Researcher University College London London, England, United Kingdom
Background: Therapies for neonatal encephalopathy (NE) are urgently needed in Low and Middle Income Countries where therapeutic hypothermia (HT) may not be safe and effective (Thayyil, 2021). In Sub-Saharan Africa infection/inflammation increases the risk of NE (Tann, 2019). Omegaven is a fish oil lipid emulsion, containing Docosahexaenoic Acid and Eicosapentaenoic Acid: Omega-3 fatty acids, (n-3-FA) essential for neuronal membrane function and precursors for lipid mediators that regulate the inflammatory response (Dyall, 2015). Preclinical studies have shown varying neuroprotective efficacy using n-3-FA but without consensus on dosing (Williams, 2013; Hunn, 2018). Clinically, the safety of Omegaven at 1g/kg/d has been established (Gura, 2007) Objective: To assess the cytoprotective efficacy of Omegaven in an established newborn piglet model of inflammation-amplified hypoxia-ischaemia (IA-HI) in which HT is not beneficial Design/Methods: Eleven newborn Large White Piglets (Male & Female) underwent inflammation-sensitisation with E.coli Lipopolysaccharide (2µg/kg bolus followed by 12h 1µg/kg/h infusion) and at 4h into infusion hypoxia-ischaemia (HI) by carotid artery occlusion and reduction of FiO2 to 6%. At 1h after HI, piglets were randomised to: i. 0.9% Saline Control (n=6): 2h infusion of 8ml/kg at 1h & 4ml/kg at 24 & 48h ii. Omegaven (n=5): 12h infusion of 1g/kg at 1, 24 & 48h For all animals, physiological parameters and electroencephalogram (aEEG/EEG) were recorded continuously. 1H magnetic resonance spectroscopy (MRS) was acquired at 60h. Serum samples were collected serially for Liver Function Test (Royal Veterinary College Diagnostic Laboratory, UK). Piglets were euthanised at 65h and the brain dissected for immunohistochemistry. We used a Bayesian approach, with a non-informative prior, and data are presented as probability of superiority (Prsup) Results: Insult severity was no different between groups. Significantly higher Triglyceride levels were observed in the Omegaven group at 65h (p=0.002). No significant group differences in other markers of liver function or physiological parameters were observed. There was no improvement in aEEG/EEG activity in the Omegaven group (PrSup = 63.9%). There was treatment inferiority in the Omegavan group on MRS, with increased Lac/NAA peak area ratio in both the Basal Ganglia/Thalamus (BGT) and White Matter (WM) voxels. The PrSup of Omegavan were 5.2% & 10% respectively
Conclusion(s): Omegaven did not demonstrate protection in this model of IA-HI; Prsup reached the futility threshold for Lac/NAA at interim analysis. Alternative therapies are needed to improve NE outcomes
.jpg)
.jpg)
.jpg)