- Email: [email protected]
Spectral Entropy Monitoring Reduces Anesthetic Dosage for Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery
Spectral Entropy Monitoring Reduces Anesthetic Dosage for Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery Ma Jiahai, MD,* Wang Xueyan, MD,† Xie Yonggang, MD,* Yu Jianhong, MD,* He Qunhui, MD,* Li Zhi, MD,* Du Juan, MD,* and Jiang Xiuliang, MD* Objectives: The measurement of the depth of anesthesia is of clinical interest for patients undergoing off-pump coronary artery bypass graft (OPCAB) surgery in order to avoid intraoperative awareness and cardiac depression. Entropy recently was introduced as a monitor of anesthetic depth. This study was conducted to investigate the feasibility of entropy monitoring during the conduct of OPCAB surgery and to find out whether it reduced the anesthetic dosage for patients undergoing OPCAB surgery. Design: A prospective, randomized, single-blind, controlled study. Setting: A teaching hospital. Participants: Seventy patients scheduled for OPCAB surgery were randomized to receive propofol-sufentanil anesthesia either with the entropy values visible (the entropy group, n ⴝ 35) or without the entropy values visible (the control group, n ⴝ 35). Interventions: In the entropy group, propofol and sufentanil infusion rates were titrated to maintain a state entropy (SE) value of 45 to 55 and a response entropy (RE)-SE difference below 10 U. In the control group, patients were anesthetized to keep the heart rate and blood pressure within 25% of the baseline values.
Measurements and Main Results: The course of surgery, the consumption of anesthetics, and intraoperative recall were recorded. Plasma levels of adrenocorticotropic hormone (ACTH) and cortisol were measured. The average SE during anesthesia was 50 ⴞ 5 in the entropy group; the entropy values were lower in the control group (p < 0.05). Compared with the control group, propofol and sufentanil consumption were significantly less in the entropy group, which shortened the time to tracheal extubation (p < 0.05). Significantly, patients in the control group needed more phenylephrine to maintain arterial pressure than patients in the entropy group (p < 0.05). ACTH and cortisol release were prevented completely, and there was no intraoperative recall reported in the 2 groups. Conclusions: Entropy monitoring reduced propofol and sufentanil dosage for patients undergoing OPCAB surgery. © 2012 Elsevier Inc. All rights reserved.
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have less cardiovascular reserve as compared with previous reports.7 A major problem of any anesthetic procedure for OPCAB surgery concerns the depth of anesthesia. One study involving patients undergoing coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB) suggested that entropies were comparable with the bispectral index (BIS) but showed significantly less resistance against artifacts. Thus, entropy is more suitable than BIS during anesthesia in cardiac surgery patients.8 The objective of this study was to test the feasibility of entropy monitoring during the conduct of OPCAB and to find out if it changed the dosage of anesthetics.
ESPITE CONSIDERABLE EFFORTS, “depth of anesthesia” still is defined poorly and thus difficult to measure. The ideal monitor of anesthesia depth should help to optimize drug administration, and decrease the incidence of awareness during anesthesia. A wide variety of electroencephalographic-derived parameters and monitoring devices has been introduced to evaluate anesthetic depth.1-3 Among these, time-frequency– balanced spectral entropy (S/5 Entropy Module; Datex-Ohmeda, Helsinki, Finland), which generates both the state entropy (SE) and response entropy (RE) value, has been introduced as a monitor of anesthetic depth.4,5 It improved patient care by aiding anesthesiologists in optimizing drug administration, which could reduce the consumption of anesthetics without increasing the incidence of awareness in “at-risk” adult surgical patients.6 Off-pump coronary artery bypass graft (OPCAB) surgery is a frequently performed procedure in many hospitals. One study has shown that patients undergoing OPCAB surgery are older, have more frequent and severe comorbidities, and
From the *Department of Anesthesiology, Yantai Yuhuangding Hospital, Medical College, Qingdao University, Yantai, China; and †Yantai Center of Disease Control and Prevention, Yantai, China. Supported by the Science and Technology Programme Fundition of Yantai, Yantai, China (grant number 2010148-03). Address reprint requests to Ma Jiahai, MD, Department of Anesthesiology, Yantai Yuhuangding Hospital, Medical College, Qingdao University, Yantai, China. E-mail: [email protected] © 2012 Elsevier Inc. All rights reserved. 1053-0770/2605-0011$36.00/0 doi:10.1053/j.jvca.2012.01.028 818
KEY WORDS: anesthesia, general, electroencephalography, entropy, coronary artery bypass graft surgery, depth of anesthesia, recall
METHODS After obtaining the approval of the Institutional Human Investigations Committee and written informed consent from all the patients, this prospective, randomized, controlled study was conducted on 70 patients undergoing first-time OPCAB surgery. Inclusion criteria were patients with good or only slightly reduced left ventricular function (ejection fraction ⬎40%, left ventricular end-diastolic pressure ⬍15 mmHg) and patients below 70 years of age. The following patients were excluded: patients requiring CPB either electively or during the course of surgery; patients with renal insufficiency (creatinine ⬎1.5 mg/dL) or hepatic impairment (alanine aminotransferase or aspartate aminotransferase ⬎40 U/mL); and patients who misused alcohol or drugs. According to computer-generated random numbers, enrolled patients (n ⫽ 35/group) were randomized to receive propofol-sufentanil anesthesia either with entropy values visible (the entropy group) or with entropy values not shown (the control group). Antihypertensive and antiangina medications were continued until the morning of surgery. Patients were premedicated with morphine, 10 mg, and scopolamine, 0.3 mg intramuscularly, 60 minutes before anesthesia. Upon arrival in the operating room, patients were admin-
Journal of Cardiothoracic and Vascular Anesthesia, Vol 26, No 5 (October), 2012: pp 818-821
