Electroencephalographic Characteristics of Emergence from Propofol

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					Electroencephalographic      Characteristics of Emergence                                                                                               from
Propofol/Sufentanil     Total Intravenous Anesthesia
Henri S. Traast,                   MD,       and Cor J. Kalkman,                 MD,   PhD
Department        of Anesthesiology,             Academic     Medical      Center, University   of Amsterdam,     The Netherlands

      We recorded the electroencephalogram         (EEG) in 16 pa-                       value during the infusion (P > 0.005). MF, F95, and the
      tients during propofol/sufentanil     total intravenous an-                        two frequency band power ratios increased during
      esthesia to determine whether EEG changes might pre-                               emergence (P > 0.05). Of the individual     spectral vari-
      dict imminent awakening       during emergence. Changes                            ables, only a 50% decrease in absolute CYpower was
      in absolute and relative power in four frequency bands,                            more than 90% sensitive and specific in predicting    eye
      median frequency       (MF), 95th percentile       frequency                       opening. We conclude that, although pronounced       EEG
       (F95), and two frequency band power ratios (P/a and                               changes occur during       emergence    from propofoll
       ((Y + /3)/S) were quantified.     One minute before eye                           sufentanil anesthesia, the EEG does not reliably predict
      opening, absolute power in the 6 and (Ybands had de-                               eye opening.
      creased to 49% (25%-73%) and 42% (25%-58%) of the                                                           (Anesth Analg 1995;81:366-71)

                                                                                         sufentanil TIVA. In addition, sensitivity and specific-

       ropofol,           as part       of a total   intravenous        anesthetic
       (TIVA) technique, combines fast recovery with                                     ity of these changes in predicting imminent awaken-
       minimal hangover effects and a reduced inci-                                      ing were computed.
dence of postanesthetic nausea and vomiting (l-3).
However, as a result of interpatient variability in
propofol kinetics, inadequate levels of anesthesia may                                   Methods
occasionally occur. Routinely used clinical signs may
                                                                                         Sixteen patients (nine female), ASA physical status I,
not always reliably detect inadequate levels of anes-
                                                                                         aged 19-47 yr, undergoing general and orthopedic
thesia (4). Use of muscle relaxants and the relative
                                                                                         surgical procedures of 60-120 min duration, gave in-
hypotension and bradycardia induced by the combi-                                        formed consent to participate in the study, which was
nation of propofol and an opioid may obscure hemo-                                       approved by the Human Studies Committee of our
dynamic and motor signs of inadequate anesthesia. A                                      hospital.
monitoring technique that could provide additional                                          Oral diazepam 10 mg was given 1 h before arrival in
information for the detection of inadequate levels of                                    the operation room. Anesthesia was induced with
propofol anesthesia is desirable. Several approaches                                     propofol 2 mg/kg, and sufentanil 1 pg/kg intrave-
for assessingthe level of anesthesia have been studied,                                  nously. Anesthesia was maintained with propofol 10
including the electroencephalogram (EEG) (5-7), fron-                                    mg * kg-i * h-’ for the first 10 min, 8 mg * kg-’ . h-i
talis muscle, electromyogram (81, and auditory evoked                                    for the next 10 min, and 6 mg * kg-’ . h-’ for the
potentials (9-111, but none of these methods has be-                                     remainder of the procedure (12). Tracheal intubation
come a generally accepted standard.                                                      was facilitated by administration of vecuronium 0.1
   The present study was designed to characterize the                                    mg/kg, and muscle relaxation was maintained with
EEG changes during emergence from propofol/                                              intravenous increments of vecuronium l-2 mg as nec-
                                                                                         essary. Ventilation was controlled with a mixture of
                                                                                         oxygen in air (Fio, 40%) to maintain an end-tidal Pco,
                                                                                         of 30-35 mm Hg. Electrocardiogram, noninvasive
   Supported by a grant from Zeneca Farma, Ridderkerk, The Neth-
erlands.                                                                                 blood pressure, pulse-oximetry, end-tidal Pco~, Fio,,
   This study was presented in part at the American Society of                           airway pressures, and tidal and minute volumes were
Anesthesiologists annual meeting, October 1991, San Francisco, CA.                       monitored during the procedure.
   Accepted for publication February 24, 1995.                                              If clinical signs of inadequate analgesia were
   Address correspondence and reprint requests to Cor J. Kalkman,
MD, PhD, Department of Anesthesiology, Academic Medical Cen-                             present, as defined by an increase in arterial blood
ter, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.                                 pressure and/or heart rate of more than 20% from

