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Impact of bispectral index monitoring on propofol administration in patients undergoing cardiopulmonary bypass.

SUMMARY

Propofol anaesthesia using target control infusion during cardiac surgery has become more popular recently. However, without depth of anaesthesia monitoring, the standard target concentration used may be higher than necessary to maintain adequate hypnosis during hypothermic cardiopulmonary bypass. The purpose of this study was to evaluate the effect of bispectral index monitoring on propofol administration during hypothermic cardiopulmonary bypass. After ethics committee approval and written informed consent, 20 New York Heart Association class I-III patients scheduled for elective cardiac surgery requiring hypothermic cardiopulmonary bypass were studied in this prospective randomised controlled trial. In group C, routine anaesthesia was practised, where patients received propofol at target concentration between 1.5 to 2.5 [micro]g/ml during cardiopulmonary bypass. In group B, the target concentration was titrated to a bispectral index value of 40 to 50. Mean arterial pressure and bispectral index were recorded at various time intervals. The use of propofol, phenylephrine, sodium nitroprusside and adrenaline were recorded. The median propofol administration in group B was significantly less than that in group C (2.9 mg/kg/h compared to 6.0 mg/kg/h). The bispectral index value during bypass was significantly lower in group C than in group B, reflecting a deeper state of anaesthesia. There was no difference in the use of inotropes, vasoconstrictors or vasodilators. Bispectral index monitoring enables a 50% reduction in propofol administration at this standard dose during hypothermic cardiopulmonary bypass.

Key Words: bispectral index monitoring, target control infusion, propofol, hypothermic, cardiopulmonary bypass

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Anaesthesia during cardiopulmonary bypass (CPB) is unique and potential awareness remains a particular problem. Previously, anaesthesia for cardiac surgery mainly incorporated large doses of opiates. Volatile anaesthetic agents were often omitted or used in minimal quantities to avoid hypotension. Recently, total intravenous anaesthesia based on propofol has been used as an anaesthetic technique in cardiac surgery (1,2). A continuous infusion of standard rate of propofol has been shown to reduce the incidence of awareness (2). Subsequently target controlled infusion (TCI), using an internal pharmacokinetic model, has been developed to induce and maintain drug concentration. It provides the anaesthetist with the ability to target the calculated plasma concentration rather than indirect control by adjusting the infusion rate.

The use of propofol TO in cardiac surgery has become increasingly popular (3-6). It can be used continuously throughout the operation to maintain hypnosis during the bypass period and for postoperative sedation. Target concentrations of 1.5 to 3.0 [micro]g/ml of propofol have been used in various studies in patients undergoing hypothermic CPB (3-6). However, both hypothermia and CPB can affect the pharmacodynamics and pharmacokinetics of propofol (7-9), therefore the standard rate of infusion during CPB may not be the same as in patients undergoing other surgery. Without depth of anaesthesia monitoring it is difficult to know the appropriate infusion rate needed to maintain hypnosis during hypothermic CPB. Standard clinical practice is cautious and in the attempt of avoiding awareness, anaesthetists may administer drug doses that may be larger than necessary for patients undergoing hypothermic CPB. This approach may result in a deeper state of anaesthesia, unstable haemodynamic status, prolonged recovery and increased cost.

Several years ago, bispectral index (BIS) monitoring was introduced to clinical practice. BIS decreases with increasing depth of anaesthesia and an adequate level of anaesthesia is achieved with BIS ranging from 40 to 60 (10). A good correlation between BIS and increasing sedation with propofol has been established (11-12). BIS-guided propofol anaesthesia has been studied widely in noncardiac surgery but there is limited study on its use during hypothermic cardiopulmonary bypass.

The aim of this study was to evaluate the impact of the use of BIS monitoring on the propofol requirements and haemodynamic stability during CPB.

