Current and Emerging Therapies in the Management of Hypoxic Ischemic Encephalopathy in Neonates

Abstract

Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its high mortality and morbidity rates globally. Therapeutic hypothermia (TH) is now standard of care for infants with moderate to severe HIE, but has not definitively changed outcomes in severe HIE. In this review, we discuss newer promising markers that may help the clinician identify severity of HIE. Therapies that are beneficial and agents that hold promise for neuroprotection are described, both for use either alone or as adjuncts to TH. These include endogenous pathway modifiers such as erythropoietin and analogues, melatonin, and remote ischemic post conditioning. Stem cells have therapeutic potential in this condition, as in many other neonatal conditions. Of the agents listed, only erythropoietin and analogues are currently being evaluated in large randomized controlled trials (RCTs). Exogenous therapies such as argon and xenon, allopurinol, monosialogangliosides, and magnesium sulfate continue to be investigated. The recognition of tertiary mechanisms of brain damage has opened up new research into therapies not only to attenuate brain damage but also to promote cell repair and regeneration in a developmentally disorganized brain long after the perinatal insult. These alternative modalities may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment and services.

Keywords: birth asphyxia; hypoxic ischemic encephalopathy; neonatal encephalopathy.

Figure 1

Schematic illustration of pathophysiology of HIE in relation to hypoxic ischemic (HI) insult resulting in primary (acute phase) and secondary energy failure (secondary phase) in the brain. Brain damage (tertiary phase) continues to occur months to years after the injury resulting in decreased plasticity and reduced number of neurons. Latent period following resuscitation is ideal for interventions to decrease the impact of secondary energy failure. However, strategies are developed to attenuate tertiary brain damage which will expand the therapeutic window, substantially increasing the beneficial effects of neuroprotection in these infants and hence its impact on long-term outcomes. CBF—cerebral blood flow; ATP—Adenosine tri phosphate; NT—neurotransmitters.

Figure 2

Potential neuroprotective therapies in the management of hypoxic-ischemic encephalopathy. Hypothermia is currently the standard of care in the management of moderate to severe HIE in infants. (A) Hypoxia stimulates erythropoietin (Epo) production by the kidneys, increasing RBC production in the bone marrow, thereby increasing O₂ carryign capacity. Epo favors neurogenesis; is an antioxidant (AO), anti-inflammatory (AI), decreases apoptosis (Apo) and excitotoxic cell injury (ECI); (B) Xenon (Xe—purple dots), neon (Ne—teal dots), and magnesium sulphate (Mgso4—brown dots) antagonize the N-methyl-D-aspartate (NMDA) mediated excitotoxicity via the NMDA receptor (NMDAR), decreasing calcium entry into the cell. SC—synaptic cleft, Pre-SC—presynaptic cleft, Post-SC—postsynaptic cleft; (C) Endogenous cannabinoids (ECBs) and melatonin are neuroprotective. Spingolipids such as gangliosides (GL) also protect against apoptotic injury; (D) Umbilical cord blood derived stem cells and mesenchymal stem cells modulate the immune system and affect long-term outcomes; (E) Allopurinol by inhibiting the enzyme xanthine oxidase (XO), decreases reactive oxygen species, mitochondrial lysis, and cell death. O₂—superoxide, H₂O₂—hydrogen peroxide, ONOO—peroxynitrite, ETC—electron transfer chain; PTP—permeability transition pore of inner mitochondrial membrane.