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Propofol infusion and the suppression of consciousness: the EEG and dose requirements
British Journal of Anaesthesia 1994; 72: 35-^11
Propofol infusion and the suppression of consciousness: the EEG and dose requirements F. C. FORREST, M. A. TOOLEY, P. R. SAUNDERS AND C. PRYS-ROBERTS
SUMMARY
KEY WORDS Anaesthetics, i.v.: propofol. Brain: electroencephalography.
Anaesthesia induces changes in the electroencephalogram (EEG), but attempts to relate these changes with adequacy of anaesthesia have been hindered by the complexity of the EEG waveform. Variables derived from the EEG, such as Median Power Frequency (MPF), or spectral edge frequency, provide a simpler way of handling and presenting processed EEG data [1]. MPF has been used in many studies investigating EEG changes during i.v. anaesthesia, including feedback control of i.v. anaesthetic infusions [2, 3].
PATIENTS AND METHODS
The study was approved by the District Ethics Committee, and verbal consent obtained from all the patients. We studied 52 females, ASA category I or II, aged 16-58 yr, who were scheduled for elective gynaecological surgery. They were not taking routine medications, and were not premedicated. They were studied in the anaesthetic room before the start of their surgery. Routine monitoring was undertaken with ECG, non-invasive arterial pressure measurement (Dinamap 1846) and pulse oximetry. Under local anaesthesia, an 18-gauge i.v. cannula was placed in one forearm for drug infusion, and another in the opposite antecubital fossa for blood sampling. EEG bipolar electrodes were positioned approximating to the C3 P3 and C4 P4 positions, with nasion reference, of the 10-20 electrode placement system. We used a modified Maudsley approach [6]
F. C. FORREST, M.B., B.S., F.R.C.A.; M. A. TOOLEY, B.SC., M.SC., PH.D., C.ENG., M.I.E.E., M.I.P.S.M.; P. R. SAUNDERS*, M.B., B.S., F.R.C.A. ; C. PRYS-ROBERTS, M.A., D.M., PH.D., F.R.C.A., F.A.N.Z.C.A. ;
Sir Humphry Davy Department of Anaesthesia, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW. Accepted for Publication: August 9, 1993. * Present address: Department of Anaesthesia, Royal Surrey County Hospital, Egcrton Road, Guildford, Surrey GU2 5XX.
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We have used Median Power Frequency (MPF) to study changes in the electroencephalogram during propofol infusions in 52 women about to undergo gynaecological surgery. Patients were allocated to receive propofol by one of nine different manuallycontrolled infusion schemes designed to achieve and maintain a stable blood propofol concentration between 1.0 and 6.0 fig mt', covering a range of states between conscious sedation and full anaesthesia. We recorded the changes in MPF and the response to clinical signs of loss of consciousness at these different doses and concentrations of propofol Using probit analysis, we derived MPF values corresponding to 50% and95% suppression of response to verbal (9.3 Hz and 6.8 Hz), eyelash (8.9 Hz and 6.7 Hz) and venepuncture (5.7 Hz and 3.0 Hz) stimuli. Likewise, we obtained dose and concentration requirements for propofol to suppress these stimuli. The mean (95 % confidence intervals) EDso (5.8 (3.5-6.8) mg kg-' h~1) and ED^ (8.3 (7.1-16.9) mg kg-' h~1) propofol doses for suppression of consciousness were similar to the values for suppression of the eyelash reflex (6.2 (5.36.8) rngkg-'h-' and 8.6 (7.8-10.8) mg kg-1 hr'. respectively). The ECso for loss of consciousness was a propofol concentration of 2.3 (1.82.7) /ig ml-' and for 50% suppression of MPF was 3.1 (2.7-3.5) fig mi-'. The dose required for 50% suppression of MPF was 7.1 (6.2-8.0) mg kg-' hr1. After 30 min, at blood propofol concentrations > 4.0 fig ml-', consistent with stable anaesthesia, the mean MPF was 5.6 (4.5-6.3) Hz. (Br. J. Anaesth. 1994; 72: 35-41)
Schuttler and his colleagues [4, 5] used MPF to characterize pharmacodynamic effects of etomidate, ketamine, thiopentone and propofol on the brain. In six young volunteers, they used an infusion scheme designed to increase the expected blood concentrations of each drug linearly as a function of time. They compared the MPF with the subject's state of consciousness, and with the predicted and measured arterial and venous blood concentrations. They derived concentration-response curves for suppression of the MPF and found an EC60 for propofol of 2.3 ng ml-1. In order to determine if these findings would also apply under conditions of stable maintenance anaesthesia, we have studied the EEG changes which occur between the induction of anaesthesia and the achievement of a state of stable anaesthesia with propofol in unstimulated subjects, and subsequently correlated MPF with the state of consciousness, and with propofol dose and concentration, during stable maintenance anaesthesia.
BRITISH JOURNAL OF ANAESTHESIA
36
Statistical analyses
We analysed patient data (age, weight, heart rate, arterial pressure) using analysis of variance (ANOVA) and paired t tests (P < 0.05 significance). To describe the data relating MPF to propofol dose and concentration, we used a curve fitting programme (Sigma Plot 5 transforms and curve fitter, Jandel Scientific, Erkrath, FRG). For MPF stimulus-response, and all dose- and concentrationresponse curves, we used probit analysis (SAS for PC, version 6.04, SAS Institute, Cary NC, U.S.A.). This analysis package transforms the response data into a straight line, allowing calculation of the mean and 95 % confidence intervals of MPF corresponding to 50 % (MPF60) and 95 % (MPF9B) suppression of response to verbal, eyelash or venepuncture stimulus. The same probit analysis calculated the mean and 95 % confidence limits of the doses (ED50 and EDe6) and concentrations (EC60 and EC96) of propofol required for 50 % and 95 % suppression of all stimuli. RESULTS
There were no significant differences in age or weight between the nine groups (table I). Propofol infusion caused decreases in systolic and diastolic arterial pressure between 0 and 30 min (table II). The changes were not significant in groups 1-3, but were significant in groups 4-9 (P < 0.01). There was a tendency for heart rate to decrease between 0 and 30 min, but this was significant only in groups 5 and 7 (P < 0.01 and P < 0.02). In those patients who were studied for 45 min, there were no further significant changes in arterial pressure or heart rate between 30 and 45 min. The correlation between whole blood propofol concentration and the final infusion rate is shown in figure 1. In those patients studied for 45 min, we obtained two blood propofol concentration measurements, at 30 and 45 min. As the predicted concentrations would be different for each group, we compared the difference between predicted and measured concentration at 30 and 45 min for each patient. There was no statistical difference in these samples between 30 and 45 min. MPF related to propofol dose and concentration
To derive the relationships between MPF and propofol dose (as final infusion rate in mg kg"1 h"1)
