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Anesthesia & Analgesia:
doi: 10.1213/ANE.0000000000000185
Anesthetic Pharmacology: Research Report

Dexmedetomidine Reduces Propofol and Remifentanil Requirements During Bispectral Index-Guided Closed-Loop Anesthesia: A Double-Blind, Placebo-Controlled Trial

Le Guen, Morgan MD*†; Liu, Ngai MD, PhD*†‡; Tounou, Felix MD§; Augé, Marion MD*; Tuil, Olivier MD*; Chazot, Thierry MD*; Dardelle, Dominique Pharm D; Laloë, Pierre-Antoine MD; Bonnet, Francis MD§#; Sessler, Daniel I. MD**; Fischler, Marc MD*†

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Author Information

From the *Department of Anesthesiology, Hôpital Foch, Suresnes, France; UVSQ—UFR des Sciences de la Santé Simone Veil, Montigny-le-Bretonneux, France; Outcomes Research Consortium, Cleveland, Ohio; §Department of Anesthesiology and Intensive Care, Hôpital Tenon, Paris, France; Pharmacy, Hôpital Foch, Suresnes, France; Department of Anesthesiology, Leeds General Infirmary, Leeds, United Kingdom; #UPMC, Paris, France; and **Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio.

Funding: Support was provided by the Service d’Anesthésie, Hôpital Foch, Suresnes, France.

Conflicts of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Marc Fischler, MD, Department of Anesthesiology, Hôpital Foch, 40 Rue Worth, 92151 Suresnes, France. Address e-mail to m.fischler@hopital-foch.org.

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Abstract

BACKGROUND: The α2-adrenergic agonist dexmedetomidine is a sedative and can be used as an adjunct to anesthetics. Our primary goal was thus to determine the extent to which dexmedetomidine reduces the requirement for propofol and remifentanil.

METHODS: This double-blinded, randomized study (NCT00921284) used an automated dual closed-loop administration to maintain the Bispectral Index between 40 and 60. Sixty-6 ASA physical status I and II patients were given either dexmedetomidine (1 μg/kg over 10 minutes followed by a continuous infusion of 0.5 μg/kg/h throughout surgery) or comparable volumes of saline as a placebo. Propofol and remifentanil requirements were compared using nonparametric tests and expressed as medians (interquartile ranges).

RESULTS: Twenty-eight patients in each group completed the study. Patients given dexmedetomidine required less propofol (1.0 [0.7–1.3] vs 1.3 [1.0–1.7] mg/kg, P = 0.002) and remifentanil (1.2 [1.0–1.4] vs 1.6 [1.1–2.8] μg/kg, P = 0.02) for anesthetic induction. The propofol dosage required for anesthetic maintenance was 29% (with a 95% confidence interval, 18–40) lower in patients given dexmedetomidine (2.2 [1.5–3.0] vs 3.1 [2.4–4.5] mg/kg/h, P = 0.005), whereas the remifentanil dosage was not significantly different (0.16 [0.09–0.17] vs 0.14 [0.13–0.21] μg/kg/h with P = 0.3). The incidence of adverse events, including hemodynamic instability and delayed recovery, was comparable with and without dexmedetomidine. The first postoperative request for morphine analgesia was delayed in patients given dexmedetomidine (median fourth hour vs first hour, P = 0.008).

CONCLUSIONS: Dexmedetomidine administration significantly reduced the requirement for both propofol and remifentanil during anesthetic induction and reduced propofol use during maintenance of anesthesia. Dexmedetomidine also delayed postoperative analgesic use. Dexmedetomidine is a useful adjuvant that reduces anesthetic requirement and provides postoperative analgesia.

Dexmedetomidine is a selective α2-adrenergic agonist that can be considered a primary anesthetic,1–3 an adjunct to propofol or volatile anesthetics, or a substitute for opioids.

