Neonatal Seizure Management: Is the Timing of Treatment Critical?

OBJECTIVE: To assess the impact of the time to treatment of the first electrographic seizure on subsequent seizure burden and describe overall seizure management in a large neonatal cohort. STUDY DESIGN: Newborns (36-44 weeks of gestation) requiring electroencephalographic (EEG) monitoring recruited to 2 multicenter European studies were included. Infants who received antiseizure medication exclusively after electrographic seizure onset were grouped based on the time to treatment of the first seizure: antiseizure medication within 1 hour, between 1 and 2 hours, and after 2 hours. Outcomes measured were seizure burden, maximum seizure burden, status epilepticus, number of seizures, and antiseizure medication dose over the first 24 hours after seizure onset. RESULTS: Out of 472 newborns recruited, 154 (32.6%) had confirmed electrographic seizures. Sixty-nine infants received antiseizure medication exclusively after the onset of electrographic seizure, including 21 infants within 1 hour of seizure onset, 15 between 1 and 2 hours after seizure onset, and 33 at >2 hours after seizure onset. Significantly lower seizure burden and fewer seizures were noted in the infants treated with antiseizure medication within 1 hour of seizure onset (P = .029 and .035, respectively). Overall, 258 of 472 infants (54.7%) received antiseizure medication during the study period, of whom 40 without electrographic seizures received treatment exclusively during EEG monitoring and 11 with electrographic seizures received no treatment. CONCLUSIONS: Treatment of neonatal seizures may be time-critical, but more research is needed to confirm this. Improvements in neonatal seizure diagnosis and treatment are also needed.

Up-Regulation of Nfat5 mRNA and Fzd4 mRNA as a Marker of Poor Outcome in Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To evaluate umbilical cord messenger RNA (mRNA) expression as biomarkers for the grade of hypoxic-ischemic encephalopathy (HIE) and long-term neurodevelopment outcome. STUDY DESIGN: Infants were recruited from the BiHiVE1 study, Ireland (2009-2011), and the BiHiVE2 study, Ireland, and Sweden (2013-2015). Infants with HIE were assigned modified Sarnat scores at 24 hours and followed at 18-36 months. mRNA expression from cord blood was measured using quantitative real-time polymerase chain reaction. RESULTS: We studied 124 infants (controls, n = 37; perinatal asphyxia, n = 43; and HIE, n = 44). Fzd4 mRNA increased in severe HIE (median relative quantification, 2.98; IQR, 2.23-3.68) vs mild HIE (0.88; IQR, 0.46-1.37; P = .004), and in severe HIE vs moderate HIE (1.06; IQR, 0.81-1.20; P = .003). Fzd4 mRNA also increased in infants eligible for therapeutic hypothermia (1.20; IQR, 0.92-2.37) vs those who were ineligible for therapeutic hypothermia group (0.81; IQR, 0.46-1.53; P = .017). Neurodevelopmental outcome was analyzed for 56 infants. Nfat5 mRNA increased in infants with severely abnormal (1.26; IQR, 1.17-1.39) vs normal outcomes (0.97; IQR, 0.83-1.24; P = .036), and also in infants with severely abnormal vs mildly abnormal outcomes (0.96; IQR, 0.80-1.06; P = .013). Fzd4 mRNA increased in infants with severely abnormal (2.51; IQR, 1.60-3.56) vs normal outcomes (0.74; IQR, 0.48-1.49; P = .004) and in infants with severely abnormal vs mildly abnormal outcomes (0.97; IQR, 0.75-1.34; P = .026). CONCLUSIONS: Increased Fzd4 mRNA expression was observed in cord blood of infants with severe HIE; Nfat5 mRNA and Fzd4 mRNA expression were increased in infants with severely abnormal long-term outcomes. These mRNA may augment current measures as early objective markers of HIE severity at delivery.

Improvement in the Prediction of Neonatal Hypoxic-Ischemic Encephalopathy with the Integration of Umbilical Cord Metabolites and Current Clinical Makers.

OBJECTIVE: To validate our previously identified candidate metabolites, and to assess the ability of these metabolites to predict hypoxic-ischemic encephalopathy (HIE) both individually and combined with clinical data. STUDY DESIGN: Term neonates with signs of perinatal asphyxia, with and without HIE, and matched controls were recruited prospectively at birth from 2 large maternity units. Umbilical cord blood was collected for later batch metabolomic analysis by mass spectroscopy along with clinical details. The optimum selection of clinical and metabolites features with the ability to predict the development of HIE was determined using logistic regression modelling and machine learning techniques. Outcome of HIE was determined by clinical Sarnat grading and confirmed by electroencephalogram grade at 24 hours. RESULTS: Fifteen of 27 candidate metabolites showed significant alteration in infants with perinatal asphyxia or HIE when compared with matched controls. Metabolomic data predicted the development of HIE with an area under the curve of 0.67 (95% CI, 0.62-0.71). Lactic acid and alanine were the primary metabolite predictors for the development of HIE, and when combined with clinical data, gave an area under the curve of 0.96 (95% CI, 0.92-0.95). CONCLUSIONS: By combining clinical and metabolic data, accurate identification of infants who will develop HIE is possible shortly after birth, allowing early initiation of therapeutic hypothermia.

