Hypoxic-Ischemic Encephalopathy: A Review for the Clinician

Perinatal hypoxic-ischemic encephalopathy (HIE) is a common cause of brain damage and death in the newborn period. HIE occurs as a result of an injury to the brain from a combination of systemic hypoxemia; which refers to an arterial concentration of oxygen that is less than normal; and diminished cerebral perfusion that leads to ischemia or insufficient blood flow to the cells to maintain their normal function. The pathogenesis involves a sequence of cerebral insults that occur initially with hypoxemia, ischemia and next by oxygenation and reperfusion of the ischemic tissue. HIE may cause multi-system organ damage with significant aberrations in clotting, renal, and cardiac functions. The incidence of HIE is 2-6 per 1,000 live birth and it appears to be much higher in the developing countries. It may occur as a result of prepartum, intrapartum, or perinatal causes, and is most commonly seen in full-term or post-term infants. Prenatal-intrapartum risk factors include fetal distress,...

Annals of Pediatrics, 2021

Background: HIE remains a significant cause of mortality and long-term disability in late preterm and term newborns. At birth, the only available distinction between mild, moderate, and severe HIE is based on the clinical ground. Nevertheless, mild HIE can be presented with subtle or subjective clinical features which may mislead the treating physician and delay his decision to intervene. Methods: This is a retrospective descriptive study examined all inborn newborns ≥ 35 weeks gestational age born at a single, tertiary level Neonatal Intensive Care Unit (NICU) in women’s hospital. The study revised newborns who were admitted to NICU during the period from November 2014 till November 2020 under the diagnoses of mild HIE. The decision to start therapeutic hypothermia in cases of mHIE was off-label and it was taken according to the clinical judgment of the treating team. Results: Out of the 265 newborns admitted with a history suggestive of HIE or neurological deficits, only 116 newbo...

Archives of Pediatrics & Adolescent Medicine, 2012

Objective: To establish the evidence of therapeutic hypothermia for newborns with hypoxic ischemic encephalopathy (HIE). Data Sources: Cochrane Central Register of Controlled Trials, Oxford Database of Perinatal Trials, MEDLINE, EMBASE, and previous reviews. Study Selection: Randomized controlled trials that compared therapeutic hypothermia to normothermia for newborns with HIE. Intervention: Therapeutic hypothermia. Main Outcome Measures: Death or major neurodevelopmental disability at 18 months.

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a challenge of perinatal medicine. It is an important cause of long term morbidity, including motor and behavio-ral deficits, mental retardation, seizures and cerebral palsy, and mortality in newborns. This paper reviews the patho-physiology and current concepts of the management of neo-natal HIE as well as the future potential neuroprotective strategies for attenuation of this disease.

Current Neurology and Neuroscience Reports, 2019

Purpose of review-therapeutic hypothermia reduces death or disability in term and near-term infants with moderate-severe hypoxic-ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite hypothermia, supporting further research into ways to further improve neurologic outcomes. Recent findings-recent clinical and experimental studies have refined our understanding of the key parameters for hypothermic neuroprotection, including timing of initiation, depth, and duration of hypothermia, and subsequent rewarming rate. However, important knowledge gaps remain. There is encouraging clinical evidence from a small phase II trial that combined treatment of hypothermia with recombinant erythropoietin further reduces risk of disability but definitive studies are still needed. Summary-In conclusion, recent studies suggest that current protocols for therapeutic hypothermia are nearoptimal, and that the key to better neurodevelopmental outcomes is earlier diagnosis and initiation of hypothermia after birth. Further research is essential to find and evaluate ways to further improve outcomes after hypoxic-ischemic encephalopathy, including add-on therapies for therapeutic hypothermia and preventing pyrexia during labor and delivery.

