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Title: Evaluation of adsorbent haemoperfusion in interventional therapy of sepsis
Author: Coutts, Euan Ross
ISNI:       0000 0004 5923 117X
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2016
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Objectives: Sepsis and its sequelae, is one of the major clinical challenges facing intensive care units across the globe, and the greatest cause of intensive care mortality. The aim of the project is to evaluate the suitability of a newly developed adsorbent for use as an interventional therapy in the treatment of sepsis. In order to achieve this, a rat model comparable to the human clinical condition and its symptoms was developed. This rat model was further developed and used to evaluate the effect of deployment of the adsorbent in a miniaturised extracorporeal haemoperfusion circuit. Materials & Methods: In order to achieve this, a rat model (adult male Sprague Dawley 480g-590g) comparable to the acute phase physiological symptoms of asystemic sepsis condition in humans was developed. Sepsis was induced by intraperitoneal injection of lipopolysacharide (LPS). Key physiological characteristics, heart rate, body temperature, and mean arterial blood pressure, were measured dynamically and recorded over a six hour time course. Cytokine profiles were also measured by time interval blood sampling and subsequent ELISAs to characterise progression. In the final phases of experimentation, a miniaturised extracorporeal haemoperfusion circuit was developed to evaluate the impact of deployment in the progression of the condition. Results: Clear trends are evident. Falling blood pressure in the sepsis group overtime when compared to controls. In addition, the sepsis group exhibited a very dynamic temperature response, progressing from hyperthermia to hypothermia over 6 hours. This would appear to be in-line with documented literature and clinical sepsis observations. There was a difference in cytokine upregulation between the control and sepsis groups. Controls exhibited an upregulation in cytokines associated with the surgical procedure, however this was dramatically lower than compared to the LPS-induced sepsis group. With confidence in the sepsis model, an in vivo experimental extracorporeal haemoperfusion circuit involving an adsorbent device was developed to investigate its impact on the sepsis condition in further groups. This resulted in an attenuation of cytokine upregulation, and impact on the physiological markers of sepsis. Cytokine regulation, particularly of TNFα, was dramatically mitigated in the treatment group. A more stable and mitigated falling blood pressure was observed in the treatment group compared to a dramatic response in the sepsis group and a similar observation was also made in regard to body temperature. It is concluded that the deployment of a novel adsorbent is a valid area of further investigation in the treatment of the progression of the sepsis condition based upon the outcome of iterative phases of experimentation using an in-vivo rodent model. Conclusions: The deviation in physiological response and cytokine levels betweenthe sepsis and control groups is in line with documented theory and clinical observations. Progression of the condition in control, sepsis and attenuated progression in experimental treatment models are discussed. The key physiological parameters and inflammatory mediators of the condition were monitored and evaluated to assess the efficacy of this therapy. It is concluded that the deployment of the adsorbent was associated with attenuation of the cytokine response in the LPS induced sepsis animals and modification of the physiological response. This work confirms that the model is a suitable analogue for clinical sepsis and that deployment of a novel adsorbent has a demonstrable mitigating impact upon the progression of the condition representing a valid area for further development of interventional therapy in the ICU setting. The following are the main achievements of this work;- A stable and repeatable in-vivo animal model capable of running a 6 hour time course to model the acute stage of sepsis and a 6 hour control model was developed for use in the Bioengineering facility at the University ofStrathclyde.- This model provided a means of dynamically and iteratively monitoring key physiological parameters and inflammatory mediators of sepsis respectively.- A series of experiments was carried out using these models; clear trends are evident in results which appear to be in-line with documented literature and clinical sepsis observations.- A device was developed for suspending an adsorbent within a miniaturised extracorporeal circuit allowing circulating whole blood to contact the adsorbent presenting a means to assess its impact on the parameters being monitored. - The animal models were further developed to provide a stable and repeatable in-vivo extracorporeal haemoperfusion model capable of running a 6 hour time course and, utilising the test device, suspending the adsorbent within thecircuit; this provided an in-vivo control, sepsis and treatment model.- This is significant as any novel therapy capitalising upon a potential window of intervention must be applicable on a systemic scale due to the nature of the sepsis condition.- A further series of experiments was carried out using these models; clear trends are evident in results which demonstrate a mitigating effect on the progression of the condition in a treatment group compared to an LPS induced sepsis group and a control group.- It is a concluding recommendation that the potential therapy be developed further in order to assess its potential impact upon the progression of the condition and potential applications in the ICU setting.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Eng.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available