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This study investigated the clinical performance of a model-based, patient-individualized closed-loop (CL) control system for propofol administration using the bispectral index (BIS) as a controlled variable during the induction and maintenance of anesthesia with propofol and remifentanil and studied the influence of the targeted effect-site concentration of remifentanil (CeREMI) on its clinical performance.In 163 patients, propofol was administered using a CL system (BIS target [BISTARGET] between 40 and 50). Initial CeREMI targets between 2 and 7.5 ng/mL were selected as deemed clinically required. Performance parameters during induction were the time required to initially cross the target BIS, the time required to reach the maximal drug effect after induction (TPEAK, BIS) and the corresponding BIS at this moment, and the time required to regain the target BIS at the end of induction. Performance during maintenance was defined as the percentage of case time with target BIS ± 10 from target and the amount of performance error (PE) between the observed and target BIS values and its derived median PE (MDPE) as a measure of control bias, median absolute PE (MDAPE) as a measure of control inaccuracy, divergence as a measure of the time-related trend of the measured BIS values relative to the target BIS values, and wobble as a measure of intrasubject variability in prediction error. The secondary end point was the hemodynamic stability of the patient during CL control.The applied CL system induced and maintained anesthesia within clinically accepted ranges. The percentage of case time [mean (standard deviation [SD]) across all study participants] with BIS ± 10 from the target was 82% (14%). The mean (SD) population MDPE and MDAPE were -6.6% (5.5%) and 11.2% (5.5%), respectively. A negative divergence [-0.001 (0.004)] and acceptable wobble [9.7% (4.0%)] were found. The correlation between the system PE and CeREMI was low and only influenced by a CeREMI2.8 ng/mL. Hemodynamic stability stayed within the clinically acceptable range.The applied CL system for propofol administration has an acceptable performance in the CeREMI range of 2.8-7.5 ng/mL during the induction and maintenance of anesthesia. There was no evidence of a strong association between CeREM and the CL performance. This study also shows that when the CeREMI is2.8 ng/mL, it might be more challenging to prevent arousal during propofol anesthesia.

Target-controlled infusion (TCI) is a technique of infusing IV drugs to achieve a user-defined predicted (target) drug concentration in a specific body compartment or tissue of interest. In this review, we describe the pharmacokinetic principles of TCI, the development of TCI systems, and technical and regulatory issues addressed in prototype development. We also describe the launch of the current clinically available systems.

Automated drug administration by closed-loop systems has been proposed to optimize drug administration during anesthesia and sedation. Closed-loop systems are able to make decision on their own and try to reach and maintain a preset target. This review describes the milestones and recent development in automated drug delivery systems applicable during sedation, anesthesia and post-operative pain relief.

In this prospective study, we compared the relationship between propofol concentrations and bispectral index (BIS) in children versus young adults anesthetized with target-controlled infusion (TCI) of propofol.Forty-five prepubertal subjects (children) and 45 postpubertal subjects (adults) were studied. All patients were anesthetized with TCI of propofol, based on the Kataria et al.'s model for children and on the Schnider et al.'s model for adults. All data from the BIS and the TCI system were continuously recorded using Rugloop software. Remifentanil was continuously administered throughout the study (0.25 microg x kg(-1) x min(-1)). In all patients, after the end of surgery, a 12-min period with a stable target plasma concentration (Ct) of propofol, randomly assigned at 2, 3, 4, 5, and 6 microg/mL, was performed. In addition, in most of the patients, another 12-min period was performed during which the BIS was targeted at 50 +/- 5. After each 12-min steady-state period, the Ct and BIS were noted and the plasma concentration of propofol was measured (Cm). The Ct and Cm corresponding to half maximal effect (BIS(50)) was determined by the Hill equation, and by targeting BIS at 50.In children, as in adults, BIS values were highly correlated with the corresponding Ct or Cm of propofol following classical E(max) dose-response curves. The ECt(50) and the ECm(50), derived from the dose-response curves, were higher in children than in adults: ECm(50): 4.0 (3.6-4.5) microg/mL vs 3.3 (3.0-3.7) microg/mL [mean (95% CI)], P0.001; as well were the Ct and Cm clinically obtained when BIS was targeted at 50 (Cm(50): 4.3 +/- 1.1 microg/mL vs 3.4 +/- 1.2 microg/mL, (mean +/- SD) P0.05, children versus adults). Cm was generally under-estimated by the Ct, and the bias was higher in children than in adults: 2.6 +/- 2.6 microg/mL vs 1.7 +/- 1.6 microg/mL (P = 0.05).The good relationship between propofol and BIS demonstrated in children as in adults suggested a slightly lower sensitivity to propofol in children. As the predictability of plasma propofol concentrations with the classical pharmacokinetic/pharmacodynamic models is limited in children, a cerebral pharmacodynamic feedback, such as BIS, may be useful in this population.

