8/12/2019 Br. J. Anaesth.-2000-Barr-749-52

1/4

British Journal of Anaesthesia84 (6): 74952 (2000)

Fentanyl and midazolam anaesthesia for coronary bypasssurgery: a clinical study of bispectral electroencephalogram

analysis, drug concentrations and recall

G. Barr1, R. E. Anderson1, S. Samuelsson1, A. Owall1 and J. G. Jakobsson1 2*

1Department of Cardiothoracic Anaesthetics and Intensive Care, Karolinska Hospital, Stockholm, Sweden.2Department of Anaesthetics, Sabbatsbergs Hospital, Stockholm, Sweden

*Corresponding author: Department of Cardiothoracic Anaesthetics and Intensive Care, Karolinska Hospital, S-171 76

Stockholm, Sweden

Bispectral index (BIS) was assessed as a monitor of depth of anaesthesia during fentanyl and

midazolam anaesthesia for coronary bypass surgery. In 10 patients given morphine premedica-

tion, anaesthesia was induced with a combination of midazolam and fentanyl and thereafter

maintained with a continuous infusion of a mixture of midazolam and fentanyl 5 and 50 g

kg1 h1, respectively. BIS was recorded continuously but not shown to the attending

anaesthetist. Plasma concentrations of midazolam and fentanyl were measured five times during

the procedure. An auditory stimulus was given during bypass. All patients were interviewedtwice after operation for explicit and implicit recall. No patient had any anaesthetic complications.

BIS decreased during anaesthesia, but varied considerably during surgery (range 3691) with

eight patients having values 60. Midazolam and fentanyl drug concentrations did not correlate

with BIS. No patient reported explicit or implicit recall. During clinically adequate anaesthesia

with midazolam and fentanyl BIS varies considerably. The most likely reason is that BIS is not

an accurate measure of the depth of anaesthesia when using this combination of agents.

Br J Anaesth 2000; 84: 74952

Keywords: analgesics opioid, fentanyl; electroencephalography; monitoring, electroencephalo-

graphy; surgery, cardiovascular

Accepted for publication: January 24, 2000

Patients about to undergo general anaesthesia may fear that after approval from the hospital ethical committee and

they will be aware of the operation and be able to remember informed consent. All patients were seen the day beforeit afterwards. Awareness with recall is rare, though, occur- surgery and informed about the study and its objectives.ring in about 0.2% of patients undergoing anaesthesia for They were told that a sound (not specified in detail) wouldgeneral surgery.1 A greater incidence, 1%, has been be presented during anaesthesia that they would laterreported during cardiac surgery.2 be asked to recall. About an hour after intramuscular

The bispectral index (BIS), derived from bispectral ana- premedication with morphine 515 mg, anaesthesia waslysis of the electroencephalogram, has recently been intro-

induced with midazolam 0.05 (0.030.12) mg kg1 andduced to monitor the depth of anaesthesia. Ideally such a

fentanyl 10 (712) g1. Pancuronium 0.1 mg1 was givenmonitor should measure the depth of anaesthesia irrespective

as a muscle relaxant to facilitate endotracheal intubation.of the anaesthetic agent(s) used or the type of surgical

A continuous infusion of fentanyl and midazolam wasprocedure. We investigated the clinical value of BIS duringstarted (5 and 50 g kg1 h1, respectively) and maintainedfentanyl and midazolam anaesthesia for coronary arteryuntil completion of surgery; supplementary doses of fentanylbypass grafting (CABG) using cardiopulmonary bypassor midazolam were given at the discretion of the anaesthetist.(CPB). A standardized auditory stimulus was presented

Standard procedures were used for CPB. Core temper-at predetermined times during CPB and patients wereature was reduced or was allowed to drift to 34C. Aninterviewed for explicit and implicit recall. Plasma concen-

trations of fentanyl and midazolam were measured. auditory stimulus (100 dB, duration 60 s) was presented

five times during CPB. BIS (Aspect Medical Systems;Methods version 3.12, Natick, MA, USA) was measured continu-

ously; the attending anaesthesiologist was not shown theTen patients with a mean age of 69 yr (range 5083 yr)

and scheduled for elective CABG surgery were studied output values.

The Board of Management and Trustees of the British Journal of Anaesthesia 2000

8/12/2019 Br. J. Anaesth.-2000-Barr-749-52

2/4

Barr et al.

Fig 2 Bispectral index plotted against midazolam plasma concentrationFig 1 Bispectral index at various times during coronary bypass surgery(ng ml1) during bypass surgery (n10).(n10): 1, before induction; 2, sternotomy; 3, heparin; 4, start of bypass;

5, end of bypass; 6, skin closure.

