19 - Azithromycin shows late improvement in aEEG/EEG recovery and modest cytoprotection following Inflammation-Amplified Hypoxia Ischaemia in the Newborn Piglet Model Relevant to Low Resource Settings

Monday, May 1, 2023

9:30 AM – 11:30 AM ET

Poster Number: 19
Publication Number: 19.434

Raymand Pang, University College London, London, England, United Kingdom; Christopher Meehan, University College London, London, England, United Kingdom; Katie Tucker, UCL, London, England, United Kingdom; Ellie Campbell, University College London, London, England, United Kingdom; Alison Mintoft, University College London, London, England, United Kingdom; Georgina L. Norris, University College London, London, England, United Kingdom; Francisco Torrealdea, UCLH, London, England, United Kingdom; Magdalena Sokolska, University College London Hospitals, London, England, United Kingdom; Alan Bainbridge, UCLH NHS Foundation Trust, London, England, United Kingdom; Xavier Golay, UCL Institute of Neurology, London, England, United Kingdom; John D.. Barks, University of Michigan Medical School, Ann Arbor, MI, United States; Nicola J. Robertson, University College London and University of Edinburgh, Bicester, England, United Kingdom

Presenting Author(s)

Raymand Pang, MB ChB

Clinical Research Fellow
University College London
London, England, United Kingdom

Background:

There is an urgent need to develop cytoprotective therapies for neonatal encephalopathy (NE) in low- and middle- income countries (LMICs), where therapeutic hypothermia (HT) is not beneficial for all infants (Thayyil et al., 2022). Infection and inflammation are independent risk factors for NE in this setting (Tann et al., 2018); we developed an inflammation-amplified hypoxia-ischaemia (IA-HI) piglet model to test potential monotherapies. In this model, brain injury is more severe and HT is not protective (Martinello et al., 2020) as in RCTs in LMICs. Azithromycin (AZI) has shown promise in rodent models of NE (Barks et al., 2019) however validation in large animal models is needed.

Objective:

We hypothesised that azithromycin monotherapy (20mg/kg I.V. at 1h, 24 and 48h) is safe and reduces brain injury in normothermic piglets following IA-HI.

Design/Methods:

This study was powered to detect a difference in Log10 Lac/NAA of 0.5 with SD 0.4 based on previous studies. Newborn piglets (male and female) underwent IA-HI by carotid artery occlusion and reduction in FiO₂ to 6% at 4h into E. coli lipopolysaccharide sensitisation (2mcg/kg bolus + 1mcg/kg/h 12h infusion). At 1h after HI, piglets were randomised to receive saline (n=12) or AZI (n=12). Continuous electroencephalogram (aEEG/EEG) was recorded and 1H magnetic resonance spectroscopy Lactate to N-acetylaspartate (Lac/NAA) peak area ratio acquired at 60h. Piglets were euthanised at 65h and brain dissected for immunohistochemistry.

Results:

There were no differences in insult severity between the two groups. AZI was not associated with QTc prolongation or systemic hypotension, and the target brain tissue levels were achieved (mean±SD 1450±450ng/g). AZI was associated with a reduction in BGT Lac/NAA of -0.143 log units (95% CrI (-0.453, 0.17)). Bayesian analysis with non-informative priors indicated a probability of treatment superiority (P_sup) of 82.7%. No significant difference was observed in the WM region. On aEEG, cerebral activity at 55-60h was significantly improved (P_sup=96.6%, see Fig). AZI was associated with suppression of microglial activation (Iba-1 ramification index) across 4 regions (see Fig).

Conclusion(s):

Intravenous AZI demonstrates modest cytoprotection following IA-HI. While the benefit on cerebral energy metabolism is modest, we observed particular benefit on suppression of neuro-inflammation and late improvement in aEEG activity at 55-60h. Longer term effects of AZI need to be assessed as well as effects of combination therapies of AZI with other acute therapies such as melatonin.