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Closed-Loop Delivery Systems Versus Manually Controlled Administration of Total IV Anesthesia: A Meta-analysis of Randomized Clinical Trials

Pasin, Laura MD; Nardelli, Pasquale MD; Pintaudi, Margherita MD; Greco, Massimiliano MD; Zambon, Massimo MD; Cabrini, Luca MD; Zangrillo, Alberto MD

doi: 10.1213/ANE.0000000000001394
Anesthetic Clinical Pharmacology: Systematic Review Article

Bispectral Index Scale (BIS)-guided closed-loop delivery of anesthetics has been extensively studied. We performed a meta-analysis of all the randomized clinical trials comparing efficacy and performance between BIS-guided closed-loop delivery and manually controlled administration of total IV anesthesia. Scopus, PubMed, EMBASE, and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocation to treatment and closed-loop delivery systems versus manually controlled administration of total IV anesthesia in any surgical setting. Exclusion criteria were duplicate publications and nonadult studies. Twelve studies were included, randomly allocating 1284 patients. Use of closed-loop anesthetic delivery systems was associated with a significant reduction in the dose of propofol administered for induction of anesthesia (mean difference [MD] = 0.37 [0.17–0.57], P for effect <0.00001, P for heterogeneity = 0.001, I 2 = 74%) and a significant reduction in recovery time (MD = 1.62 [0.60–2.64], P for effect <0.0001, P for heterogeneity = 0.06, I 2 = 47%). The target depth of anesthesia was preserved more frequently with closed-loop anesthetic delivery than with manual control (MD = −15.17 [−23.11 to −7.24], P for effect <0.00001, P for heterogeneity <0.00001, I 2 = 83%). There were no differences in the time required to induce anesthesia and the total propofol dose. Closed-loop anesthetic delivery performed better than manual-control delivery. Both median absolute performance error and wobble index were significantly lower in closed-loop anesthetic delivery systems group (MD = 5.82 [3.17–8.46], P for effect <0.00001, P for heterogeneity <0.00001, I 2 = 90% and MD = 0.92 [0.13–1.72], P for effect = 0.003, P for heterogeneity = 0.07, I 2 = 45%). When compared with manual control, BIS-guided anesthetic delivery of total IV anesthesia reduces propofol requirements during induction, better maintains a target depth of anesthesia, and reduces recovery time.

Supplemental Digital Content is available in the text.Published ahead of print August 2, 2016.

From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Published ahead of print August 2, 2016.

Accepted for publication March 31, 2016.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Laura Pasin, MD, Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132 Milan, Italy. Address e-mail to pasin.laura@hsr.it.

For decades, closed-loop control of anesthetic drug delivery has been a challenging topic to explore. As early as 1950, Mayo et al1 used electrocortical activity to automatically titrate intraoperative administration of ether during abdominal surgery. Since then, many signals have been used to guide automated titration of different anesthetic drugs in various surgical settings. Both spontaneous electroencephalogram and auditory evoked potential indices have been used in automated controlled anesthetics administration.2–9 The Bispectral Index Scale Monitor (BIS Monitor) has emerged as the most studied electroencephalographic monitor for closed-loop control of IV anesthetic drugs titration. Although researchers have published several randomized clinical trials (RCTs) comparing BIS-guided closed-loop with manually controlled delivery of IV anesthetics,10–21 no formal systemic review has yet explored differences in efficacy and performance. To that end, we performed a meta-analysis of RCTs comparing efficacy and performance between BIS-guided closed-loop and manually controlled delivery of total IV anesthesia (TIVA).

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METHODS

Search Strategy

Pertinent studies were independently searched in BioMedCentral, PubMed, EMBASE, and the Cochrane Central Register of clinical trials (updated April 15, 2015) by 4 investigators.

The full PubMed search strategy is presented in the supplemental material (Supplemental Digital Content, http://links.lww.com/AA/B425). We included any RCTs ever performed on BIS-guided closed-loop anesthetic delivery systems compared with manually controlled administration of TIVA, both manually administered TIVA and target-controlled infusion (TCI), in any surgical setting. In addition, we scanned references of retrieved articles and pertinent reviews to identify studies missed with our initial search strategy that may have been published in other languages.

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Study Selection

References were first independently examined at a title/abstract level by 4 investigators, with divergences resolved by consensus, and then, if potentially pertinent, retrieved as complete articles. The following inclusion criteria were used for potentially relevant studies: random allocation to treatment (any BIS-guided closed-loop anesthesia drug delivery system versus any manually controlled administration of propofol); studies including adult patients; studies performed in any surgical setting. The exclusion criteria were as follows: duplicate publications (in this case, we referred to the first article published while we retrieved data from the article with the longest follow-up available), nonadult patients, and lack of data on all of the following: induction time, induction dose of propofol (milligram per kilogram), recovery time (seconds), dose of administered propofol (milligram per kilogram per hour), Global Score,16 time of maintenance of mean arterial blood pressure (MAP) and heart rate (HR) within 25% of baseline, lowest BIS value after induction of anesthesia, percent decline in MAP from baseline after induction and anesthesia, and number of epinephrine boluses. Two investigators independently assessed compliance to selection criteria and selected studies for the final analysis, with divergences resolved by consensus.

