1 Department of Anaesthesia, Ullevaal University Hospital, N-0407 Oslo, Norway. 2 Oslo University College, N-0167 Oslo, Norway
*Corresponding author. E-mail: s.c.hoymork@ioks.uio.no This article is accompanied by the Editorial.
Accepted for publication: May 29, 2003
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Abstract |
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Methods. We set out to evaluate the performance of TCI devices for propofol (Diprifusor®) and remifentanil (Remifusor, prototype), during laparoscopic cholecystectomy in 21 patients. We also checked if there was any correlation between serum concentrations of propofol and BIS during individually adjusted anaesthesia.
Results. The Diprifusor and Remifusor had a median absolute performance error of 60% and 25% respectively. Propofol concentrations were underpredicted by a median of 60%, and remifentanil concentrations were slightly overpredicted by a median of 7%. When anaesthesia was adjusted to keep BIS values between 45 and 60, no correlation existed between measured concentrations of propofol and the corresponding BIS values, although both BIS and serum propofol concentration discriminated well between the awake and asleep states. Emergence was rapid and uneventful in all patients. Female patients had a more rapid emergence than male patients (6.6 and 11.6 min respectively).
Conclusions. TCI devices for remifentanil and propofol result in large variation in measured serum concentrations. The lack of correlation between BIS and serum concentrations of propofol adds to the debate about whether BIS measures hypnosis as a graded state during surgery. This study confirms that women wake up faster than men, but provides no explanation for this repeatedly shown difference.
Br J Anaesth 2003; 91: 77380
Keywords: anaesthetics i.v., TCI; gender; monitoring, bispectral index; surgery, cholecystectomy
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Introduction |
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In patients undergoing laparoscopic surgery with fixed target-controlled infusions (TCI) of propofol and remifentanil, there was a substantial prediction error for both drugs when serum samples of drug concentrations were compared with preset serum targets.7 Furthermore, there was no correlation between BIS and variations in propofol concentration. This could have been because of low BIS sensitivity at deep levels of general anaesthesia in that study.
In the present study we therefore wanted to elucidate whether BIS was better correlated with serum propofol when BIS was used as a guide to adjust the hypnotic anaesthetic level.
To reduce the prediction error of remifentanil, we also wanted to test the accuracy of the target control algorithm of Minto and colleagues8 when used in a prototype TCI system developed by Gavin Kenny and Iain Glen (Remifusor).
Finally, we wanted to measure the drug concentrations during emergence with simultaneous BIS readings, looking for gender differences, as previously suggested by Gan and colleagues9 and in our previous study.7
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Methods |
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Anaesthesia was induced and maintained with TCI of remifentanil and propofol. Remifentanil was administered using a Remifusor, a prototype TCI system with a Graseby 3500 infusion pump (Graseby Medical Ltd, Watford, UK). It had control software similar to that in the Diprifusor® TCI system (AstraZeneca) but with the pharmacokinetic parameters for remifentanil described by Minto and colleagues.8 Blood target was set at 7.5 ng ml1 during induction. One minute later a propofol infusion was started with TCI (Diprifusor), with the blood target set at 5 µg ml1. When the patient lost consciousness, he or she was intubated, and mechanical ventilation was maintained with oxygenair.
A neuromuscular blocking agent (rocuronium bromide 0.3 mg kg1) was given to most patients before intubation, or the tracheal intubation was carried out without the use of any neuromuscular block at the discretion of the responsible anaesthetist. Before rocuronium bromide was given, the TOF monitor was switched on and the right arm was isolated from neuromuscular block using a tourniquet inflated to 250 mm Hg. The tourniquet was not inflated if neuromuscular blockers were not used, and was left inflated for no more than 20 min. The purpose of isolating the forearm10 was to assess possible somatic responses. If spontaneous movements were observed, or if BIS at any time was noted to be greater than 60, indicating a light hypnotic state,3 the investigator spoke clearly into the patients ear and asked him or her to squeeze the investigators hand repeatedly.
After intubation the propofol target concentration was reduced to 2.5 µg ml1. Throughout surgery, the propofol infusion rate was adjusted to maintain a BIS value between 45 and 60. If BIS was less than 45 for >5 min, the BIS level and actual target concentrations of propofol and remifentanil were recorded and an arterial blood sample for later drug measurements was taken. The propofol target concentration was then further reduced to 2.0 µg ml1 and kept stable for 5 min before the measurements (including the arterial blood sample) were repeated. If BIS was still below 45, further reductions of the propofol target were done, initially to 1.8 µg ml1 and then in steps of 0.1 µg ml1 each time after recordings and blood samples. If the BIS value was greater than 60 at any time, the propofol target concentration was reset to 3.0 µg ml1 after noting the actual target concentrations and BIS values and blood sampling, and was kept stable for 5 min before repeated measurements. If the BIS value was still too high, the propofol target was increased in steps of 0.5 µg ml1 each time after recordings and blood sampling (Fig. 1).
