Liquid Ventilation in the Management of Preterm Infants

Complications of prematurity consistently rank as the leading cause of death in children under the age of 5 and as the leading cause of death in infants in North America according to Liu et al. Lancet (2016); 388: 3027–35 and Callaghan et al. Pediatrics (2006);118: 1566–73. Despite advances in prenatal care, prematurity remains a persistent clinical problem, with 1 in 8 births occurring prematurely (prior to 37 weeks of gestation) in the USA as discussed by Frey and Klebanoff Semin Fetal Neonatal Med (2016);21: 68–73, . Advances in neonatology including gentle ventilation strategies, permissive hypercapnia, and the use of corticosteroids have led to substantial improvements in survival; however, long-term survivors of preterm birth face considerable morbidities affecting every major organ system. Chronic lung disease represents one of the most common and significant long-term complications of preterm birth and is attributable largely to iatrogenic injury due to the underdeveloped nature of the alveoli and lack of compliance of the immature lung as stated by Behrman and Butler (2007). Conventional gas-based ventilation of the premature lung leads to barotrauma, inflammation, respiratory distress syndrome (RDS), and bronchopulmonary dysplasia (BPD) as discussed by Sinha and Donn Semin Fetal Neonatal Med (2006);11: 166–73. Since the discovery of perfluorocarbons (PFCs) over 70 years ago, liquid ventilation has been examined as a viable alternative to conventional gas-based mechanical ventilation in a variety of disease models, including that of extreme prematurity. PFCs are biologically inert organofluorine compounds with remarkably high gas dissolving properties due to weak intermolecular attractive forces, allowing dissolution of up to twenty times the amount of oxygen and three times the amount of carbon dioxide than water as discussed by Wesseler, Iltis, and Clark J Fluor Chem. Elsevier Sequoia S.A (1977);9: 137–46. These compounds have low surface tension, have low viscosity, are relatively dense, and have low vapor pressure (11–85 torr), permitting rapid evaporation from the lungs. One perfluorocarbon liquid of particular clinical interest is perflubron, a PFC with a bromine substituted for a primary fluorine. This compound has been used as a contrast medium and is radiographically opaque, allowing clinicians to examine lung filling in real time according to the study of Kazerooni et al. Radiology (1962);198: 137–42 . Initial studies of liquid ventilation have shown increased gas exchange and alveoli recruitment, in addition to the return to fluid-filled physiology similar to that experienced during gestation, as discussed by Kylstram et al. Trans Am SOC Artif Intern Organs (1962;8: 378–83, Clark and Gollan (1966), and Schoenfisch Anid and Kylstra J Appl Physiol (1973);35: 117–21, leading to the identification of liquid ventilation as a promising intervention to support critically preterm infants. This review will summarize the history of clinical and translational research studies of liquid ventilation, with a focus on studies targeting prematurity, and will explore the areas requiring further study prior to widespread clinical implementation.