MATERIALS AND METHODS

This prospective, randomised, controlled study was approved by the University of Malaya Medical Centre ethics committee. After written informed consent was obtained, we studied 20 patients (New York Heart Association class I-III) scheduled for cardiac surgery requiring CPB. Patients were randomly allocated (computer generated random numbers in closed envelopes opened when the patient arrived in the operating room) to either the BIS group (B) or the control (C) group. Exclusion criteria were previous cardiac surgery, preoperative neurological disease, ejection fraction of less than 30%, known allergy to one of the drugs used and severe renal and hepatic impairment.

All patients were premedicated with oral midazolam 0.1 mg/kg. On arrival at the holding area, Zipprep electrodes (Aspect Medical Systems) were placed on the forehead according to the manufacturer's instructions. The first BIS reading was taken as the baseline value. Baseline mean arterial pressure (MAP) was determined non-invasively at the same time.

In the operating theatre, two peripheral intravenous cannulas, a radial arterial cannula and an internal jugular triple lumen line were inserted under local anaesthesia. Invasive blood pressure, central venous pressure, six-lead ECG, pulse oximetry, end-tidal capnography, anaesthetic gases, nasal and rectal temperature and BIS were monitored.

After breathing 100% oxygen for three minutes through a facemask, anaesthesia was induced with intravenous fentanyl 10 [micro]g/kg and a small dose of propofol titrated to loss of consciousness. Patients were paralysed with rocuronium 0.9 mg/kg. After tracheal intubation the lungs were ventilated with oxygen in air (Fi[O.sub.2] 0.5), maintaining an end-tidal C[O.sub.2] between 30 and 35 mmHg. Continuous muscle paralysis was provided by atracurium infusion and this was continued until skin closure. Anaesthesia before CPB was maintained with sevoflurane (end-tidal concentration, 0.5 to 1.5%). During CPB, hypnosis was provided by propofol using a commercial target-controlled infusion (TCI, Graseby 3500, Diprifusor; AstraZeneca). Additional analgesia was provided by morphine 0.2 mg/kg, administered into the pump at the onset of rewarming.

The study period commenced at the onset of CPB and continued until the end of surgery. Continuous infusion of propofol using a target concentration of 2.0 [micro]g/ml was started in both groups once ventilation was stopped. (This target concentration is within the range of 1.5 to 3.0 [micro]g/ml used by other investigators (3-6)). In group B, BIS-controlled adjustment of the propofol infusion was used to achieve a BIS value of 40 to 50. In group C the BIS value was not made available. The target concentration of propofol was started at 2.0 [micro]g/ml. It was increased to 2.5 [micro]g/ml if perfusion pressure was consistently above 90 mmHg for over five minutes despite the use of sodium nitroprusside up to 5 [micro]g/kg/min. It was decreased to 1.5 [micro]g/ml if the perfusion pressure was persistently lower than 70 mmHg despite the repeated use of phenylephrine to a maximum of 2 mg over 30 minutes. Readings of BIS and MAP were recorded at the following time intervals: 1) baseline, 2) immediately after induction, 3) at the onset of cardiopulmonary bypass, just before starting the TCI propofol infusion, 4) immediately before cross-clamp, 5) every five minutes during the cardiopulmonary bypass after cross-clamping, 6) at the release of cross-clamp, 7) at the end of cardiopulmonary bypass, 8) at skin closure and 9) at the end of surgery.

All patients were managed by the same surgeon and anaesthetist. A standard cardiac surgical technique was used in all patients. Systemic heparinisation was achieved with 3 mg/kg of heparin. Roller pumps and membrane oxygenators using nonpulsatile flow were used in the CPB circuit which was primed with 1.0 litres lactated Ringer's solution and 0.51 colloidal gelatin (Gelofusine; B Braun, Malaysia). Haematocrit concentrations were maintained between 20% and 25% and a total flow of 2.41/min/m2 was maintained throughout CPB. Myocardial protection was achieved by antegrade application of cooled St Vincent solution into the aortic root after cross-clamping. The mean perfusion pressure was maintained at 70 to 90 mmHg where possible by small boluses of phenylepherine (100 [micro]g) and sodium nitroprusside infusion at the discretion of the perfusionist. Systemic temperature was permitted to drift to 28[degrees]C during CPB and patients were actively rewarmed to 36[degrees]C before separation from CPB.