TABLE I. Number of patients (n), mean age (SD) and mean weight (SD) for each infusion scheme (initial dose and three-stepped infusion)
Group
(yr)
Weight (kg)
1 (n = 4) 2(n = 2) 3 (n = 4) 4 (n = 6) 5 (n = 7) 6 (n = 5) l(n = T) 8 ( n = 13) 9 (n = 4)
40(13) 35(7) 24(6) 33(4) 29(9) 35(9) 39(4) 42(10) 39(10)
58(6) 66(10) 61(8) 65(13) 59(12) 70 (19) 77 (19) 76 (18) 71(17)
Age
Initial dose (mg kg"1) 0.6
0.72 0.9
1.08 1.2 1.4 1.6 1.8 2.0
Infusion 1 (mgkg-'h-')
Infusion 2 (mg kg"1 h"1)
Infusion 3 (mg kg-' h-')
6.0 7.2 9.0
4.8 5.8 7.2 8.6 9.6
3.6 4.3 5.4 6.5 7.2 8.4 9.6
10.8 12.0 14.0 16.0 180
20.0
11.2 12.8 14.4 16.0
10.8 12.0
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to facilitate easier electrode placement. Baseline EEG recordings were made with the patient awake with their eyes closed. EEG recording was continued for 30 min in all patients; where time allowed, the recording was continued to 45 min in 29 patients. The EEG signal was processed by an amplifier which had a bandwidth between 0.1 Hz and 32 Hz and the signal was sampled at 128 Hz. The sampled EEG signal was analysed in real time and stored on disc using a 286 PC which included an analog-todigital converter and an IMST 400 transputer board (Transmed Ltd, Bristol, U.K.). MPF was calculated from the spectra produced, using Fast Fourier Transform on 4-s time periods. Patients were allocated to receive propofol by one of nine different manually-controlled infusion schemes [7] designed to achieve and maintain a stable blood propofol concentration of 1.0— 6.0 ug ml"1 (table I), covering a range of states between conscious sedation and full anaesthesia [8]. The study was not randomized, and the observers were not blind to the infusion group, as groups were studied sequentially. A rapid infusion of propofol was given over 20 s, followed by a three-stepped infusion. Propofol was given by a calibrated infusion pump (Ohmeda 9000 series). The relevant infusion rates were changed at 10 and 20 min, according to the patient group. Patients breathed spontaneously throughout the study. Oxygen supplementation was given by a Lack breathing system to maintain oxygen saturation greater than 95 %. Each patient's response to the verbal command "open your eyes" and to eyelash stimuli was recorded 10, 20 and 30 min after the start of the propofol infusion. The response to venepuncture was assessed at 30 min. If the study continued for 45 min, the responses to all stimuli were recorded again. Samples of venous blood (at 30 and 45 min) were stored for subsequent assay for propofol by high performance liquid chromatography (HPLC) [9]. The coefficients of variation for the assay were 7.3% and 13.5%, respectively, at propofol concentrations of 2.0 ug ml"1 and 8.85 ug ml"1. As the study progressed, we realized that we had found neither evidence of burst suppression during stable maintenance anaesthesia after 30 min, nor very small MPF values. To confirm these findings we studied more patients in the greater dose groups. At the end of each study, the anaesthetic technique was continued and supplemented as appropriate for the intended surgery.
PROPOFOL INFUSIONS AND THE EEG
37
TABLE II. Mean (SD) heart rate (HR), systolic arterial pressure (SAP) and diastolic arterial pressure (DAP) at 0 and 30 min HR(beat min"1)
SAP (mm Hg)
DAP (mm Hg)
Group
0 min
30 min
0 min
30 min
0 min
30 min
1 2 3 4 5 6 7 8 9
72 (10) 85(2) 69(7) 72 (10) 85(2) 69(7) 74(8) 80(4) 80(9)
68(8) 86(5) 68(5) 72(2) 76(6) 77(9) 66(7) 73(13) 81(10)
125(13) 134(16) 116(11) 125(13) 126(11) 131 (5) 136 (7) 129(13) 135(11)
114(8) 110(4) 99(8) 93(7) 98(8) 103(14) 104(11) 98 (15) 104(13)
77(7) 77(6) 62(7) 75(12) 83(7) 81(4) 81(9) 76(13) 78(5)
69(9) 72(1) 50(11) 54(6) 58(8) 67(12) 63(11) 55(7) 55(10)
1 6 -i
14 12-
71 10 I
i
U_
°- a C3 UJ
ID g A
9 •T E
8
2 "
S c 5 u
6
8
10
12
FIG. 2. Relationship between MPF and propofol dose (final infusion rate). The values at infusion rate 0 are baseline MPF values in fully awake patients before the start of infusion. O = Mean baseline (9.7 Hz); • =• 30 min, Y = 45 min after the start of infusion. = 95 % confidence limits for mean MPF values.
.1 6
sI
4
Propofol infusion (mg kg" 1 h~1)
4
IO
2 o 14-
a
I2H 12-
1 -
§ 0
"N
4 5 6 7 8 9 10 11 Propofol infusion (mg kg" 1 h"1)
12 13
FIG. 1. Relationship (at 30 min (V) and 45 min ( + )) between the whole blood propofol concentration and dose (final infusion rate) for groups 1 to 9. Propofol concentration (y) is given by the linear regression: y = 0.67 (propofol dose)-1.32 (r* = 0.62). Dashed lines represent ±7.3% coefficient of variation either side of the regression line ( ).
I
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and concentration (ug ml"1), we extracted the MPF values at 0, 30 and 45 min and plotted these against the corresponding propofol dose and concentration (figs 2, 3). We tested a number of non-linear equations with the curve fitting program, and the curves that best described the relationships between MPF and propofol dose or concentration were a 3rdorder polynomial for concentration and a 2nd-order polynomial for dose (r = 0.65 for dose and r = 0.69 for concentration). Over the dose and concentration ranges studied, MPF reached minimum mean values of 5.8 Hz (dose) and 5.6 Hz (concentration). MPF stimulus-response
The relationships between MPF and the quantal response to verbal command, eyelash reflex and movement in response to venepuncture after 30 min of anaesthesia are shown in figure 4. Because we were unable to demonstrate further EEG suppression to a mean MPF value less than 5.8 Hz after 30 min (figs
n2
4
6
8
10
Propofol concentration (ug ml" 1 )
FIG. 3. Relationship between MPF and whole blood propofol concentration. The values at a concentration 0 are baseline MPF values in fully awake patients before the start of infusion. O = Mean baseline value (9.7 Hz); • = 30 min, T = 45 min after the start of infusion. = 95 % confidence limits for mean MPF values.
2, 3), the curve relating suppression of response to venepuncture and MPF (derived from probit analysis) is shown as a dotted line at values less than 5.8 Hz. Because the number of patients showing an MPF < 5.8 Hz was small, the confidence limits (fig. 4) for the 95% probability on the venepuncture curve are very wide. The values for MPF 50 and MPF 95 and their respective 95% confidence limits for each stimulus are shown in table III.
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10
38
BRITISH JOURNAL OF ANAESTHESIA
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100
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40-
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20-
4 5 6 7 8 910 EEG MPF (Hz)
20
FIG. 4. Relationship between the probability of no response to verbal command ( ), eyelash reflex ( ) and movement in response to venepuncture ( ), and MPF. The curves are reconstructed from data obtained by probit analysis, i 1 = 95 % confidence intervals at the MPF M and MPF, 5 for suppression of each response.
