CHR Citadelle, University Department of Anaesthesia and Intensive Care Medicine, Liège, Belgium
* Corresponding author. E-mail: pol.hans{at}chu.ulg.ac.be
Accepted for publication November 10, 2004.
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Abstract |
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Methods. Twenty-two women undergoing gynaecological surgery were enrolled in this double-blind, randomized study. Anaesthesia was induced i.v. and maintained with sevoflurane. Under stable surgical and anaesthetic conditions, patients were assigned to receive either a bolus of ketamine 0.5 mg kg1 or the same volume of saline. Blood pressure, heart rate, BIS, RE and SE were measured every 2.5 min from 10 min before (baseline) until 15 min after ketamine or saline administration. The maximum relative increase in BIS, RE and SE compared with baseline was calculated for each patient. Values are mean (SD).
Results. Baseline values were BIS 33 (4), RE 31 (5), SE 30 (5) for the ketamine patients and BIS 35 (3), RE 33 (5) and SE 32 (6) for the patients receiving saline. BIS, RE and SE increased significantly from 5 min (BIS) and 2.5 min (RE and SE) after ketamine administration, peaking at 46 (8) (BIS), 52 (12) (RE) and 50 (12) (SE) respectively. The maximum relative increase in RE [42.2 (10.4%)] and SE [41.6 (10.9)%] was higher than that of BIS [29.4 (10.4%)]. Blood pressure, heart rate and RESE gradient did not change in either group.
Conclusions. Ketamine administered under sevoflurane anaesthesia causes a significant increase in BIS, RE and SE without modification of the RESE gradient. This increase is paradoxical in that it is associated with a deepening level of hypnosis.
Keywords: anaesthetics i.v., ketamine ; monitoring, Bispectral Index ; monitoring, spectral entropy
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Introduction |
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Ketamine is an old drug from the anaesthetist's armamentarium and is currently used at low doses as an adjunct to improve perioperative analgesia by preventing acute opioid tolerance and postoperative hyperalgesia in surgical patients.911 When administered during propofol anaesthesia, it has been reported to increase BIS significantly despite a deepening level of hypnosis.12 13 In these conditions the relationship between BIS and hypnotic depth is modified, which could bias BIS-guided administration of hypnotic agents. Because spectral entropy, such as BIS, is an electroencephalographic measure of the hypnotic effect of anaesthetic drugs, we were interested in comparing the effect of ketamine on BIS, RE and SE during surgery under sevoflurane anaesthesia.
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Patients and methods |
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Premedication consisted in alprazolam 0.5 mg and atropine 0.5 mg given orally 1 h before surgery. Upon arrival in the operating theatre, non-invasive blood pressure monitoring, electrocardiography and pulse oximetry were instituted in all patients (Datex-OhmedaTM S/5TM, Helsinki, Finland). BIS was monitored using the XP device (version 4.0) and a specific quatro sensor (Aspect Medical Systems, Newton, MA, USA and Leiden, The Netherlands). RE and SE were monitored with the Datex-Ohmeda S/5 Entropy Module (M-EntropyTM), using a specific entropy sensor (Datex-Ohmeda Division, Instrumentarium Corporation, Helsinki, Finland). Both sensors were applied appropriately to the patient's forehead, one on each side.
In all patients, general anaesthesia was induced with propofol 1.5 mg kg1 and sufentanil 0.15 µg kg1, tracheal intubation was facilitated with rocuronium 0.5 mg kg1 and maintenance of anaesthesia was achieved with sevoflurane 2% end-tidal concentration vaporized in airoxygen (50% inspired fraction). Throughout the procedure, end-tidal was monitored and maintained in the 3540 mm Hg range. No supplementary dose of muscle relaxant was administered before the end of the study period. Under steady-state anaesthetic and surgical conditions, patients received either a bolus of ketamine 0.5 mg kg1 (group K; n=12) or the same volume of normal saline (group S; n=10). According to the randomization process, under the responsibility of a first certified anaesthetist, patients who were operated on on even days received ketamine and those operated on on odd days received saline. A second anaesthetist was in charge of conducting the anaesthetic procedure and was blinded to the randomization and to the syringe containing ketamine or saline. Mean arterial blood pressure (MAP), heart rate (HR), RE and SE were recorded automatically every 2.5 min from 10 min before (baseline conditions) until 15 min after ketamine or saline administration by the Datex-Ohmeda S/5 monitor. A numerical report was printed from the monitor at the end of the procedure. The anaesthetist in charge of the procedure collected BIS data manually each time the automatic non-invasive blood pressure measuring device started measurement (automatic interval time of 2.5 min). The first five values recorded in each patient were averaged to obtain baseline values. The baseline period of recording started 30 min after induction of anaesthesia on average, when all the following criteria were met: stable 2% end-tidal sevoflurane concentration for at least 10 min; stable haemodynamic parameters; full pneumoperitoneum installed in case of laparoscopic surgery; surgical retractors in place in case of laparotomy; and first stages of surgical dissection started in all cases. The difference between RE and SE (RESE gradient) was calculated at each time point.
