Closed-loop Anesthesia Delivery System Research Articles

Analyzing the States of Brain under Anesthesia Using ANES-metanet based on Deep Learning Models

Monitoring the depth of unconsciousness during anesthesia is beneficial in both clinical settings and neuroscience investigations to understand brain mechanisms. Electroencephalogram (EEG) has been used as an objective means of characterizing brain altered arousal and/or cognition states induced by anesthetics in real-time .Continuous monitoring of electroencephalogram (EEG) recordings in humans under general anesthesia (GA), local anesthesia (LA) and regional anesthesia (RA) has demonstrated that changes in EEG dynamics induced by an anesthetic drug are reliably associated with the altered arousal states caused by the drug. This observation suggests that an intelligent, closed-loop anesthesia delivery (CLAD) system operating in real-time could track EEG dynamics and control the infusion rate of a programmable pump to precisely maintain unconsciousness. In this process we propose a deep learning algorithm to analysis the anesthesia from EEG signal. So the deep learning algorithms are Convolution Neural Network, Long Short Term Neural Network and Artificial Neural Network will applied and analyze EEG signal and it generates the results in the form of metrics like accuracy, precision, recall and f1-score.

Closed-loop control of anesthetic state in nonhuman primates.

Research in human volunteers and surgical patients has shown that unconsciousness under general anesthesia can be reliably tracked using real-time electroencephalogram processing. Hence, a closed-loop anesthesia delivery (CLAD) system that maintains precisely specified levels of unconsciousness is feasible and would greatly aid intraoperative patient management. The US Federal Drug Administration has approved no CLAD system for human use due partly to a lack of testing in appropriate animal models. To address this key roadblock, we implement a nonhuman primate (NHP) CLAD system that controls the level of unconsciousness using the anesthetic propofol. The key system components are a local field potential (LFP) recording system; propofol pharmacokinetics and pharmacodynamic models; the control variable (LFP power between 20 and 30 Hz), a programmable infusion system and a linear quadratic integral controller. Our CLAD system accurately controlled the level of unconsciousness along two different 125-min dynamic target trajectories for 18 h and 45 min in nine experiments in two NHPs. System performance measures were comparable or superior to those in previous CLAD reports. We demonstrate that an NHP CLAD system can reliably and accurately control in real-time unconsciousness maintained by anesthesia. Our findings establish critical steps for CLAD systems' design and testing prior to human testing.

Automated Closed-Loop Propofol Anesthesia Versus Desflurane Inhalation Anesthesia in Obese Patients Undergoing Bariatric Surgery: A Comparative Randomized Analysis of Recovery Profile.

Precision general anesthesia (GA) techniques that minimize the presence of residual anesthetic and facilitate recovery, are desirable in patients with morbid obesity. Automated administration of propofol total intravenous anesthesia (TIVA), which facilitates precision propofol delivery by factoring in continuous patient input variable (bispectral index) to establish a closed feedback loop system, may help mitigate concerns related to propofol's lipid solubility and adverse accumulation kinetics in patients with morbid obesity. This randomized study evaluated the recovery of patients with morbid obesity undergoing bariatric surgery under propofol TIVA automated by a closed-loop anesthesia delivery system (CLADS) versus desflurane GA. Forty patients, randomly allocated to receive propofol TIVA (CLADS group) or desflurane GA (desflurane group), were evaluated for postoperative recovery (early and intermediate) (primary objective); they were evaluated for intraoperative hemodynamics, anesthesia depth consistency, anesthesia delivery performance characteristics, patient satisfaction, and incidence of adverse events (sedation, pain, postoperative nausea, and vomiting) (secondary objective). No difference was found for the time-to-eye-opening (CLADS group: 4.7 [3.0, 6.7] min vs. desflurane group: 5.6 [4.0, 6.9] min, P = 0.576), time-to-tracheal-extubation (CLADS group: 6.7 [4.7, 9.3] min vs. desflurane group: 7.0 [5.8, 9.2] min, P = 0.528), ability-to-shift score from operating room table to the transport bed (CLADS group: 3 [3.0, 3.5] vs. desflurane group: 3 [3.0, 4.0], P = 0.703), and time to achieve a modified Aldrete score 9/10 (CLADS group: 15 [15.0, 37.5] min vs. desflurane group: 15 [15.0, 43.7] min, P = 0.867). Automated propofol TIVA as administered by CLADS, which matched desflurane GA with respect to depth of anesthesia consistency and postanesthesia recovery profile, can be explored further as an alternative anesthesia technique in patients with morbid obesity.

