Shadi Malaeb, John Grothusen, Ferit Tuzer, Maria Delivoria-Papadopoulos
Drexel University College of Medicine.
United States
Nitric Oxide
Nitric Oxide 2026;
DOI: 10.1016/j.niox.2026.07.003
Abstract
Background: Inhaled nitric oxide (iNO) is widely used as a pulmonary vasodilator to treat infants with pulmonary hypertension (PHN). Hypoxia (Hx) and acidosis increase pulmonary vascular resistance and contribute to PHN. Perinatal asphyxia and resultant hypoxic-ischemic encephalopathy (HIE) remain major causes of neonatal death and neurological impairment, and the impact of iNO on neurodevelopmental outcomes after HIE is unclear. Although hypothermia is the standard neuroprotective therapy for HIE, many infants still do not survive or continue to experience neurological impairments despite treatment. We investigated whether iNO improves survival and reduces brain injury after Hx in a neonatal piglet model.
Methods: Anesthetized, instrumented piglets (3-5 days old) were exposed to normoxic or hypoxic conditions for 1 h. After Hx, animals were either euthanized or reoxygenated with or without iNO (20 ppm) initiated within 10 min and continued for 4 h, while maintained at normothermia or hypothermia. Piglets were then euthanized for cortical analysis of ATP, lactate, HMGB1 (a marker of cell death), and water content using enzymatic assays, Western blotting, and drying methods, and results were compared with non-reoxygenated hypoxic animals, normoxic sham controls, and non-instrumented piglets.
Results: Treatment with iNO (20 ppm) starting 10 min after Hx improved survival. However, among surviving hypoxic piglets, iNO was associated with greater ATP depletion, increased cerebral lactic acidosis, more severe cerebral edema, and elevated HMGB1 expression compared with untreated hypoxic controls. Concurrent hypothermia did not mitigate these adverse effects.
Conclusion: iNO improved survival after Hx but was associated with worsened biochemical and cellular markers of brain injury, despite hypothermia.
Category
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Medical Therapy. Efficacy or Lack of Efficacy
Medical Therapy. Adverse Effects or Lack of Adverse Effects
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes