In the past several years, intravenous drug administration to provide anaesthesia has become a popular alternative to inhalational anaesthesia. This increased use of total intravenous anaesthesia (TIVA) is mostly due to the newer, short-acting anaesthetics. Specifically, propofol has pharmacological properties that make it very suitable for administration by continuous infusion. Furthermore, the development of computer-assisted target-controlled infusion (TCI) systems allows a desired blood drug concentration to be set according to the pharmacokinetic profile, which is claimed to enhance controllability of intravenous anaesthetics. When using TCI devices, the anaesthesiologist defines a target plasma or effect site concentration. On the basis of the underlying pharmacokinetic model, the perfusor then adjusts the necessary infusion rate automatically. Thus, administration of intravenous anaesthesia has become more convenient and accurate than the convention manually controlled infusion (MCI) technique [1–3]. However, with the absence of objective measurement of anaesthetic depth, several studies comparing propofol TCI with MCI reported higher propofol consumption during TCI-guided anaesthesia [4,5]. In order to quantify depth of anaesthesia, bispectral index (BIS) and midlatency auditory-evoked potentials (MLAEPs) derived from analysis of the raw electroencephalogram (EEG) were introduced into routine clinical practice. BIS relates well to the hypnotic component of anaesthesia and accurately reflects the degree of clinical sedation with hypnotic agents [6,7]. MLAEPs are very sensitive to anaesthetics as well . Increasing anaesthetic depth is associated with an increase in latency of its peaks and a decrease in amplitude.
The present study was designed to further evaluate the advantages and disadvantages of propofol TCI vs. MCI. We hypothesized that, when maintaining a comparable depth of anaesthesia with BIS and MLAEPs, TCI and MCI would result in comparable propofol consumption and recovery times.
Patients and methods
After obtaining approval from the Institutional Ethics Committee of the University Hospital Schleswig-Holstein, Campus Kiel, and written informed consent, 50 ASA 1 or 2 patients undergoing elective ENT surgery were studied. Exclusion criteria were neurological diseases, hearing abnormalities and recent use of psychoactive medication. Patients with cardiovascular, respiratory, hepatic and renal diseases were also excluded. Patients were randomly allocated to one of two groups by opening of a sealed envelope. The TCI group (n = 25) received propofol by a TCI system. The MCI group (n = 25) received propofol by an MCI system.
Anaesthesia and research protocol
Oral midazolam, 7.5 mg, was given as a premedication 30 min prior to anaesthesia. In the operating room, routine monitoring (Datex Ohmeda S/5, Helsinki, Finland) including electrocardiogram (ECG), heart rate, respiratory rate, noninvasive arterial pressure (systolic, diastolic and mean), peripheral arterial oxygen saturation by pulse oximetry (SpO2) and end-tidal CO2 (etCO2) was established. BIS and MLAEPs were measured to monitor depth of anaesthesia. BIS recording was performed with a BIS-XP monitor (Aspect Medical Systems, Natick, Massachusetts, USA) with a disposable four-electrode sensor (BIS Sensor; Aspect Medical Systems). Impedance of electrodes was maintained below 7.5 kΩ to ensure BIS signal quality. BIS sampling rate was 128 Hz and its smoothing rate was set to 30 s . All patients received TIVA with propofol and remifentanil. In the TCI group, the propofol infusion was driven by a TCI device (Alaris Asena PK syringe pump; Alaris Medical Systems, Basingstoke, UK). The TCI software (Diprifusor; Zeneca Ltd, Macclesfield, UK) for the administration of propofol was based on the pharmacokinetic model according to Marsh et al. . Anaesthesia was induced with a plasma target concentration of propofol 4 μg ml−1 and a continuous infusion of 0.3 μg kg−1 min−1 remifentanil. In the MCI group, anaesthesia was induced with a bolus of propofol (2 mg kg−1), followed by a continuous infusion of 5 mg kg−1 h−1 propofol and 0.3 μg kg−1 min−1 remifentanil. If the BIS did not fall below 60 after the induction dose, an additional bolus of 20 mg propofol was given. After loss of consciousness (drop of syringe), tracheal intubation was facilitated with rocuronium (0.6 mg kg−1). No other relaxants were injected during maintenance of anaesthesia. After tracheal intubation, patients in both groups were mechanically ventilated with an air/oxygen mixture to maintain SpO2 greater than 95% and etCO2 within normal range. In all patients, surgery started 5–10 min after intubation. Starting at 1 min after intubation, in order to maintain adequate anaesthesia, the infusion rate of remifentanil and plasma target concentration of propofol (TCI group) or infusion rate of propofol (MCI group) were adjusted to keep the BIS between 40 and 60 and the mean arterial pressure (MAP) within 20% of baseline values. If the BIS was above the predefined range, propofol infusion was increased by 0.5 μg ml−1 in the TCI and 1 mg kg−1 h−1 in the MCI groups; if the BIS was below the predefined range, propofol infusion was comparably decreased stepwise in both groups. At least 10 consecutive BIS values had to be outside the predefined range before an adjustment was made. If the MAP was more than 20% from baseline value while the BIS was in the predefined range, remifentanil was increased by 0.1 μg kg−1 min−1, and if the MAP was below 60 mmHg three times in a row, a bolus dose of Akrinor (0.5 ml; theoadrenaline and cafedrin) was given. Coughing and movement were carefully observed during the surgical procedure. Infusions of propofol and remifentanil were stopped at the end of surgery, and this moment was identified as the starting point of patient recovery. After extubation, the patient was transferred to the postanaesthesia care unit (PACU).
Time of intubation, end of propofol administration, eye opening on command, extubation, discharge to PACU and discharge to ward were also recorded. In addition, the total duration of anaesthesia and total amounts of propofol and remifentanil during anaesthesia were documented. On the day after surgery, all patients were interviewed about awareness and memory during the perioperative period by an anaesthesiologist unaware of the type of anaesthesia performed.
Auditory-evoked potential data acquisition and measurement
The AEP/EEG Module S/5 (AEP/EEG plug-in Module S/5; Datex Ohmeda S/5) was used for auditory stimulation, recording and analysis of evoked potentials. After defining the individual hearing threshold, stimulus intensity was adjusted to about 70 dB above the individual threshold and kept constant throughout the study. Baseline recording was replicated twice. An 8.1 Hz stimulus frequency was applied and 1000 stimuli responses were averaged using binaural randomized click stimulation via earphone. Moreover, automatic artefact rejection and 30 Hz bandpass filtering were performed previously to extract AEP. AEP waveforms were recorded on two amplifier channels using zinc/lead cup electrodes placed over Cz (international 10–20 system) and the bilateral mastoid . Impedance of all electrodes was maintained below 5 kΩ. During the first 10 ms after stimulation, the brainstem AEP is generated and includes Roman numeral I–VI waves. The brainstem component V is thought to represent successive synapses in the auditory pathway . If peak V could not be determined, the following MLAEP waveform was not used in further analysis. A poststimulus period with latency of 10–100 ms, corresponding to MLAEP, was analysed. The following latencies were obtained: two negative components (Na and Nb) and one positive peak in between (Pa). The peak-to-peak amplitudes NaPa and PaNb were measured.
MLAEP recording started before anaesthesia in order to obtain baseline data in the awake situation (baseline). Then, MLAEP recording was performed immediately after intubation and every 15 min during anaesthesia. The final MLAEP recording was performed when the patient met PACU discharge criteria (postanaesthesia recovery score ≥9) .
Determination of propofol concentration by high-performance liquid chromatography
Blood samples were taken from the antecubital vein on the contra lateral side from the propofol infusion site at baseline awake (T1), at intubation (T2), 15 min after intubation (T3) and at extubation (T4) and were placed into vials containing ethylenediaminetetraacetic acid (EDTA). All blood samples were centrifuged at 3000 rpm for 10 min to separate plasma, followed by detection of the propofol concentration by high-performance liquid chromatography (Merck, Darmstadt, Germany). The limit of quantification in our laboratory is 0.05 μg ml−1 propofol. Interassay variability was calculated as 6.1% and intraassay variability as 3.2%. Assay linearity was tested in samples containing 0.05–10 μg ml−1 propofol. The recovery of propofol from spiked plasma samples from the lowest to the highest concentration ranged from 98 to 100% (n = 8).
