Evaluation of heterogeneity in effect of therapeutic hypothermia by sex among infants with neonatal encephalopathy.

BACKGROUND: Our objective was to examine heterogeneity in the effect of therapeutic hypothermia by sex in infants with moderate or severe neonatal encephalopathy. METHODS: We conducted a post hoc analysis of the Induced Hypothermia trial, which included infants born at gestational ages ≥36 weeks, admitted at ≤6 postnatal hours with evidence of severe acidosis or perinatal complications and moderate or severe neonatal encephalopathy. Multivariate modified Poisson regression models were used to compare the treatment effect of whole-body hypothermia versus control, with an evaluation of interaction by sex, on the primary outcome of death or moderate or severe disability at 18-22 months of corrected age. RESULTS: A total of 101 infants (51 male, 50 female) were randomly assigned to hypothermia treatment and 104 infants (64 male, 40 female) to control. The primary outcome occurred in 45% of the hypothermia group and 63% of the control group (RR 0.73; 95% CI 0.56, 0.94). There was no significant difference (interaction P = 0.50) in the treatment effect of hypothermia on the primary outcome between females (RR 0.79; 95% CI 0.54, 1.17) compared to males (RR 0.63; 95% CI 0.44, 0.91). CONCLUSION: We found no evidence that sex influences the treatment effect of hypothermia in infants with moderate or severe neonatal encephalopathy. IMPACT: Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females. We found no evidence of heterogeneity in the treatment effect of whole-body hypothermia by sex in this post hoc subgroup analysis of infants with moderate or severe neonatal encephalopathy from the National Institute of Child Health and Human Development Neonatal Research Network Induced Hypothermia trial.

Inotrope Needs in Neonates Requiring Extracorporeal Membrane Oxygenation for Respiratory Failure.

OBJECTIVE: To evaluate how inotropic requirements in neonates with respiratory failure are affected by extracorporeal membrane oxygenation (ECMO) mode and whether high requirements predict mortality. STUDY DESIGN: This retrospective chart review included all neonates undergoing ECMO for primary respiratory failure from 2010 to 2016 at a single institution. The vasoactive inotropy score (VIS) was calculated as described in the literature. Data were analyzed with descriptive statistics and univariate analyses. RESULTS: Of the 110 identified neonates, 96 underwent venovenous (VV) (87%), 11 (10%) venoarterial, and 3 (3%) converted from VV to venoarterial. The median precannulation VIS score was 33.02 for patients who underwent VV compared with 28.93 for venoarterial (P = .25) and 15 for infants converted. VIS decreased dramatically by 4 hours of ECMO in both groups. The VIS before cannulation was similar in survivors and nonsurvivors, but was significantly higher in nonsurvivors after 24 hours of ECMO (median VIS, 12 [IQR, 8-25] vs 8 [IQR, 3.0-14.5]; P = .035) and at decannulation (10 [IQR, 7-19] vs 3 [IQR, 0-7]; P < .001). CONCLUSIONS: Neonates with respiratory failure can be successfully managed on VV ECMO even with considerable vasoactive requirements. Vasoactive requirement after 24 hours of ECMO was predictive of mortality.

Evolution of Amplitude-Integrated Electroencephalogram as a Predictor of Outcome in Term Encephalopathic Neonates Receiving Therapeutic Hypothermia.

OBJECTIVES: This study aims to evaluate the ability of (1) a novel amplitude-integrated electroencephalogram (aEEG) background evolution classification system; and (2) specific hour of life (HOL) cut points when observation of aEEG normalization and development of cycling can predict adverse neurological outcomes in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Continuous aEEG data of term neonates with HIE were reviewed for background pattern and aEEG cycling from start of monitoring through rewarming. Infants were classified by overall background evolution pattern. Adverse outcomes were defined as death or severe magnetic resonance imaging injury, as well as developmental outcomes in a subset of patients. aEEG characteristics were compared between outcome groups by multivariate regression models, likelihood ratios (LR), and receiver operating characteristic (ROC) curve analyses. RESULTS: Overall, 80 infants receiving therapeutic hypothermia met the inclusion criteria. Background evolution pattern seemed to distinguish outcome groups more reliably than background pattern at discrete intervals in time (LR: 43.9, p value < 0.001). Infants who did not reach discontinuous background by 15.5 HOL, cycling by 45.5 HOL, and normalization by 78 HOL were most likely to have adverse outcomes. CONCLUSION: Evolution of aEEG in term neonates with HIE may be more useful for predicting outcome than evaluating aEEG at discrete intervals in time.

Antiseizure medication at discharge in infants with hypoxic-ischaemic encephalopathy: an observational study.