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istered oxygen using a facemask, and electrocardiographic monitoring (5 leads) with automated ST-segment analysis (Marquette Solar 5000; GE Medical System, Milwaukee, WI) and pulse oximetry was initiated. A 14-G intravenous catheter was inserted into a large forearm vein, and an 18-G intra-arterial catheter was introduced into the left femoral artery for monitoring of the arterial pressure. After the skin on the forehead was cleansed with 70% isopropyl alcohol, spectral entropy parameters were measured using an S/5 entropy module and entropy sensor (Datex-Ohmeda); electrode impedance was kept ⬍7.5 k⍀. Recording was started while the patient was awake. The entropy sensors were placed according to the manufacturer’s guidelines. Entropy values were collected at 5-second intervals on a laptop computer. Neuromuscular blockade was assessed by a train-of-4 stimulation of the ulnar nerve of the left hand. Induction was performed using a bolus of midazolam, 0.1 mg/kg; etomidate, 0.1 mg/kg; and sufentanil, 1 g/kg. Tracheal intubation was facilitated by pancuronium, 0.1 mg/kg. After intubation, a continuous infusion of propofol, 4 to 8 mg/kg/h, and sufentanil, 0.5 to 2.0 g/kg/h, was started using a syringe pump (Base Primea; Fresenius Vial, France). Patients were ventilated using an anesthesia machine (S/5 ADU, Datex Ohmeda) to achieve an end-tidal carbon dioxide concentration of 32 to 42 mmHg. Additional pancuronium, 0.03 mg/kg, was administered. Intraoperative hypothermia was prevented by using a warming blanket. Filling pressures and fluid balance were maintained using lactated Ringer’s solution and 6% hydroxyethyl starch (molecular weight: 130,000 Da, HAES-Steril; Fresenius Kabi, Beijing, China). All patients underwent OPCAB surgery after a median sternotomy under normothermic conditions. Traditional CABG surgery was ready as a rescue measure. Patients received heparin in a dose of 150 U/kg before anastomosis to maintain an activated coagulation time of ⬎300 seconds. Proximal anastomosis was performed with partial clamping of the ascending aorta, and distal grafting was performed using a tissue stabilizer. OPCAB surgery was converted to CABG surgery at any point should the patient not tolerate the period of ischemia required to complete the graft or for surgical reasons. In the entropy group, the propofol infusion rate was titrated to maintain an SE value of 45 to 55. An intermittent bolus dose of propofol, 20 to 50 mg, was given in case of an abrupt SE increase. Sufentanil infusion was adjusted so that the RE-SE difference would remain within 10 U. If RE exceeded SE by more than 10 U for more than 1 minute, the sufentanil infusion rate was increased, or an intermittent bolus dose of sufentanil, 5 to 10 g, was given in case of abrupt hypertension or tachycardia. Nitroglycerin or esmolol was used if necessary. Another target was to maintain stable intraoperative hemodynamics with the heart rate (HR) and blood pressure within 25% of the baseline values. When the mean arterial pressure (MAP) decreased to ⬍60 mmHg, hydroxyethyl starch was infused. When the MAP decreased to ⬍60 mmHg despite adequate volume loading, a dose of phenylephrine (0.5-1 g/kg) was administered. Nitroglycerin was used when the MAP was ⬎90 mmHg. Esmolol or anisodamine was used if the HR was ⬎85 beats/min or ⬍45 beats/min. Entropy indices were recorded on a laptop computer in 5-second intervals. Both propofol and sufentanil infusions were stopped at the end of surgery. In the control group, the propofol and sufentanil infusions were adjusted mainly based on the hemodynamic responses and clinical signs of deep or inadequate anesthesia. An intermittent bolus dose of propofol, 20 to 50 mg, or sufentanil, 5 to 10 g, was given in case of hypertension or tachycardia. Hemodynamic parameters were maintained within 25% of the baseline values with phenylephrine and nitroglycerin as in the entropy group. Entropy indices were collected at 5-second intervals on a laptop computer but were not displayed. After surgery, patients were transferred to the intensive care unit (ICU). The ICU personnel were blinded for the assignment of the patients to 1 of the 2 groups. Controlled mechanical ventilation was
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continued in the ICU. Tracheal extubation was performed when no major blood loss occurred and hemodynamic and respiratory parameters remained stable for at least 30 minutes. Arterial samples were placed in heparin-containing tubes. The samples were kept on ice and centrifuged within 10 minutes after collection. Supernatants subsequently were frozen in liquid nitrogen and stored at ⫺80°C until analysis. Adrenocorticotropic hormone (ACTH) and cortisol levels were measured by using commercial radioimmunoassay kits according to the manufacturer’s instructions (Diagnostic Products Corp, Los Angeles, CA) as described in detail previously.9 The following points were defined: T0, before the induction of anesthesia; T1, after tracheal intubation; T2, after sternotomy; T3, 30 minutes after the start of surgery; and T4, at the end of surgery. The course of anesthesia, surgery, and the actual consumption of anesthetic and additional drugs were noted manually. A standardized questionnaire (Appendix 1)10 to measure explicit intraoperative recall was completed immediately after tracheal extubation and 3 days later. Statistical analysis was performed by using SPSS 11.0 (SPSS Inc, Chicago, IL). The Kolmogorov-Smirnov test was used for the assumption of normality. Data were expressed as mean ⫾ standard deviation. The Student t test or 1-way analysis of variance was used; p ⬍ 0.05 was considered statistically significant. The sample size was based on an a priori study.11 A 25% difference in anesthetic dosage between the 2 groups was considered clinically significant. For a power of 0.8 and an ␣ value of 0.05, a sample size of 33 patients in each group was required. RESULTS
All patients tolerated the OPCAB surgery well, and none was converted to an on-pump procedure. The 2 groups were similar in demographic and preoperative data (Table 1). When the patients were awake before the induction of anesthesia, the RE was 96 ⫾ 5 and the SE was 89 ⫾ 4 in the entropy group and the RE was 97 ⫾ 5 and the SE was 88 ⫾ 4 in the control group. During anesthesia, the RE and SE values decreased progressively. The average SE during anesthesia (T1-T4) was within the intended range (50 ⫾ 5) in the entropy group, whereas entropy values were lower in the control group (p ⬍ 0.05). Therefore, along with the lighter level of anesthesia, the amount of propofol for anesthesia for OPCAB surgery was significantly less in the entropy group than in the control group (p ⬍ 0.05). Similarly, control patients received significantly more sufentanil (p ⬍ 0.05). The time to tracheal extubation was significantly reduced in the entropy group compared with the control group (p ⬍ 0.05). As for the duration of the ICU stay and hospital stay, there were no significant differences between the 2 groups (p ⬎ 0.05) (Table 2).
