- Email: [email protected]
Low Target Sufentanil Effect-Site Concentrations Allow Early Extubation After Valve Surgery
Low Target Sufentanil Effect-Site Concentrations Allow Early Extubation After Valve Surgery Mohamed R. El Tahan, MD,*† Alaa M. Khidr, MD* Objectives: To test the ability of low sufentanil effect-site concentrations (Ce) to shorten the time to tracheal extubation after valve surgery. Design: A prospective, randomized, blinded, controlled study. Setting: A single university hospital. Participants: Forty-eight patients scheduled for valve surgery under target-controlled propofol infusion. Interventions: After ethical committee approval, patients were allocated randomly to receive sufentanil concentrations of 0.2, 0.3, or 0.4 ng/mL (n ⴝ 16 per group) during target-controlled propofol infusion. Measurements and Main Results: Times to spontaneous eye opening, return of spontaneous breathing and extubation; number of changes and cumulative doses of propofol and sufentanil; incidences of light anesthesia and myocardial ischemia; intensive care unit and hospital stays; and costs of propofol, sufentanil, and ventilation were recorded. Compared with the sufentanil 0.4-ng/mL group, 0.2- and
0.3-ng/mL groups had shorter times to eye opening (24.8 min [SD 7.8] and 52.6 min [12.5] v 85.6 min [10.0], respectively), spontaneous breathing (32.7 min [19.9] and 70.1 min [27.2] v 137.5 min [20.8], respectively), and extubation (112.2 min [16.9] and 161.9 min [32.9] v 271.3 min [27.4], respectively; p < 0.001), more frequent changes in propofol concentrations (p < 0.001), higher cumulative propofol doses, lower cumulative sufentanil doses, and 33% to 44% lower total cost (p < 0.001). Incidences of light anesthesia and myocardial ischemia and intensive care unit and hospital stays were similar for all groups. Conclusions: Compared with sufentanil Ce of 0.4 ng/mL, lower concentrations (0.2 and 0.3 ng/mL) promoted faster recovery and shorter times to extubation after valve surgery performed under target-controlled propofol infusion. © 2012 Elsevier Inc. All rights reserved.
F
prospective, randomized, blinded, and controlled study at the authors’ center after obtaining approval from the local ethics committee and informed written consent from all participants. The patients were allocated randomly into 3 groups (n ⫽ 16 per group) that would receive sufentanil Ce of 0.2, 0.3, and 0.4 ng/mL, respectively; this would be continued until sternal closure was completed, as detailed in the authors’ protocol (Figs 1 and 2). This protocol was created based on a study by Forestier et al4 to control entropy and the hemodynamic responses to noxious stimuli. The subjects were allocated randomly into the 3 groups by drawing sequentially numbered sealed opaque envelopes that each contained a software-generated randomization code. Patients with documented uncontrolled hypertension; ischemic heart disease; left ventricular ejection fraction ⬍45%; severe pulmonary hypertension (mean pulmonary artery pressure ⬎45 mmHg); critical aortic stenosis; pulmonary, hepatic, renal, neuromuscular, neuropsychiatric, and endocrine diseases; body mass index ⬎35 kg/m2; pregnancy; use of antipsychotics or alcohol; drug abuse; repeat or emergency surgery; those requiring preoperative circulatory or ventilatory support; and those whose electrocardiographic characteristics would interfere with ST-segment monitoring were excluded from the study. All patients were premedicated with oral lorazepam 1 to 2 mg the night before surgery and 90 minutes before arrival in the operating room. The patients were monitored by a pulse oximeter, 5-lead electrocardiograph (leads II and V5) with continuous ST-segment recording, radial mean arterial blood pressure (MAP) measurements, endtidal carbon dioxide measurements, a pulmonary artery catheter, and rectal and nasopharyngeal temperature measurements. Significant isch-
AST-TRACK VALVE SURGERY is performed frequently at the authors’ center in unique younger patients with a lower body mass index than those in other countries. Low-dose opioid anesthesia is used commonly because of the ceiling effect of opioids in attenuating cardiovascular responses to noxious stimuli.1 Target-controlled effect-site concentrations (Ce) of sufentanil (range, 0.4-4.5 ng/mL) have been successful in providing stable analgesia and hemodynamics during coronary artery bypass grafting (CABG).2,3 Moreover, Forestier et al4 investigated the effect of different sufentanil Ce (0.5, 0.75, 1, 1.25, and 1.5 ng/mL) at the induction of anesthesia, decreased by one third after sternotomy, on the predicted propofol Ce based on bispectral index values during CABG procedures in response to a nociceptive stimulus, such as tracheal intubation. Sufentanil Ce of 1.25 ng/mL has been associated with the lowest predicted propofol Ce along with hemodynamic tolerance. However, it also has been associated with long times to spontaneous eye opening and tracheal extubation (mean, 320 and 380 min, respectively). In addition, the lower sufentanil Ce (range, 0.35-0.65 ng/mL) have been associated with similar degrees of hemodynamic tolerance to the 1.25- and 1.5-ng/mL Ce. The authors hypothesized that using low rather than high sufentanil Ce during target-controlled infusion (TCI) of propofol anesthesia for valve surgery could decrease the time to tracheal extubation. This study aimed to investigate the effects of 3 sufentanil Ce (0.2, 0.3, and 0.4 ng/mL) on the time to tracheal extubation, hemodynamics, recovery times, and incidences of myocardial ischemia, light anesthesia, and awareness during TCI of propofol anesthesia for patients undergoing elective valve surgery. METHODS Forty-eight patients 18 to 55 years old with American Society of Anesthesiologists (ASA) III-IV who were scheduled for elective valve surgery and were eligible for early extubation were included in this
KEY WORDS: anesthesia, sufentanil, propofol, target-controlled infusion, cardiac surgery, fast track
From the *Department of Anesthesiology, King Fahd Hospital, University of Dammam, Al Khubar, Saudi Arabia; and †Cardiothoracic Anesthesia Unit, Mansoura University, Mansoura City, Egypt. Address reprint requests to Mohamed R. El-Tahan, MD, Department of Anesthesiology, King Fahd Hospital, University of Dammam, Al Aqrabiah Street, PO Box 40289, Al Khubar 31952, Saudi Arabia. E-mail: [email protected] © 2012 Elsevier Inc. All rights reserved. 1053-0770/2701-0001$36.00/0 doi:10.1053/j.jvca.2012.01.023
Journal of Cardiothoracic and Vascular Anesthesia, Vol 27, No 1 (February), 2013: pp 63-70
63
64
EL TAHAN AND KHIDR
Fig 1. Algorithm for the intraoperative anesthetic management. Ce, target effect-site concentration; HR, heart rate; IV, intravenous; MAP, mean arterial blood pressure; NTG, nitroglycerin; RE-SE, difference between response entropy and state entropy; SE, state entropy.
emic responses were defined as reversible ST-segment changes from baseline, namely a ⱖ1-mV ST-segment depression or a ⱖ2-mV STsegment elevation that lasted for ⱖ1 minute.5 Response entropy (RE) and state entropy (SE) were monitored by applying entropy electrodes (Datex-Ohmeda Division, Instrumentarium Corporation, Helsinki, Finland) according to the manufacturer’s recommendations. An independent anesthesiologist who was not involved in collecting patient data initiated the sufentanil Ce (the model of Gepts et al6) according to the patient’s randomization code and was allowed to
titrate the target propofol and sufentanil Ce and to administer vasoactive medications as needed. After preoxygenation, anesthesia was induced by simultaneous target propofol and sufentanil infusions using the TCI system with syringe pumps (Injectomat TIVA Agilia, Fresenius Kabi, France). The target propofol Ce (model of Schnider et al7) was initiated at 1.0 g/mL and titrated stepwise by 0.5 g/mL every 3 minutes until loss of consciousness and until an SE ⬍50 and a difference ⬍10 between RE and SE (RE-SE) were achieved. Cisatracurium, 0.2 mg/kg, was
LOW SUFENTANIL EFFECT-SITE CONCENTRATION FOR VALVE SURGERY
Intubation
Skin incision
Sternotomy
Sternal spread
CPB
Discontinuation of CPB
65
Homeostasis
Sternal closure
Skin closure End of surgery
Sufentanil of Ce 0.2 ng/mL, in group Ce 0.2 ng/mL. Stop infusion
Sufentanil of Ce 0.3 ng/mL, in group Ce 0.3 ng/mL. Sufentanil of Ce 0.4 ng/mL, in group Ce 0.4 ng/mL. Propofol of Ce 1.0 – 4.5 µg/mL. Cisatracurium of 0.2 mg/kg, followed with 1 – 3 µg/kg/min.
Fig 2.
Stop infusion Stop infusion
Schematic presentation of the anesthetic plan. CPB, cardiopulmonary bypass; Ce, target effect-site concentration.
