Contrast-enhanced subharmonic aided pressure estimation for assessment of intracranial pressure in vivo.

BACKGROUND: Intracranial pressure (ICP) monitoring in children currently requires invasive techniques. Subharmonic aided pressure estimation (SHAPE) uses contrast-enhanced ultrasound (CEUS) to measure intravascular and interstitial pressure, but utility in ICP measurements has yet to be explored. OBJECTIVE: The objective of this study was to investigate SHAPE as a novel tool for noninvasive ICP measurements in fetal lambs. MATERIALS AND METHODS: Eighteen fetal lambs at 107-139 days gestational age (term = 145 days) underwent subdural ICP catheter placement. The brain was imaged in the coronal plane in CEUS mode optimized for SHAPE, while infusing an US contrast agent into the fetal circulation. After SHAPE calibration, saline was infused via the subdural catheter to increase ICP. Five-second SHAPE cine clips were obtained at various ICPs. Subharmonic intensity values of the whole brain and thalami were correlated with ICP values using mixed effects linear regression analyses and the strength of the relationship was evaluated by Spearman's rank-order correlation. RESULTS: Forty-nine experiments produced 723 datapoints, including SHAPE intensity values and mean ICP measurements. There was a statistically significant inverse relationship between SHAPE intensity values and ICP measurements in the whole brain and thalami (median rho value - 0.58 and - 0.56, respectively). CONCLUSION: SHAPE intensity values of the brain demonstrate an inverse and statistically significant correlation with in vivo ICP measurements in an animal model.

The fetal lamb model of congenital diaphragmatic hernia shows altered cerebral perfusion using contrast enhanced ultrasound.

BACKGROUND: Neurodevelopmental impairment is common in survivors of congenital diaphragmatic hernia (CDH). Altered cerebral perfusion in utero may contribute to abnormal brain development in CDH patients. METHODS: 5 fetal lambs with surgical left-CDH and 5 controls underwent transuterine cranial Doppler and contrast enhanced ultrasound (CEUS). Global and regional perfusion metrics were obtained. Biometric and perfusion data were compared between groups via nonparametric Mann Whitney U test and Spearman's rank order correlation. RESULTS: No significant differences in cerebral Doppler measurements were identified between groups. By CEUS, CDH animals demonstrated significantly decreased global brain perfusion and increased transit time. With focal regions-of-interest (ROIs), there was a tendency towards decreased perfusion in the central/thalamic region in CDH but not in the peripheral brain parenchyma. Transit time was significantly increased in both ROIs in CDH, whereas flux rate was decreased in the central/thalamic region but not the peripheral brain parenchyma. Biometric CDH severity was correlated to perfusion deficit. There was no difference in cardiomyocyte histology. CONCLUSION: The fetal lamb model of CDH shows altered cerebral perfusion as measured by CEUS, correlating to disease severity. This suggests a physiological abnormality in fetal cerebrovascular perfusion that may contribute to abnormal brain development and neurodevelopmental impairment in survivors.

The EXTrauterine Environment for Neonatal Development: Present and Future.

Despite advances in clinical care and modest improvement in mortality rates for extreme prematurity, morbidity remains a significant challenge. The ideal environment to support prematurity would be fluidic and rely on natural fetal circulation to mimic the natural fetal amniotic environment, yet such an environment has been unsuccessful in long-term support until recently. Our group has succeeded in developing such a support system to foster fetal growth in the premature lamb model that shows promise for clinical translation. Here, we describe the EXTrauterine Environment for Neonatal Development (EXTEND) from its conception onwards, review published literature on fetal development and support of the premature lamb model in EXTEND, and discuss future applications.

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

Extreme prematurity remains a major cause of neonatal mortality and severe long-term morbidity. Current neonatal care is associated with significant morbidity due to iatrogenic injury and developmental immaturity of extreme premature infants. A more physiologic approach, replacing placental function and providing a womb-like environment, is the foundational principle of artificial placenta (AP) and womb (AW) technology. The concept has been studied during the past 60 years with limited success. However, recent technological advancements and a greater emphasis on mimicking utero-placental physiology have improved the success of experimental models, bringing the technology closer to clinical translation. Here, we review the rationale for and history of AP and AW technology, discuss the challenges that needed to be overcome, and compare recent successful models. We conclude by outlining some remaining challenges to be addressed on the path towards clinical translation and opportunities for future research.

A pilot study of cerebrovascular reactivity autoregulation after pediatric cardiac arrest.