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Data Abstraction and Study Characteristics

Data were independently abstracted by 4 investigators.

The primary end points of the present review were the evaluation of efficacy and performance of closed-loop IV anesthesia delivery systems. Efficacy was defined as the capability to maintain the BIS value as near as possible to the anesthesiologist’s target value by administering the lowest necessary dose of propofol and allowing a shorter induction and recovery time. Therefore, efficacy was evaluated by considering the following variables: induction time, induction dose of propofol, recovery time (minutes), total dose of administered propofol, and maintenance of BIS value ±10% of target value. Performance was defined as the presence of a low Global Score. It includes the median absolute performance error, the wobble index, and the fluctuation of BIS (the percentage of time of preset adequate anesthesia with BIS usually between 40 and 60). It can be calculated using the formula:

The performance error can be defined as the difference between actual and desired values (ie, measured and calculated propofol concentrations). The wobble index is used for measuring the intrasubject variability in performance error. Excellent controller performance ensures a low median absolute performance error and a low wobble index. Because anesthesia literature does not provide a definitive guideline for clinically suitable control of propofol-induced hypnosis, some reasonable performance goals can be assumed by 2 studies on this topic.11,22 According to the published literature, a Global Score between 20 and 50 and a median absolute performance error between 10 and 20 can be considered clinically acceptable.

Secondary end points were the differences between closed-loop and manual anesthetic delivery groups in duration of maintaining MAP and HR within 25% of baseline, percentage decrease in MAP from baseline within 10 minutes after induction, low BIS values during anesthesia induction (first 5 minutes after induction), total dose of intraoperative ephedrine, and maintenance of BIS values within 10% of the target value.

Subanalyses were performed in the following groups of studies: (1) studies in which the control group received manually administered TIVA, (2) studies in which control group received TCI of propofol, and (3) studies in which the mean age of included patients was less than or more than 55 years. Further subanalyses were performed based on the infusion device used and the type (cardiac) and location of surgical procedures (ambulatory surgery setting).

Because the effectiveness of TCI propofol compared with manually administered TIVA remains controversial, subanalyses were performed including only studies in which the control group received TIVA and studies in which the control group received TCI to evaluate whether closed-loop delivery systems were superior to TIVA and/or TCI administration of propofol. Moreover, to better understand whether the different surgical stimuli had any impact on devices’ performance, subanalyses on the different surgical procedures (cardiac surgery, minor/major surgery, and ambulatory procedures) were performed. Further subanalyses were performed on the different devices used to evaluate whether one device/algorithm was superior to others.

The internal validity and risk of bias of all trials included in this analysis were appraised by 2 independent reviewers according to the latest version of the “Risk of Bias Assessment Tool” developed by The Cochrane collaboration,23 with divergences resolved by consensus. Publication bias was assessed by visually inspecting funnel plots.

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Data Analysis and Synthesis

Computations were performed with Review Manager version 5.2 (Cochrane, London, UK). Hypothesis of statistical heterogeneity was tested by means of Cochran Q test, with statistical significance set at the 2-tailed 0.10 level, whereas extent of statistical consistency was measured with I 2, defined as 100% × (Q − df)/Q, where Q is Cochran heterogeneity statistic and of the degrees of freedom. Binary outcomes from individual studies were analyzed to compute individual and pooled risk ratio with pertinent 99% confidence interval, by means of inverse variance method and with a fixed-effects model in case of low statistical inconsistency (I 2 < 25%) or with a random-effects model (which better accommodates clinical and statistical variations) in case of moderate or high statistical inconsistency (I 2 > 25%). Mean differences (MDs) and 99% confidence intervals were computed for continuous variables using the same models as just described. To evaluate whether the small study effect had an influence on the treatment effect estimate, in case of evidence of between-study heterogeneity (I 2 > 25), we compared the results of both fixed and random-effects models. Sensitivity analyses were performed by sequentially removing each study and reanalyzing the remaining data set (producing a new analysis for each study removed).

