Early respiratory dysfunction and later brain injury: double jeopardy?

Bronchopulmonary dysplasia (BPD) is the most common complication associated with prematurity and is more prevalent in extremely premature infants.¹ Due to advances in neonatal care, more extremely premature infants are surviving leading to new management challenges and the need to investigate mechanisms and risk factors influencing both short- and long-term morbidity associated with BPD.² One major morbidity associated with BPD is neurodevelopmental impairment, which is often accompanied by white matter injury (WMI). Infants with BPD may have impairment in cognition, education, and behavior.^3,4 BPD has been associated with cerebral palsy (CP) in infants born extremely preterm who continue to require both supplemental oxygen and mechanical ventilation at 36 weeks postmenstrual age (PMA).⁵ Independently, WMI may predict cognitive and motor outcomes in preschool-age children born preterm. Clinical variables, including BPD, enhance the predictive strength for cognitive and motor outcomes in these children.⁶ Prolonged duration of mechanical ventilation is associated with smaller brainstem volumes along with white matter abnormalities.⁷ Smaller pons and medulla volumes predict adverse motor outcomes at preschool age.^7,8

BPD is a consistent and strong independent risk factor for neurodevelopmental impairment and studies have investigated the effect of prolonged invasive ventilation in neonates with BPD. Increased time requiring invasive respiratory support has been associated with greater adverse neurodevelopmental impairment, leading to the development of treatment strategies that decrease invasive mechanical ventilation exposure.^9,10 Unfortunately, due to significant lung disease and respiratory dysfunction, many neonates would not survive without this higher level of support and require mechanical ventilation to provide adequate oxygenation and ventilation. Identifying potentially useful biomarkers or modifiable exposures during the patient’s need for mechanical ventilation may help mitigate severe lung injury and optimize neurodevelopment. Optimal evaluation of the roles of early respiratory support exposures on later neurodevelopmental outcomes in children with BPD is challenging. Infants with BPD who require prolonged respiratory support are more likely to be exposed to sedation and systemic corticosteroids, both associated with neurodevelopmental impairment. The chronicity of the exposures and the condition makes it challenging to assess the timing of the insult, and whether the exposure becomes an outcome in itself (infants who need more respiratory support tend to need it longer too). In addition to causing direct mechanical and oxidative lung injury, prolonged mechanical ventilation and other morbidities that are associated with BPD, such as chorioamnionitis, neonatal sepsis, and necrotizing enterocolitis (NEC), may further complicate causal pathways between BPD and brain injury. These comorbidities can aggravate lung injury through mechanical factors (due to greater and/or longer need for mechanical ventilation) or biologic alterations related to the generation of systemic inflammation, which has been linked to brain injury in premature neonates. Further exploration of the association between these pro-inflammatory conditions and brain injury may help identify other additional opportunities.

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