                                                                                                          01995   by the International   Anesthesia       Research       Society
366    An&h       Analg     1995;81:366-71                                                                                                            0003-2999/95/$5.00
ANESTH         ANALG                                                                                                   TRAAST   AND     KALKMAN    367
1995;81:366-71                                                           EEG AND    EMERGENCE   FROM   PROPOFOL/SUFENTANIL            ANESTHESIA

baseline, lacrimation,          or sweating,        a bolus of sufen-              The sensitivity    and specificity of the EEG descrip-
tanil 10 pg was administered.               In addition, a bolus of             tors in predicting eye opening were calculated using a
propofol     40 mg was administered                     if the patient          threshold of 5 Hz for MF as described by Schwilden et
moved. The propofol infusion was stopped 5 min after                            al. (6,16), and a threshold of 14 Hz for F95 as described
completion      of the surgical procedure,                 and residual         by Rampil and Matte0 (5). For the other variables, a
neuromuscular         block reversed if necessary. Patients                     value that gave the best combination of sensitivity and
were repeatedly asked to open their eyes at 30-s inter-                         specificity as determined     by a post hoc review of the
vals, and eye opening marked the return of conscious-                           data was used as a threshold. A threshold of 1.4 was
ness. Stimulating        the patient in any other way was                       used for 6 ratio, and a threshold of 0.5 for BA ratio. For
avoided.                                                                        absolute 6, (Y, and total power, an amplitude decrease
    Propofol plasma levels during emergence were de-                            to 50% or less of the value at the time of discontinua-
termined in six patients from venous blood samples,                             tion of propofol      was used as threshold.     A relative
drawn     from a cannula in the arm opposite to the                             power of 10% or more was used as threshold                for
infusion, derived at 5 min intervals from the time of                           relative p power. Sensitivity was calculated using data
stopping     the infusion         until eye opening. Propofol                   on the time points 1 and 3 min prior to eye opening.
plasma concentrations              were determined              by high-        Specificity was defined as the percentage of patients
                                                                                that, according to the chosen threshold         value, was
performance        liquid chromatography                  with fluores-
                                                                                correctly predicted not to open the eyes within 5 min.
cence detection (13).
                                                                                Specificity was calculated from EEG spectral variables
    After skin preparation,           five silver/silver           chloride
                                                                                obtained 5 min after discontinuation     of propofol using
cup electrodes were placed according to the interna-
                                                                                data from patients who were more than 5 min from
tional lo-20       system at F3, F4, Al, A2, and FpZ
                                                                                eye opening (10 patients).
(ground)      (14,15). Electrode          impedances          were 2000
ohms or less. Two channels of EEG (F3-Al, F4-A2)
were acquired simultaneously                 using the SM-200 am-                  Results
plifiers of a Nicolet Pathfinder II (Nicolet Biomedical
Instruments,      Madison, WI) and were recorded from                           The average time between stopping the infusion of
induction until eye opening on a digital tape recorder                          propofol     and eye opening was 12.8 min (9.7-15.8).
(EDR 8000, Earth Data Ltd., Southampton,                      UK) with a        Heart rate decreased from 64 bpm (57-72) to 56 bpm
sample rate of 256 Hz. Band pass filters were set at 0.5                        (52-60) (P < 0.05) 1 min before eye opening when
and 30 Hz, and amplifier sensitivity                  at 200 pV.                compared with the moment of stopping the infusion
    Power spectral analysis was performed off-line with                         (15 patients). Mean arterial pressure did not change
an epoch length of 4 s using the fast Fourier frequency                         during emergence.
analysis software        of the Nicolet Pathfinder                II. Abso-        Reversal of neuromuscular       block was needed in one
lute power in four frequency bands, 6 (0.5-3.0 Hz), f3                          patient, who received 1 mg of neostigmine and 0.2 mg
                                                                                of glycopyrrolate      before stopping the propofol infu-
(3.25-8.0 Hz), (Y (8.25-13.0 Hz), p (13.25-30.0 Hz), and
                                                                                sion. The hemodynamic          data of this patient were ex-
total power were analyzed. In addition, the following
                                                                                cluded from analysis.
frequency      descriptors        were analyzed:            median fre-
                                                                                   Propofol plasma concentration        measured in six pa-
quency (MF) and 95th percentile                      frequency         (F95).
                                                                                tients was 3.2 pg/mL (2.2-4.2) at the end of surgery
The ratio of power in the p range to power in the (Y
                                                                                immediately      before discontinuation     of propofol, and
range (BA ratio), and the ratio of power in the 8-20 Hz                         1.4 pg/mL      (1.0-1.9) at the time of eye openin
range to power in the 6 range [6 ratio (15>1 were also                                                                                 -5. T!y
                                                                                average sufentanil dose used was 0.54 pg * kg             *h
computed.                                                                       (0.48-0.60).
    To quantify EEG changes during emergence, data                                  Raw EEG traces during the various stages of the
derived from the following                 1-min intervals           (15 4-s    surgical procedure        are shown in Figure 1. During
epochs, excluding          artifacts)     were compared:              1 min     steady state propofol/sufentanil        TIVA, the EEG was
before stopping the propofol                  infusion, 5 min after             characterized     by a bimodal distribution    of power with
stopping the propofol infusion, 3 min before eye open-                          predominance        of activity in the 6 band, 51% (43%-
ing, and 1 min before eye opening.                                              59%) of total power, and the (Y band, 29% (23%-35%)
     Data were analyzed by a repeated-measures                        analy-    of total power. Large amplitude variability           was ob-
sis of variance and presented as mean and 95% con-                              served between patients. Figure 2 shows changes in
fidence interval.         Absolute        EEG power             was log-        EEG spectral variables during emergence in one pa-
transformed       before statistical           analysis.      Differences       tient. EEG spectral variables at the four time points
between means were compared using t-tests with cor-                             during emergence are shown in Table 1. The most
rection for multiple comparisons                   and a P value of             consistent EEG changes during emergence were pro-
 ~0.05 was considered significant.                                              nounced decreases in power in the 6 and (Y bands. The
368     TRAAST AND KALKMAN                                                                                                                                     ANESTH       ANALG
        EEG AND EMERGENCE          FROM    PROPOFOL/SUFENTANIL             ANESTHESIA                                                                              1995;81.366-71

