357 - Oxygenation Response to iNO Does Not Correspond with Significant Pulmonary Vascular Change in PPHN Lambs with HIE

Publication Number: 1341.357

Evan Maher, University of California, Davis, School of Medicine, Woodland, CA, United States; Deepika Sankaran, University of California Davis Children's Hospital, Sacramento, CA, United States; Payam Vali, University of California, Davis, School of Medicine, sacramento, CA, United States; Evan M. Giusto, UC Davis Health, Sacramento, CA, United States; Sylvia Bowditch, University of California Davis Children's Hospital, Sacramento, CA, United States; Rebecca Valdez, University of California Davis Children's Hospital, Sacramento, CA, United States; Victoria Hammitt, UC Davis Stem Cell Research, Davis, CA, United States; Amy Lesneski, UC Davis, Davis, CA, United States; Jocelyn Livezey, University of California, Davis, School of Medicine, Davis, CA, United States; Xiaohan Li, University of California, Davis, School of Medicine, Davis, CA, United States; Satyan Lakshminrusimha, UC Davis, Sacramento, CA, United States; Michelle J. Lim, University of California, Davis, School of Medicine, Sacramento, CA, United States

Background: Persistent pulmonary hypertension of the newborn (PPHN) is commonly associated with meconium aspiration (MAS) and hypoxic-ischemic encephalopathy (HIE). Therapeutic cooling improves neurologic outcomes but may worsen PPHN pathophysiology. Inhaled nitric oxide (iNO) is the only FDA approved pulmonary vasodilator in PPHN. Randomized trials evaluating iNO define clinical response as an increase in PaO2/FiO2 ratio of ≥ 20, with minimal attention paid to hemodynamic response.

Objective: To identify factors that influence iNO responsiveness in a novel lamb model of perinatal asphyxia, therapeutic hypothermia, and PPHN secondary to meconium aspiration.

Design/Methods: Fetal lambs were asphyxiated by umbilical cord occlusion for 5 minutes or until heart rate fell below 40 bpm, with simultaneous endotracheal instillation of 5 mL/kg of 20% meconium to model meconium aspiration syndrome. After a 2-minute recovery, a second 5-minute occlusion was performed and delivered. Following birth, lambs were ventilated to target 91-98% SpO₂ targets and treated with therapeutic hypothermia (33.5 °C) to simulate clinical conditions of HIE. Inhaled nitric oxide (iNO, 20 ppm) was then administered, and lambs were stratified as clinical responders if PaO₂/FiO₂ increased by ≥20 or non-responders if < 20 mmHg change, following iNO initiation.

Results: 19 lambs were included in the analysis and baseline fetal characteristics are shown in Figure 1. Mean PVR decreased from 1.08 ± 0.52 to 0.82 ± 0.41 mmHg/mL/min (−24.2 ± 13.0%, p = 0.001), while left pulmonary blood flow increased from 68.5 ± 25.3 to 78.7 ± 31.8 mL/min (+14.9 ± 21.7%, p = 0.04). No significant relationship was observed between changes in fetal oxygenation (P/F ratio) and PVR (Figure 2). Responders showed higher P/F ratios than non-responders, but PVR changes from baseline were similar (Figure 3). Responder status did not differ by gestational age (50% vs. 66%, p = 0.81).

Conclusion(s): Classification of subjects as responders and non-responders to iNO exclusively based on oxygenation response does not directly correlate with changes in pulmonary hemodynamics. The observed discordance between PVR reduction and oxygenation parameter improvement suggests the microselective effect of iNO (increase perfusion to ventilated alveoli) may partially impact oxygenation without direct proportional changes to pulmonary pressure. A combined outcome that includes hemodynamics and oxygenation is critical in clinical and preclinical settings to accurately assess iNO response.

Baseline Characteristics of the Lambs
Baseline characteristics of all the lambs. Baseline physiological parameters are presented as mean ± standard deviation. 


Relationship of Oxygenation and PVR following iNO
Percent change in oxygenation (P/F ratio) from baseline after inhaled nitric oxide (iNO) initiation is plotted against the corresponding percent change in pulmonary vascular resistance (PVR). No significant correlation was observed between oxygenation response and PVR change.  Correlation coefficient (r) was determined by Spearman method. PVR; pulmonary vascular resistance. iNO; inhaled nitric oxide.  

PVR and P/F Pre and Post iNO
Changes in PVR and P/F ratio before and after iNO therapy in responders and nonresponders. Responders showed significant increases in P/F ratio and decreases in PVR after iNO, whereas nonresponders had a significant PVR decrease without corresponding P/F improvement. P/F ratio improvement differed significantly between groups, while PVR response was similar. *p < 0.05, **p < 0.01. iNO: inhaled nitric oxide; PVR: pulmonary vascular resistance.  iNO; inhaled nitric oxide. PVR; pulmonary vascular resistance.