Semi-Adaptive Closed-Loop Control for Infusion of Medications With Transport Delay in Clinical Effects

This paper presents a semi-adaptive closed-loop control approach to autonomous infusion of medications exhibiting significant transport delay in clinical effects. The basic idea of the approach is to enable stable adaptive control of medication infusion by (1) incorporating transport delay explicitly into control design by way of a Pade approximation while (2) facilitating linear parameterization of control design model by desensitization of nonlinearly parameterized cooperativity constant associated with pharmacodynamics (PD). A novel dynamic dose-response model for control design is presented, in which the cooperativity constant exerts zero influence on the model output in the steady-state. Then, an adaptive pole placement control (APPC) technique was employed to fulfill adaptive control design in the presence of nonminimum phase dynamics associated with the Pade approximation of transport delay. The controller was evaluated in silico using a case study of regulating a cardiovascular variable with a sedative under a wide range of transport delay and pharmacological profiles. The results suggest that adaptation of transport delay and pharmacological characteristics may be beneficial in achieving consistent and robust regulation of medication-elicited clinical effects.