5 7 10 30 50 70 Propofol infusion (mg kg"1 h~1)
FIG. 5. Relationships between the probability of no response to verbal command ( ), eyelash reflex ( ), movement in response to venepuncture ( ) and propofol dose (final infusion rate). ••—• = Percent suppression of MPF. i 1 = 95 % confidence intervals at the ED60 and EDBS for suppression of each response. 100-1
r 100
Stimulus
MPF M (Hz)
MPF8S (Hz)
Verbal Eyelash Venepuncture
9.3 (8.6-10.7) 8.9 (8.2-9.9) 5.7 (4.8-6.4)
6.8 (5.6-7.6) 6.7 (5.9-7.3) 3.0(1.6-3.9)
obability of no respon
80-
TABLE III. MPF at which 50% (.MPF^) and 95% (MPF^) of the sample population show suppression of stimulus {95% confidence urmts)
40
20 0
Propofol dose-response and concentration-response
The dose-response and concentration-response curves for propofol suppression of consciousness, eyelash reflex and movement in response to venepuncture, are shown in figures 5 and 6, respectively. These quantal responses are compared with the curves representing the percentage suppression of MPF, using the mean value of 9.7 Hz as the baseline MPF and 5.8 Hz (dose) and 5.6 Hz (concentration) as the final mean MPF values, respectively. Percentage MPF suppression was calculated as (9.7-actual MPF) x 100/(9.7-final MPF). Mean values and their respective 95 % confidence limits for ED60, ED9B, EC60 and ECj 5 are shown in table III. MPF and time Figure 7 shows representative plots, from individual patients, of changes in MPF with time from the start of rapid infusion and the three-stepped scheme over the subsequent 30 min (a selection of infusion schemes are included). The time plots were derived from 8-s periods (shown as each data point) and the curves are a moving average over a window of five data points. In many patients receiving large infusion rates, MPF decreased to frequencies considerably less than 5 Hz during the first few minutes after the loading dose and commencing the infusion,
30 0.50.7 1 3 5 7 10 Propofol concentration (ug ml"1)
FIG. 6. Relationships between the probability of no response to verbal command ( ), eyelash reflex ( ), movement in response to venepuncture ( ) and whole blood propofol concentration. ^ — = Percent suppression of MPF. I 1 = 95 % confidence intervals at the ED60 and ED, 6 for suppression of each response.
consistent with the findings of others [4, 5]. Many of these patients (e.g. group 9) showed a pattern in which the MPF increased during the subsequent period up to 30 min (fig. 7). By contrast, in many patients who received small infusion rates (e.g. group 5) the opposite pattern was observed—MPF increased initially and then decreased progressively. In the intermediate groups, many patients demonstrated a pattern similar to that shown for group 7 in figure 7—that is, a biphasic shift of MPF shortly after the start of the infusion scheme, followed by a period of stability. However, we have been unable to demonstrate any statistical significance of these changes of MPF as a function of time (between 0 and 30 min), as a function of groups (infusion rates) or blood propofol concentration.
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3
PROPOFOL INFUSIONS AND THE EEG
39
16 CO Q. 3
12-
o
840 16-
|
8 4-
u. a.
0 16
I 8
(3
4 0 en
16 "
a 12 H
1
410 20 Time after start of infusion (min)
30
FIG. 7. Changes in MPF with time in four patients representative of groups 3, 5, 7 and 9, given different infusion rates of propofol. The continuous line represents the running average MPF for each patient; each individual point represents the MPF derived from 8-s time periods. • = Resting MPF.
Under stable conditions, we did not record any epileptogenic activity in any patient. DISCUSSION
Our main objective in this study was to determine the dose and concentration requirements for propofol to suppress consciousness, and to correlate these with the EEG. Findings in the previous, accompanying study [8] prompted us to extend the method to correlate EEG changes with clinical signs of loss of consciousness, and with anaesthetic dose and blood concentrations, under stable conditions of sedation or anaesthesia. We therefore used a well established manual infusion scheme [7] based on the computer-controlled infusion scheme of Tackley and colleagues [10,11] to achieve a range of neurophysiological states in our patients from awake but mildly sedated, through deep sedation to full anaesthesia. We anticipated that each infusion scheme would result in a predictable blood propofol concentration consistent with the observed state of the patient. In order to avoid the concurrent physiological and surgical stimuli, which might interfere with purely pharmacological effects of propofol and alter the EEG pattern, we studied patients in the controlled and quiet conditions of an anaesthetic room before surgery started. Previous studies showed that EEG changes during the onset of anaesthesia correlated well with clinical signs of loss of consciousness [4, 5]. However, it is
important to emphasize that these studies were performed under conditions in which the blood, and presumably brain, concentrations of the relevant i.v. anaesthetics were changing continuously (either increasing during drug administration, or decreasing during the recovery periods). Although derived parameters from the EEG, such as MPF, were used in those correlations, and have been used subsequently for closed loop feedback control of anaesthesia [2, 3], we found very different relationships between EEG changes and anaesthetic dose or concentrations during stable maintenance sedation or anaesthesia. We made the first measurements at 30 min after starting the infusion schemes, because the previous study [8] had found small changes in physiological performance between measurements made at 10 min and those made at 20 min. Also, we were interested in the development of EEG patterns with time during anaesthesia without surgical stimulation. It was not our original intention to re-evaluate the validity of the infusion scheme as a means of achieving stable blood concentrations. However, as die validity of both this and the previous study depended on establishing a correlation between a given neurophysiological state (consciousness, sedation and anaesthesia) and a given blood propofol concentration, we compared blood propofol concentrations achieved at 30 and 45 min in the 29 patients studied for 45 min. We found no significant differences between predicted and measured blood
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40
concentrations for each group of patients having different infusion schemes. Thus we can state that, within the limitations of the assay, we had achieved stable blood propofol concentrations, and that these were consistent with the EEG observations. Propofol dose-response and concentration—response
Despite the differences between our study under stable maintenance anaesthesia and that of the Bonn group during rapid changes of blood propofol concentration [4, 5], the EC60 value of 2.3 ug ml"1 was exactly the same in both studies. We can only assume that, by 30 min of infusion, when blood concentrations were stable, there was an equilibrium with concentrations of propofol in the near vicinity of brain cells, to produce a consistent pharmacodynamic effect. MPF—propofol dose and concentration
After 30 min of anaesthesia, we found dose- and concentration-related decreases in MPF from baseline values (figs 2, 3), in keeping with previous observations that general anaesthetics increase the power of the lower frequency bands, resulting in a decrease in MPF. The Bonn group [1,4, 5] have consistently found small (< 3 Hz) values of MPF, and burst suppression, at concentrations of i.v. anaesthetics sufficient to produce anaesthesia. We also saw commonly a considerable decrease in MPF in the first few minutes of our studies following the initial infusion dose and start of the stepped infusion scheme. However, despite studying a larger number of patients at greater doses, we found only three patients after 30 min and one patient after 45 min with values of MPF less than 4 Hz. Our findings suggest that, when equilibrium between blood and brain propofol has been achieved, the stable electroencephalogram and the lack of a further decrease in MPF with blood propofol concentrations greater
