a ≥10% increase in partial pressure of arterial oxygen (PaO<sub>2</sub>) or a ≥10% decrease in oxygenation index (OI) after initiation of study gas without the ...[more]

PMID: 30636626

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Project description:Importance:Pulmonary hypoplasia affects a very small percentage of preterm neonates, but its presence is associated with high rates of mortality. Objective:To determine whether treatment with inhaled nitric oxide during the first week of life was associated with improved in-hospital survival in a cohort of extremely preterm neonates with pulmonary hypoplasia. Design, Setting, and Participants:This cohort study used data from the Pediatrix Medical Group's Clinical Data Warehouse, a data set containing information from more than 350 neonatal intensive care units in 35 US states and Puerto Rico. Since inhaled nitric oxide was not randomly prescribed, we used 1-to-1 propensity score matching to reduce the imbalance of measured covariates between the 2 treatment groups. The initial, unmatched cohort included singleton neonates who were born between 22 and 29 weeks' gestation, had a birth weight of 400 g or more, were diagnosed with pulmonary hypoplasia as a cause of their respiratory distress, remained free of major anomalies, and were discharged between January 1, 2000, and December 31, 2014. We defined exposure as the initiation of inhaled nitric oxide on day t in days 0 to 7 of the life of a neonate. Each exposed neonate was matched 1-to-1 to a neonate who had not initiated inhaled nitric oxide on a given day. Main Outcomes and Measures:The primary outcome was mortality defined as death prior to transfer or discharge home. Secondary outcomes were any-stage necrotizing enterocolitis, retinopathy of prematurity requiring treatment, chronic lung disease, and periventricular leukomalacia. Results:Among 92?635 neonates in our study sample, we identified 767 (0.8%) with pulmonary hypoplasia who met all study inclusion criteria, of whom 185 (0.2%) were exposed to inhaled nitric oxide. Among 151 matched pairs of exposed and unexposed neonates, we did not identify a significant association between inhaled nitric oxide use and mortality (hazard ratio [HR], 0.79; 95% CI, 0.57-1.11). Subgroup analyses of neonates with and without persistent pulmonary hypertension (PPHN) likewise revealed no significant association between inhaled nitric oxide use and mortality (pulmonary hypoplasia with PPHN: HR, 0.67; 95% CI, 0.45-1.01; pulmonary hypoplasia without PPHN: HR, 1.11; 95% CI, 0.61-2.02), but these findings may have been influenced by ascertainment bias. Conclusions and Relevance:Early treatment with inhaled nitric oxide is not associated with improved survival among extremely preterm neonates with pulmonary hypoplasia. Clinical trials are warranted to clarify the matter.

Project description:BACKGROUND:Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterized by suboptimal oxygenation as a result of sustained elevation in pulmonary vascular resistance after birth. Currently, the therapeutic mainstay for PPHN is optimal lung inflation and selective vasodilatation with inhaled nitric oxide (iNO). However, iNO is not available in all countries and not all infants will respond to iNO. Milrinone is a phosphodiesterase III inhibitor which induces pulmonary vasodilatation by its actions through a cyclic adenylate monophosphate mediated signaling pathway. OBJECTIVES:To assess efficacy and safety in infants with PPHN either treated with: milrinone compared with placebo or no treatment; milrinone compared with iNO; milrinone as an adjunct to iNO compared with iNO alone; milrinone compared with potential treatments for PPHN other than iNO. SEARCH STRATEGY:We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2010), MEDLINE and EMBASE databases from their inception until January 2010. We searched the reference lists of potentially relevant studies without any language restriction. SELECTION CRITERIA:Fully published randomized controlled trials (RCTs) and quasi-RCTs comparing milrinone with placebo, iNO or potential treatments other than iNO in neonates with PPHN were included if trials reported any clinical outcome. DATA COLLECTION AND ANALYSIS:We found no studies meeting the criteria for inclusion in this review. MAIN RESULTS:We found no studies meeting the criteria for inclusion in this review. AUTHORS' CONCLUSIONS:The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs. Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or, in well resourced countries, should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone.

Dataset Information

Inhaled nitric oxide for neonates with persistent pulmonary hypertension of the newborn in the CINRGI study: time to treatment response.

Publications

Inhaled nitric oxide for neonates with persistent pulmonary hypertension of the newborn in the CINRGI study: time to treatment response.

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