title: Robust control of burst suppression for medical coma.
abstract: OBJECTIVE
  Medical coma is an anesthetic-induced state of brain inactivation, manifest in the electroencephalogram by burst suppression. Feedback control can be used to regulate burst suppression, however, previous designs have not been robust. Robust control design is critical under real-world operating conditions, subject to substantial pharmacokinetic and pharmacodynamic parameter uncertainty and unpredictable external disturbances. We sought to develop a robust closed-loop anesthesia delivery (CLAD) system to control medical coma.
  
  
  METHODS
  We developed a robust CLAD system to control the burst suppression probability (BSP). We developed a novel BSP tracking algorithm based on realistic models of propofol pharmacokinetics and pharmacodynamics. We also developed a practical method for estimating patient-specific pharmacodynamics parameters. Finally, we synthesized a robust proportional integral controller. Using a factorial design spanning patient age, mass, height, and gender, we tested whether the system performed within clinically acceptable limits. Throughout all experiments we subjected the system to disturbances, simulating treatment of refractory status epilepticus in a real-world intensive care unit environment.
  
  
  RESULTS
  In 5400 simulations, CLAD behavior remained within specifications. Transient behavior after a step in target BSP from 0.2 to 0.8 exhibited a rise time (the median (min, max)) of 1.4 [1.1, 1.9] min; settling time, 7.8 [4.2, 9.0] min; and percent overshoot of 9.6 [2.3, 10.8]%. Under steady state conditions the CLAD system exhibited a median error of 0.1 [-0.5, 0.9]%; inaccuracy of 1.8 [0.9, 3.4]%; oscillation index of 1.8 [0.9, 3.4]%; and maximum instantaneous propofol dose of 4.3 [2.1, 10.5] mg kg(-1). The maximum hourly propofol dose was 4.3 [2.1, 10.3] mg kg(-1) h(-1). Performance fell within clinically acceptable limits for all measures.
  
  
  CONCLUSIONS
  A CLAD system designed using robust control theory achieves clinically acceptable performance in the presence of realistic unmodeled disturbances and in spite of realistic model uncertainty, while maintaining infusion rates within acceptable safety limits.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: M Brandon
authors.initials: MB
authors.lastname: Westover
authors.forename: Seong-Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: ShiNung
authors.initials: S
authors.lastname: Ching
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Purdon
authors.forename: Emery N
authors.initials: EN
authors.lastname: Brown
mesh_terms: D000465:Algorithms; D001683:Biological Clocks / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D003128:Coma / Q000139:chemically induced* / Q000503:physiopathology*; D003198:Computer Simulation; D004360:Drug Therapy, Computer-Assisted / Q000379:methods; D004569:Electroencephalography / Q000187:drug effects; D006801:Humans; D008959:Models, Neurological; D015742:Propofol / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D015742:Propofol