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Title: The role of glyceryl trinitrate, a nitric oxide donor, in acute stroke
Author: Appleton, Jason Philip
ISNI:       0000 0004 7965 7610
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2019
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Nitric oxide donors (e.g. glyceryl trinitrate (GTN)) are candidate treatments for acute stroke with haemodynamic, reperfusion, and neuroprotective properties. In order to establish the safety and efficacy of NO donors in acute stroke a Cochrane systematic review and meta-analysis was performed. Transdermal GTN was assessed in 5 trials (n=4197) in acute stroke. Overall, GTN was safe and lowered blood pressure but did not influence clinical outcome. However, early treatment with GTN within 6 hours (n=312) improved clinical outcomes across a variety of domains (death and dependency, death, disability, cognition, mood, and quality of life). Using data from the large Efficacy of Nitric Oxide in Stroke (ENOS) trial, the haemodynamic properties of GTN were explored. GTN lowered BP and its derivatives including BP variability. Further, increased BP variability was associated with poor functional and cognitive outcomes and increased death at day 90. The safety and efficacy of transdermal GTN in important subgroups in acute stroke was assessed. GTN was safe in the context of blood markers of dehydration with no precipitous drops in BP seen in such patients. GTN in the context of ipsilateral or bilateral carotid stenosis was safe and may improve outcome in severe ipsilateral carotid stenosis. Although GTN was safe, it did not improve outcome in patients with lacunar syndromes either overall or within 6 hours of onset. Baseline imaging markers of small vessel disease and 'brain frailty' were associated with functional and cognitive outcomes 90 days after stroke. In summary, this thesis has confirmed the safety of transdermal GTN in acute stroke both overall and in important subgroups. Mechanistic data suggest that GTN may reduce BP variability, which seems to be more strongly associated with outcome than absolute BP or trend in BP. Transdermal GTN is safe to be administered in acute stroke patients with elevated BP prior to blood markers of dehydration or carotid stenosis status being known. Baseline imaging markers of SVD and 'brain frailty' predict clinical outcome and should be used as minimisation criteria in future acute stroke trials and may help guide future clinical decision-making.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: WL Nervous system