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After gall bladder removal, the remifentanil infusion was reduced to 5 ng ml1 or kept at 7.5 ng ml1 at the discretion of the responsible anaesthetist. At this point, the patients were given ondansetron 4 mg, ketorolac 30 mg and propacetamol 2 g i.v. to reduce postoperative nausea and pain. When the surgery was completed, the remifentanil and propofol infusions were discontinued abruptly, and the patients were given fentanyl 1 µg kg1 i.v. Bupivacaine 5 mg ml1 20 ml was injected locally in the wounds. The times from stopping the drug infusions until extubation and until response to verbal command were recorded.
The first arterial blood samples for analysis of remifentanil and propofol were taken 5 min after the start of the remifentanil infusion (i.e. 4 min after the start of the propofol infusion), with the blood target set at 7.5 ng ml1 and 5 µg ml1 respectively. Further samples were taken 5 min after gall bladder removal, if the remifentanil target had been reduced, and at the time of emergence, which was defined as the patient responding to verbal command. Blood samples were also taken just before and 5 min after every adjustment of the propofol target.
Blood for remifentanil analysis was sampled directly into heparinized tubes and transferred immediately into storage tubes containing citric acid, in order to avoid in vitro metabolism of remifentanil.12 The storage tubes were then placed in a freezer at 18°C within 10 min. Blood for propofol analysis was sampled into heparinized tubes and refrigerated until centrifugation within a few hours. Plasma was then transferred into storage tubes with no extra contents and frozen at 18°C.
Remifentanil in whole blood was analysed at Analytico Medinet, Breda, The Netherlands, using an LC/MS/MS technique.13 The limit of quantification was 0.1 ng ml1, and the coefficient of variation (CV) was less than 15% in the range 0.140 ng ml1. Propofol in plasma was determined at the Department of Clinical Chemistry, Ullevaal Hospital, by an HPLC method with fluorescence detection.14 15 The limit of quantification was 2 ng ml1, and the coefficient of variation (CV) was less than 5.5% over the concentration range examined.
Statistical analysis
The median performance error (MDPE) and the median absolute performance error (MDAPE) were calculated for all the propofol and all the remifentanil samples16 as:
100%x[CmeasuredCestimated]:Cestimated
where Cmeasured and Cestimated are the simultaneously measured and estimated drug concentrations. MDPE is a signed value showing whether the algorithm over- or underpredicts the measured concentration, whereas MDAPE takes into account the absolute value of the difference and thereby represents the precision.
The concordance between measured propofol concentrations and BIS values was studied by linear regression. Gender differences during emergence were studied with the MannWhitney U-test for data sets that were not normally distributed. The values are given as mean (SD) unless stated otherwise. P-values less than 0.05 were considered significant.
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Results |
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Whereas the target serum concentration of propofol was kept constant at 2.5 µg ml1 in six patients, adjustments of the propofol TCI according to the BIS criteria were made for most patients during surgery. In five patients the target concentration was reduced to 2.0 µg ml1, in two patients it was further reduced stepwise to 1.8 µg ml1, in one patient to 1.7 µg ml1 and in one patient to 1.6 µg ml1. In the remaining six patients the target infusions had to be increased because of periods with BIS values above 60. Two of these patients had their target reduced to 2.0 µg ml1 initially, but it was later increased to 2.5 µg ml1 because of high BIS levels. One patient had her concentration reduced stepwise to 1.5 µg ml1, followed by a temporary and sudden increase in BIS to 85 during a stable phase of surgery. No movement was observed in this female patient; she did not open her eyes and did not squeeze hands on command. Blood samples were taken, and measured serum propofol concentration at the time was 2.0 µg ml1. After the target of propofol had been increased to 2.0 µg ml1, her BIS value dropped almost immediately to 55. Blood pressure and heart rate were stable during this short episode of increased BIS, with systolic blood pressure 120 mmHg, and only a slight increase in heart rate (from 50 to 65 beats min1) was noted. One male patient had his target reduced to 1.5 µg ml1 with BIS values within or slightly below the desired range throughout surgery, but shortly after the gall bladder had been removed the BIS increased rapidly to 79, and immediately thereafter he moved and opened his eyes briefly and was given a temporary increase in the target concentration of propofol. No blood samples were obtained at this point. There was no simultaneous increase in blood pressure (systolic blood pressure 110 mm Hg) and no increase in heart rate (50 beats min1) during the episode of wakefulness in this patient. One male patient had a stable target concentration of 4.0 µg ml1 throughout surgery and one female patient had a stable concentration of 3.5 µg ml1.