Automated Closed-Loop Propofol Anesthesia Versus Desflurane Inhalation Anesthesia in Obese Patients Undergoing Bariatric Surgery: A Comparative Randomized Analysis of Recovery Profile.

Precision general anesthesia (GA) techniques that minimize the presence of residual anesthetic and facilitate recovery, are desirable in patients with morbid obesity. Automated administration of propofol total intravenous anesthesia (TIVA), which facilitates precision propofol delivery by factoring in continuous patient input variable (bispectral index) to establish a closed feedback loop system, may help mitigate concerns related to propofol's lipid solubility and adverse accumulation kinetics in patients with morbid obesity. This randomized study evaluated the recovery of patients with morbid obesity undergoing bariatric surgery under propofol TIVA automated by a closed-loop anesthesia delivery system (CLADS) versus desflurane GA. Forty patients, randomly allocated to receive propofol TIVA (CLADS group) or desflurane GA (desflurane group), were evaluated for postoperative recovery (early and intermediate) (primary objective); they were evaluated for intraoperative hemodynamics, anesthesia depth consistency, anesthesia delivery performance characteristics, patient satisfaction, and incidence of adverse events (sedation, pain, postoperative nausea, and vomiting) (secondary objective). No difference was found for the time-to-eye-opening (CLADS group: 4.7 [3.0, 6.7] min vs. desflurane group: 5.6 [4.0, 6.9] min, P = 0.576), time-to-tracheal-extubation (CLADS group: 6.7 [4.7, 9.3] min vs. desflurane group: 7.0 [5.8, 9.2] min, P = 0.528), ability-to-shift score from operating room table to the transport bed (CLADS group: 3 [3.0, 3.5] vs. desflurane group: 3 [3.0, 4.0], P = 0.703), and time to achieve a modified Aldrete score 9/10 (CLADS group: 15 [15.0, 37.5] min vs. desflurane group: 15 [15.0, 43.7] min, P = 0.867). Automated propofol TIVA as administered by CLADS, which matched desflurane GA with respect to depth of anesthesia consistency and postanesthesia recovery profile, can be explored further as an alternative anesthesia technique in patients with morbid obesity.

Evaluation of Automated Delivery of Propofol Using a Closed-Loop Anesthesia Delivery System in Patients Undergoing Thoracic Surgery: A Randomized Controlled Study

Automated propofol total intravenous anesthesia (TIVA) administered by a closed-loop anesthesia delivery system (CLADS) exhibits greater efficiency than conventional manual methods, but its use in major thoracic surgery is limited. Prospective, single-blind, randomized controlled study. Single-center tertiary care hospital. Patients undergoing thoracic surgery. Patients were randomly allocated to receive CLADS-driven (CLADS group) or manually controlled (manual group) propofol TIVA. Anesthesia depth consistency (primary objective) and anesthesia delivery performance, propofol usage, work ergonomics, intraoperative hemodynamics, and recovery profile (secondary objectives) were analyzed. No differences were found for anesthesia depth consistency (percentage of time the bispectral index was within ± 10 of target) (CLADS group: 82.5% [78.5%-87.2%] v manual group: 86.5% [74.2%-92.5%]; p = 0.581) and delivery performance, including median performance error (CLADS group: 3 [-4 to 6] v manual group: 1 [-2.5 to 6]); median absolute performance error (CLADS group: 10 [10-12] v manual group:10 [8-12]); wobble (CLADS group: 10 [8-12] v manual group: 9 [6-10.5]); and global score (CLADS group: 24.2 [21.2-29.3] v manual group: 22.1 [17.3-32.3]) (p > 0.05). However, propofol requirements were significantly lower in the CLADS group for induction (CLADS group: 1.27 ± 0.21] mg/kg v manual group: 1.78 ± 0.51 mg/kg; p = 0.014) and maintenance (CLADS group: 4.02 ± 0.99 mg/kg/h v manual group: 5.11 ± 1.40 mg/kg/h; p = 0.025) of TIVA. Ergonomically, CLADS-driven TIVA was found to be significantly superior to manual control (infusion adjustment frequency/h) (manual infusion: 9.6 [7.8-14.9] v CLADS delivery [none]). In thoracic surgery patients, CLADS-automated propofol TIVA confers significant ergonomic advantage along with lower propofol usage.

