Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series).

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

Altered biventricular function in neonatal hypoxic-ischaemic encephalopathy: a case-control echocardiographic study.

BACKGROUND: In newborns with hypoxic-ischaemic encephalopathy, more profound altered right and left ventricular function has been associated with mortality or brain injury. Mechanisms underlying cardiac dysfunction in this population are thought to be related to the persistence of increased pulmonary vascular resistance and myocardial ischaemia. We sought to compare cardiac function in newborns with hypoxic-ischaemic encephalopathy to controls using echocardiography. METHODS: We did a retrospective case-control study with moderate or severe hypoxic-ischaemic encephalopathy between 2008 and 2017. Conventional and speckle-tracking echocardiography measures were extracted to quantify right and left ventricular systolic and diastolic function. Fifty-five newborns with hypoxic-ischaemic encephalopathy were compared to 28 controls. RESULTS: Hypoxic-ischaemic encephalopathy newborns had higher estimated systolic pulmonary pressure (62.5 ± 15.0 versus 43.8 ± 17.3 mmHg, p < 0.0001) and higher systolic pulmonary artery pressure/systolic blood pressure ratio [101 ± 16 (iso-systemic) versus 71 ± 27 (2/3 systemic range) %, p < 0.0001]. Tricuspid annular plane systolic excursion was decreased (7.5 ± 2.2 versus 9.0 ± 1.4 mm, p = 0.002), E/e' increased (7.9 ± 3.3 versus 5.8 ± 2.0, p = 0.01), and right ventricle-myocardial performance index increased (68.1 ± 21.5 versus 47.8 ± 9.5, p = 0.0001) in hypoxic-ischaemic encephalopathy. Conventional markers of left ventricle systolic function were similar, but e' velocity (0.059 ± 0.019 versus 0.070 ± 0.01, p = 0.03) and left ventricle-myocardial performance index were statistically different (77.9 ± 26.2 versus 57.9 ± 11.2, p = 0.001). The hypoxic-ischaemic encephalopathy group had significantly altered right and left ventricular deformation parameters by speckle-tracking echocardiography. Those with decreased right ventricle-peak longitudinal strain were more likely to have depressed left ventricle-peak longitudinal strain. CONCLUSION: Newborns with hypoxic-ischaemic encephalopathy have signs of increased pulmonary pressures and altered biventricular systolic and diastolic function.

Early Discontinuation of Phenobarbital After Acute Symptomatic Neonatal Seizures in the Term Newborn.

Acute symptomatic seizures in the term newborn are often seen after perinatal brain injury. Common etiologies include hypoxic-ischemic encephalopathy, ischemic stroke, intracranial hemorrhage, metabolic derangements, and intracranial infections. Neonatal seizures are often treated with phenobarbital, which may cause sedation and may have significant long-term effects on brain development. Recent literature has suggested that phenobarbital may be safely discontinued in some patients before discharge from the neonatal intensive care unit. Optimizing a strategy for selective early phenobarbital discontinuation would be of great value. In this study, we present a unified framework for phenobarbital discontinuation after resolution of acute symptomatic seizures in the setting of brain injury of the newborn.

Association of EEG Background and Neurodevelopmental Outcome in Neonates With Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.

BACKGROUND AND OBJECTIVES: Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin or placebo for neonates with HIE treated with therapeutic hypothermia. METHODS: Participants had EEG recorded throughout hypothermia. EEG background was classified as normal, discontinuous, or severely abnormal (defined as burst suppression, low voltage suppressed, or status epilepticus) at 5 1-hour epochs: onset of recording, 24, 36, 48, and 72 hours after birth. The predominant background pattern during the entire continuous video EEG monitoring recording was calculated using the arithmetic mean of the 5 EEG background ratings (normal = 0; discontinuous = 1; severely abnormal = 2) as follows: "predominantly normal" (mean = 0), "normal/discontinuous" (0 < mean<1), "predominantly discontinuous" (mean = 1), "discontinuous/severely abnormal" (1 < mean<2), or "predominantly severely abnormal" (mean = 2). Primary outcome was death or neurodevelopmental impairment (NDI) defined as cerebral palsy, Gross Motor Function Classification Score ≥1, or cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition at age 2 years. Neurodevelopment was also categorized into a 5-level ordinal measure: no, mild, moderate, severe NDI, or death for secondary analysis. We used generalized linear regression models with robust standard errors to assess the relative risk of death or NDI by EEG background in both unadjusted and adjusted analyses controlling for the effects of treatment group, sex, HIE severity, and study recruitment site. RESULTS: Among 142 neonates, the predominant background EEG pattern was predominantly normal in 35 (25%), normal/discontinuous in 68 (48%), predominantly discontinuous in 11 (7.7%), discontinuous/severely abnormal in 16 (11%), and predominantly severely abnormal in 12 (8.5%). Increasing severity of background across monitoring epochs was associated with increasingly worse clinical outcomes. Children with severe EEG background abnormality at any time point (n = 36, 25%) were significantly more likely to die or have severe NDI at 2 years (adjusted relative risk: 7.95, 95% CI 3.49-18.12). DISCUSSION: EEG background is strongly associated with NDI at age 2 years. These results can be used to assist health care providers to plan follow-up care and counsel families for decision-making related to goals of care.