AIM: Improved survival after cardiac arrest has placed greater emphasis on neurologic resuscitation. The purpose of this pilot study was to evaluate the relationship between cerebrovascular autoregulation and neurologic outcomes after pediatric cardiac arrest. METHODS: Children resuscitated from cardiac arrest had autoregulation monitoring during the first 72h after return of circulation with an index derived from near-infrared spectroscopy in a pilot study. The range of mean arterial blood pressure (MAP) with optimal vasoreactivity (MAPOPT) was identified. The area under the curve (AUC) of the time spent with MAP below MAPOPT and MAP deviation below MAPOPT was calculated. Neurologic outcome measures included placement of a new tracheostomy or gastrostomy, death from a primary neurologic etiology (brain death or withdrawal of support for neurologic futility), and change in the Pediatric Cerebral Performance Category score (ΔPCPC). RESULTS: Thirty-six children were monitored. Among children who did not require extracorporeal membrane oxygenation (ECMO), children who received a tracheostomy/gastrostomy had greater AUC during the second 24h after resuscitation than those who did not (P=0.04; n=19). Children without ECMO who died from a neurologic etiology had greater AUC during the first 48h than did those who lived or died from cardiovascular failure (P=0.04; n=19). AUC below MAPOPT was not associated with ΔPCPC when children with or without ECMO were analyzed separately. CONCLUSIONS: Deviation from the blood pressure with optimal autoregulatory vasoreactivity may predict poor neurologic outcomes after pediatric cardiac arrest. This experimental autoregulation monitoring technique may help individualize blood pressure management goals after resuscitation.

Cerebrovascular autoregulation after rewarming from hypothermia in a neonatal swine model of asphyxic brain injury.

After hypoxic brain injury, maintaining blood pressure within the limits of cerebral blood flow autoregulation is critical to preventing secondary brain injury. Little is known about the effects of prolonged hypothermia or rewarming on autoregulation after cardiac arrest. We hypothesized that rewarming would shift the lower limit of autoregulation (LLA), that this shift would be detected by indices derived from near-infrared spectroscopy (NIRS), and that rewarming would impair autoregulation during hypertension. Anesthetized neonatal swine underwent sham surgery or hypoxic-asphyxic cardiac arrest, followed by 2 h of normothermia and 20 h of hypothermia, with or without rewarming. Piglets were further divided into cohorts for cortical laser-Doppler flow (LDF) measurements during induced hypotension or hypertension. We also tested whether indices derived from NIRS could identify the LDF-derived LLA. The LLA did not differ significantly among groups with sham surgery and hypothermia (29 ± 8 mmHg), sham surgery and rewarming (34 ± 7 mmHg), arrest and hypothermia (29 ± 10 mmHg), and arrest and rewarming (38 ± 11 mmHg). The LLA was not affected by arrest (P = 0.60), temperature (P = 0.08), or interaction between arrest and temperature (P = 0.73). The NIRS-derived indices detected the LLA accurately, with the area under the receiver-operator characteristic curves of 0.81-0.96 among groups. In groups subjected to arrest and hypothermia, with or without rewarming, the slope of LDF relative to cerebral perfusion pressure during hypertension was not significantly different from zero (P > 0.10). In conclusion, rewarming did not shift the LLA during hypotension or affect autoregulation during hypertension after asphyxic cardiac arrest. The NIRS-derived autoregulation indices identified the LLA accurately.

Cerebrovascular autoregulation and neurologic injury in neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Neonates with hypoxic-ischemic encephalopathy (HIE) are at risk of cerebral blood flow dysregulation. Our objective was to describe the relationship between autoregulation and neurologic injury in HIE. METHODS: Neonates with HIE had autoregulation monitoring with the hemoglobin volume index (HVx) during therapeutic hypothermia, rewarming, and the first 6 h of normothermia. The 5-mm Hg range of mean arterial blood pressure (MAP) with best vasoreactivity (MAPOPT) was identified. The percentage of time spent with MAP below MAPOPT and deviation in MAP from MAPOPT were measured. Neonates received brain magnetic resonance imaging (MRI) 3-7 d after treatment. MRIs were coded as no, mild, or moderate/severe injury in five regions. RESULTS: HVx identified MAPOPT in 79% (19/24), 77% (17/22), and 86% (18/21) of the neonates during hypothermia, rewarming, and normothermia, respectively. Neonates with moderate/severe injury in paracentral gyri, white matter, basal ganglia, and thalamus spent a greater proportion of time with MAP below MAPOPT during rewarming than neonates with no or mild injury. Neonates with moderate/severe injury in paracentral gyri, basal ganglia, and thalamus had greater MAP deviation below MAPOPT during rewarming than neonates without injury. CONCLUSION: Maintaining MAP within or above MAPOPT may reduce the risk of neurologic injuries in neonatal HIE.

