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Title: An investigation of the mechanisms underlying hypotension and vascular hyporeactivity in septic shock
Author: O'Brien, Alastair
ISNI:       0000 0001 3451 1755
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2006
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Septic shock is a common condition carrying a high mortality. The clinical features are a high cardiac output circulation with hypotension and vascular hyporeactivity and evidence of organ failure. I developed an organ culture in vitro model and a fluid-resuscitated in vivo model of sepsis to investigate potential underlying mechanisms for the vascular hyporeactivity, namely inducible nitric oxide synthase (iNOS) overproduction and ATP-sensitive K+ (Katp) channel activation. I also studied the phenomenon of vascular supersensitivity to vasopressin/terlipressin in sepsis. I could demonstrate a temporal variation in vascular hyporeactivity to lipopolysaccharide (LPS) in rat mesenteric artery (RMA) in vitro over a 46 h period. This was reversed by a variety of iNOS inhibitors (aminoguanidine, L-NAME, 1400W and GW273629) and the guanylyl cyclase inhibitor, ODQ. Likewise, inhibition of the Katp channel via its pore-forming subunit, rather than its sulphonylurea receptor (SUR), also reversed LPS-induced hyporeactivity in vitro, though vasopressin had no effect In vivo, iNOS inhibition and terlipressin all raised blood pressure in the septic animals over and above the pressor effect achieved in non-septic animals Katp channel inhibition raised blood pressure in shams more than septic animals. However, these agents failed to improve macro- or microcirculatory blood flow, nor did they attenuate the metabolic acidosis. In patients with norepinephrine-resistant septic shock, I reported the first use of terlipressin in reversing hypotension and reducing norepinephrine requirements. Although terlipressin represents a significant advance in our ability to treat septic shock, care should be taken when using it.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available