Remifentanil-Based Propofol-Supplemented Vs

Anesth Pain Med 2020;15:424-433 https://doi.org/10.17085/apm.20022 Clinical Research pISSN 1975-5171 • eISSN 2383-7977

Remifentanil-based propofol-supplemented vs. balanced sevoflurane-sufentanil anesthesia regimens on bispectral index recovery after cardiac surgery: a randomized controlled study

Tae-Yun Sung1, Dong-Kyu Lee2, Jiyon Bang3, Jimin Choi4, Saemi Shin5, and Tae-Yop Kim4

1Department of Anesthesiology and Pain Medicine, Konyang University Hospital, College of Medicine, Konyang University, Daejeon, 2Department of Anesthesiology, Korea University Guro Hospital, Korea University College of Medicine, 3Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan 4 Received May 19, 2020 College of Medicine, Department of Anesthesiology, Konkuk University Medical 5 Revised July 1, 2020 Center, Konkuk University School of Medicine, College of Life Science and Accepted July 16, 2020 Biotechnology, Korea University, Seoul, Korea

Background: The present study was to compare the potential impact of remifentanil-based propofol-supplemented anesthesia regimen vs. conventional sevoflurane-sufentanil balanced anesthesia on postoperative recovery of consciousness indicated by bispectral index (BIS) values in patients undergoing cardiac surgery. Methods: Patients undergoing cardiac surgery were randomly allocated to get the remifentanil-based propofol-supplemented anesthesia employing target-controlled infusion (TCI) of remifentanil and propofol (Group-PR, n = 15) or a balanced-anesthesia employing sevoflurane-inhalation and TCI-sufentanil (Group-C, n = 19). In Group-PR, plasma concentration (Cp) of TCI-remifentanil was fixed at 20 ng/ml, and the effect-site concentration of TCI-propofol was adjusted within 0.8–2.0 μg/ml to maintain BIS value of 40–60. In Group-C, sevoflurane dosage was adjusted within 1–1.5 minimum alveolar concentration to maintain BIS of 40– 60, and Cp of TCI-sufentanil was fixed at 0.4 ng/ml. The inter-group difference in the time for achieving postoperative BIS > 80 (T-BIS80) in the intensive care unit was determined as the primary outcome. The inter-group difference in the extubation time was determined as the secondary outcome. Results: T-BIS80, was shorter in Group-PR than Group-C (121.4 ± 64.9 min vs. 182.9 ± 85.1 min, respectively; the difference of means –61.5 min; 95% CI –115.7 to –7.4 min; ef- Corresponding author Tae-Yop Kim, M.D., Ph.D. fect size 0.812; P = 0.027). The extubation time was shorter in Group-PR than in Group-C Department of Anesthesiology, (434.7 ± 131.3 min vs. 946.6 ± 393.3 min, respectively, P < 0.001). Konkuk University Medical Center, Conclusions: Compared with the conventional sevoflurane-sufentanil balanced anesthesia, 120-1 Neungdong-ro, Gwangjin-gu, the remifentanil-based propofol-supplemented anesthesia showed significantly faster post- Seoul 05030, Korea operative conscious recovery in patients undergoing cardiac surgery. Tel: 82-2-2030-5445 Fax: 82-2-2030-5449 E-mail: [email protected] Keywords: Anesthetics; Consciousness; Propofol; Remifentanil.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © the Korean Society of Anesthesiologists, 2020