                                                                                                     Delta Power                   propofol   stop                  eyes open
                                                          oreinduction                  600


                                                          post incision

                                          stopping propofol infusion

                                                                                                   - Alpha Power

                                          1 min prior to eye opening


              1 I
                                                           ’     1 set     ’

Figure   1. Raw electroencephalogram         (EEG) traces in one patient,
during  various   stages of the procedure.      After induction,       the EEG
shows an increase in amplitude       and a bimodal   distribution     of power
with predominance      of power in the 6 and the a! band. One minute                          7-
prior to eye opening    a decrease in slow wave activity          is apparent.
                                                                                                    - delta-ratio         -
decrease in 6 power preceded the decrease in 01   power.                                       3- BA-ratio -
An increase in p power was observed 5 min after
discontinuation of the propofol infusion. With the ex-
ception of relative /3 power, that increased from 5%                                               -15              -10       -5               0           5       IO               15
(2%-8%) of total power at the moment of stopping the
                                                                                                                                          Time (min)
propofol infusion to 11% (5%-17%) 5 min later, the
power distribution of the spectrum showed only mi-                                      Figure    2. Electroencephalogram               (EEG) spectral       variables     during
nor changes.                                                                            emergence       in one patient.        After discontinuation           of the propofol
                                                                                        infusion    a decrease in 6 power,          followed      by a decrease in cy power
   MF increased from 4.0 Hz (2.7-5.3) at propofol stop                                  becomes apparent.           Five minutes       after discontinuation         of propofol
to 7.2 Hz (5.4-9.0) 1 min before eye opening, and F95                                   there is an increase in p power,             thereafter     p power decreases with
from 12.9 Hz (12-14) to 17.2 Hz (15-20) (P < 0.05). BA                                  the overall      decrease      in EEG amplitude.           Median     frequency      (MF),
                                                                                        95th percentile      frequency      (F95), and the two frequency            band power
ratio increased from 0.3 (0.1-0.4) at the time of stop-
                                                                                        ratios increase during           emergence.       S ratio = (a + PI/S power;            BA
ping the infusion, to 1.2 (0.4-2.0) 3 min, and 1.4 (0.6-                                ratio = p/a power.
2.2) 1 min before eye opening (P < 0.05). There was
considerable interpatient variability in 6 ratio. The
largest increase in 8 ratio occurred in the first 5 min                                 EEG descriptor (90%). However, sensitivity was only
after stopping the propofol infusion from 1.0 (0.5-1.5)                                 63%.
at propofol stop to 1.8 (0.7-3.0). The 6 ratio increased
to 2.0 (0.8-3.3) 1 min before eye opening (P < 0.05).                                   Discussion
   Table 2 shows sensitivity and specificity of the var-
ious threshold values. A 50% decrease in absolute a!                                    The results of our study indicate that there are pro-
power was the most sensitive (94%) and specific                                         nounced changes in the EEG during emergence from
(100%) in predicting eye opening. A decrease in abso-                                   propofol/sufentanil    TIVA. The initial EEG changes
lute 6 power and increase in MF were moderately                                         after discontinuation of propofol were a decrease in
sensitive at the same time point (88%). Using a thresh-                                 slow wave activity, followed several minutes later by
old value of 0.5, the BA ratio was a moderately specific                                a decrease in 01activity. The decrease of 6 power was
ANESTH         ANALG                                                                                                                               TRAAST    AND     KALKMAN           369
1995;81:366-71                                                                               EEG AND     EMERGENCE          FROM   PROPOFOL/SUFENTANIL             ANESTHESIA