Table 1 Plasma drug concentrations (median (range)) and bispectral index

(BIS) during bypass surgery (n10)

Time du ring Mid az olam F en tan yl B IS (no. o f p atie nts)procedure (ng ml1) (ng ml1)

60 60 75

Before induction 0 0 0 10 10

Sternotomy 78 (49133) 5.0 (3.77.8) 6 4 0

Heparin 102 (52158) 6.4 (3.411.9) 7 3 1

Start of bypass 90 (54113) 4.8 (2.87.8) 5 5 2

E nd o f b yp ass 94 (55145) 4.9 (3.06.6) 7 3 1

End of surgery 103 (87122) 5.2 (3.210.2) 6 4 1

Blood samples were drawn from the radial artery catheter

before induction, at sternotomy, when heparin was given,

at the start, middle and end of CPB, and at skin closure.Fig 3 Bispectral index plotted against fentanyl plasma concentration (ng

Samples were stored in a freezer for blinded, batch analysis. ml1) during bypass surgery (n10).Patients were interviewed on each of the first 2 days

after the operation using a fixed predefined questionnaire. Only two of the 10 patients studied did not have BISAt the first interview they were asked to describe their values or 60 at some point during surgery. The BIS values

experience of anaesthesia. At the second meeting the patients in each subject during anaesthesia varied, with a range that

were also asked specifically about recall of any special was as small as 15 or as large as 50 (median range was 30).

sound. They were given a number of associative proposals. No drug accumulation occurred. The median plasmaIf there was still no recall, the actual sound was presented concentrations of fentanyl and midazolam did not changeand the patients were asked again for recollections from during anaesthesia (Table 1). Plasma drug concentrationsthe surgical procedure. varied widely between individuals. BIS did not correlate

with fentanyl (r20.13) or midazolam plasma concentration

(r20.034; Figs 2 and 3). In individual patients, there wasResultsno correlation between drug plasma concentration changesThe 10 patients studied had mean (SD) body weight of 78and BIS.

(13) kg. All patients had an uncomplicated surgical course, No patients reported explicit recall of intraoperativewith a mean surgical time 158 (19) minand mean anaesthesiaevents at interview on thefirst or second day after operation.time 198 (35) min. Haemodynamic measurements wereNo patient could recall the acoustic stimulus presentedstable.repeatedly during CPB, either after given strong associationsAll patients were awake and fully oriented at arrival inor when actually hearing it.the operating theatre and at induction BIS was between 96

and 99. BIS decreased in all patients with induction, butDiscussionduring surgery it varied between 36 and 91. Almost 40%

of BIS values at the time of blood sampling were 60 General anaesthesia is a state of pharmacologically induced

depression of the central nervous system causing uncon-(Table 1, Fig. 3).

750

8/12/2019 Br. J. Anaesth.-2000-Barr-749-52

3/4

Cardiac surgery and BIS

sciousness. Anaesthesia is not an onoff phenomenon but a maximum effect for fentanyl occurs at a plasma level of

about 34 ng ml1.1315 The plasma concentrations in thecontinuum, a gradual depression of cognitive and autonomic

functions. Most anaesthetics cause a dose-dependent present study were greater than this, but with large differ-

ences between patients, and considerably less than thoseincrease in anaesthetic depth. Many hypnotics and anaes-

thetics also cause varying degrees of amnesia.3 Recollection found in the study by van der Maaten and colleagues of

patients having cardiac surgery.16 The large variation inof a stimulus requires an initial activation of the sensory

system, central processing of the information and, finally, plasma concentrations we found supports the observations

of van der Maaten and colleagues who also found a two toretrieval of information. The memory process can be separ-

ated into explicit or conscious learning and implicit or threefold variation when using midazolam and an opioid.16

The midazolam and fentanyl concentrations throughoutunconscious retrieval of information.

Awareness with explicit recall of intraoperative events is the procedure did not differ from their initial values,

demonstrating that the continuous drug infusion techniquea feared complication of general anaesthesia with potentially

serious adverse psychological sequelae.4 The incidence of provides unchanged drug concentrations during CPB and

that no drug accumulation occurs during the procedure.explicit awareness with recall after general anaesthesia is,

however, small: about two per thousand patients.1 Implicit The considerable variation in BIS observed here is, in

some respects, similar to that found during sedation ofprocessing has been shown to be less affected by general

anaesthesia than explicit memory processing and may intensive care patients.12 In our study BIS not only varied

considerably but was, in general, surprisingly large. Suchcontinue subconsciously during clinically adequate anaes-

thesia.5 Implicit intraoperative awareness and postoperative values are associated with a great likelihood of awareness

and the capability to follow command.17 18 A BIS value ofrecall of auditory stimuli have been reported in up to half

of patients undergoing cardiac surgery with opiate and 60 is often regarded as the criterion for adequate anaes-

thesia, while a value of 70 is frequently seen duringbenzodiazepine anaesthesia.6 7

