Other than administration of the study drugs, patient management was based on current standards of care. No specific recommendations were given for the treatment of hemodynamic abnormalities and for the use of a neuromuscular blocking drug. Nitrous oxide was not used. Morphine was given at the discretion of the physician 45 minutes before the presumed end of surgery.
In both groups, propofol and remifentanil were stopped simultaneously upon completion of surgery, and if necessary, a neuromuscular blockade reversing drug was given. Tracheal extubation was performed when all of the following were present: patient responsive and cooperative, SpO2 >95% with an oxygen inspiratory fraction <50%, T4/T1 ratio >90%, no hemodynamic instability (continuous infusion of vasoactive drugs), and temperature >36.0°C.
The primary outcome was the global score (GS),5 which characterized the overall performance of the controller including the percentage of adequate anesthesia, defined as BIS between 40 and 60 and the oscillation of the BIS determined by the median absolute performance error (MDAPE) and the wobble.16 The controller performances were calculated according to following equations.
- The performance error, or PE, calculated as the difference between actual and desired values (set point):
- The bias or median performance error (MDPE):
- The inaccuracy or MDAPE:
- The wobble, which measures the intraindividual variability in PE:
- where i = subject number, j = jth (one) measurement of observation period, n = total number of measurements during the observation period.
The GS was calculated according to the following equation5:
Excellent performance is characterized by a low MDAPE and wobble and high percentage of BIS value in the range 40 and 60, thus a low GS.
Secondary outcomes included the percentage of adequate anesthesia (defined as BIS between 40 and 60), overshoot (BIS <40) and undershoot (BIS >60) periods, occurrence of suppression ratio (SR) defined as SR >10% lasting at least a minute, and parameters of Varvel et al.16 (PE, MDPE, MDAPE, and wobble). Secondary outcomes also included the following clinical data: drug consumption, number of somatic events (i.e., movements, grimacing), time to tracheal extubation (i.e., time from discontinuation of propofol and remifentanil infusions until extubation), and recall of intraoperative events as determined by a standardized interview performed in the postanesthesia care unit and on the second or third postoperative day.17
This study is registered with ClinicalTrials.gov, number NCT00392158.
In a previous study, the GS was 50 ± 62 (mean ± SD) using manual propofol and remifentanil infusions and 21 ± 8 using closed-loop control of propofol and manual remifentanil infusion5; therefore, we expected an improvement of >50% using the closed-loop system. We thus estimated that 144 patients (72 per group) would provide a 95% power for a 2-sided α error of 0.01. We planned to recruit 200 patients under the assumption that some would be excluded for various reasons.
Categorical variables, expressed as numbers and frequencies, were compared by means of χ2 test or Fisher exact test as appropriate. Continuous variables were described as mean ± SD and median and interquartile range and compared using the Mann-Whitney U test. Comparison of serial measurements was performed with repeated-measures analysis of variance (with Bonferroni correction), and post hoc analyses were performed with nonparametric tests. Time from discontinuation of propofol and remifentanil infusions until tracheal extubation was compared using a Kaplan-Meier survival analysis followed by log-rank test. Probability values <0.05 were considered statistically significant. Data analysis was performed using SPSS® version 11.0 (SPSS, Inc., Chicago, IL).
Of the 200 patients who were approached, 196 patients were enrolled in the study, and 98 were randomized to each group. However, 15 patients in the dual-loop group and 14 patients in the manual group were excluded from analysis because of neurological disorders, BIS artifact, recording system failure, and other reasons (Fig. 2). There were thus 83 patients in the dual-loop group and 84 in the manual group available for analysis.
The groups were well balanced with respect to demographic, morphometric, and treatment characteristics. More than one-third of the study population received preoperative cardiovascular treatments and/or had a major surgical procedure (Table 2). Study participants had cardiac bypass, thoracic, vascular, urologic, orthopedic, gynecologic, or otolaryngologic surgery.
This study was conducted at 4 different sites, involving 17 anesthesiologists and 22 nurse anesthetists. No significant site differences or group-by-site interaction were found for any end points. Results were therefore pooled from all sites for analysis.
