Chronic hypoxia in pregnant mice impairs the placental and fetal vascular response to acute hypercapnia in BOLD-MRI hemodynamic response imaging.

INTRODUCTION: Brief hypercapnic challenge causes acute placental hypoperfusion with fetal brain sparing on BOLD-MRI. We hypothesize that this non-invasive imaging strategy can distinguish between normal pregnancy and chronic placental hypoperfusion (using the maternal hypoxia model). METHODS: Eighteen pregnant female ICR mice were randomized to three groups: normoxia, late-onset hypoxia (12%O2;E13.5-17.5) and early-onset hypoxia (12%O2;E10.5-17.5). On E17.5, animals were imaged in a 4.7-T Bruker-Biospec MRI scanner. Fast coronal True-FISP was performed to identify organs of interest (placenta and fetal heart, liver and brain). BOLD-MRI was performed at baseline and during a 4-min hypercapnic challenge (5%CO2). %-change in placental and fetal signal was analyzed from T2*-weighted gradient echo MR images. Following MRI, fetuses and placentas were harvested, weighed and immuno-stained. RESULTS: In normoxic mice, hypercapnia caused reduction in BOLD-MRI signal in placenta (-44% ± 7%; p < 0.0001), fetal liver (-32% ± 7%; p < 0.0001) and fetal heart (-54% ± 12%; p < 0.002), with relative fetal brain sparing (-12% ± 5%; p < 0.0001). These changes were markedly attenuated in both hypoxia groups. Baseline fetal brain/placenta SI ratio was highest in normoxic mice (1.14 ± 0.017) and reduced with increasing duration of hypoxia (late-onset hypoxia: 1.00 ± 0.026; early-onset hypoxia: 0.91 ± 0.016; p = 0.02). Both hypoxic groups exhibited fetal growth restriction with prominent placental glycogen-containing cells, particularly in early-onset hypoxia. There was increased fetal neuro- and intestinal-apoptosis in early-onset hypoxia only. CONCLUSIONS: BOLD-MRI with brief hypercapnic challenge distinguished between normoxia and both hypoxia groups, while fetal neuroapoptosis was only observed after early-onset hypoxia. This suggests that BOLD-MRI with hypercapnic challenge can identify chronic fetal asphyxia before the onset of irreversible brain injury.

BOLD-MRI demonstrates acute placental and fetal organ hypoperfusion with fetal brain sparing in response to phenylephrine but not ephedrine.

INTRODUCTION: We previously reported blood oxygen level dependent MRI (BOLD-MRI) for monitoring placental and fetal hemodynamic changes in mice following maternal hypercapnia. Here we use BOLD-MRI to compare the placental and fetal hemodynamic effects of different maternal vasopressors in mice. METHODS: Pregnant ICR mice (n = 16; E17.5) anesthetized with pentobarbital (80 mg/kg i.p.) were placed supine in a 4.7-T Bruker Biospec MRI. Following baseline images, equipotential doses of ephedrine (10 mg/kg) or phenylephrine (10mcg/kg) were administered intravenously. Changes in placental and fetal signal were analyzed from T2*-weighted gradient echo MR images (TR/TE = 147/10 ms). Different regions of interest (placenta, fetal heart, fetal liver and fetal brain) were identified. Percentage change of BOLD-MRI signal intensity (SI) were presented as time curves. RESULTS: Ephedrine and phenylephrine elicited markedly different effects. Phenylephrine caused an approximate 50% reduction in placental, fetal heart and fetal liver BOLD-MRI-SI, but fetal brain BOLD-MRI-SI was unchanged (statistically different from placenta and other fetal organs; p < 0.001), and the fetal brain/liver BOLD-MRI-SI ratio was markedly increased versus baseline (p < 0.001). Following ephedrine, placental BOLD-MRI-SI increased 30% and fetal heart BOLD-MRI-SI was reduced 26%; other fetal organs were unchanged. Blood gases were unchanged. DISCUSSION: Phenylephrine induced BOLD-MRI-SI changes suggestive of placental and fetal hypoperfusion with brain sparing. Ephedrine induced BOLD-MRI-SI changes suggestive of increased cardiac output; we speculate that reduced fetal heart BOLD-MRI-SI may be due to increased fetal myocardial oxygen extraction or metabolic acidosis. The result demonstrates the potential of BOLD-MRI as a non-invasive hemodynamic tool for assessing pharmacodynamics effects in the placental and fetus.

Inhaled carbon dioxide causes dose-dependent paradoxical bradypnea in animals anesthetized with pentobarbital, but not with isoflurane or ketamine.

INTRODUCTION: In spontaneously breathing mice anesthetized with pentobarbital, we observed unexpected paradoxical bradypnea following 5% inhaled CO2. METHODS: Observational study 7-8 week CB6F1/OlaHsd mice (n = 99), anesthetized with 30 mg/kg intraperitoneal pentobarbital. Interventional study: Adult male Wistar rats (n = 18), anesthetized either with 30 mg/kg intraperitoneal pentobarbital, 100 mg/kg intraperitoneal ketamine or 1.5% isoflurane. Rats had femoral artery cannulas inserted for hemodynamic monitoring and serial arterial blood gas measurements. RESULTS: Observational study: There was a marked reduction in respiratory rate following 4 min of normoxic hypercapnia; average reduction of 9 breaths/min (p < 0.001) (17% reduction from baseline). Interventional study: increasing CO2 caused dose-dependent increase in respiratory rate for ketamine-xylazine (p = 0.007) and isoflurane (p = 0.016) but dose-dependent decrease in respiratory rate for pentobarbital (p = 0.046). Increasing inspired CO2 caused dose-dependent acidosis following pentobarbital and isoflurane (p = 0.013 and p = 0.017, respectively); but not following ketamine-xylazine (p = 0.58). CONCLUSIONS: Inhaled CO2 caused paradoxical dose-dependent bradypnea in animals anesthetized with pentobarbital, an observation not hitherto reported as a part of anesthesia-related respiratory depression.