Clamping the Umbilical Cord in Premature Deliveries (CUPiD): Neuromonitoring in the Immediate Newborn Period in a Randomized, Controlled Trial of Preterm Infants Born at <32 Weeks of Gestation.

OBJECTIVE: To compare cerebral activity and oxygenation in preterm infants (<32 weeks of gestation) randomized to different cord clamping strategies. STUDY DESIGN: Preterm infants born at <32 weeks of gestation were randomized to immediate cord clamping, umbilical cord milking (cord stripped 3 times), or delayed cord clamping for 60 seconds with bedside resuscitation. All infants underwent electroencephalogram (EEG) and cerebral near infrared spectroscopy for the first 72 hours after birth. Neonatal primary outcome measures were quantitative measures of the EEG (17 features) and near infrared spectroscopy over 1-hour time frames at 6 and 12 hours of life. RESULTS: Forty-five infants were recruited during the study period. Twelve infants (27%) were randomized to immediate cord clamping, 19 (42%) to umbilical cord milking, and 14 (31%) to delayed cord clamping with bedside resuscitation. There were no significant differences between groups for measures of EEG activity or cerebral near infrared spectroscopy. Three of the 45 infants (6.7%) were diagnosed with severe IVH (2 in the immediate cord clamping group, 1 in the umbilical cord milking group; P = .35). CONCLUSIONS: There were no differences in cerebral EEG activity and cerebral oxygenation values between cord management strategies at 6 and 12 hours. TRIAL REGISTRATION: ISRCTN92719670.

Electrographic Seizures during the Early Postnatal Period in Preterm Infants.

OBJECTIVE: To investigate the frequency and characteristics of electrographic seizures in preterm infants in the early postnatal period. STUDY DESIGN: Infants <32 weeks gestational age (GA) (n = 120) were enrolled for continuous multichannel electroencephalography (EEG) recording initiated as soon as possible after birth and continued for approximately up to 72 hours of age. Electrographic seizures were identified visually, annotated, and analyzed. Quantitative descriptors of the temporal evolution of seizures, including total seizure burden, seizure duration, and maximum seizure burden, were calculated. RESULTS: Median GA was 28.9 weeks (IQR, 26.6-30.3 weeks) and median birth weight was 1125 g (IQR, 848-1440 g). Six infants (5%; 95% CI, 1.9-10.6%) had electrographic seizures. Median total seizure burden, seizure duration, and maximum seizure burden were 40.3 minutes (IQR, 5.0-117.5 minutes), 49.6 seconds (IQR, 43.4-76.6 seconds), and 10.8 minutes/hour (IQR, 1.6-20.2 minutes/hour), respectively. Seizure burden was highest in 2 infants with significant abnormalities on neuroimaging. CONCLUSION: Electrographic seizures are infrequent within the first few days of birth in very preterm infants. Seizures in this population are difficult to detect accurately without continuous multichannel EEG monitoring.

A Randomized Controlled Trial of End-Tidal Carbon Dioxide Detection of Preterm Infants in the Delivery Room.

OBJECTIVE: To compare the ability of qualitative versus quantitative methods of end-tidal carbon dioxide (EtCO2) detection to maintain normocarbia during face mask ventilation (FMV) of preterm infants (<32 weeks) in the delivery room. STUDY DESIGN: Preterm infants <32 weeks were randomly assigned to the use of a disposable PediCap EtCO2 detector (Covidien, Dublin, Ireland) (qualitative) or a Microstream side stream capnography device (Covidien) (quantitative) for FMV in the delivery room, via a NeoPuff T-piece resuscitator (Fisher and Paykel, Auckland, New Zealand). The primary outcome was the presence of normocarbia, based on partial pressure of CO2 (PaCO2) readings obtained in the neonatal intensive care unit within an hour of birth. Normocarbia was defined as a PaCO2 measure between 37.5 and 60 mm Hg (5-8 kPa). RESULTS: Of the 59 infants included, 59% (35/59) were within the PaCO2 target range within an hour of birth. There was no difference in the primary outcome; 64% (21/33) of infants in the quantitative group were within the PaCO2 range compared with 54% (14/26) in the qualitative group (P = .594); and 93% of participants <28 weeks' gestation were within the PaCO2 normocarbic range (90% [9/10] in quantitative group and 100% [5/5] in the qualitative group [P = 1]). There was no difference in the intubation rate, days of ventilation, or bronchopulmonary dysplasia rates between the 2 groups. CONCLUSIONS: Quantitative or qualitative EtCO2 detection methods are both feasible for FMV in the delivery room. Although there was no difference in the incidence of normocarbia, the use of either form of EtCO2 monitoring should be considered during newborn stabilization, especially in infants less than 28 weeks' gestation. TRIAL REGISTRATION: ISRCTN: ISRCTN10934870.