The closed-loop system maintained anesthesia for 312 hours. During this time, 3843 propofol and 4981 remifentanil target modifications were made automatically. The loop was opened in 2 cases; both were manual remifentanil modifications related to an episode of hypertension during laparoscopic procedures. Data for these patients were analyzed in the dual-loop group.
BIS values and calculated effect-site concentrations of propofol and remifentanil from induction to discontinuation of infusion are shown for dual-loop and manual groups in Figure 3.
Induction phase duration was significantly shorter in the dual-loop group than in the manual group (289 ± 122 vs 345 ± 166 seconds, P = 0.01). The initial effect-site concentrations and the amount of propofol were similar between the 2 groups whereas these values were larger for remifentanil in the dual-loop group (Table 3). There were more propofol and remifentanil modifications in the dual-loop group than in the manual group (Table 3). Overshoot, undershoot, and occurrence of SR were all less frequent in the dual-loop group during induction (Table 3).
During maintenance, the mean GS was 26 ± 11 in the dual-loop group versus 43 ± 40 in the manual group (P = 0.0001, Table 4, Fig. 4). The amount of time that BIS was maintained between 40 and 60 was significantly longer in the dual-loop group compared with the manual group (Table 4 and Fig. 5). MDAPE was significantly lower in the dual-loop group whereas wobble was similar between groups (Table 4). Overshoot, undershoot, and occurrence of SR were all less frequent in the dual-loop group (Table 4). The dose and the mean calculated effect-site concentration of propofol were similar in both groups whereas both values were larger for remifentanil in the dual-loop group (Table 4). More propofol and remifentanil modifications were made in the dual-loop than in the manual group, and the adjustments were smaller (Table 4 and Fig. 3). The Feedforward term (Appendix) was triggered 2 ± 2, 2 (1–3) times per hour for propofol and 5 ± 2, 5 (4–6) times per hour for remifentanil (P < 0.0001).
Heart rate, systolic blood pressure, and BIS values were similar between groups before and after painful stimuli (Fig. 6). This analysis was based on 33 patients in the manual group and 31 in the dual-loop group for laryngoscopy, and on 44 patients in the manual group and 49 in the dual-loop group for surgical incision because electronic recording of hemodynamic data and notes of these events were available only for these patients. No patient received combined general/regional anesthesia.
The mean time to tracheal extubation was shorter in the dual-loop than the manual group (Table 4 and Fig. 7). This analysis was based on 70 patients in the manual group and 72 in the dual-loop group because the remaining patients remained intubated because of hypothermia (n = 8), residual neuromuscular block (n = 5), or planned extubation in the intensive care unit (n = 12).
A subgroup of patients corresponds to those who received combined general and regional anesthesia. Patients in the dual-loop group had a nonsignificant decrease in remifentanil consumption (0.22 ± 0.7, 0.20 [0.16–0.27] vs 0.19 ± 0.7, 0.20 [0.16–0.23] μg · kg−1 · min−1, general anesthesia versus combined general/regional anesthesia, P = 0.52). Patients in the manual group had a significant decrease in remifentanil consumption (0.17 ± 0.7, 0.16 [0.11–0.21] vs 0.12 ± 0.6, 0.10 [0.07–0.16] μg · kg−1 · min−1, general anesthesia versus combined general/regional anesthesia, P = 0.003).
Use of neuromuscular blocking drugs, ephedrine treatment, antihypertensive therapy, blood loss, Ringer solution infusion, somatic events, and morphine dose were similar in the 2 groups (Table 4). No cases of awareness with recall were reported.
Our results indicate that automated coadministration of propofol and remifentanil using BIS for the controller allows an improvement in GS: increase in time spent with BIS values within predetermined boundaries (i.e., the interval 40–60) and decrease of MDAPE without an improvement of wobble. It permits a decrease in the duration of the induction phase and the time to extubation.