Most studies of recall suggest that hearing is one of the awakening.18 Several factors may have led to the observed

variation in BIS. Hypothermia may have affected the BISmost receptive sensory channels for perception during

general anaesthesia.8 9 Although explicit recall, especially measurements during bypass, as discussed by Doi and

colleagues.19 Cardiac surgery with profound hypothermiaof pain and paralysis, is a serious complication, adjusting

anaesthetic depth to preserve implicit processing of auditory affects electroencephalographic recordings because of

changes in conductance,19 but our patients were operatedinformation could be useful. Several studies suggest new

therapeutic possibilities with implicit processing10 that on at 34C and gave no problems with recording apart from

during diathermy. Furthermore, the variability was presentwould need carefully titrated depth of anaesthesia however

this places additional demands on monitoring. both before and after the bypass period. The variability

may, of course, be explained by inadequate depth ofThe ideal monitor of depth of anaesthesia should be able

to measure accurately different degrees of anaesthetic depth, anaesthesia. Although we detected no apparent awareness

during surgery, and although haemodynamic measurmentssuch as the transition from wakefulness to unconsciouness,loss of explicit as well as implicit memory processing, loss were stable, muscle relaxants, beta-blocking drugs and

blood volume changes could have masked many of theseof motor response to surgical stimulation and loss of

autonomic response. Furthermore, all common anaesthetics clincial indicators of adequate anaesthesia. No patient

reported recall when actively interviewed on two occasionsshould be comparable on the same scale. Bispectral analysis

of the electroencephalogram can estimate the hypnotic after operation, even though auditory stimuli are resistant

to suppresion by fentanyl and midazolam anaesthesia. Noeffects of propofol and halogenated agents. BIS has been

proposed to be a useful monitor during cardiac surgery with consistent decrease in BIS was found with increasing

plasma concentrations of either drug. The most plausibleCPB11 when the usual haemodynamic responses and signs

such as sweating or tear production are less dependable explanation for the high BIS values seems to be that BIS

reflects anaesthetic depth less accurately when fentanyl andmarkers of anaesthetic depth. In addition, the requirement

for early extubation in some patients would make such a midazolam are used as anaesthetics. We have shown in a

previous study that increasing concentrations of nitrousmonitor useful to avoid excessive anaesthesia. BIS may

also be useful in determining the degree of sedation in oxide have no effect on BIS,20

and addition of fentanyl topropofol anaesthesia causes large BIS values.21 22 Theintensive care patients.12

Anaesthesia for coronary surgery is frequently based on weak correlation between decreasing BIS and an increasing

fentanyl concentration supports results obtained ina combination of a large dose of an opioid with a hypnotic

or a volatile agent. In this study a combination of fentanyl volunteers.17

As discussed above, no patient recalled events during theand midazolam was used and anaesthesia was adjusted

according to clinical needs at the discretion of the anaesthesi- operation. The timing of, and technique for, evaluating

awareness and recall have considerable impact on theologist. Midazolam and fentanyl have a synergic effect on

cognitive depression. In studies of the interactions between results.1 The lack of any explicit recall in this study with

so few patients is not surprising, as explicit recall isfentanyl and sevoflurane, and fentanyl and propofol, a

751

8/12/2019 Br. J. Anaesth.-2000-Barr-749-52

4/4

Barr et al.

8 Hilgenberg JC. Intraoperative awareness during high-doseinfrequent.1 The lack of implicit recall of the auditoryfentanyloxygen anesthesia. Anesthesiology1981; 54: 3413stimulation during surgery, which should be detectable even

9 Jones JG. Hearing and memory in anaesthetised patients. BMJin the small number of patients in this study, confirms the1986; 292: 12913

adequacy of the anaesthetic depth. Technique and time of10 Dreher H. Mindbody interventions for surgery: evidence and

stimulation are important for implicit memory testing.23 exigency. Adv MindBody Med1998; 14: 20722In conclusion, this study has shown that although anaes- 11 Sebel PS. Central nervous system monitoring during open heart

surgery: an update. J Cardiothorac Vasc Anesth1998; 12: 38thetic depth was adequate and no recall was reported,12 DeDeyne C, Struys M, Decruyenere J, Creuplandt J, Hoste E,BIS varied widely and values that are usually related to

