Sepsis is an overwhelming inflammatory response to infection that can progress to septic shock, characterised by refractory hypotension and insufficient organ perfusion. It is predominantly associated with nosocomial infections, and tends to occur in extremes of age, where it is associated with very high mortality rates. Sepsis and sepsis-associated multi-organ failure represent a tremendous healthcare burden and a significant cause of morbidity and mortality worldwide. Incidence has continued to increase over several decades, and septic shock is now the leading cause of death in intensive care units, claiming an estimated 20,000 lives per day worldwide. Despite decades of endeavour, research has not produced any specific pharmacological treatments shown definitively to improve survival in septic patients. Cardiovascular collapse plays a key role in mortality, and correspondingly, pre-clinical and clinical assessment of the impact of interventions on disease progression has been based upon systemic haemodynamics and achieving target blood pressures. In recent years, however, it has become increasingly clear that systemic stabilisation does not necessarily prevent the onset of organ failure, and may actually be achieved at the expense of visceral perfusion. Sepsis is now increasingly understood to be a ‘disease of the microcirculation’, though pre-clinical models rarely assess this parameter, perhaps accounting for the lack of research translatability. There is thus a critical need to develop more clinically relevant pre-clinical models, which focus on clinically prognostic endpoints, in order to identify novel drug targets for the treatment of sepsis. This thesis will describe the development of a novel approach to monitoring cardiovascular dysfunction in two widely used pre-clinical models of sepsis: lipolysaccharide (LPS)-induced endotoxaemia, and cecal ligation and puncture (CLP). This approach comprises a multi-parameter monitoring system in which all levels of the cardiovascular system – global haemodynamics, cardiac function, microcirculatory blood flow and haematological markers – can be evaluated in a single animal. Using a novel application of laser speckle contrast imaging technology, in combination with gold standard haemodynamic monitoring techniques, we demonstrate that mesenteric blood flow is severely and time-dependently decreased following the induction of sepsis, despite stabilisation of arterial pressure, heart rate and cardiac output. Decreased mesenteric perfusion is shown to correlate with the development of metabolic acidosis and organ dysfunction, suggesting that global haemodynamic indices are insufficiently predictive of syndrome progression. Mesenteric blood flow, on the other hand, appears to be a sensitive and clinically relevant prognostic marker of disease severity, correlating with haematological markers of organ dysfunction, and sensitive to standard clinical interventions known to improve survival in patients. This thesis will go on to describe a mechanistic investigation of sepsis-induced microcirculatory flow impairment, using vasodilatory and anti-coagulant agents. Finally, it will describe the use of this model, in addition to in vitro models, for assessing the potential role of two ion channels – transient receptor potential vanilloid (TRPV) 1 and 4 – in modulating vascular dysfunction during sepsis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:656889 |
| Date | January 2014 |
| Creators | Sand, Claire Alexandra |
| Contributors | Nandi, Manasi ; Brain, Susan Diana |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://kclpure.kcl.ac.uk/portal/en/theses/investigation-of-vascular-dysfunction-in-preclinical-models-of-sepsis(91e4be7f-12da-456d-945e-a0a40fe83702).html |
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