Developmental and Neuropathological Consequences of Ductal Ligation in the Preterm Baboon

Abstract

A patent ductus arteriosus (PDA) alters pulmonary mechanics and regional blood flow in the preterm infant. Its significance with respect to brain injury and brain development are unclear. We evaluated the effects of surgical ductal ligation on the preterm baboon brain. Baboons were delivered at 125 d of gestation (dg, term approximately 185 dg) and ventilated for 14 d (n ϭ 12). The PDA was ligated 6 d after delivery (n ϭ 7) or left untreated (n ϭ 5). Animals were euthanized at 139 dg and brains compared histologically with gestational control fetuses (n ϭ 7) at 140 dg. Brain and body weights were reduced (p Ͻ 0.05) in both groups of ventilated preterm animals; however, the brain to body weight ratio was increased (p Ͻ 0.01) in ligated, but not unligated newborns compared with gestational controls. No overt lesions were observed in either premature newborn group. Astrocyte density in the neocortex and hippocampus were greatest in the unligated newborns (p Ͻ 0.01). Myelination and oligodendrocytes were reduced (p Ͻ 0.05) in both premature newborn groups. The brain growth and development index was reduced, and the damage index was increased in prematurely delivered baboons. Surgical ligation of the PDA does not increase the incidence of brain injury and may be beneficial if the PDA is contributing to persistent pulmonary and hemodynamic instability. H emodynamic symptoms from a patent ductus arteriosus (PDA) are present in 55-70% of infants delivered below 1000 g or before 28 wk of gestation with the PDA resulting in increased pulmonary blood flow and redistribution of flow to other organs (1). However, the impact of the PDA on the brain remains uncertain. Current therapy for PDA includes medical therapy with indomethacin or ibuprofen and/or surgical ligation. There has been considerable debate about the benefits and risks of surgical ligation for PDA on subsequent neurodevelopmental outcome. Surgery in the neonatal period is associated with a systemic inflammatory response; in addition, the use of sedative and/or anesthetic drugs may adversely impact the immature brain (2). An increased incidence of neurosensory impairment has been observed among infants who underwent ductal ligation (3). On the other hand, in a single center study where infants received prophylactic Indocin and no infant was exposed to patency of the ductus arteriosus for more than 5-7 d, ductal ligation was not associated with abnormal neurodevelopmental outcome (4). No experimental studies have been done to try to answer the impact of ligating a PDA on the developing brain.The premature baboon, delivered at 125 d of gestation (dg; term approximately 185 dg), has a similar neonatal course to the premature human delivered between 26 and 27 wk of gestation: they both develop respiratory distress and fail to close their PDA after birth (5). In addition, despite antenatal glucocorticoids, surfactant treatment, total parenteral nutrition, low tidal volume ventilation, and low supplemental oxygen administration during the first 2 wk after de...

MR imaging correlates of white-matter pathology in a preterm baboon model

“…One of the cell types most vulnerable in the premature brain is the pre-oligodendrocyte. Previous investigations in this baboon model have shown reduced oligodendrocyte densities in preterm brains compared to gestational controls (29–31). In the present analysis, lower oligodendrocyte densities correlated with higher radial diffusivity, but not axial diffusivity.…”

“…After sacrifice, brains were removed, weighed and immersed in 4% paraformaldehyde in 0.1M phosphate buffer. Cerebral outcomes of specific ventilatory strategies in this preterm baboon model have been previously evaluated by histopathology (29,30,39,40) and will not be discussed here.…”

“…Histopathological analysis was performed at the University of Melbourne, Australia as published previously (29,30,39,40). Five-millimeter coronal blocks from the right forebrain were processed to paraffin, and 10 8-µm sections were cut from the rostral surface of each block.…”

Patent ductus arteriosus in the preterm infant: to treat or not to treat?

“…To investigate the effect of ligation on short-term brain development, preterm baboons were ventilated for 14 days, and on day 6, the ductus arteriosus was either ligated or left untreated. 58 The growth and developmental index scores were decreased in both the unligated and ligated groups compared with gestational-age matched controls. However, there was some evidence of brain growth sparing in the ligated group that was lacking in the unligated group.…”

Therapeutic strategies, including a high surgical ligation rate, for patent ductus arteriosus closure in extremely premature infants in a North American centre

“…As well, 2009 Vermont-Oxford data showed a mean ligation rate of 21% for all 24 to 26 weeks' gestational age infants. PDA ligation has its place in the management of a PDA (9,10,22), but defining those that need it and when it is best performed remain issues of much debate (23). In the present population, ligation was associated with a prolonged duration of mechanical ventilation and hospital stay in survivors, but trended toward a decrease in mortality.…”