A simulation-based comparative analysis of PID and LQG control for closed-loop anesthesia delivery

Closed loop anesthesia delivery (CLAD) systems can help anesthesiologists efficiently achieve and maintain desired anesthetic depth over an extended period of time. A typical CLAD system would use an anesthetic marker, calculated from physiological signals, as real-time feedback to adjust anesthetic dosage towards achieving a desired set-point of the marker. Since control strategies for CLAD vary across the systems reported in recent literature, a comparative analysis of common control strategies can be useful. For a nonlinear plant model based on well-established models of compartmental pharmacokinetics and sigmoid-Emax pharmacodynamics, we numerically analyze the set-point tracking performance of three output-feedback linear control strategies: proportional-integral-derivative (PID) control, linear quadratic Gaussian (LQG) control, and an LQG with integral action (ILQG). Specifically, we numerically simulate multiple CLAD sessions for the scenario where the plant model parameters are unavailable for a patient and the controller is designed based on a nominal model and controller gains are held constant throughout a session. Based on the numerical analyses performed here, conditioned on our choice of model and controllers, we infer that in terms of accuracy and bias PID control performs better than ILQG which in turn performs better than LQG. In the case of noisy observations, ILQG can be tuned to provide a smoother infusion rate while achieving comparable steady state response with respect to PID. The numerical analysis framework and findings reported here can help CLAD developers in their choice of control strategies. This paper may also serve as a tutorial paper for teaching control theory for CLAD.

The Effect of Dexmedetomidine on Propofol Requirements During Anesthesia Administered by Bispectral Index-Guided Closed-Loop Anesthesia Delivery System: A Randomized Controlled Study.

Dexmedetomidine, a selective α2-adrenergic agonist currently approved for continuous intensive care unit sedation, is being widely evaluated for its role as a potential anesthetic. The closed-loop anesthesia delivery system (CLADS) is a method to automatically administer propofol total intravenous anesthesia using bi-spectral index (BIS) feedback and attain general anesthesia (GA) steady state with greater consistency. This study assessed whether dexmedetomidine is effective in further lowering the propofol requirements for total intravenous anesthesia facilitated by CLADS. After ethics committee approval and written informed consent, 80 patients undergoing elective major laparoscopic/robotic surgery were randomly allocated to receive GA with propofol CLADS with or without the addition of dexmedetomidine. Quantitative reduction of propofol and quality of depth-of-anesthesia (primary objectives), intraoperative hemodynamics, incidence of postoperative adverse events (sedation, analgesia, nausea, and vomiting), and intraoperative awareness recall (secondary objectives) were analyzed. There was a statistically significant lowering of propofol requirement (by 15%) in the dexmedetomidine group for induction of anesthesia (dexmedetomidine group: mean ± standard deviation 0.91 ± 0.26 mg/kg; nondexmedetomidine group: 1.07 ± 0.23 mg/kg, mean difference: 0.163, 95% CI, 0.04-0.28; P = .01) and maintenance of GA (dexmedetomidine group: 3.25 ± 0.97 mg/kg/h; nondexmedetomidine group: 4.57 ± 1.21 mg/kg/h, mean difference: 1.32, 95% CI, 0.78-1.85; P < .001). The median performance error of BIS control, a measure of bias, was significantly lower in dexmedetomidine group (1% [-5.8%, 8%]) versus nondexmedetomidine group (8% [2%, 12%]; P = .002). No difference was found for anesthesia depth consistency parameters, including percentage of time BIS within ±10 of target (dexmedetomidine group: 79.5 [72.5, 85.3]; nondexmedetomidine group: 81 [68, 88]; P = .534), median absolute performance error (dexmedetomidine group: 12% [10%, 14%]; nondexmedetomidine group: 12% [10%, 14%]; P = .777), wobble (dexmedetomidine group: 10% [8%, 10%]; nondexmedetomidine group: 8% [6%, 10%]; P = .080), and global score (dexmedetomidine group: 25.2 [23.1, 35.8]; nondexmedetomidine group: 24.7 [20, 38.1]; P = .387). Similarly, there was no difference between the groups for percentage of time intraoperative heart rate and mean arterial pressure remained within 20% of baseline. However, addition of dexmedetomidine to CLADS propofol increased the incidence of significant bradycardia (dexmedetomidine group: 14 [41.1%]; nondexmedetomidine group: 3 [9.1%]; P = .004), hypotension (dexmedetomidine group: 9 [26.5%]; nondexmedetomidine group: 2 [6.1%]; P = .045), and early postoperative sedation. The addition of dexmedetomidine to propofol administered by CLADS was associated with a consistent depth of anesthesia along with a significant decrease in propofol requirements, albeit with an incidence of hemodynamic depression and early postoperative sedation.

