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Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.

In randomized trials, therapeutic hypothermia (TH) is associated with reduced prevalence of the composite outcome mortality or neurodevelopmental morbidity in infants with neonatal encephalopathy (NE). Following systematic review, the reduction in prevalence of both mortality and infant neuromorbidity is clear. Among three trials reporting school age outcomes, the effects of NE and TH suggest that such benefit persists into middle childhood, but none of the major trials were powered to detect differences in these outcomes. Cognitive, educational and behavioural outcomes are all adversely affected by NE in children without moderate or severe neuromorbidity. High-quality longitudinal studies of neurocognitive and educational outcomes following NE in the era of TH, including studies incorporating multimodal neuroimaging assessments, are required to characterise deficits more precisely so that robust interventional targets may be developed, and resource planning can occur. Understanding the impact of NE on families and important educational, social, and behavioural outcomes in childhood is critical to attempts to optimise outcomes through interventions. [ABSTRACT FROM AUTHOR]

Neonates and families face challenges in hypothermic therapy, including trauma to parents, extreme emotions, and unfamiliarity with the medical system. Communication is an essential element to supporting parents while their children are in the NICU, and beyond, building the foundation for the ongoing relationship the family has with the medical system. Significant consideration needs to be given to the critical element of integrating the family into the care of a baby being treated with therapeutic hypothermia. Clinicians can promote healing of accumulated traumas of parents through ensuring parent's emotional safety, facilitating a trusting relationship, and promoting parent empowerment. Connecting parents with resources, especially peer support, is an essential part of a hospital stay. In this chapter, we explore best practices to support families during and after hypothermic therapy. [ABSTRACT FROM AUTHOR]

Neuroimaging is widely used to aid in the diagnosis and clinical management of neonates with neonatal encephalopathy (NE). Yet, despite widespread use clinically, there are few published guidelines on neuroimaging for neonates with NE. This review outlines the primary patterns of brain injury associated with hypoxic-ischemic injury in neonates with NE and their frequency, associated neuropathological features, and risk factors. In addition, it provides an overview of neuroimaging methods, including the most widely used scoring systems used to characterize brain injury in these neonates and their utility as predictive biomarkers. Last, recommendations for neuroimaging in neonates with NE are presented. [ABSTRACT FROM AUTHOR]

Neonates with neonatal encephalopathy (NE) often present with multi-organ dysfunction that requires multidisciplinary specialized management. Care of the neonate with NE is thus complex with interaction between the brain and various organ systems. Illness severity during the first days of birth, and not only during the initial hypoxia-ischemia event, is a significant predictor of adverse outcomes in neonates with NE treated with therapeutic hypothermia (TH). We thus propose a care practice bundle dedicated to support the injured neonatal brain that is based on the current best evidence for each organ system. The impact of using such bundle on outcomes in NE remains to be demonstrated. [ABSTRACT FROM AUTHOR]

Neonatal encephalopathy (NE) describes the clinical syndrome of a newborn with abnormal brain function that may result from a variety of etiologies. HIE should be distinguished from neonatal encephalopathy due to other causes using data gathered from the history, physical and neurological exam, and further investigations. Identifying the underlying cause of encephalopathy has important treatment implications. This review outlines conditions that cause NE and may be mistaken for HIE, along with their distinguishing clinical features, pathophysiology, investigations, and treatments. NE due to brain malformations, vascular causes, neuromuscular causes, genetic conditions, neurogenetic disorders and inborn errors of metabolism, central nervous system (CNS) and systemic infections, and toxic/metabolic disturbances are discussed. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia is now well established to significantly improve survival without disability after neonatal encephalopathy (NE). To further improve outcomes, we need to better understand the mechanisms of brain injury. The central finding, which offers the potential for neuroprotective and neurorestorative interventions, is that brain damage after perinatal hypoxia-ischemia evolves slowly over time. Although brain cells may die during profound hypoxia-ischemia, even after surprisingly severe insults many cells show transient recovery of oxidative metabolism during a "latent" phase characterized by actively suppressed neural metabolism and activity. Critically, after moderate to severe hypoxia-ischemia, this transient recovery is followed after ~6 h by a phase of secondary deterioration, with delayed seizures, failure of mitochondrial function, cytotoxic edema, and cell death over ~72 h. This is followed by a tertiary phase of remodeling and recovery. This review discusses the mechanisms of injury that occur during the primary, latent, secondary and tertiary phases of injury and potential treatments that target one or more of these phases. By analogy with therapeutic hypothermia, treatment as early as possible in the latent phase is likely to have the greatest potential to prevent injury ("neuroprotection"). In the secondary phase of injury, anticonvulsants can attenuate seizures, but show limited neuroprotection. Encouragingly, there is now increasing preclinical evidence that late, neurorestorative interventions have potential to improve long-term outcomes. [ABSTRACT FROM AUTHOR]

