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

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.

Attenuation of ductus arteriosus intimal thickening in preterm sheep twins compared with singletons.

Preterm twins have a higher morbidity rate of patent ductus arteriosus (PDA) than do singletons. However, the effect of multiple births on maturation of the ductus arteriosus (DA) has not been reported. Because intimal thickening (IT) is required for DA anatomical closure, we examined IT development in the DA of preterm twins and singletons. Sheep DA tissues obtained from preterm fetuses were subjected to elastica van Gieson staining to evaluate IT. The total IT score in each DA was the sum of the IT scores obtained from six evenly divided parts of the DA, which was positively correlated with gestational ages in singletons. Total IT scores were smaller in preterm twins than in singletons, although no difference in gestational age, birth weight, or gender ratio was observed. These data suggest that IT development of the DA is attenuated in sheep preterm twins, which may affect the higher morbidity of PDA.

Potential Role of Prenatal Inflammation in the Impairment of Lung Development Following Mechanical Ventilation of Preterm Lambs.

BACKGROUND: Our objective was to determine the effects of severe fetal inflammation, associated with an increase in the number and activation state of fetal polymorphonuclear leukocytes (PMNLs), on postnatal lung development in mechanically ventilated preterm lambs. METHODS: Four groups of preterm fetal sheep (0.85 term) were surgically prepared: (1) a granulocyte-colony stimulating factor (GCSF) group received intravenous GCSF to increase fetal PMNL count, (2) a lipopolysaccharide (LPS) group received intra-amniotic LPS to activate the fetal PMNLs, (3) a GCSF + LPS group received both GCSF and LPS, and (4) a control group received saline. After 10-day mechanical ventilation following preterm delivery, the lungs were examined histologically and analyzed morphometrically. RESULTS: Compared to the control group, the GCSF + LPS group exhibited necrotizing funisitis, lower surface density of alveolar walls, lower numerical density of alveoli, greater alveolar radius, and lower volume density of secondary septal crests (all P < .05). There was no evidence of tissue destruction, or elastin fragmentation or thick deposits of elastin, in the alveolar walls in any of the 4 groups. CONCLUSION: The mechanical ventilation following severe prenatal inflammation did not lead to overt lung injury or degradation of elastin but resulted in arrested alveolarization in the lungs of preterm lambs.

Surgical Ligation for Patent Ductus Arteriosus in Extremely Premature Infants: Strategy to Reduce their Risk of Neurodevelopmental Impairment.

Surgical ligation for patent ductus arteriosus (PDA) in extremely low birth weight infants (ELBWIs) has been shown a possible association with neurodevelopmental impairment (NDI) because of its invasiveness. However, we have undergone surgical ligation for ELBWIs immediately after cyclooxygenase inhibitor failed to close a hemodynamically significant PDA (hsPDA) to maintain proper systemic circulation. We aimed to determine the effect of surgical ligation for hsPDA on NDI in ELBWIs. In enrolled 71 ELBWIs, the clinical parameters, including the developmental quotient (DQ), were collected and compared among three groups that were divided by closure mode: spontaneous closure (n = 11), cyclooxygenase inhibitor therapy (n = 37) and surgical ligation (n = 23). No significant differences in DQ at the age of 36 months among the three groups were found: Median (interquartile range): 92.0 (31.0), 89.0 (22.0) and 92.0 (24.5), respectively. In a comparison between groups of DQ < 70 (n = 15) and DQ ≥ 70 (n = 56), a significant difference was found in the parameters related to prematurity (p < 0.05 for each): gestational age [23.9 (1.70) vs. 25.4 (2.50) weeks], birth weight [595 (183) vs. 714 (192) g], Apgar score < 5 (1 min) (67% vs. 36%), and laser photocoagulation for retinopathy of prematurity (73% vs. 43%), but there was no significant association with hsPDA. Therefore, we propose that surgical ligation for hsPDA in ELBWIs should be immediately carried out for preventing future neurodevelopmental deterioration if the cyclooxygenase inhibitor failed to close hsPDA.

Distraction osteogenesis of the sternum for thoracic expansion in a severe case of jeune syndrome: a preliminary report.

Severe asphyxiating thoracic dystrophy (Jeune syndrome) is usually fatal. The authors used distraction osteogenesis in a severe case and achieved 45 mm distraction of the sternum and improvement in tidal volume, lung compliance, and mean airway pressure.

A Parallelized Pumpless Artificial Placenta System Significantly Prolonged Survival Time in a Preterm Lamb Model.

