The rate of injury and death inadvertently caused by medical treatment is too high and exacts enormous human and financial costs. Each year in Britain and the United States alone, hundreds of thousands of patients are injured, ten of thousands are killed and billions of dollars are spent on additional health care due to iatrogenic harm. Health care organisations remain predominately human-centred in their approach to safety-that is, methods of avoiding error rely primarily on the resolve and vigilance of individual clinicians to avoid bad outcomes. However, this approach is becoming increasingly inadequate in the face of the steadily rising complexity of modern health care and the increasing number of procedures carried out each year. In other high-reliability organisations such as aviation and nuclear power generation, safety results not from the sheer effort of “operators”, but from in-depth analysis of problems and the removal and redesign of dangerous aspects of systems-the so-called systems approach. Here I present an evaluation of the integrated drug administration system (IDAS) as an example of the systems approach, intended to reorganise the way in which anaesthetists give drugs to improve performance and facilitate safe practice. The problem of drug error in anaesthesia is an important subset of iatrogenic harm in medicine. From the prospective study of 10806 conventional anaesthetics I define the rate of drug error in anaesthesia as one error in every 133 anaesthetics conducted-a rate five times higher than anything previously reported. In addition, anaesthetists rated the risk of harming a patient through drug error in the course of their career as high. I discuss the principles of safe system design, the psychology of error, and advanced systems safety concepts with respect to the design of the IDAS and the future of safety in medicine. In clinical use, the IDAS saved time before and during anaesthesia, and was rated by anaesthetists as significantly safer and more useable than conventional methods of drug administration. This work supports the hypothesis that error in anaesthesia can be reduced through the systematic analysis of its causes and the implementation of appropriate countermeasure strategies. / Subscription resource available via Digital Dissertations only.

The rate of injury and death inadvertently caused by medical treatment is too high and exacts enormous human and financial costs. Each year in Britain and the United States alone, hundreds of thousands of patients are injured, ten of thousands are killed and billions of dollars are spent on additional health care due to iatrogenic harm. Health care organisations remain predominately human-centred in their approach to safety-that is, methods of avoiding error rely primarily on the resolve and vigilance of individual clinicians to avoid bad outcomes. However, this approach is becoming increasingly inadequate in the face of the steadily rising complexity of modern health care and the increasing number of procedures carried out each year. In other high-reliability organisations such as aviation and nuclear power generation, safety results not from the sheer effort of “operators”, but from in-depth analysis of problems and the removal and redesign of dangerous aspects of systems-the so-called systems approach. Here I present an evaluation of the integrated drug administration system (IDAS) as an example of the systems approach, intended to reorganise the way in which anaesthetists give drugs to improve performance and facilitate safe practice. The problem of drug error in anaesthesia is an important subset of iatrogenic harm in medicine. From the prospective study of 10806 conventional anaesthetics I define the rate of drug error in anaesthesia as one error in every 133 anaesthetics conducted-a rate five times higher than anything previously reported. In addition, anaesthetists rated the risk of harming a patient through drug error in the course of their career as high. I discuss the principles of safe system design, the psychology of error, and advanced systems safety concepts with respect to the design of the IDAS and the future of safety in medicine. In clinical use, the IDAS saved time before and during anaesthesia, and was rated by anaesthetists as significantly safer and more useable than conventional methods of drug administration. This work supports the hypothesis that error in anaesthesia can be reduced through the systematic analysis of its causes and the implementation of appropriate countermeasure strategies. / Subscription resource available via Digital Dissertations only.