Statistical comparisons were performed using SPSS for Windows, version 12.0 (SPSS Inc., Chicago, Illinois, USA). Sample size was calculated based on two previous studies [4,12] and was sufficient to detect a mean difference in propofol consumption of 1.5 mg kg−1 h−1 between groups with 80% power and an α error of less than 0.05. Data are given as mean (SD) unless indicated otherwise. Differences within a study group were evaluated by one-way analysis of variance (ANOVA). Significance of differences between study groups was tested by two-way ANOVA, factoring for time and treatment group (TCI vs. MCI). The percentage performance error was calculated as
where Cmeasured and Cpredicted are the simultaneously measured and predicted drug concentrations, respectively. Also, median performance error (MDPE) and the median absolute performance error (MDAPE) were calculated for all propofol samples. MDPE is a value indicating whether the TCI pump overpredicts or underpredicts the measured concentration, whereas MDAPE represents the absolute value of the difference and thereby indicates the precision. In order to report the interpatient range of deviation and to identify possible outliers, these measures of deviation were also calculated for each individual patient. Correlation between measured and predicted propofol plasma concentration and between measured propofol plasma concentration and EEG-derived variables was performed with Spearman's rank correlation. The influence of different propofol administration modes (TCI vs. MCI) on haemodynamics was analysed by calculating mean ± SD of all blood pressure values obtained during anaesthesia in each individual patient followed by comparison of SDs between groups. Also, for each patient, the mean BIS between intubation and the end of anaesthesia was calculated, and the population mean and SD of this intra-anaesthesia BIS in the two groups was compared. Further, as a measure for the constancy of the EEG effect, the wobble (wobble is a measure of intraindividual variability during a certain period) of BIS in each patient in this period was calculated . A P value of less than 0.05 was considered statistically significant.
There were no significant differences between the TCI group and the MCI group with regard to age, sex, height and weight (Table 1). Induction time (time from the start of propofol infusion to intubation) and duration of anaesthesia did not show any difference between the two groups (Table 2). Also, time of eye opening, extubation, discharge to the PACU and discharge to the ward were not significantly prolonged in the TCI group compared with the MCI group (Table 3).
Propofol consumption during anaesthesia did not differ between groups (induction dose, mean ± SD: TCI, 2.09 ± 0.36 mg kg−1; MCI, 2.06 ± 0.16 mg kg−1; total dose: TCI, 5.57 ± 0.96 mg kg−1 h−1; MCI, 5.79 ± 0.87 mg kg−1 h−1). Only two patients in the MCI group required an additional propofol bolus. The use of remifentanil also did not show any difference (Table 2).
The BIS decreased from more than 90 in both the groups at baseline to (mean ± SD) 40 ± 6 in the MCI patients and 41 ± 7 in the TCI patients at intubation. Then, BIS values were always maintained between 40 and 60 and did not differ between the two groups during maintenance of anaesthesia (the time from intubation to the end of propofol infusion). The mean BIS between intubation and the end of anaesthesia (intra-anaesthesia BIS) calculated in each patient and summed up to a population mean was 44 ± 3 in the TCI group and 44 ± 4 in the MCI group (P = NS). There was also no difference with respect to the wobble of intra-anaesthesia BIS values calculated in each individual in the TCI and MCI groups (Fig. 1).
After the end of the propofol infusion, there was a gradual increase in BIS. When patients followed a verbal command to open their eyes, the average BIS ( ± SD) was 73 ± 4 in the MCI group and 73 ± 4 in the TCI group (P = NS). In the PACU, if patients met the criteria for discharge to the ward, the BIS was similar to baseline values (Fig. 2).
The latency of Pa and Nb at awake, during maintenance of anaesthesia, after extubation and at discharge to the ward for the TCI and MCI groups are presented in Fig. 3. Changes of MLAEP latency were similar in both the groups. During maintenance of anaesthesia, the latency of both Pa and Nb increased significantly compared with baseline awake (P < 0.01). After extubation, the latency of peaks Pa and Nb significantly decreased and basically returned to baseline level. There was a moderate correlation between Pa and Nb values and measured propofol plasma concentration (r = 0.48 and r = 0.46, P < 0.0001). SDs of all BIS values obtained from individual patients in both the groups (n = 50) were significantly (P < 0.0001) lower than the respective values of Pa and Nb, with Nb showing the largest data variability (P < 0.0001 vs. BIS and Pa; Fig. 4).
The MDPE calculated for the propofol samples (n = 44) was more than 24 (54)%, whereas the MDAPE was 42 (41)%. The predicted vs. measured propofol values are shown in Fig. 5. The MDPE calculated only for the propofol samples taken 15 min after intubation (after the first adjustment of the propofol target concentration) (n = 22) was more than 35 (56)% and MDAPE was 40 (52)%. The MDPE and the MDAPE values calculated for each individual patient in the TCI group are shown in Fig. 6.
The measured plasma propofol concentration and the corresponding BIS values are shown in Fig. 7. For all data points obtained, there was an inverse correlation between the measured propofol concentration and BIS values [r = −0.56, 95% confidence interval (CI) −0.6676 to −0.4260, P < 0.001]. To account for any correlation falsely yielded by data inhomogeneity, we also analysed correlation only for BIS values within the recommended range (40–60). No correlation was found for these values (r = −018, 95% CI −0.4091 to 0.06233, P = 0.13; Fig. 8).