Table 1. Patient Characteristics and Preoperative Data
Age (y) Sex (M/F) Weight (kg) Left ventricular ejection fraction (%) Surgical time (min) Anesthesia time (min) Pre-existing arterial hypertension Diabetes mellitus Pre-existing hyperlipoproteinemia
Control Group
Entropy Group
60 ⫾ 6 20/5 83 ⫾ 16 53 ⫾ 6 186 ⫾ 23 264 ⫾ 34 29 9 19
59 ⫾ 7 19/6 81 ⫾ 13 52 ⫾ 7 174 ⫾ 28 256 ⫾ 42 30 7 17
NOTE. Data are presented as mean ⫾ standard deviation. There were no no significant differences between the 2 groups (p ⬎ 0.05).
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Table 2. Consumption of Anesthetics, Time to Tracheal Extubation, Duration of the ICU Stay and Hospital Stay, and Entropy Values
Cumulative doses of propofol (mg) Consumption of propofol (mg/kg) Cumulative doses of sufentanil (g) Consumption of sufentanil (g/kg) Time to tracheal extubation (min) Duration of the ICU stay (d) Duration of hospital stay (d) Average RE during anesthesia Average SE during anesthesia
Control Group
Entropy Group
1,536 ⫾ 86 19.2 ⫾ 4.2 624 ⫾ 34 7.3 ⫾ 2.4 405 ⫾ 38 1.4 ⫾ 0.2 11.3 ⫾ 0.4 45 ⫾ 4 41 ⫾ 6
1,085 ⫾ 56* 13.6 ⫾ 3.5* 468 ⫾ 41* 5.8 ⫾ 3.2* 312 ⫾ 41* 1.4 ⫾ 0.3 11.1 ⫾ 0.3 56 ⫾ 6* 50 ⫾ 5*
Note. Data are presented as mean ⫾ standard deviation. *p ⬍ 0.05 (entropy group v the control group).
Hemodynamic data with regard to HR and blood pressures were similar between the 2 groups. Patients in the control group needed more phenylephrine (6.2 ⫾ 3.7 g/kg in the control group and 3.8 ⫾ 2.4 g/kg in the entropy group, p ⬍ 0.05) to maintain an MAP within 25% of the baseline values, whereas the need for nitroglycerin, esmolol, and anisodamine did not differ between the 2 groups (p ⬎ 0.05). None of the patients in the 2 groups reported intraoperative recall in the postoperative interview. The plasma levels of ACTH and cortisol are presented in Table 3. Plasma ACTH and cortisol concentrations at T1-T4 largely were unaffected by surgery compared with respective baseline values (T0) (p ⬎ 0.05). Plasma ACTH and cortisol concentrations at T1-T4 in the 2 groups had no significant differences (p ⬎ 0.05). DISCUSSION
This study showed a reduction in the anesthetic dosage using entropy monitoring during OPCAB surgery when compared with anesthesia guided by routine clinical signs. Total intravenous anesthesia using propofol and sufentanil has been proposed as a safe anesthetic procedure for patients undergoing cardiac surgery, even in those with substantially impaired left ventricular function.12,13 The coadministration of an opioid (sufentanil) with a hypnotic drug (propofol) at variable concentrations was investigated. This approach was similar to the clinical practice of anesthesia. This underlined the usefulness of entropy monitoring in daily clinical practice with varying proportions of hypnotics and opioids.
To provide anesthesia for cardiac surgery, anesthetics frequently are titrated to variables, such as MAP and HR, but these hemodynamic variables may be correlated poorly to anesthetic depth.14 The potential benefit of individual titration of anesthetic drugs based on electroencephalographic monitoring is particularly obvious in patients undergoing cardiac surgery who are at risk for adverse effects of anesthesia, most notably hemodynamic instability and intraoperative recall. The recommended range of adequate anesthesia with entropy monitoring is 40 to 60.4,5 During anesthesia, when SE increases above 60, more hypnotic medication should be given. When SE is in the recommended range for adequate anesthesia but RE increases 10 U above it, this can be interpreted as a sign of uncovered nociception, and more analgesic should be administered. Clinical studies have suggested that entropy is useful in improving the titration of anesthetics and is more sensitive than BIS in detecting deepening of anesthesia.15,16 In the current study, the amounts of propofol and sufentanil for anesthesia in OPCAB surgery were significantly higher in the control group than in the entropy group, whereas entropy values were lower in the control group. The duration of ICU stay and hospital stay between the 2 groups did not differ; however, there was a difference in the time to tracheal extubation. The shortened time to tracheal extubation might be due to the use of a lesser amount of anesthetics in the entropy group. As for the duration of ICU stay and hospital stay, there are factors other than the dosage of anesthetics used in this study, such as the ward’s capacity to accept new patients from the ICU and the discharge criteria from the ICU to the ward, that influenced the differences between the 2 groups. Hemodynamic profiles were similar in the entropy and control groups. This is to be expected because hemodynamic responses guided the anesthetic dosage in the study protocol in both groups, not only in the control group. There are concerns that light anesthesia can put the patient in danger of awareness, hypertension, or myocardial ischemia. The substantial neuroendocrine stress response with significant increases in the concentrations of circulating cortisol and catecholamines during CABG surgery had been reported.17 Attenuation of the neuroendocrine stress response, most notably the release of catecholamines to noxious stimulation resulting from intubation or sternotomy, is important in patients undergoing cardiac surgery. Myocardial ischemia was not evaluated in this study. The levels of ACTH and cortisol were maintained in the
Table 3. Plasma Levels of ACTH and Cortisol T0
ACTH (pg/mL) Control group Entropy group Cortisol (ng/mL) Control group Entropy group
T1
T2
T3
T4
28.2 ⫾ 9.3 30.1 ⫾ 11.5
25.5 ⫾ 8.3 28.2 ⫾ 7.6
31.5 ⫾ 1.5 33.7 ⫾ 13.6
25.3 ⫾ 10.2 27.8 ⫾ 8.5
26.7 ⫾ 8.7 29.7 ⫾ 9.4
108.6 ⫾ 44.2 110.6 ⫾ 41.6
112.5 ⫾ 42.6 118.6 ⫾ 30.5
113.6 ⫾ 31.2 115.8 ⫾ 35.7
99.80 ⫾ 36.4 103.7 ⫾ 34.5
100.8 ⫾ 32.5 105.7 ⫾ 30.2
NOTE. Data are presented as mean ⫾ standard deviation. There were no significant differences between the 2 groups (p ⬎ 0.05). Abbreviations: T0, before the induction of anesthesia; T1, after tracheal intubation; T2, after sternotomy; T3, 30 minutes after the start of surgery; T4, at the end of surgery.
