Management of Hypoxic-Ischemic Encephalopathy Using Measures Other Than Therapeutic Hypothermia

Definition

Neonatal encephalopathy (NE) is an alteration in consciousness or neurologic exam in the neonate. The possible etiologies of NE are broad ( Table 47.1 ) but it is most commonly (approximately 50%) caused by hypoxic-ischemic encephalopathy (HIE). ^, The following sections are focused on HIE, although many details are applicable to other NE etiologies.

Diagnosis

The initial diagnosis of HIE relies on evidence of an acute or subacute (prolonged) perinatal event leading to brain injury and exam findings consistent with encephalopathy. Initial evaluation of an infant with suspected HIE should include perinatal history, neurologic exam, and in some cases, electroencephalogram (EEG) and imaging, when available.

Perinatal History

Evidence of intrauterine distress such as an abnormal biophysical profile, decreased fetal movements, fetal bradycardia, or acidosis on umbilical cord/initial infant blood gas (within 1 hour of birth), along with need for extensive resuscitation and/or low Apgar scores (<5) at 5 and 10 minutes, are needed for the diagnosis. ^,

Neurologic Examination

The clinical presentation depends on the duration, timing, and severity of the insult and may evolve over the subsequent hours to days. Although it is not the only scoring system, clinical staging of encephalopathy is often based on the Sarnat criteria ( Table 47.2 ). Using the modified Sarnat criteria, which do not include EEG, the current recommendations are to offer therapeutic hypothermia (TH) to infants with moderate to severe encephalopathy, although the efficacy of TH in severe encephalopathy is the subject of ongoing studies (see Chapter 32 ). The Sarnat score was used as an inclusion criterion in the first randomized controlled trials of TH ^{, ,} and is still used by most neonatal intensive care units for evaluation of the neonate needing TH. Longitudinal follow-up of Sarnat scoring suggests that worsening staging regardless of the initial staging is more predictive than the initial score alone.

Acute Phase

The fetal brain requires blood flow to deliver oxygen and glucose for cellular energy and metabolic homeostasis. Interruption of blood flow leads to hypoxemia and eventually decreases cardiac output. Depending on the severity and timing of the disruption of blood flow, cerebral injury may occur and lead to HIE. Abrupt disruption of cerebral blood flow is classically associated with deep grey matter (basal ganglia and thalamus) injury. Chronic and less severe (partial) disruption of cerebral blood flow is associated with cortical injury, particularly in the watershed regions.

The initial disruption of cerebral blood flow leads to mitochondria failure. The resulting adenosine triphosphate (ATP) depletion and lactic acid build-up impairs the function of excitatory amino acid transporters within the astrocytic membrane forming the synaptic cleft. As a result, excitatory amino acids such as glutamate accumulate and activate N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, leading to an intracellular influx of sodium, calcium, and water. Cell death results from the progression of cytotoxic edema, protease activation, and free radical production ( Fig. 47.1 ).

Latent/Chronic Phase

Restoration of cerebral blood flow, or reperfusion, after disruption and injury begins the latent phase of injury. The latent phase is the therapeutic target of TH. Secondary energy failure, which signals the end of the latent phase, is marked by irreversible mitochondrial failure and involves oxidative stress, intracellular calcium accumulation, inflammation, and cell death. This neuronal death includes cell death along the entire cell death continuum, including apoptosis, autophagy, continuum cell death, necroptosis, and necrosis. Many of the therapeutic agents tested in the past decade have targeted many of these downstream mechanisms ( Figs. 47.2 and 47.3 ).

Gestational Age/Prematurity

HIE is classically reported in full-term and late preterm infants and rarely in preterm infants. Although HIE occurs at all gestational ages, the assessment of encephalopathy in preterm infants is difficult and the clinical presentation of seizures may be subtle. There have been several small studies on preterm HIE, ^, which have found that due to differences in neurodevelopmental stage, injury mechanisms and patterns differ from those of the full-term neonate. Oligodendrocyte maturity, vascular and blood-brain barrier permeability, and selective vulnerability of certain cell lines such as developing oligodendroglia, astrocytes, and microglia likely determine the severity and type of injury. Preterm infants appear to exhibit greater susceptibility to white matter injury, most often associated with concurrent basal ganglia and thalamic injury, than do full-term infants (see Fig. 47.8 ahead).

Encephalopathy Score

Multiple scoring systems have been developed to assess severity of encephalopathy and predict long-term risk of neurodevelopmental disability (see Table 47.2 ). The first of these was the Sarnat scoring system. Clinically, in settings where other prognostic tools (magnetic resonance imaging [MRI], EEG) can be used, these scores are most commonly used to assess eligibility for TH. Regardless of the scoring or staging system used, trending the score/exam over time while in the acute period is important, because the examination will evolve over time and persistently high encephalopathy scores are generally predictive of worse outcomes. Of note, administration of sedation and/or antiepileptic drugs may alter the exam, which should considered.

Findings of moderate or severe encephalopathy on exam are inclusion criteria for treatment with TH; traditionally, children with mild encephalopathy were not thought to be at significant risk for neurodevelopmental disability, but there is growing evidence that neonates with mild encephalopathy may be at risk for long-term neurodevelopmental abnormalities. Neonates with mild HIE have been described to have abnormal short-term outcomes such as longer time to reach full feeds, seizures, need for a surgical feeding device, or abnormal MRI or neurologic exam findings at discharge. In a retrospective analysis of infants who had received TH, MRI abnormalities after TH were equally common among infants with mild HIE compared with those with moderate or severe HIE. Mild encephalopathy on early EEG is associated with lower IQ at age 5 years. The PRIME (Prospective Research in Infants with Mild Encephalopathy) study revealed that over half of infants with mild HIE had an abnormal short-term outcome. A recent meta-analysis showed that 20% of infants with mild encephalopathy have adverse neurologic outcomes at 18 months. Study of long-term outcomes in infants with mild HIE as well as the efficacy of TH for this group is ongoing.