Closed-loop systems are able to make their own decisions and to try to reach and maintain a preset target. As a result, they might help the anaesthetist to optimise the titration of drug administration without any overshoot, controlling physiological functions and guiding monitoring variables. Thanks to the development of fast computer technology and more reliable pharmacological effect measures, the study of automation in anaesthesia has regained popularity. This short review focuses on the most recently developed and tested feedback systems in anaesthesia. Various new approaches for controlling the administration of intravenous and inhaled hypnotic-anaesthetic drugs have recently been published. For analgesics, a framework for further research has been presented in the literature. For other drugs, such as muscle relaxants and haemodynamic agents, only short reviews can be found. Until now, most of these systems have had to be under development. The challenge is now fully to establish the safety, efficacy, reliability and utility of closed-loop anaesthesia so that it can be adopted in the clinical setting. Besides, their role in optimising the controlled variables and control models, these systems have to be tested in extreme circumstances in order to test their robustness.

BACKGROUND: The Composite Variability Index (CVI), derived from the electroencephalogram, was developed to assess the antinociception–nociception balance, whereas the Bispectral Index (BIS) was developed to assess the hypnotic state during anesthesia. We studied the relationships between these indices, level of hypnosis (BIS level), and antinociception (predicted remifentanil effect-site concentrations, CeREMI) before and after stimulation. Also, we measured their association with movement in response to a noxious stimulus. METHODS: We randomized 120 patients to one of 12 groups targeting different hypnotic levels (BIS 70, 50, and 30) and various CeREMI (0, 2, 4, or 6 ng/mL). At pseudo-steady state, baseline values were observed, and a series of stimuli were applied. Changes in BIS, CVI, heart rate (HR), and mean arterial blood pressure (MAP) between baseline and response period were analyzed in relation to level of hypnosis, antinociception, and somatic response to the stimuli. RESULTS: CVI and BIS more accurately correlate with somatic response to an Observer Assessment of Alertness and Sedation-noxious stimulation than HR, MAP, CeREMI, and propofol effect-site concentration (Tukey post hoc tests P < 0.01). Change in CVI is more adequate to monitor response to stimulation than changes in BIS, HR, or MAP (as described by the Mathews Correlation Coefficient with significance level set at P < 0.001). In contrast, none of the candidate analgesic state indices was uniquely related to a specific opioid concentration and is extensively influenced by the hypnotic state as measured by BIS. CONCLUSIONS: CVI appears to correlate with somatic responses to noxious stimuli. However, unstimulated CVI depends more on hypnotic drug effect than on opioid concentration. (Anesth Analg 2014;XXX:00–00)

