Design and Evaluation of a Closed-Loop Anesthesia System With Robust Control and Safety System

Anesth Analg. 2018 Oct;127(4):883-894. doi: 10.1213/ANE.0000000000002663.


Background: Closed-loop control of anesthesia involves continual adjustment of drug infusion rates according to measured clinical effect. The NeuroSENSE monitor provides an electroencephalographic measure of depth of hypnosis (wavelet-based anesthetic value for central nervous system monitoring [WAVCNS]). It has previously been used as feedback for closed-loop control of propofol, in a system designed using robust control engineering principles, which implements features specifically designed to ensure patient safety. Closed-loop control of a second drug, remifentanil, may be added to improve WAVCNS stability in the presence of variable surgical stimulation. The objective of this study was to design and evaluate the feasibility of a closed-loop system for robust control of propofol and remifentanil infusions using WAVCNS feedback, with an infusion safety system based on the known pharmacological characteristics of these 2 drugs.

Methods: With Health Canada authorization, research ethics board approval, and informed consent, American Society of Anesthesiologists I-III adults, requiring general anesthesia for elective surgery, were enrolled in a 2-phase study. In both phases, infusion of propofol was controlled in closed loop during induction and maintenance of anesthesia, using WAVCNS feedback, but bounded by upper- and lower-estimated effect-site concentration limits. In phase I, remifentanil was administered using an adjustable target-controlled infusion and a controller was designed based on the collected data. In phase II, remifentanil was automatically titrated to counteract rapid increases in WAVCNS.

Results: Data were analyzed for 127 patients, of median (range) age 64 (22-86) years, undergoing surgical procedures lasting 105 (9-348) minutes, with 52 participating in phase I and 75 in phase II. The overall control performance indicator, global score, was a median (interquartile range) 18.3 (14.2-27.7) in phase I and 14.6 (11.6-20.7) in phase II (median difference, -3.25; 95% confidence interval, -6.35 to -0.52). The WAVCNS was within ±10 of the setpoint for 84.3% (76.6-90.6) of the maintenance of anesthesia in phase I and 88.2% (83.1-93.4) in phase II (median difference, 3.7; 95% confidence interval, 0.1-6.9). The lower propofol safety bound was activated during 30 of 52 (58%) cases in phase I and 51 of 75 (68%) cases in phase II.

Conclusions: Adding closed-loop control of remifentanil improved overall controller performance. This controller design offers a robust method to optimize the control of 2 drugs using a single sensor. The infusion safety system is an important component of a robust automated anesthesia system, but further research is required to determine the optimal constraints for these safe conditions.

Trial registration: NCT01771263.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / adverse effects
  • Anesthesia, Intravenous / adverse effects
  • Anesthesia, Intravenous / instrumentation*
  • Anesthetics, Intravenous / administration & dosage*
  • Anesthetics, Intravenous / adverse effects
  • Consciousness / drug effects*
  • Drug Delivery Systems / adverse effects
  • Drug Delivery Systems / instrumentation*
  • Electroencephalography / instrumentation*
  • Equipment Design
  • Feasibility Studies
  • Female
  • Hemodynamics / drug effects
  • Humans
  • Infusion Pumps* / adverse effects
  • Infusions, Intravenous
  • Intraoperative Neurophysiological Monitoring / instrumentation*
  • Male
  • Middle Aged
  • Patient Safety
  • Predictive Value of Tests
  • Propofol / administration & dosage*
  • Propofol / adverse effects
  • Remifentanil / administration & dosage*
  • Remifentanil / adverse effects
  • Risk Factors
  • Wavelet Analysis
  • Young Adult


  • Analgesics, Opioid
  • Anesthetics, Intravenous
  • Remifentanil
  • Propofol

Associated data


Grant support