Anaesthetic depth control using closed loop anaesthesia delivery system vs. target controlled infusion in patients with moderate to severe left ventricular systolic dysfunction

ObjectivesTo compare the efficacy of anaesthetic depth control using Closed Loop Anaesthesia Delivery System (CLADS) and Target Controlled Infusion (TCI) in patients with moderate to severe left ventricular dysfunction (LVSD). DesignRandomized control trial. PatientsForty ASA III/IV adult patients with moderate to severe LVSD scheduled for open heart surgery. InterventionsPropofol was administered using CLADS or TCI for maintaining BIS of 50. Induction and maintenance doses were controlled automatically in CLADS. Dixon's up and down method was used to estimate the plasma concentration needed for induction in TCI. MeasurementPercentage of total anaesthesia time (“valid CLADS time”) for which BIS remained within ±10 of target (BIS=50). Main resultsBIS remained within ±10 of the target for a significantly longer duration of time in CLADS group (p=0.001). Performance parameters like Median Performance Error (MDPE), p=0.024; Median Absolute Performance Error (MDAPE), p=0.0212; and global score p=0.017 were significantly better in CLADS group. Total propofol consumption was significantly less in CLADS group (p=0.014). Mean value (95% CI) of EC50 and EC95 for target plasma propofol concentration for induction was 1.62 (1.45–1.79) μgml−1 and 1.87 (1.73–2.96) μgml−1 respectively using probit analysis. ConclusionsClosed loop delivery of propofol using CLADS performed significantly better than TCI in this subset of patients. Clinical trials registration no.www.ClinicalTrials.gov-NCT02645994

Efficacy of closed-loop infusion of propofol for surgery on body surface in preschool and school-age pediatric patients

Objective To evaluate the efficacy of closed-loop infusion of propofol for surgery on the body surface in preschool and school-age pediatric patients. Methods American Society of Anesthesiologists physical status Ⅰ pediatric patients of both sexes, undergoing elective surgery on the body surface, were included in the study.One hundred twenty-four preschool pediatric patients (aged 3-6 yr) were divided into 2 groups (n=62 each) using a random number table: closed-loop group (CPRE group) and open-loop group (OPRE group). Thirty-eight school-age pediatric patients (aged 7-12 yr) were divided into 2 groups (n=19 each) using a random number table: closed-loop group (CSTU group) and open-loop group (OSTU group). The target bispectral index (BIS) value was set at 50 during maintenance of anesthesia.Propofol was delivered using closed-loop anesthesia delivery system, and the target plasma concentration of propofol was automatically regulated in CPRE and CSTU groups.Propofol was given using open-loop anesthesia delivery system, and the target plasma concentration of propofol was manually regulated in OPRE and OSTU groups.The adequate anesthesia time ratio (BIS40-60%) and global score (GS) of the delivery system were recorded during maintenance of anesthesia.The consumption of propofol, frequency of regulation and mean BIS value were recorded.The delivery system-related complications were recorded during the perioperative period. Results Compared with group OPRE, the consumption of propofol, GS and mean BIS value were significantly decreased, BIS40-60% was increased (P 0.05). Compared with group OSTU, GS was significantly decreased, BIS40-60% was increased (P 0.05). Compared with group CPRE, the consumption of propofol and GS were significantly decreased, BIS40-60% was increased (P 0.05). One pediatric patient in group CSTU developed airway spasm, and no severe complications were found in the other pediatric patients. Conclusion For surgery on the body surface in preschool and school-age pediatric patients, closed-loop infusion of propofol is safe and effective, the stability and precision of anesthesia is superior to that of open-loop anesthesia delivery system, and it provides better efficacy in school-age pediatric patients than in preschool pediatric patients. Key words: Propofol; Drug delivery systems; Child

The effect of sevoflurane on propofol with closed-loop target controlled infusion anesthesia system

