Alfentanil and sufentanil in fast-track anesthesia for coronary artery bypass graft surgery

Alfentanil and Sufentanil in Fast-Track Anesthesia for Coronary Artery Bypass Graft Surgery Luigi Tritapepe, MD, Paolo Voci, MD, PhD, Claudio Di Giovanni, MD, Francesco Pizzuto, MD, Enrica Cuscianna, MD, Quintilio Caretta, MD, and Paolo Pietropaoli, MD Objective: To evaluate alfentanil, sufentanil, and the combination of both opioids in patients undergoing cardiac surgery. Design: Prospective, randomized study. Setting: University hospital. Participants: Patients undergoing coronary artery bypass graft (CABG) surgery (n ⴝ 195), randomly assigned to 3 groups of 65 each. Interventions: Patients in group A received alfentanil, induction (15 ␮g/kg) and maintenance (15 ␮g/kg/hr); patients in group S received sufentanil, induction (1 ␮g/kg) and maintenance (1 ␮g/kg/h); and patients in group AS received alfentanil and sufentanil, induction with alfentanil (15 ␮g/kg) and maintenance with sufentanil (1 ␮g/ kg/hr). Measurements and Main Results: Hemodynamic data showed a reduction of all parameters at induction in the 3 groups (p < 0.05). Cardiac index decreased at induction in all groups (p < 0.05) but increased in groups S and AS toward baseline values

at the end of surgery. The intubation time and length of stay in the intensive care unit were less in group AS (2.3 ⴞ 1.2 hours; p < 0.001 and 20 ⴞ 8 hours; p < 0.05), than in groups A (4.2 ⴞ 1.7 hours and 28 ⴞ 13 hours) and S (3.1 ⴞ 1.1 hours; p < 0.05 and 26 ⴞ 12 hours). Length of hospital stay and patients’ outcome were similar in the 3 groups. Conclusion: Although the differences among groups regarding extubation time, intensive care unit length of stay, and some hemodynamic data were statistically significant, the differences were clinically small. All 3 anesthetic protocols were shown to be safe and appropriate for patients undergoing elective coronary artery bypass graft surgery and early postoperative tracheal extubation. Copyright 2002, Elsevier Science (USA). All rights reserved.

O

investigation was to determine if the association of alfentanil with sufentanil minimizes the side effects of each compound, while maintaining their effectiveness in controlling the hyperdynamic reaction to induction and intubation and providing fast-track anesthesia and early extubation.

PIOIDS, ALONE OR IN combination with benzodiazepines or propofol, provide profound analgesia and hemodynamic stability, a positive balance between myocardial oxygen supply and demand, and preservation of circulatory autoregulation during coronary artery bypass graft (CABG) surgery.1-3 Appropriate plasma and cerebral opioid concentrations are maintained by a continuous infusion or titration of bolus injections4,5 and obtund or prevent noxious stimulations during anesthesia. In the 1980s, opioids were used in high doses to achieve hemodynamic stability and prevent hyperdynamic responses to tracheal intubation and surgical stress. Hypotension, delayed extubation, respiratory depression, and muscle rigidity were the most common side effects of this approach. Today, it is important to achieve early extubation, minimizing the length of intensive care unit (ICU) and hospital stays. The goal is to administer the minimal dose for the patient for the shortest possible time to improve recovery.6 This goal usually cannot be obtained by frequent intravenous bolus injections7 but can be obtained by infusion because the observed drug effect in the biophase more closely parallels the plasma concentration of the drug.8 Combinations of opioids in patients undergoing cardiac surgery may minimize the side effects of each compound. In particular, the different time of onset and drug kinetics allow for selection of different opioids for each phase of anesthesia and surgery. The use of combinations of opioids and propofol may impair cardiac output but has proved to be safe at low doses. In this study, the authors have made use of previous experience with alfentanil and sufentanil for induction in CABG surgery patients. Doses have been chosen and alfentanil and sufentanil have been combined to minimize the side effects of each compound. Alfentanil was followed by sufentanil because of their different onset times (1 to 2 minutes for alfentanil, 4 to 6 minutes for sufentanil), which allowed for better blunting of the circulatory responses to tracheal intubation. One aim of this

KEY WORDS: alfentanil, sufentanil, cardiac anesthesia, early extubation, hemodynamic, pharmacokinetics, pharmacodynamics, opioids