424 KSAP ------425 ], several ], several 12 – 10 [ ]. 5 , 4 [ ]. Most of all, BIS does not require physical or au physical does not require of all, BIS ]. Most MATERIALS AND METHODS MATERIALS 12 , 10 , 5 Intraoperative exclusion criteria 1) cardiopulmo exclusion were Intraoperative After obtaining the Institutional Review Board approval approval Board Review Institutional the obtaining After (allocation allocated randomly were patients Thirty-eight criteria exclusion were and intraoperative Preoperative Our study compared the time of achieving the BIS value value the BIS the time of achieving compared study Our , 4 > reg anesthesia two different applying 80 in the ICU after cardial infarction, 5) neurologic deficit or cognitive impair 5) neurologic infarction, cardial or pulmonary 7) hepatic or acute disease, 6) chronic ment, medica 9) inotropic pacing, 8) cardiac impairment, renal tion. of application nary (CPB) bypass > 300 min, 2) transfusion blood cell of red of packed > use of 3) post-CPB 5 units, Population and study protocol Population the informed obtained was KUH1160080), consent (no. prospective, This starting the study. before all patients from clinical to trial registered was and controlled randomized, elective undergoing NCT02400879). Patients (no. trials.org surgery included were or replacement repair valve cardiac in this study. method: sealed using envelope two groups 1:1) into ratio anesthesia propofol-supplemented remifentanil-based (n in Group-PR applied was regimen = 19) and conven regimen balanced anesthesia sevoflurane-sufentanil tional (n in Group-C applied was = blinded to was 19). All patient their allocation. or criteria 1) urgent exclusion were Preoperative applied. surgery, emergent ejection 2) left ventricle fraction < 50%, 4) myo (IABP), balloon pump of intra-aortic 3) application Despite controversies and its limitations and its limitations Despite controversies objec as an the efficacy speculated BIS, of investigations and man of sedation the depth modalityassessing for tive unit (ICU) care the intensive in sedation patient aging [ is necessarily which used the ditory in assessing stimulus, modalities but other subjective using by depth of sedation level. sedation patients' established interrupts the already of evaluation seamless and objective enables feature This in the ICU sedation postoperative regi propofol-supplemented remifentanil-based a imens, balanced sevoflurane-sufentanil a conventional men vs. times of the surgery. extubation The for cardiac anesthesia as also compared, were regimens anesthesia two different a secondary study. of our outcome ------]. Bindra et ]. Bindra 6 , 3 , 2 ]. Administering ]. Administering [ 5 , 4 Remifentanil-based anesthesia on postoperative BIS postoperative on anesthesia Remifentanil-based ]. Remifentanil is an ul ]. Remifentanil 3 , 2 [ INTRODUCTION INTRODUCTION ]. 9 , 8 [ ] showed that sevoflurane could be preferred to to be preferred could sevoflurane ] showed that ]. 1 7 [ [ Intraoperative electroencephalography (EEG)-based se electroencephalography Intraoperative We assumed that the remifentanil-based regimen sup regimen the remifentanil-based that assumed We If a balanced regimen employing sevoflurane and sufen sevoflurane employing If a balanced regimen Propofol-remifentanil combination can be employed as as be employed can combination Propofol-remifentanil While various anesthesia regimens can be employed for for be employed can regimens anesthesia While various www.anesth-pain-med.org dation monitors, including bispectral index (BIS), have have (BIS), index bispectral including monitors, dation (hypnosis) been sedation depth of the used for assessing agents. (hypnotic) of anesthetic the dosage and titrating balanced sevoflurane and sufentanil regimen in patients in patients regimen and sufentanil balanced sevoflurane surgery. cardiac undergoing plemented by the reduced dosage of propofol would pro of propofol dosage the reduced by plemented with the compared recovery conscious faster vide relatively be a major determinant for the speed of postoperative re speed the for postoperative of determinant be major a covery must be adjusted to avoid intraoperative awareness. awareness. intraoperative avoid to be adjusted must would action of duration longer used, is tanil sufentanil's eficial for reducing the potential delay in postoperative re postoperative in delay potential the reducing for eficial combined propofol-remifentanil the covery applying after reduction of the dosage the degree Of course, regimen. covery, even in non-cardiac surgery. Therefore, a strategy strategy a surgery.Therefore, non-cardiac in covery,even would be ben dosage propofol or minimizing for reducing half-life and variable elimination half-life half-life elimination and variable half-life al. re and cognitive emergence rapid for achieving propofol propofol during a prolonged period, especially in higher period, during especially a prolonged in higher propofol recovery, overall the patient's compromise may dosage, context-sensitive long a relatively