Several studies have reported a dexmedetomidine–propofol pharmacodynamic interaction, leading to a reduction in the propofol dosage required for sedation in healthy subjects,4 in patients having superficial surgery,5 in lower abdominal surgery with intraoperative epidural analgesia,6 and during spine surgery.7 Dexmedetomidine also reduced the amount of isoflurane needed to prevent a response to tetanic stimulation in volunteers,8 to maintain a Bispectral Index (BIS) near 45 during abdominal surgery,6 and the amount of desflurane needed for laparoscopic bariatric surgery.9 Dexmedetomidine can replace opioids, thus decreasing the incidence of postoperative respiratory depression, especially after supratentorial craniotomy10 and gastric bypass surgery.9

Other potential benefits of systemic α2-adrenergic agonists are improved analgesia, reduced opioid use, and reduced postoperative nausea as reported recently in a systematic review and meta-analysis of randomized controlled trials.11 That analysis did not report adverse intraoperative hemodynamic effects of dexmedetomidine because there were too few suitable studies; however, there are numerous reports of hemodynamic complications associated with α2-adrenergic agonists including several cases of cardiac arrest.12

Blaudszun et al.11 suggested that α-2 agonists produce a hypnotic-sparing effect without prolonging recovery; however, previous studies have been based on drugs dosaged by clinicians in response to general guidelines, often hemodynamic, rather than objectively evaluating hypnotic requirement. None has been strictly based on objective measures of anesthetic need. BIS provides a simple measure of anesthetic depth through analysis of electrocortical activity.13 Moreover, some studies performed during steady-state hypnosis with standardized nociceptive stimuli and various opioid dosages suggest that BIS variation indicates inadequate analgesia.14,15

Automated titration of propofol and remifentanil with a dual-loop controller maintains BIS values between 40 and 60 better than manual control during routine cases.16 The system, based on a Proportional-Integrative-Derivative algorithm, automates anesthetic administration and is thus independent of clinicians and investigators. As such, it is an ideal way to quantify the anesthetic-sparing effect of an adjuvant such as dexmedetomidine.

We therefore used a dual closed-loop algorithm guided by BIS to quantify the sparing effects of intraoperative dexmedetomidine on propofol and remifentanil requirements. Specifically, we tested the primary hypothesis that dexmedetomidine decreases dual-loop administration of propofol and remifentanil drugs during both induction and maintenance of general anesthesia. We simultaneously evaluated the effects of dexmedetomidine on intraoperative hemodynamic responses, postoperative analgesia, and postoperative nausea and vomiting.

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METHODS

This randomized, double-blind, placebo-controlled clinical trial was approved by an Institutional Ethics Committee (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale, Hôpital A. Paré, N°081282, Boulogne Billancourt, France) and the relevant French regulatory office (Agence Française de Sécurité Sanitaire des Produits de Santé) and registered on ClinicalTrials.gov (NCT00921284). Patients scheduled for nonhemorrhagic elective surgery with ASA physical status I and II who gave written informed consent preoperatively were recruited. Exclusion criteria were as follows: (1) age <18 years; (2) allergy to an α2-adrenergic agonist or to one of the anesthetic agents used during the study (propofol, remifentanil, atracurium, or morphine); (3) neurological, cardiovascular, or hepatic comorbidity; (4) treatment with psychotropic medication or an opioid agonist or antagonist in the 24 hours before surgery; (5) hypovolemia suspected from the medical history or by arterial hypotension at baseline; (6) any cardiovascular treatment, including antihypertensive medications; and (7) planned intraoperative use of regional analgesia.

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Protocol

Patients were allocated 1:1 without stratification to dexmedetomidine or saline placebo in blocks of 4 by a Web-based computer system that was accessed just before induction of anesthesia. Dexmedetomidine (100 μg/mL) and isotonic saline placebo were supplied by the Orion Corporation (FI-02101 Espoo, Finland) in identical 2-mL ampules. The study drug was diluted by the anesthesiologist in charge of the patient with 98 mL normal saline. The final concentration of dexmedetomidine was thus 2 μg/mL and was given as a bolus of 1 μg/kg administered over 10 minutes followed by a continuous infusion of 0.5 μg/kg/h until skin closure. A comparable volume of saline was given to patients assigned to placebo. Investigators, attending anesthesiologists, operating room, recovery, and ward nurses, surgeons, and patients were all blinded to treatment allocation.

Patients were admitted to the operating room with the attending anesthesiologist and a nurse anesthetist. No premedication was given. In the operating room, health care providers were instructed to keep the patient calm and to avoid any unnecessary noise. Patients were covered with a forced-air blanket before and during anesthetic induction. The bolus dosage of isotonic saline or dexmedetomidine was started after baseline measurements of heart rate, mean arterial blood pressure, SpO2, and BIS. After the 10-minute bolus infusion of study drug, anesthetic induction was performed by a closed-loop BIS-guided system that coadministers propofol and remifentanil. Clinicians and investigators were able to override the automated system if necessary or to switch between closed-loop and manual control.