MATERIALS AND METHODS After obtaining approval by the ethics committee of the institutional review board and informed written consent, 195 consecutive American Society of Anesthesiologists III patients, class 2-3 of the Canadian Cardiovascular Society, who were undergoing elective CABG surgery, were enrolled and randomly assigned to 3 groups of 65 patients each. The demographic data are shown in Table 1. Patients with previous myocardial infarction, congestive heart failure, pulmonary hypertension, chronic pulmonary disease, or associated valvular disease were excluded from the study. Ejection fraction was ⬎40% in all cases. All patients continued their cardiac medications (nitrates, calcium channel blockers, and ␤-blockers) until surgery. Anesthetic premedication was diazepam, 0.1 mg/kg orally, and morphine sulfate, 0.1 mg/kg intramuscularly, 1 hour before surgery. Electrocardiogram, pulse oximetry, and blood pressure were monitored on arrival in the operating room. Heart rate (HR) was monitored from leads II and V5 of the electrocardiogram. A continuous ST-segment analysis was performed throughout the study. ST-segment depression of ⱖ1 mm and ST-segment elevation of ⱖ2 mm for a minimum of 1 minute were considered significant. Myocardial ischemia was defined as the association between ST-segment changes and some hemodynamic variations (HR elevation, blood pressure reduction, pulmonary

From the Departments of Anesthesia and Intensive Care and Cardiac Surgery, University of Rome “La Sapienza,” Rome, Italy. Address reprint requests to Luigi Tritapepe, MD, Istituto di Anestesiologia e Rianimazione, Universita` “La Sapienza,” Policlinico Umberto I, Viale del Policlinico, 155, 00161 Rome, Italy. E-mail: [email protected] Copyright 2002, Elsevier Science (USA). All rights reserved. 1053-0770/02/1602-0005$35.00/0 doi:10.1053/jcan.2002.31056

Journal of Cardiothoracic and Vascular Anesthesia, Vol 16, No 2 (April), 2002: pp 157-162

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Table 1. Patient Characteristics

Sex(M/F) Age (y) Weight (kg) BSA (m2) LVEF (%) Oral hypoglycemics Insulin ACE inhibitors Diuretics Nitrates Calcium channel blockers ␤-Blockers Nitrates ⫹ calcium channel blockers Nitrates ⫹ ␤-blockers

Group A

Group S

Group AS

42/23 62 ⫾ 19 69 ⫾ 15 1.78 ⫾ 0.13 46 ⫾ 5 8 3 7 3 0 0 0

47/18 65 ⫾ 15 72 ⫾ 14 1.80 ⫾ 0.11 48 ⫾ 8 6 2 5 2 0 0 0

45/20 64 ⫾ 17 70 ⫾ 16 1.79 ⫾ 0.15 47 ⫾ 6 7 4 7 3 0 0 0

39 26

37 28

38 27

NOTE. Data are mean ⫾ SD or number of patients. Abbreviations: Group A, alfentanil; Group S, sufentanil; Group AS, alfentanil ⫹ sufentanil; BSA, body surface area; LVEF, left ventricular ejection fraction; ACE, angiotensin-converting enzyme.

