Figure 10-18 Vertical axes all represent drug dose in milligrams per kilogram. On the right, median effective dose (ED₅₀ ) isobolograms for the hypnotic interactions among midazolam, alfentanil, and propofol are shown. The dotted lines are additive effect lines; note that all combinations fall within the line representing synergism or supra-additive effect. On the left, a triple interaction is depicted. The shaded area represents an additive plane passing through three single-drug ED₅₀ points (small open circles). The largest closed circle (with arrows) is the ED₅₀ point for the triple combination. The smaller closed circles are ED₅₀ points for the binary combinations. R ratios on all graphs represent the interaction (1.0 indicates an additive effect) of the various drug combinations. Note that the combination of midazolam and alfentanil produces the greatest synergism, but the combination of all three is also synergistic. P values denote the significance of the additive effects. (Redrawn with modification from Vinik HR, Bradley EL Jr, Kissin I: Triple anesthetic combination: Propofol-midazolam-alfentanil. Anesth Analg 76:S450, 1993.)