Adenosine A2A receptor contributes to ischemic brain damage in newborn piglet.

Pharmacologic inactivation or genetic deletion of adenosine A2A receptors protects ischemic neurons in adult animals, but studies in neonatal hypoxia-ischemia (H-I) are inconclusive. The present study in neonatal piglets examined the hypothesis that A2A receptor signaling after reoxygenation from global H-I contributes to injury in highly vulnerable striatal neurons where A2A receptors are enriched. A2A receptor immunoreactivity was detected in striatopallidal neurons. In nonischemic piglets, direct infusion of the selective A2A receptor agonist CGS 21680 through microdialysis probes into putamen increased phosphorylation of N-methyl-D-aspartic acid (NMDA) receptor NR1 subunit and Na(+),K(+)-ATPase selectively at protein kinase A (PKA)-sensitive sites. In ischemic piglets, posttreatment with SCH 58261, a selective A2A receptor antagonist, improved early neurologic recovery and preferentially protected striatopallidal neurons. SCH 58261 selectively inhibited the ischemia-induced phosphorylation of NR1, Na(+),K(+)-ATPase, and cAMP-regulated phosphoprotein 32 KDa (DARPP32) at PKA-sensitive sites at 3 hours of recovery and improved Na(+),K(+)-ATPase activity. SCH 58261 also suppressed ischemia-induced protein nitration and oxidation. Thus, A2A receptor activation during reoxygenation contributes to the loss of a subpopulation of neonatal putamen neurons after H-I. Its toxic signaling may be related to DARPP32-dependent phosphorylation of PKA-sensitive sites on NR1 and Na(+),K(+)-ATPase, thereby augmenting excitotoxicity-induced oxidative stress after reoxygenation.

Cerebrovascular autoregulation in pediatric moyamoya disease.

BACKGROUND: Moyamoya syndrome carries a high risk of cerebral ischemia, and impaired cerebrovascular autoregulation may play a critical role. Autoregulation indices derived from near-infrared spectroscopy (NIRS) may clarify hemodynamic goals that conform to the limits of autoregulation. OBJECTIVES: The aims of this pilot study were to determine whether the NIRS-derived indices could identify blood pressure ranges that optimize autoregulation and whether autoregulatory function differs between anatomic sides in patients with unilateral vasculopathy. METHODS: Pediatric patients undergoing indirect surgical revascularization for moyamoya were enrolled sequentially. NIRS-derived autoregulation indices, the cerebral oximetry index (COx) and the hemoglobin volume index (HVx), were calculated intraoperatively and postoperatively to measure autoregulatory function. The 5-mmHg ranges of optimal mean arterial blood pressure (MAPOPT ) with best autoregulation and the lower limit of autoregulation (LLA) were identified. RESULTS: Of seven enrolled patients (aged 2-16 years), six had intraoperative and postoperative autoregulation monitoring and one had only intraoperative monitoring. Intraoperative MAPOPT was identified in six (86%) of seven patients with median values of 60-80 mmHg. Intraoperative LLA was identified in three (43%) patients with median values of 55-65 mmHg. Postoperative MAPOPT was identified in six (100%) of six patients with median values of 70-90 mmHg. Patients with unilateral disease had higher intraoperative HVx (P = 0.012) on side vasculopathy. CONCLUSIONS: NIRS-derived indices may identify hemodynamic goals that optimize autoregulation in pediatric moyamoya.

Early antioxidant treatment and delayed hypothermia after hypoxia-ischemia have no additive neuroprotection in newborn pigs.