The controller was implemented using Infusion Toolbox 95® version 4.11 software17 (ULB, Brusselss, Belgium) that served as a platform: (1) to provide a user interface to key in patient’s demographic data (sex, age, weight, and height); (2) to calculate effect-site concentrations using the model of Schnider et al.18 for propofol and the model of Minto et al.19 for remifentanil; (3) to steer the propofol and remifentanil infusion pumps (GH infusion pumps, Alaris Medical UK Ltd., Basingstoke, United Kingdom); (4) to display the calculated effect-site concentration in real time; and 5) to continuously record BIS, calculated effect-site concentrations, and hemodynamic data (heart rate and blood pressure) at 5-second intervals.

The controller has previously been described in detail.16 Briefly, it has a dual proportional-integral-derivative algorithm for the administration of propofol and remifentanil. The input variable is the BIS value, whereby the system titrates propofol and remifentanil infusions to maintain the BIS between 40 and 60. The first effect-site concentration of propofol was between 3 and 5 μg/mL chosen by the anesthesiologists as they do during routine care.

A remifentanil effect-site concentration was automatically determined for each first effect-site concentration of propofol to limit the number of initial propofol-remifentanil combinations. The corresponding volumes were infused as a bolus (i.e., at the maximal speed infusion). Every 5 seconds throughout anesthesia, the controller calculated the “error,” that is, the difference between the measured BIS and the set point (BIS = 50). 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; a small error leads to a change of remifentanil target only, and a large error leads to a change of both drug concentrations (propofol and remifentanil).

The minimal interval between 2 consecutive controls is equal to the time to peak effect of each drug in its pharmacokinetic model. This time interval is shorter for remifentanil than for propofol, thus remifentanil modifications are performed more frequently than propofol modifications. To ensure safety of the system, minimal and maximal effect-site concentrations are set at 1 and 5 μg/mL for propofol and at 3 and 12 ng/mL for remifentanil during maintenance.

Atracurium, used to facilitate tracheal intubation and surgery, was administered after testing manual ventilation as soon as the set point (BIS, 50) was reached. Patients’ lungs were ventilated with 40–60% oxygen in air.

Hemodynamic alterations were treated per protocol. Specifically, atropine was given when the heart rate was <45 bpm; esmolol was given when the heart rate exceeded 140 bpm; ephedrine (6–12 mg) followed, if necessary, by phenylephrine (100 μg) when blood pressure was <70% of the preinduction value; and nicardipine (titration of 1 mg every 10 minutes) when systolic blood pressure exceeded 150 mm Hg. Each of the clinicians involved in this study have several years experience with the dual-loop controller.

Morphine 0.1 mg/kg and paracetamol 1 g were given IV 45 minutes before the anticipated end of surgery. On completion of surgery, patients were given neostigmine 0.4 mg/kg if necessary to achieve a T4/T1 ratio >0.9. Propofol and remifentanil infusions were stopped at this time. Tracheal extubation was performed immediately after recovery from anesthesia.

Patients were transferred to the postanesthesia care unit (PACU) for 6 hours of postoperative observation and care. Pain was recorded using a numeric rating scale from 0 (no pain) to 10 (worst pain). When pain scores exceeded 3, 5 mg of IV morphine was given, followed as necessary by 2.5 mg boluses at 5-minute intervals. Patients were then given a patient-controlled analgesia delivery system providing IV morphine, 1 mg boluses with a 7-minute lockout interval. IV ondansetron 4 mg was given if necessary for nausea or vomiting.

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Measurements

Standard monitoring was applied including electrocardiography, noninvasive or invasive blood pressure measurements as preferred by the attending anesthesiologist, pulse oximetry, adductor pollicis strength (AS/5 Datex-Ohmeda S/5 monitor, Helsinki, Finland), and BIS (A-2000 XP version 3.11, Aspect Medical System, Newton, MA). Before induction and from administration of the bolus dosage onward, heart rate and blood pressure were recorded at 5-minute intervals and BIS at 5-second intervals.

Intraoperative data (i.e., data from the AS/5 and BIS monitors, data from the Infusion ToolBox 95) were stored in real time on a standard personal computer running with Windows 98 (Microsoft, Redmond, WA) via RS232 serial ports. Calculated effect-site concentrations of propofol and remifentanil, BIS values, and burst suppression ratio (the fraction of electroencephalogram [EEG] detected as isoelectric by the BIS monitor) were recorded at 5-second intervals. These data were split into 2 consecutive periods: induction and maintenance. Anesthetic induction was defined as the time from starting propofol and remifentanil administration until BIS was <60 for at least 30 seconds; the maintenance period lasted from this point until the end of propofol and remifentanil administration. The interval from discontinuation of IV anesthetic drugs to tracheal extubation was recorded.