MEDICC Review, 2021

INTRODUCTION Hypoxic ischemic encephalopathy is a neurological condition occurring immediately after birth following a perinatal asphytic episode. Therapeutic hypothermia is a safe and effective intervention to reduce mortality and major disability in survivors. In Latin America, perinatal asphyxia is a major problem, but no data are available characterizing its current situation in the region or the impact of hypoxic ischemic encephalopathy on its management. OBJECTIVE Understand the prevalence, mortality and use of therapeutic hypothermia in newborns at ≥36 weeks gestational age with hypoxic ischemic encephalopathy admitted to neonatal units reporting to the Ibero-American Society of Neonatology Network. METHODS The Ibero-American Society of Neonatology Network groups various neonatology centers in Latin America that share information and collaborate on research and medical care. We evaluated data on newborns with ≥36 weeks gestational age reported during 2019. Each unit received a guide with defi nitions and questions based on the Society's 7th Clinical Consensus. Evaluated were encephalopathy frequency and severity, Apgar score, need for resuscitation at birth, use of therapeutic hypothermia and clinical evolution at discharge. Our analysis includes descriptive statistics and comparisons made using the chi-square test. RESULTS We examined reports of 2876 newborns from 33 units and 6 countries. In 2849 newborns with available data, hypoxic encephalopathy prevalence was 5.1% (146 newborns): 27 (19%) mild, 36 (25%) moderate, 43 (29%) severe, and 40 (27%) of unknown intensity. In those with moderate and severe encephalopathy, frequencies of Apgar scores ≤3 at the fi rst minute (p = 0.001), Apgar scores ≤3 at the fi fth minute (p <0.001) and advanced resuscitation (p = 0.007) were higher. Therapeutic hypothermia was performed in only 13% of newborns (19). Neonatal mortality from encephalopathy was 42% (61). CONCLUSION Hypoxic ischemic encephalopathy is a neonatal condition that results in high mortality and severe neurological sequelae. In this study, the overall prevalence was 5.1% with a mortality rate of 42%. Although encephalopathy was moderate or severe in 54% of reported cases, treatment with hypothermia was not performed in 87% of newborns. These data refl ect a regional situation that requires urgent action.

Journal of Perinatology, 2019

Objective To compare the characteristics and outcomes of neonates with mild hypoxic-ischemic encephalopathy (HIE) who received hypothermia versus standard care. Study design We conducted a retrospective cohort study of neonates ≥35 weeks' gestation and ≥1800 g admitted with a diagnosis of Sarnat stage 1 encephalopathy. We evaluated length of hospital stay, duration of ventilation, evidence of brain injury on MRI, and neonatal morbidities. Results Of 1089 eligible neonates, 393 (36%) received hypothermia and 595 (55%) had neuroimaging. The hypothermia group was more likely to be outborn, born via C-section, had lower Apgar scores, and required extensive resuscitation. They had longer durations of stay (9 vs. 6 days, P < 0.001), respiratory support (3 vs. 2 days, P < 0.001), but lower odds of brain injury on MRI (adjusted odds ratio 0.33, 95% CI: 0.22-0.52) compared with standard care group. Conclusion Despite prolongation of hospital stay, hypothermia may be potentially beneficial in neonates with mild HIE; however, selection bias cannot be ruled out.

Obstetrical & Gynecological Survey, 2008

To systematically review the effectiveness, as determined by survival without moderate to severe neurodevelopmental disability in infancy and childhood, and the safety of hypothermia vs normothermia in neonates with postintrapartum hypoxic-ischemic encephalopathy and to perform subgroup analyses based on severity of encephalopathy (moderate or severe), type of hypothermia (systemic or selective head cooling), and degree of hypothermia (moderate [Յ32.0-33.5°C] or mild [Ն33.6°C]). Data Sources: MEDLINE, EMBASE, CINAHL (Cumulative Index for Nursing and Allied Health Literature), the Cochrane Library, abstracts of annual meetings of the Pediatric Academic Societies, and bibliographies of identified articles. Study Selection: Randomized and quasi-randomized controlled trials without language restriction were assessed by 2 reviewers independently and discrepancies were resolved by involving a third reviewer. Quality of the trials was assessed on the basis of concealment of allocation, method of randomization, masking of outcome assessment, and completeness of follow-up. Intervention: Systemic or selective head hypothermia compared with normothermia. Main Outcome Measure: Death or moderate to severe neurodevelopmental disability. Results: Eight studies of acceptable quality were included. The combined outcome of death or neurodevelopmental disability in childhood was reduced in infants receiving hypothermia compared with control infants (4 studies including 497 infants; relative risk, 0.76, 95% confidence interval, 0.65-0.88; number needed to treat, 6; 95% confidence interval, 4-14), as were death and moderate to severe neurodevelopmental disability when analyzed separately. Cardiac arrhythmias and thrombocytopenia were more common with hypothermia; however, they were clinically benign. Conclusions: In neonates with postintrapartum asphyxial hypoxic-ischemic encephalopathy, hypothermia is effective in reducing death and moderate to severe neurodevelopmental disability either in combination or separately and is a safe intervention.