OBJECTIVES: To assess variability in continuation of antiseizure medication (ASM) at discharge and to evaluate if continuation of ASM at discharge is associated with death or disability among infants with hypoxic-ischaemic encephalopathy (HIE) and seizures. DESIGN: Retrospective study of infants enrolled in three National Institute of Child Health and Human Development Neonatal Research Network Trials of therapeutic hypothermia. SETTING: 22 US centres. PATIENTS: Infants with HIE who survived to discharge and had clinical or electrographic seizures treated with ASM. EXPOSURES: ASM continued or discontinued at discharge. OUTCOMES: Death or moderate-to-severe disability at 18-22 months, using trial definitions. Multivariable logistic regression evaluated the association between continuation of ASM at discharge and the primary outcome, adjusting for severity of HIE, hypothermia trial treatment arm, use of electroencephalogram, discharge on gavage feeds, Apgar Score at 5 min, birth year and centre. RESULTS: Of 302 infants included, 61% were continued on ASMs at discharge (range 13%-100% among 22 centres). Electroencephalogram use occurred in 92% of the cohort. Infants with severe HIE comprised 24% and 22% of those discharged with and without ASM, respectively. The risk of death or moderate-to-severe disability was greater for infants continued on ASM at discharge, compared with those infants discharged without ASM (44% vs 28%, adjusted OR 2.14; 95% CI 1.13 to 4.05). CONCLUSIONS: In infants with HIE and seizures, continuation of ASM at discharge varies substantially among centres and may be associated with a higher risk of death or disability at 18-22 months of age.

Association between anti-seizure medication and outcomes in infants.

OBJECTIVE: To compare treatment failure between: (1) infants treated with phenobarbital versus levetiracetam for first-line treatment and (2) infants treated with phenytoin versus levetiracetam for second-line treatment following phenobarbital. STUDY DESIGN: This retrospective cohort study included infants with seizures receiving phenobarbital or levetiracetam as the initial anti-seizure medication. Treatment failure was defined as the need for additional anti-seizure medication within 24-72 h and compared using mixed-effect logistic regression after adjustment for confounding factors, including center. RESULTS: In this cohort of 6842 infants, the incidence of treatment failure was 31% vs. 38% in infants receiving first-line phenobarbital versus levetiracetam (adjusted OR: 0.70; 95% CI 0.58-0.84). There was no significant difference in second-line treatment failure (adjusted OR: 1.31; 95% CI 0.92-1.86). CONCLUSIONS: First-line treatment of neonatal seizures with phenobarbital is associated with a lower rate of treatment failure than levetiracetam. There was no significant difference in second-line treatment failure.

Neuroimaging for Neurodevelopmental Prognostication in High-Risk Neonates.

Predicting neurodevelopmental outcomes in high-risk neonates remains challenging despite advances in neonatal care. Early and accurate characterization of infants at risk for neurodevelopmental delays is necessary to best identify those who may benefit from existing early interventions and novel therapies that become available. Although neuroimaging is a promising biomarker in the prediction of neurodevelopmental outcomes in high-risk infants, it requires additional resources and expertise. Despite many advances in neonatal neuroimaging, there remain limitations in relating early neuroimaging findings with long-term outcomes; further studies are necessary to determine the optimal protocols to best identify high-risk patients and improve neurodevelopmental outcome prediction.

Perinatal Care of Infants with Congenital Birth Defects.

Prenatal diagnosis has changed perinatal medicine dramatically, allowing for additional fetal monitoring, referral and counseling, delivery planning, the option of fetal intervention, and targeted postnatal management. Teams participating in the delivery room care of infants with known anomalies should be knowledgeable about specific needs and expectations but also ready for unexpected complications. A small number of neonates will need rapid access to postnatal interventions, such as surgery, but most can be stabilized with appropriate neonatal care. These targeted perinatal interventions have been shown to improve outcome in selected diagnoses.

Thromboelastography in term neonates: an alternative approach to evaluating coagulopathy.

OBJECTIVE: To develop normative ranges for citrate-modified and heparinase-modified thromboelastography (TEG) in term neonates. DESIGN: Prospective observational study. SETTING: An outborn neonatal and cardiac intensive care unit in a free-standing academic children's hospital. PATIENTS: Thirty term neonates were enrolled as control subjects. Seventeen infants with clinically documented bleeding requiring blood transfusion were enrolled in the comparison group. MAIN OUTCOME MEASURES: Citrate-modified and heparinase-modified TEG parameters were calculated from blood specimens drawn via peripheral arterial stick or arterial line. RESULTS: TEG in neonates differs from older children and adults; clotting time (R) and clot kinetics (K) values are generally lower while fibrinolysis or rate of clot breakdown (LY30) and coagulation index (CI) are often higher in neonates. TEG values in term neonates calculated as median (Q1-Q3) are as follows: R 4.150 (3.200-6.200), K 1.550 (1.200-1.800), α angle (α) 70.100 (66.000-72.900), maximum amplitude (MA) 61.850 (59.400-66.000), LY30 1.050 (0.100-1.600) and CI 1.950 (0.100 to 2.900). Cut points selected for optimal predictive value for bleeding using receiver operating curve analyses were R>6.3 (sensitivity 82.4%, specificity 80%); K>2.5 (sensitivity 82.4%, specificity 96.7%); α<59 (sensitivity 82.4%, specificity 96.7%); MA<57 (sensitivity 82.4%, specificity 86.7%); CI<-0.15 (sensitivity 88.2%, specificity 83.3%). CONCLUSIONS: The reference ranges and cut points for citrate-modified and heparinase-modified TEG can be used to diagnose and evaluate coagulopathy in term neonates.