Neonatal encephalopathy (NE) is a significant complication of the peripartum period. It can lead to lifelong neurologic disabilities, including cerebral palsy, cognitive impairments, developmental delays, and epilepsy. Induced hypothermia is the first therapy, which has shown promise in improving the outcomes for neonates with moderate to severe NE following a presumed intrapartum insult. NE is also a frequent source of medical malpractice litigation. In this paper, we will review salient features of the American Tort System as it pertains to medical malpractice. We will discuss the obstetric medico-legal implications of therapeutic hypothermia and suggest a five-step approach to analyzing neonatal cases for causation, etiology, timing of occurrence, responsibility, and liability. We will close with three illustrative clinical cases. [ABSTRACT FROM AUTHOR]

Engaging with ethical issues is central to the management of neonatal encephalopathy (NE). As treatment for these neonates evolves, new ethical issues will arise and many existing challenges will remain. We highlight three key ethical issues that arise in the care of neonates with NE treated with therapeutic hypothermia: facilitating shared decision making, understanding futility, and defining the boundaries between standard of care and research. Awareness of these issues will help clinicians counsel families in light of evolving treatments and outcomes. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia (TH) is now well established to improve intact survival after neonatal encephalopathy (NE). However, many questions could not be addressed by the randomized controlled trials. Should late preterm newborns with NE be cooled? Is cooling beneficial for mild NE? Is the current therapeutic time window optimal, or could it be shortened or prolonged? Will either milder or deeper hypothermia be effective? Does infection/inflammation exposure in the perinatal period in combination with NE offer potentially beneficial preconditioning or might it obviate hypothermic neuroprotection? In the present review, we dissect the evidence, for whom, when and how can TH best be delivered, and highlight areas that need further research. [ABSTRACT FROM AUTHOR]

In term and near-term neonates with neonatal encephalopathy, therapeutic hypothermia protocols are well established. The current focus is on how to improve outcomes further and the challenge is to find safe and complementary therapies that confer additional protection, regeneration or repair in addition to cooling. Following hypoxia-ischemia, brain injury evolves over three main phases (latent, secondary and tertiary), each with a different brain energy, perfusion, neurochemical and inflammatory milieu. While therapeutic hypothermia has targeted the latent and secondary phase, we now need therapies that cover the continuum of brain injury that spans hours, days, weeks and months after the initial event. Most agents have several therapeutic actions but can be broadly classified under a predominant action (e.g., free radical scavenging, anti-apoptotic, anti-inflammatory, neuroregeneration, and vascular effects). Promising early/secondary phase therapies include Allopurinol, Azithromycin, Exendin-4, Magnesium, Melatonin, Noble gases and Sildenafil. Tertiary phase agents include Erythropoietin, Stem cells and others. We review a selection of promising therapeutic agents on the translational pipeline and suggest a framework for neuroprotection and neurorestoration that targets the evolving injury. [ABSTRACT FROM AUTHOR]

Perinatal asphyxia remains one of the major causes of morbidity and mortality for term newborns. Though access to health care and birth attendants have decreased the rate, Neonatal encephalopathy (NE) has not been eliminated. Worldwide, women at socioeconomic disadvantage have the highest risk of delivering a neonate with NE. Neonates that will experience perinatal asphyxia cannot be easily identified prospectively and the intrapartum testing available is not specific enough to clearly indicate the best course of action in most cases. Despite this, training programs that aim to decrease morbidity and mortality from all causes appear to be associated with fewer cases of perinatal asphyxia. The current best approach is to support education and communication for all people involved in the care of birthing women. Ideally, new technology will address identification of the fetus likely to be affected or the fetus who is beginning to experience injury in advance of delivery. [ABSTRACT FROM AUTHOR]

Neonatal encephalopathy (NE) is the most common etiology of acute neonatal seizures - about half of neonates treated with therapeutic hypothermia for NE have EEG-confirmed seizures. These seizures are best identified with continuous EEG monitoring, as clinical diagnosis leads to under-diagnosis of subclinical seizures and over-treatment of events that are not seizures. High seizure burden, especially status epilepticus, is thought to augment brain injury. Treatment, therefore, is aimed at minimizing seizure burden. Phenobarbital remains the mainstay of treatment, as it is more effective than levetiracetam and easier to administer than fosphenytoin. Emerging evidence suggests that, for many neonates, it is safe to discontinue the phenobarbital after acute seizures resolve and prior to hospital discharge. [ABSTRACT FROM AUTHOR]

