Perfluorocarbons Prevent Lung Injury and Promote Development during Artificial Placenta Support in Extremely Premature Lambs

Abstract

Background: Extremely premature neonates suffer high morbidity and mortality. An artificial placenta (AP) using extracorporeal life support (ECLS) is a promising therapy. Objectives: We hypothesized that intratracheal perfluorocarbon (PFC) instillation during AP support would reduce lung injury and promote lung development relative to intratracheal amniotic fluid or crystalloid. Methods: Lambs at an estimated gestational age (EGA) 116–121 days (term 145 days) were placed on venovenous ECLS with jugular drainage and umbilical vein reinfusion and intubated. Airways were managed by the instillation of amniotic fluid and tracheal occlusion (TO; n = 4), or lactated Ringer’s (LR; n = 4) or perfluorodecalin (a PFC) without occlusion (n = 4). After 7 days, the animals were sacrificed. Early (EGA 116–121 days) and late (EGA 125–131 days) tissue control lambs were delivered and sacrificed. Lungs were formalin-inflated to 30 cm H₂O and sectioned for histology. Injury was scored by an unbiased pathologist. Slides were immunostained for PDGFR-α and α-actin; development was quantified by the area fraction of double-positive tips. Surfactant protein-C (SP-C) concentration in bronchoalveolar lavage fluid was quantified using ELISA. Results: Total injury scores were lower in PFC lungs (1.8 ± 1.7) than in TO (6.5 ± 2.1; p = 0.01) and LR lungs (5.5 ± 2.4; p = 0.01). The area fraction of double-positive alveolar tips appeared higher in PFC lungs than in TO lungs (0.18 ± 0.007 vs. 0.008 ± 0.004; p = 0.07). SP-C concentration was higher in PFC lungs than in TO lungs (37.9 ± 7.6 vs. 20.0 ± 5.4 pg/mL; p = 0.005), and both early (12.4 ± 1.7 g/mL; p = 0.007) and late tissue control lungs (15.1 ± 5.0 pg/mL; p = 0.0008). Conclusion: During AP support, intratracheal PFC prevents lung injury and promotes normal lung development better than crystalloid or amniotic fluid with TO.

Achieving sustained extrauterine life: Challenges of an artificial placenta in fetal pigs as a model of the preterm human fetus

“…The concept of an artificial placenta (AP), whereby gas exchange is achieved using an extracorporeal membrane oxygenator (ECMO) connected to the fetal circulation via the umbilical vessels has been investigated since the 1950s (Westin et al, 1958). Recent research has established the feasibility of AP support of preterm sheep for periods of up to a month using a pumpless ECMO circuit (Arens et al, 2011; Church, Coughlin, et al, 2018; Church, Perkins, et al, 2018; Church, Werner, et al, 2018; El‐Sabbagh et al, 2018; Gray et al, 2013; Hornick et al, 2018; Lawrence et al, 2018; Miura et al, 2012, 2015, 2016; Partridge, Davey, Hornick, McGovern, et al, 2017; Reoma et al, 2009; Rochow et al, 2013; Schoberer et al, 2014; Usuda et al, 2017, 2019; Westin et al, 1958; Zapol et al, 1969). Importantly, two groups have provided evidence of near‐normal fetal growth and development using this approach without any of the typical organ injury associated with preterm birth (Hornick et al, 2018; Partridge, Davey, Hornick, McGovern, et al, 2017; Usuda et al, 2017, 2019).…”

“…Despite these successes, there are some limitations of the preterm sheep as a model for the extremely preterm human infant. Importantly, extremely preterm human fetuses during their canalicular phase of lung development are 500–750 g (Kiserud et al, 2018), while the smallest sheep used in AP studies are twice that size (~1.0 kg) (Arens et al, 2011; Church, Coughlin, et al, 2018; Church, Perkins, et al, 2018; Church, Werner, et al, 2018; El‐Sabbagh et al, 2018; Gray et al, 2013; Hornick et al, 2018; Lawrence et al, 2018; Miura et al, 2012, 2015, 2016; Partridge, Davey, Hornick, McGovern, et al, 2017; Reoma et al, 2009; Rochow et al, 2013; Schoberer et al, 2014; Usuda et al, 2017; Westin et al, 1958; Zapol et al, 1969). Fetal size is associated with hemodynamic factors such as umbilical vessel caliber and blood pressure that are important for ECMO support (Rafat & Schaible, 2019; Tanaka et al, 2019).…”

Pediatric and neonatal extracorporeal life support: current state and continuing evolution

“…This system could be applied after birth to infants failing maximal medical therapy or preemptively after proper risk stratification. Many systems in development have been shown to provide adequate respiratory support for a developing fetus and promote largely normal development of lungs [ 44 , 46 , 47 ], brain [ 48 , 49 ], spleen [ 50 ], and intestine [ 51 , 52 ]. Early efforts at miniaturization of the circuit to support animals weighing 500–800 g—comparable in size but more physiologically premature than ELGANs—have been promising but require further refinement [ 53 , 54 ].…”

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

“…Disturbances to alveolar development (97) and altered pulmonary vascular mechanics, including pulmonary hypertension (288), and cardiac performance (514) are also known to occur in uteroplacental insufficiency (549) and the resultant intrauterine growth restriction (IUGR). Notable recent developments include the first data describing the utility of placenta support using an artificial placenta to protect lungs from injury and facilitate lung development during extracorporeal life support (92). An inflammatory component has recently been identified in IUGR: the neuropeptide Y (NPY)/IL-6 axis, which was suggested to underlie alveolar simplification associated with IUGR that resulted from maternal isocaloric low protein diet (578).…”

“…Studies have also been performed in animal models other than the mouse-based models, such as maternal intravenous melatonin infusion in a fetal lamb placental insufficiency and growth restriction model, where chronic fetal growth restriction disrupted secondary septation, and melatonin administration did not impact the disrupted secondary septation (466). Remaining with lambs, intratracheal administration of perfluorocarbons such as perfluordecalin prevented lung injury and promoted lung development during artificial placenta support in extremely preterm lambs (92).…”