Closed-loop administration of propofol using BIS as the controlled variable during general anesthesia is becoming a reality as demonstrated by the number of successful cases published.4–7,18–25 On the contrary, the choice of the controlled variable remains when discussing closed-loop administration of an opioid. Most investigators propose the use of heart rate and mean arterial blood pressure to control opioid delivery.26–28 However, hemodynamics are not specific for the response to painful stimulation and may be affected by a number of covariates such as blood loss, heart failure, arrhythmia, manipulation of great blood vessels, and a variety of drugs. Schwilden and Stoeckel8 used the median EEG frequency to steer alfentanil administration. Morley et al.4 described closed-loop control of a propofol/ alfentanil mixture using BIS, but showed no clinical advantage between closed-loop and manual control. The use of an isobole controller has been reported for the closed-loop coadministration of a hypnotic and an opioid drug29 and was tested in 1 dog. We have reported 2 cases using the propofol-remifentanil closed-loop controller in a 9-year-old boy requiring emergency lung volume reduction30 and in a patient with gigantism.31 The dual-loop controller successfully administered propofol and remifentanil. Because our controller continuously titrates drug effect against BIS, it compensates for the shortcomings of pharmacokinetic models.
Clinical hypotheses for the development of our controller were that closed-loop control of propofol maintains a continuous stable hypnotic level (BIS between 40 and 60) in the absence of noxious stimuli and that painful intraoperative stimuli provokes cortical activation with consequent increases in BIS.11,12 Description of the controller is detailed in Figure 1, the Appendix, and in Table 1. Briefly, the controller in the current study measures and calculates the error (BISerror), which is the difference between the set point (BIS = 50) and the measured BIS. If the BIS error is different from 0, the controller determines a new propofol and/or remifentanil concentration. The error size determines which drug will be modified: if the BIS error is small, only the remifentanil is changed; if the BIS error is higher, the 2 drug concentrations are changed (Table 1). The minimal interval between 2 consecutive controls is set equal to the time to peak effect of each drug with an additional delay of 60 seconds; this time interval is shorter for remifentanil14 than for propofol,13 thus remifentanil modifications are made more frequently.
The GS was chosen as the primary outcome for evaluation of controller performance. This score has previously been used5,6,22 but it has not been extensively validated, leaving our primary outcome consequently open to criticism. However, a particular goal of automated control is to keep the average value of the controlled variable within defined limits with low oscillations.32 These criteria are summarized by the GS, which weights the inaccuracy or MDAPE and the wobble16 against the percentage of time with BIS values between 40 and 60. The MDAPE represents the precision or the oscillation around the set point (BIS = 50). The wobble measures the intraindividual variability of PE, but the wobble can be low (or excellent) while the BIS values are outside of the range (40–60). Consequently, the wobble cannot alone assess the controller performance and the GS avoids a misinterpretation.5 Finally, GS, MDAPE, percentage of BIS in the range 40 to 60 (Fig. 4), <40, >60, or period of SR are in agreement and demonstrate a better control of the BIS using the closed-loop controller. The controller decreases the episodes of too deep anesthesia (BIS <40) associated with the occurrence of SR (Table 4). The occurrence of SR may be attributable to a variety of factors other than hypnotic drug overdosing such as changes in metabolism and/or perfusion pressure, hypothermia, or hypoxemia. However, the occurrence of an isoelectric EEG increases mortality in critically ill patients33,34 and SR is related to too deep anesthesia, which has been proposed as a cause of increased long-term mortality.35–38
Hemodynamic responses to painful stimuli (laryngoscopy or surgical incision), recorded in only a fraction of patients, were similar with closed-loop and manual control, which suggests that closed-loop control provides acceptable control of heart rate and arterial blood pressure. However, in the absence of specific or objective clinical signs or specific analgesia monitors, we cannot evaluate whether remifentanil administration was optimal.
