Lingam, Ingran; (2020) Magnesium Sulphate Neuroprotection in Neonatal Encephalopathy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The efficacy of therapeutic hypothermia (HT) in neonatal encephalopathy (NE) is incomplete; mortality and morbidity remain high at almost 50% despite treatment. This is likely due to both limitations in hypothermic neuroprotection and heterogeneity in aetiology. Improving hypothermia therefore requires both adjunctive neuroprotective agents as well as improved diagnostic tools to differentiate injury subtypes. In Part (I), we established the safety and efficacy of MgSO4 combined with HT (Mg+HT; n=8) compared to HT (HT; n=7) in piglets after hypoxia ischaemia (HI). MgSO4 (180mg/kg bolus; 8mg/kg/h infusion) was administered 1h post-HI and HT for 12h. In Part (II), we explored whether MgSO4 attenuates cytokine gene expression in the same animals. Inflammation exacerbates brain injury, therefore anti-inflammatory agents such as MgSO4 may be particularly efficacious in patients with prior inflammation-sensitisation. There are however no biomarkers available to identify this patient subgroup. In Part (III), we utilised advanced biological techniques to distinguish hypoxia (Hypoxia; n=6), inflammation (LPS; n=5) and inflammation-sensitised hypoxia (LPS+Hypoxia; n=5) in a piglet model of inflammation-sensitised NE. LPS was commenced 4h prior to hypoxia (2μg/kg bolus; 1μg/kg infusion). We demonstrated that MgSO4 bolus and infusion provided a stable, raised serum magnesium without significant hypotension in hypothermic piglets post-HI. MgSO4 reduced overall cell death, however did not demonstrate a significant reduction in the primary outcome of MRS Lac/NAA. This suggests that the observed improvement was incremental and most likely insufficient to provide long-term benefit. MgSO4 did not alter microglial activation or astrogliosis, suggesting combination therapy did not attenuate inflammation post-HI. Consistent with this finding, magnesium exposure did not alter serum mRNA levels of inflammatory cytokines, chemokines or inducible nitric oxide synthetase. Whilst there is insufficient evidence to translate MgSO4 to clinical trials, magnesium remains an agent of interest which may yet find its place as part of a cocktail of neuroprotective medications that work incrementally and synergistically.

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