given to facilitate tracheal intubation, and the lungs were ventilated with a fraction of inspired oxygen of 0.5 to maintain normocapnia. The time from induction to intubation was recorded. Anesthesia was maintained by changing the propofol Ce at increments of 0.5 g/mL (range, 1-4.5 g/mL) every 3 minutes as necessary to maintain an SE ⬍50, an RE-SE difference ⬍10, and an MAP and heart rate (HR) that were ⱕ20% of the baseline values. The sufentanil Ce was increased by a maximum of 4 increments of 0.05 ng/mL when the SE was ⬎50, the RE-SE difference was ⬎10, and the MAP and HR were ⱖ20% of the baseline values despite a target propofol Ce ⬎4.5 g/mL. When the SE was ⬍50 and the RE-SE difference was ⬍10, the propofol Ce was decreased gradually to ⱖ1 g/mL, followed by gradual decreases in sufentanil Ce by 0.05 ng/mL, until the randomized Ce was achieved. The HR and MAP were kept within 20% of baseline values by achieving an adequate depth of anesthesia (SE ⬍50 and RE-SE difference ⬍10), optimum analgesia, and the administration of nitroglycerin, 0.05 mg, and esmolol, 20 mg (Fig 1). Cisatracurium, 1 to 3 g/kg/min, was used to maintain surgical relaxation. All patients received tranexamic acid, 50 mg/kg. Light anesthesia was defined as an episode with SE values ⬎50 and/or MAP and HR values ⬎20% above baseline that lasted for ⬎3 consecutive minutes. The incidences of light anesthesia in response to intubation, skin incision, sternotomy, maximal sternal spread, and sternal wire placement were recorded. Hemodynamic control was standardized according to the authors’ protocol.5 Hypotension (defined as ⬍20% decrease in mean baseline MAP) was treated with boluses of fluids, ephedrine 5 mg, or epinephrine, 5 g, as needed. Hypertension (defined as ⬎20% increase in mean baseline MAP) was treated by deepening anesthesia and administering doses of nitroglycerin, 0.05 mg, or labetalol, 20 mg. Tachycardia (defined as ⬎20% increase in mean baseline HR) was treated with esmolol, 20 mg. All operations were performed by the same surgeons. Heparin, 300 IU/kg, was given to achieve an activated coagulation time ⬎480 seconds. A standardized hypothermic cardiopulmonary bypass (CPB) was used. Similar to a previous study,8 the target propofol Ce and sufentanil Ce were continued throughout surgery and CPB without any further adjustments because of CPB per se. Before separation from CPB, all patients were rewarmed to a rectal temperature of 36°C and dobutamine, epinephrine, norepinephrine, and nitroglycerin were used as needed. Heparin was neutralized with protamine sulfate. The cisatracurium infusion was discontinued after surgical homeostasis was achieved. The target sufentanil Ce and propofol Ce were discontinued after sternal closure and skin closure, respectively (Fig 2). The HR, MAP, and cardiac and systemic vascular resistance indices were recorded before (baseline) and 15 minutes after endotracheal intubation, 15 minutes after skin incision, 15 minutes after sternotomy, and 15 and 45 minutes after discontinuing CPB. Patients were transferred to the intensive care unit (ICU) in a ventilated state using the synchronized intermittent mandatory mode or
the pressure support mode. Postoperative analgesia was provided by intravenous paracetamol, lornoxicam, and patient-controlled analgesia (PCA), morphine 1 mg, with a lockout interval of 8 minutes and a maximum 4-hourly limit of 30 mg. Extubation criteria included alertness, a train-of-four ratio ⱖ0.9, spontaneous breathing with a tidal volume ⬎5 mL/kg, respiratory rates ⬎10 and ⬍28 breaths/min, a maximum inspiratory pressure ⱕ⫺20 cm H2O, stable hemodynamics without high doses of inotropic support or severe arrhythmias, bleeding ⬍100 mL/h, a core temperature ⬎35.5°C, a urine output ⬎0.5 mL/ kg/h, an arterial carbon dioxide tension ⱕ45 mmHg, an arterial oxygen tension ⬎100 mmHg, and a fraction of inspired oxygen ⬍0.5. Blood samples were drawn before CPB and 3, 12, 24, and 48 hours after CPB to measure cardiac troponin I levels. Intraoperative explicit awareness was assessed on the second postoperative day by asking the patients 3 simple questions in a standard interview: What was the last thing you remember happening before you went to sleep? What is the first thing you remember happening on waking? Did you dream or have any other experiences while you were asleep?9 An independent investigator blinded to the study groups who was not involved in the patients’ management collected the patient data. The primary outcome was the time to tracheal extubation. Secondary outcome variables included the times from skin closure to spontaneous eye opening and the return of spontaneous breathing (defined as a respiratory rate ⬎12 breaths/min and an arterial oxygen saturation ⬎95%); the number of changes in propofol Ce and sufentanil Ce; the cumulative doses of propofol and sufentanil (from induction through the end of the related infusion); the number of patients who needed changes in sufentanil Ce and rescue doses of nitroglycerin, esmolol, and ephedrine; the number and total duration of intraoperative ischemic episodes; the incidences of light anesthesia and awareness; the amount of PCA morphine that was consumed during the first 24 hours after extubation; the durations of the ICU and hospital stays; the costs; and the 30-day mortality. The costs of cumulative doses of propofol, sufentanil, and postoperative mechanical ventilation were calculated at the authors’ center to be equivalent to US $3.8/200 mg, US $0.5/10 g, and US $50 per hour ventilation, respectively. A pilot study showed that the normally distributed mean time to tracheal extubation after sufentanil, 0.4 ng/mL, was 290 minutes (SD, 46.9 min). A priori power analysis indicated that a sample size of 14 for each group was sufficiently large to detect 25% changes in the time to extubation after the administration of sufentanil, 0.4 ng/mL, with a type-I error of 0.017 (0.05/3 possible comparisons) and a power of 90%. This sample size was increased by 10% to compensate for patients dropping out during the study. The data were tested for normality using the Kolmogorov-Smirnov test. Repeated-measures analysis of variance was used to analyze serial changes in the patient data at different times. The Fisher exact test was used for categoric data. Repeated measures analysis of variance (ANOVA) was used for continuous parametric variables and the differences were corrected by
66
EL TAHAN AND KHIDR
Table 1. Patient Data for Target Effect-Site Concentrations of Sufentanil, 0.2, 0.3, or 0.4 ng/mL
Age (years) Men/women Weight (kg) Height (cm) EuroSCORE LVEF -Blockers CCBs ACE inhibitors Types of surgery Aortic valve Mitral valve Double-valve surgery Triple-valve surgery Underlying pathology Aortic stenosis Aortic regurgitation Mitral stenosis Mitral regurgitation Tricuspid regurgitation Aortic stenosis and mitral regurgitation Aortic regurgitation and mitral stenosis CPB time (min) Aortic clamping time (min) Surgical duration (min)
0.2 ng/mL (n ⫽ 16)
0.3 ng/mL (n ⫽ 16)
0.4 ng/mL (n ⫽ 16)
39.5 [23] 11/5 69.9 (8.95) 167.4 (6.39) 3.9 [13] 0.56 (0.07) 6 (37.5%) 1 (6.25%) 6 (37.5%)
38.5 [31] 14/2 70.9 (10.82) 166.3 (4.35) 4.2 [9] 0.54 (0.04) 9 (56.3%) 4 (25%) 8 (50%)
35 [29] 12/4 70.3 (7.84) 165.8 (5.34) 4.3 [13] 0.52 (0.09) 8 (50%) 2 (12.5%) 10 (62.5%)
5 (31.3%) 9 (56.3%) 2 (12.5%) 0 (0.0%)
6 (37.5%) 8 (50%) 1 (6.25%) 1 (6.25%)
4 (25%) 10 (62.5%) 2 (12.5%) 0 (0.0%)
3 (18.8%) 2 (12.5%) 8 (50%) 1 (6.25%) 0 (0.0%) 1 (6.25%) 1 (6.25%) 124.9 (30.92) 48.4 (21.8) 263.5 (26.9)
5 (31.3%) 1 (6.25%) 6 (37.5%) 2 (12.5%) 1 (6.25%) 0 (0.0%) 1 (6.25%) 117.9 (20.65) 52.1 (17.6) 255.9 (28.9)
2 (12.5%) 2 (12.5%) 8 (50%) 2 (12.5%) 0 (0.0%) 1 (6.25%) 1 (6.25%) 125.4 (15.73) 59.4 (19.7) 278.9 (31.4)
NOTE. Data are presented as median [range], number (percentage), or mean (SD). Abbreviations: ACE, angiotensin-converting enzyme; CCBs, calcium channel blockers; CPB, cardiopulmonary bypass; EuroSCORE, European System for Cardiac Operative Risk Evaluation; LVEF, left ventricular ejection fraction.
the post hoc Bonferroni test. The Kruskal-Wallis test was performed for intergroup comparisons for nonparametric values and post hoc pairwise comparisons were performed using the Wilcoxon rank-sum t test. The data were expressed as means (SD), number (percentage), or median [range]. A p value ⬍0.05 was considered to represent statistical significance. Univariate variables included age; sex; European System for Cardiac Operative Risk Evaluation (EuroSCORE); left ventricular ejection fraction; the durations of CPB, aortic cross-clamping, and surgery; the number of changes in target propofol Ce; and the cumulative doses of propofol and sufentanil. To identify the independent predictors that influenced the times to spontaneous eye opening, return of spontaneous breathing, and tracheal extubation, these variables were examined in a stepwise manner in a multivariate logistic regression model, with entry and retention set at a significance level of p ⬍ 0.05. RESULTS
All 48 patients with valve disease who were enrolled completed the study. These patients were assigned randomly into 3 groups (n ⫽ 16 per group) that received sufentanil, 0.2, 0.3, and 0.4 ng/mL, respectively. The patient characteristics and intraoperative hemodynamic variables of the 3 groups are presented in Tables 1 and 2, respectively. Compared with the sufentanil Ce 0.4-ng/mL group, the Ce 0.2- and 0.3-ng/mL groups had significantly shorter times to eye opening, spontaneous breathing, and extubation (112.2 min [SD, 16.9] and 161.9 min [32.9] v 271.3 min [27.4], respectively; p ⬍ 0.001) and required more frequent changes in propofol Ce (p ⬍ 0.001) and higher cumulative doses of propofol (p ⬍ 0.001; Table 3). Compared with the sufentanil Ce
0.4-ng/mL group, the sufentanil Ce 0.2-ng/mL group had a significantly longer duration from induction to intubation (p ⬍ 0.05) and required smaller cumulative doses of sufentanil (p ⬍ 0.001) and a larger number of changes in propofol Ce (p ⬍ 0.001; Table 3). The sufentanil Ce 0.2-ng/mL group also differed significantly from the Ce 0.3-ng/mL group in terms of the cumulative dose of propofol and the times to eye opening, spontaneous breathing, and extubation (p ⬍ 0.001; Table 3). The 3 groups did not differ significantly in the number of changes in sufentanil Ce the number of episodes with SE values ⬎50; the incidence of light anesthesia; the number and total duration of intraoperative ischemic episodes; the number of patients who received rescue doses of nitroglycerin, esmolol, and ephedrine; the incidence of awareness; the amount of PCA morphine that was consumed; the durations of ICU and hospital stays; 30-day mortality (Table 3); or cardiac troponin I Ce (Table 4). There was 1 death on postoperative day 10 from postoperative mediastinitis that was unrelated to sufentanil administration (Table 3). Compared with the sufentanil Ce 0.4-ng/mL group, the costs of sufentanil and postoperative ventilation were significantly lower in the groups that received sufentanil Ce 0.2 and 0.3 ng/mL (Table 3). Moreover, compared with the sufentanil Ce 0.3-ng/mL group, the costs of cumulative propofol and cumulative sufentanil were 56% higher and 34% lower for the Ce 0.2-ng/mL group, respectively (Table 3). Multivariate logistic regression showed that the number of changes in propofol Ce and the cumulative doses of propofol
LOW SUFENTANIL EFFECT-SITE CONCENTRATION FOR VALVE SURGERY
67
Table 2. Intraoperative Hemodynamic Changes in Target Effect-Site Concentrations of Sufentanil, 0.2, 0.3, or 0.4 ng/mL (n ⴝ 16 for Each) After CPB Baseline
Heart rate (beats/min) 0.2 ng/mL 0.3 ng/mL 0.4 ng/mL MAP (mmHg) 0.2 ng/mL 0.3 ng/mL 0.4 ng/mL CI (L/min/m2) 0.2 ng/mL 0.3 ng/mL 0.4 ng/mL SVRI (dynes · s · cm⫺5/m2) 0.2 ng/mL 0.3 ng/mL 0.4 ng/mL
Intubation
Skin Incision
Sternotomy
15 min
45 min
77 (14.76) 81 (13.06) 76 (13.66)
90 (11.90) 85 (12.62) 88 (11.42)
84 (8.17) 87 (7.94) 90 (6.16)
75 (11.20) 87 (12.39) 79 (5.38)
92 (6.37) 89 (11.40) 95 (7.31)
85 (8.66) 91 (11.12) 86 (9.54)
97 (16.19) 99 (17.75) 101 (11.09)
108 (19.49) 112 (15.81) 105 (15.03)
98 (15.38) 105 (10.34) 96 (12.94)
104 (11.64) 100 (15.21) 98 (14.01)
78 (14.84) 75 (12.86) 77 (12.84)
96 (13.23) 93 (9.27) 99 (7.13)
2.6 (0.35) 2.7 (0.44) 2.6 (0.30)
2.5 (0.44) 2.6 (0.38) 2.7 (0.48)
2.6 (0.46) 2.8 (0.63) 2.7 (0.55)
2.5 (0.42) 2.4 (0.35) 2.5 (0.49)
2.9 (0.53) 2.8 (0.45) 3.2 (0.60)
2157 (527.6) 2190 (480.6) 2157 (545.2)
2045 (443.8) 2240 (490.9) 1982 (355.6)
2138 (460.1) 2016 (391.0) 2095 (470.3)
1740 (213.8) 1895 (341.4) 1967 (424.6)
2335 (512.6) 1960 (466.6) 2149 (495.9)
NOTE. Data are presented as mean (SD). Abbreviations: CI, cardiac index; CPB, cardiopulmonary bypass; MAP, mean arterial blood pressure; SVRI, systemic vascular resistance index.