The propofol infusion was stopped in both groups when ventilation commenced and anaesthesia was then maintained with sevoflurane 0.3 to 1% until the end of surgery. The total amount of the propofol used during the study period (not including the induction dose) and the duration of the infusion were noted. These were used to calculate the propofol administration for the patient and recorded as mg per kg of body weight per hour.

Adrenaline by infusion was administered as required for weaning from CPB. The total amount of the sodium nitroprusside and phenylephrine used were recorded. The duration of bypass and the duration of cross-clamp were also recorded. Postoperative analgesia was titrated with intravenous boluses of morphine as required. Patients were extubated the next morning or thereafter according to standard protocols and based on the decision of the attending cardiac surgeon.

Using Altman's nomogram (13) it was estimated that a sample size of 10 patients per group would be able to detect a 30% difference in the dosage of propofol with 80% power and a type I error of 0.05. Analysis of data was performed with the SPSS 10.0 PC program. Data are presented as mean (SD) or range, or median (percentile). Continuous data were analysed using Student's t-test, categorical data were analysed using chi-square test. MAP and BIS score were analysed using ANOVA for repeated measures. Propofol administration, total dosage of sodium nitroprusside and phenylephrine were analysed using Mann-Whitney U tests. A P value of less than 0.05 was considered statistically significant.

RESULTS

Twenty patients were enrolled in the study, 10 in group B and 10 in group C. Age, weight, gender, type of surgery, New York Heart Association classification, duration of bypass and duration of TCI anaesthesia were similar in the two groups (Table 1). The propofol administration was significantly higher in group C where standard practice (no BIS monitoring) was employed, with a median propofol dose of 6.0 mg/kg/h, whereas in group B (BIS monitoring) there was a 50% reduction of the median dose to 2.9 mg/kg/h in group B (ANOVA for repeated measurements, P=0.003).

The cumulative doses of sodium nitroprusside and phenylephrine were similar between the groups. After weaning from CPB, a similar number of patients required inotropic support (Table 1). MAP and BIS recordings are presented in Figures 1 and 2. The MAP values during the study period were similar between the two groups (P=0.608, ANOVA for repeated measurements). The BIS recordings were significantly different between the two groups (P=0.026, ANOVA for repeated measurements). In group B where TCI propofol was titrated to maintain a BIS value of 40-50, the BIS values at each time interval during CPB were consistently higher when compared to group C, where the BIS values were not made available to the attending anaesthetist.

DISCUSSION

Our results demonstrate that BIS guidance for the titration of target concentration of propofol resulted in a 50% reduction of propofol administration, while the MAP values were similar between the groups.

Studies conducted on patients undergoing major surgery (14) and orthopaedic surgery (15) reported that the adequate target plasma concentration of propofol for the maintenance of anaesthesia varied from 3.5 to 4.5 [micro]g/ml and 4 to 6 [micro]g/ml respectively. However, the concentration needed to maintain hypnosis during hypothermic CPB is less clearcut. It is common practice to use a slightly reduced target concentration of propofol in cardiac patients and supplement it with a higher dosage of opiate. In our institution we routinely use a target concentration between 1.5 to 2.5 [micro]g/ml during hypothermic CPB. This is comparable to the target concentrations of 1.5 to 3.0 [micro]g/ml of propofol reported by other investigators in patients undergoing hypothermic CPB (3-6). The differences in dosages are related to the study design and the type and dosage of opiate used to supplement anaesthesia.

[FIGURE 1 OMITTED]

During maintenance of anaesthesia, TO has been shown to deliver significantly larger doses of propofol than a manual infusion technique (10). This is thought to be due to the inherent prediction error in all pharmacokinetic models. In this study the total dose of propofol used in the control group (standard practice) was 6.0 mg/kg/h which is comparable to the 6.8 mg/kg/h, 5.8 mg/kg/h and 5.7 mg/kg/h reported by Bauer et al (4), Lehmann et al (16) and Lehmann et al (3) respectively. However these dosages are higher than the 2 mg/kg/h (17) and 3.7 mg/kg/h (16) reported using the manual infusion technique. We showed that when BIS was used to titrate the target concentration of propofol during hypothermic CPB, the total dosage of propofol necessary to maintain acceptable BIS value, was 50% lower than the standard dose used. This is similar to the 30% reduction shown by Bauer et al (4). Such low propofol administration was achievable only because hypnosis was titrated on the BIS values and should probably not be used in the absence of BIS monitoring.

