Valerie Y. Chock

INFLAMMATION AND NFκB ACTIVATION IS DECREASED BY HYPOTHERMIA FOLLOWING GLOBAL CEREBRAL ISCHEMIA

We previously showed that hypothermia attenuates inflammation in focal cerebral ischemia (FCI) by suppressing activating kinases of nuclear factor-kappa B (NFkappaB). Here we characterize the inflammatory response in global cerebral ischemia (GCI), and the influence of mild hypothermia. Rodents were subjected to GCI by bilateral carotid artery occlusion. The inflammatory response was accompanied by microglial activation, but not neutrophil infiltration, or blood brain barrier disruption. Mild hypothermia reduced CA1 damage, decreased microglial activation and decreased nuclear NFkappaB translocation and activation. Similar anti-inflammatory effects of hypothermia were observed in a model of pure brain inflammation that does not cause brain cell death. Primary microglial cultures subjected to oxygen glucose deprivation (OGD) or stimulated with LPS under hypothermic conditions also experienced less activation and less NFkappaB translocation. However, NFkappaB regulatory proteins were not affected by hypothermia. The inflammatory response following GCI and hypothermias anti-inflammatory mechanism is different from that observed in FCI.

Inhaled Nitric Oxide for Preterm Premature Rupture of Membranes, Oligohydramnios, and Pulmonary Hypoplasia

We sought to determine if inhaled nitric oxide (iNO) administered to preterm infants with premature rupture of membranes (PPROM), oligohydramnios, and pulmonary hypoplasia improved oxygenation, survival, or other clinical outcomes. Data were analyzed from infants with suspected pulmonary hypoplasia, oligohydramnios, and PPROM enrolled in the National Institute of Child Health and Development Neonatal Research Network Preemie Inhaled Nitric Oxide (PiNO) trial, where patients were randomized to receive placebo (oxygen) or iNO at 5 to 10 ppm. Outcome variables assessed were PaO (2) response, mortality, bronchopulmonary dysplasia (BPD), and severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Twelve of 449 infants in the PiNO trial met criteria. Six infants received iNO and six received placebo. The iNO group had a mean increase in PaO (2) of 39 +/- 50 mm Hg versus a mean decrease of 11 +/- 15 mm Hg in the control group. Mortality was 33% versus 67%, BPD (2/5) 40% versus (2/2) 100%, and severe IVH or PVL (1/5) 20% versus (1/2) 50% in the iNO and control groups, respectively. None of these changes were statistically significant. Review of a limited number of cases from a large multicenter trial suggests that iNO use in the setting of PPROM, oligohydramnios, and suspected pulmonary hypoplasia improves oxygenation and may decrease the rate of BPD and death without increasing severe IVH or PVL. However, the small sample size precludes definitive conclusions. Further studies are required to determine if iNO is of benefit in this specific patient population.

Cerebral Autoregulation in Neonates with a Hemodynamically Significant Patent Ductus Arteriosus

OBJECTIVE Very low birth weight (VLBW) preterm infants are at risk for impaired cerebral autoregulation with pressure passive blood flow. Fluctuations in cerebral perfusion may occur in infants with a hemodynamically significant patent ductus arteriosus (hsPDA), especially during ductal closure. Our goal was to compare cerebral autoregulation using near-infrared spectroscopy in VLBW infants treated for an hsPDA. STUDY DESIGN This prospective observational study enrolled 28 VLBW infants with an hsPDA diagnosed by echocardiography and 12 control VLBW infants without an hsPDA. Near-infrared spectroscopy cerebral monitoring was applied during conservative treatment, indomethacin treatment, or surgical ligation. A cerebral pressure passivity index (PPI) was calculated, and PPI differences were compared using a mixed-effects regression model. Cranial ultrasound and magnetic resonance imaging data were also assessed. RESULTS Infants with surgically ligated hsPDAs were more likely to have had a greater PPI within 2 hours following ligation than were those treated with conservative management (P=.04) or indomethacin (P=.0007). These differences resolved by 6 hours after treatment. CONCLUSIONS Cerebral autoregulation was better preserved after indomethacin treatment of an hsPDA compared with surgical ligation. Infants requiring surgical hsPDA ligation may be at increased risk for cerebral pressure passivity in the 6 hours following surgery.

