Infusion systems, infusion devices, and related operating methods are provided. An exemplary method of alerting a user associated with an infusion device delivering fluid to the body of the user involves obtaining a measurement value for a physiological condition being influenced by the fluid, obtaining a current amount of active fluid in the body of the user, determining a homeostasis metric based at least in part on the current amount of active fluid and the measurement value for the physiological condition, and generating an alert based at least in part on the homeostasis metric.