SPECTRAL ENTROPY MONITORING
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range of 45 to 55, suggesting that adequate depth of general anesthesia was achieved. Many anesthesiologists prefer to limit the dosage of anesthetics because of the concern for myocardial depression during OPCAB surgery, especially during grafting of the distal vessels. The current results showed that it was possible that patients anesthetized using routine clinical signs received more anesthesia than necessary when entropy was not monitored. The reduction of anesthetic drugs during OPCAB surgery that resulted from entropy monitoring can be extrapolated to less myocardial depression, less decrease in system vascular resistance, and less need for inotropic support. The anesthetic state consists of at least 2 components: hypnosis and analgesia. According to Vakkuri et al,15 2-parameter entropy should be superior to single-number indicators of depth of anesthesia in differentiating between nociception (RE) and the hypnotic state (SE). One volunteer study indicated that entropy revealed information on the hypnotic and analgesic states using coadministration of propofol and remifentanil.18 However, Ellerkmann et al4 failed to detect any differentiation between RE and SE, and the 2 parameters did not provide any additional information. In the present study, propofol and sufentanil infusion rates were adjusted mainly depending on the SE value or the RE-SE difference, respectively, and the dosage of anesthetics needed for OPCAB surgery was reduced significantly in the entropy group. Whether entropy can reveal both hypnosis and analgesia changes warrants further study. An incidence of awareness of 0.3% to 2.3% in patients
undergoing cardiac surgery has been reported.10,19 Although none of the patients in the 2 groups reported intraoperative recall, a much larger study population would be required to detect whether entropy could help to decrease intraoperative awareness in patients undergoing OPCAB surgery. Another limitation of this study was that cardiac outputs and myocardial ischemia were not studied. In conclusion, entropy might aid OPCAB surgery in 3 ways: (1) it monitors the depth of anesthesia and probably prevents intraoperative awareness; (2) it reduces the anesthetic dosage and hence reduces the cost of anesthesia; and (3) it helps avoid untoward side effects of anesthesia, such as hemodynamic instability and cardiac depression. Further studies are needed in elderly patients with poor left ventricular function or severe comorbidities undergoing highrisk OPCAB surgery. APPENDIX 1. STANDARDIZED QUESTIONNAIRE
1. Were you satisfied with the anesthesia you received? (Satisfaction was evaluated using a scoring system ranging from 1 to 6 (1, best; 6, worst).) 2. What was your last memory before the operation? 3. What was your first memory after the operation? 4. What of your anesthesia was very pleasant? 5. What of your anesthesia did you not like at all? 6. If you need anesthesia again, would you like the type of anesthesia you had, or do you prefer another type of anesthesia? 7. Did you dream during anesthesia?
REFERENCES 1. Tempe DK: In search of a reliable awareness monitor. Anesth Analg 92:801-804, 2001 2. Iselin-Chaves IA, El Moalem HE, Gan TJ, et al: Changes in the auditory evoked potentials and the bispectral index following propofol or propofol and alfentanil. Anesthesiology 92:1300-1310, 2000 3. Recart A, White PF, Wang A, et al: Effect of auditory evoked potential index monitoring on anesthetic drug requirements and recovery profile after laparoscopic surgery: A clinical utility study. Anesthesiology 99:813-818, 2003 4. Ellerkmann RK, Liermann VM, Alves TM, et al: Spectral entropy and bispectral index as measures of the electroencephalographic effects of sevoflurane. Anesthesiology 101:1275-1282, 2004 5. Vanluchene AL, Vereecke H, Thas O, et al: Spectral entropy as an electroencephalographic measure of anesthetic drug effect: A comparison with bispectral index and processed midlatency auditory evoked response. Anesthesiology 101:34-42, 2004 6. Schmidt GN, Bischoff P, Standl T, et al: Comparative evaluation of the Datex-Ohmeda S/5 entropy module and the bispectral index monitor during propofol–remifentanil anesthesia. Anesthesiology 101:1283-1290, 2004 7. Rady MY, Ryan T, Starr NJ: Perioperative determinants of morbidity and mortality in elderly patients undergoing cardiac surgery. Crit Care Med 26:225-235, 1998 8. 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 9. Grundmann U, Rensing H, Adams HA, et al: Endotoxin desensitization of human mononuclear cells after cardiopulmonary bypass: Role of humoral factors. Anesthesiology 93:359-369, 2000 10. Dowd NP, Cheng DC, Karski JM, et al: Intraoperative awareness in fast-track cardiac anesthesia. Anesthesiology 89:1068-1073, 1998
11. Lehmann A, Schmidt M, Zeitler C, et al: Bispectral index and electroencephalographic entropy in patients undergoing aortocoronary bypass grafting. Eur J Anesthesiol 24:751-760, 2007 12. Jain U, Body SC, Bellows W, et al: Multicenter study of targetcontrolled infusion of propofol-sufentanil or sufentanil-midazolam for coronary artery bypass graft surgery. Multicenter study of perioperative ischemia (McSPI) research group. Anesthesiology 85:522-535, 1996 13. 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 14. Flaishon R, Windsor A, Sigl J, et al: Recovery of consciousness after thiopental or propofol: Bispectral index and isolated forearm technique. Anesthesiology 86:613-619, 1997 15. Vakkuri A, Yli-Hankala A, Talja P, et al: Time-frequency balanced spectral entropy as a measure of anesthetic drug effect in central nervous system during sevoflurane, propofol, and thiopental anesthesia. Acta Anaesthesiol Scand 48:145-153, 2004 16. Bruhn J, Bouillon TW, Shafer SL: Onset of propofol-induced burst suppression may be correctly detected as deepening of anaesthesia by approximate entropy but not by bispectral index. Br J Anaesth 87:505-507, 2001 17. Høymork SC, Raeder J, Grimsmo B, et al: Bispectral index, predicted and measured drug levels of target controlled infusions of remifentanil and propofol during laparoscopic cholecystectomy and emergence. Acta Anaesthesiol Scand 44:1138-1144, 2000 18. Bruhn J, Bouillon TW, Radulescu L, et al: Correlation of approximate entropy, bispectral index and spectral edge frequency 95(SEF95) with clinical signs of “anesthetic depth” during coadministration of propofol and remifentanil. Anesthesiology 98:621-627, 2003 19. Ranta SO, Herranen P, Hynynen M: Patients’ conscious recollections from cardiac anesthesia. J Cardiothorac Vasc Anesth 16:426-430, 2002