Neurologic events in neonates treated surgically for congenital heart disease

Objective:The incidence of acute neurologic events prior to discharge in neonates with congenital heart disease (CHD) was determined and peri-operative characteristics predictive of a neurologic event were identified.Study design:A retrospective chart review over 1 year was conducted of infants <1 month of age with a diagnosis of CHD. Outcomes were measured by the occurrence of an acute neurologic event defined as electroencephalogram (EEG)-proven seizure activity, significant hypertonia or hypotonia, or choreoathetosis prior to hospital discharge. Stepwise logistic regression identified variables most likely to be associated with an acute neurologic event.Results:Surgical intervention occurred in 95 infants who were admitted with a diagnosis of CHD. The survival rate was 92%. Of the survivors, 16 (17%) had an acute neurologic event, with 19% of events occurring preoperatively. Factors associated with neurologic events included an elevated nucleated red blood cell (NRBC) count, an abnormal preoperative brain imaging study, and a 5-min Apgar score <7 (P<0.05).Conclusions:Neonates with CHD have a significant risk of neurologic events. Preoperative brain imaging, the 5-min Apgar score, and initial serum NRBC counts may identify infants at highest risk for central nervous system injury.

Cerebral Oxygenation during Different Treatment Strategies for a Patent Ductus Arteriosus

Background: Preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA) are at risk for fluctuations in cerebral blood flow, but it is unclear how different hsPDA treatment strategies may affect cerebral oxygenation. Objective: To compare regional cerebral oxygen saturation (rSO2) as measured by near-infrared spectroscopy (NIRS) in very low birth weight (VLBW) infants with a hsPDA treated with conservative management, indomethacin, or surgical ligation. Methods: This prospective observational study enrolled 33 VLBW infants with a hsPDA diagnosed by echocardiogram and 12 control VLBW infants without a hsPDA. Infants had NIRS cerebral monitoring applied prior to conservative treatment, indomethacin, or surgical ligation. Cranial ultrasound and magnetic resonance imaging data were also collected. Results: Infants undergoing surgical ligation had a greater time period with >20% change in rSO2 from baseline (30%) compared to those receiving indomethacin (7.4%, p = 0.001) or control infants without a hsPDA (2.6%, p = 0.0004). NIRS measures were not associated with abnormal neuroimaging in this small cohort. Conclusion:These findings suggest that infants requiring surgical ligation for a hsPDA are at high risk for significant changes in cerebral oxygenation, whereas those receiving either indomethacin or conservative management maintain relatively stable cerebral oxygenation levels. Additional research is necessary to determine if NIRS monitoring identifies infants with a hsPDA at highest risk for brain injury.

Failed endotracheal intubation and adverse outcomes among extremely low birth weight infants.

Objective:To quantify the importance of successful endotracheal intubation on the first attempt among extremely low birth weight (ELBW) infants who require resuscitation after delivery.Study Design:A retrospective chart review was conducted for all ELBW infants ⩽1000 g born between January 2007 and May 2014 at a level IV neonatal intensive care unit. Infants were included if intubation was attempted during the first 5 min of life or if intubation was attempted during the first 10 min of life with heart rate <100. The primary outcome was death or neurodevelopmental impairment. The association between successful intubation on the first attempt and the primary outcome was assessed using multivariable logistic regression with adjustment for birth weight, gestational age, gender and antenatal steroids.Results:The study sample included 88 ELBW infants. Forty percent were intubated on the first attempt and 60% required multiple intubation attempts. Death or neurodevelopmental impairment occurred in 29% of infants intubated on the first attempt, compared with 53% of infants that required multiple attempts, adjusted odds ratio 0.4 (95% confidence interval 0.1 to 1.0), P<0.05.Conclusion:Successful intubation on the first attempt is associated with improved neurodevelopmental outcomes among ELBW infants. This study confirms the importance of rapid establishment of a stable airway in ELBW infants requiring resuscitation after birth and has implications for personnel selection and role assignment in the delivery room.

Susceptibility to apoptosis varies with time in culture for murine neurons and astrocytes: changes in gene expression and activity

Abstract Apoptotic pathways in the brain may differ depending on cell type and developmental stage. To understand these differences, we studied several apoptotic proteins in the murine cortex and primary cultures of neurons and astrocytes of various ages in culture. We then induced apoptosis in our cultures using serum deprivation (SD) and observed changes in these apoptotic proteins. When analyzed by nuclear morphology and TUNEL staining, early cultures showed greater apoptotic injury compared with late cultures, and neuronal cultures showed greater apoptosis than astrocyte cultures. The decrease in apoptosis with development correlated best with a down-regulation of procaspase-3 and bax and decreasing caspase activation. Early culture astrocytes had higher caspase-11 levels compared with neurons. Mitogen-activated protein (MAP) kinases were also differentially expressed with activation of extracellular signal-regulated kinase (ERK) and p38 higher in early culture astrocytes and stress-activated protein kinase/C-jun N-terminal kinase (SAPK/JNK) greater in early culture neurons. However, caspase inhibitors, but not MAP kinase inhibitors reduced cell death. Our findings demonstrate that apoptosis regulatory proteins display cell type and developmentally specific expression and activation.