Heart rate, blood pressure, and pulse oximetry were recorded in the PACU every 15 minutes for 6 hours postoperatively. Time to the first rescue analgesic request was recorded, and the numerical pain score (from 0 for no pain to 10 for the worst imaginable pain) was noted hourly at rest and at mobilization defined as a substantial coughing effort or getting out of bed, effort depending on the surgical procedure and the patient’s ability. The White-Song recovery score20 was recorded hourly until full scoring was achieved. “Ready for discharge” time was defined as the period between discontinuation of anesthetic drugs and achievement of a White-Song score of at least 10. Complications during the initial 6 postoperative hours were recorded, including nausea, vomiting, hemodynamic instability, and desaturation or apnea.

A standardized interview by an anesthesiologist not involved in the study was performed in the PACU and on the third postoperative day to detect explicit memory during anesthesia and to assess the quality of recovery. This questionnaire explored domains including pain, noise, and the sensation of intraoperative paralysis.21

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Statistical Analysis

The number of patients to be included was estimated from the average propofol dosage required for maintenance of anesthesia (4.7 ± 1.6 mg/kg/h) when using manual propofol and remifentanil target-controlled infusion.16 Our study was designed to provide 90% power for detecting a 30% decrease of the propofol dosage among patients given dexmedetomidine, with a bilateral α risk value of 0.05. We thus planned to recruit 66 patients.

Data are expressed as means ± SDs or medians (with interquartile ranges), percentage (with 95% confidence interval [CI]), and number (n) when appropriate. For continuous variables, except for postoperative longitudinal data, Student t test (with Aspin-Welch correction for degrees of freedom) was used for between-group comparison. Wilcoxon test was used for paired comparison. For categorical variables, χ2 test and Fisher exact test were used. For longitudinal data, an analysis of variance with generalized linear models fitted on aligned ranks with treatment arms, hour and hour × treatment interaction terms. This allows for pairwise testing if significant differences are present.

P < 0.05 was considered statistically significant. Bonferroni corrections were performed for variables with multiple comparisons over time (i.e., generalized linear models for repeated measures on aligned ranks with treatment arms scores for Numerical Rating Scale at rest or at mobilization). Details of the individual tests are provided as notes in the tables. Statistical analyses were performed using SPSS version 11.0 (SPSS Science Inc., Chicago, IL) and R 2.12.0 (The R Foundation for Statistical Computing, Wien, Austria).

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RESULTS

Seventy patients were screened for eligibility, and 66 were subsequently allocated to saline or dexmedetomidine groups. Complete preoperative and postoperative data were available for analysis in 28 patients per group (Fig. 1). Demographic and surgical characteristics were comparable (Table 1). Laparoscopic procedures were 40% of the whole sample.

Table 1
Table 1
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Figure 1
Figure 1
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Dexmedetomidine and saline boluses were associated with decreased BIS values (P = 0.001); these values did not differ significantly at the end of the infusion (Table 2, Fig. 2).

Table 2
Table 2
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Figure 2
Figure 2
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Figure 3 shows the progression of BIS and estimated effect-site concentrations of propofol and remifentanil. BIS values were similar in each group, as were the percentages of patients whose BIS value was <40 or in burst suppression (Tables 3 and 4).

Table 3
Table 3
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Table 4
Table 4
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Figure 3
Figure 3
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Anesthetic induction was quicker in patients randomized to dexmedetomidine infusion (156 [123–361] seconds compared with 240 [144–360] seconds) (P = 0.003), and they required 23% less propofol (95% CI, 8–38, P = 0.002) and 25% less remifentanil (95% CI, 9–41, P = 0.02) (Table 3). During maintenance of anesthesia, the same patients required 29% less propofol with 95% CI, 11–40 (2.2 [1.5–3.0] vs 3.1 [2.4–4.5] mg/kg/h, P = 0.005) but comparable amounts of remifentanil. The between-groups ratio of propofol and remifentanil requirements expressed in weight dosages was significantly different during induction: 0.7 [0.5–0.8] in the saline group and 0.9 [0.7–1.1] in the dexmedetomidine group (P = 0.02). This ratio was also different during maintenance: 48 [39–52] and 50 [41–60] (P = 0.04) (Fig. 4). Time to tracheal extubation was similar in each group (Table 4).