Data were expressed as mean (SD) and analysed using two-way mixed-designed analysis of variance (ANOVA) and Tukey's honestly significant difference (HSD) test for post hoc comparisons. Normality of distribution was checked when appropriate. Maximum relative increases in BIS, RE and SE, expressed as a percentage of baseline, were calculated using the formula 100x[(maximum observed increasebaseline)/maximum increase] and compared using Bonferroni-corrected Wilcoxon tests. P<0.05 was considered statistically significant. Power calculation was performed using G-Power software (version 2.0; Franz Faul & Edgar Erdfelder, Trier, Germany).14 For the RESE gradient, a clinically relevant difference of 10, a standard deviation of 2 and a Bonferroni-corrected value of 0.001 were chosen. Regarding MAP and HR, the clinically relevant difference was set at 30 mm Hg and 30 beats min1, respectively, the standard deviation at 15, and the same
value was used.
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Results |
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Discussion |
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The increase in BIS induced by ketamine has already been described in patients under propofol anaesthesia.12 13 In the study by Vereecke and colleagues, BIS increased a few minutes after the administration of ketamine 0.4 mg kg1 and then decreased progressively in spite of ketamine being continuously infused at 1 mg kg1 h1.13 In the present study, the increase in BIS was noted 5 min after ketamine 0.5 mg kg1 and remained statistically significant up to 15 min after ketamine administration in the absence of a continuous infusion. The fact that BIS remained elevated for a longer time in our study may be related to methodological differences in ketamine administration or to the presence of surgical stimulation during our period of recording. The magnitude of BIS increase in our study is comparable to that observed by Hirota and colleagues12 after a bolus of ketamine 0.4 mg kg1 [from 44 (1) to 59 (1)]. Baseline BIS values, which were considerably lower in our patients under sevoflurane anaesthesia than in the patients studied by Hirota and Vereecke, who received a propofol infusion, reflect a deeper level of hypnosis. Under the above-defined stable surgical and anaesthetic conditions, the increase in BIS after ketamine is probably related to the effect of this drug on the EEG. The BIS algorithm was elaborated from the statistical analysis of an EEG data bank, allowing identification of parameters significantly correlated to anaesthetic agent concentration and patient reactivity. Those parameters take into account the amount of suppression of activity, ß power and slow synchronized activity of the EEG. Each parameter is given weighted coefficients to obtain a linear relationship between BIS on the one hand and plasma concentration of the anaesthetic agent and clinical response of patients on the other hand.15 The hypnotic effect of ketamine is characterized by a dissociative mechanism, and this drug has been shown to increase activity of the EEG.16 The BIS increase in response to ketamine is paradoxical in so far as the anaesthesia level is deepened by the administration of an additional anaesthetic agent. However, as discussed by Sleigh and Barnard,17 BIS must be considered to reflect cortical activity rather than the level of consciousness.14 Ketamine administered in patients anaesthetized with GABAergic agents that depress cortical activity, such as propofol or sevoflurane, induces a change in the EEG pattern towards higher frequencies and desynchronization. This modification is reflected in a BIS increase and has no relationship with anaesthetic depth.