Objective The primary goal was to determine the influence of sevoflurane on propofol with closed-loop target controlled infusion(TCI) delivery system in combined intravenous-inhalation anesthesia. Methods Sixty patients with ASA Ⅰ or Ⅱ were enrolled in this double-blinded study and randomly devided into three groups using the random number table method: group A, in which patients were only administrated propofol, group B and C, in which patients were given propofol for 20 min, followed with 0.6 MAC or 0.8 MAC sevoflurane for 40 min, respectively and the inhalation concentration was adjusted according to MAC. Serum propofol concentration was monitored continuouslyin. Results There was no difference in BIS among three groups (P>0.05). Serum concentration of propofol in group B and group C decreased constantly after the inhalation of sevoflurane but increased slowly when the inhalation was terminated(P<0.05), while it remained unchanged in group A. Compared with group A[(2.53±0.55), (2.54±0.61) mg/L], the decline of serum concentration was more evident in group C[(1.81±0.63), (1.24±0.4) mg/L] than group B[(1.92±0.58), (1.67±0.64) mg/L] at 30 min and 40 min during the surgery. The changing rate in group C was higher than that of group B and became stable 40 min after the stop point of propofol. Conclusions The administration of propofol with closed-loop anesthesia delivery system could adjust the anesthesia depth automatically and effectively, when the sevoflurane was inhaled with the MAC under 0.8. Key words: Sevoflurane; Propofol; Blood drug level; Closed-loop anesthesia delivery system

A Multicenter Evaluation of a Closed-Loop Anesthesia Delivery System: A Randomized Controlled Trial.

Closed-loop systems for anesthesia delivery have been shown to outperform traditional manual control in different clinical settings. The present trial was aimed at evaluating the feasibility and efficacy of Bispectral Index (BIS)-guided closed-loop anesthesia delivery system (CLADS) in comparison with manual control across multiple centers in India. Adult patients scheduled for major surgical procedures of an expected duration of 1 to 3 hours were randomized across 6 sites into 2 groups: a CLADS group and a manual group. In the manual control group, propofol infusion was titrated manually by the attending anesthesiologist to a BIS of 50 during induction and maintenance. Analgesia was maintained with fentanyl infusion and nitrous oxide in both groups. In the CLADS group, both induction and maintenance of anesthesia were performed automatically using CLADS. The primary outcome measure was the performance of the system as assessed by the percentage of total anesthesia time BIS remained ±10 of target BIS. The secondary outcome measures were a percentage of anesthesia-time heart rate and mean arterial pressure within 25% of the baseline, median absolute performance error, wobble, and global score. Wobble indicates intraindividual variability in the control of BIS, and global score reflects the overall performance; lower values indicate superior performance for both parameters. The performance parameters of the system also were compared among the participating sites. Two hundred forty-two patients were randomized. BIS was maintained within ±10 of target for significantly longer time in the CLADS group (81.4% ± 8.9 % of anesthesia duration) than in the manual group (55.34% ± 25%, P < 0.0001). The indices that assess performance were significantly better in the CLADS group than the manual group as follows: median absolute performance error was 10 (10, 12) (median [interquartile range]) in the CLADS group versus 18 (14, 24) in the manual group, P < 0.0001; wobble was 9 (8, 10) in CLADS group versus 10 (8, 14) in the manual group, P = 0.0009; and Global score, which reflects overall performance, was 24 (19, 30) in the CLADS group versus 51 (31, 99) in the manual group, P < 0.0001. The percentage of time heart rate was within 25% of the baseline was significantly greater in the CLADS group (heart rate of 95 [87, 99], median [interquartile range], in the CLADS group versus 90 [75, 98] in the manual group P = 0.0031). On comparison of data between the centers, the performance parameters did not differ significantly among the centers in the CLADS group (P = 0.94), but the parameters differed significantly among the centers in the manual group (P < 0.001). Our study in a multicenter setting proves the consistently better performance of automated anesthesia drug delivery compared with conventional manual control. This highlights an important advantage of an automated system for delivering standardized anesthesia, thereby overcoming differences in practices among anesthesiologists.

Robust control of burst suppression for medical coma

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. Approach. 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. Main 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. Significance. 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.

Evaluation of closed‐loop anesthesia delivery for propofol anesthesia in pediatric cardiac surgery

The objective of this study was to compare the feasibility of closed-loop anesthesia delivery with manual control of propofol in pediatric patients during cardiac surgery. Forty ASA II-III children, undergoing elective cardiac surgery under cardiopulmonary bypass (CPB) in a tertiary care hospital, were randomized to receive propofol either through a closed-loop anesthesia delivery system (CL group) or through traditional manual control (manual group) to achieve a target BIS of 50. Patients were induced and subsequently maintained with a propofol infusion. The propofol usage and the efficacy of closed-loop system in controlling BIS within ±10 of the target were compared with that of manual control. The maintenance of BIS within ±10 of target and intraoperative hemodynamic stability were similar between the two groups. However, induction dose of propofol was less in the CL group (2.06±0.79mg·kg(-1) ) than the manual group (2.95±1.03mg·kg(-1) ) (P=0.006) with less overshoot of BIS during induction in the closed-loop group (P=0.007). Total propofol used in the off-CPB period was less in the CL group (6.29±2.48mg·kg(-1) h(-1) vs 7.82±2.1mg·kg(-1) h(-1) ) (P=0.037). Phenylephrine use in the pre-CPB period was more in the manual group (16.92±10.92μg·kg(-1) vs 5.79±5.98μg·kg(-1) ) (P=0.014). Manual group required a median of 18 (range 8-29) dose adjustments per hour, while the CL group required none. This study demonstrated the feasibility of closed-loop controlled propofol anesthesia in children, even in challenging procedures such as cardiac surgery. Closed-loop system needs further and larger evaluation to establish its safety and efficacy.