An artificial placenta (AP) is an arterio-venous extracorporeal life support system that is connected to the fetal circulation via the umbilical vasculature. Previously, we published an article describing a pumpless AP system with a small priming volume. We subsequently developed a parallelized system, hypothesizing that the reduced circuit resistance conveyed by this modification would enable healthy fetal survival time to be prolonged. We conducted experiments using a premature lamb model to test this hypothesis. As a result, the fetal survival period was significantly prolonged (60.4 ± 3.8 vs. 18.2 ± 3.2 h, P < 0.01), and circuit resistance and minimal blood lactate levels were significantly lower in the parallel circuit group, compared with our previous single circuit group. Fetal physiological parameters remained stable until the conclusion of the experiments. In summary, parallelization of the AP system was associated with reduced circuit resistance and lactate levels and allowed preterm lamb fetuses to survive for a significantly longer period when compared with previous studies.

Cerebral ischemia or intrauterine inflammation promotes differentiation of oligodendroglial precursors in preterm ovine fetuses: possible cellular basis for white matter injury.

White matter injury in premature infants is known to be major cause of long-term neurocognitive disability, but the pathogenic mechanism remains unclear, hampering our ability to develop preventions. Periventricular leukomalacia is a severe form of white matter injury. In the present study, we explored the effects of cerebral ischemia and/or intrauterine inflammation on the development of oligodendroglia in the cerebral white matter using chronically instrumented fetal sheep. Each fetus received one of three insults: hemorrhage, inflammation and their combination. In the hemorrhage group, 40% of the fetoplacental blood volume was acutely withdrawn, and 24 hours after removal, the blood was returned to the fetus. The inflammation group received intravenous granulocyte-colony stimulating factor and intra-amniotic endotoxin and thus suffered from necrotizing funisitis and chorioamnionitis. The inflammatory hemorrhage group underwent acute hemorrhage under the inflammatory state. The sham group received no insults. Importantly, periventricular leukomalacia was not detected in the sham and the inflammation groups. Differentiating oligodendroglia at various developmental stages were identified by immunohistochemical analysis with specific antibodies. No difference in the density of oligodendroglial progenitors was detected among the four groups, whereas oligodendroglial precursors were significantly reduced in the three insult groups, compared to sham control. Moreover, the density of immature oligodendroglia was higher in the inflammation group and the inflammatory hemorrhage group, while the density of mature oligodendroglia was highest in the hemorrhage group. We propose that cerebral ischemia or intrauterine inflammation induces the differentiation of oligodendroglial precursors in preterm fetuses, eventually resulting in their exhaustion.

Novel modification of an artificial placenta: pumpless arteriovenous extracorporeal life support in a premature lamb model.

BACKGROUND: Previous studies aimed at developing an artificial placenta have had limited success. We hypothesized that the introduction of a high-performance membranous oxygenator to a pumpless artificial placenta could prolong the survival time of premature lambs. METHODS: Immediately after delivery of the fetuses, the umbilical vessels were cannulated and connected to the pumpless artificial placenta. Both the fetuses and the circuit were submerged in a warm saline bath. RESULTS: Five fetuses survived for 18.2 ± 3.2 (mean ± SEM) h after attachment to the artificial placenta, which maintained fetal circulation. Circuit blood flow was positively correlated with mean arterial pressure and negatively correlated with blood lactate levels. Milrinone administration transiently decreased lactate levels, although dopamine administration unexpectedly induced a marked increase in the lactate levels despite an elevated arterial pressure and improved circuit blood flow. CONCLUSION: We prolonged the survival of fetal lambs using a high-performance membranous oxygenator with a small priming volume. The increased systemic resistance induced by vasoconstrictors may increase the circuit blood flow excessively, resulting in circulation failure in systemic organs; therefore, vasodilators may be more useful than vasoconstrictors for maintaining organ blood flow within this circuit.

Effect of intrauterine inflammation on fetal cerebral hemodynamics and white-matter injury in chronically instrumented fetal sheep.

OBJECTIVE: The purpose of this study was to analyze the effects of intrauterine inflammation on cerebral hemodynamics and white-matter injury in premature fetal sheep. STUDY DESIGN: Fetuses were given an intravenous infusion of granulocyte colony-stimulating factor and an intraamniotic infusion of endotoxin; the fetuses were then assigned randomly to an acute hemorrhage group, an exchange transfusion group, or a control group. During each insult, the cerebral hemodynamics were assessed with near-infrared spectroscopy. Finally, the fetuses were processed for neuropathologic analysis and compared statistically. RESULTS: Necrotizing funisitis and chorioamnionitis were induced in all the fetuses. A significant decrease in the blood oxygen content and an increase in the brain total hemoglobin level were observed after the endotoxin infusion. Soon after hemodynamic insult, the fetuses in both the acute hemorrhage and the exchange transfusion groups showed an abrupt decrease in the total brain hemoglobin level; 4 of the 5 fetuses in each treatment group, but none of the fetuses in the control group, exhibited periventricular leukomalacia. CONCLUSION: Hemorrhagic hypotension or anemic hypoxemia might induce a sudden cessation of fetal brain-sparing effects through progressive inflammatory hypoxemia, which results in focal white-matter injuries.