capillary wedge pressure [PCWP] elevation). Peripheral venous catheters, arterial catheters, and a flow-directed pulmonary artery catheter (Intellicath, Model 139H-7, 7F; Baxter-Edwards, Irvine, CA), through the right internal jugular vein, were introduced under local anesthesia. A bolus volume of 200 mL of crystalloid solution was rapidly infused until reaching a central venous pressure (CVP) of 8 mmHg, then an infusion of crystalloid solution was maintained at a rate of 80 mL/h to keep CVP constant. Patients were randomly assigned to 3 groups. Group A (alfentanil) received a loading dose of alfentanil, 15 ␮g/kg over 1 minute, and anesthesia was maintained with infusions of alfentanil, 15 ␮g/kg/h, and propofol, 2 mg/kg/h. Group S (sufentanil) received a loading dose of sufentanil, 1 ␮g/kg over 1 minute, and anesthesia was maintained with infusion of sufentanil, 1 ␮g/kg/h, and propofol, 2 mg/kg/h. Group AS (combination of alfentanil and sufentanil) received a loading dose of alfentanil, 15 ␮g/kg over 1 minute, and anesthesia was maintained with infusion of sufentanil, 1 ␮g/kg/h, and propofol, 2 mg/kg/h. After a loading dose of chosen opioid, all patients received the same inductive drug (propofol, 1 mg/kg) and, immediately following it, the same muscle relaxant (vecuronium, 0.1 mg/kg). Intubation was performed after 5 minutes of mask ventilation with 100% oxygen administration from the start of loading dose of opioid. Patients were ventilated with oxygen and air (fraction of inspired oxygen 50%), keeping PaCO2 between 35 and 38 mmHg (Servo Ventilator 900 D; Siemen, Elema, Sweden). After systemic anticoagulation with heparin, 300 IU/kg, cardiopulmonary bypass (CPB) was instituted with moderate hypothermia (32°C), using antegrade intermittent cold blood cardioplegia to arrest the heart. Opioids and propofol infusions were continued, at the same dosage, during CPB. Hypertension (systolic blood pressure ⬎150 mmHg for ⬎2 minutes) was treated with a bolus of urapidil, 10 mg. Alfentanil and sufentanil infusions were stopped at skin closure, whereas the propofol infusion was continued at a dose of 1 mg/kg/h for 1 hour after skin closure, to avoid exaggerated hemodynamic modifications during awakening from anesthesia. Baseline recordings of HR, mean arterial pressure (MAP), CVP, mean pulmonary artery pressure (MPAP), and PCWP were obtained (Sirecust 961; Siemens, Elema, Sweden). Cardiac output was obtained continuously by thermodilution by way of a continuous cardiac output monitor (Baxter Vigilance Monitor, Irvine, CA). Cardiac index (CI),

stroke volume index (SVI), systemic and pulmonary vascular resistance indices (SVRI and PVRI), and left ventricular stroke work index (LVSWI) were derived from the measured hemodynamic values by the cardiac output computer. Hemodynamic data were collected at baseline, the first time of recording after obtaining a CVP of 8 mmHg (T0); 2 minutes after anesthesia induction (T1); 2 minutes after tracheal intubation (T2); 2 minutes after sternotomy (T3); 2 minutes after weaning from CPB (T4); 2 minutes after skin closure (T5); and 2 hours after skin closure (T6). When the patient was completely conscious in the ICU, he or she was immediately placed on spontaneous ventilation. This test was considered successful when the oxygen percent saturation was ⬎95% with a respiratory rate of ⬎12 breaths/min after a 30-minute period. From that moment, the patient was considered ready for extubation if hemodynamics were stable and bleeding was ⬍80 mL/h. If needed, patients were treated with dopamine. The criteria for administering dopamine (3 to 5 ␮g/kg/min) were systolic arterial pressure ⬍90 mmHg, CVP ⬎10 mmHg, and HR ⬍80 beats/min. Practitioners caring for the patients postoperatively were blinded to the treatment group. All patients remained overnight in the ICU and were discharged the next morning if their hemodynamics were stable, inotropic or vasoactive drugs were stopped, chest tubes were removed, and their general clinical condition was good. The time of extubation, the need for inotropes, and the length of ICU and hospital stay were calculated in each group. All patients were interviewed about any details or sensation of intraoperative recall. Randomization was performed by a computerized procedure of sequential allocation. Preoperative and intraoperative data of the patients were compared using chi-square analysis. The hemodynamic data were compared among time points using repeated measures analysis of variance (ANOVA) followed by a paired t-test within each group. For all tests, ␣ was set at 0.05, and a Bonferroni adjustment was used for multiple pairwise comparisons. Comparisons for each variable among the 3 groups were made using ANOVA by applying a split plot model to evaluate group-time interaction. The results are expressed as mean ⫾ SD. Statistical significance was defined as p ⬍ 0.05. Statistical analysis was performed by SPSS 7.5 program for Windows (Chicago, IL). RESULTS