Measurements and Main Results: The course of surgery, the consumption of anesthetics, and intraoperative recall were recorded. Plasma levels of adrenocorticotropic hormone (ACTH) and cortisol were measured. The average SE during anesthesia was 50 ⴞ 5 in the entropy group; the entropy values were lower in the control group (p < 0.05). Compared with the control group, propofol and sufentanil consumption were significantly less in the entropy group, which shortened the time to tracheal extubation (p < 0.05). Significantly, patients in the control group needed more phenylephrine to maintain arterial pressure than patients in the entropy group (p < 0.05). ACTH and cortisol release were prevented completely, and there was no intraoperative recall reported in the 2 groups. Conclusions: Entropy monitoring reduced propofol and sufentanil dosage for patients undergoing OPCAB surgery. © 2012 Elsevier Inc. All rights reserved.
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have less cardiovascular reserve as compared with previous reports.7 A major problem of any anesthetic procedure for OPCAB surgery concerns the depth of anesthesia. One study involving patients undergoing coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB) suggested that entropies were comparable with the bispectral index (BIS) but showed significantly less resistance against artifacts. Thus, entropy is more suitable than BIS during anesthesia in cardiac surgery patients.8 The objective of this study was to test the feasibility of entropy monitoring during the conduct of OPCAB and to find out if it changed the dosage of anesthetics.
ESPITE CONSIDERABLE EFFORTS, “depth of anesthesia” still is defined poorly and thus difficult to measure. The ideal monitor of anesthesia depth should help to optimize drug administration, and decrease the incidence of awareness during anesthesia. A wide variety of electroencephalographic-derived parameters and monitoring devices has been introduced to evaluate anesthetic depth.1-3 Among these, time-frequency– balanced spectral entropy (S/5 Entropy Module; Datex-Ohmeda, Helsinki, Finland), which generates both the state entropy (SE) and response entropy (RE) value, has been introduced as a monitor of anesthetic depth.4,5 It improved patient care by aiding anesthesiologists in optimizing drug administration, which could reduce the consumption of anesthetics without increasing the incidence of awareness in “at-risk” adult surgical patients.6 Off-pump coronary artery bypass graft (OPCAB) surgery is a frequently performed procedure in many hospitals. One study has shown that patients undergoing OPCAB surgery are older, have more frequent and severe comorbidities, and
From the *Department of Anesthesiology, Yantai Yuhuangding Hospital, Medical College, Qingdao University, Yantai, China; and †Yantai Center of Disease Control and Prevention, Yantai, China. Supported by the Science and Technology Programme Fundition of Yantai, Yantai, China (grant number 2010148-03). Address reprint requests to Ma Jiahai, MD, Department of Anesthesiology, Yantai Yuhuangding Hospital, Medical College, Qingdao University, Yantai, China. E-mail: [email protected] © 2012 Elsevier Inc. All rights reserved. 1053-0770/2605-0011$36.00/0 doi:10.1053/j.jvca.2012.01.028 818
KEY WORDS: anesthesia, general, electroencephalography, entropy, coronary artery bypass graft surgery, depth of anesthesia, recall
METHODS After obtaining the approval of the Institutional Human Investigations Committee and written informed consent from all the patients, this prospective, randomized, controlled study was conducted on 70 patients undergoing first-time OPCAB surgery. Inclusion criteria were patients with good or only slightly reduced left ventricular function (ejection fraction ⬎40%, left ventricular end-diastolic pressure ⬍15 mmHg) and patients below 70 years of age. The following patients were excluded: patients requiring CPB either electively or during the course of surgery; patients with renal insufficiency (creatinine ⬎1.5 mg/dL) or hepatic impairment (alanine aminotransferase or aspartate aminotransferase ⬎40 U/mL); and patients who misused alcohol or drugs. According to computer-generated random numbers, enrolled patients (n ⫽ 35/group) were randomized to receive propofol-sufentanil anesthesia either with entropy values visible (the entropy group) or with entropy values not shown (the control group). Antihypertensive and antiangina medications were continued until the morning of surgery. Patients were premedicated with morphine, 10 mg, and scopolamine, 0.3 mg intramuscularly, 60 minutes before anesthesia. Upon arrival in the operating room, patients were admin-
Journal of Cardiothoracic and Vascular Anesthesia, Vol 26, No 5 (October), 2012: pp 818-821
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istered oxygen using a facemask, and electrocardiographic monitoring (5 leads) with automated ST-segment analysis (Marquette Solar 5000; GE Medical System, Milwaukee, WI) and pulse oximetry was initiated. A 14-G intravenous catheter was inserted into a large forearm vein, and an 18-G intra-arterial catheter was introduced into the left femoral artery for monitoring of the arterial pressure. After the skin on the forehead was cleansed with 70% isopropyl alcohol, spectral entropy parameters were measured using an S/5 entropy module and entropy sensor (Datex-Ohmeda); electrode impedance was kept ⬍7.5 k⍀. Recording was started while the patient was awake. The entropy sensors were placed according to the manufacturer’s guidelines. Entropy values were collected at 5-second intervals on a laptop computer. Neuromuscular blockade was assessed by a train-of-4 stimulation of the