1 - Low and high dose Caffeine Citrate are not cytoprotective after Inflammation-Amplified Hypoxia Ischaemia in a Newborn Piglet Model.

Monday, May 1, 2023

9:30 AM – 11:30 AM ET

Poster Number: 1
Publication Number: 1.433

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

Presenting Author(s)

CM

Christopher Meehan, MSc

Researcher
University College London
London, England, United Kingdom

Background:

Therapies for neonatal encephalopathy (NE) are urgently needed, particularly in LMICs, where there are concerns around the safety and efficacy of therapeutic hypothermia (Thayyil, 2021) and where infection/inflammation may increase the risk of NE (Tann, 2018). Caffeine citrate is used routinely for apnoea of prematurity (AoP) with beneficial effects on clinical outcome. Neuroprotective efficacy has been observed in rodent models when given after hypoxia-ischaemia (HI) (Alexander, 2013).

Objective:

To assess neuroprotective efficacy of low and high dose caffeine citrate in a piglet model of inflammation-amplified Hypoxia Ischaemia (IA-HI)

Design/Methods:

18 newborn Large White Piglets (Male & Female) underwent inflammation-sensitization with E.coli Lipopolysaccharide (2µg/kg bolus & 12h 1µg/kg/h infusion), and at 4h a HI insult from carotid artery occlusion and reduction of FiO2 to 6%. 1h after HI, piglets were randomized (n=6 for all):

i) Control; Saline 8ml/kg at 1h & 4ml/kg at 24 & 48h

ii) Low dose caffeine citrate, 20mg/kg at 1h & 10mg/kg at 24 & 48h

iii) High dose caffeine citrate, 60mg/kg at 1h & 30mg/kg at 24 & 48h

For all animals, physiological parameters and electroencephalogram (aEEG/EEG) were recorded continuously. 1H and 31P magnetic resonance spectroscopy were acquired at 60h. Piglets were euthanized at 65h and the brain dissected for immunohistochemistry.

Results:

There were no differences in insult severity between groups. Caffeine citrate plasma concentration accumulated with each dose and reached final concentration of 18mg/L in low & 48mg/L in high dose. Plasma levels were never below target therapeutic range for AoP (Fig1). Neither dose produced lasting significant adverse physiological effects (Meehan 2022). There was no reduction in Lactate to N-Acetylaspartate (Lac/NAA) peak area ratio associated with either low or high dose caffeine citrate in either the Basal Ganglia/Thalamic or White Matter voxels. Bayesian analysis with non-informative priors showed probability of treatment superiority (PrSup) of ≤53%, meeting the threshold of futility. There was no preservation in PCr/Epp ratio associated with either caffeine citrate dose, (PrSup ≤62%) (Fig2). There was no improvement in aEEG/EEG recovery for either caffeine dose compared to control (Fig3).

Conclusion(s):

Neither low nor high dose caffeine citrate demonstrated cytoprotection as a monotherapy after IA-HI. Both caffeine doses met the Lac/NAA PrSup futility threshold for early study termination. Other therapies need to be considered to improve NE outcomes in LMIC setting.