Our study also shows some limits of our controller. The first limitation is the duration of the induction phase, which is mostly comprised between 3.4 and 6.1 minutes (interquartile range values). Such a duration, obviously too long for low-risk patients, is related to the delay between each new modification of propofol or remifentanil concentration (Appendix). An evolution of our controller could be the decrease of this delay in low-risk patients. The second limitation is remifentanil consumption. Whereas propofol consumption was similar in both groups, consumption of remifentanil was higher in the dual-loop group (Tables 3 and 4, and Fig. 3). Similarly, remifentanil effect-site concentrations were higher in the dual-loop group both during the induction phase and during maintenance. We plan to modify the controller, gain constant and limits of remifentanil, to decrease remifentanil consumption. Comparison of drug consumption or drug concentration with other studies is difficult because of different populations: one-third had major surgery, and 15% had combined general anesthesia and regional block. Finally, high remifentanil consumption can be considered harmful if it increases the occurrence of adverse events such as hemodynamic instability or awareness. Our trial lacks power to determine the incidence of awareness. The third limitation is the number of dropouts (Fig. 2). Some were attributable to errors in the conduct of the study by the investigators, i.e., patients with neurological disorders, dilution, or drug errors. Prolonged artifacts of BIS cannot be attributed to our system unlike recording system failures and computer failure. All of these cases are explained by the use of a prototype device in a conventional personal computer with Windows XP as the directory operating system.
Other points must be discussed. We defined an induction phase as the delay between the beginning of drug infusion and BIS value ≤60 for 30 seconds. We chose such a definition to avoid the risk of human error at the appearance of a clinical sign such as loss of verbal contact and the risk of a modification of the hypnotic state caused by repeated patient stimulation. The period of 30 seconds was arbitrary but it is usual to see the BIS value oscillating around 50 after an initial abrupt decrease. A shorter period would not have been enough. Second, our study was unblinded, multicentered, and had many investigators. The relatively high number of investigators is a strength showing that the controller works in other hands than those of the inventors. However, it is also a weakness because several points of patient care were left to the usual practice of the investigators, making the comparisons between the groups imprecise. This is particularly true when discussing hemodynamic profiles, requirement for fluid or vasoactive drugs, and extubation. Third, we compared our controller against an anesthesiologist-based control; this methodology has been used to study a single BIS-propofol closed-loop controller.5–7,23 Other approaches could be proposed in case of a dual controller to clarify the interaction between drugs: comparison of the propofol-remifentanil closed-loop controller to a single closed loop of propofol with a continuous and fixed infusion at different targets of remifentanil, or with a continuous fixed infusion of propofol at different targets associated with a single remifentanil closed-loop controller guided by BIS. Finally, our aim was to compare the current closed-loop controller as a new method for drug administration, with manual TCI of propofol and remifentanil, a present-day practice.
In conclusion, electrocortical activity given by the BIS monitor allows computerized control of simultaneous propofol and remifentanil administration. Several improvements of the controller are required before trials on large populations to demonstrate that automated control of anesthetic delivery is a useful tool.
Conflict of Interest: Hôpital Foch, N. Liu, T. Chazot, and B. Trillat are patent holders in France for the gain constants and the control algorithm (No. BFF08P669, Institut National de la Propriété Industrielle, France).
Name: Ngai Liu, MD, PhD.
Conflicts of Interest: Dr. Liu is a patent holder in France for the gain constants and the control algorithm (No. BFF08P669, Institut National de la Propriété Industrielle, France).
Name: Thierry Chazot, MD.
Conflicts of Interest: Dr. Chazot is a patent holder in France for the gain constants and the control algorithm (No. BFF08P669, Institut National de la Propriété Industrielle, France).
Name: Sophie Hamada, MD.
Conflicts of Interest: None
Name: Alain Landais, MD.
Conflicts of Interest: None
Name: Nathalie Boichut, MD.
Conflicts of Interest: None
Name: Corinne Dussaussoy, MD.
Conflicts of Interest: None
Name: Bernard Trillat, MSc.
Conflicts of Interest: Dr. Trillat is a patent holder in France for the gain constants and the control algorithm (No. BFF08P669, Institut National de la Propriété Industrielle, France).
Name: Laurent Beydon, MD.
Conflicts of Interest: None
Name: Emmanuel Samain, MD.
Conflicts of Interest: None
Name: Daniel I. Sessler, MD.
Conflicts of Interest: None
Name: Marc Fischler, MD.
