Design of Cycles by Impulsive Feedback: Application to Discrete Dosing

TL;DR

This paper presents a novel impulsive feedback control method for discrete dosing in pharmacology, ensuring desired drug levels with minimized underdosing, based on stability analysis of a nonlinear plant model.

Contribution

It introduces a new amplitude- and frequency-modulated impulsive controller design for discrete dosing, with stability guarantees and application to neuromuscular blockade.

Findings

Controller effectively maintains drug levels within desired range.

Application reduces underdosing events in clinical pharmacokinetic models.

Demonstrates improved dosing precision over standard regimens.

Abstract

The task of maintaining a predefined level of effect in a dynamical plant by applying periodic control actions often arises in e.g. process control and medicine. When the state variables of the plant represent the concentrations of chemical substances and the control action constitutes an instantaneous introduction of a certain quantity of a chemical or drug, this control setup is referred to as a (discrete) dosing problem. The present paper examines an amplitude- and frequency-modulated impulsive controller that, under stationary conditions, generates a desired sequence of uniform and equidistant control impulses based on continuous measurements of the output of a smooth positive nonlinear time-invariant single-input single-output plant with Wiener structure. The controller design method is based on constructing and stabilizing the fixed point of a discrete map that describes the evolution of the state vector of the continuous plant between successive impulsive control action instants. Stability of the fixed point ensures the existence of a basin of attraction along the stationary trajectory, where the solution of a perturbed closed-loop system converges to the stationary solution. The convergence rate is determined by the slopes of the amplitude and frequency modulation functions of the impulsive controller. The proposed controller is applied to the dosing of the drug \emph{atracurium} in closed-loop neuromuscular blockade, and its performance is evaluated on a database of patient-specific pharmacokinetic-pharmacodynamic models estimated from clinical data. It is demonstrated that an implementation of the standard regimen as a pulse-modulated feedback controller significantly minimizes the incidence of underdosing events.