has propofol because brief period usually does not show any dose-dependent brief dose-dependent period any does not show usually administering speed. in recovery However, difference ative dosage of remifentanil, even during a prolonged peri during even a prolonged of remifentanil, dosage ative in car recovery postoperative od, would not compromise during surgery.diac a administering propofol Likewise, and it has a supra-additive interaction with propofol re with propofol interaction a supra-additive and it has effects [ and analgesic hypnotic garding intraoper a high employing anesthesia remifentanil-based probably due to their shorter duration of clinical effects effects of clinical their shorter due to duration probably recovery faster providing half-life, with a very short context-sensitive tra-short-acting total intravenous anesthesia (TIVA) for cardiac surgery, surgery, for cardiac (TIVA) anesthesia intravenous total lation. The patient's conscious recovery speed is one of the recovery conscious patient's The lation. recov postoperative for determining factors overall major ery cardiac anesthesia, the postoperative recovery is depen recovery the postoperative anesthesia, cardiac agents of anesthetic wear-off achieve to on the time dent venti and spontaneous recovery conscious and adequate Anesth Pain Med Vol. 15 No. 4 double inotropic support for > 30 min, 4) post-CPB pacing, duction. All surgeries were performed by one surgeon and 5) intra- and post-operative IABP application, 6) postoper- four surgical assistants. They were blinded to patient allo- ative hemodialysis, 7) number of administration of addi- cation and the purpose of this study. After completing a tional propofol ≥ 2, 8) postoperative use of sedatives (e.g., sternotomy and administering 300 units/kg of heparin, ar- midazolam, propofol) before extubation, 9) excessive terial and venous cannulations for CPB were performed at bleeding of > 500 ml during postoperative 6 h, 10) reopera- activated clotting time > 400–450 s and CPB was conduct- tion due to excessive bleeding. ed using a reservoir, a membrane oxygenator, a roller pump, and a heat exchanger. CPB flow, MBP, and hemodi- Anesthesia regimens lution were adjusted to maintain the values of cerebral oximetry within 120% of preinduction values during the CPB After establishing a routine invasive arterial blood pres- period. sure and a noninvasive patient monitoring such as pulse During surgery, if the BIS value exceeded 60 for 3 min oximetry (SpO2), electrocardiography, BIS (BIS XP monitor, and persisted against the increased dosage of sevoflurane Model A2000, Aspect Medical Systems, USA) and cerebral to 1.5 MAC in Group-C or Ce of propofol to 2.0 μg/ml in oximetry, anesthesia was induced by two groups of anes- Group-PR, bolus propofol 10–20 mg was administered. thesiologists each consisting of two anesthesiologists (AA and BB) using different regimens: a target-controlled infu- Protocols of ventilator weaning and extubation sion (TCI) of propofol (effect-site concentration [Ce] of 1.0– in the ICU 2.0 µg/ml) and remifentanil (plasma concentration [Cp], 20 ng/ml with the time to reach target concentration of 7 After the surgery, patients were transferred to the ICU in min) in Group-PR (by AA); and anesthesia was induced by intubated status and received controlled or assisted venti- a bolus injection of thiopental sodium 3–4 mg/kg and lation till the time of extubation. For the postoperative in- TCI-sufentanil (Cp of 0.4 ng/ml) in Group-C (by BB). Tra- travenous patient-control analgesia (IV-PCA) in Group-PR, cheal intubation was facilitated by bolus rocuronium un- remifentanil infusion of 0.25–0.3 μg/kg/min was continued der the guidance of neuromuscular train-of-four monitor- till the time of performing extubation. According to the in- ing in both groups. For anesthesia maintenance, stitutional protocols, the IV-PCA of Group-PR was started TCI-remifentanil (fixed Cp of 20 ng/ml) and TCI-propofol at the decision of performing extubation; in contrast, it in (variable Ce 0.8–2.0 µg/ml to maintain BIS of 40–60) was Group-C was started at the time of the sternum closure. For used in Group-PR, and TCI-sufentanil (fixed Cp of 0.4 ng/ the IV-PCA in Group-PR, the alfentanil-ketorolac-ondan- ml) and sevoflurane (variable 1.0–1.5 minimum alveolar setron combination was set to deliver alfentanil of 1.0 μg/ concentration [11] to maintain BIS of 40–60) was used in kg/h and a bolus dose of alfentanil 1.0 μg/kg with a 10-min Group-C. lockout interval. For the IV-PCA in Group-C, the fentan- Hemodynamic parameters including mean blood pres- yl-ketorolac-ondansetron combination was set to fentanyl sure (MBP) and heart rate were maintained within 80– of 0.2 μg/kg/h and a bolus dose fentanyl 0.2 μg/kg with 15- 120% of preoperative value in both groups. Neuromuscular min lockout interval. block during the operation was achieved by continuous in- The mode of the ventilator was converted from vol- fusion of rocuronium (3 µg/kg/min) in both groups. ume-controlled ventilation to synchronized intermittent

