Infusion systems, infusion devices, and related operating methods are provided. An exemplary method of operating an infusion device capable of delivering fluid to a user involves determining a current value for a physiological condition of the user influenced by the fluid violates a first threshold value, determining a predicted value for the physiological condition of the user violates a second threshold value, and automatically altering operation of the infusion device to modify delivery of the fluid to the user after determining the predicted value violates the second threshold value when the current value violates the first threshold value.