The groups were comparable with respect to age, weight, body surface area, and left ventricular ejection fraction (Table 1). There were no significant differences among the groups with respect to preoperative medications. Hemodynamic data and their significant differences are shown in Table 2. There was a reduction of HR at induction in all 3 groups (p ⬍ 0.05), but it was more pronounced in groups A and AS. With respect to baseline, HR had different courses: in group A, HR was reduced throughout the study period; whereas in groups S and AS, HR was higher, especially at the end of surgery; significant differences among groups were present at T2 through T6 (p ⬍ 0.05). MAP was also decreased after induction in all 3 groups, but in group S, MAP increased after intubation (p ⬍ 0.05). During the study period, mean pulmonary artery pressure, CVP, and PCWP did not change compared with baseline. CI decreased after induction in all 3 groups (p ⬍ 0.05); it remained decreased in group A, whereas in groups S and AS, it decreased initially and returned to baseline at T6. Stroke volume index was reduced in groups A and S at induction and intubation (p ⬍ 0.05), whereas it was more stable in group AS. There was a statistical difference (p ⬍ 0.05) among groups at T2 in group AS and T5 in group A. Left ventricular stroke work index decreased in all groups at T2

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Table 2. Hemodynamic Data Parameter

HR (beats/min)

MAP (mmHg)

MPAP (mmHg)

CVP (mmHg)

PCWP (mmHg)

CI (L/min/m2)

SVI (mL/beat/m2)

LVSWI (g/beat/m2)

SVRI (dyne 䡠 sec 䡠 cm⫺5/m2) PVRI (dyne 䡠 sec 䡠 cm⫺5/m2)

Group

T0

T1

T2

T3

T4

T5

T6

A S AS A S AS A S AS A S AS A S AS A S AS A S AS A S AS A S AS A S AS

74 ⫾ 8 76 ⫾ 7 75 ⫾ 9 84 ⫾ 5 82 ⫾ 4 83 ⫾ 6 21 ⫾ 5 20 ⫾ 4 20 ⫾ 6 7⫾2 8⫾3 8⫾4 13 ⫾ 4 12 ⫾ 5 13 ⫾ 5 2.9 ⫾ 0.6 3.0 ⫾ 0.4 2.9 ⫾ 0.7 39 ⫾ 4 39 ⫾ 5 38 ⫾ 4 37 ⫾ 5 37 ⫾ 6 36 ⫾ 6 2,124 ⫾ 326 1,973 ⫾ 311 2,068 ⫾ 266 220 ⫾ 53 186 ⫾ 47 193 ⫾ 58

64 ⫾ 10* 70 ⫾ 8* 63 ⫾ 11* 73 ⫾ 9* 75 ⫾ 6* 71 ⫾ 8* 19 ⫾ 6 17 ⫾ 5 20 ⫾ 4 6⫾3 7⫾2 6⫾2 12 ⫾ 4 11 ⫾ 4 12 ⫾ 3 2.2 ⫾ 0.5* 2.4 ⫾ 0.4* 2.2 ⫾ 0.5* 34 ⫾ 3 34 ⫾ 4 34 ⫾ 3 29 ⫾ 6* 29 ⫾ 6* 27 ⫾ 4* 2,436 ⫾ 457 2,266 ⫾ 390 2,363 ⫾ 299 254 ⫾ 74 200 ⫾ 51† 290 ⫾ 85*

66 ⫾ 11 78 ⫾ 10*† 65 ⫾ 9 76 ⫾ 5 86 ⫾ 9*† 74 ⫾ 9 20 ⫾ 5 19 ⫾ 6 20 ⫾ 5 7⫾2 6⫾2 7⫾4 13 ⫾ 4 12 ⫾ 3 12 ⫾ 3 2.1 ⫾ 0.6 2.2 ⫾ 0.5 2.3 ⫾ 0.5 31 ⫾ 3 28 ⫾ 4* 35 ⫾ 3† 30 ⫾ 4 28 ⫾ 4 29 ⫾ 3 2,628 ⫾ 563 2,909 ⫾ 398* 2,330 ⫾ 218† 266 ⫾ 61 254 ⫾ 55 278 ⫾ 70

67 ⫾ 8 79 ⫾ 11† 77 ⫾ 6† 85 ⫾ 7 88 ⫾ 5 81 ⫾ 6 21 ⫾ 4 20 ⫾ 5 20 ⫾ 5 8⫾3 7⫾2 7⫾3 13 ⫾ 3 14 ⫾ 2 13 ⫾ 2 2.0 ⫾ 0.7 2.5 ⫾ 0.6† 2.6 ⫾ 0.5† 29 ⫾ 4 31 ⫾ 2 33 ⫾ 2 28 ⫾ 3 31 ⫾ 4 30 ⫾ 4 3,080 ⫾ 471* 2,592 ⫾ 279† 2,276 ⫾ 250† 320 ⫾ 57* 192 ⫾ 44† 215 ⫾ 61†