Controlled ventilation of O2/air mixture (FiO2 0.5–0.6) mandatory ventilation (SIMV) when the following criteria was applied with the following settings: tidal volume of 6–7 were met: stable hemodynamics, spontaneous respiration, ml/ideal body weight, respiratory rate maintaining the and the respiratory rate 10–25 breaths/min. state of normocapnia (end-tidal CO2 tension 35–40 The decision for tracheal extubation was made when the mmHg), and inspiration to expiration ratio of 1:2. The in- following criteria were met: awake state (or BIS > 80), sta- termittent lung-recruit maneuver was applied with con- ble hemodynamics, normal airway reflex, respiratory rate stant application of positive end-expiratory pressure of 6–8 of 10–25 breaths/min, SpO2 > 95% at FiO2 < 0.6, pH ≥ 7.3 mmHg. and PaCO2 < 55 mmHg. Extubation was performed at 20 Pulmonary artery catheter and a probe of transesopha- min after the decision in all patients. In Group-PR, the IV- geal echocardiography were placed after the anesthesia in- PCA was started at the decision for extubation, and the

426 www.anesth-pain-med.org KSAP ------). 427 64.9 64.9 ± ). Dura Table 3 Table ( ). Preoperative ). Preoperative Table 2 Table ( 64 min, respec ± ). Table 1 Table 51.7 mg/dl, respective 51.7 mg/dl, ± Fig. 1 Fig. ( 393.3 min, respectively; dif 393.3 min, respectively; ± ). 151 min vs. 319 151 min vs. RESULTS RESULTS , pH, electrolyte, lactate, and glucose lactate, , pH, electrolyte, ± 2 53.0 vs. 163.9 53.0 vs. Table 4 Table ± ( /FiO 85.1 min, respectively; the difference of of the difference 85.1 min, respectively; 2 ± , pH, electrolyte, and lactate did not show inter did not show lactate and , pH, electrolyte, 2 131.3 min vs. 946.6 131.3 min vs. ). CPB and ACC time, intraoperative fluid adminis intraoperative ). time, and ACC CPB ± /FiO 2 The incidence of agitation in the ICU did not show inter in the ICU did not show incidence of agitation The At the time of admission to the ICU, BIS, hematocrit, hematocrit, BIS, the ICU, to the time of admission At significantly was T-BIS80, primaryThe variable, outcome in As the secondary T-extubation variable, outcome A total of 43 patients was evaluated for eligibility. Ac eligibility. for evaluated was of 43 patients A total types and surgical profiles demographic patients' The Table 3 Table (434.7 ferences –312.4 min; –511.9 min; 95% CI –711.4 to of means 1.746; P effect size < inter-group did not show 0.001). T-SIMV differences. differences group tion of surgery in Group-PR was significantly longer than than longer significantly was surgery of tion Group-PR in (445 in Group-C that 126 min; 95% confidence in of means the difference tively, terval 1.094; P [95% CI] 39–214 min; effect size = 0.007) ( intraoperative requirements, transfusion quantity, tration addi who received of patients and the number urine output, differences intergroup did not show propofol tional PaO the to admission of time the at However, differences. group than in Group-PR lower significantly glucose was level ICU, C (109.7 in group –17.5 95% CI –91.0 to –54.2 mg/dl; of means differences ly; 1.035; P effect size mg/dl; = 0.005). (121.4 Group-C to compared shorter in Group-PR 182.9 min vs. –7.4 min; effect –61.5 min; 95% CI –115.7 to means size 0.812; P = 0.027). in Group-C that shorter than significantly was Group-PR P value P value < significant. considered 0.05 was crite exclusion preoperative and inclusion the to cording 2 (3 declined excluded participate, to were patients five ria, in were and 38 patients impairment), or renal hepatic had from patients four Additionally, cluded in this study. required one patient because withdrawn were Group-PR post- required patients and three pacing, cardiac post-CPB support inotropic useCPB of double > 34 30 min. Thus, in were and 15 for Group-PR) (19 for Group-C patients analysis cluded in the statistical ( differences intergroup did not show PaO hematocrit, between the two groups comparable were - - - Remifentanil-based anesthesia on postoperative BIS postoperative on anesthesia Remifentanil-based -test (2- tailed) or the (2- tailed) or the -test error probability; 0.05 0.05 probability; error t α test. Categorical variables were analyzed analyzed were variables Categorical test. U ratio were recorded. In the ICU, patients who who patients the ICU, In recorded. were ratio 2 /FiO ]. 2 13 Statistical analysis was performed using Sigmastat ver performedwas Sigmastat using analysis Statistical The required sample size was 38 (19 for each group) to to group) 38 (19 for each was size sample required The The primary outcome variable was T-BIS80. According to to According primaryThe T-BIS80. was variable outcome All data were collected by trained observers trained collected by who did not were All data The duration from the end of surgery the of extu the time from to duration The As a primary outcome of this study, the duration from from As a primary duration the of this study, outcome Operation time, CPB time, aortic cross-clamp (ACC) (ACC) aortic cross-clamp time, CPB time, Operation , 5 www.anesth-pain-med.org by a chi-square test or a Fisher's exact test, as applicable. as applicable. exact test, or a Fisher's test a chi-square by and standard as mean expressed collected were data The (%). A of patients 3Q), or numbers median (1Q, deviation, normality test using the Shapiro–Wilk test, continuous continuous test, the Shapiro–Wilk using normality test a using analyzed were variables Mann–Whitney sion 3.1 (Systat Software Inc., USA). performingAfter Inc., the Software 3.1 (Systat sion fulfill the study protocol assumption, considering the 20% 20% the considering assumption, protocol study the fulfill rate. out drop effect size was 1.083, assuming 1.083, assuming was effect size (2-tailed), power; 1:1, the calculated ratio; 0.80, allocation 30. was size sample our pilot test results (n results pilot test our = deviation and standard 10), mean min 40 69.6 and and Group-C, for min 47.6 and 117.2 were the estimated result, on this pilot test Based for Group-PR. study. study. Statistical analysis measured in the ICU. in the ICU. measured blinded the current to and were care in patient participate bation (T-extubation) and the duration from the end of end of the from the duration and (T-extubation) bation also was SIMVsurgery (T-SIMV) the time of initiating to (persisting (persisting in the ICU > measured was 3 min, T-BIS80) [ the end of the surgery, is defined which as the completion value the BIS time of achieving the to closure, of skin > 80 who were restless or combative, excited, disoriented, and disoriented, excited, and or combative, restless who were as "agitated." regarded were restraints physical required also recorded. were incidences of agitation The PaO instructions and verbal the frequent despite not calm were time, intraoperative fluid administration quantity, transfu quantity, fluid administration intraoperative time, hematocrit urine output, intraoperative requirements, sion and postoperative preoperative the ICU, to admission at Measurements Measurements remifentanil infusion was stopped immediately before the the before stopped immediately was infusion remifentanil extubation. Anesth Pain Med Vol. 15 No. 4