Neuroprotection for hypoxic-ischemic encephalopathy: Contributions from the neonatal research network.

Therapeutic hypothermia (TH) is now well established as the standard of care treatment for moderate to severe neonatal encephalopathy secondary to perinatal hypoxic ischemic encephalopathy (HIE) in infants ≥36 weeks gestation in high income countries. The Neonatal Research Network (NRN) contributed greatly to the study of TH as a neuroprotectant with three trials now completed in infants ≥36 weeks gestation and the only large randomized-controlled trial of TH in preterm infants now in the follow-up phase. Data from the first NRN TH trial combined with data from other large trials of TH affirm the safety and neuroprotective qualities of TH and highlight the importance of providing TH to all infants who qualify. In this review we will highlight the findings of the three NRN trials of TH in the term infant population and the secondary analyses that continue to inform the care of patients with HIE.

Association between multi-organ dysfunction and adverse outcome in infants with hypoxic ischemic encephalopathy.

OBJECTIVE: To evaluate multi-organ dysfunction (MOD) in newborns treated with therapeutic hypothermia (TH) for hypoxic ischemic encephalopathy (HIE), and to compare MOD in those with normal/mild magnetic resonance imaging (MRI) findings to those with moderate to severe MRI findings or death. STUDY DESIGN: Retrospective single-center observational study of infants treated with TH. A total of 16 parameters across 7 organ systems were analyzed. Primary outcome was death or moderate to severe brain injury on MRI. RESULT: Of 157 infants treated with TH, 77% had ≥2 organ systems with dysfunction. The number of organ systems with dysfunction was strongly associated with death or moderate-to-severe brain injury (p < 0.0001). Hematologic (68%) and hepatic (65%) dysfunction were most common. Neurologic and renal dysfunction were most strongly associated with the primary outcome (OR 13.5 [6.1-29.8] and 11.2 [4.1-30.3], respectively), while pulmonary hypertension was not. CONCLUSION: MOD is prevalent in infants undergoing TH for HIE, and the association between MOD and adverse outcomes may impact clinical care and counseling.

The Term Newborn: Evaluation for Hypoxic-Ischemic Encephalopathy.

Neonatal encephalopathy due to perinatal hypoxia-ischemia (hypoxic-ischemic encephalopathy [HIE]) occurs at a rate of 1 to 3 per 1000 live births. Therapeutic hypothermia is the standard of care and the only currently available therapy to reduce the risk of death or disability in newborns with moderate to severe HIE. Hypothermia therapy needs to be initiated within 6 hours after birth in order to provide the best chance for neuroprotection. All pediatricians and delivery room attendants should be trained to recognize encephalopathy and understand the eligibility criteria for treatment. The modified Sarnat examination is the most frequently used tool to assess the degree of encephalopathy and has six categories, each of which can have mild, moderate, severe abnormalities. Apart from historical and biochemical criteria, a neonate must have 3 of 6 categories scored in the moderate or severe range in order to qualify for hypothermia as was done in the randomized trials. Whether an infant qualifies or there is concern that an infant might have HIE, transfer to a center that can perform treatment should be initiated immediately. Hypothermia significantly reduces the risk of death or moderate to severe impairments at 2 years and at school age. On average, only 7 neonates need to be treated for one neonate to benefit. Although easy in concept, implementation of hypothermia does require expertise and should be carried out under the guidance of a neonatologist. If infants are passively cooled prior to transport, core temperature needs to be closely monitored with a target of 33.5°C ± 0.5°C. Maintenance of homeostasis is important in order to prevent conditions that may result in additional brain injury. Seizures are common in neonates with HIE, but electrographic seizures are rare in the first few hours after birth if the insult occurred during labor and delivery. Prophylactic antiepileptic drugs should not be administered. Brain monitoring in the form of electroencephalogram (EEG) and or amplitude-integrated EEG should be implemented as soon as possible to help with prognosis and to accurately diagnose seizures.

Outcomes of infants with hypoxic ischemic encephalopathy and persistent pulmonary hypertension of the newborn: results from three NICHD studies.