and sufentanil were independent factors that influenced the times to spontaneous eye opening, spontaneous breathing, and extubation in patients undergoing valve surgery (Table 5). In addition, the duration of surgery and the EuroSCORE values were independent factors for the times to spontaneous eye opening and extubation, respectively (Table 5). DISCUSSION
Changing the anesthetic technique by switching from highdose to low-dose opioid anesthesia has been shown to shorten the extubation time and length of hospitalization,10 decrease persistent hypersensitivity and allodynia,11,12 and lessen postoperative complications.10 RE and SE are superior to the bispectral index for monitoring the depth of anesthesia during cardiac surgery because of their greater resistance to artifacts.13,14 Entropy is used to guide the management of anesthesia in which the endpoints are an SE ⬍50 and an SE-RE difference ⬍10.15 Noxious stimulation widens the difference between RE and SE without predicting the analgesic requirements of paralyzed patients.16,17 The present study showed that, compared with a target sufentanil Ce of 0.4 ng/mL, a target sufentanil Ce of 0.2 to 0.3 ng/mL during TCI of propofol anesthesia for valve surgery was associated with shorter times to spontaneous breathing, eye opening, and extubation; more frequent changes in target propofol Ce; higher cumulative doses of propofol; and comparable hemodynamic stability and incidences of light anesthesia, awareness, and myocardial ischemia. Multivariate logistic regression showed that the number of changes in target propofol Ce, the cumulative doses of propofol and sufentanil, and the EuroSCORE values were independent factors that influenced the time to extubation in patients undergoing valve surgery. In one study, compared with lower sufentanil Ce (0.35 and 0.5 ng/mL), the higher sufentanil Ce of 0.65, 0.8, and 1.0 ng/mL did not provide further advantages for the time to extubation and stress response control.4 This was because these
investigators continued target propofol infusion in the ICU for ⱖ2 hours. Other studies have reported that the electroencephalographic responses during CABG procedures can be controlled with a sufentanil Ce as low as 0.5 ng/mL.3,4 Moreover, two studies have reported that sufentanil Ce 0.2 ng/mL is associated with a favorable response to intubation.18,19 In the present study, the highest sufentanil Ce that was used, which is similar to the lowest Ce used by others,3,4 served as the comparative control arm for the sufentanil Ce 0.2- and 0.3-ng/mL groups. The low sufentanil Ce of 0.2 and 0.3 ng/mL were found to be of clinical importance in the present study because, compared with sufentanil Ce 0.4 ng/mL, they were associated with significant decreases in the times to eye opening (⫺71% and ⫺39%, respectively), spontaneous breathing (⫺76% and ⫺49%, respectively), and extubation (⫺59% and ⫺40%, respectively). The cumulative sufentanil doses of the Ce 0.2-, 0.3-, and 0.4-ng/mL groups were 1.3 g/kg (0.5), 2.0 g/kg (0.35), and 2.2 g/kg (0.42), respectively. Similarly, others have reported that the use of sufentanil, 1.7 g/kg (1.4-2.0), was associated with an extubation time of 4.7 hours after cardiac surgery.20 The ranges in time to extubation after cardiac surgery under standardized fentanyl and remifentanil anesthesia are 0.25 to 7.82 and 0.18 to 6.81 hours, respectively,20,21 which were comparable to the ranges in times to extubation of the sufentanil Ce 0.2- and 0.3-ng/mL groups in the present study (1.5 to 2.7 and 1.8 to 3.7 h, respectively). In the present study, the anesthetic depth during heart valve surgery was standardized using a propofol Ce of 1.0 to 4.5 g/mL. As observed previously,4 compared with sufentanil Ce 0.4 ng/mL, the low sufentanil Ce of 0.2 and 0.3 ng/mL required frequent adaptation of the target propofol Ce to achieve the authors’ predefined targets. The higher cumulative propofol doses that were used in the sufentanil Ce 0.2- and 0.3-ng/mL groups are comparable to the median cumulative propofol doses that have been reported by others4; similarly, the authors
68
EL TAHAN AND KHIDR
Table 3. Outcome Data in Target Effect-Site Concentrations of Sufentanil, 0.2, 0.3, or 0.4 ng/mL 0.2 ng/mL (n ⫽ 16)
0.3 ng/mL (n ⫽ 16)
0.4 ng/mL (n ⫽ 16)
7.9 (1.22)* 12 [5-20]‡ 0 [0-3] 3 (18.8%) 2672 (280)†‡ 91 (13.9)‡ 4.5 [2-10]
5.7 (1.36) 8 [3-13]‡ 0 [0-2] 2 (12.5%) 1705 (294.5)‡ 136 (14.1) 7 [3-11]
4.0 (1.31) 5.5 [3-13] 0 [0-2] 1 (6.25%) 1444 (269.6) 153 (26.8) 5 [2-9]
2 (12.5%) 1 (6.25%) 3 (18.8%) 2 (12.5%) 1 (6.25%) 0 [5] 1.6 (2.85) 4 (25%) 1 (6.25%) 3 (18.8%) 24.8 (7.8)†‡ 32.7 (19.9)†‡ 112.2 (16.9)†‡ 1 (6.25%) 17 [7-42] 3.7 (1.62) 14.2 (5.13) 0 (0.0%)
1 (6.25%) 1 (6.25%) 2 (12.5%) 2 (12.5%) 0 (0.0%) 0.5 [4] 2.4 (3.03) 4 (25%) 1 (6.25%) 4 (25%) 52.6 (12.5)‡ 70.1 (27.2)‡ 161.9 (32.9)‡ 0 (0.0%) 18.5 [9-40] 4.2 (1.72) 12.3 (3.40) 1 (6.25%)
1 (6.25%) 1 (6.25%) 1 (6.25%) 1 (6.25%) 0 (0.0%) 0 [3] 1.5 (2.25) 5 (31.3%) 0 (0.0%) 2 (12.5%) 85.6 (10.0) 137.5 (20.8) 271.3 (27.4) 0 (0.0%) 19 [8-40] 3.5 (1.03) 11.6 (4.87) 0 (0.0%)
50.76 (5.32)†‡ 4.5 (0.69)†‡ 93.5 (14.11)†‡
32.4 (5.59)* 6.8 (0.70) 134.9 (27.45)‡
27.4 (5.12) 7.6 (1.34) 226.0 (22.85)
Time from induction to intubation (min) Changes of propofol target (n) Changes of sufentanil target (n) Patients needed changes in sufentanil target Cumulative doses of propofol (mg) Cumulative doses of sufentanil (g) Number of SE episodes ⬎50 Incidences of light anesthesia in response to Intubation Skin incision Sternotomy Maximal sternal spread Sternal wire placement Intraoperative ischemic episodes (n) Total time of intraoperative ischemic episodes (min) Rescue nitroglycerin Rescue esmolol Rescue ephedrine Time to eye opening (min) Time to spontaneous breathing (min) Time to extubation (min) Awareness and recall PCA morphine consumption (mg) ICU length of stay (days) Hospital length of stay (days) 30-Day mortality rate Costs (US$) Propofol Sufentanil Postoperative ventilation
NOTE. Data are presented as mean (SD), median [minimum-maximum], median [range], or number (percentage). Abbreviations: ICU, intensive care unit; PCA, patient-controlled analgesia; rescue, number of patients who received rescue doses of nitroglycerin, ephedrine, and esmolol; SE, state entropy; US$, US dollars. *p ⬍ 0.05 significant compared with 0.4 ng/dL. †p ⬍ 0.001 significant compared with 0.3 ng/dL ‡p ⬍ 0.001 significant compared with 0.4 ng/dL.
did not observe any hemodynamic derangements or increases in the need for vasoactive medications. The 0.2-ng/mL Ce clearly doubled the time to intubation. However, this was not of clinical importance and it did not increase the total cost because the Ce 0.2-ng/mL Ce also markedly decreased the time to extubation. There were 10, 11, and 9 episodes of SE that exceeded 50 in the sufentanil Ce 0.2-, 0.3-, and 0.4-ng/mL groups, respectively. Sim-
Table 4. Perioperative Cardiac Troponin I Changes in Target EffectSite Concentrations of Sufentanil, 0.2, 0.3, or 0.4 ng/mL
Baseline (g/L) Postoperative (g/L) 3h 12 h 24 h 48 h
0.2 ng/mL (n ⫽ 16)
0.3 ng/mL (n ⫽ 16)
0.4 ng/mL (n ⫽ 16)
0.20 (0.15)
0.25 (0.19)
0.30 (0.23)
8.71 (4.09) 19.93 (6.54) 26.86 (5.97) 18.52 (6.54)
7.76 (3.37) 16.58 (5.93) 27.53 (7.68) 16.37 (6.59)
8.8 (4.58) 17.06 (4.58) 28.09 (7.48) 15.50 (4.27)
NOTE. Data are presented as mean (SD).