Real-Time Measurement and Closed Loop Control of Burst Suppression for Management of Medical Coma

This talk will provide an overview of recent results on the design of a closed-loop anesthesia delivery (CLAD) system for controlling burst suppression for management of medical coma. I. EXTENDED ABSTRACT Medical coma is a state of profound unconsciousness and brain inactivation induced to treat status epilepticus – unrelenting seizures – and to facilitate recovery following traumatic brain injuries [1], [2]. Typically, an anesthetic drug such as propofol is titrated to achieve a specific clinical target that indicates a coma-like state of large-scale brain inactivation. The standard approach is to monitor the patient’s brain activity with the electroencephalogram (EEG) and use a specified level of burst suppression as an electrophysiological target. Burst suppression is an EEG pattern indicating a state of highly reduced electrical and metabolic activity in the brain defined by periods of high-voltage bursts that alternate with flatline periods termed suppressions [3]. Burst suppression can be controlled systematically, once the state is achieved, as the level of suppression can be increased or decreased by adjusting the infusion rate of the anesthetic. In general, there are no established guidelines for specifying the level of burst suppression. A target level is agreed upon by the intensive care unit staff and control of the level is undertaken by continually monitoring the EEG and manually adjusting the drug infusion rate. A common goal of medical coma is to maintain a stable state of reduced brain activity and metabolism for 12 to 48 hours, a period significantly longer than any human operator can be expected to maintain tight control by visually monitoring the EEG and manually changing the infusion rate of the anesthetic. Defining a precise, quantitative target for the level of burst suppression and designing an automated system for maintaining that level would be a more prudent approach. Automation could be achieved by implementing a closed loop anesthesia delivery system. *This work has been supported by NIH DP1-OD003646 (to ENB), DP2OD006454 (to PLP) and K08-GM094394 (to KS). S.C. holds a Career Award at the Scientific Interface from the Burroughs-Wellcome Fund Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital & Harvard Medical School, Boston, MA Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA Institute for Medical Engineering and Sciences, Massachusetts Institute of Technology, Cambridge, MA The essential elements of a CLAD system are: a specific control or target criterion; a means of measuring or estimating the value of the criterion in real time from EEG recordings; and a controller that adjusts the instantaneous dosing of the anesthetic based on the difference between the current value of the criterion and its target value. We present a CLAD system to automatically and precisely control the EEG state of burst suppression and efficiently maintain a medically-induced coma. Specifically, we constructed a CLAD system to control burst suppression reliably and accurately in real-time in both simulation [4] and in a rodent model using EEG and a computer-controlled infusion of propofol [5]. The CLAD system uses a two-compartment pharmacokinetics model to characterize the effect of propofol on the EEG. We introduce the burst suppression probability (BSP) algorithm [6], [7] to compute from the EEG in real time the instantaneous probability of the brain being in a state of suppression. We estimate the parameters of a pharmacokinetics model online and use them to define a proportional-integral (PI) controller. To assess performance of our CLAD system, we establish new statistical criteria to assess reliability and accuracy at individual target levels of burst suppression and a Bayesian statistical approach to assess reliability and accuracy across target levels and animals. We illustrate the application of our CLAD system by demonstrating precise control of burst suppression in individual rats. Finally, we discuss outstanding problems and forthcoming work related to translating the CLAD system for use in human patients.

