Centre for Neuroscience - Theses
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ItemAn investigation of the role of the sympathetic nervous system in the pathophysiology of kidney dysfunction in severe sepsis( 2013)Sepsis is a leading cause of hospital morbidity and mortality causing organ failure with the kidney being commonly affected. Unfortunately, the pathophysiology of septic acute kidney injury (AKI) is poorly understood. Renal hypoperfusion has been traditionally proposed as the major pathophysiological mechanism of injury, but both human and animal research questions this belief. It is therefore critical to investigate alternative pathophysiological mechanisms causing septic AKI. Increasing evidence suggests that prolonged increased activity of the sympathetic nervous system (SNS) is detrimental to kidney function. Studies in rodent models of sepsis suggest that selective β1-adrenoceptor blockade improves mortality and centrally acting α2-adrenoceptor agonist therapy has recently been proposed for the treatment of septic AKI. The potential beneficial effect of these therapies may be due to inhibition of the action of the SNS on organ function or on the immune response, which can affect organ function via release of inflammatory cytokines. Currently little is known about the effects of excessive SNA in sepsis on the regulation of organ function. Accordingly, in my Ph.D. I aimed to assess the role of the SNS in septic organ failure, with particular focus on the kidney and heart. I addressed 4 questions: 1) What is the role of the SNS in determining the changes in renal function observed in sepsis? 2) Can selective β1-blockade be administered in sepsis without major haemodynamic consequences? 3) Can clonidine, a centrally acting α2-adrenoceptor agonist that decreases SNS outflow, restore renal function when administered in established sepsis? 4) What is the effect of sepsis on renal regional perfusion and oxygenation? To address these questions, I used an established ovine model of severe sepsis with a hypotensive, hyperdynamic state and AKI. Sepsis was induced with live Escherichia coli. Hyperdynamic sepsis was defined as tachycardia, vasodilatation with hypotension, and increases in cardiac output, arterial lactate level, temperature and respiratory rate. These alterations are similar to those observed in humans and they were achieved reproducibly. These changes were associated with reduced creatinine clearance (CreatCl) and urine output, despite increased total renal blood flow (RBF). Taken together, my studies showed no evidence that changes in renal SNS activation (RSNA) in sepsis contributed to the alterations in RBF or CreatCl. The studies indicate that the initial sepsis-induced diuresis resulted from inhibition of RSNA, but the final degree of oliguria was independent of the later increase in RSNA. Selective β1-adrenoceptor blockade did not adversely affect tissue perfusion, despite a significant reduction in heart rate, cardiac output and blood pressure, nor did it adversely affect RBF or renal function. Alpha2-agonism in established sepsis was safe. It transiently increased urine output in established sepsis without affecting CreatCl, thus suggesting a predominantly tubular effect. These findings suggest that this treatment could be safely tested in human trials. Finally, sepsis caused regional renal mismatches in perfusion and oxygenation in the cortex and medulla, with decreased perfusion and oxygenation observed in the latter, suggesting that septic AKI is a disease of the microcirculation rather than the macrocirculation.