Rakesh Rao

Treating EEG Seizures in Hypoxic Ischemic Encephalopathy: A Randomized Controlled Trial

BACKGROUND: The impact of treating electrographic seizures in hypoxic ischemic encephalopathy (HIE) is unknown. METHODS: Neonates ≥36 weeks with moderate or severe HIE were randomly assigned to either treatment of electrographic seizures alone (ESG) or treatment of clinical seizures (CSG). Conventional EEG video was monitored in both groups for up to 96 hours. Cumulative electrographic seizure burden (SB) was calculated in seconds and converted to log units for analysis. MRI scans were scored for severity of brain injury. Infants underwent neurodevelopmental evaluation at 18 to 24 months. Statistical analyses were performed by using SAS 9.3 version (SAS Institute, Inc, Cary, NC). RESULTS: Thirty-five of 69 neonates (51%) who were randomly assigned and included in the study developed seizures (15 in ESG and 20 in CSG). Excluding infants with status epilepticus, median SB (interquartile range) in seconds in ESG (n = 10) was lower than in CSG (n = 16) (449 [113–2070] vs 2226 [760–7654]; P = .02). ESG had fewer seizures with shorter time to treatment (P = .04). Twenty-four of 30 (80%) surviving infants with seizures underwent neurodevelopmental evaluation at 18 to 24 months. Increasing SB in the combined cohort was significantly associated with higher brain injury scores (P < .03) and lower performance scores across all 3 domains on BSID III (P = .03). CONCLUSIONS: In neonates with HIE, EEG monitoring and treatment of electrographic seizures results in significant reduction in SB. SB is associated with more severe brain injury and significantly lower performance scores across all domains on BSID III.

Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children’s Hospitals Neonatal Consortium HIE focus group

Objective:To characterize infants affected with perinatal hypoxic ischemic encephalopathy (HIE) who were referred to regional neonatal intensive care units (NICUs) and their related short-term outcomes.Study Design:This is a descriptive study evaluating the data collected prospectively in the Children’s Hospital Neonatal Database, comprised of 27 regional NICUs within their associated children’s hospitals. A consecutive sample of 945 referred infants born ⩾36 weeks’ gestation with perinatal HIE in the first 3 days of life over approximately 3 years (2010–July 2013) were included. Maternal and infant characteristics are described. Short-term outcomes were evaluated including medical comorbidities, mortality and status of survivors at discharge.Result:High relative frequencies of maternal predisposing conditions, cesarean and operative vaginal deliveries were observed. Low Apgar scores, profound metabolic acidosis, extensive resuscitation in the delivery room, clinical and electroencephalographic (EEG) seizures, abnormal EEG background and brain imaging directly correlated with the severity of HIE. Therapeutic hypothermia was provided to 85% of infants, 15% of whom were classified as having mild HIE. Electrographic seizures were observed in 26% of the infants. Rates of complications and morbidities were similar to those reported in prior clinical trials and overall mortality was 15%.Conclusion:Within this large contemporary cohort of newborns with perinatal HIE, the application of therapeutic hypothermia and associated neurodiagnostic studies appear to have expanded relative to reported clinical trials. Although seizure incidence and mortality were lower compared with those reported in the trials, it is unclear whether this represented improved outcomes or therapeutic drift with the treatment of milder disease.

Brain-Derived Neurotrophic Factor in Infants <32 Weeks Gestational Age: Correlation With Antenatal Factors and Postnatal Outcomes

Neurotrophins (NTs) play important roles in brain growth and development. Cord blood (CB) brain-derived neurotrophic factor (BDNF) concentrations increase with gestational age but data regarding postnatal changes are limited. We measured BDNF concentrations after birth in 33 preterm infants <32-wk gestation. Serum was collected at birth (CB), at day 2, between day 6 and 10 (D6), at day 30 (D30), and at day 60 (D60). BDNF concentrations fell on D2 (p = 0.03), recovered by D6 (p = 0.10), and continued to rise thereafter at D30 (p = 0.06) and D60 (p = 0.01) compared with CB. CB BDNF concentrations positively correlated with duration of rupture of membranes (r = 0.43, p = 0.04). Antenatal steroids (ANS, p = 0.02), postnatal steroids (PNS, p = 0.04), and retinopathy of prematurity (ROP, p = 0.02) were identified as significant factors in multivariate analyses. The median (25–75th interquartile range) CB BDNF concentrations were higher in infants who received a complete course ANS compared with those who received a partial course [1461 (553–2064) versus 281 (171–536) pg/mL, p = 0.04]. BDNF concentrations negatively correlated with the use of PNS at D30 (r = −0.53, p = 0.002) and at D60 (r = −0.55, p = 0.009). PNS use was associated with reduced concentrations of BDNF at D30 [733 (101–1983) versus 2224 (1677–4400) pg/mL, p = 0.004] and at D60 [1149 (288–2270) versus 2560 (1337–5166) pg/mL, p = 0.01]. BDNF concentrations on D60 in infants who developed ROP (n = 16) were lower than those who did not develop ROP (n = 7) [1417 (553–2540) versus 3593 (2620–7433) pg/mL, respectively, p = 0.005]. Our data suggests that BDNF concentrations rise beyond the first week of age. BDNF concentrations correlate with factors that influence neurodevelopment outcomes.