Figure 4
Figure 4
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Postoperative morphine use was significantly delayed in patients given dexmedetomidine, with the initial request being a median of 4 hours versus only 1 hour in patients given saline. A White-Song score >10 was quickly achieved in both groups, with 75% of the patients having that score by the end of the first postoperative hour (Fig. 5). Pain scores at rest (interaction term, P = 0.48) or at mobilization (P = 0.54) were similar during the first 6 postoperative hours (Table 5, Fig. 6).

Table 5
Table 5
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Figure 5
Figure 5
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Figure 6
Figure 6
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The amount of ephedrine required in each group was similar both during induction and maintenance of anesthesia (Table 6). Postoperative shivering, pruritus, and nausea and vomiting occurred at comparable rates in each group. Manual intervention of the practitioner on the closed-loop system occurred only once in each group: 1 [0–2] vs 1 [0–2] (P = 0.83). No patient reported intraoperative awareness with explicit recall.

Table 6
Table 6
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DISCUSSION

The effects of a continuous administration of dexmedetomidine on propofol and remifentanil requirements were measured using a dual closed-loop system guided by BIS.16 Therefore, adding any drug, dexmedetomidine, or any factor, patient comorbidities, that modified the depth of anesthesia would indirectly interact with propofol and/or remifentanil administration. Because the automated controller determines anesthetic dosing independently from the anesthesiologist, it is unbiased by clinician preferences. The dual-loop controller is thus a reproducible method for titrating anesthetic drugs, although anesthetic use is obviously related to the gain constants of the controller. The effect of dexmedetomidine on propofol and remifentanil use may thus have differed with alternative approaches such as titration to clinical end points, particularly during surgical procedures not requiring paralysis, or use of a single closed-loop control of consciousness using propofol.

A relatively low-dosage intraoperative dexmedetomidine infusion (bolus of 1 μg/kg then a continuous administration of 0.5 μg/kg/h) significantly reduced the propofol induction dosage by 30% and remifentanil by 25%. The maintenance propofol requirement was also reduced by 29%, although the remifentanil requirement was not. A similar hypnotic-sparing effect has been reported with volatile anesthetics.6,8,9 Two studies in children and adolescents2,22 reported a similar effect on propofol during maintenance, but no previous study has specifically quantified this effect in adults.

The lack of a remifentanil-sparing effect during maintenance of anesthesia possibly results from the potency of remifentanil. Ngwenyama et al.2 described similar results in adolescents during spine surgery with posterior spinal fusion. The controller has a predominantly analgesic balance to counteract surgical stimulation. Nevertheless, this was not associated with high consumption of remifentanil since the average remifentanil dosage during maintenance was only 0.22 ± 0.07 μg/kg/h in our dual-loop controller which is well within Food and Drug Administration practical guidelines that suggest infusion rates of 0.1 to 0.5 μg/kg/h.a Divergent effects between propofol- and remifentanil-sparing effects are unsurprising since dexmedetomidine is more sedative than analgesic and are consistent with previous studies performed on volunteers4 and patients.2,5–7 Finally, our results are due to the combination of dexmedetomidine and the gain constants of the controller.

Recovery times were not prolonged by dexmedetomidine administration, which is consistent with the results of Blaudszun et al.11 Indeed, we found that: (1) tracheal extubation was performed in the operating theater in all patients and (2) White-Song scores were high and similar in each group. These results are consistent with those of a study on bariatric surgery.23 Despite comparable recovery speeds, the initial request for analgesia was significantly delayed in patients given dexmedetomidine, suggesting an analgesic profile.

Prolonged analgesia is consistent with the study by Arain et al.24 that also observed delayed analgesia, with more than half of the dexmedetomidine-treated patients requiring no additional analgesia an hour after admission to the PACU. The most obvious explanation for prolonged analgesia, as suggested by Arain et al.,24 is that dexmedetomidine has a half-life of approximately 2 hours and thus remained pharmacologically active well after the infusion was terminated at the end of anesthesia. They observed a significant 66% reduction in postoperative morphine requirements whereas we did not, probably because many of our procedures were laparoscopic and thus required only modest amounts of morphine early in recovery. Reduction in morphine requirements during the 6-hour postoperative period cannot be explained by the sedation effect of dexmedetomidine because 75% of the patients had a White-Song score >10 by the end of the first postoperative hour.