ilarly, when sufentanil Ce 0.8 ng/mL was used previously during TCI of propofol for CABG procedures; 10 episodes of the bispectral index that exceeded 60 were observed.4 In the present study, as in other studies,3,4 the use of sufentanil Ce 0.2, 0.3, and 0.4 ng/mL was associated with hemodynamic stability. Based on a previous study,22 the authors considered that using 0.05-ng/mL increments in sufentanil Ce would obtund the entropy and hemodynamic responses to noxious stimuli. In contrast, others have used higher sufentanil Ce increments of 0.25 ng/mL4 or 0.34 ng/mL.3 The latter investigators did not need to increase the sufentanil Ce in any patient to suppress hemodynamic responsiveness during the use of a constant sufentanil Ce of 0.59 ⫾ 0.13 ng/mL; their cumulative sufentanil dose was 1.59 g/kg (0.40), which was comparable to the present results.3 The authors expected that 4 sufentanil Ce increments of 0.05 ng/mL would double the infusion rate in the Ce 0.2-ng/mL group to 0.4 ng/mL ([0.05 ng/mL ⫻ 4] ⫹ 0.2 ng/mL). In the Ce 0.4-ng/mL group, the authors expected that the 4 increments would result in only a 50% increase (ie, 0.2 ⫹ 0.4 ng/mL) in the Ce. However, the 3 groups had similar
LOW SUFENTANIL EFFECT-SITE CONCENTRATION FOR VALVE SURGERY
69
Table 5. Independent Factors for Primary Outcomes by Multivariate Analysis Spontaneous Eye Opening
Age Sex EuroSCORE LVEF CPB time Aortic cross-clamping time Surgery time Changes of propofol target Cumulative doses of propofol Cumulative doses of sufentanil
95% CI
p Value
⫺0.63 to 2.00 ⫺21.70 to 32.14 ⫺3.32 to 2.92 ⫺163.37 to 128.68 ⫺0.34 to 0.35 ⫺0.93 to 1.22 ⫺0.63 to 1.25 ⫺4.89 to 0.81 ⫺0.06 to ⫺0.001 ⫺0.12 to 1.01
0.409 0.984 0.461 0.25 0.991 0.418 0.019 0.032 ⬍0.001 ⬍0.001
Spontaneous Breathing 95% CI
⫺0.34 to 0.84 ⫺8.26 to 16.01 ⫺1.18 to 1.63 ⫺73.88 to 57.78 ⫺0.71 to 0.56 ⫺0.46 to 0.51 ⫺0.48 to 0.37 ⫺2.37 to 0.20 ⫺0.04 to ⫺0.008 ⫺0.01 to 0.50
Extubation Time
p Value
95% CI
p Value
0.974 0.985 0.171 0.608 0.819 0.79 0.994 0.045 0.002 0.007
⫺0.10 to 3.46 ⫺32.10 to 40.64 ⫺3.28 to 5.14 ⫺113.62 to 280.81 ⫺0.71 to 1.14 ⫺1.92 to 0.98 ⫺1.34 to 1.20 ⫺7.76 to ⫺0.05 ⫺0.09 to 0.02 ⫺0.34 to 1.18
0.468 0.854 0.001 0.537 0.636 0.816 0.382 ⬍0.001 ⬍0.001 0.006
Abbreviations: CI, confidence interval; CPB, cardiopulmonary bypass; EuroSCORE, European System for Cardiac Operative Risk Evaluation; LVEF, left ventricular ejection fraction.
numbers of changes in the sufentanil Ce. TCI of sufentanil was discontinued after sternal closure to shorten the recovery and extubation times, because others23 have found that terminating sufentanil, 0.3 to 0.5 ng/mL, 50 minutes before the end of colon surgery was associated with a faster recovery. Brice et al9 defined intraoperative awareness as the presence of explicit memory. In contrast to others who have reported an intraoperative awareness of only 0.2% to 0.3%,24 awareness in the present study in 1 patient in the sufentanil 0.2-ng/mL group was as high as 6.25%. However, the present study was not powered to test the risk of intraoperative awareness and recall. Further powered studies are needed to test the incidence of awareness during the use of low sufentanil Ce for cardiac surgery. The cumulative PCA morphine consumptions of the 3 groups were similar. The use of low sufentanil Ce did not shorten the median durations of ICU and hospital stays, which were longer than those reported for standard remifentanil and fentanyl cardiac anesthesia,18 because patients who were referred from far distances to the authors’ district hospital had to have longer hospital stays (1-2 days before surgery and ⱖ9 days after surgery). Moreover, the authors’ center mandates a stay of ⱖ2 days in the ICU after cardiac surgery. It is becoming increasingly important to lower the costs of fast-track cardiac anesthesia. In the present study, the use of low
sufentanil Ce decreased the overall cost of propofol, sufentanil, and postoperative ventilation by 44% (Ce 0.2-ng/mL group) and 33% (Ce 0.3-ng/mL group). The authors did not include the costs of the operating room equipment, medications other than anesthetics, disposables, and ICU and hospital stays in their cost analyses because the costs of these factors vary depending on the manufacturer and supplier, and this would have complicated the present calculations. The authors’ costs may not have been comparable to those reported by others because of the variations in the costs of controlled drugs from 1 country to another and the rapid changes in the prices of these drugs over time. The present study had several limitations. First, the benefits of a low target sufentanil Ce could be extended to patients who are eligible for early on-table extubation, but this could not be tested because it is not approved by the authors’ center. Second, the present study was not powered statistically to test the incidences of intraoperative awareness and myocardial ischemia in the study population. Third, a double-blinded study design was not used for the intraoperative titration protocol that was used to control entropy and hemodynamic variables. However, this bias was limited by ensuring that the assessor who collected the patient data was blinded to the assigned group. In conclusion, compared with sufentanil Ce of 0.4 ng/mL, lower Ce (0.2 and 0.3 ng/mL) promoted faster recovery and times to extubation after valve surgery performed under TCI of propofol.
REFERENCES 1. Steinlechner B, Dworschak M, Birkenberg B, et al: Low-dose remifentanil to suppress haemodynamic responses to noxious stimuli in cardiac surgery: A dose-finding study. Br J Anaesth 98:598603, 2007 2. Hudson RJ, Henderson BT, Thomson IR, et al: Pharmacokinetics of sufentanil in patients undergoing coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 15:693-699, 2001 3. Thomson IR, Harding G, Hudson RJ: A comparison of fentanyl and sufentanil in patients undergoing coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 14:652-656, 2000 4. Forestier F, Hirschi M, Rouget P, et al: Propofol and sufentanil titration with the bispectral index to provide anesthesia for coronary artery surgery. Anesthesiology 99:334-346, 2003 5. El-Tahan MR: Preoperative ephedrine counters hypotension with propofol anesthesia during valve surgery: A dose dependent study. Ann Card Anaesth 14:30-40, 2011
6. Gepts E, Shafer SL, Camu F, et al: Linearity of pharmacokinetics and model estimation of sufentanil. Anesthesiology 83:1194-1204, 1995 7. Schnider TW, Minto CF, Shafer SL, et al: The influence of age on propofol pharmacodynamics. Anesthesiology 90:1502-1516, 1999 8. Hirschi M, Meistelman C, Longrois D: Effects of normothermic cardiopulmonary bypass on bispectral index. Eur J Anaesthesiol 17: 499-505, 2000 9. Brice DD, Hetherington RR, Utting JE: A simple study of awareness and dreaming during anaesthesia. Br J Anaesth 42:535-542, 1970 10. Cheng D: Anesthetic techniques and early extubation: Does it matter? J Cardiothorac Vasc Anesth 14:627-630, 2000 11. Célèrier E, Rivat C, Jun Y, et al: Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine. Anesthesiology 92:465-472, 2000
70
12. Célèrier E, Laulin J, Larcher A, et al: Evidence for opiateactivated NMDA processes masking opiate analgesia in rats. Brain Res 847:18-25, 1999 13. Baulig W, Seifert B, Schmid ER, et al: Comparison of spectral entropy and bispectral index electroencephalography in coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 24:544-549, 2010 14. Arutiunian OM, Iavorovskiı˘ AG, Guleshov VA, et al: [Role of entropy-based neuromonitoring during cardiac surgery]. Anesteziol Reanimatol 5:78-82, 2010 15. Riad W, Schreiber M, Saeed AB: Monitoring with EEG entropy decreases propofol requirement and maintains cardiovascular stability during induction of anaesthesia in elderly patients. Eur J Anaesthesiol 24:684-688, 2007 16. Dierckens E, Fleyfel M, Robin E, et al: [Is entropy a monitor for the guidance of intraoperative analgesia?] Ann Fr Anesth Reanim 26:113-118, 2007 17. Takamatsu I, Ozaki M, Kazama T: Entropy indices vs the bispectral index for estimating nociception during sevoflurane anaesthesia. Br J Anaesth 96:620-626, 2006 18. Jung SM, Yang CW, Oh JY, et al: Predicted effect-site concentration of propofol and sufentanil for gynecological laparoscopic surgery. Acta Anaesthesiol Scand 55:110-117, 2011
EL TAHAN AND KHIDR
19. Sun CJ, Gu MN, Xu JS: Narcotrend index monitoring can predict the recovery of consciousness in patients undergoing abdominal surgery. Nan Fang Yi Ke Xue Xue Bao 30:1379-1381, 2010 20. Engoren M, Luther G, Fenn-Buderer N: A comparison of fentanyl, sufentanil, and remifentanil for fast-track cardiac anesthesia. Anesth Analg 93:859-864, 2001 21. Cheng DC, Newman MF, Duke P, et al: The efficacy and resource utilization of remifentanil and fentanyl in fast-track coronary artery bypass graft surgery: A prospective randomized, doubleblinded controlled, multi-center trial. Anesth Analg 92:1094-1102, 2001 22. Slepchenko G, Simon N, Goubaux B, et al: Performance of target-controlled sufentanil infusion in obese patients. Anesthesiology 98:65-73, 2003 23. Yang XY, Xu X, Wu XM: [Effect of target-controlled infusion sufentanil in different doses combined with nitrogen monoxide inhalation on hemodynamics and postoperative recovery]. Zhonghua Yi Xue Za Zhi 87:3325-3328, 2007 24. Groesdonk HV, Pietzner J, Borger MA, et al: The incidence of intraoperative awareness in cardiac surgery fast-track treatment. J Cardiothorac Vasc Anesth 24:785-789, 2010
0.3-ng/mL groups had shorter times to eye opening (24.8 min [SD 7.8] and 52.6 min [12.5] v 85.6 min [10.0], respectively), spontaneous breathing (32.7 min [19.9] and 70.1 min [27.2] v 137.5 min [20.8], respectively), and extubation (112.2 min [16.9] and 161.9 min [32.9] v 271.3 min [27.4], respectively; p < 0.001), more frequent changes in propofol concentrations (p < 0.001), higher cumulative propofol doses, lower cumulative sufentanil doses, and 33% to 44% lower total cost (p < 0.001). Incidences of light anesthesia and myocardial ischemia and intensive care unit and hospital stays were similar for all groups. Conclusions: Compared with sufentanil Ce of 0.4 ng/mL, lower concentrations (0.2 and 0.3 ng/mL) promoted faster recovery and shorter times to extubation after valve surgery performed under target-controlled propofol infusion. © 2012 Elsevier Inc. All rights reserved.
