Low-Dose Unfractionated Heparin Administration Inhibits Pulmonary Growth and Development

Background: Pulmonary hypoplasia (PH) is a major cause of morbidity and mortality in newborns with congenital diaphragmatic hernia (CDH). PH is characterized by immature pulmonary growth and development. Neonates with severe PH necessitating extracorporeal membrane oxygenation (ECMO) and therapeutic anticoagulation have mortality rates of nearly 50%. Previously, we demonstrated that following pneumonectomy, therapeutic or high-dose heparin administration significantly decreased compensatory lung growth and development. While only a minority of neonates with CDH-associated PH will require ECMO and therapeutic heparin, many will require central or peripheral venous access. Low-dose heparin infusions are commonly used to maintain line patency and reduce the risk of thrombus-related catheter dysfunction. Here, we investigated the effect of low-dose heparin administration on pulmonary growth and development in a compensatory lung growth model.

Methods: Eight-week old C57BL/6 mice received three doses of normal saline (control), low- (250U/kg), or high-dose (500U/kg) unfractionated heparin via intraperitoneal injections every twelve hours. Anti-factor Xa levels were determined from plasma drawn one hour after the last injection. In a separate study, C57BL/6 mice underwent unilateral pneumonectomy and received either daily control or low-dose heparin injections. On post-operative day eight, lung volume measurements, inspiratory capacity, and morphometrics were evaluated.

Results: Compared to controls, high-dose heparin administration significantly increased anti-factor Xa activity to therapeutic levels while low-dose heparin did not. Low-dose heparin significantly decreased lung volume, inspiratory capacity, alveolar volume, and septal surface area. Notably, low-dose heparin decreased alveolar capillary volume and increased mean septal thickness which may adversely affect efficient gas exchange.

Conclusions: Low-dose heparin administration significantly impaired pulmonary growth and development following pneumonectomy. This finding is concerning as many critically ill newborns will receive low-dose heparin infusions through central or peripheral venous catheters to maintain line patency. Therefore, heparin administration in neonates with CDH-associated PH or other hypoplastic lung disease may need reconsideration.