Therapeutic Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy: Effects on Neurodevelopmental Outcomes

Introduction. Background: Literature Review. Methods. Discussion. Conclusion. References. Appendices. Hypothermia for Neonates 3 III. Abstract Therapeutic hypothermia is a standardized protocol in the management of termor nearterm neonates who have suffered asphyxia in the perinatal period. Birth asphyxia, if sustained, may develop into a more serious condition known as hypoxic ischemic encephalopathy (HIE). Depending on severity, HIE is associated with adverse cognitive and neurodevelopmental outcomes, yet through various physiological mechanisms, hypothermia sustained for a 72-hour period has been shown to attenuate, or even prevent, permanent brain damage by decreasing cerebral energy demands. Unfortunately, cognitive and neurodevelopmental outcomes are difficult to prognosticate before or after completion of hypothermia protocol, but existing standards and technology allow for reliable prognostication up at 18 months of age. Currently, research is underway to identify certain imaging and biochemical modalities that may help predict cognitive and neurodevelopmental outcomes at various stages of childhood beyond 18 months of age, even before hypothermia is initiated, as well as to evaluate methods holding potential to strengthen hypothermia protocol as it presently stands. IV. Introduction Perinatal asphyxia is not an infrequent incidence, occurring between 1 to 2 per 1000 live births in the United States. When asphyxia is sustained, hypoxic ischemic encephalopathy (HIE) may result. While the main sequelae of moderate to severe HIE are neuromotor delays, such as cerebral palsy (CP), which accounts for 20% of cases of neonatal HIE, cognitive impairments can also occur. When compared to neonates who do not experience hypoxic insults in the perinatal period, neonates with at least a moderate degree of HIE have a 10% increased risk of death, and those that survive carry a 30% increased risk of neurodevelopmental disabilities. Hypothermia for Neonates 4 Hypoxic insults that progress to HIE in the perinatal period are caused by cerebral ischemia. This lack of blood flow to the brain leads to deficiencies in oxygen, adenosine triphosphate (ATP), and glucose, creating an environment reliant on the anaerobic metabolism of lactate to meet energy needs, which in excess, leads to acidosis. Additionally, HIE triggers a release of excitatory glutamate that may cause neuronal hyperexcitability, seizure activity, and/or neuronal cell injury and death. Excess glutamate also increases production of reactive oxygen species (ROS) and nitric oxide (NO). ROS recruit inflammatory cytokines and enzymes that degrade the blood-brain barrier, leading to cerebral edema and a resultant increase in intracranial pressure (ICP), as well as increase apoptosis of neuronal cells. NO promotes cerebral capillary leakiness, which also increases ICP. Mechanistically, therapeutic hypothermia, or cooling core body temperature below 37.5 degrees Celsius (°C), decreases cerebral demand for oxygen, ATP, and glucose, to ultimately decrease lactate production and thwart acidosis. This cooling process also decreases release of glutamate from the brain, thereby attenuating ROS and NO production, which preserves the integrity of the blood-brain barrier, maintains normal ICP, and decreases inflammation and neuronal apoptosis. Therapeutic hypothermia experienced resurgence in the medical community in the 1950s, for notably decreasing cerebral blood flow, oxygen consumption, and ICP in patients undergoing cardiac surgery. Clinical application of and research into therapeutic hypothermia waned until the 1980s, until experimentation with milder hypothermic temperatures (i.e., greater than 32°C) began, including pilot research into applications for neonatal HIE in the late 1990s. In 2010, therapeutic hypothermia become a standard of practice for neonates of at least 36 weeks gestational age who had sustained asphyxia within 6 hours of birth, to minimize neurodevelopmental sequelae associated with HIE. Hypothermia for Neonates 5 The objective of the current research is to evaluate the efficacy of therapeutic hypothermia in improving neurodevelopmental outcomes in neonates with HIE, specifically by: 1) exploring protocol-defining research into therapeutic hypothermia for neonatal HIE; 2) assessing subsequent neurodevelopmental outcomes at various stages in childhood; 3) examining the utility of certain imaging tests and biochemical measures at predicting neurodevelopmental outcomes before therapeutic HIE is initiated; and 4) reviewing potential mechanisms