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Title: Preclinical neonatal neuroprotection : neuroprotective effect of remote ischemic postconditioning and dexmedetomidine in a piglet model of perinatal asphyxia
Author: Ezzati, Mojgan
ISNI:       0000 0004 7964 9848
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Perinatal hypoxic ischemic events are a global burden leading to 1.1 million babies with neonatal encephalopathy (NE) annually. Therapeutic hypothermia is a standard practice in developed countries. Still almost 50% of cooled babies have morbidities; Adjunct therapies are needed. This thesis consists of two different preclinical neuroprotection studies. We used a piglet model of perinatal hypoxic ischemia for both studies. Our endpoint biomarkers were immunohistochemistry and in vivo proton (1 H) and phosphorus31 (31P) MRS markers. The first part explores the neuroprotective properties of remote ischemic postconditioning (RIPostC). The second part explores the neuroprotective effect of dexmedetomidine. RIPostC is defined as short cycles of ischemia/reperfusion (I/R) in a remote nonvital organ following a major hypoxic ischemic insult (HI). The first objective was to develop a practical method to achieve intermittent and reversible femoral artery occlusion for remote ischemic stimulus. Second objective was to investigate whether RIPostC immediately applied at resuscitation is neuroprotective following a global cerebral HI in this piglet model. RIPostC cycles were four, 10 minutes cycles of bilateral hind limb I/R immediately after HI. The study showed that RIPostC was neuroprotective in cerebral white matter and also significantly increased whole brain ATP. Immediate RIPostC is a safe procedure. Dexmedetomidine, a highly selective α2-adrenoreceptor agonist exerts analgesic and anti- inflammatory properties. The first objective of this study was to find an optimal safe dose for pre-clinical studies and second objective was to investigate whether substitution of fentanyl with dexmedetomidine for sedation during cooling is neuroprotective. Dexmedetomidine clearance was reduced by 32.7% and 55.8% during cooling and following HI respectively. The PK modelling suggested that a loading dose of 2μg/kg followed by 0.028μg/kg/h provide a safe plasma level. However, the second part of study revealed that dexmedetomidine combined with cooling is neurotoxic and associated with haemodynamic instability.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available