Decreased Variability and Low Values of Perfusion Index on Day One Are Associated with Adverse Outcome in Extremely Preterm Infants.

OBJECTIVE: To develop new quantitative features for the Perfusion Index signal recorded continuously over the first 24 hours of life in a cohort of extremely low gestational age newborns and to assess the association of these features with normal and adverse short-term outcome. STUDY DESIGN: A cohort study of extremely low gestational age newborns. Adverse outcome was defined as early mortality before 72 hours of life, acquired severe periventricular-intraventricular hemorrhage, or severe cystic leukomalacia. Perfusion Index values were obtained from the plethysmographic signal of a pulse oximeter. Perfusion Index signals were separated into low-frequency (trend) and high-frequency (detrend) components. Three features were extracted during four 6-hour epochs: mean of the trend component (mean-trend), SD of the trend component (SD-trend), and SD of the detrend component (SD-detrend). The SD features represent long-term variability (SD-trend) and short-term variability (SD-detrend) of the Perfusion Index. A mixed-effects model was fitted to each feature. RESULTS: Ninety-nine infants were included in the analysis. Quadratic-time mixed-effects models provided the best fit for all 3 features. The mean-trend component was lower for the adverse outcome compared with the normal outcome group with a difference of 0.142 Perfusion Index (P = .001). SD-detrend component was also lower for the adverse compared with the normal outcome group, although this difference of 0.031 Perfusion Index/days2 was dependent on time (P < .001). CONCLUSION: Low values and reduced short-term variability of Perfusion Index on day 1 are associated with adverse outcome.

Effects of Fractional Inspired Oxygen on Cerebral Oxygenation in Preterm Infants following Delivery.

OBJECTIVES: To explore regional cerebral oxygen saturations (rcSO2) in preterm neonates initially stabilized with 0.3 fractionated inspired oxygen (FiO2) concentrations. We hypothesized that those infants who received >0.3 FiO2 during stabilization following delivery would have relatively higher rcSO2 postdelivery compared with those stabilized with a lower FiO2. STUDY DESIGN: A single center prospective observational study of 47 infants born before 32 weeks. Using near infrared spectroscopy, rcSO2 values were recorded immediately after birth. All preterm infants were initially given 0.3 FiO2 and were divided into 2 groups according to subsequent FiO2 requirements of either ≤0.3 or >0.3 FiO2. Using a mixed-effects model, we compared the difference between the groups over time. Also, the area measures below 55% (hypoxia) and above 85% (hyperoxia) were compared between the groups. RESULTS: The mean (SD) gestation was 29.4 (1.6) weeks and the mean (SD) weight was 1.3 (0.4) kg. Less than one-half of the infants (20/45; 43%) required ≤0.3 FiO2. In the delivery suite, the median (IQR) rcSO2 in the low and high FiO2 groups were 81% (66%-86%) and 72% (62%-86%), respectively. Patients in the high FiO2 group had a larger rcSO2 area below 55% (P = .01). There was a significant difference in rcSO2 between the groups (P < .05), with the low group having higher rcSO2 values initially, but this difference changed over time. In the neonatal intensive care unit (NICU), rcSO2 values were lower by 7.1% (CI 12.13 to 2.06%) P = .008 in the high FiO2 group. CONCLUSIONS: Infants given >0.3 FiO2 had more cerebral hypoxia than infants requiring ≤0.3 FiO2 but no difference in the degree of cerebral hyperoxia, both in the delivery suite and the NICU. This suggests that a more rapid increase in oxygen titration maybe be required initially for preterm infants.

Downregulation of Umbilical Cord Blood Levels of miR-374a in Neonatal Hypoxic Ischemic Encephalopathy.

OBJECTIVE: To investigate the expression profile of microRNA (miRNA) in umbilical cord blood from infants with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: Full-term infants with perinatal asphyxia were identified under strict enrollment criteria. Degree of encephalopathy was defined using both continuous multichannel electroencephalogram in the first 24 hours of life and modified Sarnat score. Seventy infants (18 controls, 33 with perinatal asphyxia without HIE, and 19 infants with HIE [further graded as 13 mild, 2 moderate, and 4 severe]) were included in the study. MiRNA expression profiles were determined using a microarray assay and confirmed using quantitative real-time polymerase chain reaction. RESULTS: Seventy miRNAs were differentially expressed between case and control groups. Of these hsa-miR-374a was the most significantly downregulated in infants with HIE vs controls. Validation of hsa-miR-374a expression using quantitative real-time polymerase chain reaction confirmed a significant reduction in expression among infants with HIE compared with those with perinatal asphyxia and healthy controls (mean relative quantification [SD] = 0.52 [0.37] vs 1.10 [1.52] vs 1.76 [1.69], P < .02). CONCLUSIONS: We have shown a significant step-wise downregulation of hsa-miR-374a expression in cord blood of infants with perinatal asphyxia and subsequent HIE.