Table 1. Electroencephalographic                       Spectral Variables           During       Emergence             from Propofol/Sufentanil        Total
Intravenous Anesthesia
                                                                                                  Propofol stop                          Eyes open                    Eyes open
                                                                  Propofol     stop                  + 5 min                              - 3 min                      - 1 min
     Total power (pV2)                                           388 (238-632)                   295 (187465)*                     171 (108-274)*                  159 (98-259)*
     6 power (pV*)                                               194 (110-340)                   113 (62-205)+                      72 (43-118)”                    69 (41-116)*
     Rel. 6 power (%)                                             51 (43-59)                      42 (34-50)*                       45 (37-53)*                     46 (36-57)
     0 power (pV*)                                                52 (33-81)                      47 (31-71)                        26 (1642)*                      21 (1240)*
     Rel. 8 power (%)                                             15 (12-18)                      16 (14-19)                        17 (13-21)                      16 (12-20)
     a power (r*V2)                                              100 (61-165)                     86 (53-141)                       38 (20-72)*                     23 (9-61)*
     Rel. a! power (%)                                            29 (23-35)                      31 (25-37)                        25 (18-33)                      21 (15-27)*
     P power           (PV~)                                      14 (7-28)                       19 (lo-38Y                        18 (9-33)                       21 (1141)
     Rel. p power (%)                                              5 (2-8)                        11 (5-171%                        13 (8-18Y+                      16 (11-22)”
     Median frequency (Hz)                                         4.0 (2.7-5.3)                   6.1 (4.6-7.7)*                    5.8 (4.4-7.2)*                  7.2 (5/l--9.0)*
     95th percentile frequency                 (Hz)               12.9 (12-14)                    14.0 (13-16)*                     15.2 (13-17)*                   17.2 (15-20)*
     BA ratio                                                      0.3 (0.1-0.4)                   0.5 (0.1-0.9)                     1.2 (0.4-2.0)*                  1.4 (0.6-2.2)*
     6 ratio                                                       1.0 (0.5-l .5)                   1.8 (0.7-3.0)*                   1.9 (l.O-2.8Y                   2.0 (0.8-3.3Y+
    Data are mean (95% confidence         limits).
    Rel. = relative  power,    % of total power;      BA ratio     = P/CI power;   6 ratio    = (01 + @/S     power.
    * P < 0.05 versus propofol     stop.

Table       2. Sensitivity        and Specificity           of Electroencephalogram              (EEG) Spectral            Variables     in the Prediction     of Eye Opening
                                                                                                                  Sensitivity      (%)
                                                                                                 Eye opening,                       Eye opening,                    (%): propofol
        EEG spectral variable                                    Threshold                          3 min                              1 min                        stop + 5 min
     Absolute 6 power                                        50% decrease                                50                                88                               60
     Absolute (Y power                                       50% decrease                                63                                94                              100
     Total power                                             50% decrease                                56                                81                               90
     Relative /3 power                                       10% increase                                56                                75                               80
     Median frequency                                        5.0 Hz (6,16)                               62                                88                               60
     95th percentile frequency                               14 Hz (5)                                   60                                73                               78
     BA ratio                                                0.5                                         50                                63                               90
     6 ratio                                                 1.4                                         64                                57                               78
    BA ratio     = /~/IY power;   6 ratio   = (01 + 0)/S.