Statistical significance was set at the 2-tailed 0.01 level for hypothesis testing. Unadjusted P values are reported throughout. This study was performed in compliance with The Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.23–25

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RESULTS

Study Characteristics

Database searches, snowballing (ie, scanning of references of retrieved articles and pertinent reviews), and contacts with experts yielded 313 articles. Two hundred ninety-five articles were excluded based on titles or abstracts that were not pertinent (Figure 1). Of the 19 remaining studies, 7 were excluded based on our prespecified exclusion criteria: 1 because both groups received close-loop anesthesia,26 1 because it was retracted,27 1 because data were collected in the postoperative period,28 2 because they were performed in nonadult patients,29,30 1 because propofol was titrated in the control group to hemodynamic variables instead of BIS, and 1 because propofol in the closed-loop group was titrated to hemodynamic variables instead of BIS.6

Figure 1

Figure 1

The remaining 12 articles randomly allocating 1284 patients, 642 to closed-loop and 642 to manual or target-controlled anesthetic delivery (Table 1). Study quality appraisal indicated that trials were of medium quality (Supplemental Digital Content, Supplemental Table 1, http://links.lww.com/AA/B425); in particular, 5 of them had a low risk of bias11,17,18,20,21 and 4 were multicentric.15,16,18,21

Table 1

Table 1

Table 2

Table 2

Clinical heterogeneity was primarily because of surgical setting, the types of closed-loop device, and the method of propofol administration in the control group (Tables 1 and 2; Supplemental Digital Content, http://links.lww.com/AA/B425). One trial was performed in a cardiac surgery setting,10 1 during gynecologic procedures,11 1 during elective vascular and thoracic surgery,12 3 in major surgery,13,18,21 and 6 during both major and minor elective surgical procedures.14–17,19,20 Different closed-loop delivery systems were used. The closed-loop delivery systems identified in our analysis are presented in Table 1. Control groups received manually controlled TIVA in 7 trials10,13,14,18–21 and TCI in 5 trials (Table 2).11,12,15–17

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Quantitative Data Synthesis

Primary End Points

Evaluation of Efficacy:

The overall analysis showed that the use of closed-loop anesthetic delivery systems was associated with a significant reduction in the dose (milligram per kilogram) of propofol administered for anesthesia induction and a significant reduction in recovery time (minutes; Figure 2 and Table 3; Supplemental Digital Content, Supplemental Figure 1, http://links.lww.com/AA/B425). Results were both confirmed in subanalysis including studies in which the control group received manually administered TIVA and in studies including patients with mean age of <55 years. (Table 3) Results were both confirmed even excluding studies performed in cardiac surgery and ambulatory care setting (Table 3).

Table 3

Table 3

Figure 2

Figure 2

Moreover, desired anesthesia target (BIS value ±10% of preset) was maintained more frequently in the closed-loop anesthetic delivery systems group than in control groups (MD = −15.17 [−23.11 to −7.24], P for effect <0.00001, P for heterogeneity <0.00001, I 2 = 83% with 8 studies and 828 patients included; Supplemental Digital Content, Supplemental Figure 2, http://links.lww.com/AA/B425). Results were confirmed in all performed subanalysis (Table 3).

No differences in time (seconds) to anesthesia induction and total dose (milligram per kilogram per hour) of administered propofol were recorded (Figure 3, Table 3; Supplemental Digital Content, Supplemental Figure 3, http://links.lww.com/AA/B425).

Figure 3

Figure 3

Visual inspection of the funnel plot did not identify a skewed or asymmetrical shape, excluding the presence of publication bias (Supplemental Digital Content, Supplemental Figures 4–6, http://links.lww.com/AA/B425). Results were confirmed by sensitivity analyses.

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Evaluation of Performance.

The overall analysis showed that closed-loop anesthetic delivery systems were associated with a significantly improved performance when compared with manually controlled administration of TIVA. In fact, both median absolute performance error and wobble index were significantly lower in closed-loop anesthetic delivery systems groups (MD = 5.82 [3.17–8.46], P for effect <0.00001, P for heterogeneity <0.00001, I 2 = 90% with 9 studies and 1038 patients included for median absolute performance error and MD = 0.92 [0.13–1.72], P for effect = 0.003, P for heterogeneity = 0.07, I 2 = 45% with 9 studies and 1038 patients included for wobble index, respectively, Figure 4 and Table 3; Supplemental Digital Content, Supplemental Figure 7, http://links.lww.com/AA/B425).

Figure 4

Figure 4

Results were confirmed in subanalysis including studies in which the control group received TIVA, in studies using the CLADS™ device, and in studies performed in a general surgical setting and in younger patients (Table 3).

Accordingly, closed-loop anesthetic delivery systems were associated with a low Global Score (MD = 0.60 [0.41–0.79], P for effect <0.00001, P for heterogeneity = 0.38, I 2 = 2% with 4 studies and 798 patients included; Figure 5).