There were no differences in the measured concentration of propofol between the two groups (Table 4) throughout the study period. Fifteen minutes after intubation, the measured concentration of propofol in the TCI group was significantly higher than the predicted concentration at this time point (P < 0.05) (Table 4). At the same time, the measured concentrations of propofol ranged from 1.8 to 6.5 μg ml−1, whereas the predicted plasma concentration ranged from 2.0 to 2.5 μg ml−1 in the patients in the TCI group. There was no correlation between the measured and the predicted propofol plasma concentrations in the TCI group (r = 0.14, P = 0.37; Fig. 5). Number of adjustments made also did not differ between [median, 25th–75th percentile (range)] the TCI group [4, 2–5 (1–7)] and the MCI group [3, 1.5–11.5 (1–11)]. Blood pressure variability did not show any difference between groups during anaesthesia.
No patient showed any sign of possible inadequate anaesthesia, such as coughing or movement throughout the study period. No patient reported intraoperative recall at the postoperative visit.
Owing to its favourable pharmacokinetic properties with rapid onset and elimination, propofol is an ideal agent for the induction and maintenance of intravenous anaesthesia. TCI was designed to control the level of anaesthesia by choosing a specific blood concentration. Previous studies have shown advantages compared with MCI with respect to haemodynamic and respiratory stabilities [4,14]. On the contrary, however, TCI resulted in higher propofol consumption and delayed recovery [4,5], probably due to inaccurate prediction of propofol effect site concentration.
In the present study, the measured plasma concentration of propofol (2.8 ± 1.2 μg ml−1) at 15 min after intubation was significantly higher than the predicted concentration (2.2 ± 0.2 μg ml−1). A great variation from 1.8 to 6.5 μg ml−1 in the measured plasma concentrations of propofol was also shown. Moreover, there was no correlation between the measured and the predicted propofol plasma concentrations. This finding is in agreement with the results of other investigators who also found a great difference between the predicted propofol blood concentration and the measured propofol concentration. Hoymork et al. showed that, while the propofol TCI was set at 2.5 μg ml−1, the actual propofol value was between 2.2 and 8.1 μg ml−1. A similar bias was shown in a study of 18 human volunteers, in which the actual propofol plasma concentration showed a wide range (0.44–1.38 μg ml−1) when 1 μg ml−1 had been targeted . It was therefore suggested that TCI is not very precise in clinical routine. Consequently, this inaccuracy may result in excess propofol dosing or underdosing, which could cause adverse clinical events including haemodynamic compromise, movement and awareness. It is not unavoidable, however, that the inaccuracy of TCI will produce adverse events by underdosing or overdosing because there is also interindividual variability in the pharmacodynamics. In addition, the inaccuracy is not caused by the TCI system but by the interindividual variability in the pharmacokinetics . Therefore, one will most probably also achieve quite different concentrations in different patients with manual control if propofol is administered with an identical bolus dose or infusion rate. Consequently, it may be advantageous to adjust the TCI target based on pharmacodynamic observations. Our results suggest that occurrence of possible adverse events may be prevented by monitoring the depth of anaesthesia with the BIS.
In ENT surgery, TIVA with propofol combined with an opioid is often performed. It was suggested that target propofol concentrations should vary from 4.0 to 8.0 μg ml−1 for induction of anaesthesia. In this study, the initial target propofol concentration was 4.0 μg ml−1. Our results demonstrated that TCI and MCI both ensured adequate induction of anaesthesia with similar induction dose and time.