66 ⫾ 7 82 ⫾ 8† 84 ⫾ 9† 80 ⫾ 6 85 ⫾ 7 86 ⫾ 6 19 ⫾ 5 16 ⫾ 6 17 ⫾ 5 8⫾2 10 ⫾ 3 10 ⫾ 2 12 ⫾ 2 11 ⫾ 3 10 ⫾ 2 2.2 ⫾ 0.4 2.6 ⫾ 0.6† 2.7 ⫾ 0.7† 33 ⫾ 3 31 ⫾ 3 32 ⫾ 4 30 ⫾ 4 31 ⫾ 5 33 ⫾ 2 2,618 ⫾ 236 2,307 ⫾ 301 2,251 ⫾ 273 254 ⫾ 41 153 ⫾ 66† 207 ⫾ 57

67 ⫾ 8 87 ⫾ 11† 88 ⫾ 10† 81 ⫾ 7 88 ⫾ 5 89 ⫾ 6 20 ⫾ 3 19 ⫾ 5 18 ⫾ 5 9⫾3 10 ⫾ 2 11 ⫾ 2 12 ⫾ 2 11 ⫾ 3 10 ⫾ 4 2.3 ⫾ 0.6 2.5 ⫾ 0.4 2.8 ⫾ 0.5† 34 ⫾ 2§ 28 ⫾ 3 31 ⫾ 3 31 ⫾ 3 29 ⫾ 3 33 ⫾ 2 2,504 ⫾ 254 2,496 ⫾ 223 2,228 ⫾ 244 278 ⫾ 46 256 ⫾ 58 228 ⫾ 60

73 ⫾ 8 85 ⫾ 9† 89 ⫾ 8† 85 ⫾ 8 90 ⫾ 7 91 ⫾ 8 21 ⫾ 4 20 ⫾ 4 20 ⫾ 5 10 ⫾ 2 10 ⫾ 3 12 ⫾ 1 13 ⫾ 2 12 ⫾ 3 13 ⫾ 3 2.4 ⫾ 0.6 2.7 ⫾ 0.5 2.8 ⫾ 0.4 32 ⫾ 4 31 ⫾ 4 31 ⫾ 2 31 ⫾ 4 32 ⫾ 4 31 ⫾ 2 2,500 ⫾ 238 2,370 ⫾ 215 2,257 ⫾ 221 266 ⫾ 49 237 ⫾ 51 200 ⫾ 55

NOTE. Data are mean ⫾ SD. Abbreviations: T0, baseline; T1, 2 minutes after induction; T2, 2 minutes after intubation; T3, 2 minutes after sternotomy; T4, 2 minutes after weaning from CPB; T5, end of surgery; T6, 2 hours after end of surgery; A, alfentanil; S, sufentanil; AS, alfentanil ⫹ sufentanil; HR, heart rate; MAP, mean arterial pressure; MPAP, mean pulmonary artery pressure; CVP, central venous pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; SVI, stroke volume index; LVSWI, left ventricular stroke work index, SVRI, systemic vascular resistance index; PVRI, pulmonary vascular resistance index. *Significant (p ⬍ 0.05) difference in the same group at different times. †Significant (p ⬍ 0.05) difference among groups at the same time in study.

(p ⬍ 0.05). SVRI increased in all groups after induction and intubation, reaching statistical significance at T2 in group S (p ⬍ 0.05) and at T3 in group A (p ⬍ 0.05). PVRI minimally increased after induction (p ⬍ 0.05 in group AS) but was stable during the study period in groups S and AS. In group A, PVRI was higher at T3 compared with baseline (p ⬍ 0.05). Computerized ST-segment monitoring and hemodynamic modifications did not meet criteria for myocardial ischemia. No difference among the 3 groups in duration of CPB, aortic cross-clamp time, or duration of surgery was observed. The number of hypertensive events in the study time intervals was similar in each group (7 patients in group A, 9 patients in group S, and 7 patients in group AS) and did not show statistical significance (Table 3). Significant difference among the 3 groups occurred with regard to extubation time: group AS (p ⬍ 0.001) was extubated faster (2.3 ⫾ 1.2 hours) than group A (4.2 ⫾ 1.7 hours) and group S (3.1 ⫾ 1.1 hours; p ⬍ 0.05) (Table 4). The patients who were extubated early comprised 91% in group A, 92% in