ulnar nerve of the left hand. Induction was performed using a bolus of midazolam, 0.1 mg/kg; etomidate, 0.1 mg/kg; and sufentanil, 1 g/kg. Tracheal intubation was facilitated by pancuronium, 0.1 mg/kg. After intubation, a continuous infusion of propofol, 4 to 8 mg/kg/h, and sufentanil, 0.5 to 2.0 g/kg/h, was started using a syringe pump (Base Primea; Fresenius Vial, France). Patients were ventilated using an anesthesia machine (S/5 ADU, Datex Ohmeda) to achieve an end-tidal carbon dioxide concentration of 32 to 42 mmHg. Additional pancuronium, 0.03 mg/kg, was administered. Intraoperative hypothermia was prevented by using a warming blanket. Filling pressures and fluid balance were maintained using lactated Ringer’s solution and 6% hydroxyethyl starch (molecular weight: 130,000 Da, HAES-Steril; Fresenius Kabi, Beijing, China). All patients underwent OPCAB surgery after a median sternotomy under normothermic conditions. Traditional CABG surgery was ready as a rescue measure. Patients received heparin in a dose of 150 U/kg before anastomosis to maintain an activated coagulation time of ⬎300 seconds. Proximal anastomosis was performed with partial clamping of the ascending aorta, and distal grafting was performed using a tissue stabilizer. OPCAB surgery was converted to CABG surgery at any point should the patient not tolerate the period of ischemia required to complete the graft or for surgical reasons. In the entropy group, the propofol infusion rate was titrated to maintain an SE value of 45 to 55. An intermittent bolus dose of propofol, 20 to 50 mg, was given in case of an abrupt SE increase. Sufentanil infusion was adjusted so that the RE-SE difference would remain within 10 U. If RE exceeded SE by more than 10 U for more than 1 minute, the sufentanil infusion rate was increased, or an intermittent bolus dose of sufentanil, 5 to 10 g, was given in case of abrupt hypertension or tachycardia. Nitroglycerin or esmolol was used if necessary. Another target was to maintain stable intraoperative hemodynamics with the heart rate (HR) and blood pressure within 25% of the baseline values. When the mean arterial pressure (MAP) decreased to ⬍60 mmHg, hydroxyethyl starch was infused. When the MAP decreased to ⬍60 mmHg despite adequate volume loading, a dose of phenylephrine (0.5-1 g/kg) was administered. Nitroglycerin was used when the MAP was ⬎90 mmHg. Esmolol or anisodamine was used if the HR was ⬎85 beats/min or ⬍45 beats/min. Entropy indices were recorded on a laptop computer in 5-second intervals. Both propofol and sufentanil infusions were stopped at the end of surgery. In the control group, the propofol and sufentanil infusions were adjusted mainly based on the hemodynamic responses and clinical signs of deep or inadequate anesthesia. An intermittent bolus dose of propofol, 20 to 50 mg, or sufentanil, 5 to 10 g, was given in case of hypertension or tachycardia. Hemodynamic parameters were maintained within 25% of the baseline values with phenylephrine and nitroglycerin as in the entropy group. Entropy indices were collected at 5-second intervals on a laptop computer but were not displayed. After surgery, patients were transferred to the intensive care unit (ICU). The ICU personnel were blinded for the assignment of the patients to 1 of the 2 groups. Controlled mechanical ventilation was
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continued in the ICU. Tracheal extubation was performed when no major blood loss occurred and hemodynamic and respiratory parameters remained stable for at least 30 minutes. Arterial samples were placed in heparin-containing tubes. The samples were kept on ice and centrifuged within 10 minutes after collection. Supernatants subsequently were frozen in liquid nitrogen and stored at ⫺80°C until analysis. Adrenocorticotropic hormone (ACTH) and cortisol levels were measured by using commercial radioimmunoassay kits according to the manufacturer’s instructions (Diagnostic Products Corp, Los Angeles, CA) as described in detail previously.9 The following points were defined: T0, before the induction of anesthesia; T1, after tracheal intubation; T2, after sternotomy; T3, 30 minutes after the start of surgery; and T4, at the end of surgery. The course of anesthesia, surgery, and the actual consumption of anesthetic and additional drugs were noted manually. A standardized questionnaire (Appendix 1)10 to measure explicit intraoperative recall was completed immediately after tracheal extubation and 3 days later. Statistical analysis was performed by using SPSS 11.0 (SPSS Inc, Chicago, IL). The Kolmogorov-Smirnov test was used for the assumption of normality. Data were expressed as mean ⫾ standard deviation. The Student t test or 1-way analysis of variance was used; p ⬍ 0.05 was considered statistically significant. The sample size was based on an a priori study.11 A 25% difference in anesthetic dosage between the 2 groups was considered clinically significant. For a power of 0.8 and an ␣ value of 0.05, a sample size of 33 patients in each group was required. RESULTS
All patients tolerated the OPCAB surgery well, and none was converted to an on-pump procedure. The 2 groups were similar in demographic and preoperative data (Table 1). When the patients were awake before the induction of anesthesia, the RE was 96 ⫾ 5 and the SE was 89 ⫾ 4 in the entropy group and the RE was 97 ⫾ 5 and the SE was 88 ⫾ 4 in the control group. During anesthesia, the RE and SE values decreased progressively. The average SE during anesthesia (T1-T4) was within the intended range (50 ⫾ 5) in the entropy group, whereas entropy values were lower in the control group (p ⬍ 0.05). Therefore, along with the lighter level of anesthesia, the amount of propofol for anesthesia for OPCAB surgery was significantly less in the entropy group than in the control group (p ⬍ 0.05). Similarly, control patients received significantly more sufentanil (p ⬍ 0.05). The time to tracheal extubation was significantly reduced in the entropy group compared with the control group (p ⬍ 0.05). As for the duration of the ICU stay and hospital stay, there were no significant differences between the 2 groups (p ⬎ 0.05) (Table 2).
