Review Question - QID 217089

This newborn with a sentinel hypoxic event during labor and delivery (abruptio placentae), Apgar scores persistently less than 5, clinical signs of peripartum HIE (poor tone, diminished movements, absent primitive reflexes), and cord gases suggestive of metabolic acidosis (umbilical artery pH < 7, low PO2, low PCO2) most likely has hypoxic-ischemic encephalopathy. The only proven neuroprotective treatment for HIE is therapeutic hypothermia, with a target temperature of 33.5°C.

Hypoxic-ischemic injury leads to depletion of high energy metabolites, severe cytotoxic edema, neuronal depolarization, extracellular accumulation of excitatory neurotransmitters, and excitatory neurotoxicity. There can be secondary neuronal damage with reperfusion due to oxidative damage. Therapeutic hypothermia helps mitigate neuronal injury by decreasing neuronal energy demand by decreasing cellular metabolism; in addition, hypothermia slows reperfusion and thus decreases oxidative damage. Therapeutic hypothermia should be started on all infants with moderate to severe encephalopathy, gestational age >= 36 weeks and less than 6 hours of age, and evidence of ischemia (metabolic acidosis with pH < 7, 10-minute Apgar less than 6, or ongoing resuscitation for greater than 10 minutes).

Davidson et al. review the epidemiology, pathophysiology, and standard treatment of HIE with hypothermia. They also review emerging treatments for HIE including EPO, melatonin, xenon, and IGF-1.

Incorrect Answers:
Answer 1: Erythropoietin (EPO) is routinely used to treat anemia in premature infants and may have some neuroprotective effects in HIE. EPO can promote the expression of anti-apoptotic genes, attenuate oxygen free radicals, and decrease the inflammatory response to hypoxia. However, there is still limited evidence that EPO alone provides adequate neuroprotection or that EPO augments hypothermic neuroprotection.

Answer 3: Permissive hypertension of systolic blood pressure up to 180 mmHg is used for early acute ischemic stroke. However, hypertension can worsen cerebral edema and should be avoided in HIE. If patients are hypotensive, volume replacement and inotropic agents should be used to maintain adequate blood pressure and cerebral perfusion.

Answer 4: Phenobarbital is an anticonvulsant that can be used as supportive therapy in HIE to treat seizures. While anticonvulsants may theoretically reduce excitotoxicity, there is limited evidence either from retrospective studies or in animal models that anticonvulsants augment neuroprotection from hypothermia.

Answer 5: Xenon is used in some nuclear medicine studies and may play a role in neuroprotection after hypoxic-ischemic injury by competitive inhibition of N-methyl-D-aspartate (NMDA) receptors. However, evidence is still mixed, and the limited natural availability and high cost of xenon make this treatment prohibitive outside of clinical trials at tertiary centers.

Bullet Summary:
Neuronal injury in the setting of ischemia can be mitigated by therapeutic hypothermia, which decreases cellular metabolism and slows reperfusion.