Safety and Short-Term Outcomes of Therapeutic Hypothermia in Preterm Neonates 34-35 Weeks Gestational Age with Hypoxic-Ischemic Encephalopathy

Objective To evaluate the safety and short‐term outcomes of preterm neonates born at 34‐35 weeks gestation with hypoxic‐ischemic encephalopathy (HIE) treated with therapeutic hypothermia. Study design Medical records of preterm neonates born at 34‐35 weeks gestational age with HIE treated with therapeutic hypothermia were retrospectively reviewed. Short‐term safety outcomes and the presence, severity (mild, moderate, severe), and patterns of brain injury on magnetic resonance imaging were reviewed using a standard scoring system, and compared with a cohort of term neonates with HIE treated with therapeutic hypothermia. Results Thirty‐one preterm and 32 term neonates were identified. Therapeutic hypothermia‐associated complications were seen in 90% of preterm infants and 81.3% of term infants (P = .30). In the preterm infants, hyperglycemia (58.1% vs31.3%, P = .03) and rewarming before completion of therapeutic hypothermia (19.4% vs 0.0%, P = .009) were more likely compared with term infants. All deaths occurred in the preterm group (12.9% vs 0%, P = .04). Neuroimaging showed the presence of injury in 80.6% of preterm infants and 59.4% of term infants (P = .07), with no differences in injury severity. Injury to the white matter was more prevalent in preterm infants compared with term infants (66.7% vs 25.0%, P = .001). Conclusions Therapeutic hypothermia in infants born at 34‐35 weeks gestational age appears feasible. Risks of mortality and side effects warrant caution with use of therapeutic hypothermia in preterm infants.

Gastrointestinal complications associated with ibuprofen therapy for patent ductus arteriosus

Objective:To review intestinal complications associated with ibuprofen treatment of patent ductus arteriosus (PDA).Study Design:Data from preterm infants treated with ibuprofen were retrospectively reviewed. χ 2 test and Fischers exact test were used for univariate analyses. Multivariate analyses with logistic regression modeling were used to identify risk factors.Result:One hundred and two infants were treated with ibuprofen for PDA. Nine (9/102, 8.8%) infants developed spontaneous intestinal perforation (SIP), whereas 93/102 (91.2%) did not. The mean (±s.d.) gestational age (GA) at birth in infants with and without SIP was 25.2 (±1.3) vs 27.6 (±2.4) weeks (P=0.02) and the median (interquartile) length of stay (LOS) was 109.5 (91.0 to 116.5) vs 75.0 (53.0 to 94.5) days (P=0.002), respectively. The mean (±s.d.) age at starting ibuprofen was 3.3 (±1.3) vs 5.8 (±3.5) days in infants with and without SIP, respectively (P=0.03). In logistic regression analyses, increasing GA and later initiation of ibuprofen treatment were protective against risk of SIP; odds ratio, 95% confidence interval (OR, 95% CI)=0.26 (0.09 to 0.75), P=0.01 and 0.63 (0.41 to 0.95), P=0.03, respectively.Conclusion:Infants at lower GA are at risk of SIP when treated early with ibuprofen for symptomatic PDA.

Depth of bacterial invasion in resected intestinal tissue predicts mortality in surgical necrotizing enterocolitis.

Objective:Up to a third of all infants who develop necrotizing enterocolitis (NEC) require surgical resection of necrotic bowel. We hypothesized that the histopathological findings in surgically resected bowel can predict the clinical outcome of these infants.Study Design:We reviewed the medical records and archived pathology specimens from all patients who underwent bowel resection/autopsy for NEC at a regional referral center over a 10-year period. Pathology specimens were graded for the depth and severity of necrosis, inflammation, bacteria invasion and pneumatosis, and histopathological findings were correlated with clinical outcomes.Result:We performed clinico-pathological analysis on 33 infants with confirmed NEC, of which 18 (54.5%) died. Depth of bacterial invasion in resected intestinal tissue predicted death from NEC (odds ratio 5.39 per unit change in the depth of bacterial invasion, 95% confidence interval 1.33 to 21.73). The presence of transmural necrosis and bacteria in the surgical margins of resected bowel was also associated with increased mortality.Conclusion:Depth of bacterial invasion in resected intestinal tissue predicts mortality in surgical NEC.

