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A novel therapy to maintain blood pressure and kidney function in septic shock

Our laboratory has made several important discoveries in a clinically relevant ovine model of septic shock that we believe will improve management of patients with septic shock. 

Aims

The specific aims of this project are:

To investigate if a combination therapy of clonidine with noradrenaline allows a lower dose of noradrenaline to be used to maintain blood pressure in septic shock.

To examine if reducing the doses of noradrenaline with clonidine, will reduce the degree of renal medullary hypoxia and the progression of AKI in septic shock.

To determine if using clonidine in combination with noradrenaline in sepsis has beneficial or deleterious effects on cardiovascular function, metabolism and kidney function.

Septic shock is the leading cause of death from infections in Intensive Care Units around the world. Septic shock is characterized by life-threatening falls in blood pressure.

Vasopressors are hence a cornerstone of therapy to counteract low blood pressure and maintain hemodynamic stability. Noradrenaline is currently the first choice vasopressor used to maintain blood pressure in patients with septic shock.

A major unresolved problem for clinicians treating septic shock is that patients become unresponsive to vasopressor therapy, leading to severe uncontrolled hypotension, reduced organ perfusion, organ failure and death. Vasopressor insensitivity has the potential to lead to septic acute kidney injury (AKI), which develops in up to 50% of patients, one-third of whom do not leave hospital alive. Developing a therapy to reverse vascular hypo-responsiveness and AKI in septic shock would be of enormous benefit to patients.

1)Treatment with the α2-adrenoceptor agonist clonidine helped maintain blood pressure and restored vasopressor responsiveness in septic shock.

2) In septic shock, there is an early onset of ischemia and hypoxia within the inner zone of the kidney (medulla), which may lead to the development of AKI.

3) In septic shock, restoration of blood pressure with noradrenaline further worsened the degree of renal medullary ischemia and hypoxia.

These pre-clinical studies are essential to confirm the safety and feasibility of using clonidine as a novel adjunct therapy in septic shock, prior to initiating clinical trials. Techniques that will be mastered during this honours project include – assisting in large animal surgery, chronic recordings of cardiovascular and renal hemodynamics and function in conscious sheep, data analysis and statistical analysis.

Further Reading:

Lankadeva et al 2016 Kidney International 90 (1): 100-8; PMID: 27165831

Lankadeva et al 2015 Critical Care Medicine 43 (7): e221-9; PMID: 25860204

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