F
prospective, randomized, blinded, and controlled study at the authors’ center after obtaining approval from the local ethics committee and informed written consent from all participants. The patients were allocated randomly into 3 groups (n ⫽ 16 per group) that would receive sufentanil Ce of 0.2, 0.3, and 0.4 ng/mL, respectively; this would be continued until sternal closure was completed, as detailed in the authors’ protocol (Figs 1 and 2). This protocol was created based on a study by Forestier et al4 to control entropy and the hemodynamic responses to noxious stimuli. The subjects were allocated randomly into the 3 groups by drawing sequentially numbered sealed opaque envelopes that each contained a software-generated randomization code. Patients with documented uncontrolled hypertension; ischemic heart disease; left ventricular ejection fraction ⬍45%; severe pulmonary hypertension (mean pulmonary artery pressure ⬎45 mmHg); critical aortic stenosis; pulmonary, hepatic, renal, neuromuscular, neuropsychiatric, and endocrine diseases; body mass index ⬎35 kg/m2; pregnancy; use of antipsychotics or alcohol; drug abuse; repeat or emergency surgery; those requiring preoperative circulatory or ventilatory support; and those whose electrocardiographic characteristics would interfere with ST-segment monitoring were excluded from the study. All patients were premedicated with oral lorazepam 1 to 2 mg the night before surgery and 90 minutes before arrival in the operating room. The patients were monitored by a pulse oximeter, 5-lead electrocardiograph (leads II and V5) with continuous ST-segment recording, radial mean arterial blood pressure (MAP) measurements, endtidal carbon dioxide measurements, a pulmonary artery catheter, and rectal and nasopharyngeal temperature measurements. Significant isch-
AST-TRACK VALVE SURGERY is performed frequently at the authors’ center in unique younger patients with a lower body mass index than those in other countries. Low-dose opioid anesthesia is used commonly because of the ceiling effect of opioids in attenuating cardiovascular responses to noxious stimuli.1 Target-controlled effect-site concentrations (Ce) of sufentanil (range, 0.4-4.5 ng/mL) have been successful in providing stable analgesia and hemodynamics during coronary artery bypass grafting (CABG).2,3 Moreover, Forestier et al4 investigated the effect of different sufentanil Ce (0.5, 0.75, 1, 1.25, and 1.5 ng/mL) at the induction of anesthesia, decreased by one third after sternotomy, on the predicted propofol Ce based on bispectral index values during CABG procedures in response to a nociceptive stimulus, such as tracheal intubation. Sufentanil Ce of 1.25 ng/mL has been associated with the lowest predicted propofol Ce along with hemodynamic tolerance. However, it also has been associated with long times to spontaneous eye opening and tracheal extubation (mean, 320 and 380 min, respectively). In addition, the lower sufentanil Ce (range, 0.35-0.65 ng/mL) have been associated with similar degrees of hemodynamic tolerance to the 1.25- and 1.5-ng/mL Ce. The authors hypothesized that using low rather than high sufentanil Ce during target-controlled infusion (TCI) of propofol anesthesia for valve surgery could decrease the time to tracheal extubation. This study aimed to investigate the effects of 3 sufentanil Ce (0.2, 0.3, and 0.4 ng/mL) on the time to tracheal extubation, hemodynamics, recovery times, and incidences of myocardial ischemia, light anesthesia, and awareness during TCI of propofol anesthesia for patients undergoing elective valve surgery. METHODS Forty-eight patients 18 to 55 years old with American Society of Anesthesiologists (ASA) III-IV who were scheduled for elective valve surgery and were eligible for early extubation were included in this
KEY WORDS: anesthesia, sufentanil, propofol, target-controlled infusion, cardiac surgery, fast track
From the *Department of Anesthesiology, King Fahd Hospital, University of Dammam, Al Khubar, Saudi Arabia; and †Cardiothoracic Anesthesia Unit, Mansoura University, Mansoura City, Egypt. Address reprint requests to Mohamed R. El-Tahan, MD, Department of Anesthesiology, King Fahd Hospital, University of Dammam, Al Aqrabiah Street, PO Box 40289, Al Khubar 31952, Saudi Arabia. E-mail: [email protected] © 2012 Elsevier Inc. All rights reserved. 1053-0770/2701-0001$36.00/0 doi:10.1053/j.jvca.2012.01.023
Journal of Cardiothoracic and Vascular Anesthesia, Vol 27, No 1 (February), 2013: pp 63-70
63
64
EL TAHAN AND KHIDR
Fig 1. Algorithm for the intraoperative anesthetic management. Ce, target effect-site concentration; HR, heart rate; IV, intravenous; MAP, mean arterial blood pressure; NTG, nitroglycerin; RE-SE, difference between response entropy and state entropy; SE, state entropy.
emic responses were defined as reversible ST-segment changes from baseline, namely a ⱖ1-mV ST-segment depression or a ⱖ2-mV STsegment elevation that lasted for ⱖ1 minute.5 Response entropy (RE) and state entropy (SE) were monitored by applying entropy electrodes (Datex-Ohmeda Division, Instrumentarium Corporation, Helsinki, Finland) according to the manufacturer’s recommendations. An independent anesthesiologist who was not involved in collecting patient data initiated the sufentanil Ce (the model of Gepts et al6) according to the patient’s randomization code and was allowed to
titrate the target propofol and sufentanil Ce and to administer vasoactive medications as needed. After preoxygenation, anesthesia was induced by simultaneous target propofol and sufentanil infusions using the TCI system with syringe pumps (Injectomat TIVA Agilia, Fresenius Kabi, France). The target propofol Ce (model of Schnider et al7) was initiated at 1.0 g/mL and titrated stepwise by 0.5 g/mL every 3 minutes until loss of consciousness and until an SE ⬍50 and a difference ⬍10 between RE and SE (RE-SE) were achieved. Cisatracurium, 0.2 mg/kg, was
LOW SUFENTANIL EFFECT-SITE CONCENTRATION FOR VALVE SURGERY
Intubation
Skin incision
Sternotomy
Sternal spread
CPB
Discontinuation of CPB
65
Homeostasis
Sternal closure
Skin closure End of surgery
Sufentanil of Ce 0.2 ng/mL, in group Ce 0.2 ng/mL. Stop infusion
Sufentanil of Ce 0.3 ng/mL, in group Ce 0.3 ng/mL. Sufentanil of Ce 0.4 ng/mL, in group Ce 0.4 ng/mL. Propofol of Ce 1.0 – 4.5 µg/mL. Cisatracurium of 0.2 mg/kg, followed with 1 – 3 µg/kg/min.
Fig 2.
Stop infusion Stop infusion
Schematic presentation of the anesthetic plan. CPB, cardiopulmonary bypass; Ce, target effect-site concentration.