than 5-6 ug ml"1, suggest that, in the absence of noxious stimuli, this reflects a maximal degree of neural depression. The curves shown in figures 2 and 3 suggest that, after 30 min of infusion, very small doses and concentrations of propofol are associated with activation of the EEG, that is an increase in MPF to greater than baseline values. We have insufficient data from studies with small doses to state this with conviction, but this concept is consistent with a previous study of the changes in the EEG power spectrum during propofol sedation [12]. In that study, sedation was achieved by an initial dose of propofol, followed by a single infusion rate for 45 min. The increase in MPF to values greater than baseline recorded throughout the study period reflected the increase in power of the greater frequencies. MPF and time Is it possible to reconcile the differences between the MPF values at blood propofol concentrations of 5 ug ml"1 and greater in the present study, and the much smaller MPF values described by Schuttler [5] for all anaesthetics studied (propofol, thiopentone, methohexitone and ketamine) during the rapid onset and offset of anaesthesia? The representative plots of MPF with time (fig. 7) show what appears to be an interesting phenomenon—that is, the rapid onset of low MPF at the onset of anaesthesia, comparable to the values observed by Schuttler and his colleagues. The subsequent pattern appears to depend on the final infusion rate and therefore the final blood concentration. Patients receiving small infusion rates (groups 1—5), 40% of whom were responding to command, appear to have an increased MPF following a transient decrease, followed by a steady decrease over the subsequent 30 min. By contrast, patients in groups 8 and 9 who received high propofol infusion rates, showed the converse pattern in which the MPF progressively increased from a small value towards a final MPF which was less at both 30 and 45 min after the start of the infusion (figs 2, 3). The different patterns of MPF as a function of time (fig. 7) may contain additional information which may help in predicting move-no move situations, although we have not yet been able to identify any statistically significant variables. It is indeed surprising that, after 148 years of inhalation anaesthesia, we have so little information [13] on the dose requirement for volatile or gaseous anaesthetics to suppress consciousness during stable maintenance anaesthesia. Although the so-called "MAC-awake" values are available, they are not quite the same, in that they are obtained as measurements of alveolar (end-tidal) concentration at the time of recovery of consciousness [13, 14], when it is clear that brain and blood concentrations of anaesthetics are not in equilibrium. Comparison of MAC-awake data with MAC reveals a ratio of approximately 0.25 whereas, for i.v. anaesthetics, the ratio of blood concentration at awakening to that at an ED50 dose for suppression of motor movement is closer to 0.48 [15]. If we are to have reliable data upon which to make correlations of neurophysio-
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The dose—response curves for suppression of the responses to verbal and eyelash stimuli and for venepuncture are broadly similar to those found in the previous study [8], especially for ED95. It is difficult to make direct comparisons because of the timing of the measurements and the wider range of ages in the present study. Nevertheless, the general finding of close juxtaposition of the curves for suppression of consciousness and eyelash reflex confirms the value of the latter as an indicator of the former in clinical practice. The relationship to these other curves, of the curve representing percentage suppression of the MPF (figs 5 and 6), and the correlation between MPF and these two variables (fig. 4), suggest that, during stable maintenance anaesthesia with propofol alone, MPF values smaller than 6.8 Hz are good predictors of unconsciousness. However, it must be remembered that these studies pertain only to quiescent, anaesthetized patients not subjected to surgical stimuli. The larger doses required to prevent movement in response to such a slight stimulus as venepuncture indicate that much greater doses would be required to suppress the response to a more powerful stimulus such as skin incision.
BRITISH JOURNAL OF ANAESTHESIA
PROPOFOL INFUSIONS AND THE EEG logical variables such as MPF or auditory evoked potentials against consciousness, then such studies should be performed under the conditions of this and the accompanying study [8], during stable maintenance infusions of i.v. drugs, or stable endtidal concentrations of inhaled anaesthetics.
ACKNOWLEDGEMENTS We thank Mrs A. Dye and Mrs S. Gorman for assaying blood propofol concentrations.
6. Margerison JH, Binnie CD, McCaul IR. Electroencephalographic signs employed in the location of ruptured intracranial arterial ancurysms. Electroencephalography and Clinical Neurophysiology 1970; 28: 296-306. 7. Roberts FL, Dixon J, Lewis GTR, Tackley RM, PrysRoberts C. Induction and maintenance of propofol anaesthesia: A manual infusion scheme. Anaesthesia 1988; 43 (Suppl.): 14-17. 8. Dunnet JM, Prys-Roberts C, Holland DE, Browne BL. Propofol infusion and the suppression of consciousness: dose requirements to induce loss of consciousness and to suppress noxious and non-noxious stimuli. British Journal of Anaesthesia 1994; 72: 29-34. 9. Plummer GF. An improved method for the determination of propofol (ICI 35,868) in blood. Journal of Chromatography 1987; 421: 171-176. 10. Tackley RM, Lewis GTR, Prys-Roberts C, Boaden RW, Harvey JR. Computer controlled infusion of propofol. British Journal of Anaesthesia 1989; 62: 46-53. 11. Dixon J, Roberts FL, Tackley RM, Lewis GTR, Connell H, Prys-Roberts C. Study of the possible interaction between fentanyl and propofol using a computer-controlled infusion of propofol. British Journal of Anaesthesia 1990; 64: 142-147. 12. Veselis RA, Reinsel RA, Marino P, Wronski M. EEG power spectrum changes during propofol sedation. Anesthesiology 1991; 75: A181. 13. Stoelting RK, Longnecker DE, Eger El II. Minimum alveolar concentrations in man on awakening from methyoxyflurane, halothane, ether and fluroxene anesthesia. Anesthesiology 1970; 33: 5-9. 14. Gross JB, Alexander CM. Awakening concentrations of isoflurane are not affected by analgesic doses of morphine. Anesthesta and Analgesia 1988; 67: 27-30. 15. Prys-Roberts C, Sear JW. Non-barbiturate intravenous anaesthetics and continuous infusion anaesthesia. In: PrysRoberts C, Hug CC jr, eds. Pharmacokinetics of Anaesthesia. Oxford: Blackwell Scientific Publications, 1984; 128-156.
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REFERENCES 1. Schwilden H. Use of median EEG frequency and pharmacokinetics in determining the depth of anaesthesia. In: Jones JG, ed. Clinical Anaesthesiology. Depth of Anaesthesia. Vol. 3, No. 3. London: Baillierc-Tindall, 1989; 603-622. 2. Schwilden H, Stoeckel H, Schuttler J. Closed-loop feedback control of propofol anaesthesia by quantitive EEG analysis in humans. British Journal of Anaesthesia 1989; 62: 290-296. 3. Schwilden H, Schuttler J, Stoeckel H. Closed-loop feedback control of methohexitone anesthesia by quantitative EEG analysis in humans. Anesthesiology 1987; 67: 341-347. 4. Schwilden H, Schuttler J, Stoeckel H. Quantitation of the EEG and pharmacodynamic modelling of hypnotic drugs: etomidate as an example. European Journal of Anaesthesiology 1985; 2: 121-131. 5. Schuttler J. Pharmakokinetik und Dynamik des intravenosen Anasthetikums Propofol. Anaesthesiologie und Intensivemediz, Bd 202. Stuttgart: Springer Verlag, 1990.