Remifentanil infusion during surgery was kept at a constant target of 7.5 ng ml1 until removal of the gall bladder for all 21 patients, and was kept at this concentration throughout surgery in 12 patients. In nine patients, the clinically responsible anaesthetist lowered the target to 5.0 ng ml1 after gall bladder removal.
For 16 of the patients, stable BIS values within the desired range (4560) were achieved. For the remaining five patients, the greatest BIS values recorded during surgery were just below the lower limit (two patients at BIS 43, one patient at BIS 42 and two patients at BIS 41). In one of these five patients no attempts were made to reduce the target of propofol because of quite high blood pressure throughout the procedure. The BIS values varied a lot in this female patient, with repeated minor spikes up to 50, although the values noted at the times for concordant blood sampling (and thereby included in the further analysis) were lower. For three of the patients with maximal BIS values noted below 45, the propofol targets were decreased by regular intervals according to the protocol, to 2.0, 1.8 and 1.7 µg ml1 respectively. The responsible anaesthetist was reluctant to reduce the values further because of clinical assessment of the circulation and possible sudden awakening and movement, which might have interfered with the surgical procedure. The fifth patient, who had BIS values noted slightly below the preset limits during surgery, was the male patient, who suddenly woke up after gall bladder removal with a BIS of 79. At the time of this unexpected awakening, his propofol target concentration had been stable at 1.5 µg ml1 (measured 2.8 µg ml1) for 65 min.
Pharmacokinetics
Propofol
MDPE calculated for all the propofol samples (n=115) was +60 (40)%, whereas MDAPE was 60 (38)%. The estimated vs measured propofol values are shown in Fig. 2. MDPE calculated only for those propofol samples taken before change of target (e.g. after longer periods with constant target) (n=52) was +51 (45)% and MDAPE was 51 (48)%.
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Pharmacodynamics
The measured serum propofol concentration and the corresponding BIS values are shown in Fig. 4. For the data points obtained during ongoing surgery, there was an inverse correlation between the measured propofol concentration and the BIS for these observations (r2=0.13, ß=1.4, SD(ß)=0.38, 95% CI 2.19, 0.67, P<0.001). On the other hand, regression analysis performed only for the values falling between the desired BIS levels of 45 and 60 showed no correlation (r2=0.01, ß=0.15, SD(ß)=0.34, 95% CI 0.54, 0.85, P=0.66) (Fig. 5).
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Gender differences during emergence
After the infusions were stopped, the women woke up faster than the men (6.6 (3.5) vs 11.6 (3.2) min, P<0.01). There was no significant difference between the genders in the measured concentrations of propofol or remifentanil at emergence or at the last point of measurement before stopping the infusions, and no difference in surgery time. There was no gender difference in the last measured BIS level during surgery. At emergence the BIS level for women was 94.5 (4.3) and that for men was 89.1 (7.8) (not significantly different, P=0.13).
Adverse events
One patient was given atropine 0.5 mg and two were given ephedrine 10 mg shortly after the induction of anaesthesia, because of bradycardia and hypotension respectively. Sixteen patients were given rocuronium 0.3 mg kg1 before intubation. Two of the five patients who were intubated without the use of a neuromuscular blocker had to be given a low dose (510 mg) of rocuronium bromide later to ease the surgical procedure. One patient moved and opened her eyes when the gall bladder was extracted (see above). No other patients showed any movement either spontaneously or when asked to squeeze the investigators hand during episodes with higher BIS levels. No patients had any recall of the operation when asked just after emergence, 4 h later and by telephone interview the next day.
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Discussion |
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For remifentanil, with the target set at 7.5 ng ml1, we measured actual values between 3.3 and 13.9 ng ml1. The prototype Remifusor, based on Mintos kinetic parameter set, showed no general over- or underprediction of the actual values in our study, as the MDPE was 7%, quite close to zero. The variation, though, was considerable.
TCI for remifentanil is not yet licensed for commercial use. Although more accurate, the advantages with remifentanil TCI may be less obvious because the serum concentration of remifentanil is easier to stabilize manually because of rapid and less variable elimination and distribution compared with propofol. However, compared with previous algorithms for remifentanil, the present Remifusor device with Mintos kinetics seems promising.
