This paper presents a coordinated and semi‐adaptive closed‐loop control approach to the infusion of 2 interacting medications. The proposed approach consists of an upper‐level coordination controller and a lower‐level semi‐adaptive controller. The coordination controller recursively adjusts the reference targets based on the estimated dose‐response relationship of a patient to ensure that they can be achieved by the patient. The semi‐adaptive controller drives the patient outputs to the reference targets while estimating the patient's dose‐response relationship online. In this way, the controller is resilient to unachievable caregiver‐specified reference targets and responsive to the medication needs of individual patients. To establish the proposed approach, we developed the following: (1) a linear two‐input–two‐output dose‐response model; (2) a two‐input–two‐output semi‐adaptive controller to regulate the patient outputs while adapting high‐sensitivity parameters in the patient model; and (3) a coordination controller to adjust the reference targets that reconcile caregiver inputs and medication use. The proposed approach was applied to an example scenario in which cardiac output and respiratory rate are regulated via infusion of propofol and remifentanil in an in silico simulation setting. The results show that the coordinated semi‐adaptive control could (1) track achievable reference targets with consistent transient and steady‐state performance and (2) resiliently adjust the unachievable reference targets to achievable ones
