Closed-loop vasopressor control: in-silico study of robustness against pharmacodynamic variability

Initial feasibility of a novel closed-loop controller created by our group for closed-loop control of vasopressor infusions has been previously described. In clinical practice, vasopressor potency may be affected by a variety of factors including other pharmacologic agents, organ dysfunction, and vasoplegic states. The purpose of this study was therefore to evaluate the effectiveness of our controller in the face of large variations in drug potency, where ‘effective’ was defined as convergence on target pressure over time. We hypothesized that the controller would remain effective in the face up to a tenfold variability in drug response. To perform the robustness study, our physiologic simulator was used to create randomized simulated septic patients. 250 simulated patients were managed by the closed-loop in each of 7 norepinephrine responsiveness conditions: 0.1 ×, 0.2 ×, 0.5 ×, 1 ×, 2 ×, 5 ×, and 10 × expected population response to drug dose. Controller performance was evaluated for each level of norepinephrine response using Varvel’s criteria as well as time-out-of-target. Median performance error and median absolute performance error were less than 5% in all response levels. Wobble was below 3% and divergence remained negative (i.e. the controller tended to converge towards the target over time) in all norepinephrine response levels, but at the highest response level of 10 × the value approached zero, suggesting the controller may be approaching instability. Response levels of 0.1 × and 0.2 × exhibited significantly higher time-out-of-target in the lower ranges (p < 0.001) compared to the 1 × response level as the controller was slower to correct the initial hypotension. In this simulation study, the closed-loop vasopressor controller remained effective in simulated patients exhibiting 0.1 to 10 × the expected population drug response.