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Observational Study
. 2025 Feb 3;8(2):e2458843.
doi: 10.1001/jamanetworkopen.2024.58843.

Response to Inhaled Nitric Oxide and Mortality Among Very Preterm Neonates With Pulmonary Hypertension

Michelle Baczynski  1 , Dany Weisz  2 , Laura Thomas  1 , Stephanie Fevrier  2 , Michael Castaldo  3 , Amuchou Soraisham  4 , Abbas Hyderi  5 , Rula Agarushi  5 , Soume Bhattacharya  6 , Renjini Lalitha  6 , Amneet Sidhu  7 , Muzafar Gani Abdul Wahab  7 , Gabriel Altit  8 , Audrey Hébert  9 , Deepak Louis  10 , Yasser Elsayed  11 , Souvik Mitra  12 , Poorva Deshpande  1 , Ashraf Kharrat  1 , Faith Zhu  1 , Joseph Ting  13 , Eugene Yoon  1 , Prakesh S Shah  1 , Amish Jain  1 ; Canadian Neonatal Network Investigators
Collaborators, Affiliations
Observational Study

Response to Inhaled Nitric Oxide and Mortality Among Very Preterm Neonates With Pulmonary Hypertension

Michelle Baczynski et al. JAMA Netw Open. .

Abstract

Importance: Clinical observations of immediate improvement in fraction of inspired oxygen (FiO2) in a proportion of cases is often cited as the rationale for using inhaled nitric oxide (iNO) in the management of acute pulmonary hypertension among very preterm neonates (gestational age, <32 weeks). However, the clinical effectiveness of such a response pattern remains underinvestigated.

Objective: To identify factors associated with predischarge mortality among very preterm neonates receiving iNO for acute pulmonary hypertension, with specific a priori emphasis on iNO responsiveness.

Design, setting, and participants: This prospective observational cohort study was conducted from January 1, 2018, to December 31, 2022, at 12 Canadian tertiary neonatal intensive care units. Consecutive very preterm neonates who received iNO for a diagnosis of acute pulmonary hypertension and pretreatment FiO2 of 0.50 or more were included. Neonates with congenital anomalies or those who were treated for chronic pulmonary hypertension with iNO were excluded. Early acute pulmonary hypertension (≤72 hours of age) and late acute pulmonary hypertension (>72 hours of age) cohorts were analyzed separately. Statistical analysis was performed from January 2023 to January 2024.

Exposure: Treatment with iNO for acute pulmonary hypertension.

Main outcomes and measures: The study cohorts were divided for comparison based on the primary outcome of predischarge mortality. Logistic regression analyses were used with predefined variables, including iNO responsiveness, to identify factors associated with mortality. A positive response to iNO was defined as a pre-iNO minus 4-hour post-iNO FiO2 of 0.20 or more.

Results: The early acute pulmonary hypertension group (mean [SD] birth gestational age, 26.3 [2.4] weeks; median treatment age, 1 day [IQR, 1-2 days]; 147 boys [56%]) included 262 neonates; 179 (68%) had a pre-iNO FiO2 of 1.0. The late acute pulmonary hypertension group (mean [SD] birth gestational age, 24.9 [1.7] weeks; median treatment age, 13 days [IQR, 9-20 days]; 72 boys [66%]) included 109 neonates; 51 (47%) had a pre-iNO FiO2 of 1.0. Neonates with early acute pulmonary hypertension more frequently had a positive iNO response (71% [186 of 262] vs 41% [45 of 109]) and lower mortality (34% [90 of 262] vs 49% [53 of 109]) than those with late acute pulmonary hypertension. Accounting for pretreatment illness factors, greater reduction in FiO2 with iNO remained associated with lower mortality for neonates with early acute pulmonary hypertension (adjusted odds ratio per FiO2 reduction of 0.10, 0.74 [95% CI, 0.65-0.84]). For those with late acute pulmonary hypertension, however, only pretreatment illness severity (lower pre-iNO FiO2 and higher pre-iNO pH), and not positive response to iNO (adjusted odds ratio, 0.47 [95% CI, 0.17-1.30]), was associated with mortality.

Conclusions and relevance: In this cohort study of very preterm neonates with acute pulmonary hypertension treated with iNO, responsiveness to iNO was associated with improved outcomes during the first 72 hours of age. The prognostic role of iNO response in acute pulmonary hypertension presenting after 72 hours of age remains unclear. Future studies should investigate the distinct pathophysiological mechanisms associated with late acute pulmonary hypertension in this population.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shah reported receiving grants from the Canadian Institutes of Health Research during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Inclusion Flowchart
Neonates had a gestational age of less than 32 weeks at birth. FiO2 indicates fraction of inspired oxygen; iNO, inhaled nitric oxide; and NICU, neonatal intensive care unit. aNine neonates had both early acute pulmonary hypertension and late acute pulmonary hypertension episodes and were included in both cohorts.
Figure 2.
Figure 2.. Kaplan-Meier Survival Curves Based on Inhaled Nitric Oxide (iNO) Responsiveness Among Neonates With Early and Late Acute Pulmonary Hypertension
Responsiveness was defined by a minimum reduction in fraction of inspired oxygen of 0.20 or more at 4 hours after initiation of iNO. Circles indicate censoring.
See this image and copyright information in PMC

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