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Statements of Disclosure of Relevant Financial Relationships have been obtained from Ulrike Mietzsch, MD. Dr. Mietzsch has disclosed that she has no relevant financial relationships with any commercial interests.
After reading this article, the reader should be able to:
- Describe the clinical manifestations of neonatal hypoxic-ischemic encephalopathy (HIE) and its underlying mechanisms.
- Discuss the evolution of brain injury associated with HIE.
- Identify the primary method for evaluating newborns diagnosed with HIE.
- Summarize the use and timing of hypothermia for neonatal HIE and expected outcomes.
- Justify the need for long-term follow-up posthypothermia and describe what it entails.
Date of original release: September 2015
Date of expiration: September 2016
Note: While it offers CME credits, this activity is not intended to provide extensive training or certification in the field.
Overview of Neonatal Hypoxic-Ischemic Encephalopathy (HIE)
Neonatal HIE, also called birth asphyxia, is a clinical syndrome of disturbed neurologic function in the earliest days after birth of an infant. It is manifested by difficulty initiating and maintaining respiration; depression of tone and reflexes; subnormal level of consciousness; and often, seizures.1 In the United States, HIE occurs in two to three per 1000 live births, meaning that an estimated 8000 to 12,000 infants are diagnosed with the condition each year.2 As many as 20 percent of term newborns with HIE die during the neonatal period.1 Among those who survive, approximately 50 percent sustain permanent neurologic disability, including cerebral palsy, intellectual disabilities, and hearing deficit. Survivors without physical disability may have delayed entry into primary school, fine-motor dysfunction, and behavioral abnormalities.
“HIE may result from a number of acute perinatal events, such as placental abruption, hemorrhage, and umbilical cord prolapse, all of which reduce the oxygen supply to the baby,” explains Ulrike Mietzsch, MD, co-director of the neuro-neonatal intensive care unit (NeuroNICU) at Riley Hospital for Children at IU Health and assistant professor of clinical pediatrics at Indiana University School of Medicine. “Gestational age together with the nature, severity, and duration of the hypoxic-ischemic insult influence the extent of neuronal injury.”
A 29-year-old woman presents at a local hospital in labor with her first child. She has had an uncomplicated 40-week gestation and at presentation is 6 cm dilated and 90 percent effaced; membranes are intact. Shortly after admission, her water spontaneously breaks. The discharged fluid is clear, but a nurse observes part of the umbilical cord protruding from the patient’s vagina. The fetal heart rate drops from 130 to 80 bpm, and the patient is emergently taken to the operating room for a cesarean delivery.
At delivery, the baby girl is floppy and apneic, and her heart rate is 50 bpm. Positive pressure ventilation is started but fails to increase the heart rate. Chest compressions are initiated, and an emergent umbilical venous catheter is placed to administer epinephrine. At eight minutes after birth, heart rate stabilizes at >100bpm. Apgar scores are 0/0/2/3/4, and venous cord blood gases are: pH 6.85, pCO2 98 mm Hg, pO2 = <20 mm Hg, HCO3 12 mEq/L, base deficit (BD) 24 mEq/L. The infant is intravenously given two boluses of normal saline. Baby blood gas results obtained at 34 minutes after birth show minimal improvement: pH 6.99, pCO2 54 mm Hg, pO2 35 mm Hg, HCO3 12 mEq/L, BD 21 mEq/L.
On examination, the infant’s heart rate is normal, but she is flaccid, has dilated pupils, and is minimally responsive to stimuli; Moro and suck reflexes are absent. The findings suggest acute encephalopathy following cord prolapse, and she is transferred to the NeuroNICU at Riley Hospital for Children at Indiana University Health at 4.5 hours after birth. The admission exam is consistent with a diagnosis of severe neonatal HIE, according to modified Sarnat criteria (Table 1). Electroencephalographic (EEG) leads are placed to allow continuous monitoring of the baby’s brain activity.
Evolution of Brain Injury in HIE
Perinatal brain injury is a complex evolving process that begins during the hypoxic-ischemic insult and extends into the recovery period (Figure 1).
The primary phase, which can last minutes to hours, is caused by cellular hypoxia and energy depletion and is chiefly characterized by cell necrosis and minimal apoptosis. It is followed by a latent phase, during which the body attempts to restore blood and oxygen flow and replenish the energy supply. This phase lasts six to 15 hours, culminating in an inflammatory response that attracts monocytes and cytokines.3
“Transition to the secondary phase, the final phase of injury, occurs hours to days after the acute insult and is typified by secondary energy failure owing to mitochondrial malfunction and inflammatory and cytokine responses,” Dr. Mietzsch describes. “Excitatory amino acids accumulate, rendering the brain more susceptible to seizure activity, which is subclinical in about 50 percent of patients.”
In the United States, HIE occurs in two to three per 1000 live births, meaning that an estimated 8000 to 12,000 infants are diagnosed with the condition each year.2
Diagnosis and Evaluation
The diagnosis of neonatal HIE is challenging because encephalopathy can develop for reasons other than acute hypoxia-ischemia. The diagnosis of acute neonatal HIE is based on a combination of clinical indications, such as an acute perinatal event and abnormal neurologic exam, and biochemical findings, including evidence of metabolic acidosis on blood gas analysis within the first hour after birth (Table 2). Multisystem organ failure is commonly present in the affected infant, in particular the kidneys, heart, and liver, as blood is shifted to the brain.
“Magnetic resonance imaging (MRI) is the primary method used to evaluate brain injury patterns and determine the extent of injury,” says Dr. Mietzsch. “Spectroscopy provides additional information about the injury by evaluating the metabolic status of different areas of the brain.”