[FIGURE 2 OMITTED]

It is well known that CPB and hypothermia creates a myriad of pharmacological and physiological changes such as haemodilution, increased volume of distribution, reduced plasma binding, reduction in hepatic blood flow, reduced metabolism and elimination of the drug by the liver and kidney. Bailey et al showed that the pharmacokinetics of propofol in adult patients undergoing cardiac surgery with CPB is dissimilar to those reported for other adult patient populations'. It has been shown that during CPB the unbound concentration of propofol is increased in response to reduced plasma binding, without any alteration in the total drug concentration (7). This has significantly increased the anaesthetic effect of propofol during CPB (8). In addition, CPB being the cause of complex systemic inflammatory and stress hormone responses may also increase end organ sensitivity of the drug. Hypothermia itself decreased metabolic rate and may reduce the propofol administration. Schmidlin et al (17) showed that either a higher dose of propofol for normothermic patients or a lower dose for hypothermic patients is required to achieve the same target BIS value. This could be the result of increased propofol blood concentration due to decreased propofol biotransformation during hypothermia. All these factors may have explained the reduced requirement of propofol during hypothermic CPB.

Without the benefit of the use of BIS, the standard dose of propofol used may be higher than necessary to maintain adequate hypnosis during CPB especially if TCI is used. We showed that using the usual recommended target concentration of 1.5-2.5 [micro]g/ml, an inadvertently deep plane of anaesthesia was observed in the control group. This relative overdosage of propofol may result in lower perfusion pressure, requiring higher usage of vasopressor drugs during bypass, or an increased need of the use of inotropic drugs after the separation of CPB (18,19). However, despite the higher propofol administration and a much lower BIS value in the control group, we did not find an increased usage of phenylephrine and inotropes. This is most probably because propofol does not affect haemodynamics during CPB, which is mostly under the control of the CPB pump, and the effects of propofol on separation of CPB are short-lived.

BIS-guided anaesthesia has been shown to reduce the amount of anaesthetic used, thus allowing shorter awakening time and earlier extubation. In this study we did not examine the extubation time, because in cardiac surgery, time to extubation depends on many different factors, such as weaning protocol, surgeons' preference, preoperative status and postoperative bleeding. Anaesthesia only partly influences the time to extubation. Furthermore, two different types of anaesthesia were used in this study. At our institution it is neither usual nor feasible to add sevoflurane to the CPB circuit. Therefore sevoflurane was used before and after CPB and TCI of propofol was used during CPB.

The reduced administration of propofol may reduce the drug cost. However whether this translates into sufficient savings to justify the cost of the monitoring, including the cost of the disposable BIS electrodes, will depend on the cost and protocol structure of individual clinical facilities.

The following points must be considered when assessing the clinical relevance of our study. First, hypothermic CPB reduces BIS values (17,20) but it is unknown that whether it reflects an actual increase in the depth of hypnosis or whether it is the effect of brain cooling and reduced electrical activity of the brain. Further study is needed concerning the effect of hypothermia on the EEG. Second, the effect of co-administered opiates on BIS during general anaesthesia is controversial. Some investigators found that opiates potentiate the hypnotic effect of propofol and thus reduce BIS when combined with propofol (21-22), while others have reported BIS to be insensitive to opiates (23). The differences may be related to study design. Further investigations on the pharmacodynamic interaction between opiates and propofol on BIS values are necessary to document the effects of opiates on BIS value. In this study the temperature and the dosages of opiate are comparable in both groups, thus the influence of hypothermia or opiates on BIS is unlikely to have affected the result. Third, despite the BIS value of lower than 50, we can not totally exclude the possibility of awareness. Anecdotal cases of awareness with BIS value of around 50 have been reported (24-25). Because of its low incidence, to detect cases of explicit awareness during CPB would require a huge study population. This study was not designed with the statistical power to detect differences for rare events such as perioperative awareness.