given to facilitate tracheal intubation, and the lungs were ventilated with a fraction of inspired oxygen of 0.5 to maintain normocapnia. The time from induction to intubation was recorded. Anesthesia was maintained by changing the propofol Ce at increments of 0.5 g/mL (range, 1-4.5 g/mL) every 3 minutes as necessary to maintain an SE ⬍50, an RE-SE difference ⬍10, and an MAP and heart rate (HR) that were ⱕ20% of the baseline values. The sufentanil Ce was increased by a maximum of 4 increments of 0.05 ng/mL when the SE was ⬎50, the RE-SE difference was ⬎10, and the MAP and HR were ⱖ20% of the baseline values despite a target propofol Ce ⬎4.5 g/mL. When the SE was ⬍50 and the RE-SE difference was ⬍10, the propofol Ce was decreased gradually to ⱖ1 g/mL, followed by gradual decreases in sufentanil Ce by 0.05 ng/mL, until the randomized Ce was achieved. The HR and MAP were kept within 20% of baseline values by achieving an adequate depth of anesthesia (SE ⬍50 and RE-SE difference ⬍10), optimum analgesia, and the administration of nitroglycerin, 0.05 mg, and esmolol, 20 mg (Fig 1). Cisatracurium, 1 to 3 g/kg/min, was used to maintain surgical relaxation. All patients received tranexamic acid, 50 mg/kg. Light anesthesia was defined as an episode with SE values ⬎50 and/or MAP and HR values ⬎20% above baseline that lasted for ⬎3 consecutive minutes. The incidences of light anesthesia in response to intubation, skin incision, sternotomy, maximal sternal spread, and sternal wire placement were recorded. Hemodynamic control was standardized according to the authors’ protocol.5 Hypotension (defined as ⬍20% decrease in mean baseline MAP) was treated with boluses of fluids, ephedrine 5 mg, or epinephrine, 5 g, as needed. Hypertension (defined as ⬎20% increase in mean baseline MAP) was treated by deepening anesthesia and administering doses of nitroglycerin, 0.05 mg, or labetalol, 20 mg. Tachycardia (defined as ⬎20% increase in mean baseline HR) was treated with esmolol, 20 mg. All operations were performed by the same surgeons. Heparin, 300 IU/kg, was given to achieve an activated coagulation time ⬎480 seconds. A standardized hypothermic cardiopulmonary bypass (CPB) was used. Similar to a previous study,8 the target propofol Ce and sufentanil Ce were continued throughout surgery and CPB without any further adjustments because of CPB per se. Before separation from CPB, all patients were rewarmed to a rectal temperature of 36°C and dobutamine, epinephrine, norepinephrine, and nitroglycerin were used as needed. Heparin was neutralized with protamine sulfate. The cisatracurium infusion was discontinued after surgical homeostasis was achieved. The target sufentanil Ce and propofol Ce were discontinued after sternal closure and skin closure, respectively (Fig 2). The HR, MAP, and cardiac and systemic vascular resistance indices were recorded before (baseline) and 15 minutes after endotracheal intubation, 15 minutes after skin incision, 15 minutes after sternotomy, and 15 and 45 minutes after discontinuing CPB. Patients were transferred to the intensive care unit (ICU) in a ventilated state using the synchronized intermittent mandatory mode or
the pressure support mode. Postoperative analgesia was provided by intravenous paracetamol, lornoxicam, and patient-controlled analgesia (PCA), morphine 1 mg, with a lockout interval of 8 minutes and a maximum 4-hourly limit of 30 mg. Extubation criteria included alertness, a train-of-four ratio ⱖ0.9, spontaneous breathing with a tidal volume ⬎5 mL/kg, respiratory rates ⬎10 and ⬍28 breaths/min, a maximum inspiratory pressure ⱕ⫺20 cm H2O, stable hemodynamics without high doses of inotropic support or severe arrhythmias, bleeding ⬍100 mL/h, a core temperature ⬎35.5°C, a urine output ⬎0.5 mL/ kg/h, an arterial carbon dioxide tension ⱕ45 mmHg, an arterial oxygen tension ⬎100 mmHg, and a fraction of inspired oxygen ⬍0.5. Blood samples were drawn before CPB and 3, 12, 24, and 48 hours after CPB to measure cardiac troponin I levels. Intraoperative explicit awareness was assessed on the second postoperative day by asking the patients 3 simple questions in a standard interview: What was the last thing you remember happening before you went to sleep? What is the first thing you remember happening on waking? Did you dream or have any other experiences while you were asleep?9 An independent investigator blinded to the study groups who was not involved in the patients’ management collected the patient data. The primary outcome was the time to tracheal extubation. Secondary outcome variables included the times from skin closure to spontaneous eye opening and the return of spontaneous breathing (defined as a respiratory rate ⬎12 breaths/min and an arterial oxygen saturation ⬎95%); the number of changes in propofol Ce and sufentanil Ce; the cumulative doses of propofol and sufentanil (from induction through the end of the related infusion); the number of patients who needed changes in sufentanil Ce and rescue doses of nitroglycerin, esmolol, and ephedrine; the number and total duration of intraoperative ischemic episodes; the incidences of light anesthesia and awareness; the amount of PCA morphine that was consumed during the first 24 hours after extubation; the durations of the ICU and hospital stays; the costs; and the 30-day mortality. The costs of cumulative doses of propofol, sufentanil, and postoperative mechanical ventilation were calculated at the authors’ center to be equivalent to US $3.8/200 mg, US $0.5/10 g, and US $50 per hour ventilation, respectively. A pilot study showed that the normally distributed mean time to tracheal extubation after sufentanil, 0.4 ng/mL, was 290 minutes (SD, 46.9 min). A priori power analysis indicated that a sample size of 14 for each group was sufficiently large to detect 25% changes in the time to extubation after the administration of sufentanil, 0.4 ng/mL, with a type-I error of 0.017 (0.05/3 possible comparisons) and a power of 90%. This sample size was increased by 10% to compensate for patients dropping out during the study. The data were tested for normality using the Kolmogorov-Smirnov test. Repeated-measures analysis of variance was used to analyze serial changes in the patient data at different times. The Fisher exact test was used for categoric data. Repeated measures analysis of variance (ANOVA) was used for continuous parametric variables and the differences were corrected by
66
EL TAHAN AND KHIDR
Table 1. Patient Data for Target Effect-Site Concentrations of Sufentanil, 0.2, 0.3, or 0.4 ng/mL
Age (years) Men/women Weight (kg) Height (cm) EuroSCORE LVEF -Blockers CCBs ACE inhibitors Types of surgery Aortic valve Mitral valve Double-valve surgery Triple-valve surgery Underlying pathology Aortic stenosis Aortic regurgitation Mitral stenosis Mitral regurgitation Tricuspid regurgitation Aortic stenosis and mitral regurgitation Aortic regurgitation and mitral stenosis CPB time (min) Aortic clamping time (min) Surgical duration (min)
0.2 ng/mL (n ⫽ 16)
0.3 ng/mL (n ⫽ 16)
0.4 ng/mL (n ⫽ 16)
39.5 [23] 11/5 69.9 (8.95) 167.4 (6.39) 3.9 [13] 0.56 (0.07) 6 (37.5%) 1 (6.25%) 6 (37.5%)
38.5 [31] 14/2 70.9 (10.82) 166.3 (4.35) 4.2 [9] 0.54 (0.04) 9 (56.3%) 4 (25%) 8 (50%)
35 [29] 12/4 70.3 (7.84) 165.8 (5.34) 4.3 [13] 0.52 (0.09) 8 (50%) 2 (12.5%) 10 (62.5%)
5 (31.3%) 9 (56.3%) 2 (12.5%) 0 (0.0%)
6 (37.5%) 8 (50%) 1 (6.25%) 1 (6.25%)
4 (25%) 10 (62.5%) 2 (12.5%) 0 (0.0%)
3 (18.8%) 2 (12.5%) 8 (50%) 1 (6.25%) 0 (0.0%) 1 (6.25%) 1 (6.25%) 124.9 (30.92) 48.4 (21.8) 263.5 (26.9)
5 (31.3%) 1 (6.25%) 6 (37.5%) 2 (12.5%) 1 (6.25%) 0 (0.0%) 1 (6.25%) 117.9 (20.65) 52.1 (17.6) 255.9 (28.9)
2 (12.5%) 2 (12.5%) 8 (50%) 2 (12.5%) 0 (0.0%) 1 (6.25%) 1 (6.25%) 125.4 (15.73) 59.4 (19.7) 278.9 (31.4)
NOTE. Data are presented as median [range], number (percentage), or mean (SD). Abbreviations: ACE, angiotensin-converting enzyme; CCBs, calcium channel blockers; CPB, cardiopulmonary bypass; EuroSCORE, European System for Cardiac Operative Risk Evaluation; LVEF, left ventricular ejection fraction.
the post hoc Bonferroni test. The Kruskal-Wallis test was performed for intergroup comparisons for nonparametric values and post hoc pairwise comparisons were performed using the Wilcoxon rank-sum t test. The data were expressed as means (SD), number (percentage), or median [range]. A p value ⬍0.05 was considered to represent statistical significance. Univariate variables included age; sex; European System for Cardiac Operative Risk Evaluation (EuroSCORE); left ventricular ejection fraction; the durations of CPB, aortic cross-clamping, and surgery; the number of changes in target propofol Ce; and the cumulative doses of propofol and sufentanil. To identify the independent predictors that influenced the times to spontaneous eye opening, return of spontaneous breathing, and tracheal extubation, these variables were examined in a stepwise manner in a multivariate logistic regression model, with entry and retention set at a significance level of p ⬍ 0.05. RESULTS
All 48 patients with valve disease who were enrolled completed the study. These patients were assigned randomly into 3 groups (n ⫽ 16 per group) that received sufentanil, 0.2, 0.3, and 0.4 ng/mL, respectively. The patient characteristics and intraoperative hemodynamic variables of the 3 groups are presented in Tables 1 and 2, respectively. Compared with the sufentanil Ce 0.4-ng/mL group, the Ce 0.2- and 0.3-ng/mL groups had significantly shorter times to eye opening, spontaneous breathing, and extubation (112.2 min [SD, 16.9] and 161.9 min [32.9] v 271.3 min [27.4], respectively; p ⬍ 0.001) and required more frequent changes in propofol Ce (p ⬍ 0.001) and higher cumulative doses of propofol (p ⬍ 0.001; Table 3). Compared with the sufentanil Ce
0.4-ng/mL group, the sufentanil Ce 0.2-ng/mL group had a significantly longer duration from induction to intubation (p ⬍ 0.05) and required smaller cumulative doses of sufentanil (p ⬍ 0.001) and a larger number of changes in propofol Ce (p ⬍ 0.001; Table 3). The sufentanil Ce 0.2-ng/mL group also differed significantly from the Ce 0.3-ng/mL group in terms of the cumulative dose of propofol and the times to eye opening, spontaneous breathing, and extubation (p ⬍ 0.001; Table 3). The 3 groups did not differ significantly in the number of changes in sufentanil Ce the number of episodes with SE values ⬎50; the incidence of light anesthesia; the number and total duration of intraoperative ischemic episodes; the number of patients who received rescue doses of nitroglycerin, esmolol, and ephedrine; the incidence of awareness; the amount of PCA morphine that was consumed; the durations of ICU and hospital stays; 30-day mortality (Table 3); or cardiac troponin I Ce (Table 4). There was 1 death on postoperative day 10 from postoperative mediastinitis that was unrelated to sufentanil administration (Table 3). Compared with the sufentanil Ce 0.4-ng/mL group, the costs of sufentanil and postoperative ventilation were significantly lower in the groups that received sufentanil Ce 0.2 and 0.3 ng/mL (Table 3). Moreover, compared with the sufentanil Ce 0.3-ng/mL group, the costs of cumulative propofol and cumulative sufentanil were 56% higher and 34% lower for the Ce 0.2-ng/mL group, respectively (Table 3). Multivariate logistic regression showed that the number of changes in propofol Ce and the cumulative doses of propofol
LOW SUFENTANIL EFFECT-SITE CONCENTRATION FOR VALVE SURGERY
67
Table 2. Intraoperative Hemodynamic Changes in Target Effect-Site Concentrations of Sufentanil, 0.2, 0.3, or 0.4 ng/mL (n ⴝ 16 for Each) After CPB Baseline
Heart rate (beats/min) 0.2 ng/mL 0.3 ng/mL 0.4 ng/mL MAP (mmHg) 0.2 ng/mL 0.3 ng/mL 0.4 ng/mL CI (L/min/m2) 0.2 ng/mL 0.3 ng/mL 0.4 ng/mL SVRI (dynes · s · cm⫺5/m2) 0.2 ng/mL 0.3 ng/mL 0.4 ng/mL
Intubation
Skin Incision
Sternotomy
15 min
45 min
77 (14.76) 81 (13.06) 76 (13.66)
90 (11.90) 85 (12.62) 88 (11.42)
84 (8.17) 87 (7.94) 90 (6.16)
75 (11.20) 87 (12.39) 79 (5.38)
92 (6.37) 89 (11.40) 95 (7.31)
85 (8.66) 91 (11.12) 86 (9.54)
97 (16.19) 99 (17.75) 101 (11.09)
108 (19.49) 112 (15.81) 105 (15.03)
98 (15.38) 105 (10.34) 96 (12.94)
104 (11.64) 100 (15.21) 98 (14.01)
78 (14.84) 75 (12.86) 77 (12.84)
96 (13.23) 93 (9.27) 99 (7.13)
2.6 (0.35) 2.7 (0.44) 2.6 (0.30)
2.5 (0.44) 2.6 (0.38) 2.7 (0.48)
2.6 (0.46) 2.8 (0.63) 2.7 (0.55)
2.5 (0.42) 2.4 (0.35) 2.5 (0.49)
2.9 (0.53) 2.8 (0.45) 3.2 (0.60)
2157 (527.6) 2190 (480.6) 2157 (545.2)
2045 (443.8) 2240 (490.9) 1982 (355.6)
2138 (460.1) 2016 (391.0) 2095 (470.3)
1740 (213.8) 1895 (341.4) 1967 (424.6)
2335 (512.6) 1960 (466.6) 2149 (495.9)
NOTE. Data are presented as mean (SD). Abbreviations: CI, cardiac index; CPB, cardiopulmonary bypass; MAP, mean arterial blood pressure; SVRI, systemic vascular resistance index.
