Therapeutic hypothermia is standard of care for infants with hypoxic ischemic encephalopathy. Murine models of hypoxic-ischemic injury exist; however, a well-established mouse model of therapeutic hypothermia following hypoxic-ischemic injury is lacking. The goal of this study was to develop a full-term-equivalent murine model of therapeutic hypothermia after hypoxia-ischemia and examine magnetic resonance imaging, behavior, and histology in a region and sex specific manner. Hypoxic-ischemic injury was induced at postnatal day 10 in C57BL6 mice using a modified Vannucci model. Mice were randomized to control, hypothermia (31˚C for 4h), or normothermia (36˚C) following hypoxic-ischemic injury and stratified by sex. T2-weighted magnetic resonance imaging was obtained at postnatal day 18 and 30 and regional and total cerebral and cerebellar volumes measured. Behavioral assessments were performed on postnatal day 14, 21, and 28. On postnatal day 18, normothermic mice had smaller cerebral volumes (p < 0.001 vs. controls and p = 0.009 vs. hypothermia), while at postnatal day 30 both injured groups had smaller volumes than controls. When stratified by sex, only normothermia treated male mice had smaller cerebral volumes (p = 0.001 vs. control; p = 0.008 vs. hypothermia) at postnatal day 18, which persisted at postnatal day 30 (p = 0.001 vs. control). Female mice had similar cerebral volumes between groups at both day 18 and 30. Cerebellar volumes of hypothermia treated male mice differed from control at day 18, but not at 30. Four hours of therapeutic hypothermia in this murine hypoxic-ischemic injury model provides sustained neuroprotection in the cerebrum of male mice. Due to variable degree of injury in female mice, response to therapeutic hypothermia is difficult to discern. Deficits in female behavior tests are not fully explained by imaging measures and likely represent injury not detectable by volume measurements alone.
BackgroundApnea of Prematurity (AOP) is common, affecting the majority of infants born at <34 weeks gestational age. Apnea and periodic breathing are accompanied by intermittent hypoxia (IH). Animal and human studies demonstrate that IH exposure contributes to multiple pathologies, including retinopathy of prematurity (ROP), injury to sympathetic ganglia regulating cardiovascular action, impaired pancreatic islet cell and bone development, cerebellar injury, and neurodevelopmental disabilities. Current standard of care for AOP/IH includes prone positioning, positive pressure ventilation, and methylxanthine therapy; these interventions are inadequate, and not optimal for early development.ObjectiveThe objective is to support breathing in premature infants by using a simple, non-invasive vibratory device placed over limb proprioceptor fibers, an intervention using the principle that limb movements trigger reflexive facilitation of breathing.MethodsPremature infants (23–34 wks gestational age), with clinical evidence of AOP/IH episodes were enrolled 1 week after birth. Caffeine treatment was not a reason for exclusion. Small vibration devices were placed on one hand and one foot and activated in 6 hour ON/OFF sequences for a total of 24 hours. Heart rate, respiratory rate, oxygen saturation (SpO2), and breathing pauses were continuously collected.ResultsFewer respiratory pauses occurred during vibration periods, relative to baseline (p<0.005). Significantly fewer SpO2 declines occurred with vibration (p<0.05), relative to control periods. Significantly fewer bradycardic events occurred during vibration periods, relative to no vibration periods (p<0.05).ConclusionsIn premature neonates, limb proprioceptive stimulation, simulating limb movement, reduces breathing pauses and IH episodes, and lowers the number of bradycardic events that accompany aberrant breathing episodes. This low-cost neuromodulatory procedure has the potential to provide a non-invasive intervention to reduce apnea, bradycardia and intermittent hypoxia in premature neonates.Trial RegistrationClinicalTrials.gov NCT02641249
The carotid body (CB) substantially influences breathing in premature infants by affecting the frequency of apnea and periodic breathing. In adult animals, inflammation alters the structure and chemosensitivity of the CB, yet it is not known if this pertains to neonates. We hypothesized that early postnatal inflammation leads to morphological and functional changes in the developing rat CB, which persists for 1 wk after the initial provoking insult. To test our hypothesis, we exposed rat pups at postnatal day 2 (P2) to lipopolysaccharide (LPS; 100 μg/kg) or saline (SAL) intraperitoneally. At P9-10 (1 wk after treatment), LPS-exposed animals had significantly more spontaneous intermittent hypoxic (IH) events, attenuated ventilatory responses to changes in oxygen tension (measured by whole body plethysmography), and attenuated hypoxic chemosensitivity of the carotid sinus nerve (measured in vitro), compared with SAL-exposed controls. These functional changes were associated with the following: 1) increased inflammatory cytokine mRNA levels; 2) decreased volume of supportive type II cells; and 3) elevated dopamine levels (a major inhibitory neuromodulator) within the CB. These findings suggest that early postnatal inflammation in newborn rats adversely affects the structure and function of the CB and is associated with increased frequency of intermittent desaturations, similar to the phenomenon observed in premature infants. Furthermore, this is the first newborn model of spontaneous intermittent desaturations that may be used to understand the mechanisms contributing to IH events in newborns.
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