The incidence of postoperative nausea and vomiting was similar in our 2 groups. However, our study was not powered for this outcome, especially given the low incidence in our patients who received total IV anesthesia. A recent meta-analysis identifies an increased incidence of postoperative bradycardia in patients given dexmedetomidine, with a number needed-to-harm of only 3.11 Arterial hypotension and bradycardia with some cases of extreme bradycardia leading to asystole25,26 have been reported, especially in patients older than 50 years, having cardiac disease, given cardiodepressant drugs, or given high dosages of dexmedetomidine. We report only rare episodes of bradycardia requiring atropine, probably because we restricted enrollment to ASA physical status I or II patients.

Hypotensive events during the maintenance of anesthesia that required vasopressor administration were nonetheless common in both groups: 26% in the dexmedetomidine group and 43% in the saline group. This frequent incidence in patients without hypovolemia or cardiac comorbidity contrasts with reassuring data reported in volunteers.27 However, propofol overdosage was not the reason since patients were given less than the commonly recommended dosage of propofol: 2 to 2.5 mg/kg for induction and 100 to 200 μg/kg/min for maintenance.b More likely, the frequent incidence of intraoperative hypotension resulted from our strict definition rather than excessive propofol.

A limitation of BIS guidance is that dexmedetomidine provokes spindle-type EEG activity, as does physiological sleep.28 Huupponen et al.29 showed that EEG activity during dexmedetomidine sedation was comparable to physiological stage 2 sleep with a slight-to-moderate amount of slow-wave activity and abundant sleep spindle activity corresponding to a transient EEG activation. Spindle activity may be misinterpreted by the BIS algorithm as light anesthesia because spindles mimic arousal and an α-pattern EEG. Consequently, more propofol than actually necessary may have been delivered by the dual-loop controller in the dexmedetomidine patients, thus reducing the difference in propofol requirements between the 2 groups. On the other hand, there is no validated analgesic monitor that could have permitted us to describe the antinociceptive effect of dexmedetomidine.

In summary, using an automated administration of anesthetics shows that dexmedetomidine infusion significantly spares both propofol and remifentanil requirements during induction and reduces propofol requirement during maintenance. No significant adverse effects (bradycardia and prolonged recovery) were encountered. Dexmedetomidine administration significantly delayed the initial request for postoperative analgesia by a median of 3 hours without changing opioid requirements over the initial 6 hours. Dexmedetomidine is a useful adjuvant that reduces anesthetic requirement and provides postoperative analgesia.

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DISCLOSURES

Name: Morgan Le Guen, MD.

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

Attestation: Le Guen has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study file.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Ngai Liu, MD, PhD.

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

Attestation: Liu has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Hôpital Foch, N. Liu, and T. Chazot have a patent in France for the gain constants in the control algorithm (N°BFF08P669, Institut National de la Propriété Industrielle, France).

Name: Felix Tounou, MD.

Contribution: This author helped conduct the study.

Attestation: Tounou approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Marion Augé, MD.

Contribution: This author helped conduct the study.

Attestation: Augé approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Olivier Tuil, MD.

Contribution: This author helped conduct the study.

Attestation: Tuil approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Thierry Chazot, MD.

Contribution: This author helped design the study and conduct the study.

Attestation: Chazot approved the final manuscript.

Conflicts of Interest: Hôpital Foch, N. Liu, and T. Chazot have a patent in France for the gain constants in the control algorithm (N°BFF08P669, Institut National de la Propriété Industrielle, France).

Name: Dominique Dardelle, Pharm D.

Contribution: This author helped conduct the study.

Attestation: Dardelle approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Pierre-Antoine Laloë, MD.

Contribution: This author helped write the manuscript.

Attestation: Laloë approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Francis Bonnet, MD.

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

Attestation: Bonnet approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Daniel I. Sessler, MD.

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

Attestation: Sessler approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Marc Fischler, MD.

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

Attestation: Fischler has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Conflicts of Interest: The author has no conflicts of interest to declare.

This manuscript was handled by: Tony Gin, FANZCA, FRCA, MD.

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ACKNOWLEDGMENTS

Orion Corporation (FI-02101 Espoo, Finland) provided placebo and dexmedetomidine vials but had no role in study design, data collection, or analysis.

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