title: The variability of response to propofol is reduced when a clinical observation is incorporated in the control: a simulation study.
abstract: BACKGROUND
  When using a target-controlled infusion of propofol to produce sedation, the operator assumes that the individual patient's pharmacokinetic parameters match those in the control system so that the specified effect-site target is achieved, and that the specified target is appropriate for the individual patient's sensitivity. These inaccuracies cascade, and this produces error in the desired level of sedation, termed "target error." To address this issue, we designed a control system that incorporates the operator's observation of loss of responsiveness to determine patient sensitivity. Our hypothesis was that this control system would reduce the impact of pharmacokinetic parameter error and uncertainty in sensitivity on the system's target error.
  
  
  METHODS
  A novel control system was implemented that produces a slow transition in the probability of loss of responsiveness, providing the operator with greater resolution to observe the time of this transition. The system uses the time of this transition to infer the effect-site concentration associated with loss of responsiveness, and the infusion sequence necessary to maintain this concentration. We used computer simulation to generate a population of 10,000 patients with randomly distributed pharmacokinetic parameters and sensitivity to propofol, and compared the target error of our system with that of a target-controlled infusion system targeting the effect-site concentration associated with 50% probability of loss of responsiveness.
  
  
  RESULTS
  Our system exhibited a target error of -0.75% ± 8.96%, compared with 0% ± 27.6% for target-controlled infusion, reducing the variability in achieving the specified target by a factor of 3.1 compared with target-controlled infusion, which was significant at P < 0.0001.
  
  
  CONCLUSIONS
  Our system reduces the impact of biological variability by including the operator in the control loop. The utility of this approach in clinical practice will require further evaluation.
authors.affiliation: Department of Anesthesiology & Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. jemandel@verizon.net
authors.forename: Jeff E
authors.initials: JE
authors.lastname: Mandel
authors.forename: Elie
authors.initials: E
authors.lastname: Sarraf
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D018686:Anesthetics, Intravenous / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001835:Body Weight; D003198:Computer Simulation; D003243:Consciousness / Q000187:drug effects*; D016503:Drug Delivery Systems; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D008954:Models, Biological; D016343:Monitoring, Intraoperative; D009716:Numerical Analysis, Computer-Assisted; D015588:Observer Variation; D015742:Propofol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015203:Reproducibility of Results
chemical_list: D018686:Anesthetics, Intravenous; D015742:Propofol