group S, and 94% in group AS. No patients were reintubated for gas exchange failure. Data regarding extubation are shown in Table 5. Length of stay in the ICU was shorter in group AS (p ⬍ 0.05) than in groups A and S, although hospital discharge and outcome of patients were similar in the 3 groups (Tables 4 and 6). In group A (p ⬍ 0.05) more patients (n ⫽ 13) were treated with dopamine (4.5 ⫾ 1.8 ␮g/kg/min) at the end of Table 3. Intraoperative Use of Urapidil Group A

No. of hypertensive EVENTS No. of patients treated for increased BP No. of boluses of urapidil* Total amount of urapidil (mg)

Group S

Group AS

11

12

10

7 12 120

9 14 140

7 10 100

Abbreviations: Group A, alfentanil; Group S, sufentanil; Group AS, alfentanil ⫹ sufentanil; BP, blood pressure. *10-mg bolus.

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Table 4. Main Patient Characteristics

Length of CPB (min) Length of aortic cross-clamping (min) Length of surgery (h) Total amount of propofol (mg) Total amount of alfentanil (␮g) Total amount of sufentanil (␮g) Bypass grafts (no.) LIMA (no.) RIMA (no.) Extubation time (h) Length of stay in ICU (h) Length of postoperative stay (days) Length of stay in hospital (days)

Group A

Group S

Group AS

78 ⫾ 41 56 ⫾ 19 3.6 ⫾ 1.7 636.8 ⫾ 56.8 4761 ⫾ 524 — 3.1 ⫾ 1.3 62 6 4.2 ⫾ 1.7 28 ⫾ 13 12.6 ⫾ 4.5 7.4 ⫾ 2.1

76 ⫾ 50 55 ⫾ 21 3.8 ⫾ 1.5 691.7 ⫾ 65.4 — 345.6 ⫾ 46 3.3 ⫾ 1.6 61 5 3.1 ⫾ 1.1* 26 ⫾ 12 12.1 ⫾ 3.9 7.8 ⫾ 3.0

74 ⫾ 38 58 ⫾ 20 3.7 ⫾ 1.2 658.3 ⫾ 57.5 1050 ⫾ 121 259.4 ⫾ 32 3.1 ⫾ 0.9 63 5 2.3 ⫾ 1.2† 20 ⫾ 15* 10.2 ⫾ 3.7 7.5 ⫾ 2.7

NOTE. Data are mean ⫾ SD. Abbreviations: Group A, alfentanil; Group S, sufentanil; Group AS, alfentanil ⫹ sufentanil; CPB, cardiopulmonary bypass; LIMA, left internal mammary artery; RIMA, right internal mammary artery; ICU, intensive care unit. *Significant (p ⬍ 0.05) difference among groups. †Significant (p ⬍ 0.001) difference among groups.

CPB. There was neither awareness during anesthesia nor intraoperative recall. DISCUSSION

Reducing hospital stay and minimizing costs have become important in cardiac surgery.9 Early extubation and new surgical approaches are aspects of a fast-track procedure and reduce ICU and hospital stay.10,11 In particular, early extubation protocols in cardiac surgery are feasible and safe.12,13 Generally, it is believed that an inhalation-based technique is the key to fast-track anesthesia.14 Inhalation agents produce hemodynamic instability, however, and supplemental intrathecal or thoracic epidural analgesia15,16 is often needed intraoperatively and postoperatively. The inconsistent results and frequency of side effects with these techniques suggest caution for routine use in cardiac surgery. More recent pharmacokinetic-pharmacodynamic modeling techniques have changed the concepts of intravenous anesthesia, in particular regarding the use of opioids.8,17 By increasing the precision of titrating the dose of these agents, it is possible to maintain the minimal therapeutic concentrations, reducing side effects.7,18 To understand drug kinetic modeling, the first concept to understand is the biophase (ie, the site of action).17 The time required for steady concentration of the drugs in