Enrollment Assessed for eligibility (n = 43)

Excluded (n = 5) ◆ Declined to participate (n = 2) ◆ Other reasons (n = 3)

Randomized (n = 38)

Allocation Allocated to Group-PR (n = 19) Allocated to Group-C (n = 19) ◆ Recevied allocated intervention (n = 19) ◆ Recevied allocated intervention (n = 19)

Follow-up Discontinued intervention (n = 4) (post-CPB pacing n = 1, post-CPB double Discontinued intervention (n = 0) inotropic support n = 3)

Analysis Analysed (n = 15) Analysed (n = 19)

Fig. 1. Flow chart. Thirty-eight patients were randomly allocated into the Group-PR or Group-C, and four patients in the Group-PR were excluded because one patient required post-CPB cardiac pacing, and 3 patients were applied post-CPB use of double inotropic support. Group-PR: remifentanil-based propofol-supplemented regimen, Group-C: combined sevoflurane-sufentanil regimen, CPB: cardiopulmonary bypass.

Table 1. Demographic Data Variable Group-PR (n = 15) Group-C (n = 19) P value Age (yr) 49.5 ± 14.8 47.0 ± 13.7 0.618 Sex (M/F) 8/7 10/9 0.986 Height (cm) 162.6 ± 7.8 166.4 ± 8.8 0.201 Weight (kg) 55.0 (50.0, 65.0) 63.8 (58.0, 68.0) 0.058 Present illness Diabetes mellitus 0 (0) 1 (5.3) 1.000 Hypertension 7 (46.7) 6 (31.6) 0.070 Diabetes and hypertension 0 (0) 0 (0) NA Previous medication Angiotensin blocker 5 (33.3) 4 (21.1) 0.462 ACE-inhibitor 4 (26.7) 1 (5.3) 0.146 Calcium channel blocker 3 (20.0) 0 (0) 0.076 Beta-blocker 3 (20.0) 3 (15.8) 1.000 Statin 2 (13.3) 1 (5.3) 0.571 Warfarin 2 (13.3) 3 (15.8) 1.000 Operation type 0.934 Mitral valve repair 6 (40.0) 9 (47.4) Aortic valve repair 5 (33.3) 4 (21.1) Double valve repair 4 (26.7) 6 (31.6) Values are presented as mean ± SD, numbers of patients (%), or median (1Q, 3Q). Group-PR: propofol-remifentanil regimen, Group-C: sevoflurane-sufentanil regimen, ACE: angiotensin-converting enzyme, NA: not applicable.

428 www.anesth-pain-med.org KSAP

2 429 760 007 621 621 535 703 450 736 382 986 369 176 662 871 296 802 413 129 005 001 154 027 112 ...... 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 P value P value < 476 716 081 138 182 082 689 622 544 ...... 0 0 0 0 0 0 0 0 0 P value ) 4 ) % CI) ) . % CI) 4 5 . . 95 7 95 ) 312 17 in arterial blood/the fraction (percent) (percent) fraction blood/the in arterial 214 2 to – to – – to – 7 . 4 0 . . NA NA NA NA NA NA NA NA 39 NA NA NA NA NA NA NA NA NA NA NA ( 91 115 711 ) ) ) (– ) 0 ) (– 126 . (– 2 ) ) ) ) 19 5 45 . 9 . . . 0 2 7 1 38 . . . . 7 142 137 , 54 4 1 0 1 61 , , , 208 0 , , , ,

– – . 511 in arterial blood/the fraction (percent) of inspired O inspired of (percent) fraction blood/the in arterial 41 5 1 5 7 . . . . . 2 ± –

Difference of means ( means of Difference 33 7 138 3 1 0 0 100 Difference of means ( means of Difference ( ( ( ( ( ( ( ( 5 7 1 5 8 . . . . . 451 44 3 1 0 0 . 119 140 35 7 Group-C (n Group-C = ) ) ) 7 3 ) ) . . ) ratio: partial O of ratio: pressure 19 1 7 44 . . 2 ) 19 . 4 1 1 1 . . . . ) 7 431 146 4 51 7 0 0 1 126 85 393 3 31 6 ,

, . ) , . , , 64 56 682 413 41 387 2 671 3 /FiO 0 ± ± ± ± ± ± ± ±

. . 39 2

. 5 26 4 ± ± ± ± ± ± ± ± 141 223 9 ( 1 7 8 7 9 6 7 ( ( ......