Near-infrared spectroscopy for detection of a significant patent ductus arteriosus.

Background:Near-infrared spectroscopy (NIRS) may assist with characterization of a hemodynamically significant patent ductus arteriosus (hsPDA) by measuring cerebral and renal saturation (Csat and Rsat) levels. We hypothesized that Csat and Rsat in preterm infants with an hsPDA would be decreased compared to those with no PDA or nonsignificant PDA.Methods:This non a-priori designed study retrospectively investigated clinical and ECHO characteristics of preterm infants <29 wk gestation who underwent routine NIRS monitoring. Logistic regression assessed association between NIRS measures and an hsPDA by ECHO.Results:Of 47 infants, 21 had a confirmed hsPDA by ECHO, 14 had a nonsignificant PDA, and 12 had no ECHO performed due to low clinical suspicion for PDA. Logistic regression adjusted for gestational age found that lower Rsat was associated with an hsPDA by ECHO (OR 0.9, 95% CI 0.83–0.98, P = 0.01). Using ROC curves, Rsat < 66% identified an hsPDA with a sensitivity of 81% and specificity of 77%, while Csat was not significant.Conclusion:Low Rsat < 66% was associated with the presence of an hsPDA in the preterm infant. Csat may be preserved if cerebral autoregulation is largely intact. Bedside NIRS monitoring may reasonably increase suspicion for a significant PDA in the preterm infant.

Development of neonatal murine microglia in vitro : Changes in response to lipopolysaccharide and ischemia-like injury

Hypoxic/ischemic brain injury in the neonate can activate an inflammatory cascade, which potentiates cellular injury. The role of microglia in this inflammatory response has not been studied extensively. We used an in vitro model of murine microglia to investigate changes in microglial cytokine release and injury during early development. Isolated microglia were subjected to lipopolysaccharide (LPS) activation or injury by glucose deprivation (GD), serum deprivation (SD), or combined oxygen-glucose deprivation (OGD) for varying durations. The extent and the type of cell death were determined by trypan blue, terminal deoxynucleotidyl end-nick labeling, and annexin staining. Early-culture microglia (2–3 d in purified culture) showed significantly more apoptotic cell death after SD, GD, and OGD compared with microglia maintained in culture for 14–17 d. Measurements of tumor necrosis factor-α (TNF-α) and IL-1β in culture media demonstrated that OGD induced greater release of both TNF-α and IL-1β than LPS activation, with early-culture microglia producing more TNF-α compared with late-culture microglia. Microglia that are cultured for a short time are more sensitive to ischemia-like injury in vitro than those that are cultured for longer durations and may contribute to worsening brain injury by increased release of inflammatory cytokines. Inhibition of microglial activation and decreasing proinflammatory cytokine release may be targets for reduction of neonatal hypoxic/ischemic brain injury.

Predictors of bronchopulmonary dysplasia or death in premature infants with a patent ductus arteriosus

Background:Preterm infants with a patent ductus arteriosus (PDA) are at risk for death or development of bronchopulmonary dysplasia (BPD). However, PDA treatment remains controversial. We investigated if PDA treatment and other clinical or echocardiographic (ECHO) factors were associated with the development of death or BPD.Methods:We retrospectively studied clinical and ECHO characteristics of preterm infants with birth weight <1,500 g and ECHO diagnosis of a PDA. Logistic regression and classification and regression tree analyses were performed to assess variables associated with the combined outcome of death or BPD.Results:Of 187 preterm infants with a PDA, 75% were treated with indomethacin or surgical ligation and 25% were managed conservatively. Death or BPD occurred in 80 (43%) infants. The results of logistic regression analyses showed that lower gestational age (odds ratio (OR): 0.5), earlier year of birth during the study period (OR: 0.9), and larger ductal diameter (OR: 4.3) were associated with the decision to treat the PDA, whereas gestational age was the only variable associated with death or BPD (OR: 0.6; 95% confidence interval: 0.5–0.8).Conclusion:Only lower gestational age and not PDA treatment or ECHO score was associated with the adverse outcome of death or BPD. Further investigation of PDA management strategies and effects on adverse outcomes of prematurity is needed.