blood and the biophase is fast for alfentanil and remifentanil (1 to 2 minutes) and intermediate for fentanyl and sufentanil (4 to 6 minutes).19 To obtain a constant, stable drug effect, a constant drug concentration in the biophase should be achieved. By infusion, rather than by repeated bolus injection, the observed drug effect in the biophase more closely parallels the plasma concentration.8 Opioid agents, used in the past in high doses, provide profound analgesia with hemodynamic stability, positive balance between myocardial oxygen supply and demand, and preservation of circulatory autoregulation.1-3 Several studies reported that large doses of fentanyl effectively prevent HR and MAP increases resulting from laryngoscopy and intubation. They may cause hypotension, bradycardia, respiratory depression, skeletal muscle rigidity, and delayed recovery, 20, 21 however. Alfentanil shows about one fifth the potency of fentanyl, it has a shorter action and a faster onset to peak effect, but its context-sensitive half-time after a 2-hour infusion is 51 minutes.19 Alfentanil is not short-acting after 2 hours of infusion and may be longer acting than fentanyl.22 Sufentanil is 7 to 10 times more potent than fentanyl. It has a higher affinity for stereospecific receptor-binding sites but shows minimal binding to nonspecific sites23 and a slower dissociation rate from the ␮ receptor. Sufentanil and fentanyl have similar onset times,

Table 5. Extubation Data

pH (spontaneous ventilation) pH (postextubation) PaCO2 (spontaneous ventilation) PaCO2 (postextubation) SaO2 (spontaneous ventilation) SaO2 (postextubation) No. patients extubated early (%)

Group A

Group S

Group AS

7.36 ⫾ 0.02 7.35 ⫾ 0.01 44.2 ⫾ 1.1 46.6 ⫾ 1.7 98.3 ⫾ 0.9 98.0 ⫾ 0.5 59 (91%)

7.35 ⫾ 0.01 7.34 ⫾ 0.02 43.1 ⫾ 1.1 45.8 ⫾ 1.5 98.6 ⫾ 0.7 98.1 ⫾ 0.9 60 (92%)

7.37 ⫾ 0.01 7.36 ⫾ 0.01 42.3 ⫾ 1.2 43.7 ⫾ 1.2 98.9 ⫾ 0.5 98.7 ⫾ 0.7 61 (94%)

NOTE. Values are mean ⫾ SD. Abbreviations: Group A, alfentanil; Group S, sufentanil; Group AS, alfentanil ⫹ sufentanil.

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Table 6. Patient Outcomes Group A

Survival (no. patients/%) Death* Myocardial infarction† Sternal wound infection‡ (grade) IABP use in ICU Dopamine infusion Infusion of dopamine (h)㛳 Readmission in ICU Reoperation for bleeding

63/97% 2/3% 4/6%

Group S

64/98.5% 1/1.5% 3/4%

2/3% (II) 2/3% (II) 1/1.5% 0 13§/20% 5/8% 3.4 ⫾ 1.6 2.7 ⫾ 1.3 2/3% 1/1.5% 5/8% 4/6%

Group AS

64/98.5% 1/1.5% 3/4% 1/1.5% (III) 0 4/6% 2.9 ⫾ 1.2 1/1.5% 4/6%

Abbreviations: Group A, group alfentanil; Group S, group sufentanil; Group AS, group alfentanil ⫹ sufentanil; IABP, intra-aortic balloon pump; ICU, intensive care unit. *Causes of death in group A: 1 sepsis, 1 cardiogenic shock; in group S: 1 sepsis; group AS: 1 cerebral ischemia. †Perioperative myocardial infarction: appearance of new Q waves in the electrocardiogram or by elevation of the serum levels of myocardial enzymes, as troponin I and MB fraction of the CK isoenzymes. ‡Sternal wound infections on the basis of different anatomic structure involvement and distinguished as: superficial wound, grade I (skin involvement); grade II (skin and subcutaneous involvement); deep wound, grade III (bone involvement); grade IV (mediastinal involvement). §p ⬍ 0.05. 㛳Mean ⫾ SD.