Neonatal encephalopathy due to a hypoxic-ischemic event is commonly associated with cardiac dysfunction and acute pulmonary hypertension; both therapeutic hypothermia and rewarming modify loading conditions and blood flow. The pathophysiological contributors to disease are complex with a high degree of clinical overlap and traditional bedside measures used to assess circulatory adequacy have multiple confounders. Comprehensive, quantitative echocardiography may be used to delineate the relative contribution of lung parenchymal, pulmonary vascular, and cardiac disease to hypotension and/or hypoxemic respiratory failure. In this review, we provide a detailed overview of the contributors to hemodynamic instability following perinatal hypoxic-ischemic injury. Our proposed approach to therapy focuses on physiopathological considerations with interventions individualized to this potentially complex condition and considers the pharmacological idiosyncrasies, which may occur among neonates with NE presenting with multiorgan dysfunction while undergoing therapeutic hypothermia. [ABSTRACT FROM AUTHOR]

Placental assessment, although currently underused, can inform our understanding of the etiology and timing of Neonatal Encephalopathy (NE). We review our current understanding of the links between placental dysfunction and NE and how this information may inform clinical decisions, now and in the future, emphasizing the four major placental lesions associated with NE. In addition, we discuss maternal and fetal factors that are hypothesized to contribute to specific placental pathologies, especially innate or acquired thrombophilias. We outline the importance of assessing placenta across trimesters and after delivery. As this field continues to evolve, currently available placental histopathological examination methods may need to be combined with advanced prenatal molecular and imaging assessments of placenta and be applied in well-designed studies in large representative populations to better define the links between placental dysfunction and NE. [ABSTRACT FROM AUTHOR]

Neonatal encephalopathy (NE) is associated with abnormality of neurological function and involves multiorgan dysfunction. There are long-term complications such as cerebral palsy and developmental delay. Cardiac, renal, neurological and other organ dysfunctions are well described. Haematological dysfunction is relatively common and includes anaemia, thrombocytopenia, monocyte and neutrophil activation, hypofibrinogenemia and coagulopathy. There is a lack of consensus definitions of hematological parameters and optimal levels for intervention due to the lack of interventional studies in term neonates and the lack of knowledge of the optimal values during therapeutic hypothermia. However, derangements in hematological values are also associated with neurodevelopmental outcomes. This article outlines the different hematological complications associated with NE and therapeutic hypothermia and suggests a framework for management. [ABSTRACT FROM AUTHOR]

Subcutaneous fat necrosis of the newborn (SFNN) is a rare, self-resolving panniculitis. The onset of skins lesions occurs within the first week of life, with a median age of onset around day 6 of life (range 1-70). About 50% of neonates with SFNN will develop hypercalcemia in the first month though some present later. Typically, SFNN develops prior to hypercalcemia. Only half of the neonates have classic symptoms of hypercalcemia; routine screening for hypercalcemia is recommended for neonates with SFNN or at-risk. The mechanism for hypercalcemia is usually aberrant 1,25-dihydroxyvitamin D synthesis in the necrotic tissue increasing intestinal absorption of calcium. Prompt recognition and treatment is required, often in hospital. Treatment options are low calcium-vitamin D formula or sometimes intravenous bisphosphonates. Regular monitoring post-intervention is required when normalizing the diet. Outcomes are good with routine surveillance and interventions. A multidisciplinary team approach (neonatologists, pediatric endocrinologists and nephrologists, dieticians) is optimal. [ABSTRACT FROM AUTHOR]

Adequate nutrition and glycemic homeostasis are increasingly recognized as potentially neuroprotective for the developing brain. In the context of hypoxia-ischemia, evidence is scarce regarding optimal nutritional support and administration route, as well as the short- and long-term consequences of such interventions. In this review, we summarize current knowledge on disturbances of brain metabolism of glucose and substrates by hypoxia-ischemia, and compound effects of these mechanisms on brain injury characterized by specific patterns on EEG and MRI. Risks and benefits of nutrition delivery via parenteral or enteral routes are examined. Nutrition could mitigate adverse neurodevelopmental outcomes, and the impact of nutritional strategies and specific nutritional interventions are reviewed. Limited literature highlights the need for further studies to understand the changes in energy metabolism during and after hypoxic-ischemic injury, to optimize nutritional regimens and glucose management, and to inform the neuroprotective role of nutrition. [ABSTRACT FROM AUTHOR]