BACKGROUND: The implementation and clinical efficacy of hypothermia in neonatal hypoxic-ischemic (HI) encephalopathy are limited, in part, by the delay in instituting hypothermia and access to equipment. In a piglet model of HI, half of the neurons in putamen already showed ischemic cytopathology by 6 hours of recovery. We tested the hypothesis that treatment with the superoxide dismutase-catalase mimetic EUK-134 at 30 minutes of recovery provides additive neuronal protection when combined with 1 day of whole-body hypothermia implemented 4 hours after resuscitation. METHODS: Anesthetized piglets were subjected to 40 minutes of hypoxia (10% inspired oxygen) followed by 7 minutes of airway occlusion and resuscitation. Body temperature was maintained at 38.5°C in normothermic groups and at 34°C in hypothermic groups. All groups were mechanically ventilated, sedated, and received muscle relaxants during the first day of recovery. Neuropathology was assessed by profile and stereological cell-counting methods. RESULTS: At 10 days of recovery, neuronal viability in putamen of a normothermic group treated with saline vehicle was reduced to 17% ± 6% (±95% confidence interval) of the value in a sham-operated control group (100% ± 15%). Intravenous infusion of EUK-134 (2.5 mg/kg at 30 minutes of recovery + 1.25 mg/kg/h until 4 hours of recovery) with normothermic recovery resulted in 40% ± 12% viable neurons in putamen. Treatment with saline vehicle followed by delayed hypothermia resulted in partial protection (46% ± 15%). Combining early EUK-134 treatment with delayed hypothermia also produced partial protection (47% ± 18%) that was not significantly greater than single treatment with EUK-134 (confidence interval of difference: -15% to 29%) or delayed hypothermia (-16% to 19%). Furthermore, no additive neuroprotection was detected in caudate nucleus or parasagittal neocortex, where neuronal loss was less severe. CONCLUSIONS: We conclude that early treatment with this antioxidant does not substantially enhance the therapeutic benefit of delayed hypothermia in protecting highly vulnerable neurons in HI-insulted newborns, possibly because basal ganglia neurons are already undergoing irreversible cell death signaling by the time EUK-134 is administered or because this compound and hypothermia attenuate similar mechanisms of injury.

Noninvasive autoregulation monitoring in a swine model of pediatric cardiac arrest.

BACKGROUND: Cerebrovascular autoregulation after resuscitation has not been well studied in an experimental model of pediatric cardiac arrest. Furthermore, developing noninvasive methods of monitoring autoregulation using near-infrared spectroscopy (NIRS) would be clinically useful in guiding neuroprotective hemodynamic management after pediatric cardiac arrest. We tested the hypotheses that the lower limit of autoregulation (LLA) would shift to a higher arterial blood pressure between 1 and 2 days of recovery after cardiac arrest and that the LLA would be detected by NIRS-derived indices of autoregulation in a swine model of pediatric cardiac arrest. We also tested the hypothesis that autoregulation with hypertension would be impaired after cardiac arrest. METHODS: Data on LLA were obtained from neonatal piglets that had undergone hypoxic-asphyxic cardiac arrest and recovery for 1 day (n = 8) or 2 days (n = 8), or that had undergone sham surgery with 2 days of recovery (n = 8). Autoregulation with hypertension was examined in a separate cohort of piglets that underwent hypoxic-asphyxic cardiac arrest (n = 5) or sham surgery (n = 5) with 2 days of recovery. After the recovery period, piglets were reanesthetized, and autoregulation was monitored by standard laser-Doppler flowmetry and autoregulation indices derived from NIRS (the cerebral oximetry [COx] and hemoglobin volume [HVx] indices). The LLA was determined by decreasing blood pressure through inflation of a balloon catheter in the inferior vena cava. Autoregulation during hypertension was evaluated by inflation of an aortic balloon catheter. RESULTS: The LLAs were similar between sham-operated piglets and piglets that recovered for 1 or 2 days after arrest. The NIRS-derived indices accurately detected the LLA determined by laser-Doppler flowmetry. The area under the curve of the receiver operator characteristic curve for cerebral oximetry index was 0.91 at 1 day and 0.92 at 2 days after arrest. The area under the curve for hemoglobin volume index was 0.92 and 0.89 at the respective time points. During induced hypertension, the static rate of autoregulation, defined as the percentage change in cerebrovascular resistance divided by the percentage change in cerebral perfusion pressure, was not different between postarrest and sham-operated piglets. At 2 days recovery from arrest, piglets exhibited neurobehavioral deficits and histologic neuronal injury. CONCLUSIONS: In a swine model of pediatric hypoxic-asphyxic cardiac arrest with confirmed brain damage, the LLA did not differ 1 and 2 days after resuscitation. The NIRS-derived indices accurately detected the LLA in comparison with laser-Doppler flow measurements at those time points. Autoregulation remained functional during hypertension.