Closed loop anaesthesia at high altitude (3505 m above sea level): Performance characteristics of an indigenously developed closed loop anaesthesia delivery system

Background:Closed loop anaesthesia delivery systems (CLADSs) are a recent advancement in accurate titration of anaesthetic drugs. They have been shown to be superior in maintaining adequate depth of anaesthesia with few fluctuations as compared with target-controlled infusion or manual titration of drug delivery.Methods:Twenty patients scheduled to undergo general abdominal or orthopaedic procedures under general anaesthesia at Leh (3505 m above sea level) were recruited as subjects. Anaesthesia was delivered by a patented closed loop system that uses the Bispectral Index (BIS™) as a feedback parameter to titrate the rate of propofol infusion. All vital parameters, drug infusion rate and the BIS™ values were continuously recorded and stored online by the system. The data generated was analysed for the adequacy of anaesthetic depth, haemodynamic stability and post-operative recovery parameters.Results:The CLADS was able to maintain a BIS™ within ±10 of the target of 50 for 85.0±7.8% of the time. Haemodynamics were appropriately maintained (heart rate and mean arterial blood pressure were within 25% of baseline values for 91.2±2.2% and 94.1±3% of the total anaesthesia time, respectively). Subjects were awake within a median of 3 min from cessation of drug infusion and achieved fitness to recovery room discharge within a median of 15 min. There were no adverse events or report of awareness under anaesthesia.Conclusions:The study demonstrates the safety of our CLADS at high altitude. It seeks to extend the use of our system in challenging anaesthesia environments. The system performance was also adequate and no adverse events were recorded.

Closed-loop isoflurane administration with bispectral index in open heart surgery: Randomized controlled trial with manual control

Objective Improved anesthetic agent delivery system (IAADS), a modification of closed-loop anesthesia delivery system (CLADS), is designed to deliver inhalational anesthetics and propofol through closed-loop control with bispectral index (BIS) as target. We compared the performance of IAADS with the manual control isoflurane administration during cardiac surgery. Methods Forty patients of ASA (American Society of Anesthesiologists) physical status class II–III, undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) in a tertiary care hospital in India were randomized to receive isoflurane through a closed-loop system (IAADS group) or through a Tech 7 vaporizer adjusted manually (manual group) to achieve a target BIS of 50. Patients were induced with a propofol infusion and isoflurane was started after intubation. During CPB, patients received propofol; isoflurane was restarted after separation from CPB. The efficacy of IAADS in controlling depth of anesthesia and hemodynamic variations was compared with that of manual control. Results IAADS was able to maintain BIS within ± 10 of target for significantly longer period (84.6 ± 7.2% in IAADS group vs. 75.9 ± 11.2 in manual group, p < 0.01). Both overall performance, as assessed by global score ( p < 0.01), and precision, as judged by median absolute performance error (MDAPE) ( p < 0.04), were significantly better in the IAADS group. The IAADS group required significantly less propofol for induction (1.3 ± 0.4 mg/kg in IAADS vs. 1.6 ± 0.5 mg/kg in manual, p < 0.05) and less isoflurane during maintenance of anesthesia (3.3 ± 0.8 ml/h vs. 3.4 ± 0.9 ml/h, p < 0.01). Conclusion The present study proves the feasibility and efficacy of inhalation anesthetic administration through closed-loop control. This is the first system that has been developed to control intravenous and inhalational anesthetic agents in a closed-loop model using BIS.

Bispectral index-controlled postoperative sedation in cardiac surgery patients: a comparative trial between closed loop and manual administration of propofol

Postoperative cardiac surgery patients are usually sedated according to clinical sedation scores. Electrophysiological data derived from electroencephalography, such as the bispectral index (BIS), have been reported to assess and quantify the level of sedation, although experience in these patients is limited. In the current study, we evaluated a closed-loop system - closed-loop anaesthesia delivery system (CLADS) - for postoperative sedation after open heart surgery using BIS. Forty-one postoperative cardiac surgery patients in the age group 18-65 years were included. In the postanaesthesia care unit, they were randomly allocated to two groups: a CLADS group, which received a continuous infusion of propofol using CLADS, and a manual group, which received propofol at a rate manually adjusted by the clinician. Propofol was administered in both groups to maintain the BIS at a target of 70 for adequate sedation. Patients were weaned from mechanical ventilation and the trachea extubated after confirmation of haemodynamic stability, haemostasis, normothermia and mental orientation. The percentage of total sedation time during which BIS remained within +/-10 of the target value (BIS of 70 during sedation) was significantly higher in the CLADS group than in the manual group (P = 0.002). The assessment of performance parameters using median performance error and median absolute performance error indicated better performance in the CLADS group. Manual control required the propofol infusion rate to be changed frequently, taking up considerable time and attention of the clinician. Closed-loop delivery of propofol to control BIS for postoperative sedation is feasible and efficient after cardiac surgery.