reflected in an increase of both MF and F95. Com-                                                      in /3 power during emergence is related to a change
parable EEG changes have been reported during                                                          in benzodiazepine concentration.
emergence from isoflurane/nitrous     oxide anesthesia                                                    Although the present study demonstrates a consis-
(7,15). Both authors observed a decrease in amplitude                                                  tent pattern of decreasing absolute power and an in-
and a shift toward faster frequencies after disconti-                                                  crease in relative amount of fast activity in most pa-
nuation of isoflurane. However, during emergence                                                       tients, the sensitivity and specificity of the individual
from fentanyl/nitrous    oxide anesthesia only minimal                                                 spectral descriptors was limited. An exception was
changes in 6 ratio, MF, and F95 were observed, and                                                     absolute (Ypower; that proved the best predictor of eye
they were only apparent in the final minute before eye                                                 opening with a sensitivity of 94% and a specificity of
opening (15).                                                                                          100%.
   The transient increase in absolute p power ob-                                                         Because of the difficulty in interpreting EEG ampli-
served in our study 5 min after stopping the propo-                                                    tude changes, most authors have emphasized fre-
fol infusion may be related to the high amplitude p                                                    quency variables rather than power variables to meas-
activity observed during propofol sedation (17-19).                                                    ure anesthetic depth. Schwilden et al. (6,16) reported
The increase in /3 activity might then be considered                                                   that the median frequency showed the greatest degree
to mark the transition from hypnotic propofol con-                                                     of discrimination of all spectral variables. A MF lower
centrations to the sedative concentration range. Ben-                                                  than 5 Hz was always associated with unconscious-
zodiazepines in sedative doses are known to in-                                                        ness. Although in our study MF changed from 4.0 Hz
crease /3 activity in awake patients (20). The oral                                                    to 7.2 Hz during emergence, a MF threshold of 5 Hz
diazepam premeditation might have contributed to                                                       did not reliably predict eye opening.
the amount of absolute p activity during surgery.                                                         Similarly, the spectral edge frequency has been used
However, it is not likely that the transient increase                                                  as an indicator of anesthetic depth in several studies
370   TRAAST AND KALKMAN                                                                                                                                ANESTH       ANALG
      EEG AND EMERGENCE      FROM   l’ROPOFOL/SUFENTANIL    ANESTHESIA                                                                                      1995;81:366-71

(5,7,14,21,22). Rampil and Matte0 (5) reported that a                    exclude that some of our patients were “light.” The
spectral edge frequency of less than 14 Hz was asso-                     value of the frequency variables MF and F95 at the
ciated with a minimal hemodynamic               response to in-          time of stopping the propofol infusion was not rele-
tubation after induction of anesthesia with thiopental.                  vant to the calculation of sensitivity       at 1 and 3 min
In our study F95 changed from 12.9 to 17.2 Hz during                     before eye opening. For the calculation of sensitivity of
emergence, yet a threshold          of 14 Hz was not very                absolute band powers,         we used the power changes
sensitive in predicting eye opening. One possible ex-                    relative to the time of stopping the propofol infusion.
planation might be that with progressively            lower EEG          Here low power at the time of stopping the propofol
amplitude the contribution       of random noise increased               infusion (an “awake type” EEG) might decrease the
the variability of the percentile frequencies. This might                apparent sensitivity     of the variable.
also explain the observation         that in several patients                In conclusion,    the present data demonstrate        that
MF and F95 increased initially but decreased in the                      discontinuation     of propofol administration    as part of a
final minutes before eye opening. Patient movement                       TIVA technique is accompanied             by minor hemody-
and frowning     may contaminate the EEG with electro-                   namic changes, decreases in power in the (Y and 6
myogram activity, especially with frontal placement                      band, and a shift toward higher frequencies. The de-
of electrodes. This can result in an apparent increase in                crease in amplitude is more prominent than the shift
p activity. However,       no movement         or bucking was            toward     faster frequencies,   and results in a gradual
observed in any patient until the time of eye opening.                   shift of MF and F95 toward higher frequencies            after
    Long et al. (15) suggested that the ratio between fast               discontinuation     of propofol. The sensitivity   and spec-
((Y + /3) and slow (6) activity might be an indicator of                 ificity of the individual spectral variables in predicting
anesthetic depth and found an increase in 6 ratio to be                  actual eye opening was limited, with the exception of
more abrupt and of larger magnitude than an increase                     absolute a! power. Nonetheless,        the data suggest that
in median frequency        or spectral edge during emer-                 the EEG may be of use during propofol               TIVA in
gence from isoflurane        anesthesia. In our study the                alerting the anesthesiologist      to an inadvertently     de-
maximum increase in 6 ratio occurred in the first 5 min                  creasing propofol concentration.
after stopping the propofol infusion. Thereafter, only a
slight increase was observed until eye opening. This                     We are grateful    to Dr. John C. Drummond        MD, Professor        of Anes-
suggests that the decrease in 6 activity is an early                     thesiology, University    of California,  San Diego, for critically     review-
indicator of a diminishing       propofol concentration.                 ing the manuscript     and providing     us with his valuable       comments.
    Because power in the 6 and the CY        band decreased in
parallel, a ratio of power in the p band divided by
power in the (Y band (BA ratio) seemed a reasonable                      References
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