Table 1. Patient Characteristics and Preoperative Data
Age (y) Sex (M/F) Weight (kg) Left ventricular ejection fraction (%) Surgical time (min) Anesthesia time (min) Pre-existing arterial hypertension Diabetes mellitus Pre-existing hyperlipoproteinemia
Control Group
Entropy Group
60 ⫾ 6 20/5 83 ⫾ 16 53 ⫾ 6 186 ⫾ 23 264 ⫾ 34 29 9 19
59 ⫾ 7 19/6 81 ⫾ 13 52 ⫾ 7 174 ⫾ 28 256 ⫾ 42 30 7 17
NOTE. Data are presented as mean ⫾ standard deviation. There were no no significant differences between the 2 groups (p ⬎ 0.05).
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Table 2. Consumption of Anesthetics, Time to Tracheal Extubation, Duration of the ICU Stay and Hospital Stay, and Entropy Values
Cumulative doses of propofol (mg) Consumption of propofol (mg/kg) Cumulative doses of sufentanil (g) Consumption of sufentanil (g/kg) Time to tracheal extubation (min) Duration of the ICU stay (d) Duration of hospital stay (d) Average RE during anesthesia Average SE during anesthesia
Control Group
Entropy Group
1,536 ⫾ 86 19.2 ⫾ 4.2 624 ⫾ 34 7.3 ⫾ 2.4 405 ⫾ 38 1.4 ⫾ 0.2 11.3 ⫾ 0.4 45 ⫾ 4 41 ⫾ 6
1,085 ⫾ 56* 13.6 ⫾ 3.5* 468 ⫾ 41* 5.8 ⫾ 3.2* 312 ⫾ 41* 1.4 ⫾ 0.3 11.1 ⫾ 0.3 56 ⫾ 6* 50 ⫾ 5*
Note. Data are presented as mean ⫾ standard deviation. *p ⬍ 0.05 (entropy group v the control group).
Hemodynamic data with regard to HR and blood pressures were similar between the 2 groups. Patients in the control group needed more phenylephrine (6.2 ⫾ 3.7 g/kg in the control group and 3.8 ⫾ 2.4 g/kg in the entropy group, p ⬍ 0.05) to maintain an MAP within 25% of the baseline values, whereas the need for nitroglycerin, esmolol, and anisodamine did not differ between the 2 groups (p ⬎ 0.05). None of the patients in the 2 groups reported intraoperative recall in the postoperative interview. The plasma levels of ACTH and cortisol are presented in Table 3. Plasma ACTH and cortisol concentrations at T1-T4 largely were unaffected by surgery compared with respective baseline values (T0) (p ⬎ 0.05). Plasma ACTH and cortisol concentrations at T1-T4 in the 2 groups had no significant differences (p ⬎ 0.05). DISCUSSION
This study showed a reduction in the anesthetic dosage using entropy monitoring during OPCAB surgery when compared with anesthesia guided by routine clinical signs. Total intravenous anesthesia using propofol and sufentanil has been proposed as a safe anesthetic procedure for patients undergoing cardiac surgery, even in those with substantially impaired left ventricular function.12,13 The coadministration of an opioid (sufentanil) with a hypnotic drug (propofol) at variable concentrations was investigated. This approach was similar to the clinical practice of anesthesia. This underlined the usefulness of entropy monitoring in daily clinical practice with varying proportions of hypnotics and opioids.
To provide anesthesia for cardiac surgery, anesthetics frequently are titrated to variables, such as MAP and HR, but these hemodynamic variables may be correlated poorly to anesthetic depth.14 The potential benefit of individual titration of anesthetic drugs based on electroencephalographic monitoring is particularly obvious in patients undergoing cardiac surgery who are at risk for adverse effects of anesthesia, most notably hemodynamic instability and intraoperative recall. The recommended range of adequate anesthesia with entropy monitoring is 40 to 60.4,5 During anesthesia, when SE increases above 60, more hypnotic medication should be given. When SE is in the recommended range for adequate anesthesia but RE increases 10 U above it, this can be interpreted as a sign of uncovered nociception, and more analgesic should be administered. Clinical studies have suggested that entropy is useful in improving the titration of anesthetics and is more sensitive than BIS in detecting deepening of anesthesia.15,16 In the current study, the amounts of propofol and sufentanil for anesthesia in OPCAB surgery were significantly higher in the control group than in the entropy group, whereas entropy values were lower in the control group. The duration of ICU stay and hospital stay between the 2 groups did not differ; however, there was a difference in the time to tracheal extubation. The shortened time to tracheal extubation might be due to the use of a lesser amount of anesthetics in the entropy group. As for the duration of ICU stay and hospital stay, there are factors other than the dosage of anesthetics used in this study, such as the ward’s capacity to accept new patients from the ICU and the discharge criteria from the ICU to the ward, that influenced the differences between the 2 groups. Hemodynamic profiles were similar in the entropy and control groups. This is to be expected because hemodynamic responses guided the anesthetic dosage in the study protocol in both groups, not only in the control group. There are concerns that light anesthesia can put the patient in danger of awareness, hypertension, or myocardial ischemia. The substantial neuroendocrine stress response with significant increases in the concentrations of circulating cortisol and catecholamines during CABG surgery had been reported.17 Attenuation of the neuroendocrine stress response, most notably the release of catecholamines to noxious stimulation resulting from intubation or sternotomy, is important in patients undergoing cardiac surgery. Myocardial ischemia was not evaluated in this study. The levels of ACTH and cortisol were maintained in the
Table 3. Plasma Levels of ACTH and Cortisol T0
ACTH (pg/mL) Control group Entropy group Cortisol (ng/mL) Control group Entropy group
T1
T2
T3
T4
28.2 ⫾ 9.3 30.1 ⫾ 11.5
25.5 ⫾ 8.3 28.2 ⫾ 7.6
31.5 ⫾ 1.5 33.7 ⫾ 13.6
25.3 ⫾ 10.2 27.8 ⫾ 8.5
26.7 ⫾ 8.7 29.7 ⫾ 9.4
108.6 ⫾ 44.2 110.6 ⫾ 41.6
112.5 ⫾ 42.6 118.6 ⫾ 30.5
113.6 ⫾ 31.2 115.8 ⫾ 35.7
99.80 ⫾ 36.4 103.7 ⫾ 34.5
100.8 ⫾ 32.5 105.7 ⫾ 30.2
NOTE. Data are presented as mean ⫾ standard deviation. There were no significant differences between the 2 groups (p ⬎ 0.05). Abbreviations: T0, before the induction of anesthesia; T1, after tracheal intubation; T2, after sternotomy; T3, 30 minutes after the start of surgery; T4, at the end of surgery.
