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A Piglet Model of Neonatal Hypoxic-Ischemic Encephalopathy
Published on: May 16, 2015
Inhaled nitric oxide and hypoxic brain injury in newborn piglets
Shadi Malaeb1, John Grothusen1, Ferit Tuzer2
1Department of Pediatrics, Division of Neonatology at Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
Insights
Inhaled nitric oxide (iNO) improved survival in piglets after hypoxia but worsened brain injury markers. Hypothermia did not alter these effects, suggesting caution when using iNO in neonatal hypoxic-ischemic encephalopathy.
Area of Science:
- Neonatal physiology
- Neuroprotection
- Cardiovascular research
Background:
- Inhaled nitric oxide (iNO) is a pulmonary vasodilator for neonatal pulmonary hypertension.
- Hypoxia and acidosis exacerbate pulmonary hypertension.
- Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity.
- The effect of iNO on neurodevelopmental outcomes in HIE is unknown.
- Hypothermia is standard HIE neuroprotection but has limitations.
Purpose of the Study:
- To investigate if iNO improves survival and reduces brain injury in a neonatal piglet model of hypoxia.
- To assess the impact of iNO on biochemical and cellular markers of brain injury.
Main Methods:
- Neonatal piglets were exposed to hypoxia (Hx) and treated with or without iNO (20 ppm) during reoxygenation.
- Animals were maintained at normothermia or hypothermia.
- Cortical tissue was analyzed for ATP, lactate, HMGB1 (cell death marker), and water content.
Main Results:
- iNO treatment improved survival after hypoxia.
- However, surviving piglets showed increased ATP depletion, cerebral lactic acidosis, edema, and HMGB1 levels with iNO.
- Hypothermia did not mitigate these adverse effects of iNO on brain injury markers.
Conclusions:
- iNO improved survival following hypoxia in neonatal piglets.
- iNO was associated with exacerbated biochemical and cellular indicators of brain injury.
- These findings highlight potential risks of iNO in HIE, even with hypothermia.
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.