( ( ( 6 44 ( 1 1 0 2 9 1 . . 30 82 1 4 43 163 319 441 537 143 182 946 426 942 595 . 144 , , 352 7 1 1 Group-C (n Group-C = Group-C (n Group-C = ) ) ) ratio: partial O of ratio: pressure 2 ) 0 . 15 ) 46 ) ) ) ) . 1 1 6 5 40 7 . . . . 140 /FiO , , 4 1 0 1 , 119 2 164 0 , , , ,

. , 40 6 1 5 7 . . . . . ±

) 7 138 3 1 0 0 94 35 ) ) ( ( ( ( ( ( ( ( 2 3 ) ) 15 . . 0 8 1 5 7 ) . . . . . 9 0 15 362 45 . . 43 ) . 5 . 3 1 0 0 1 1 0 . 101 . . . 140 ) 7 7 38 148 447 4 131 136 0 0 1 ) 53 64 2 5 30 7 ,

, , . , Group-PR (n Group-PR = 3 , . 151 60 50 409 187 302 2 496 Remifentanil-based anesthesia on postoperative BIS postoperative on anesthesia Remifentanil-based 7 ± ± ± ± ± ± ± ±

. 39

. 28 3 ± ± ± ± ± ± ± ± 13 181 143 7 8 1 6 2 7 4 ( 7 . ( ......

( ( ( ( 47 7 ( 1 0 2 3 1 2 . . 29 94 2 4 42 907 434 257 109 121 352 155 460 553 445 . 347 145 , , 7 1 1 Group-PR (n Group-PR = Group-PR (n Group-PR = (min) 80 Variable ) ratio 2 Variable Variable ratio 100 2 – Intraoperative Variables Intraoperative Postoperative Variables in the Intensive Care Unit Care Intensive in the Variables Postoperative Preoperative Variables Preoperative /FiO (mmol/L) 0 (mg/dl) 2 (mmol/L) ++ + ++ /FiO (mmol/L) (mmol/L) (mg/dl) 2 + (mmol/L) ++ + ++ Hematocrit (%) Hematocrit BIS ( ACC time ACC CPB time Glucose (mg/dl) Glucose (mmol/L) Lactate (mmol/L) + Na PaO pH At admission* At

Duration of surgery (min) surgery of Duration Lactate (mmol/L) Lactate (mg/dl) Glucose K Ca Mg PaO pH Na Hematocrit (%) Hematocrit Agitation Time to BIS to Time > (min) SIMV to Time (min) extubation to Time Mg K Ca Colloid Intraoperative fluid (ml) fluid Intraoperative Crystalloid Additional propofol* Additional Packed RBC (unit) Packed (ml) urine Intraoperative www.anesth-pain-med.org Table 4. Table ratio. 3. Table Values are presented as median (1Q, 3Q) or mean ± SD. Values are measured just after anesthesia induction. Group-PR: propofol-remifentanil propofol-remifentanil Group-PR: induction. anesthesia after just measured are ± SD. Values mean (1Q, 3Q) or as median presented are Values PaO regimen, sevoflurane-sufentanil Group-C: regimen, Table 2. Table of inspired oxygen ratio. oxygen inspired of Values are presented as mean ± SD, median (1Q, 3Q), or numbers of patients (%). Group-PR: propofol-remifentanil regimen, Group-C: Group-C: regimen, propofol-remifentanil (%). Group-PR: patients of numbers 3Q), or (1Q, median ± SD, mean as presented are Values ventilation, mandatory intermittent synchronized SIMV: index, BIS: bispectral interval, 95% CI: 95% confidence regimen, sevoflurane-sufentanil unit, PaO care intensive the to admission after *Just applicable. NA: not *Number of patients required additional propofol bolus due to BIS value > 60. BIS value to due bolus propofol additional required patients of *Number Values are presented as mean ± SD or numbers of patients (%). Group-PR: propofol-remifentanil regimen, Group-C: sevoflurane-sufentanil sevoflurane-sufentanil Group-C: regimen, propofol-remifentanil Group-PR: (%). patients of numbers or SD ± mean as presented are Values index. BIS: bispectral applicable, NA: not aortic bypass, cross-clamp, ACC: CPB: cardiopulmonary interval, 95% confidence 95% CI: regimen, Anesth Pain Med Vol. 15 No. 4