41
Propofol infusion and the suppression of consciousness: the EEG and dose requirements F. C. FORREST, M. A. TOOLEY, P. R. SAUNDERS AND C. PRYS-ROBERTS
SUMMARY
KEY WORDS Anaesthetics, i.v.: propofol. Brain: electroencephalography.
Anaesthesia induces changes in the electroencephalogram (EEG), but attempts to relate these changes with adequacy of anaesthesia have been hindered by the complexity of the EEG waveform. Variables derived from the EEG, such as Median Power Frequency (MPF), or spectral edge frequency, provide a simpler way of handling and presenting processed EEG data [1]. MPF has been used in many studies investigating EEG changes during i.v. anaesthesia, including feedback control of i.v. anaesthetic infusions [2, 3].
PATIENTS AND METHODS
The study was approved by the District Ethics Committee, and verbal consent obtained from all the patients. We studied 52 females, ASA category I or II, aged 16-58 yr, who were scheduled for elective gynaecological surgery. They were not taking routine medications, and were not premedicated. They were studied in the anaesthetic room before the start of their surgery. Routine monitoring was undertaken with ECG, non-invasive arterial pressure measurement (Dinamap 1846) and pulse oximetry. Under local anaesthesia, an 18-gauge i.v. cannula was placed in one forearm for drug infusion, and another in the opposite antecubital fossa for blood sampling. EEG bipolar electrodes were positioned approximating to the C3 P3 and C4 P4 positions, with nasion reference, of the 10-20 electrode placement system. We used a modified Maudsley approach [6]
F. C. FORREST, M.B., B.S., F.R.C.A.; M. A. TOOLEY, B.SC., M.SC., PH.D., C.ENG., M.I.E.E., M.I.P.S.M.; P. R. SAUNDERS*, M.B., B.S., F.R.C.A. ; C. PRYS-ROBERTS, M.A., D.M., PH.D., F.R.C.A., F.A.N.Z.C.A. ;
Sir Humphry Davy Department of Anaesthesia, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW. Accepted for Publication: August 9, 1993. * Present address: Department of Anaesthesia, Royal Surrey County Hospital, Egcrton Road, Guildford, Surrey GU2 5XX.
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We have used Median Power Frequency (MPF) to study changes in the electroencephalogram during propofol infusions in 52 women about to undergo gynaecological surgery. Patients were allocated to receive propofol by one of nine different manuallycontrolled infusion schemes designed to achieve and maintain a stable blood propofol concentration between 1.0 and 6.0 fig mt', covering a range of states between conscious sedation and full anaesthesia. We recorded the changes in MPF and the response to clinical signs of loss of consciousness at these different doses and concentrations of propofol Using probit analysis, we derived MPF values corresponding to 50% and95% suppression of response to verbal (9.3 Hz and 6.8 Hz), eyelash (8.9 Hz and 6.7 Hz) and venepuncture (5.7 Hz and 3.0 Hz) stimuli. Likewise, we obtained dose and concentration requirements for propofol to suppress these stimuli. The mean (95 % confidence intervals) EDso (5.8 (3.5-6.8) mg kg-' h~1) and ED^ (8.3 (7.1-16.9) mg kg-' h~1) propofol doses for suppression of consciousness were similar to the values for suppression of the eyelash reflex (6.2 (5.36.8) rngkg-'h-' and 8.6 (7.8-10.8) mg kg-1 hr'. respectively). The ECso for loss of consciousness was a propofol concentration of 2.3 (1.82.7) /ig ml-' and for 50% suppression of MPF was 3.1 (2.7-3.5) fig mi-'. The dose required for 50% suppression of MPF was 7.1 (6.2-8.0) mg kg-' hr1. After 30 min, at blood propofol concentrations > 4.0 fig ml-', consistent with stable anaesthesia, the mean MPF was 5.6 (4.5-6.3) Hz. (Br. J. Anaesth. 1994; 72: 35-41)
Schuttler and his colleagues [4, 5] used MPF to characterize pharmacodynamic effects of etomidate, ketamine, thiopentone and propofol on the brain. In six young volunteers, they used an infusion scheme designed to increase the expected blood concentrations of each drug linearly as a function of time. They compared the MPF with the subject's state of consciousness, and with the predicted and measured arterial and venous blood concentrations. They derived concentration-response curves for suppression of the MPF and found an EC60 for propofol of 2.3 ng ml-1. In order to determine if these findings would also apply under conditions of stable maintenance anaesthesia, we have studied the EEG changes which occur between the induction of anaesthesia and the achievement of a state of stable anaesthesia with propofol in unstimulated subjects, and subsequently correlated MPF with the state of consciousness, and with propofol dose and concentration, during stable maintenance anaesthesia.
BRITISH JOURNAL OF ANAESTHESIA
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Statistical analyses
We analysed patient data (age, weight, heart rate, arterial pressure) using analysis of variance (ANOVA) and paired t tests (P < 0.05 significance). To describe the data relating MPF to propofol dose and concentration, we used a curve fitting programme (Sigma Plot 5 transforms and curve fitter, Jandel Scientific, Erkrath, FRG). For MPF stimulus-response, and all dose- and concentrationresponse curves, we used probit analysis (SAS for PC, version 6.04, SAS Institute, Cary NC, U.S.A.). This analysis package transforms the response data into a straight line, allowing calculation of the mean and 95 % confidence intervals of MPF corresponding to 50 % (MPF60) and 95 % (MPF9B) suppression of response to verbal, eyelash or venepuncture stimulus. The same probit analysis calculated the mean and 95 % confidence limits of the doses (ED50 and EDe6) and concentrations (EC60 and EC96) of propofol required for 50 % and 95 % suppression of all stimuli. RESULTS
There were no significant differences in age or weight between the nine groups (table I). Propofol infusion caused decreases in systolic and diastolic arterial pressure between 0 and 30 min (table II). The changes were not significant in groups 1-3, but were significant in groups 4-9 (P < 0.01). There was a tendency for heart rate to decrease between 0 and 30 min, but this was significant only in groups 5 and 7 (P < 0.01 and P < 0.02). In those patients who were studied for 45 min, there were no further significant changes in arterial pressure or heart rate between 30 and 45 min. The correlation between whole blood propofol concentration and the final infusion rate is shown in figure 1. In those patients studied for 45 min, we obtained two blood propofol concentration measurements, at 30 and 45 min. As the predicted concentrations would be different for each group, we compared the difference between predicted and measured concentration at 30 and 45 min for each patient. There was no statistical difference in these samples between 30 and 45 min. MPF related to propofol dose and concentration
To derive the relationships between MPF and propofol dose (as final infusion rate in mg kg"1 h"1)
