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Optimal Administration of Analgesics in Humans


E. Zanderigo

no. ETH Diss 16499

The main contribution of this thesis is the definition of innovative techniques for the identification of optimal analgesics administration in humans. The goal is to ensure adequate analgesia while minimizing at the same time both risks for the patient and costs for the hospital. In particular, this thesis contributes to the improvement of analgesic care in the postoperative setting, during conscious sedation and under general anesthesia. In Chapter 1, we first illustrate the importance of optimal analgesic dosing and the problems related to its implementation - problems that still limit its achievement nowadays. Further we outline how this thesis aims at improving the current state of the art treatment in the different settings considered. As the thesis deals in large extent with the effects of drug administration on the human body, acquaintance with the mechanisms involved from drug injection to observed effect and with the different approaches to model them is fundamental. For these purposes, Chapter 2 provides an introduction to the basic concepts of drug disposition and action and their modelling. Chapter 3 deals with the optimization of analgesic treatment in the postoperative care unit. We present two approaches for the identification of optimal dosing in this setting. First, we design a novel black-box optimization procedure for a straight-forward application to clinical practice. The application of the procedure allows the clinicians to identify in a limited number of steps drug combinations leading to adequate analgesia while minimizing the drugs’ side effects. The efficacy of the method is illustrated by the reported results of a clinical study. Second, we develop a comprehensive model of drug interactions, considering at the same time the drugs’ positive and negative effects. The model allows us to characterize different kinds of interactions among drugs and to analytically compute optimal drug administration regimen representing an innovative framework for the analysis of drug combinations. The potential of the model is illustrated on two clinically relevant drugs. In Chapter 4 we focus on the identification of optimal analgesics administration during conscious sedation. The goal is to avoid the occurrence of pharmacological ventilatory depression, a major cause of morbidity in conscious sedation procedures. We present the innovative idea of regulating drug infusion by means of a feedback control system based on measurements of carbon-dioxide body content. To validate the feasibility of the concept, we first develop a novel model for the ventilatory depressant effect of drugs. The model proves to reliably reproduce the ventilatory depression induced by different analgesics widely used in conscious sedation procedures. The model is then implemented as patient simulator for controller design. The designed controller allows for tailoring drug infusion to the patient’s needs, always maintaining sufficient ventilation despite external disturbances and large inter-patient variability in drug sensitivity. Chapter 5 concentrates on the characterization of the body’s response to painful stimulation under general anesthesia. For this, data from a volunteer study are analyzed in detail. The analysis allows for a first characterization of the pain-induced response of different physiological signals and of its dependance on different administered drugs. A further major outcome of the analysis is the design of a novel procedure for the non-invasive monitoring of mean arterial blood pressure. The procedure allows for a real-time estimation of mean arterial blood pressure providing the anesthetist with continuous, vital information about the stress level of the patient without requiring additional sensors. In Chapter 6 we summarize the main achievements of the present thesis and outline potential future research areas and their challenges.


Type of Publication:

(03)Ph.D. Thesis

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% Autogenerated BibTeX entry
@PhDThesis { Xxx:2006:IFA_2453,
    author={E. Zanderigo},
    title={{Optimal Administration of Analgesics in Humans}},
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