The Fetal Lamb Model of Congenital Diaphragmatic Hernia Shows Altered Cerebral Perfusion Using Contrast Enhanced Ultrasound

Background: Children born with congenital diaphragmatic hernia (CDH) are more likely to have neurodevelopmental impairment and delay irrespective of the need for extracorporeal membrane oxygenation. Compression on the heart and disruption of the normal fetal left ventricular cardiac output in fetal CDH have been speculated to alter cerebral perfusion in utero as shown with middle cerebral artery (MCA) doppler findings. Our study was aimed to assess whether the fetal lamb model of CDH has altered cerebral perfusion by contrast enhanced ultrasound (CEUS).

Methods: Left-sided CDH was surgically created in 5 fetal lambs at 70-78 days gestational age (GA). At 135-141 GA (term = 145 GA), after the maternal uterus was delivered through midline laparotomy, CDH fetuses and 5 age matched controls underwent MCA and umbilical artery (UA) doppler measurements as well as CEUS of the whole brain (Figure 1). MCA and UA pulsatility indexes (PIs) and resistive indexes (RIs), cerebroplacental ratios (CPR), and CEUS perfusion parameters including flux rate, transit time, and perfusion of the whole were compared between groups. Fetal brain, heart, lung, and body weights were measured at necropsy. Data were compared using Welch’s t-tests or Mann Whitney-U tests, as appropriate.

Results: There was no statistical difference in MCA and UA Doppler indices or CPR, although CDH fetuses trended towards lower measurements for each (data not shown). There was no difference in brain weight/body weight (0.98% CDH vs 0.98% control, p=0.49). There was a significant difference in lung weight/body weight (1.49 ± 0.42% vs 2.68 ± 0.22%) and heart weight/body weight (0.62 ± 0.02% vs 0.67 ± 0.04%) (both p<0.02). Brain perfusion parameters between groups with CDH animal demonstrated significantly decreased flux rate, increased transit time, and decreased global perfusion (p < 0.05; Figure 2).

Conclusion: The fetal lamb model of CDH shows significantly altered cerebral perfusion as measured by CEUS, with significantly lower heart/body weight and lung/body weight ratios. This suggests a physiological abnormality in fetal cerebrovascular perfusion in CDH, possibly explained by abnormal left sided cardiac output and decreased cerebral capillary density. These findings could contribute to abnormal fetal cerebrovascular development and predispose patients with CDH to neurodevelopmental impairment. Furthermore, CEUS appears to offer more sensitive detection of brain perfusion abnormalities than MCA doppler measurements.