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Ex-Vivo Uterine Environment (EVE) Therapy Induced Limited Fetal Inflammation in a Premature Lamb Model.

Miura Y, Saito M, Usuda H, Woodward E, Rittenschober-Böhm J, Kannan PS, Musk GC, Matsuda T, Newnham JP, Kemp MW - PLoS ONE (2015)

Bottom Line: Meanwhile, elevations in fetal inflammation are associated with adverse neonatal outcomes.There was no significant difference (p>0.05) in surfactant protein mRNA expression level between the two groups.Despite this, EVE therapy only induced a modest fetal inflammatory response and did not promote lung maturation.

View Article: PubMed Central - PubMed

Affiliation: School of Women's and Infants' Health, The University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan.

ABSTRACT

Introduction: Ex-vivo uterine environment (EVE) therapy uses an artificial placenta to provide gas exchange and nutrient delivery to a fetus submerged in an amniotic fluid bath. Development of EVE may allow us to treat very premature neonates without mechanical ventilation. Meanwhile, elevations in fetal inflammation are associated with adverse neonatal outcomes. In the present study, we analysed fetal survival, inflammation and pulmonary maturation in preterm lambs maintained on EVE therapy using a parallelised umbilical circuit system with a low priming volume.

Methods: Ewes underwent surgical delivery at 115 days of gestation (term is 150 days), and fetuses were transferred to EVE therapy (EVE group; n = 5). Physiological parameters were continuously monitored; fetal blood samples were intermittently obtained to assess wellbeing and targeted to reference range values for 2 days. Age-matched animals (Control group; n = 6) were surgically delivered at 117 days of gestation. Fetal blood and tissue samples were analysed and compared between the two groups.

Results: Fetal survival time in the EVE group was 27.0 ± 15.5 (group mean ± SD) hours. Only one fetus completed the pre-determined study period with optimal physiological parameters, while the other 4 animals demonstrated physiological deterioration or death prior to the pre-determined study end point. Significant elevations (p<0.05) in: i) inflammatory proteins in fetal plasma; ii) selected cytokine/chemokine mRNA expression levels in fetal tissues; and iii) histological inflammatory score in fetal lung, were observed in the EVE group compared to the Control group. There was no significant difference (p>0.05) in surfactant protein mRNA expression level between the two groups.

Conclusion: In this study, we achieved limited fetal survival using EVE therapy. Despite this, EVE therapy only induced a modest fetal inflammatory response and did not promote lung maturation. These data provide additional insight into markers of treatment efficacy for the assessment of future studies.

No MeSH data available.


Related in: MedlinePlus

Changes in fetal parameters over time in EVE group.The horizontal axes represent the time after induction of EVE therapy (hours). The grey dotted lines show mean arterial pressure (mm Hg), the grey solid lines show total circuit blood flow (mL·kg-1·min-1), the black dotted lines show arterial oxygen saturation (%), and the diamonds show blood lactate level (mmol/L). Only the blood lactate levels use the right scale bars. Individual case information is as follows: A) The blood lactate level started to elevate at 19 hours, and continued increasing although other parameters kept stable. Congestive heart failure resulted in a sudden drop of circuit blood flow at 24 hours and euthanasia. B) All the parameters remained within the reference range after stabilisation; however the circuit corrupted (embolism of artificial amniotic fluid) at 12.5 hours, resulting in euthanasia. C) All the parameters remained within the reference range before sudden fatal arrhythmia occurred at 12.5 hours, resulting in euthanasia. D) One membranous oxygenator was blocked with a blood clot at 23 hours (arrow). Despite gradual fetal deterioration including increased the blood lactate levels and decreased circuit blood flow, the fetus completed the pre-determined 40-hour study period. E) Although some fluctuations of parameters were observed in the former period, the fetus completed the pre-determined 40-hour study period with stable physiological parameters.
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pone.0140701.g002: Changes in fetal parameters over time in EVE group.The horizontal axes represent the time after induction of EVE therapy (hours). The grey dotted lines show mean arterial pressure (mm Hg), the grey solid lines show total circuit blood flow (mL·kg-1·min-1), the black dotted lines show arterial oxygen saturation (%), and the diamonds show blood lactate level (mmol/L). Only the blood lactate levels use the right scale bars. Individual case information is as follows: A) The blood lactate level started to elevate at 19 hours, and continued increasing although other parameters kept stable. Congestive heart failure resulted in a sudden drop of circuit blood flow at 24 hours and euthanasia. B) All the parameters remained within the reference range after stabilisation; however the circuit corrupted (embolism of artificial amniotic fluid) at 12.5 hours, resulting in euthanasia. C) All the parameters remained within the reference range before sudden fatal arrhythmia occurred at 12.5 hours, resulting in euthanasia. D) One membranous oxygenator was blocked with a blood clot at 23 hours (arrow). Despite gradual fetal deterioration including increased the blood lactate levels and decreased circuit blood flow, the fetus completed the pre-determined 40-hour study period. E) Although some fluctuations of parameters were observed in the former period, the fetus completed the pre-determined 40-hour study period with stable physiological parameters.

Mentions: Fig 2 shows changes in mean arterial pressure, circuit blood flow, arterial oxygen saturation, and blood lactate levels after induction of EVE therapy from fetuses euthanised prior to 40 hours EVE therapy due to irreversible deterioration of circuit blood flow (Fig 2A–2C) and fetuses that completed pre-determined 40 hours under EVE therapy (Fig 2D and 2E).