In conclusion, we found that BIS monitoring during hypothermic CPB enabled a reduction in the propofol administration, although the lower propofol administration did not affect the need for inotropic support or the use of vasoconstrictors during CPB. Our data support the notion that titration of propofol based on pharmacodynamic effects such as electroencephalographic suppression, is superior to administration based on pharmacokinetic modelling alone.

Accepted for publication on December 19, 2006.

REFERENCES

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(2.) Dowd NP, Cheng DC, Karski JM, Wong DT, Munro JAC, Sandler AN. Intraoperative awareness in fast track cardiac anesthesia. Anesthesiology 1998; 89:1068-1073.

(3.) Lehmann A, Zeitler C, Thaler E, Isgro F, Boldt J. Comparison of two different anesthesia regimens in patients undergoing aortocoronary bypass grafting surgery: sufentanil-midazolam versus remifentanil-propofol. J Cardiothorac Vase Anesth 2000;14:416-420.

(4.) Olivier P, Sirieix D, Dassier P, D'Attellis N, Baron JE Continuous infusion of remifentanil and target controlled infusion of propofol for patients undergoing cardiac surgery: a new approach for scheduled early extubation. J Cardiothorac Vase Anesth 2000; 14:29-35.

(5.) Bauer M, Wilhelm W, Kraemer T, Kreuer S, Brandt A, Adams HA et al. Impact of bispectral index monitoring on stress response and propofol consumption in patients undergoing coronary bypass surgery. Anesthesiology 2004; 101:1096-1104.

(6.) Ouattara A, Boccara G, Lemaire S, Kockler U, Landi M, Vaissier E et al. Target-controlled infusion of propofol and remifentanil in cardiac anaesthesia: influence of age on predicted effect-site concentrations. Br J Anaesth 2003; 90:617622.

(7.) Hiraoka H, Yamamoto K, Okano N, Morita T, Goto F, Horiuchi R. Changes in drug plasma concentrations of an extensively bound and highly extracted drug, propofol, in response to altered plasma binding. Clin Pharmacol Ther 2004; 75:324-330.

(8.) Takizawa E, Hiraoka H, Takizawa D, Goto E Changes in the effect of propofol in response to altered plasma protein binding during normothermic cardiopulmonary bypass. Br J Anaesth 2006;96:179-185.

(9.) Bailey JM, Mora CT, Shafer SL. Pharmacokinetics of propofol in adult patients undergoing coronary revascularization. The multicenter study of perioperative ischaemia research group. Anesthesiology 1996; 84:1288-1297.

(10.) Johansen JW, Sebel PS. Development and clinical application of electroencephalographic bispectrum monitoring. Anesthesiology 2000; 93:1336-1344.

(11.) Liu J, Singh H, White PE Electroencephalographic bispectral index correlates with intraoperative recall and depth of propofol-induction sedation. Anesth Analg 1997; 84:185-189.

(12.) Kearse L, Rosow C, Zaslavsky A, Connors P, Dershwitz M, Denman W Bispectral analysis of the encephalogram predicts conscious processing of information during propofol sedation and hypnosis. Anesthesiology 1998; 88:25-34.

(13.) Altman DG. Statistics and ethics in medical research III: how large a sample? BMJ 1980; 281:1336-1339.

(14.) Swinhoe CF, Peacock JE, Glen JB, Reilly CS. Evaluation of the predictive performance of a 'Diprifusor' TCI system. Anaesthesia 1998; 53:61-67.

(15.) Servin FS, Marchand-Maillet F, Desmonts JM. Influence of analgesic supplementation on the target propofol concentrations for anaesthesia with 'Diprifusor' TCI. Anaesthesia 1998; 53:72-76.

(16.) Lehmann A, Boldt J, Thaler E, Piper S, Weisse U. Bispectral index in patients with target controlled or manually controlled infusion of propofol. Anesth Analg 2002; 95:639-644.