Conflicts of Interest: None
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In both groups, patients received total IV anesthesia in target-controlled infusion (TCI) mode using the Infusion Toolbox 95® version 4.11 software.15 Infusion Toolbox 95 is programmed in Visual Smalltalk, an object oriented language (VisualAge for Smalltalk® version 5.5; IBM, Armonk, NY). The software allows calculated plasma and effect-site concentrations (Ce) of propofol and remifentanil. The population pharmacokinetic sets of Schnider et al.13 and Minto et al.14 were selected for propofol and remifentanil, respectively. The software steers 2 Asena GH® infusion pumps (Alaris Medical UK Ltd., Basingstoke, Hampshire, UK). The Bispectral Index (BIS) electrodes were positioned on the forehead and connected to either an A-2000 XP (version 3.11) BIS monitor (Covidien, Mansfield, MA) or a BIS Module (Datex-Ohmeda™ S/5™, Helsinki, Finland). A standard personal computer running with Windows 98® or XP® (Microsoft, Redmond, WA) is used to provide a user interface, to store BIS, signal quality index, electromyographic (EMG) activity, and suppression ratio data every 5 seconds and to control communication via an RS232 serial port between the monitor and the 2 infusion pumps.
1. Main Elements of the Controller
The controller has a cascade structure including 2 proportional-integral-derivative (PID) controllers, each one having its own PID algorithm, and an interaction rule (Fig. 1). The controller includes 6 main elements:
- Calculation of the BISerror (difference between the set point of 50 and the actual unfiltered BIS value): it allows the titration until the target level of BIS = 50 is obtained. This parameter is calculated only if the signal quality index given by the monitor is >50%. New drug concentrations are calculated according to the “error” size and sign and to actual concentrations. The controller increases or decreases the drug concentrations according to the “error” sign (positive or negative). The “error” size determines which drug will be modified. If the BISerror is small, only the remifentanil is changed; if the BISerror is higher than a threshold, the 2 drug concentrations are changed. Finally, the 2 agents are continuously modified by the controller. The delay between each modification is shorter and the trigger threshold lower for the remifentanil than for the propofol. Consequently, the controller is more reactive for remifentanil.
- Amplification of the feedback (AFB): a specific AFB has been determined for each drug and for each BIS “error.” A new target is determined by the following equation, which corresponds to an integral controller:
The controller continuously modifies the target concentration until a BISerror = 0 is obtained. The new target is calculated by using the current target, which was determined by the previous BISerror. In fact, the controller sums the instantaneous errors over time (integrating the error every 5 seconds throughout the maintenance phase), giving the accumulated offset that should have been corrected previously. The new target calculated by the use of this accumulated error provides the PID integral action.
The values of the gain constants or K values for propofol and remifentanil are given in Table 1; these values were determined empirically using the simulator included in the Infusion Toolbox 95 software.
- Delay between each new modification of propofol or remifentanil concentration: it is determined by the time necessary for equilibration of the previous effect-site compartment given by the pharmacokinetic models (Fig. 1). For a given patient, the delay given by the pharmacokinetic model is constant. It depends especially on age. For propofol, the delay varies linearly between 96 seconds (20 years old) and 120 seconds (80 years old). For remifentanil, the delay varies nonlinearly between 80 seconds (20 years old) and 151 seconds (80 years old). Remifentanil delays were calculated using the simulator included in the Infusion Toolbox 95 software.15 An additional period of 60 seconds is added systematically during the maintenance phase.
- Feedforward, derivative term of PID algorithm: its 2 components, 1 for propofol and 1 for remifentanil, check the profile every 5 seconds and decide on a concentration correction proportionally to the BISerror. It is activated in 3 circumstances: (i) when the BIS is >62 (propofol component) or 60 (remifentanil component), (ii) when the slope of the BIS increases >15 (propofol component) or 10 (remifentanil component) in 10 seconds, and (iii) when the EMG activity is >37 dB (propofol component) or 35 dB (remifentanil component).
It is deactivated when the EMG is >42 dB for 1 minute, a figure related to an artifact. The derivative action has the priority for the decisions of concentration modifications. Furthermore, when the current propofol concentration is <1.3 μg · mL−1or the current remifentanil concentration is <4 ng · mL−1, default corrections (1.8 μg · mL−1 and 6 ng · mL−1, propofol and remifentanil, respectively) are performed to avoid a too small or not clinically relevant correction. The derivative action is inhibited during induction. Finally, during the maintenance phase, when the BIS or EMG limits are exceeded, then the propofol and remifentanil target concentrations are updated according to AFB.