but the half-time of sufentanil is shorter, particularly when given in multiple boluses or continuous infusion.8 The elimination half-life of sufentanil (140 to 200 minutes) is shorter than that of fentanyl (150 to 400 minutes),19 and when given in doses of 10 to 25 ␮g/kg, as a single agent for induction in cardiac and major vascular surgery, it improves outcome.24 Some authors were unable to define plasma concentrations associated with safe intubation and sternotomy, however.25 There is some evidence that in cardiac surgery sufentanil decreases hypertension and tachycardia events, provides better intraoperative stability, reduces myocardial oxygen consumption, and reduces postoperative respiratory depression compared with fentanyl.2 Remifentanil is a new opioid that undergoes extensive hepatic and extrahepatic breakdown by nonspecific tissue and blood esterases and has a rapid clearance and short duration of action.26 The short context-sensitive half-time of remifentanil is considered a potential advantage in fast-tracking patients undergoing CABG surgery.27 Because remifentanil rapidly produces hypotension, bradycardia, apnea, and muscle rigidity,19,28 it is given best as a short infusion (over 1 minute) rather than as a bolus, and patients should be pretreated with anticholinergics.19 In cardiac surgery, it should be administered with adequate postoperative analgesic medications to treat severe chest pain and to avoid potentially dangerous sympathetic cardiovascular reactions.29 Drugs used with remifentanil, such as ketorolac, paracetamol, and tramadol, are not devoid of side effects, however, and may increase bleeding, cause hepatic disturbances, or cause moderate respiratory depression.30 Lowdose opioids and propofol seem to be the best combination for induction and maintenance of anesthesia because they provide

intraoperative hemodynamic stability, early extubation, and fast ICU discharge and avoid administration of supplementary and potentially dangerous drugs until extubation.31,32 In the present study, as reported in Table 2, intraoperative hemodynamic stability was obtained with the opioid-propofol protocol. Differences among the 3 groups were observed at induction and intubation because of the different context-sensitive half-times of alfentanil and sufentanil.19 As a result of its faster onset to peak effect, alfentanil is preferred to sufentanil or fentanyl at the induction of anesthesia to blunt the circulatory responses to tracheal intubation.33,34 In these patients, HR and MAP were more stable in groups A and AS. From the literature, sufentanil seems to be more protective against the hyperdynamic responses to surgical stimuli.2 The hemodynamic profile of groups S and AS was similar to that of group A, with the exception of CI, which was lower in group A. Considering the lower values of SVRI and higher MAP at the end of surgery, the change in CI should be attributable to variations in HR. The sequential administration of alfentanil and sufentanil may minimize the side effects of each agent and reduce the intubation time in the ICU.8 The combination of vagomimetic properties of alfentanil19 and hypotensive effects of propofol may cause a vasoplegic effect, which required the postoperative use of dopamine in group A. In accordance with the specific properties of the drugs used, no patient required an analgesic supplement until extubation compared with other series in which remifentanil was used.19,30 In the patients who were extubated early, none required reintubation; all remained overnight in the ICU and were discharged the next morning. The most important goal in this study was hemodynamic stability, which was achieved by the use of opioids in the perioperative period. Another important goal was to perform early extubation without exaggerated hyperdynamic responses.6,27 The shorter intubation time of group AS compared with groups A and S was related to the kinetics of sufentanil compared with alfentanil when used in an infusion.19 The context-sensitive half-times for alfentanil and sufentanil after a 2-hour infusion are 51 and 21 minutes,8 and the elimination half-life of alfentanil is 3 times longer than normal after CPB because of an increase in its distribution volume. A decrease of protein-bound plasma alfentanil, owing to CPB-related hemodilution, contributed to the change in distribution volume.5 Using a computersimulated pharmacokinetic, pharmacodynamic model, Shafer and Varvel8 predicted for sufentanil a relatively short contextsensitive half-time (30 to 60 minutes) that is not modified by the duration of infusion (1 to 10 hours) because of a large distribution volume, which cannot be filled completely during infusion. Despite a long terminal half-life for sufentanil, it may be predicted to produce a more rapid recovery time.8 Although the differences among groups regarding extubation time, ICU length of stay, and some hemodynamic data were statistically significant, they were clinically small (and overall outcome was equivalent). All 3 anesthetic protocols were found to be safe and appropriate for patients undergoing elective CABG surgery and early postoperative tracheal extubation. ACKNOWLEDGMENT This study is dedicated to the memory of our close friend and colleague, Enrico Zupancich, who died suddenly and prematurely.

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