This huge variation in measured concentrations of anaesthetic drugs, even in a very standardized setting, suggests that serum TCI systems do not necessarily improve the precision of dosing. TCI research is developing further to target the predetermined effect-site concentration instead of plasma concentration,21 but the performance of effect-site TCI is even less studied under clinical conditions.
Despite the huge variation in measured serum and blood concentrations of the two drugs, almost all our patients experienced uneventful anaesthesia. One patient showed clinical signs of being awake followed by a sudden increase in BIS when the gall bladder was removed, but reported no awareness after surgery. Three out of 21 patients needed minor temporary cardiovascular support with ephedrine or atropine shortly after induction. The emergence times for all the patients were acceptable (maximum 18 min after termination of surgery).
Previous work has shown clearly and repeatedly that BIS differentiates between the awake and asleep states, both during normal sleep22 and during sleep induced by different anaesthetics.35 In the present study, BIS generally discriminated between the awake and asleep states. In Fig. 4 all the BIS values above 70 were obtained from patients regarded as awake, except from the one patient with the spike up to 85, who did not show other clear signs of waking up before she was given additional hypnotics. All the BIS values below 65 were obtained from patients asleep. When we included all the values during anaesthesia, there was a significant correlation between BIS and serum propofol, but the correlation is poor (0.13) and disappears if the outliers are removed. Our results do not support the idea that BIS represents a continuous measurement of depth of anaesthetic-induced hypnosis, assuming that increased serum concentrations of propofol correspond to deeper hypnotic levels. However, as we have too few data points to test the correlation between serum concentration and BIS in the individual patient, we cannot rule out the possibility that there is interindividual variation in sensitivity to propofol; a correlation could exist in the individual patient but not be seen with data from many subjects.
BIS has been proposed as a monitor to prevent awakening and awareness during general anaesthesia. One problem is that BIS measures brain activity with some delay and cannot predict what will happen in the brain. This is very well illustrated with our two patients who ended up with sudden BIS spikes instead of slow increases in BIS values when hypnotics were gradually reduced. The version of BIS available for our study (A1050, 1.21) has a delay in the recorded signal of about 45 s. In the latest version (XP) the delay is stated to be 1530 s. This delay is caused partly by data handling in the equipment, but is also due to the fact that the EEG varies considerably and constantly, and EEG values need to be collected over some time to get enough stable information for a reliable index. We did not get any warning from the BIS recording in the patient who woke up when the gall bladder was removed. The clinical signs came first, followed by an increase in BIS. There were no obvious changes in heart rate and blood pressure. If the patient had been paralysed at that time, the delayed but substantial increase in BIS could have been the only indicator of awakening. It would, of course, have been an advantage if we had had a sleep monitor able to predict sudden awakening, but in anaesthesia we do not have any monitors capable of predicting any change in the patients condition. However, the use of a sleep monitor may possibly prevent prolonged episodes of awakening, and conscious recall is probably not expected after very brief episodes of awakening.23
We could not find any relationship between the BIS values obtained before the end of anaesthesia and emergence time. We have demonstrated this absence of correlation previously in a similar study.7 We speculated whether the lack of correlation in the former study could be explained by undesirably deep anaesthetic levels, judged from the general low BIS values (mean values between 40 and 42 during surgery) and the prolonged emergence time (mean 16 min). In the present study of the same surgical procedure, the anaesthetic dosing was individually tailored with BIS values mostly above 45, resulting in a subsequent reduction in mean emergence time to 8.3 min, but still without such a correlation.
Our study confirms that women wake up faster than men from combined propofol/opioid anaesthesia. Partly because of the small sample size in this study, we cannot tell whether this gender difference is caused by a difference in pharmacokinetics or pharmacodynamics. It has been shown that females require more propofol than men during surgery,24 and recently it has been shown that women need more propofol than men to lose consciousness.25 When sampling propofol from 270 humans, Schuttler and Ihmsen26 did not find gender to be a significant covariate for propofol kinetics. More recently, however, the kinetics of propofol have been shown to differ between the two genders in the elderly.27 There is a need for more specific studies to find an explanation for the repeatedly shown faster emergence of women, and whether this gender difference is valid also for anaesthetic regimens based on other drugs.
In summary, we have shown that TCI for propofol and remifentanil gives large variations in measured serum values. When anaesthesia was adjusted to keep BIS values between 45 and 60, we found no correlation between measured values of propofol and the corresponding BIS values among the 21 patients, although BIS discriminated well between the awake and asleep states. Furthermore, the study confirms that female patients emerge more rapidly than male patients from propofol- and opioid-based anaesthesia.
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Acknowledgements |
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