Figure 5

Figure 5

Visual inspection of the funnel plot did not identify a skewed or asymmetrical shape, excluding the presence of publication bias (Supplemental Digital Content, Supplemental Figures 4–6, http://links.lww.com/AA/B425). Results were confirmed at sensitivity analysis.

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Secondary End Points.

When compared with closed-loop anesthetic delivery systems, manually controlled administration of TIVA was associated with significantly lower BIS values during induction of anesthesia (MD = −5.86 [−8.14 to −3.58], P for effect <0.00001, P for heterogeneity = 0.60, I 2 = 0% with 4 studies and 366 patients included; Figure 6).

Figure 6

Figure 6

No differences in maintenance of MAP and HR within 25% of baseline and percentage of decrease in MAP from baseline after anesthesia induction were recorded (Table 3). The use of epinephrine boluses was similar between groups (Table 3).

Visual inspection of the funnel plot did not identify a skewed or asymmetrical shape, excluding the presence of publication bias. Results were confirmed at sensitivity analysis.

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DISCUSSION

Our most important findings were that closed-loop anesthetic delivery systems, when compared with manually controlled administration, especially TIVA, (1) were associated with a significant reduction in propofol dose required for induction of anesthesia and reduction in recovery times, (2) more precisely maintained preestablished target BIS values with higher performance scores, and (3) were associated with significantly lower BIS values during anesthesia induction.

No differences were observed between groups in the maintenance of MAP and HR within 25% of baseline and percentage of decrease in MAP from baseline after induction of anesthesia with propofol. The available data did not allow us to determine the safety of closed-loop anesthetic delivery systems, when compared with manually controlled administration of propofol. In addition, available data exploring differences in outcomes between different surgical settings, patients’ age, and devices used did not permit us to draw conclusions regarding these important subsets of patients.

In addition, our analysis showed that closed-loop control systems allow induction of anesthesia in comparable times to manually controlled propofol delivery while giving less drug. These results were achieved, even though both the closed-loop and control groups started with the same propofol concentration.

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Clinical Implications

Although the subtle advantages of closed-loop delivery to maintain a target BIS value may not be evident to practicing anesthesiologists, decreasing the percentage of time with BIS > 60 might help to reduce the risk of awareness.

Moreover, reducing the workload of anesthesiologists with an automated system could have clinical significance by leaving anesthesiologists more time to control hemodynamics, to manage the airway and ventilation, and to be even more attentive to the surgical procedure and the assessment of blood loss, etc.

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Limitations

Our analysis included several limitations. Our study included few, small, medium-quality RCTs with high heterogeneity. Moreover, although statistically significant, the small reduction in the dose of propofol administered could have limited clinical implications. Another limitation was that none of the studies included in our analysis provided data on relevant outcomes such as postoperative cognitive dysfunction, delirium, major morbidity, and/or mortality. Another limitation was that even though the anesthesiologists responsible for assessing the tracheal extubation criteria were blinded to group assignment in most of the trials and followed strict extubation criteria, assessment of readiness for extubation remains subjective, and differences in recovery time should be interpreted with caution. Moreover, it is important to recognize that BIS values are difficult to interpret in the presence of propofol combined with an opioid because higher BIS values may be well tolerated in the presence of high-dose opioids. A final limitation was that it is important to recognize that results from each RCT were limited and highly dependent on the controller algorithms used.

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CONCLUSIONS

In conclusion, our analysis supports the notion that closed-loop delivery of propofol as a TIVA is superior to manually controlled delivery. By contrast, our results do not provide a clinically relevant advantage of closed-loop propofol delivery when compared with TCI. The efficacy of the 2 techniques is similar. Large, multicenter RCTs are warranted to confirm these promising results. Based on the limitation of the data available for our analysis, future work in the following areas is desirable: (1) short-term and long-term outcomes such as postoperative cognitive dysfunction, (2) special populations such as the elderly and obese, (3) different surgical settings such as cardiac, neuro, and ambulatory surgery, and (4) an assessment of the performance of the various algorithms (ie, single or dual-control loops) and available closed-loop feedback monitors (ie, analgesia and hypnosis monitors).

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DISCLOSURES

Name: Laura Pasin, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Name: Pasquale Nardelli, MD.

Contribution: This author helped conduct the study and write the manuscript.

Name: Margherita Pintaudi, MD.

Contribution: This author helped analyze the data and write the manuscript.

Name: Massimiliano Greco, MD.

Contribution: This author helped analyze the data and write the manuscript.

Name: Massimo Zambon, MD.

Contribution: This author helped design the study and write the manuscript.

Name: Luca Cabrini, MD.

Contribution: This author helped analyze the data and write the manuscript.

Name: Alberto Zangrillo, MD.

Contribution: This author helped design the study and write the manuscript.

This manuscript was handled by: Ken B. Johnson, MD.

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