TABLE I. Number of patients (n), mean age (SD) and mean weight (SD) for each infusion scheme (initial dose and three-stepped infusion)
Group
(yr)
Weight (kg)
1 (n = 4) 2(n = 2) 3 (n = 4) 4 (n = 6) 5 (n = 7) 6 (n = 5) l(n = T) 8 ( n = 13) 9 (n = 4)
40(13) 35(7) 24(6) 33(4) 29(9) 35(9) 39(4) 42(10) 39(10)
58(6) 66(10) 61(8) 65(13) 59(12) 70 (19) 77 (19) 76 (18) 71(17)
Age
Initial dose (mg kg"1) 0.6
0.72 0.9
1.08 1.2 1.4 1.6 1.8 2.0
Infusion 1 (mgkg-'h-')
Infusion 2 (mg kg"1 h"1)
Infusion 3 (mg kg-' h-')
6.0 7.2 9.0
4.8 5.8 7.2 8.6 9.6
3.6 4.3 5.4 6.5 7.2 8.4 9.6
10.8 12.0 14.0 16.0 180
20.0
11.2 12.8 14.4 16.0
10.8 12.0
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to facilitate easier electrode placement. Baseline EEG recordings were made with the patient awake with their eyes closed. EEG recording was continued for 30 min in all patients; where time allowed, the recording was continued to 45 min in 29 patients. The EEG signal was processed by an amplifier which had a bandwidth between 0.1 Hz and 32 Hz and the signal was sampled at 128 Hz. The sampled EEG signal was analysed in real time and stored on disc using a 286 PC which included an analog-todigital converter and an IMST 400 transputer board (Transmed Ltd, Bristol, U.K.). MPF was calculated from the spectra produced, using Fast Fourier Transform on 4-s time periods. Patients were allocated to receive propofol by one of nine different manually-controlled infusion schemes [7] designed to achieve and maintain a stable blood propofol concentration of 1.0— 6.0 ug ml"1 (table I), covering a range of states between conscious sedation and full anaesthesia [8]. The study was not randomized, and the observers were not blind to the infusion group, as groups were studied sequentially. A rapid infusion of propofol was given over 20 s, followed by a three-stepped infusion. Propofol was given by a calibrated infusion pump (Ohmeda 9000 series). The relevant infusion rates were changed at 10 and 20 min, according to the patient group. Patients breathed spontaneously throughout the study. Oxygen supplementation was given by a Lack breathing system to maintain oxygen saturation greater than 95 %. Each patient's response to the verbal command "open your eyes" and to eyelash stimuli was recorded 10, 20 and 30 min after the start of the propofol infusion. The response to venepuncture was assessed at 30 min. If the study continued for 45 min, the responses to all stimuli were recorded again. Samples of venous blood (at 30 and 45 min) were stored for subsequent assay for propofol by high performance liquid chromatography (HPLC) [9]. The coefficients of variation for the assay were 7.3% and 13.5%, respectively, at propofol concentrations of 2.0 ug ml"1 and 8.85 ug ml"1. As the study progressed, we realized that we had found neither evidence of burst suppression during stable maintenance anaesthesia after 30 min, nor very small MPF values. To confirm these findings we studied more patients in the greater dose groups. At the end of each study, the anaesthetic technique was continued and supplemented as appropriate for the intended surgery.
PROPOFOL INFUSIONS AND THE EEG
37
TABLE II. Mean (SD) heart rate (HR), systolic arterial pressure (SAP) and diastolic arterial pressure (DAP) at 0 and 30 min HR(beat min"1)
SAP (mm Hg)
DAP (mm Hg)
Group
0 min
30 min
0 min
30 min
0 min
30 min
1 2 3 4 5 6 7 8 9
72 (10) 85(2) 69(7) 72 (10) 85(2) 69(7) 74(8) 80(4) 80(9)
68(8) 86(5) 68(5) 72(2) 76(6) 77(9) 66(7) 73(13) 81(10)
125(13) 134(16) 116(11) 125(13) 126(11) 131 (5) 136 (7) 129(13) 135(11)
114(8) 110(4) 99(8) 93(7) 98(8) 103(14) 104(11) 98 (15) 104(13)
77(7) 77(6) 62(7) 75(12) 83(7) 81(4) 81(9) 76(13) 78(5)
69(9) 72(1) 50(11) 54(6) 58(8) 67(12) 63(11) 55(7) 55(10)
1 6 -i
14 12-
71 10 I
i
U_
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ID g A
9 •T E
8
2 "
S c 5 u
6
8
10
12
FIG. 2. Relationship between MPF and propofol dose (final infusion rate). The values at infusion rate 0 are baseline MPF values in fully awake patients before the start of infusion. O = Mean baseline (9.7 Hz); • =• 30 min, Y = 45 min after the start of infusion. = 95 % confidence limits for mean MPF values.
.1 6
sI
4
Propofol infusion (mg kg" 1 h~1)
4
IO
2 o 14-
a
I2H 12-
1 -
§ 0
"N
4 5 6 7 8 9 10 11 Propofol infusion (mg kg" 1 h"1)
12 13
FIG. 1. Relationship (at 30 min (V) and 45 min ( + )) between the whole blood propofol concentration and dose (final infusion rate) for groups 1 to 9. Propofol concentration (y) is given by the linear regression: y = 0.67 (propofol dose)-1.32 (r* = 0.62). Dashed lines represent ±7.3% coefficient of variation either side of the regression line ( ).
I
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and concentration (ug ml"1), we extracted the MPF values at 0, 30 and 45 min and plotted these against the corresponding propofol dose and concentration (figs 2, 3). We tested a number of non-linear equations with the curve fitting program, and the curves that best described the relationships between MPF and propofol dose or concentration were a 3rdorder polynomial for concentration and a 2nd-order polynomial for dose (r = 0.65 for dose and r = 0.69 for concentration). Over the dose and concentration ranges studied, MPF reached minimum mean values of 5.8 Hz (dose) and 5.6 Hz (concentration). MPF stimulus-response
The relationships between MPF and the quantal response to verbal command, eyelash reflex and movement in response to venepuncture after 30 min of anaesthesia are shown in figure 4. Because we were unable to demonstrate further EEG suppression to a mean MPF value less than 5.8 Hz after 30 min (figs
n2
4
6
8
10
Propofol concentration (ug ml" 1 )
FIG. 3. Relationship between MPF and whole blood propofol concentration. The values at a concentration 0 are baseline MPF values in fully awake patients before the start of infusion. O = Mean baseline value (9.7 Hz); • = 30 min, T = 45 min after the start of infusion. = 95 % confidence limits for mean MPF values.
2, 3), the curve relating suppression of response to venepuncture and MPF (derived from probit analysis) is shown as a dotted line at values less than 5.8 Hz. Because the number of patients showing an MPF < 5.8 Hz was small, the confidence limits (fig. 4) for the 95% probability on the venepuncture curve are very wide. The values for MPF 50 and MPF 95 and their respective 95% confidence limits for each stimulus are shown in table III.
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2 -
10
38
BRITISH JOURNAL OF ANAESTHESIA
100 n
100
r 100
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20-
4 5 6 7 8 910 EEG MPF (Hz)
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FIG. 4. Relationship between the probability of no response to verbal command ( ), eyelash reflex ( ) and movement in response to venepuncture ( ), and MPF. The curves are reconstructed from data obtained by probit analysis, i 1 = 95 % confidence intervals at the MPF M and MPF, 5 for suppression of each response.