Closed-loop Control of Anesthesia Using the Bispectral Index in Open Heart Surgery

The introduction of the bispectral index (BIS) as a comprehensive indicator of depth of anesthesia has prompted research in the automated delivery of anesthetics. This trial aimed to evaluate the usefulness of the BIS as the feedback variable in a closed-loop anesthesia control system during cardiac surgery under cardiopulmonary bypass (CPB). Thirty-four adult patients of American Society of Anesthesiologists grade I-III undergoing elective cardiac surgery under hypothermic CPB were evaluated prospectively in a tertiary care teaching hospital. The anesthesia was induced and maintained throughout surgery using a closed-loop anesthesia delivery system (502/DEL/2003) to control the BIS. The closed-loop system was functional during 96% of the anesthesia duration. The BIS was maintained at +/- 10 of the target of 50 during 86% of the automated anesthesia. The closed-loop system was also functional during CPB despite a fall in BIS probably resulting from hypothermia. None of the patients had recall of events or experiences during the procedure. The closed-loop control of anesthetic delivery adjusted to BIS is feasible and may be useful in open heart surgery under hypothermic CPB.

Bi-spectral index guided closed-loop anaesthesia delivery system (CLADS™) in pheochromocytoma

Anaesthetic management of pheochromocytoma is far from satisfactory even though various techniques are available. Feasibility as well as safety of Bi-spectral Index (BIS)-guided closed-loop control of anaesthesia has been shown in various clinical settings. We evaluated the performance of BIS-guided closed-loop-anaesthesia-delivery system (CLADS) in patients undergoing resection of pheochromocytoma. Thirteen patients (7 males and 6 females, 15-65 years) who underwent adrenalectomy for pheochromocytoma in the past 4 years operated by a single surgeon were included in the study. Closed-loop-control of propofol-anaesthesia was induced and maintained with target BIS value =50. Median performance error and median absolute performance error of target BIS control were 2 (2-7) [median (IQR)] and 10 (8-10), respectively. BIS was maintained within 50 +/- 10 for 87 +/- 8.6% (mean +/- SD) of the valid CLAD time. Heart rate (HR) and mean arterial pressure (MAP) were maintained within +/-25% of the baseline value for 90.3 +/- 12.1% and 76.3 +/- 13.2% of the time duration, respectively. BIS increased significantly following intubation, incision and tumor handling (P = 0.001, 0.001 and 0.03 respectively). There was a significant fall in both HR and MAP following induction of anaesthesia (P = 0.001), and MAP following tumor excision (P = 0.045) as compared to the baseline. Though maximum HR within 5 min post-intubation, post-incision and during tumor handling were significantly higher (P = 0.001, 0.014 and 0.037) compared to just before the respective event, they were not statistically different from the baseline. Though maximum MAP within 5 min post-intubation, post-incision and during tumor handling were significantly higher compared to MAP just before the respective event (P = 0.001, 0.021 and 0.001), they were not significantly different compared to the baseline value except maximum MAP during tumor handling (P = 0.001). CLADS performed well in patients undergoing pheochromocytoma surgeries which represent one of the few clinically extreme situations.

Comparison of closed loop vs. manual administration of propofol using the Bispectral index in cardiac surgery

In recent years, electroencephalographic indices of anaesthetic depth have facilitated automated anaesthesia delivery systems. Such closed-loop control of anaesthesia has been described in various surgical settings in ASA I-II patients (1-4), but not in open heart surgery characterized by haemodynamic instability and higher risk of intra-operative awareness. Therefore, a newly developed closed-loop anaesthesia delivery system (CLADS) to regulate propofol infusion by the Bispectral index (BIS) was compared with manual control during open heart surgery. Forty-four adult ASA II-III patients undergoing elective cardiac surgery under cardiopulmonary bypass were enrolled. The study participants were randomized to two groups: the CLADS group received propofol delivered by the CLADS, while in the manual group, propofol delivery was adjusted manually. The depth of anaesthesia was titrated to a target BIS of 50 in both the groups. During induction, the CLADS group required lower doses of propofol (P<0.001), resulting in lesser overshoots of BIS (P<0.001) and mean arterial blood pressure (P=0.004). Subsequently, BIS was maintained within +/- 10 of the target for a significantly longer time in the CLADS group (P=0.01). The parameters of performance assessment, median absolute performance error (P=0.01), wobble (P=0.04) and divergence (P<0.001), were all significantly better in the CLADS group. Haemodynamic stability was better in the CLADS group and the requirement of phenylephrine in the pre-cardiopulmonary bypass period as well as the cumulative dose of phenylephrine used were significantly higher in the manual group. The automated delivery of propofol using CLADS was safe, efficient and performed better than manual administration in open heart surgery.