Hypothermia: the Only Effective Therapy for HIE
To date, hypothermia is the only therapy shown to improve outcomes associated with moderate to severe neonatal HIE. The goal of treatment is to lower the temperature of the vulnerable deep brain structures in order to:1
- Decrease cerebral metabolism, energy consumption, and concentrations of oxygen free radicals, and excitatory amino acids.
- Suppress apoptosis and the inflammatory cascade.
- Reduce the extension of brain injury.
“Large randomized clinical trials (RCT) have shown that in appropriately selected infants with HIE (Table 2), lowering body temperature to 33 to 34ºC (91-93ºF) for 72 hours, when initiated within six hours after birth, reduces the risk of death or disability and increases the rate of survival free of disability at 18 to 24 months of age,”4 -7 Dr. Mietzsch reports.
Hypothermia can be applied to the head only (Cool Cap) or to the entire body (whole body hypothermia [WBH]). Although the two techniques have not been compared in a head-to-head trial, individual studies of each cooling method suggest that long-term outcomes are superior with WBH, which is used at Riley at IU Health. Treatment-related side effects include relative bradycardia that is benign and physiologic (caused by slowing of the atrial pacemaker), platelet dysfunction, hypoglycemia, hypocalcemia, and fat necrosis.
Case Study (cont.)
The decision is made to initiate WBH, and the baby is placed on an infant-sized precooled blanket. An esophageal probe is inserted, and the core body temperature is rapidly lowered to 33.5ºC over a 30-minute period. Both core body and abdominal wall skin temperatures are continuously monitored.
At 15 hours after birth, seizure activity is noted on EEG monitoring that progresses over the next few hours and requires treatment with two anticonvulsant medications. All seizure activity stops at 36 hours after birth, and anticonvulsant monotherapy is continued. A repeat neurologic exam performed at that time shows marked improvement and is now consistent with moderate HIE.
After 72 hours of hypothermia, the rewarming process is initiated. The baby’s body temperature is raised by 0.5ºC every hour and reaches normothermia (36.5ºC) after six hours. The esophageal temperature probe is removed.
MRI with spectroscopy obtained on day after birth 5 shows changes consistent with moderate to severe hypoxic-ischemic injury (Figure 2). Neurologic and physical exams continue to improve, and the baby starts partial oral feedings on day 7. On day 16, she continues nasogastric (NG) and oral feedings; decreased central muscle tone is noted on physical exam. No further seizures occur, and anticonvulsant therapy is discontinued.
Outcomes After Hypothermia
“Post-hypothermia treatment outcomes are generally improved for patients with moderate or moderate to severe HIE, but such therapy continues to be controversial for severely affected neonates,” Dr. Mietzsch says. “Nonetheless, HIE is a dynamic process, and the initial impression of the patient does not necessarily correlate with outcome. During the first 48 hours, changes in the EEG background have the best prognostic capability. Return of normal brain activity and sleep-wake cycles within 48 hours is linked to a more favorable prognosis.”
Outcome data for 190 of 208 babies with moderate or severe HIE enrolled in a major hypothermia RCT4 was published in 2012.8 The investigators reported that the rate of the combined end point of death or an IQ score <70 at age six to seven years was lower among children who had undergone WBH than for those who received usual care. Although these differences were not significant, hypothermia did result in lower death rates and, importantly, did not increase rates of severe disability among survivors.
Case Study (cont.)
The infant is discharged home on day 19 on a combination of NG and oral feedings. During the next six months, she is closely followed by her pediatrician and a pediatric neurologist. No further seizures are observed. The neurologic exam at one year of age continues to show some deficits, including increased muscle tone in the lower extremities, and the child is subsequently diagnosed with mild cerebral palsy and speech delay.
Long-term Follow-up and Ongoing Challenges
Long-term follow-up is a key component of care for babies with HIE treated with hypothermia, according to Dr. Mietzsch. Follow-up includes regular evaluation by a pediatric neurologist and general pediatrician to assure that developmental milestones of early infancy and childhood are met. If concerns about abnormal development arise, the child is referred to a developmental specialist, who assesses the level of disability, including cognitive and motor function and psychosocial health, and arranges for any necessary services (e.g., physical therapy).
Increasing Access to Hypothermia Throughout Indiana
“The progression of brain injury following neonatal hypoxia-ischemia provides a window of opportunity for the initiation of hypothermia to arrest or ameliorate secondary damage,” emphasizes Dr. Mietzsch. “Outcomes are optimized when treatment is initiated within the first six hours after birth.
“A significant challenge in Indiana is long travel times to a brain cooling center—times that can increase substantially during bad weather,” Dr. Mietzsch adds. “To ensure access to hypothermia regardless of the place of birth, IU Health Lifeline, in partnership with Riley Hospital for Children at IU Health, has recently launched a program whereby active whole body hypothermia can be initiated during transport (Figure 3) to the NeuroNICU.”
Dr. Mietzsch received her medical degree from Humboldt University in Berlin, Germany and completed residency training in pediatrics and a fellowship in neonatal/perinatal medicine at the University of Texas Health Sciences Center in Houston. Her primary research interest is optimizing neurodevelopmental outcomes in very preterm neonates and infants with hypoxic-ischemic encephalopathy. Additionally, she founded the NeuroNICU program at Riley Hospital for Children at IU Health, which is focused on minimizing brain injury in term and preterm babies.
A member of the American Academy of Pediatrics and the Society for Neuroscience, Dr. Mietzsch is the author of several peer-reviewed journal articles and has been an invited lecturer at national and international medical conferences.
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