Stable Control of Physiological Parameters, But Not Infection, in Preterm Lambs Maintained on Ex Vivo Uterine Environment Therapy

Abstract

Ex vivo uterine environment (EVE) therapy is an experimental neonatal intensive care strategy wherein gas exchange is performed by membranous oxygenators attached to the umbilical vessels. Our aim was to assess the ability of a newly refined EVE system to maintain key physiological parameters in preterm lambs within optimal ranges for 48 h. EVE group; n = 6: Preterm lambs were delivered under general anesthesia at 115 ± 2 days of gestational age. Animals were submerged in a bath of artificial amniotic fluid on EVE therapy for 48 h. Physiological parameters were monitored in real-time over the length of the experiment. Control group; n = 11: Ewes carrying a single fetus (115 ± 2 days of gestational age) underwent recovery surgery to allow placement of a fetal carotid artery catheter. Fetuses received an infusion of sterile saline only. After euthanasia, EVE and Control group fetuses underwent necroscopy to perform static pressure-volume curves and for sampling of lung and cord blood plasma for molecular analyses. Five out of six fetuses in the EVE group completed the study period with key physiological variables remaining within their respective reference ranges for the duration of the 48 h study. Bacteremia was identified in four out of five EVE fetuses, and was associated with a systemic inflammatory response. Using our refined EVE therapy platform, preterm lambs were maintained in a stable physiological condition for 48 h. These findings represent a significant advance over earlier work with this system; however, the identification of bacteremia and a fetal inflammatory response suggests that further refinement to the EVE therapy platform is required.

Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability

“…In previous reports based on our EVE system we demonstrated healthy fetal survival for a period of hours (h), and further extended that to 336 h in a subsequent set of unpublished experiments. [7][8][9][10] Other investigators have reported the successful application of artificial-placenta based therapies for up to h with similar concepts and extracorporeal gas exchange systems. [11][12][13][14] Accordingly, the feasibility of long survival with a pumpless extracorporeal system has been well documented in the experimental literature.…”

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“…In 2019, several groups have shown that important components of fetal physiology are maintained on artificial placental support and develop more naturally than in a ventilated newborn. Stable cardiovascular physiology has been shown both in short‐ and in long‐term experiments using a pumpless system . Even after longer term support, animals can be transitioned to normal care and maintain normal behaviour and mitochondrial respiration .…”

“…Stable cardiovascular physiology has been shown both in short-and in long-term experiments using a pumpless system. 54,55 Even after longer term support, animals can be transitioned to normal care 53 and maintain normal behaviour and mitochondrial respiration. 56 Previous experiments with a pump-driven system had already shown that fetal splenic development 57 and cerebral oxygenation can be maintained 58 and that white matter integrity is preserved with this type of life support.…”

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“…Thus, the artificial placenta may be characterized as an ex vivo uterine environment (EVE) wherein gas exchange is performed by membrane oxygenators attached to the umbilical vessels 88‐90 . Experimental use of a newly refined EVE system in five out of six preterm lambs showed maintenance of stable key physiological parameters within optimal ranges for 48 hours 90 .…”