5 7 10 30 50 70 Propofol infusion (mg kg"1 h~1)
FIG. 5. Relationships between the probability of no response to verbal command ( ), eyelash reflex ( ), movement in response to venepuncture ( ) and propofol dose (final infusion rate). ••—• = Percent suppression of MPF. i 1 = 95 % confidence intervals at the ED60 and EDBS for suppression of each response. 100-1
r 100
Stimulus
MPF M (Hz)
MPF8S (Hz)
Verbal Eyelash Venepuncture
9.3 (8.6-10.7) 8.9 (8.2-9.9) 5.7 (4.8-6.4)
6.8 (5.6-7.6) 6.7 (5.9-7.3) 3.0(1.6-3.9)
obability of no respon
80-
TABLE III. MPF at which 50% (.MPF^) and 95% (MPF^) of the sample population show suppression of stimulus {95% confidence urmts)
40
20 0
Propofol dose-response and concentration-response
The dose-response and concentration-response curves for propofol suppression of consciousness, eyelash reflex and movement in response to venepuncture, are shown in figures 5 and 6, respectively. These quantal responses are compared with the curves representing the percentage suppression of MPF, using the mean value of 9.7 Hz as the baseline MPF and 5.8 Hz (dose) and 5.6 Hz (concentration) as the final mean MPF values, respectively. Percentage MPF suppression was calculated as (9.7-actual MPF) x 100/(9.7-final MPF). Mean values and their respective 95 % confidence limits for ED60, ED9B, EC60 and ECj 5 are shown in table III. MPF and time Figure 7 shows representative plots, from individual patients, of changes in MPF with time from the start of rapid infusion and the three-stepped scheme over the subsequent 30 min (a selection of infusion schemes are included). The time plots were derived from 8-s periods (shown as each data point) and the curves are a moving average over a window of five data points. In many patients receiving large infusion rates, MPF decreased to frequencies considerably less than 5 Hz during the first few minutes after the loading dose and commencing the infusion,
30 0.50.7 1 3 5 7 10 Propofol concentration (ug ml"1)
FIG. 6. Relationships between the probability of no response to verbal command ( ), eyelash reflex ( ), movement in response to venepuncture ( ) and whole blood propofol concentration. ^ — = Percent suppression of MPF. I 1 = 95 % confidence intervals at the ED60 and ED, 6 for suppression of each response.
consistent with the findings of others [4, 5]. Many of these patients (e.g. group 9) showed a pattern in which the MPF increased during the subsequent period up to 30 min (fig. 7). By contrast, in many patients who received small infusion rates (e.g. group 5) the opposite pattern was observed—MPF increased initially and then decreased progressively. In the intermediate groups, many patients demonstrated a pattern similar to that shown for group 7 in figure 7—that is, a biphasic shift of MPF shortly after the start of the infusion scheme, followed by a period of stability. However, we have been unable to demonstrate any statistical significance of these changes of MPF as a function of time (between 0 and 30 min), as a function of groups (infusion rates) or blood propofol concentration.
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3
PROPOFOL INFUSIONS AND THE EEG
39
16 CO Q. 3
12-
o
840 16-
|
8 4-
u. a.
0 16
I 8
(3
4 0 en
16 "
a 12 H
1
410 20 Time after start of infusion (min)
30
FIG. 7. Changes in MPF with time in four patients representative of groups 3, 5, 7 and 9, given different infusion rates of propofol. The continuous line represents the running average MPF for each patient; each individual point represents the MPF derived from 8-s time periods. • = Resting MPF.
Under stable conditions, we did not record any epileptogenic activity in any patient. DISCUSSION
Our main objective in this study was to determine the dose and concentration requirements for propofol to suppress consciousness, and to correlate these with the EEG. Findings in the previous, accompanying study [8] prompted us to extend the method to correlate EEG changes with clinical signs of loss of consciousness, and with anaesthetic dose and blood concentrations, under stable conditions of sedation or anaesthesia. We therefore used a well established manual infusion scheme [7] based on the computer-controlled infusion scheme of Tackley and colleagues [10,11] to achieve a range of neurophysiological states in our patients from awake but mildly sedated, through deep sedation to full anaesthesia. We anticipated that each infusion scheme would result in a predictable blood propofol concentration consistent with the observed state of the patient. In order to avoid the concurrent physiological and surgical stimuli, which might interfere with purely pharmacological effects of propofol and alter the EEG pattern, we studied patients in the controlled and quiet conditions of an anaesthetic room before surgery started. Previous studies showed that EEG changes during the onset of anaesthesia correlated well with clinical signs of loss of consciousness [4, 5]. However, it is
important to emphasize that these studies were performed under conditions in which the blood, and presumably brain, concentrations of the relevant i.v. anaesthetics were changing continuously (either increasing during drug administration, or decreasing during the recovery periods). Although derived parameters from the EEG, such as MPF, were used in those correlations, and have been used subsequently for closed loop feedback control of anaesthesia [2, 3], we found very different relationships between EEG changes and anaesthetic dose or concentrations during stable maintenance sedation or anaesthesia. We made the first measurements at 30 min after starting the infusion schemes, because the previous study [8] had found small changes in physiological performance between measurements made at 10 min and those made at 20 min. Also, we were interested in the development of EEG patterns with time during anaesthesia without surgical stimulation. It was not our original intention to re-evaluate the validity of the infusion scheme as a means of achieving stable blood concentrations. However, as die validity of both this and the previous study depended on establishing a correlation between a given neurophysiological state (consciousness, sedation and anaesthesia) and a given blood propofol concentration, we compared blood propofol concentrations achieved at 30 and 45 min in the 29 patients studied for 45 min. We found no significant differences between predicted and measured blood
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40
concentrations for each group of patients having different infusion schemes. Thus we can state that, within the limitations of the assay, we had achieved stable blood propofol concentrations, and that these were consistent with the EEG observations. Propofol dose-response and concentration—response
Despite the differences between our study under stable maintenance anaesthesia and that of the Bonn group during rapid changes of blood propofol concentration [4, 5], the EC60 value of 2.3 ug ml"1 was exactly the same in both studies. We can only assume that, by 30 min of infusion, when blood concentrations were stable, there was an equilibrium with concentrations of propofol in the near vicinity of brain cells, to produce a consistent pharmacodynamic effect. MPF—propofol dose and concentration
After 30 min of anaesthesia, we found dose- and concentration-related decreases in MPF from baseline values (figs 2, 3), in keeping with previous observations that general anaesthetics increase the power of the lower frequency bands, resulting in a decrease in MPF. The Bonn group [1,4, 5] have consistently found small (< 3 Hz) values of MPF, and burst suppression, at concentrations of i.v. anaesthetics sufficient to produce anaesthesia. We also saw commonly a considerable decrease in MPF in the first few minutes of our studies following the initial infusion dose and start of the stepped infusion scheme. However, despite studying a larger number of patients at greater doses, we found only three patients after 30 min and one patient after 45 min with values of MPF less than 4 Hz. Our findings suggest that, when equilibrium between blood and brain propofol has been achieved, the stable electroencephalogram and the lack of a further decrease in MPF with blood propofol concentrations greater