DISCUSSION reducing or minimizing the propofol-induced myocardial depressive effect in the propofol-remifentanil combination Our result demonstrated that the remifentanil-based for cardiac surgery [17,18]. propofol-supplemented regimen is superior to the conven- In Group-PR, the increased dosage of remifentanil tional balanced-anesthesia regimen in providing a faster throughout anesthesia did not seem to produce any resid- time to achieve postoperative BIS > 80 in cardiac surgery. ual effect due to its very short plasma elimination half-life Despite the random allocation and surgery by the same (8–10 min) and a context-sensitive half-time (3–5 min) [16]. surgeon, the duration of surgery was longer in Group-PR. The reduced dosage of propofol (Ce 0.8–2.0 μg/ml), which Considering that the longer duration of surgery is a risk was similar to that of making patient awake (Ce 1.8 ± 0.7 factor for delayed patient awakening after anesthesia [14], μg/ml) in a previous study [19], also facilitated postopera- our result with the shorter recovery despite the longer du- tive recovery. Only stopping of its infusion might provide ration of surgery in Group-PR (445 min vs. 319 min in immediate resolution of its effects. Group-C) may be of much more significant meaning. Since sevoflurane has a short context-sensitive half time So far, few studies have compared postoperative con- (< 5 min) and the time for conscious recovery (< 8 min) scious recovery time after applying the remifentanil-based [20], the dosage of sufentanil in Group-C and its duration propofol-supplemented anesthesia regimens vs. conven- of administration might be a critical factor for producing tional sevoflurane-sufentanil balanced anesthesia regi- the inter-group difference in T-BIS80. Previous reports also mens for cardiac surgery. According to our result, remifen- showed residual effects after administering opioids, in- tanil-based propofol-supplemented TIVA can be favored, cluding sufentanil [8,9]. especially for patients requiring fast postoperative con- However, the dosage of sufentanil in Group-C was still scious recovery in cardiac surgery. minimal, Cp 0.4 ng/ml, and far less than the dosage pro- We employed the BIS values > 80, as the indicator of the ducing postoperative residual effects in previous studies patient's conscious recovery in the ICU, since previous re- [9,21]. Therefore, the dosage and the duration of adminis- ports showed that BIS values ranging 64–80 corresponded tration might play an essential role in terms of achieving to a transitional status from unconsciousness to conscious- faster postoperative recovery. Previous studies also sup- ness [15]. BIS > 80 was comparable to the sedation status ported this discrepancy upon longer vs. shorter period responding to the command, "open your eyes" [13]. As (e.g., in non-cardiac surgeries) of sufentanil infusion: the mentioned earlier, BIS monitoring enables a seamless and recovery profiles were not different between remifentanil objective evaluation of the depth of sedation in the ICU and sufentanil anesthesia for thyroidectomy [3], and the [4,5]. Our result indicating the remifentanil's superiority in extubation time was not different between remifentanil providing faster BIS recovery corresponds to a previous and sufentanil anesthesia for craniotomy [2]. Measures for study employing a subjective sedation scale, in which reducing sufentanil's residual effect, such as earlier discon- remifentanil-anesthesia provided a shallower depth of tinuation of its infusion 30 min before the ending of the postoperative sedation than sufentanil-anesthesia did in surgery, seem to be useful [2]. cardiac surgery [8]. Most previous studies had focused on the contribution of In the meantime, remifentanil or sufentanil alone cannot respiratory recovery as an indicator of the overall postoper- provide sufficient sedation, but they can potentiate the ative recovery in evaluating anesthesia regimens [22]. The sedative effect of concomitantly administered propofol or extubation time (less than 6–10 h) has been used as a typi- sevoflurane, as the opioid-sedative synergism [16]. In our cal indicator for evaluating postoperative recovery and results, remifentanil and sufentanil could potentiate the ef- fast-track anesthesia protocol [22]. The earlier recovery of fects and reduce the requirement concomitantly adminis- consciousness may contribute to the earlier extubation in tered propofol or sevoflurane (Ce of propofol or MAC of our study. sevoflurane) in the context of propofol-remifentanil syner- The shorter extubation time in the present study sup- gy for producing intraoperative hypnosis [16]. The dosage ports the superiority of remifentanil-based regimen to oth- of propofol was also guided by the BIS monitor to avoid in- er anesthesia regimens employing sufentanil or fentanyl in traoperative awareness. The reduced dosage of propofol in providing faster postoperative respiratory recovery in car- Group-PR, Ce of < 2.0 μg/ml, might also be beneficial in diac surgery. The extubation time in Group-PR was signifi-