OxyContin and neonatal abstinence syndrome.

Opioids are a commonly abused class of drugs. OxyContin® abuse, a long-acting oxycodone derivative, has been increasingly identified as a potent narcotic resulting in drug dependence, overdose and even death. Use during pregnancy may result in withdrawal symptoms in the neonate. However, detection of the drug and its metabolites needs special methods in order to initiate appropriate therapy.

Cerebrospinal fluid levels of amyloid precursor protein are associated with ventricular size in post-hemorrhagic hydrocephalus of prematurity

Background Neurological outcomes of preterm infants with post-hemorrhagic hydrocephalus (PHH) remain among the worst in infancy, yet there remain few instruments to inform the treatment of PHH. We previously observed PHH-associated elevations in cerebrospinal fluid (CSF) amyloid precursor protein (APP), neural cell adhesion molecule-L1 (L1CAM), neural cell adhesion molecule-1 (NCAM-1), and other protein mediators of neurodevelopment. Objective The objective of this study was to examine the association of CSF APP, L1CAM, and NCAM-1 with ventricular size as an early step toward developing CSF markers of PHH. Methods CSF levels of APP, L1CAM, NCAM-1, and total protein (TP) were measured in 12 preterm infants undergoing PHH treatment. Ventricular size was determined using cranial ultrasounds. The relationships between CSF APP, L1CAM, and NCAM-1, occipitofrontal circumference (OFC), volume of CSF removed, and ventricular size were examined using correlation and regression analyses. Results CSF levels of APP, L1CAM, and NCAM-1 but not TP paralleled treatment-related changes in ventricular size. CSF APP demonstrated the strongest association with ventricular size, estimated by frontal-occipital horn ratio (FOR) (Pearson R = 0.76, p = 0.004), followed by NCAM-1 (R = 0.66, p = 0.02) and L1CAM (R = 0.57,p = 0.055). TP was not correlated with FOR (R = 0.02, p = 0.95). Conclusions Herein, we report the novel observation that CSF APP shows a robust association with ventricular size in preterm infants treated for PHH. The results from this study suggest that CSF APP and related proteins at once hold promise as biomarkers of PHH and provide insight into the neurological consequences of PHH in the preterm infant.

Head position change is not associated with acute changes in bilateral cerebral oxygenation in stable preterm infants during the first 3 days of life

OBJECTIVE Several recent intraventricular hemorrhage prevention bundles include midline head positioning to prevent potential disturbances in cerebral hemodynamics. We aimed to study the impact of head position change on regional cerebral saturations (SctO2) in preterm infants (< 30 weeks gestational age) during the first 3 days of life. STUDY DESIGN Bilateral SctO2 was measured by near-infrared spectroscopy. The infants head was turned sequentially to each side from midline (baseline) in 30-minute intervals while keeping the body supine. Bilateral SctO2 before and after each position change were compared using paired t-test. RESULTS In relatively stable preterm infants (gestational age 26.5 ± 1.7 weeks, birth weight 930 ± 220 g; n = 20), bilateral SctO2 remained within normal range (71.1-75.3%) when the head was turned from midline position to either side. CONCLUSION Stable preterm infants tolerated brief changes in head position from midline without significant alternation in bilateral SctO2; the impact on critically ill infants needs further evaluation.

Intercenter Cost Variation for Perinatal Hypoxic-Ischemic Encephalopathy in the Era of Therapeutic Hypothermia.

OBJECTIVE To quantify intercenter cost variation for perinatal hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia across childrens hospitals. STUDY DESIGN Prospectively collected data from the Childrens Hospitals Neonatal Database and Pediatric Health Information Systems were linked to evaluate intercenter cost variation in total hospitalization costs after adjusting for HIE severity, mortality, length of stay, use of extracorporeal support or nitric oxide, and ventilator days. Secondarily, costs for intensive care unit bed, electroencephalography (EEG), and laboratory and neuroimaging testing were also evaluated. Costs were contextualized by frequency of favorable (survival with normal magnetic resonance imaging) and adverse (death or need for gastric tube feedings at discharge) outcomes to identify centers with relative low costs and favorable outcomes. RESULTS Of the 822 infants with HIE treated with therapeutic hypothermia at 19 regional neonatal intensive care units, 704 (86%) survived to discharge. The median cost/case for survivors was