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The central compartment is the volume in which initial mixing of the drug occurs, and thus can be thought to include the vascular system (blood volume) and for some drugs the interstitial fluid. The fast peripheral compartment represents a compartment of the body that absorbs drug rapidly from the central compartment, and thus can be thought of as comprising tissues of the body that are well-perfused (such as muscles and vital organs). Finally the slow peripheral compartment is used to mathematically represent a compartment into which re-distribution occurs more slowly, and thus can be thought of as including tissues with a poor blood supply (such as adipose tissue). The drug is infused in central compartment and then distributed to the slow and fast compartment and eliminated trough metabolism. Defining the drug concentration variable of the i-th compartment as Ci, the propofol distribution can be described as: C1 V 1  V 2C2()tk21  V 3C3()tk31  V 1C1()t(k10  k12  k13) u()t (1) t C 2 V 2  V 1C1()tk12  V 2C2()tk21 (2) t C3 V 3  V 1C1()tk13  V 3C3()tk31 (3) t C e  C1()tke0  Ce()tke0 (4) t where u(t) represents the drug infusion rate in the central compartment and Vi is the volume of the i-th compartment. The dynamics of the compartmental model is defined by the following diffusion constants: k10 (rate constant for drug metabolism), k12 (rate constant for re-distribution of drug from central to fast peripheral compartment), k21 (rate constant for re- distribution of drug from fast to central compartment), k13 (rate constant for redistribution of drug from central to slow compartment) and k31 (rate constant for redistribution of drug from slow to central compartment). From the point of view of hypnosis control, the variable of interest is not the blood concentration but the concentration in the place where the effect on the controlled variable is produced (effect site concentration). Thus, when there is a simultaneous measure of the drug concentration in blood and its effect on the brain, drug latency can be observed that produces a temporal displacement between the peak of blood concentration and the drug effect. Closed-Loop Control of Anaesthetic Effect 457 To include this dynamics in the model a fourth compartment is added. It is assumed that this compartment is attached to the central compartment and has negligible volume. This parameter can be seen as index that measures the degree of nonlinearity of the model. According to the response observed through his vital signs the drug rates can be modified (the anaesthetist is the controller). The main idea in closed-loop control is to use information of the state of the patient to automatically adjust the drug dosing. Many efforts have been made to provide the anaesthetist with more reliable methods for monitoring this state. Thus, it can be used as a feedback system to the controller in order to compute the adequate infusion rate, as can be seen in figure 4. The controller algorithm used for anaesthesia control can be based on signals or in models.

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