and sufentanil were independent factors that influenced the times to spontaneous eye opening, spontaneous breathing, and extubation in patients undergoing valve surgery (Table 5). In addition, the duration of surgery and the EuroSCORE values were independent factors for the times to spontaneous eye opening and extubation, respectively (Table 5). DISCUSSION
Changing the anesthetic technique by switching from highdose to low-dose opioid anesthesia has been shown to shorten the extubation time and length of hospitalization,10 decrease persistent hypersensitivity and allodynia,11,12 and lessen postoperative complications.10 RE and SE are superior to the bispectral index for monitoring the depth of anesthesia during cardiac surgery because of their greater resistance to artifacts.13,14 Entropy is used to guide the management of anesthesia in which the endpoints are an SE ⬍50 and an SE-RE difference ⬍10.15 Noxious stimulation widens the difference between RE and SE without predicting the analgesic requirements of paralyzed patients.16,17 The present study showed that, compared with a target sufentanil Ce of 0.4 ng/mL, a target sufentanil Ce of 0.2 to 0.3 ng/mL during TCI of propofol anesthesia for valve surgery was associated with shorter times to spontaneous breathing, eye opening, and extubation; more frequent changes in target propofol Ce; higher cumulative doses of propofol; and comparable hemodynamic stability and incidences of light anesthesia, awareness, and myocardial ischemia. Multivariate logistic regression showed that the number of changes in target propofol Ce, the cumulative doses of propofol and sufentanil, and the EuroSCORE values were independent factors that influenced the time to extubation in patients undergoing valve surgery. In one study, compared with lower sufentanil Ce (0.35 and 0.5 ng/mL), the higher sufentanil Ce of 0.65, 0.8, and 1.0 ng/mL did not provide further advantages for the time to extubation and stress response control.4 This was because these
investigators continued target propofol infusion in the ICU for ⱖ2 hours. Other studies have reported that the electroencephalographic responses during CABG procedures can be controlled with a sufentanil Ce as low as 0.5 ng/mL.3,4 Moreover, two studies have reported that sufentanil Ce 0.2 ng/mL is associated with a favorable response to intubation.18,19 In the present study, the highest sufentanil Ce that was used, which is similar to the lowest Ce used by others,3,4 served as the comparative control arm for the sufentanil Ce 0.2- and 0.3-ng/mL groups. The low sufentanil Ce of 0.2 and 0.3 ng/mL were found to be of clinical importance in the present study because, compared with sufentanil Ce 0.4 ng/mL, they were associated with significant decreases in the times to eye opening (⫺71% and ⫺39%, respectively), spontaneous breathing (⫺76% and ⫺49%, respectively), and extubation (⫺59% and ⫺40%, respectively). The cumulative sufentanil doses of the Ce 0.2-, 0.3-, and 0.4-ng/mL groups were 1.3 g/kg (0.5), 2.0 g/kg (0.35), and 2.2 g/kg (0.42), respectively. Similarly, others have reported that the use of sufentanil, 1.7 g/kg (1.4-2.0), was associated with an extubation time of 4.7 hours after cardiac surgery.20 The ranges in time to extubation after cardiac surgery under standardized fentanyl and remifentanil anesthesia are 0.25 to 7.82 and 0.18 to 6.81 hours, respectively,20,21 which were comparable to the ranges in times to extubation of the sufentanil Ce 0.2- and 0.3-ng/mL groups in the present study (1.5 to 2.7 and 1.8 to 3.7 h, respectively). In the present study, the anesthetic depth during heart valve surgery was standardized using a propofol Ce of 1.0 to 4.5 g/mL. As observed previously,4 compared with sufentanil Ce 0.4 ng/mL, the low sufentanil Ce of 0.2 and 0.3 ng/mL required frequent adaptation of the target propofol Ce to achieve the authors’ predefined targets. The higher cumulative propofol doses that were used in the sufentanil Ce 0.2- and 0.3-ng/mL groups are comparable to the median cumulative propofol doses that have been reported by others4; similarly, the authors
68
EL TAHAN AND KHIDR
Table 3. Outcome Data in Target Effect-Site Concentrations of Sufentanil, 0.2, 0.3, or 0.4 ng/mL 0.2 ng/mL (n ⫽ 16)
0.3 ng/mL (n ⫽ 16)
0.4 ng/mL (n ⫽ 16)
7.9 (1.22)* 12 [5-20]‡ 0 [0-3] 3 (18.8%) 2672 (280)†‡ 91 (13.9)‡ 4.5 [2-10]
5.7 (1.36) 8 [3-13]‡ 0 [0-2] 2 (12.5%) 1705 (294.5)‡ 136 (14.1) 7 [3-11]
4.0 (1.31) 5.5 [3-13] 0 [0-2] 1 (6.25%) 1444 (269.6) 153 (26.8) 5 [2-9]
2 (12.5%) 1 (6.25%) 3 (18.8%) 2 (12.5%) 1 (6.25%) 0 [5] 1.6 (2.85) 4 (25%) 1 (6.25%) 3 (18.8%) 24.8 (7.8)†‡ 32.7 (19.9)†‡ 112.2 (16.9)†‡ 1 (6.25%) 17 [7-42] 3.7 (1.62) 14.2 (5.13) 0 (0.0%)
1 (6.25%) 1 (6.25%) 2 (12.5%) 2 (12.5%) 0 (0.0%) 0.5 [4] 2.4 (3.03) 4 (25%) 1 (6.25%) 4 (25%) 52.6 (12.5)‡ 70.1 (27.2)‡ 161.9 (32.9)‡ 0 (0.0%) 18.5 [9-40] 4.2 (1.72) 12.3 (3.40) 1 (6.25%)
1 (6.25%) 1 (6.25%) 1 (6.25%) 1 (6.25%) 0 (0.0%) 0 [3] 1.5 (2.25) 5 (31.3%) 0 (0.0%) 2 (12.5%) 85.6 (10.0) 137.5 (20.8) 271.3 (27.4) 0 (0.0%) 19 [8-40] 3.5 (1.03) 11.6 (4.87) 0 (0.0%)
50.76 (5.32)†‡ 4.5 (0.69)†‡ 93.5 (14.11)†‡
32.4 (5.59)* 6.8 (0.70) 134.9 (27.45)‡
27.4 (5.12) 7.6 (1.34) 226.0 (22.85)
Time from induction to intubation (min) Changes of propofol target (n) Changes of sufentanil target (n) Patients needed changes in sufentanil target Cumulative doses of propofol (mg) Cumulative doses of sufentanil (g) Number of SE episodes ⬎50 Incidences of light anesthesia in response to Intubation Skin incision Sternotomy Maximal sternal spread Sternal wire placement Intraoperative ischemic episodes (n) Total time of intraoperative ischemic episodes (min) Rescue nitroglycerin Rescue esmolol Rescue ephedrine Time to eye opening (min) Time to spontaneous breathing (min) Time to extubation (min) Awareness and recall PCA morphine consumption (mg) ICU length of stay (days) Hospital length of stay (days) 30-Day mortality rate Costs (US$) Propofol Sufentanil Postoperative ventilation
NOTE. Data are presented as mean (SD), median [minimum-maximum], median [range], or number (percentage). Abbreviations: ICU, intensive care unit; PCA, patient-controlled analgesia; rescue, number of patients who received rescue doses of nitroglycerin, ephedrine, and esmolol; SE, state entropy; US$, US dollars. *p ⬍ 0.05 significant compared with 0.4 ng/dL. †p ⬍ 0.001 significant compared with 0.3 ng/dL ‡p ⬍ 0.001 significant compared with 0.4 ng/dL.
did not observe any hemodynamic derangements or increases in the need for vasoactive medications. The 0.2-ng/mL Ce clearly doubled the time to intubation. However, this was not of clinical importance and it did not increase the total cost because the Ce 0.2-ng/mL Ce also markedly decreased the time to extubation. There were 10, 11, and 9 episodes of SE that exceeded 50 in the sufentanil Ce 0.2-, 0.3-, and 0.4-ng/mL groups, respectively. Sim-
Table 4. Perioperative Cardiac Troponin I Changes in Target EffectSite Concentrations of Sufentanil, 0.2, 0.3, or 0.4 ng/mL
Baseline (g/L) Postoperative (g/L) 3h 12 h 24 h 48 h
0.2 ng/mL (n ⫽ 16)
0.3 ng/mL (n ⫽ 16)
0.4 ng/mL (n ⫽ 16)
0.20 (0.15)
0.25 (0.19)
0.30 (0.23)
8.71 (4.09) 19.93 (6.54) 26.86 (5.97) 18.52 (6.54)
7.76 (3.37) 16.58 (5.93) 27.53 (7.68) 16.37 (6.59)
8.8 (4.58) 17.06 (4.58) 28.09 (7.48) 15.50 (4.27)
NOTE. Data are presented as mean (SD).