- Interaction rule between propofol and remifentanil: if the controller increases the remifentanil concentration successively >3 times, then the controller increases the propofol concentration.
- Safety feature: the system automatically maintains the calculated drug concentrations in the case of controller or BIS dysfunction or low signal quality index (SQI <50). Furthermore, minimum and maximum (default values) of concentrations are set at 1 and 5 μg · mL−1 for propofol and at 3 and 12 ng · mL−1 for remifentanil during maintenance. The user can modify these values without limits.
2. Clinical Use of the Controller
All investigators were clinically experienced in the use of BIS to titrate propofol and remifentanil, and all received 2 days' training on the dual closed-loop controller at our center. The user enters the patient's demographic data (sex, age, weight, and height) and the initial propofol target concentration for induction. The controller decides the first remifentanil concentration related to initial propofol concentration: if the initial propofol target is <2.5 μg · mL−1, then the initial remifentanil target is 4 ng · mL−1; if the initial propofol target is between 2.5 and 2.9 μg · mL−1, then the initial remifentanil target is 5 ng · mL−1; if the initial propofol concentration is >3 μg · mL−1, then the initial remifentanil target is 6 ng · mL−1. The derivative action or feedforward is inhibited during induction. After the induction phase (i.e., BIS ≤60 for 30 seconds), the controller switches automatically to the maintenance phase. Throughout the procedure, the user can adjust the targets if necessary or switch between closed-loop and manual control.
3. Summary of the Controller
When starting a procedure, the clinician enters an initial target value of Ce for the propofol Ceprop (I) and the controller sets an initial target value of Ce for the remifentanil Ceremi (I):
- if Ceprop (I) < 2.5 μg · mL−1, then Ceremi (I) = 4.0 ng · mL−1
- if 2.5 μg · mL−1 < Ceprop (I) < 2.9 μg · mL−1, then Ceremi (I) = 5.0 ng · mL−1
- if Ceprop (I) > 3.0 μg · mL−1, then Ceremi (I) = 6.0 ng · mL−1
The following rules are used to update the new concentrations until BISerror = 0 is obtained:
where Ceprop (k) and Ceremi (m) are the new target of propofol or remifentanil, Ceprop (k − 1) and Ceremi (m − 1) are the current values of Ce, and BISerror is the difference between the current BIS value and 50. Table 1 gives the value for Kprop and Kremi as a function of the error BISerror.
A new target was updated after the time necessary for equilibration of the previous effect-site compartment given by the pharmacokinetic models. For a given patient, the delay given by the pharmacokinetic model is constant. It depends especially on age. The propofol delay varies linearly between 96 seconds (20 years old) and 120 seconds (80 years old).13 For remifentanil, the delay varies nonlinearly between 80 seconds (20 years old) and 151 seconds (80 years old).14 Remifentanil delays were calculated using the simulator included in the Infusion Toolbox 95 software.15 An additional period of 60 seconds is added systematically during the maintenance phase.
However, every 5 seconds a new correction is possible while the concentration between plasmatic and effect-site compartment is not in steady state, thanks to the derivative term if:
© 2011 International Anesthesia Research Society
- BIS >62, then Ceprop (k) is updated.
- BIS >60, then Ceremi (m) is updated.
- BISerror >15, then Ceprop (k) is updated.
- BISerror >10, then Ceremi (m) is updated.
- EMG >37 dB and EMG <42 dB, then Ceprop (k) is updated.
- EMG >35 dB and EMG <42 dB, then Ceremi (m) is updated. If none of the 6 conditions listed above are met, the previous actions or rules 1 and 2 are invoked. During the maintenance phase, which is the period after the induction phase (defined as the time from the start of propofol and remifentanil administration to BIS <60 during 30 seconds) until the end of drug administration, we have added a supplementary delay of 60 seconds between each concentration modification. Moreover, if Ceremi is updated 3 times in a row, then Ceprop is automatically updated once.