than 5-6 ug ml"1, suggest that, in the absence of noxious stimuli, this reflects a maximal degree of neural depression. The curves shown in figures 2 and 3 suggest that, after 30 min of infusion, very small doses and concentrations of propofol are associated with activation of the EEG, that is an increase in MPF to greater than baseline values. We have insufficient data from studies with small doses to state this with conviction, but this concept is consistent with a previous study of the changes in the EEG power spectrum during propofol sedation [12]. In that study, sedation was achieved by an initial dose of propofol, followed by a single infusion rate for 45 min. The increase in MPF to values greater than baseline recorded throughout the study period reflected the increase in power of the greater frequencies. MPF and time Is it possible to reconcile the differences between the MPF values at blood propofol concentrations of 5 ug ml"1 and greater in the present study, and the much smaller MPF values described by Schuttler [5] for all anaesthetics studied (propofol, thiopentone, methohexitone and ketamine) during the rapid onset and offset of anaesthesia? The representative plots of MPF with time (fig. 7) show what appears to be an interesting phenomenon—that is, the rapid onset of low MPF at the onset of anaesthesia, comparable to the values observed by Schuttler and his colleagues. The subsequent pattern appears to depend on the final infusion rate and therefore the final blood concentration. Patients receiving small infusion rates (groups 1—5), 40% of whom were responding to command, appear to have an increased MPF following a transient decrease, followed by a steady decrease over the subsequent 30 min. By contrast, patients in groups 8 and 9 who received high propofol infusion rates, showed the converse pattern in which the MPF progressively increased from a small value towards a final MPF which was less at both 30 and 45 min after the start of the infusion (figs 2, 3). The different patterns of MPF as a function of time (fig. 7) may contain additional information which may help in predicting move-no move situations, although we have not yet been able to identify any statistically significant variables. It is indeed surprising that, after 148 years of inhalation anaesthesia, we have so little information [13] on the dose requirement for volatile or gaseous anaesthetics to suppress consciousness during stable maintenance anaesthesia. Although the so-called "MAC-awake" values are available, they are not quite the same, in that they are obtained as measurements of alveolar (end-tidal) concentration at the time of recovery of consciousness [13, 14], when it is clear that brain and blood concentrations of anaesthetics are not in equilibrium. Comparison of MAC-awake data with MAC reveals a ratio of approximately 0.25 whereas, for i.v. anaesthetics, the ratio of blood concentration at awakening to that at an ED50 dose for suppression of motor movement is closer to 0.48 [15]. If we are to have reliable data upon which to make correlations of neurophysio-
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The dose—response curves for suppression of the responses to verbal and eyelash stimuli and for venepuncture are broadly similar to those found in the previous study [8], especially for ED95. It is difficult to make direct comparisons because of the timing of the measurements and the wider range of ages in the present study. Nevertheless, the general finding of close juxtaposition of the curves for suppression of consciousness and eyelash reflex confirms the value of the latter as an indicator of the former in clinical practice. The relationship to these other curves, of the curve representing percentage suppression of the MPF (figs 5 and 6), and the correlation between MPF and these two variables (fig. 4), suggest that, during stable maintenance anaesthesia with propofol alone, MPF values smaller than 6.8 Hz are good predictors of unconsciousness. However, it must be remembered that these studies pertain only to quiescent, anaesthetized patients not subjected to surgical stimuli. The larger doses required to prevent movement in response to such a slight stimulus as venepuncture indicate that much greater doses would be required to suppress the response to a more powerful stimulus such as skin incision.
BRITISH JOURNAL OF ANAESTHESIA
PROPOFOL INFUSIONS AND THE EEG logical variables such as MPF or auditory evoked potentials against consciousness, then such studies should be performed under the conditions of this and the accompanying study [8], during stable maintenance infusions of i.v. drugs, or stable endtidal concentrations of inhaled anaesthetics.
ACKNOWLEDGEMENTS We thank Mrs A. Dye and Mrs S. Gorman for assaying blood propofol concentrations.
6. Margerison JH, Binnie CD, McCaul IR. Electroencephalographic signs employed in the location of ruptured intracranial arterial ancurysms. Electroencephalography and Clinical Neurophysiology 1970; 28: 296-306. 7. Roberts FL, Dixon J, Lewis GTR, Tackley RM, PrysRoberts C. Induction and maintenance of propofol anaesthesia: A manual infusion scheme. Anaesthesia 1988; 43 (Suppl.): 14-17. 8. Dunnet JM, Prys-Roberts C, Holland DE, Browne BL. Propofol infusion and the suppression of consciousness: dose requirements to induce loss of consciousness and to suppress noxious and non-noxious stimuli. British Journal of Anaesthesia 1994; 72: 29-34. 9. Plummer GF. An improved method for the determination of propofol (ICI 35,868) in blood. Journal of Chromatography 1987; 421: 171-176. 10. Tackley RM, Lewis GTR, Prys-Roberts C, Boaden RW, Harvey JR. Computer controlled infusion of propofol. British Journal of Anaesthesia 1989; 62: 46-53. 11. Dixon J, Roberts FL, Tackley RM, Lewis GTR, Connell H, Prys-Roberts C. Study of the possible interaction between fentanyl and propofol using a computer-controlled infusion of propofol. British Journal of Anaesthesia 1990; 64: 142-147. 12. Veselis RA, Reinsel RA, Marino P, Wronski M. EEG power spectrum changes during propofol sedation. Anesthesiology 1991; 75: A181. 13. Stoelting RK, Longnecker DE, Eger El II. Minimum alveolar concentrations in man on awakening from methyoxyflurane, halothane, ether and fluroxene anesthesia. Anesthesiology 1970; 33: 5-9. 14. Gross JB, Alexander CM. Awakening concentrations of isoflurane are not affected by analgesic doses of morphine. Anesthesta and Analgesia 1988; 67: 27-30. 15. Prys-Roberts C, Sear JW. Non-barbiturate intravenous anaesthetics and continuous infusion anaesthesia. In: PrysRoberts C, Hug CC jr, eds. Pharmacokinetics of Anaesthesia. Oxford: Blackwell Scientific Publications, 1984; 128-156.
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REFERENCES 1. Schwilden H. Use of median EEG frequency and pharmacokinetics in determining the depth of anaesthesia. In: Jones JG, ed. Clinical Anaesthesiology. Depth of Anaesthesia. Vol. 3, No. 3. London: Baillierc-Tindall, 1989; 603-622. 2. Schwilden H, Stoeckel H, Schuttler J. Closed-loop feedback control of propofol anaesthesia by quantitive EEG analysis in humans. British Journal of Anaesthesia 1989; 62: 290-296. 3. Schwilden H, Schuttler J, Stoeckel H. Closed-loop feedback control of methohexitone anesthesia by quantitative EEG analysis in humans. Anesthesiology 1987; 67: 341-347. 4. Schwilden H, Schuttler J, Stoeckel H. Quantitation of the EEG and pharmacodynamic modelling of hypnotic drugs: etomidate as an example. European Journal of Anaesthesiology 1985; 2: 121-131. 5. Schuttler J. Pharmakokinetik und Dynamik des intravenosen Anasthetikums Propofol. Anaesthesiologie und Intensivemediz, Bd 202. Stuttgart: Springer Verlag, 1990.
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