Ex-Vivo Uterine Environment (EVE) Therapy Induced Limited Fetal Inflammation in a Premature Lamb Model.

Miura Y, Saito M, Usuda H, Woodward E, Rittenschober-Böhm J, Kannan PS, Musk GC, Matsuda T, Newnham JP, Kemp MW - PLoS ONE (2015)

Changes in fetal parameters over time in EVE group.The horizontal axes represent the time after induction of EVE therapy (hours). The grey dotted lines show mean arterial pressure (mm Hg), the grey solid lines show total circuit blood flow (mL·kg-1·min-1), the black dotted lines show arterial oxygen saturation (%), and the diamonds show blood lactate level (mmol/L). Only the blood lactate levels use the right scale bars. Individual case information is as follows: A) The blood lactate level started to elevate at 19 hours, and continued increasing although other parameters kept stable. Congestive heart failure resulted in a sudden drop of circuit blood flow at 24 hours and euthanasia. B) All the parameters remained within the reference range after stabilisation; however the circuit corrupted (embolism of artificial amniotic fluid) at 12.5 hours, resulting in euthanasia. C) All the parameters remained within the reference range before sudden fatal arrhythmia occurred at 12.5 hours, resulting in euthanasia. D) One membranous oxygenator was blocked with a blood clot at 23 hours (arrow). Despite gradual fetal deterioration including increased the blood lactate levels and decreased circuit blood flow, the fetus completed the pre-determined 40-hour study period. E) Although some fluctuations of parameters were observed in the former period, the fetus completed the pre-determined 40-hour study period with stable physiological parameters.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608829&req=5

pone.0140701.g002: Changes in fetal parameters over time in EVE group.The horizontal axes represent the time after induction of EVE therapy (hours). The grey dotted lines show mean arterial pressure (mm Hg), the grey solid lines show total circuit blood flow (mL·kg-1·min-1), the black dotted lines show arterial oxygen saturation (%), and the diamonds show blood lactate level (mmol/L). Only the blood lactate levels use the right scale bars. Individual case information is as follows: A) The blood lactate level started to elevate at 19 hours, and continued increasing although other parameters kept stable. Congestive heart failure resulted in a sudden drop of circuit blood flow at 24 hours and euthanasia. B) All the parameters remained within the reference range after stabilisation; however the circuit corrupted (embolism of artificial amniotic fluid) at 12.5 hours, resulting in euthanasia. C) All the parameters remained within the reference range before sudden fatal arrhythmia occurred at 12.5 hours, resulting in euthanasia. D) One membranous oxygenator was blocked with a blood clot at 23 hours (arrow). Despite gradual fetal deterioration including increased the blood lactate levels and decreased circuit blood flow, the fetus completed the pre-determined 40-hour study period. E) Although some fluctuations of parameters were observed in the former period, the fetus completed the pre-determined 40-hour study period with stable physiological parameters.
Mentions: Fig 2 shows changes in mean arterial pressure, circuit blood flow, arterial oxygen saturation, and blood lactate levels after induction of EVE therapy from fetuses euthanised prior to 40 hours EVE therapy due to irreversible deterioration of circuit blood flow (Fig 2A–2C) and fetuses that completed pre-determined 40 hours under EVE therapy (Fig 2D and 2E).

Bottom Line: Meanwhile, elevations in fetal inflammation are associated with adverse neonatal outcomes.There was no significant difference (p>0.05) in surfactant protein mRNA expression level between the two groups.Despite this, EVE therapy only induced a modest fetal inflammatory response and did not promote lung maturation.

View Article: PubMed Central - PubMed

Affiliation: School of Women's and Infants' Health, The University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan.

ABSTRACT

Introduction: Ex-vivo uterine environment (EVE) therapy uses an artificial placenta to provide gas exchange and nutrient delivery to a fetus submerged in an amniotic fluid bath. Development of EVE may allow us to treat very premature neonates without mechanical ventilation. Meanwhile, elevations in fetal inflammation are associated with adverse neonatal outcomes. In the present study, we analysed fetal survival, inflammation and pulmonary maturation in preterm lambs maintained on EVE therapy using a parallelised umbilical circuit system with a low priming volume.

Methods: Ewes underwent surgical delivery at 115 days of gestation (term is 150 days), and fetuses were transferred to EVE therapy (EVE group; n = 5). Physiological parameters were continuously monitored; fetal blood samples were intermittently obtained to assess wellbeing and targeted to reference range values for 2 days. Age-matched animals (Control group; n = 6) were surgically delivered at 117 days of gestation. Fetal blood and tissue samples were analysed and compared between the two groups.

Results: Fetal survival time in the EVE group was 27.0 ± 15.5 (group mean ± SD) hours. Only one fetus completed the pre-determined study period with optimal physiological parameters, while the other 4 animals demonstrated physiological deterioration or death prior to the pre-determined study end point. Significant elevations (p<0.05) in: i) inflammatory proteins in fetal plasma; ii) selected cytokine/chemokine mRNA expression levels in fetal tissues; and iii) histological inflammatory score in fetal lung, were observed in the EVE group compared to the Control group. There was no significant difference (p>0.05) in surfactant protein mRNA expression level between the two groups.

Conclusion: In this study, we achieved limited fetal survival using EVE therapy. Despite this, EVE therapy only induced a modest fetal inflammatory response and did not promote lung maturation. These data provide additional insight into markers of treatment efficacy for the assessment of future studies.

No MeSH data available.


Related in: MedlinePlus