Effect of Ductus Ligation on Cardiopulmonary Function in Premature Baboons

Abstract

Although a patent ductus arteriosus (PDA) increases fluid and protein efflux from the pulmonary vasculature in preterm infants (1, 2), a compensatory increase in pulmonary lymph flow appears to prevent pulmonary edema during the first 72 h after delivery in both premature animals (3, 4) and humans (5). However, a symptomatic left-to-right ductus shunt that persists beyond the first week of life increases the likelihood of edema formation and respiratory compromise. Several studies (performed in the presurfactant era) found that, by 7 d after birth, a PDA can alter pulmonary mechanics (6-8). In addition, preterm infants with a PDA have increased ventilatory needs compared with infants whose PDA has been closed (6, 7, 9-12). Whether these alterations are due to increasing pulmonary edema or to more permanent histopathologic changes is currently unknown. Chronic pulmonary histopathologic changes consisting of alveolar simplification, fibrosis, and chronic inflammation frequently follow preterm birth (13). These changes, known as bronchopulmonary dysplasia (BPD), appear to be due to inflammatory and repair processes that interfere with normal lung development (14-17). Airway aspirates from infants that develop BPD contain proinflammatory cytokines (e.g., interleukin [IL] 6 and IL-8) during the first days after delivery (18), and ventilation of preterm animals initiates a similar inflammatory response (13,18). Although numerous studies have found an association between the presence of a PDA and development of BPD, there is little information suggesting a cause-and-effect relationship (19,20). Infants with a persistent PDA frequently require prolonged ventilatory support similar to infants with a more severe form of BPD; however, previous studies have failed to demonstrate consistent worsening in the radiographic features of BPD among infants with a persistent PDA (11,12,21). Studies to unravel the mechanisms responsible for the late pulmonary deterioration associated with a persistent PDA have been hampered by both the absence of randomized controlled clinical trials that address this question and by the absence of an appropriate animal model.The premature baboon (delivered at 125 d gestation; term ϭ 185 d) has a similar postnatal course as humans delivered between 25 and 27 wk of gestation. As in very-low-birthweight human infants, the ductus arteriosus of the premature baboon has only a 20 to 30% chance of closing spontaneously after birth (22). Despite surfactant treatment, low tidal volume breathing, and low supplemental oxygen administration, premature baboons develop pulmonary histopathologic changes during the first 2 wk after delivery that are similar to those described in premature human infants (13,23). The purpose of the present study was to examine the effectiveness of surgical ligation as a means of treating infants with a PDA by assessing its effects on cardiopulmonary function and the development of lung injury in mechanically ventilated premature baboons during the first 2 wk after delivery. We hypot...

Ductus Arteriosus Ligation and Alveolar Growth in Preterm Baboons With a Patent Ductus Arteriosus

“…Premature delivery and mechanical ventilation of preterm baboons have also been shown to increase proinflammatory cytokines/ chemokines (1,12,13). However, in studies we have previously reported, IL-6 and IL-8 expression did not seem to differ between control animals (with a PDA) and those with a surgically ligated ductus (14).…”

“…A complete description of the details of animal care and the surgical procedures have been published elsewhere (1,12,14) (see also online data supplement for Refs. 1,12,14). Briefly, timed pregnant baboon (Papio papio) dams were delivered at 125 Ϯ 1 d gestation (full term ϭ 185 d) and their newborns were mechanically ventilated for 14 d.…”

“…Findings in these study animals related to the clinical course, cardiovascular performance, and proinflammatory cytokines have been published elsewhere (14).…”

Postoperative cardiorespiratory instability following ligation of the preterm ductus arteriosus is related to early need for intervention

“…This study confirmed oxygenation failure in the first 72 h but an improvement in lung compliance and pulmonary hemodynamics 1 week after the procedure. 28 …”

Patent Ductus Arteriosus: Evidence for and against Treatment

“…Recent findings in premature baboons support the concept that surgical ligation may have a detrimental effect on lung function and growth. Although pharmacologic closure prevents the arrest in alveolar development caused by a PDA (19), no benefit on alveolar growth has been observed following surgical ligation (35,36).…”