OBJECTIVE: To determine the association of persistent pulmonary hypertension of the newborn (PPHN) with death or disability among infants with moderate or severe hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia. METHODS: We compared infants with and without PPHN enrolled in the hypothermia arm from three randomized controlled trials (RCTs): Induced Hypothermia trial, "usual care" arm of Optimizing Cooling trial, and Late Hypothermia trial. Primary outcome was death or disability at 18-22 months adjusted for severity of HIE, center, and RCT. RESULTS: Among 280 infants, 67 (24%) were diagnosed with PPHN. Among infants with and without PPHN, death or disability was 47% vs. 29% (adjusted OR: 1.65, 0.86-3.14) and death was 26% vs. 12% (adjusted OR: 2.04, 0.92-4.53), respectively. CONCLUSIONS: PPHN in infants with moderate or severe HIE was not associated with a statistically significant increase in primary outcome. These results should be interpreted with caution given the limited sample size.

Seizure Control in Neonates Undergoing Screening vs Confirmatory EEG Monitoring.

OBJECTIVE: To determine whether screening continuous EEG monitoring (cEEG) is associated with greater odds of treatment success for neonatal seizures. METHODS: We included term neonates with acute symptomatic seizures enrolled in the Neonatal Seizure Registry (NSR), a prospective, multicenter cohort of neonates with seizures. We compared 2 cEEG approaches: (1) screening cEEG, initiated for indications of encephalopathy or paralysis without suspected clinical seizures; and (2) confirmatory cEEG, initiated for the indication of clinical events suspicious for seizures, either alone or in addition to other indications. The primary outcome was successful response to initial seizure treatment, defined as seizures resolved without recurrence within 30 minutes after initial loading dose of antiseizure medicine. Multivariable logistic regression analyses assessed the association between cEEG approach and successful seizure treatment. RESULTS: Among 514 neonates included, 161 (31%) had screening cEEG and 353 (69%) had confirmatory cEEG. Neonates with screening cEEG had a higher proportion of successful initial seizure treatment than neonates with confirmatory cEEG (39% vs 18%; p < 0.0001). After adjusting for covariates, there remained a greater odds ratio (OR) for successful initial seizure treatment in the screening vs confirmatory cEEG groups (adjusted OR 2.44, 95% confidence interval 1.45-4.11, p = 0.0008). CONCLUSIONS: These findings provide evidence from a large, contemporary cohort of neonates that a screening cEEG approach may improve odds of successful treatment of acute seizures. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for neonates a screening cEEG approach, compared to a confirmatory EEG approach, increases the probability of successful treatment of acute seizures.

Management of Multi Organ Dysfunction in Neonatal Encephalopathy.

Neonatal Encephalopathy (NE) describes neonates with disturbed neurological function in the first post-natal days of life. NE is an overall term that does not specify the etiology of the encephalopathy although it often involves hypoxia-ischaemia. In NE, although neurological dysfunction is part of the injury and is most predictive of long-term outcome, these infants may also have multiorgan injury and compromise, which further contribute to neurological impairment and long-term morbidities. Therapeutic hypothermia (TH) is the standard of care for moderate to severe NE. Infants with NE may have co-existing immune, respiratory, endocrine, renal, hepatic, and cardiac dysfunction that require individualized management and can be impacted by TH. Non-neurological organ dysfunction not only has a negative effect on long term outcome but may also influence the efficacy of treatments in the acute phase. Post resuscitative care involves stabilization and decisions regarding TH and management of multi-organ dysfunction. This management includes detailed neurological assessment, cardio-respiratory stabilization, glycaemic and fluid control, sepsis evaluation and antibiotics, seizure identification, and monitoring and responding to biochemical and coagulation derangements. The emergence of new biomarkers of specific organ injury may have predictive value and improve the definition of organ injury and prognosis. Further evidence-based research is needed to optimize management of NE, prevent further organ dysfunction and reduce neurodevelopmental impairment.

Risk factors for EEG seizures in neonates treated with hypothermia: a multicenter cohort study.

OBJECTIVE: To assess the risk factors for electrographic seizures among neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE). METHODS: Three-center observational cohort study of 90 term neonates treated with hypothermia, monitored with continuous video-EEG (cEEG) within the first day of life (median age at onset of recording 9.5 hours, interquartile range 6.3-14.5), and continued for >24 hours (total recording 93.3 hours, interquartile range 80.1-112.8 among survivors). A pediatric electroencephalographer at each site reviewed cEEGs for electrographic seizures and initial EEG background category. RESULTS: A total of 43 (48%) had electrographic seizures, including 9 (10%) with electrographic status epilepticus. Abnormal initial EEG background classification (excessively discontinuous, depressed and undifferentiated, burst suppression, or extremely low voltage), but not clinical variables (including pH <6.8, base excess ≤-20, or 10-minute Apgar ≤ 3), was strongly associated with seizures. CONCLUSIONS: Electrographic seizures are common among neonates with HIE undergoing hypothermia and are difficult to predict based on clinical features. These results justify the recommendation for cEEG monitoring in neonates treated with hypothermia.