|Adjunct therapy||Mode of action||Examples of recent preclinical trials||Clinical RCTs|
|Melatonin||Endogenous hormone which entrains the circadian rhythm at physiological doses. At high pharmacological doses melatonin is a powerful antioxidant and antiapoptotic agent.||Systematic review and meta-analysis of 400 adult rodents showed a 43% reduction in stroke infarct size with melatonin.74 A piglet study showed augmentation of brain protection with high dose melatonin at 10 min and cooling versus cooling alone.75||Oral melatonin (10 mg/kg/day 5 doses) tablets crushed in 5 mL distilled water. n=15 cooled, n=15 cooled plus melatonin, n=15 controls.76|
|Erythropoietin (Epo)||Acute actions: neurotrophic, anti-inflammatory, antiapoptotic, antioxidant|
Chronic actions: erythropoiesis, angiogenesis, oligodendrogenesis, neurogenesis.
|Non-human primate model—hypothermia+Epo treatment improved outcomes in non-human primates exposed to umbilical cord occlusion.77||NEAT trial—safety and PK.78|
Phase II trial of hypothermia and Epo showed less MRI injury and better short-term outcome.79
Phase III trial is now underway in the USA.
|Xenon||Inhibits NMDA signalling, antiapoptotic.||Preclinical piglet studies showed benefit of combined cooling and xenon compared with no treatment.80 81||No evidence of short-term benefit with xenon and cooling above cooling alone, using MRS lactate/NAA as a surrogate outcome.82|
|Argon||GABA agonist and oxygen type properties. Antiapoptotic.||Preclinical piglet study showed brain protection on MRS and histology with 50% argon and cooling compared with cooling alone.83||Phase II trials pending regulatory approval.|
|Allopurinol||Reduces free radical production and in high doses acts as a free radical scavenger and free iron chelator.||Improved 31P MRS metabolites and MRI values with allopurinol in piglets.84||ALBINO trial to start in Europe 2017—to assess benefit of early allopurinol at 30 min plus cooling versus cooling alone.|
|Stem cells||Paracrine signalling—not cellular integration or direct proliferative effects.||Evidence of improved neurological outcome and reduced histological injury.85||Autologous umbilical cord cells in HIE demonstrated feasibility.86|
|Magnesium||Prevention of excitatory injury by stabilisation of neuronal membranes and blockade of excitatory neurotransmitters, for example, glutamate.||Magnesium alone has not been protective in piglet models of hypoxia.87 Combinations of magnesium with cooling has shown benefit.88||Recent meta-analysis shows no evidence of benefit.88|
A multicentre pilot RCT reported safety but no outcome data, larger RCT to follow89
HIE, hypoxic-ischaemic encephalopathy; GABA, gamma-aminobutyric acid; MRS, magnetic resonance spectroscopy; NAA, N-acetylasparate; NMDA, N-methyl-D-aspartate; PK, pharmacokinetics; RCT, randomised controlled trials.