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range of 45 to 55, suggesting that adequate depth of general anesthesia was achieved. Many anesthesiologists prefer to limit the dosage of anesthetics because of the concern for myocardial depression during OPCAB surgery, especially during grafting of the distal vessels. The current results showed that it was possible that patients anesthetized using routine clinical signs received more anesthesia than necessary when entropy was not monitored. The reduction of anesthetic drugs during OPCAB surgery that resulted from entropy monitoring can be extrapolated to less myocardial depression, less decrease in system vascular resistance, and less need for inotropic support. The anesthetic state consists of at least 2 components: hypnosis and analgesia. According to Vakkuri et al,15 2-parameter entropy should be superior to single-number indicators of depth of anesthesia in differentiating between nociception (RE) and the hypnotic state (SE). One volunteer study indicated that entropy revealed information on the hypnotic and analgesic states using coadministration of propofol and remifentanil.18 However, Ellerkmann et al4 failed to detect any differentiation between RE and SE, and the 2 parameters did not provide any additional information. In the present study, propofol and sufentanil infusion rates were adjusted mainly depending on the SE value or the RE-SE difference, respectively, and the dosage of anesthetics needed for OPCAB surgery was reduced significantly in the entropy group. Whether entropy can reveal both hypnosis and analgesia changes warrants further study. An incidence of awareness of 0.3% to 2.3% in patients
undergoing cardiac surgery has been reported.10,19 Although none of the patients in the 2 groups reported intraoperative recall, a much larger study population would be required to detect whether entropy could help to decrease intraoperative awareness in patients undergoing OPCAB surgery. Another limitation of this study was that cardiac outputs and myocardial ischemia were not studied. In conclusion, entropy might aid OPCAB surgery in 3 ways: (1) it monitors the depth of anesthesia and probably prevents intraoperative awareness; (2) it reduces the anesthetic dosage and hence reduces the cost of anesthesia; and (3) it helps avoid untoward side effects of anesthesia, such as hemodynamic instability and cardiac depression. Further studies are needed in elderly patients with poor left ventricular function or severe comorbidities undergoing highrisk OPCAB surgery. APPENDIX 1. STANDARDIZED QUESTIONNAIRE
1. Were you satisfied with the anesthesia you received? (Satisfaction was evaluated using a scoring system ranging from 1 to 6 (1, best; 6, worst).) 2. What was your last memory before the operation? 3. What was your first memory after the operation? 4. What of your anesthesia was very pleasant? 5. What of your anesthesia did you not like at all? 6. If you need anesthesia again, would you like the type of anesthesia you had, or do you prefer another type of anesthesia? 7. Did you dream during anesthesia?
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11. Lehmann A, Schmidt M, Zeitler C, et al: Bispectral index and electroencephalographic entropy in patients undergoing aortocoronary bypass grafting. Eur J Anesthesiol 24:751-760, 2007 12. Jain U, Body SC, Bellows W, et al: Multicenter study of targetcontrolled infusion of propofol-sufentanil or sufentanil-midazolam for coronary artery bypass graft surgery. Multicenter study of perioperative ischemia (McSPI) research group. Anesthesiology 85:522-535, 1996 13. 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 14. Flaishon R, Windsor A, Sigl J, et al: Recovery of consciousness after thiopental or propofol: Bispectral index and isolated forearm technique. Anesthesiology 86:613-619, 1997 15. Vakkuri A, Yli-Hankala A, Talja P, et al: Time-frequency balanced spectral entropy as a measure of anesthetic drug effect in central nervous system during sevoflurane, propofol, and thiopental anesthesia. Acta Anaesthesiol Scand 48:145-153, 2004 16. Bruhn J, Bouillon TW, Shafer SL: Onset of propofol-induced burst suppression may be correctly detected as deepening of anaesthesia by approximate entropy but not by bispectral index. Br J Anaesth 87:505-507, 2001 17. Høymork SC, Raeder J, Grimsmo B, et al: Bispectral index, predicted and measured drug levels of target controlled infusions of remifentanil and propofol during laparoscopic cholecystectomy and emergence. Acta Anaesthesiol Scand 44:1138-1144, 2000 18. Bruhn J, Bouillon TW, Radulescu L, et al: Correlation of approximate entropy, bispectral index and spectral edge frequency 95(SEF95) with clinical signs of “anesthetic depth” during coadministration of propofol and remifentanil. Anesthesiology 98:621-627, 2003 19. Ranta SO, Herranen P, Hynynen M: Patients’ conscious recollections from cardiac anesthesia. J Cardiothorac Vasc Anesth 16:426-430, 2002