Technical feasibility of umbilical cannulation in midgestation lambs supported by the EXTra‐uterine Environment for Neonatal Development (EXTEND)

Abstract

EXTEND (EXTra‐uterine Environment for Neonatal Development) is a novel system for supporting extremely premature infants that replicates in utero conditions by maintaining a sterile fluid environment and providing gas exchange via a pumpless arteriovenous oxygenator circuit connected to the umbilical vessels. Target gestational age (GA) for EXTEND support in human infants is 23‐27 weeks, when immature lungs are most susceptible to injury in the setting of air ventilation. We previously demonstrated physiologic support of premature lambs cannulated at 105‐117 days GA (lungs developmentally analogous to the 23‐27 week GA human infant) for up to 28 days on EXTEND. In the present study, we sought to determine the technical feasibility of umbilical vessel cannulation in 85‐96 days GA lambs delivered to EXTEND at weights equivalent to the 23‐27 week GA human infant (500‐850 g). Five preterm lambs were cannulated at 85‐96 days GA (term 145 days) and supported on EXTEND for 4‐7 days. All lambs underwent umbilical artery and umbilical vein cannulation. Circuit flows and pressures were monitored continuously, and blood gases were obtained at regular intervals for assessment of oxygen parameters. Systemic pH and lactate were measured at least once daily. Mean body weight at cannulation was 641 ± 71 g (range 480‐850 g). All lambs were cannulated successfully (cannula size varied from 8 to 12 Fr), and mean survival on EXTEND was 140 ± 7 hours. Mean circuit flow was 213 ± 15 mL/kg*min, mean pH was 7.37 ± 0.01, and mean lactate was 1.6 ± 0.2 mmol/L. During the initial 120 hours after EXTEND cannulation, there were no significant differences between 85‐96 days GA lambs and 105‐117 days GA lambs in weight‐adjusted circuit flows, oxygen delivery, pH, or lactate levels. This study demonstrates successful umbilical cord cannulation and adequate circuit flows and oxygen delivery in midgestation lambs size‐matched to the 23‐27 week GA human fetus, which represents an important step in the translation of EXTEND to clinical practice.

Artificial placenta and womb technology: Past, current, and future challenges towards clinical translation

“…The lambs used in those experiments, although developmentally equivalent from the perspective of lung development (Figure 1), are considerably larger (1.0‐2.0 kg) than EPIs at the border of viability (<1.0 kg) 109,118 . To address this discrepancy, the group cannulated size equivalent but developmentally far less mature lambs of 85 to 95 days' GA, weighing 0.48 to 0.85 kg 119 . Although umbilical cannulation was technically feasible, circuit flows were supraphysiologic (300‐350 mL/min/kg) which resulted in refractory hydrops limiting survival on circuit to 5 to 8 days.…”

“…size equivalent but developmentally far less mature lambs of 85 to 95 days' GA, weighing 0.48 to 0.85 kg 119. Although umbilical cannulation was technically feasible, circuit flows were supraphysiologic (300-350 mL/min/kg) which resulted in refractory hydrops limiting survival on circuit to 5 to 8 days.…”

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

“…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 ]. Given these significant advances, clinical translation may be on the horizon; however, significant hurdles remain, including the consistent recovery of animals after long-term artificial placenta support, reliable cannulation of 500 g animals with adequate support, infrastructure development within hospitals, and patient risk stratification.…”

Artificial Organs 2019: A year in review

“…Matthew A. Hornick et al of the Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA, USA investigated the technical feasibility of umbilical cannulation in 85‐96 day gestational age (GA) (mid‐gestation) lambs supported by EXTra‐uterine Environment for Neonatal Development (EXTEND). Five preterm lambs were cannulated (term 145 days) and supported on EXTEND for 4‐7 days.…”