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Refining the use of magnesium in neonatal encephalopathy: magnesiumaugmented therapeutic hypothermia compared to hypothermia alone

Presented at the Neonatal Society 2017 Autumn Meeting.

Lingam I1, Meehan C, Avdic-Belltheus A, Martinello K, Hristova M, Kaynezhad P, Bauer C, Tachtsidis I, Golay X, Robertson NJ

1 Institute for Womens Health, University College London, London, United Kingdom
2 Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
3 Institute of Neurology, University College London, London, United Kingdom

Background: Therapeutic hypothermia (TH) was a significant milestone in the treatment of term neonatal encephalopathy (NE), however mortality and risks of long-term disability remain unacceptably high. Magnesium is a NMDA receptor inhibitor and has shown promise in the prevention of cerebral palsy in the preterm population (1). Both cooling and magnesium dampen excitotoxicity and therefore may be synergistic in combination (2). We aim to assess the efficacy of magnesium (constant infusion over 48h) as an adjunct to TH in a piglet model of NE.

Methods: 15 large white piglets were randomised following HI to receive i) MgSO4 (bolus 180mg/kg; infusion 8-10mg/kg/h over 48h) and TH or ii) saline (3.6ml/kg bolus; 0.5ml/h infusion) and TH. Treatments were initiated at 1h post-HI and total body cooling continued for 12h at 33.5ºC. HI was performed by transient carotid occlusion and inhalation of 6%O2 for 20-25min (titrated to BP, oxCCO, isoelectric EEG). Amplitude integrated EEG (aEEG) was monitored continuously, magnetic resonance spectroscopy (MRS) was performed at 24 and 48h post-insult. Animals were euthanised at the end of experimentation and regional TUNEL analysis performed.

Results: All animals had similar baseline cardiovascular parameters and had a similar severity of HI performed, as defined by the duration of hypotension (BP < 30mmHg), isoelectric EEG and total fall in oxCCO. MgSO4 infusions were well-tolerated with no significant increase in inotrope requirements and no difference in survival between magnesium-treated and control animals (8/8 vs 6/7, p=0.47). MgSO4 administration increased levels significantly in the serum (0.72 vs 1.52 mmol/L, p<0.01) and CSF (1.04 vs 1.22 mmol/L, p<0.01). There was a trend towards aEEG improvement after 36h in magnesium augmented hypothermia (p=0.08), which appeared significant on exclusion of 2 animals with mild HI on a post-hoc analysis. Magnesium augmented hypothermia did not demonstrate significant benefit on MRS biomarkers (lac/naa, PCr/Pi, NTP/epp) or overall TUNEL analysis. Regional histology however demonstrated a reduction in TUNEL +ve cells in the internal capsule.

Conclusion: Magnesium infusion was safe (no hypotension), demonstrated some improvement in aEEG and reduced apoptosis in the internal capsule. Although there was no clear superiority over therapeutic hypothermia alone, optimising serum magnesium levels in babies with NE may be an important part of neuro-critical care support.

Corresponding author: ingran@gmail.com

References
1. Conde-Agudelo et al. Antenatal magnesium sulphate for the preventation of cerebral palsy in preterm infants < 34 weeks gestation. Am J Obstet Gynecol. (2009)
2. Zhu et al. Post-ischemic modest hypothermia (358C) combined with intravenous magnesium is more effective at reducing CA1 neuronal death than either treatment used alone following global cerebral ischemia in rats. Exp Neu 193 (2005)

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