(17.) Schmidlin D, Hager P, Schmid ER. Monitoring level of sedation with bispectral EEG analysis comparison between hypothermic and normothermic cardiopulmonary bypass. Br J Anaesth 2001; 86:769-776.

(18.) Lehmann A, Karzau J, Boldt J, Thaler E, Lang J, Isgro E Bispectral index-guided anaesthesia in patients undergoing aortocoronary bypass grafting. Anesth Analg 2003; 96:336343.

(19.) Lehmann A, Boldt J, Rompert R, Thaler E, Kumle B, Weisse U. Target controlled infusion (TCI) or manual controlled infusion (MCI) of propofol in high risk patients with severely reduced left ventricular function. J Cardiothorac Vase Anesth 2001; 15:445-450.

(20.) Mathew JP, Weatherwax KJ, East CJ, White WD, Reves JG. Bispectral analysis during cardiopulmonary bypass: the effect of hypothermia on the hypnotic state. J Clin Anesth 2001; 13:301-305.

(21.) Koitabashi T, Johansen JW, Sebel PS. Remifentanil dose/ electroencephalogram bispectral response during combined propofol/regional anesthesia. Anesth Analg 2002; 94:15301533.

(22.) Strachan AN, Edwards ND. Randomized placebo-controlled trial to assess the effect of remifentanil and propofol on bispectral index and sedation. Br J Anaesth 2000; 84:489-490.

(23.) Guignard B, Menigaux C, Dupont X, Fletcher D, Chauvin M. The effect of remifentanil on the bipectral index change and hemodynamic responses after orotracheal intubation. Anesth Analg 2000; 90:161-167.

(24.) Mychaskiw G, Horowitz M, Sachdev V, Heath BJ. Explicit intraoperative recall at a bispectral index of 47. Anesth Analg 2001;92:808-809.

(25.) Kakinohana M, Nakamura S, Miyata Y, Sugahara K. Emergence from propofol anesthesia in a nonagenarian at a Bispectral Index of 52. Anesth Analg 2005; 101:169-170.

C. L. CHIU *, G. ONG ([dagger]), A. A. MAJID ([double dagger])

Departments of Anaesthesia and Surgery, University of Malaya Medical Centre, Kuala Lumpur, Malaysia

* M.B.Ch.B., ER.C.A., Associate Professor, Department of Anaesthesia.

([dagger]) M.B., B.S., EA.N.Z.C.A., Professor.

([double dagger]) M.B., B.S., ER.C.S., Professor, Department of Surgery, University of Malaya Medical Centre.

Address for reprints: Dr C. L. Chiu, Department of Anaesthesia, University of Malaya Medical Centre, Lembah Pantai, Kuala Lumpur 50603, Malaysia. chiuchiawling@yahoo.com.my
TABLE 1
Demographic data

 Group B Group C

Age, years 52 (12) 51 (16)

Gender, M:F 7:3 8:2

Weight, kg 67 (14) 71 (19)

NYHA, II:III 4:06 4:06

Surgery, CABG: 6:1:3 7:3:0
MVR: AVR

Duration of 138 (120, 181) 128 (120, 175)
bypass, min

Duration of cross 120 (101, 140) 107 (95, 136)
clamp, min

Median propofol 2.9 (2.5, 4.3) 6.0 (4.5, 7.1) 0.003
administration,
mg/kg/h

Mean propofol 3.1 (2.0-4.4) 5.7 (2.4-8.4) 0.002
administration,
mg/kg/h

Phenylephrine, mg 0.9 (0.3, 2.0) 1.0 (0.18, 2.0) 0.684

Sodium 0.46 (0.36, 0.57) 0.46 (0.28, 0.75) 0.912
nitroprusside,
[micro]g/kg/min

Number of 8/10 10/10 0.47
patients needed
inotropes

Values are mean (SD) or (range) or median (25th, 75th
percentile).
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Title Annotation:Original Papers
Author:Chiu, C.L.; Ong, G.; Majid, A.A.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:9MALA
Date:Jun 1, 2007
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