The BIS has been shown to have high sensitivity and objectivity to assess the depth of anaesthesia during maintenance of anaesthesia, with BIS values ranging between 40 and 60 reflecting an adequate depth of hypnosis. However, Sebel et al. indicated that, during co-administration of hypnotics and opioids, BIS predicts movement in response to surgical stimulation less reliably. Therefore, in our study, MLAEPs were used to evaluate adequacy of anaesthesia simultaneously. Several studies indicated a close relationship between MLAEPs and intraoperative movement and awareness. Schwender et al. proved that a threshold MLAEP peak Nb latency of 60 ms is most predictive of movement during anaesthesia. An increase in MLAEP Pa latency of greater than 12 ms may identify the absence of implicit memory postoperatively . In the present study, irrespective of whether TCI-based or MCI-based anaesthesia was performed, a BIS level of 40–60 was always maintained. Also, the increase in Pa latency was greater than 15 ms and the latency of Nb was prolonged more than 70 ms. These results show that both TCI and MCI provided adequate anaesthesia. Furthermore, similar depth of anaesthesia in the two groups was achieved with no significant differences in BIS values and MLAEP components between the TCI and MCI groups. Consequently, TCI and MCI did not differ significantly with respect to propofol administration including induction dose and infusion rate during anaesthesia. In contrast, several studies reported that TCI significantly increased the propofol dose used compared with MCI when titrated to haemodynamic response [3,4,7,20,21]. This was explained, at least in part, by the more rapid adjustment of the drug plasma concentration with TCI systems, achieving a deeper level of anaesthesia in a shorter period . Breslin et al. also indicated that, despite similar haemodynamic parameters between the TCI and MCI groups, TCI patients had a greater depth of anaesthesia associated with a higher propofol infusion. It was suggested that anaesthesia titrated to haemodynamic parameters results in an overshoot in propofol blood and effect site concentration with TCI. In a recent study in patients with severely reduced left ventricular function, TCI patients needed more inotropic support with dobutamine than MCI patients, which was closely related to the increased propofol dose in the TCI group . Accordingly, our findings also indicate that propofol infusion guided by BIS may result in a more appropriate dose and provide safer anaesthesia. Interestingly, there was only a moderate correlation between BIS values and propofol plasma concentration. More importantly, this correlation disappeared when only BIS values in the predefined range (40–60) were included. This observation is also in agreement with previous results of other studies either that discourage the idea that BIS represents a continuous measurement of depth of anaesthesia or that indicate that there is interindividual variation in sensitivity to propofol . One should keep in mind, however, that the propofol plasma concentration itself is also not a measure of depth of anaesthesia. It should be noted that BIS values above 75 were obtained in awake patients without supplemental remifentanil, whereas the remaining BIS values were obtained in anaesthetized patients during remifentanil administration, possibly distorting the correlation between BIS and propofol plasma concentration. This holds comparably true for the correlation between propofol plasma concentration and the BIS values in the recommended range (40–60), as these BIS values were also obtained during remifentanil administration. As we have too few data points in individual patients, we cannot comment on this issue but rather believe that further research in this field is warranted.
During recovery, there were no differences in total propofol dose and the propofol infusion rates between the groups resulted in similar time of emergence, extubation and discharge to the ward. BIS and MLAEPs both appeared to be able to differentiate between the awake and anaesthetized state. Both measurements showed higher awake values before anaesthesia and on emergence than values recorded during anaesthesia. After discontinuing anaesthesia, BIS values increased gradually. No patient recovered consciousness with a BIS less than 62. The SD of BIS values obtained from individual patients was significantly smaller than those of MLAEPs. This does not support the assumption that MLAEPs show a clearer cut or threshold like behaviour, whereas BIS reflects depth of anaesthesia in a more gradual fashion. More importantly, we found MLAEPs of only limited use in the operating theatre, as MLAEPs have to be obtained intermittently and need considerable time (approximately 2–3 min) to generate a response. Also, MLAEP curves have to be analysed manually, which may introduce interobserver bias and requires a considerable time for training. Compared with continuous display of BIS values, MLAEPs are too slow to detect rapid changes in anaesthetic depth from unconsciousness to consciousness, which limits its clinical application during emergence.
Some limitations to this study should be noted. We performed the current study in patients undergoing routine ENT surgery, and a crticism may be that manipulation of the head and neck means that EEG-derived measures such as BIS and MLAEPs are prone to artefacts. In our experience, however, artefacts are not a major problem for either EEG or AEP, as, in our ENT department, only bipolar electrocautery is used (causing little interference). More importantly, the ENT surgeons kindly stopped electrocautery or moving the patient's head during AEP measurements.
In the present study, there was no correlation between measured propofol concentrations and BIS in the range of 40–60. However, this was found in a pooled analysis. For BIS-guided titration of propofol during anaesthesia, it is crucial that there is an individual correlation between propofol plasma concentration and BIS. An individual correlation analysis of propofol plasma concentration and BIS, however, was not feasible in the present study, as there were only three propofol concentrations measured in each patient. Similarly, it is conceivable that there exists a correlation between Cpredicted and Cmeasured in the individual patient, which is distorted by interindividual variability in clearance and distribution volume, if data of different individuals are examined in a pooled analysis. Finally, only one attending anaesthesiologist performed all procedures. As he was experienced with both the TCI and MCI techniques (>200 anaesthesias performed with each), we cannot comment on results obtained by novice users.
In summary, both TCI and MCI propofol administrations were associated with good controllability, haemodynamic stability and early recovery. During BIS-controlled depth of anaesthesia, there was no difference with regard to both propofol and remifentanil requirement between groups.
G.C. has received an unrestricted research grant from DRAEGER MEDICAL, AG, Luebeck, Germany.
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