Background This report describes a new closed-loop control system for propofol that uses the Bispectral Index (BIS) as the controlled variable in a patient-individualized, adaptive, model-based control system, and compares this system with manually controlled administration of propofol using hemodynamic and somatic changes to guide anesthesia. Methods Twenty female patients, American Society of Anesthesiologists physical status I or II, who were scheduled for gynecologic laparotomy were included to receive propofolremifentanil anesthesia. In group I, propofol was titrated using a BIS-guided, model-based, closed-loop system. The BIS target was set at 50. In group II, propofol was titrated using classical hemodynamic signs of (in)adequate anesthesia. Performance of control during induction and maintenance of anesthesia were compared between both groups using BIS as the controlled variable in group I and the reference variable in group II, and, conversely, the systolic blood pressure as the controlled variable in group II and the reference variable in group I. At the end of anesthesia, recovery profiles between groups were compared. Results Although patients undergoing manual induction of anesthesia in group II at 300 ml/h reached a BIS level of 50 faster than patients undergoing open-loop, computer-controlled induction in group I, manual induction caused a more pronounced initial overshoot of the BIS target. This resulted in a more pronounced decrease in blood pressure in group II. During the maintenance phase, better control of BIS and systolic blood pressure was found in group I compared with group II. Recovery was faster in group I. Conclusion A closed-loop system for propofol administration using the BIS as a controlled variable together with a model-based controller is clinically acceptable during general anesthesia.

BACKGROUND: Closed-loop control of the hypnotic component of anesthesia has been proposed in an attempt to optimize drug delivery. Here, we introduce a newly developed Bayesian-based, patient-individualized, model-based, adaptive control method for bispectral index (BIS) guided propofol infusion into clinical practice and compare its accuracy and clinical feasibility under direct observation of all anesthesiologist versus BIS guided, effect compartment controlled propofol administration titrated by the anesthesiologist during ambulatory gynecological procedures.METHODS: Forty ASA patients were randomly allocated to the closed-loop or manual control group. All patients received miclazolam 1 mg IV and alfentanil 0.5 mg IV before induction. In the closed-loop control group, propofol was administered using the previously described closed-loop control system to reach and maintain a target BIS of 50. In the manual control group, the propofol effect-site concentration was adapted at the discretion of the anesthesiologist to reach and maintain a BIS as close as possible to 50. Induction characteristics, performance, and robustness during maintenance and recovery times were compared. Hemodynamic and respiratory stability were calculated as clinical feasibility parameters.RESULTS: The closed-loop control system titrated propofol administration accurately resulting in BIS values close to the set point. The closed-loop control system was able to induce the patients within clinically accepted time limits and with less overshoot than the manual control group. Automated control resulted in beneficial recovery times. Our closed-loop control group showed similar acceptable clinical performance specified by similar hemodynamic, respiratory stability, comparable movement rates, and quality scores than the manual control group.CONCLUSIONS: The Bayesian-based closed-loop control system for propofol administration using the BIS as a controlled variable performed accurate during anesthesia for ambulatory gynecological procedures. This control system is clinical feasibility and can be further validated in clinical practice.

Implementing Bayesian methods in a model-based closed-loop system requires the integration of a standard response model with a patient-specific response model. This process makes use of specific modeling weights, called Bayesian variances, which determine how the specific model can deviate from the standard model. In this study we applied simulations to select the Bayesian variances yielding the optimal controller for a Bayesian-based closed-loop system for propofol administration using the Bispectral Index (BIS) as a controlled variable.The relevant Bayesian variances determining the modeling process were identified. Each set of such Bayesian variances represents a potential controller. The set, which will result in optimal control, was estimated using calculations on a simulated population. We selected 625 candidate sets. Similar to our previous closed-loop performance study, we applied a simulation protocol to evaluate controller performance. Our population consisted of 416 virtual patients, generated using population characteristics from previous work. A BIS offset trajectory similar to a surgical case was used.We were able to develop, describe, and optimize the parameter setting for a patient-individualized model-based closed-loop controller using Bayesian optimization. Selection of the optimal set yields a controller performing with the following median absolute prediction errors at BIS targets 30, 50, and 70: 12.9 +/- 2.87, 7.59 +/- 0.74, and 5.76 +/- 1.03 respectively.We believe this system can be introduced safely into clinical testing for both induction and maintenance of anesthesia under direct observation of an anesthesiologist.