430 www.anesth-pain-med.org KSAP ------431 3 7 9 ORCID https://orcid.org/0000-0002-4068-236 https://orcid.org/0000-0002-0714-147 CONFLICTS OF INTEREST CONFLICTS https://orcid.org/0000-0002-1031-953 AUTHOR CONTRIBUTIONS AUTHOR CONTRIBUTIONS No potential conflict of interest relevant to this article this article to relevant conflict of interest potential No cu Data Sung. Tae-Yun Kim, Tae-Yop Conceptualization: In conclusion, the remifentanil-based propofol-supple the remifentanil-based conclusion, In final manuscript:final all authors. Sung, Tae-Yun Lee, Dong-Kyu Bang, Jiyon postoperative consciousness in using the propo in using consciousness postoperative surgery. for cardiac regimen anesthesia fol-remifentanil reported. was Lee. analysis: Dong-Kyu Formal Sung. Tae-Yun ration: Tae-Yop Investigation: Kim. Tae-Yop acquisition: Funding Tae-Yun Kim, Tae-Yop Methodology: Sung. Tae-Yun Kim, administration Project Bang. Jiyon Lee, Dong-Kyu Sung, Lee, Dong-Kyu Sung, Tae-Yun Kim, Tae-Yop and resource: Dong-Kyu Software: Shin. Saemi Choi, Jimin Bang, Jiyon Vi all authors. Validation: Kim. Lee. Supervision: Tae-Yop Writing-original Lee. Dong-Kyu Sung, Tae-Yun sualization: Writ Lee. Dong-Kyu Sung, Tae-Yun Kim, draft: Tae-Yop Dong- Sung, Tae-Yun Kim, Tae-Yop & editing: ing-review of Approval Shin. Saemi Choi, Jimin Bang, Jiyon Lee, Kyu have to consider the variation of residual effects (or offset effects (or of residual the variation consider to have capabil monitor's BIS and agent anesthetic speed)each all the possible cortical EEG activity. Finally, manifest ity to and the ef recovery on patient's of other variables impact such outcomes, method on clinical fects anesthesia of each hos of length or ICU, the in stay of length mortalityas rate, limitedsample the to due evaluated not were stay, pital further be necessary this through may evaluate to It size. size. sample larger a much employing studies reduced the relatively employing which regimen, mented of remifent dosage and the increased of propofol dosage of postoperative recovery faster significantly anil, provided anesthesia balanced sevoflurane-sufentanil than value, BIS It surgeries. cardiac undergoing did in patients regimen Further time. extubation faster significantly also provided determine to whether the be warranted may investigation speed of recovery the affects remifentanil-ratio propofol- ] ------]. 5 23 , [ 4 [ ]. 25 , 24 ]. 22 Remifentanil-based anesthesia on postoperative BIS postoperative on anesthesia Remifentanil-based ] showed no difference in the ven no difference ] showed 8 [ ]. Furthermore, some reports showed that early early showed that some reports ]. Furthermore, 23 , 21 , ] also showed that remifentanil anesthesia was not su was anesthesia remifentanil ] also showed that ]. There might be an inter-group discrepancy in the BIS discrepancy in the BIS be an inter-group might ]. There ], the possible sedative effect by the extra-cortical path the extra-cortical effect by sedative ], the possible This study had limitations. First, the inter-group differ the inter-group First, limitations. had study This In our study, despite the significant inter-group differ inter-group the significant despite study, our In 17 23 27 26 www.anesth-pain-med.org other determinant for extubation time, was not significant not was time, for extubation other determinant Lison et al. different. ly ence in the extubation time, the time to switch to SIMV, an switch the time to SIMV, to time, ence in the extubation ant: higher intraoperative dosage would prolong postoper ant:prolong would dosage intraoperative higher odds ratio, of intubation, time (duration extubation ative [ increment) 1 μg/kg 1.54 per sufentanil recovery area. Furthermore, the dosage of the intermedi the dosage Furthermore, area. recovery ad sufentanil) fentanyl, morphine, (e.g., opioid ate-acting period is also import during the intraoperative ministered cantly shorter (7 h vs. 15 h in Group-C). Bhavsar et al. Bhavsar 15 h in Group-C). shorter h vs. (7 cantly in re effective more was regimen remifentanil showed that in the of stay length and extubation tracheal time to ducing propofol-remifentanil combination would be higher than than be would higher combination propofol-remifentanil comparing In as in this study. alone, propofol in using that we values, BIS postoperative in differences inter-group the values indicating the conscious recovery and those corre the conscious recovery indicating values BIS The of sedation/awakeness. level the same to sponding a in using of consciousness the return indicating value way (e.g., sedative effects by opioids) was not evaluated not evaluated opioids) was effects by sedative (e.g., way [ values. Third, since the BIS monitor only manifests cortical manifests only monitor the BIS since Third, values. agents hypnotic the affected by mainly is which activity, [ of postoperative BIS monitoring in the ICU setting monitoring in the ICU setting BIS of postoperative the annoy to the potential had their application However, BIS the stabilized and abruptly change sedated patients did not include the postoperative evaluation of the Ramsay the Ramsay of evaluation postoperative the not include did These subjec scale. sedation-agitation or the Riker score the controversy help overcome might scales sedation tive times greater than fentanyl in the equivalent-dosage calcu in the equivalent-dosage fentanyl than times greater Second, we recovery. earlier a significantly provided lation) ings of the PCA might affect the degree of pain intensity as of the PCAings intensity of pain affect the degree might the greater even However, characteristics. well as recovery 8–9 (approximately in Group-PR remifentanil of dosage ence in the regimens for postoperative pain control control pain for postoperative ence in the regimens and the start tim fentanyl) vs. and alfentanil (remifentanil extubation (

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