Colardyn F. Use of continuous bispectral EEG monitoring toexcessively light anaesthesia or wakefulness were occasion-assess depth of sedation in IDU patients. Intens Care Med 1998;ally observed. BIS did not correlate with midazolam and24: 12948

fentanyl plasma concentrations. A measurement such as13 Thomson AR, Henderson BR, Singh K, Hudson RJ. Concentration

BIS should, ideally, be suitable for determining the depth response relationships for fentanyl and sufentanil in patientsof anaesthesia for all anaesthetics on a common scale. For undergoing coronary artery bypass grafting. Anesthesiology 1998;

89: 85261coronary surgery with fentanyl and midazolam anaesthesia,14 Katoh T, Ikeda K. The effects of fentanyl on sevofluranethe BIS algorithm too often underestimates the depth

requirements for loss of consciousness and skin incision.of anaesthesia and does not accurately reflect plasmaAnesthesiology1998; 88 : 1824concentrations. Administering more anaesthetic to try to

15 Kazama T, Ikeda K, Morita K. Reduction by fentanyl of the Cp 50decrease large BIS values would result in an excessivevalues of propofol and hemodynamic responses to various noxious

depth of anaesthesia with delayed awakening and, perhaps, stimuli. Anesthesiology1997; 87: 21327haemodynamic instability. BIS may be well suited to 16 Van der Maaten JMAA, Epema AH, Gallandat Huet RCG, Hennis

PJ. The effect of midazolam at two plasma concentrations onpredominantly hypnotic drugs, but it is not useful forhemodynamics and sufentanil requirement in coronary arterythe midazolamfentanyl combination commonly used forsurgery. J Cardiothor Vasc Anesth 1996; 10 : 35663cardiac surgery.

17 Glass P, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P.

Bispectral analysis measures sedation and memory effects ofReferences propofol, midazolam, isoflurane, and alfentanil. Anaesthesiology

1997; 86: 836471 Nordstrom O, Engstrom AM, Persson S, Sandin R. Incidence of18 Katoh T, Suzuki A, Ikeda K. Electroencephalographic derivativesawareness in total i.v. anaesthesia based on propofol, alfentanil

as a tool for predicting depth of sedation and anaesthesia inducedand neuromuscular blockade. Acta Anaesthiol Scand 1997; 41:by sevoflurane. Anaesthesiology1998; 88 : 6425097884

19 Doi M, Gajraj RJ, Mantzaridis H, Kenny GN. Effects of2 Phillips AA, McLean RF, Devitt JH, Harrington EM. Recall ofcardiopulmonary bypass and hypothermia on electroence-intraoperative events after general anaesthesia andphalographic variables. Anaesthesia 1997; 52 : 104855cardiopulmonary bypass. Can J Anaesth 1993; 40 : 9226

20 Barr G, Jakobsson JG, Owall A, Anderson RE. Nitrous oxide does3 Polster MR, Gray PA, OSullivan G, McCarthy RA, Park GR.not alter bispectral index: a study with nitrous oxide as sole agentComparison of the sedative and amnestic effects of midazolam

and as adjunct to intravenous anaesthesia.Br J Anaesth 1999; 82:and propofol. Br J Anaesth 1993; 70: 61216827304 Bailey AR, Jones JG. Patients memories of events during general

21 Iselin-Chaves I, Flaishon R, Sebel P, Howell S, Gan TJ, Sigl J,anaesthesia.Anesthesia 1997; 52 : 46076Ginsberg B, Glass P. The effect of the interaction of propofol and5 Bethune DW, Bhosh S, Gray B, Kerr L, Walker IA, Doolan LA,

alfentanil on recall, loss of consciousness, and the bispectral index.Harwood RJ, Sharples LD. Learning during general anaesthesia:

Anesth Analg1998; 87: 94955implicit recall after methohexitone or propofol infusion. Br J

22 Mi WD, Sakai T, Singh H, Kudo T, Kudo M, Matsuki A. HypnoticAnaesth 1992; 69 : 1979

endpoints vs the bispectral index, 95% spectral edge frequency6 Goldman L, Shah MV, Hebden MW. Memory and cardiac

and median frequency during propofol infusion with or withoutanaesthesia.Anesthesiology1987; 42: 596603

fentanyl. Eur J Anaesth 1999; 16: 47527 Schwender D, Kaiser A, Klasing S, Peter K, Po ppel E. Midlatency

23 Munte S, Kobbe I, Demertzis A, Lullwitz E, Munte TF, Piepenbrockauditory evoked potentials and explicit and implicit memory in

S, Leuwer M. Increased reading speed for stories presented duringpatients undergoing cardiac surgery. Anesthesiology 1994; 80:

493501 general anesthesia. Anesthesiology1999; 90: 6629

752