for strengthening current hypothermia protocol for neonatal HIE. V. Background: Literature Review Standardizing Cooling Protocol for Neonatal HIE Before therapeutic hypothermia became standardized protocol for term or near-term neonates who had suffered perinatal asphyxia, intensive care unit level management was still indicated, along with maintenance of physiological parameters within normal range and treatment of seizure activity with anti-epileptic drugs. There were some experimental pharmaceutical treatments being used, such as phenobarbital for potential reduction of neurodevelopmental handicap at 3 years of age, or allopurinol, which was thought to improve electroencephalogram (EEG) activity and reduce formation of ROS. Nevertheless, there was a paucity of data exploring the long-term effects of said interventions, so there did not exist any standardized protocol before the advent of therapeutic hypothermia. After the resurgence of interest and research into utilization of therapeutic hypothermia in reducing cerebral metabolism in the late 1990s, small-scale randomized controlled trials (RCTs) examining the effects of mild hypothermia (i.e., core temperature of 33.5-34.5°C) on neurodevelopmental outcomes in neonates who had suffered perinatal asphyxia were conducted, but participant sizes were insufficient to yield adequate power to determine effectiveness in Hypothermia for Neonates 6 clinical application. However, these initial studies did pioneer the methods for inducing hypothermia that would come to be used in protocol-defining RCTs: whole body and/or selective head cooling. The former provides homogenous cooling to peripheral and central brain structures, namely, the posterior limb of the internal capsule, white matter cortex, basal ganglia, and thalamus. The latter provides a greater degree of cooling to the periphery of the brain than to the central brain structures, so, it was found that whole body cooling, combined with a degree of head cooling, minimizes temperature gradient differences across the brain and facilitates more effective cooling to the deeper brain structures. Soon after the launch of these pilot studies, larger scale, multi-center RCTs of neonates with moderate to severe HIE assigned to hypothermia protocol, with matched controls receiving intensive care unit level management and euthermia, emerged. 2,4,9 The Eunice Kennedy Shriver National Institute of Child Health and Human Development Research Network (NICHD NRN) 4 utilized whole-body cooling, and the CoolCap study employed selective head-cooling. The Total Body Hypothermia for Neonatal Encephalopathy (TOBY) began in 2002, and additionally summarized data from other RCTs, including NICHD NRN and CoolCap, to maximize participant size and study power, so the most effective assessment of therapeutic hypothermia in the setting of neonatal HIE and neurodevelopmental outcomes could be conducted. Per TOBY, neonates that met criteria for therapeutic hypothermia were at least 36 weeks gestational age and admitted to the neonatal intensive care unit, with at least one of the following: a) Apgar score of less than or equal to 5 at 10 minutes after birth; b) continued need for mechanical ventilation at 10 minutes after birth; c) acidosis within 60 minutes of birth; and/or d) base deficit greater than or equal to 16 mmol/L in any blood sample within 60 minutes of birth. Next, moderate or severe encephalopathy was defined as an altered state of consciousness, Hypothermia for Neonates 7 characterized by lethargy, stupor, or coma, and at least one of the following (Table 1): a) hypotonia; b) abnormal reflexes, including oculomotor and pupillary; c) absent or weak suck; and/or d) clinical seizures. Within 6 hours of birth, whole-body cooling was initiated, with a rectal or esophageal probe monitoring temperature at 33.5°C for a duration of 72 hours. After 72 hours, body temperature was raised gradually, at a rate of 0.5°C per hour, until 36.5°C was reached. Immediately following the re-warming phase, magnetic resonance imaging (MRI) scans of the brain were conducted, along with assessments of both cognitive outcome per the Bayley Scales of Infant Development II (BSID II) and neurodevelopmental disability per the Gross Motor Function Classification System (GMFCS). Additionally, evaluations to assess hearing and vision impairment, as well as the existence of CP and/or seizure disorders, were performed. An identical battery of examinations was also performed when study participants reached 18 months of age. Neurodevelopmental Outcomes at 18 Months of Age The general results ascertained from TOBY and the aforementioned RCTs were that across both c