The rate of injury and death inadvertently caused by medical treatment is too high and exacts enormous human and financial costs. Each year in Britain and the United States alone, hundreds of thousands of patients are injured, ten of thousands are killed and billions of dollars are spent on additional health care due to iatrogenic harm. Health care organisations remain predominately human-centred in their approach to safety-that is, methods of avoiding error rely primarily on the resolve and vigilance of individual clinicians to avoid bad outcomes. However, this approach is becoming increasingly inadequate in the face of the steadily rising complexity of modern health care and the increasing number of procedures carried out each year. In other high-reliability organisations such as aviation and nuclear power generation, safety results not from the sheer effort of “operators”, but from in-depth analysis of problems and the removal and redesign of dangerous aspects of systems-the so-called systems approach. Here I present an evaluation of the integrated drug administration system (IDAS) as an example of the systems approach, intended to reorganise the way in which anaesthetists give drugs to improve performance and facilitate safe practice. The problem of drug error in anaesthesia is an important subset of iatrogenic harm in medicine. From the prospective study of 10806 conventional anaesthetics I define the rate of drug error in anaesthesia as one error in every 133 anaesthetics conducted-a rate five times higher than anything previously reported. In addition, anaesthetists rated the risk of harming a patient through drug error in the course of their career as high. I discuss the principles of safe system design, the psychology of error, and advanced systems safety concepts with respect to the design of the IDAS and the future of safety in medicine. In clinical use, the IDAS saved time before and during anaesthesia, and was rated by anaesthetists as significantly safer and more useable than conventional methods of drug administration. This work supports the hypothesis that error in anaesthesia can be reduced through the systematic analysis of its causes and the implementation of appropriate countermeasure strategies. / Subscription resource available via Digital Dissertations only.

The rate of injury and death inadvertently caused by medical treatment is too high and exacts enormous human and financial costs. Each year in Britain and the United States alone, hundreds of thousands of patients are injured, ten of thousands are killed and billions of dollars are spent on additional health care due to iatrogenic harm. Health care organisations remain predominately human-centred in their approach to safety-that is, methods of avoiding error rely primarily on the resolve and vigilance of individual clinicians to avoid bad outcomes. However, this approach is becoming increasingly inadequate in the face of the steadily rising complexity of modern health care and the increasing number of procedures carried out each year. In other high-reliability organisations such as aviation and nuclear power generation, safety results not from the sheer effort of “operators”, but from in-depth analysis of problems and the removal and redesign of dangerous aspects of systems-the so-called systems approach. Here I present an evaluation of the integrated drug administration system (IDAS) as an example of the systems approach, intended to reorganise the way in which anaesthetists give drugs to improve performance and facilitate safe practice. The problem of drug error in anaesthesia is an important subset of iatrogenic harm in medicine. From the prospective study of 10806 conventional anaesthetics I define the rate of drug error in anaesthesia as one error in every 133 anaesthetics conducted-a rate five times higher than anything previously reported. In addition, anaesthetists rated the risk of harming a patient through drug error in the course of their career as high. I discuss the principles of safe system design, the psychology of error, and advanced systems safety concepts with respect to the design of the IDAS and the future of safety in medicine. In clinical use, the IDAS saved time before and during anaesthesia, and was rated by anaesthetists as significantly safer and more useable than conventional methods of drug administration. This work supports the hypothesis that error in anaesthesia can be reduced through the systematic analysis of its causes and the implementation of appropriate countermeasure strategies. / Subscription resource available via Digital Dissertations only.

The rate of injury and death inadvertently caused by medical treatment is too high and exacts enormous human and financial costs. Each year in Britain and the United States alone, hundreds of thousands of patients are injured, ten of thousands are killed and billions of dollars are spent on additional health care due to iatrogenic harm. Health care organisations remain predominately human-centred in their approach to safety-that is, methods of avoiding error rely primarily on the resolve and vigilance of individual clinicians to avoid bad outcomes. However, this approach is becoming increasingly inadequate in the face of the steadily rising complexity of modern health care and the increasing number of procedures carried out each year. In other high-reliability organisations such as aviation and nuclear power generation, safety results not from the sheer effort of “operators”, but from in-depth analysis of problems and the removal and redesign of dangerous aspects of systems-the so-called systems approach. Here I present an evaluation of the integrated drug administration system (IDAS) as an example of the systems approach, intended to reorganise the way in which anaesthetists give drugs to improve performance and facilitate safe practice. The problem of drug error in anaesthesia is an important subset of iatrogenic harm in medicine. From the prospective study of 10806 conventional anaesthetics I define the rate of drug error in anaesthesia as one error in every 133 anaesthetics conducted-a rate five times higher than anything previously reported. In addition, anaesthetists rated the risk of harming a patient through drug error in the course of their career as high. I discuss the principles of safe system design, the psychology of error, and advanced systems safety concepts with respect to the design of the IDAS and the future of safety in medicine. In clinical use, the IDAS saved time before and during anaesthesia, and was rated by anaesthetists as significantly safer and more useable than conventional methods of drug administration. This work supports the hypothesis that error in anaesthesia can be reduced through the systematic analysis of its causes and the implementation of appropriate countermeasure strategies. / Subscription resource available via Digital Dissertations only.

Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / Michael D. Apley / The discovery of modern antimicrobials in the early 20th century revolutionized treatment of infectious diseases. Less than 100 years later, antimicrobial resistance has become a global threat to public health. With the rise of antimicrobial resistance, the question that remains to be answered is: Can dosing regimens provide maximal clinical efficacy, yet minimize the development of antimicrobial resistance? A pharmacokinetic / pharmacodynamic approach was utilized to investigate oxytetracycline regimens that would impart efficacy while minimizing the potential for resistance development due to plasmid transfer. An in vitro pharmacodynamic model was used to quantify the response of a Pasteurella multocida isolate to two oxytetracycline dosing regimens. The PK/PD index most closely related to efficacy was the Cmax:MIC. The in vitro pharmacodynamic model was then used to investigate the effects of antimicrobial exposure on plasmid transfer. A mixed population of oxytetracycline-susceptible and resistant bacteria was exposed to two dosing regimens and plasmid transfer was quantified. When oxytetracycline concentrations exceeded the MIC of the recipient, development of resistance was suppressed. The same donor and recipient bacteria were used in an in situ swine model to validate the in vitro findings. Following surgical implantation of porous membrane straws containing the mixed bacterial population, animal subjects in the treatment groups received one of two oxytetracycline treatments. Oxytetracycline concentrations in the plasma and interstitial fluid were quantified. Plasmid transfer within the implant membranes was quantified and correlated to pharmacokinetic measures in the animal. Plasmid transfer rates in the implant membranes did not correlate to the investigated pharmacokinetic parameters. The study methodologies in this dissertation should serve as a foundation for future studies in antimicrobial pharmacokinetic/pharmacodynamic research. The results presented here show that the bacterial response to oxytetracycline can be optimized in a concentration dependent manner and that antimicrobial resistance development through plasmid transfer can be suppressed in vitro when oxytetracycline concentrations exceed the MIC of the recipient bacteria. These results suggest that a proper balance between clinical efficacy and minimizing antimicrobial resistance can be achieved for oxytetracycline through appropriate dosing regimens and drug formulations.

Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / Ronette Gehring / Milk composition has a dynamic nature, and the composition varies with stage of lactation, age, breed, nutrition and health status of the udder. The changes in milk composition seem to match the changes in the expression of membrane proteins in secretory mammary epithelial cells that are needed for the movement of molecules from blood to milk and vice versa (Nouws and Ziv, 1982). Thus, an understanding of transporter expression, function and regulation in mammary epithelial cells can provide insight into mammary gland function and regulation. The goal of this project was to elucidate (molecularly and functionally) the role of drug transporters in the barrier function of an epithelial monolayer cultured from an immortalized bovine mammary epithelial cell line (BME-UV). To characterize the regulation (expression and function) of these drug transporters in BME-UV cells after exposure to cytokine TNF-α for selected periods of time. Representative members of drug transporters of the SLC (OCT and OAT) and ABC (P-glycoprotein) superfamilies were chosen for this project. In the first study, the involvement of a carrier-mediated transport system in the passage of organic cation (TEA) and anion (EsS) compounds was elucidated across the BME-UV monolayer. In the second study, molecular and functional expression of bOAT isoforms in BME-UV cells were studied. The final study characterized the effects of cytokine TNF-α on the expression and function of P-glycoprotein, an efflux pump, in BME-UV cells. Cytokine TNF-α exposure induced the expression of ABCB1 mRNA and increased P-glycoprotein production in BME-UV cells, resulting in a greater efflux of digoxin, a known P-glycoprotein substrate, back into the apical fluid. The expression, function, and regulation of these transporters in the mammary gland has important implications for understanding the barrier function of the mammary epithelium and, in more specific, for characterizing the role of these transporters in the accumulation and/or removal of specific substrates from milk and/or plasma. Moreover, this study provides an in vitro cell culture model of mammary epithelium to characterize mammary epithelial cell function during inflammation.