Neonatal Encephalopathy (NE) is a neurologic syndrome in term and near-term infants who have depressed consciousness, difficulty initiating and maintaining respiration, and often abnormal tone, reflexes and neonatal seizures in varying combinations. Moderate/severe NE affects 0.5-3/1000 live births in high-income countries, more in low- and middle-income countries, and carries high risk of mortality or disability, including cerebral palsy. Reduced blood flow and/or oxygenation around the time of birth, as with ruptured uterus, placental abruption or umbilical cord prolapse can cause NE. This subset of NE, with accompanying low Apgar scores and acidemia, is termed Hypoxic-Ischemic Encephalopathy. Other causes of NE that can present similarly, include infections, inflammation, toxins, metabolic disease, stroke, placental disease, and genetic disorders. Aberrant fetal growth and congenital anomalies are strongly associated with NE, suggesting a major role for maldevelopment. As new tools for differential diagnosis emerge, their application for prevention, individualized treatment and prognostication will require further systematic studies of etiology of NE. [ABSTRACT FROM AUTHOR]

Ensuring comfort for neonates undergoing therapeutic hypothermia (TH) after neonatal encephalopathy (NE) exemplifies a vital facet of neonatal neurocritical care. Physiologic markers of stress are frequently present in these neonates. Non-pharmacologic comfort measures form the foundation of care, benefitting both the neonate and parents. Pharmacological sedatives may also be indicated, yet have the potential to both mitigate and intensify the neurotoxicity of a hypoxic-ischemic insult. Morphine represents current standard of care with a history of utilization and extensive pharmacokinetic data to guide safe and effective dosing. Dexmedetomidine, as an alternative to morphine, has several appealing characteristics, including neuroprotective effects in animal models; robust pharmacokinetic studies in neonates with NE treated with TH are required to ensure a safe and effective standard dosing approach. Future studies in neonates treated with TH must address comfort, adverse events, and long-term outcomes in the context of specific sedation practices. [ABSTRACT FROM AUTHOR]

Neonatal encephalopathy (NE) is a serious condition with devastating neurological outcomes that can impact oxygenation and ventilation. The currently recommended therapeutic hypothermia (TH) for these infants may also has several respiratory implications. It decreases metabolic rate and oxygen demands; however, it increases oxygen solubility in the blood and impacts its release to peripheral tissue including the brain. Respiratory management of infants treated with TH should aim for minimizing exposure to hypocapnia or hyperoxia. Inspiratory gas should be heated to 37 °C and humidified to prevent airway and alveolar injury. Blood gas values should be corrected to the core temperature during TH and the use of alkaline buffers is discouraged. While mild sedation/analgesia may ameliorate the discomfort related to cooling, paralytic agents/heavy sedation should be used with caution considering their side effects. Finally, the use of caffeine still needs careful investigation in this population. [ABSTRACT FROM AUTHOR]

One million two hundred thousand neonatal lives are lost each year due to intrapartum-related events; 99% of these deaths occur in low- and lower middle-income countries. Neonates exposed to intrapartum-related events present with failure to breathe at birth. Quick and effective delivery room management of these neonates is critical in the prevention of brain injury. Given the prominent role of lung aeration in the cardiopulmonary transition at birth, the mainstay of neonatal resuscitation is effective ventilation. Basic neonatal resuscitation focuses on simple stimulation, airway positioning and clearing, and bag-mask ventilation. Although principles for basic neonatal resuscitation remain the same for high- and low-resource settings, guidelines may differ based on available human and material resources. Formal training in basic resuscitation reduces intrapartum-related neonatal mortality in low-resource settings. However, there remain opportunities to improve provider performance for increased impact with other strategies such as regular practice and continuous quality improvement. [ABSTRACT FROM AUTHOR]

Kidney dysfunction and acute kidney injury (AKI) frequently accompanies neonatal encephalopathy and contributes to neonatal morbidity and mortality. While there are currently no proven therapies for the treatment of AKI, understanding the pathophysiology along with early recognition and treatment of alterations in fluid, electrolyte and metabolic homeostasis that accompany AKI offer opportunity to reduce associated morbidity. Promising new tests and technologies, including urine and serum biomarkers and renal near-infrared spectroscopy offer opportunities to improve diagnosis and monitoring of neonates at risk for kidney injury. Furthermore, recent advances in neonatal kidney supportive therapies such as hemofiltration and hemodialysis may further improve outcomes in this population. This chapter provides an overview of disorders of fluid balance, electrolyte homeostasis and kidney function associated with neonatal encephalopathy and therapeutic hypothermia. Recommendations for fluid and electrolyte management based upon published literature and authors' opinions are provided. [ABSTRACT FROM AUTHOR]