Although automated closed-loop control systems may improve quality of care, their safety must be proved under extreme control conditions. This study describes a simulation methodology to test automated controllers and its application in a comparison of two published controllers for Bispectral Index (BIS)-guided propofol administration.A patient simulator was developed to compare controllers. Using input scripts to dictate patient characteristics, target BIS values, and the time course of surgical events, the simulator continuously monitors the infusion pump under control and generates BIS values as a composite of modeled response to drug, perceived stimulation, and random noise. The simulator formats the output stream of BIS data as input to the controller under test to emulate the serial output of the actual BIS monitor. A published model-based controller and a classic proportional integral derivative controller were compared when using the BIS value as a controlled variable. Each controller was tested using a set of 10 virtual patients undergoing a fixed surgical profile that was repeated with BIS targets set at 30, 50, and 70. Controller performance was assessed using median (absolute) prediction error, divergence, wobble, and percentage time within BIS target range metrics.The median prediction error was significantly smaller for the proportional integral derivative controller than for the model-based controller. The median absolute prediction error was smaller for the model-based controller than for the proportional integral derivative controller for each BIS target, reaching statistical significance for targets 30 and 50.When simulating closed-loop control of BIS using propofol, the use of a patient-individualized, model-based adaptive closed-loop system with effect site control resulted in better control of BIS compared with a standard proportional integral derivative controller with plasma site control. Even under extreme conditions, the modeled-based controller exhibited no behavioral problems.

Background Although automated closed-loop control systems may improve quality of care, their safety must be proved under extreme control conditions. This study describes a simulation methodology to test automated controllers and its application in a comparison of two published controllers for Bispectral Index (BIS)-guided propofol administration. Methods A patient simulator was developed to compare controllers. Using input scripts to dictate patient characteristics, target BIS values, and the time course of surgical events, the simulator continuously monitors the infusion pump under control and generates BIS values as a composite of modeled response to drug, perceived stimulation, and random noise. The simulator formats the output stream of BIS data as input to the controller under test to emulate the serial output of the actual BIS monitor. A published model-based controller and a classic proportional integral derivative controller were compared when using the BIS value as a controlled variable. Each controller was tested using a set of 10 virtual patients undergoing a fixed surgical profile that was repeated with BIS targets set at 30, 50, and 70. Controller performance was assessed using median (absolute) prediction error, divergence, wobble, and percentage time within BIS target range metrics. Results The median prediction error was significantly smaller for the proportional integral derivative controller than for the model-based controller. The median absolute prediction error was smaller for the model-based controller than for the proportional integral derivative controller for each BIS target, reaching statistical significance for targets 30 and 50. Conclusions When simulating closed-loop control of BIS using propofol, the use of a patient-individualized, model-based adaptive closed-loop system with effect site control resulted in better control of BIS compared with a standard proportional integral derivative controller with plasma site control. Even under extreme conditions, the modeled-based controller exhibited no behavioral problems.

PURPOSE OF REVIEW Closed-loop systems are able to make decisions on their own and try to reach and maintain a preset target. As a result, they might help the anaesthesiologist in optimizing the titration of drug administration without overshooting, controlling physiological functions and guiding monitoring variables. Thanks to the development of fast computer technology and more reliable pharmacological effect measures, the study of automation in anaesthesia has regained popularity. RECENT FINDINGS This short review focuses on the most recently developed and tested feed-back systems in anaesthesia. Various new approaches for controlling the administration of intravenous and inhaled hypnotic-anaesthetic drugs have been published recently. For analgesics, a framework for further research has been presented in the literature. For other drugs, such as muscle relaxants and haemodynamics, a short review can be found. SUMMARY Until now, most of these systems are still under development. The challenge is now to establish fully the safety, efficacy, reliability and utility of closed-loop anaesthesia for its adoption into the clinical setting. Besides the optimization of controlled variables and control models, these systems have to be tested in extreme circumstances.