Miscellanea on Encephalopathies - A Second Look, 2012

The basal ganglia-thalamus pattern (BGT) affects bilaterally the deep gray nuclei and perirolandic cortex, occurring more often after an acute sentinel event, such as placental abruption, uterine rupture or umbilical cord prolapse. Hippocampus, brain stem and white matter may also be affected (de Vries & Groenendaal, 2010). BGT is associated with cerebral palsy in 70% of the survivors, and with epilepsy in 30-40% of HIE survivors. Visual impairments and dysarthria are also common in children with HIE and BGT injury (Martinez-Biarge et al., 2010). 2. The watershed predominant pattern (WS) is the second pattern of injury and involves the white matter, particularly the vascular watershed zones (anterior-middle cerebral artery and posterior-middle cerebral artery), and also the cortex when severe (de Vries & Groenendaal, 2010). WS is associated with cognitive deficits and epilepsy, but usually is not the cause of severe motor impairment (Martinez-Biarge et al., 2010). Besides the imaging studies performed in human infants, most of the observations related to the mechanisms of brain damage and brain plasticity after HIE came from preclinical studies using the Rice-Vannucci animal model of HIE. The model consists of unilateral common carotid artery ligation followed by systemic hypoxia (8% oxygen-balance nitrogen) in post-natal day 7 (P7) rats (Vannucci et al., 1999). The damage is restricted to the hemisphere ipsilateral to the common carotid artery occlusion, affecting the cerebral cortex, thalamus, striatum, hippocampus and subcortical white matter. Importantly, the HI animals develop several cognitive and motor deficits (Lubics et al., 2005). In this book chapter, we will discuss possible new treatments for HIE, focusing on neuroprotective strategies and on cell therapies. 2. Neuroprotective strategies for HIE Since, in most cases, the hypoxic-ischemic (HI) insult occurs near birth, it is feasible that neuroprotection could be achieved in the first few hours after birth. Accordingly, therapeutic hypothermia, when started within 6 hours of birth, modestly improves the neurologic outcome of full-term infants with moderate HIE and is becoming a standard therapy for this condition (Edwards et al., 2010). Besides the neurological improvement, therapeutic hypothermia was associated with a decreased injury in basal ganglia/thalamus and white matter in MRI scans (Rutherford et al., 2010), confirming the neuroprotective effect of this treatment, as observed in animal models of HIE (Gunn et al., 1997). However, given the limited benefits of therapeutic hypothermia, new neuroprotective treatments that could reduce or prevent the long-term neurodevelopmental sequelae of children with HIE, affecting one (or a combination) of the mechanisms that contribute to secondary brain injury, are urgently needed. The therapeutic window of hypothermia coincides with a latent phase, when cerebral energy metabolism returns to normal following perinatal asphyxia. Using phosphorus magnetic resonance spectroscopy (31 P-RMS), it was showed that brain energy metabolism returns to normal levels after a successful resuscitation. After 6-24 hours, this latent phase is followed by a secondary energy failure (Lorek et al., 1994), when there is a correlation between the degree of derangement of oxidative metabolism and the neurodevelopmental outcome (Martin et al., 1996). Thereby, it has been suggested that irreversible cell death occurs with a certain delay after HIE.

Frontiers in Pediatrics