ilarly, when sufentanil Ce 0.8 ng/mL was used previously during TCI of propofol for CABG procedures; 10 episodes of the bispectral index that exceeded 60 were observed.4 In the present study, as in other studies,3,4 the use of sufentanil Ce 0.2, 0.3, and 0.4 ng/mL was associated with hemodynamic stability. Based on a previous study,22 the authors considered that using 0.05-ng/mL increments in sufentanil Ce would obtund the entropy and hemodynamic responses to noxious stimuli. In contrast, others have used higher sufentanil Ce increments of 0.25 ng/mL4 or 0.34 ng/mL.3 The latter investigators did not need to increase the sufentanil Ce in any patient to suppress hemodynamic responsiveness during the use of a constant sufentanil Ce of 0.59 ⫾ 0.13 ng/mL; their cumulative sufentanil dose was 1.59 g/kg (0.40), which was comparable to the present results.3 The authors expected that 4 sufentanil Ce increments of 0.05 ng/mL would double the infusion rate in the Ce 0.2-ng/mL group to 0.4 ng/mL ([0.05 ng/mL ⫻ 4] ⫹ 0.2 ng/mL). In the Ce 0.4-ng/mL group, the authors expected that the 4 increments would result in only a 50% increase (ie, 0.2 ⫹ 0.4 ng/mL) in the Ce. However, the 3 groups had similar
LOW SUFENTANIL EFFECT-SITE CONCENTRATION FOR VALVE SURGERY
69
Table 5. Independent Factors for Primary Outcomes by Multivariate Analysis Spontaneous Eye Opening
Age Sex EuroSCORE LVEF CPB time Aortic cross-clamping time Surgery time Changes of propofol target Cumulative doses of propofol Cumulative doses of sufentanil
95% CI
p Value
⫺0.63 to 2.00 ⫺21.70 to 32.14 ⫺3.32 to 2.92 ⫺163.37 to 128.68 ⫺0.34 to 0.35 ⫺0.93 to 1.22 ⫺0.63 to 1.25 ⫺4.89 to 0.81 ⫺0.06 to ⫺0.001 ⫺0.12 to 1.01
0.409 0.984 0.461 0.25 0.991 0.418 0.019 0.032 ⬍0.001 ⬍0.001
Spontaneous Breathing 95% CI
⫺0.34 to 0.84 ⫺8.26 to 16.01 ⫺1.18 to 1.63 ⫺73.88 to 57.78 ⫺0.71 to 0.56 ⫺0.46 to 0.51 ⫺0.48 to 0.37 ⫺2.37 to 0.20 ⫺0.04 to ⫺0.008 ⫺0.01 to 0.50
Extubation Time
p Value
95% CI
p Value
0.974 0.985 0.171 0.608 0.819 0.79 0.994 0.045 0.002 0.007
⫺0.10 to 3.46 ⫺32.10 to 40.64 ⫺3.28 to 5.14 ⫺113.62 to 280.81 ⫺0.71 to 1.14 ⫺1.92 to 0.98 ⫺1.34 to 1.20 ⫺7.76 to ⫺0.05 ⫺0.09 to 0.02 ⫺0.34 to 1.18
0.468 0.854 0.001 0.537 0.636 0.816 0.382 ⬍0.001 ⬍0.001 0.006
Abbreviations: CI, confidence interval; CPB, cardiopulmonary bypass; EuroSCORE, European System for Cardiac Operative Risk Evaluation; LVEF, left ventricular ejection fraction.
numbers of changes in the sufentanil Ce. TCI of sufentanil was discontinued after sternal closure to shorten the recovery and extubation times, because others23 have found that terminating sufentanil, 0.3 to 0.5 ng/mL, 50 minutes before the end of colon surgery was associated with a faster recovery. Brice et al9 defined intraoperative awareness as the presence of explicit memory. In contrast to others who have reported an intraoperative awareness of only 0.2% to 0.3%,24 awareness in the present study in 1 patient in the sufentanil 0.2-ng/mL group was as high as 6.25%. However, the present study was not powered to test the risk of intraoperative awareness and recall. Further powered studies are needed to test the incidence of awareness during the use of low sufentanil Ce for cardiac surgery. The cumulative PCA morphine consumptions of the 3 groups were similar. The use of low sufentanil Ce did not shorten the median durations of ICU and hospital stays, which were longer than those reported for standard remifentanil and fentanyl cardiac anesthesia,18 because patients who were referred from far distances to the authors’ district hospital had to have longer hospital stays (1-2 days before surgery and ⱖ9 days after surgery). Moreover, the authors’ center mandates a stay of ⱖ2 days in the ICU after cardiac surgery. It is becoming increasingly important to lower the costs of fast-track cardiac anesthesia. In the present study, the use of low
sufentanil Ce decreased the overall cost of propofol, sufentanil, and postoperative ventilation by 44% (Ce 0.2-ng/mL group) and 33% (Ce 0.3-ng/mL group). The authors did not include the costs of the operating room equipment, medications other than anesthetics, disposables, and ICU and hospital stays in their cost analyses because the costs of these factors vary depending on the manufacturer and supplier, and this would have complicated the present calculations. The authors’ costs may not have been comparable to those reported by others because of the variations in the costs of controlled drugs from 1 country to another and the rapid changes in the prices of these drugs over time. The present study had several limitations. First, the benefits of a low target sufentanil Ce could be extended to patients who are eligible for early on-table extubation, but this could not be tested because it is not approved by the authors’ center. Second, the present study was not powered statistically to test the incidences of intraoperative awareness and myocardial ischemia in the study population. Third, a double-blinded study design was not used for the intraoperative titration protocol that was used to control entropy and hemodynamic variables. However, this bias was limited by ensuring that the assessor who collected the patient data was blinded to the assigned group. In conclusion, compared with sufentanil Ce of 0.4 ng/mL, lower Ce (0.2 and 0.3 ng/mL) promoted faster recovery and times to extubation after valve surgery performed under TCI of propofol.
REFERENCES 1. Steinlechner B, Dworschak M, Birkenberg B, et al: Low-dose remifentanil to suppress haemodynamic responses to noxious stimuli in cardiac surgery: A dose-finding study. Br J Anaesth 98:598603, 2007 2. Hudson RJ, Henderson BT, Thomson IR, et al: Pharmacokinetics of sufentanil in patients undergoing coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 15:693-699, 2001 3. Thomson IR, Harding G, Hudson RJ: A comparison of fentanyl and sufentanil in patients undergoing coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 14:652-656, 2000 4. Forestier F, Hirschi M, Rouget P, et al: Propofol and sufentanil titration with the bispectral index to provide anesthesia for coronary artery surgery. Anesthesiology 99:334-346, 2003 5. El-Tahan MR: Preoperative ephedrine counters hypotension with propofol anesthesia during valve surgery: A dose dependent study. Ann Card Anaesth 14:30-40, 2011
6. Gepts E, Shafer SL, Camu F, et al: Linearity of pharmacokinetics and model estimation of sufentanil. Anesthesiology 83:1194-1204, 1995 7. Schnider TW, Minto CF, Shafer SL, et al: The influence of age on propofol pharmacodynamics. Anesthesiology 90:1502-1516, 1999 8. Hirschi M, Meistelman C, Longrois D: Effects of normothermic cardiopulmonary bypass on bispectral index. Eur J Anaesthesiol 17: 499-505, 2000 9. Brice DD, Hetherington RR, Utting JE: A simple study of awareness and dreaming during anaesthesia. Br J Anaesth 42:535-542, 1970 10. Cheng D: Anesthetic techniques and early extubation: Does it matter? J Cardiothorac Vasc Anesth 14:627-630, 2000 11. Célèrier E, Rivat C, Jun Y, et al: Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine. Anesthesiology 92:465-472, 2000
70
12. Célèrier E, Laulin J, Larcher A, et al: Evidence for opiateactivated NMDA processes masking opiate analgesia in rats. Brain Res 847:18-25, 1999 13. Baulig W, Seifert B, Schmid ER, et al: Comparison of spectral entropy and bispectral index electroencephalography in coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 24:544-549, 2010 14. Arutiunian OM, Iavorovskiı˘ AG, Guleshov VA, et al: [Role of entropy-based neuromonitoring during cardiac surgery]. Anesteziol Reanimatol 5:78-82, 2010 15. Riad W, Schreiber M, Saeed AB: Monitoring with EEG entropy decreases propofol requirement and maintains cardiovascular stability during induction of anaesthesia in elderly patients. Eur J Anaesthesiol 24:684-688, 2007 16. Dierckens E, Fleyfel M, Robin E, et al: [Is entropy a monitor for the guidance of intraoperative analgesia?] Ann Fr Anesth Reanim 26:113-118, 2007 17. Takamatsu I, Ozaki M, Kazama T: Entropy indices vs the bispectral index for estimating nociception during sevoflurane anaesthesia. Br J Anaesth 96:620-626, 2006 18. Jung SM, Yang CW, Oh JY, et al: Predicted effect-site concentration of propofol and sufentanil for gynecological laparoscopic surgery. Acta Anaesthesiol Scand 55:110-117, 2011
EL TAHAN AND KHIDR
19. Sun CJ, Gu MN, Xu JS: Narcotrend index monitoring can predict the recovery of consciousness in patients undergoing abdominal surgery. Nan Fang Yi Ke Xue Xue Bao 30:1379-1381, 2010 20. Engoren M, Luther G, Fenn-Buderer N: A comparison of fentanyl, sufentanil, and remifentanil for fast-track cardiac anesthesia. Anesth Analg 93:859-864, 2001 21. Cheng DC, Newman MF, Duke P, et al: The efficacy and resource utilization of remifentanil and fentanyl in fast-track coronary artery bypass graft surgery: A prospective randomized, doubleblinded controlled, multi-center trial. Anesth Analg 92:1094-1102, 2001 22. Slepchenko G, Simon N, Goubaux B, et al: Performance of target-controlled sufentanil infusion in obese patients. Anesthesiology 98:65-73, 2003 23. Yang XY, Xu X, Wu XM: [Effect of target-controlled infusion sufentanil in different doses combined with nitrogen monoxide inhalation on hemodynamics and postoperative recovery]. Zhonghua Yi Xue Za Zhi 87:3325-3328, 2007 24. Groesdonk HV, Pietzner J, Borger MA, et al: The incidence of intraoperative awareness in cardiac surgery fast-track treatment. J Cardiothorac Vasc Anesth 24:785-789, 2010