The increase in entropy observed after ketamine is not surprising since entropy, like BIS, quantifies the degree of regularity or synchronization of EEG frequency signals. This increase reflects some desynchronization of the EEG signal resulting from the dissociative action of ketamine rather than any lightening of the anaesthetic depth. As noted for BIS, baseline entropy values in our patients were lower than those usually considered to reflect appropriate depth of anaesthesia (below 60). Those low values reflect the deep level of anaesthesia provided by 2% end-tidal sevoflurane in the absence of major surgical stimulation. Ketamine administration did not change the gradient between RE and SE, which remained very low during the study period [overall mean 1.4 (2.3), range 014]. This absence of modification of the RESE gradient by ketamine under sevoflurane anaesthesia can be accepted with a reasonably low risk of type 2 error (power >0.9).
Regarding the maximum relative increase of the recorded variables after ketamine, those of RE and SE were significantly higher than that observed for BIS. The reason for this difference probably relies on the calculation algorithm of these variables, but a clear understanding would also require further investigation with simultaneous EEG recording and analysis to determine what EEG component is affected by ketamine administration.
A potential limitation of this study is that the results might have been affected by surgical stimulation. This cannot be considered a major concern. Indeed, baseline parameters were recorded for 10 min during surgery before patient randomization, and therefore constitute a valid control for statistical comparisons. Stability of recorded parameters was checked before ketamine or saline administration, during the baseline period of recording. In addition, patients underwent a moderately painful procedure and no difference was observed in blood pressure and heart rate between the two groups at any time throughout the study. Finally, the time points of recording were similar in the two groups. Vanluchene et al. have demonstrated that BIS, RE and SE are fairly good measures of anaesthetic drug effect during propofol-alone anaesthesia.7 The same has been demonstrated when using sevoflurane alone.18 19 However, the relationship between depth of anaesthesia and EEG-derived indices is less clear during surgery and during concomitant use of more than one anaesthetic agent.20 In these circumstances, correct interpretation of the indices must take into account the effect-site concentration of anaesthetic agents, their interactions and the intensity of painful stimulation.21 In the present study, the recording period can be assumed to reflect a stable balance between anaesthetic regimen and surgical stimulation, as indicated by low baseline values of BIS, RE and SE with small standard deviations. The administration of ketamine introduces an additional potentially confounding factor for correct interpretation of the recorded indices, as it not only modifies the balance between anaesthetic regimen and surgical stimulation towards a deeper anaesthetic level, but also increases the recorded EEG-derived indices.
The choice of the ketamine dose was guided by the studies investigating the effect of ketamine on BIS that have already been cited.12 13 Furthermore, as ketamine is recommended to prevent opioid tolerance and improve postoperative analgesia,911 our study was designed to mimic a clinically relevant situation. In such circumstances, practitioners must be aware that ketamine administration impairs the interpretation of BIS and entropy monitoring.
Another limitation could be related to a difference in the degree of muscle relaxation between groups. Although this cannot be definitely ruled out in the absence of neuromuscular monitoring, such an eventuality is not likely. Data were recorded after a similar delay from the muscle relaxant induction dose in all patients and no additional dose of muscle relaxant was administered thereafter. We can therefore assume a similar degree of recovery of neuromuscular function in both groups on average. The XP version of BIS has been improved from previous BIS versions for optimal EMG activity rejection. BIS has been shown to vary according to muscle relaxation in awake and sedated patients,22 23 but Greif and colleagues have demonstrated that non-depolarizing muscle relaxation does not affect BIS in deeply unconscious patients.8 Calculation of state entropy is based on a frequency range that does not include the frequency band of EMG activity and response entropy does take into account facial EMG activity. A between-groups difference in EMG activity would have affected RESE gradient rather than state entropy. The mechanism of the increase in BIS and entropy after ketamine administration was not the primary goal of the present study. However, these arguments suggest that this increase cannot be reasonably explained by the ability of ketamine to increase muscle tone.24 Even if this were the case, it remains that BIS and entropy increase in response to ketamine administration, and this must be taken into account when assessing hypnotic depth with those parameters.
We conclude that, during surgery, ketamine administered as a bolus in patients under sevoflurane anaesthesia increases BIS and entropy of the EEG used to monitor hypnotic depth, despite a deepening level of anaesthesia. Regardless of the mechanism, this increase modifies the relationship between these parameters and the hypnotic component of anaesthesia. Ignoring this effect could lead to inappropriately deepening anaesthesia and overdosing of hypnotic agents. Further studies are needed to determine if this effect of ketamine on spectral entropy is dose-dependent and if it can be observed to the same extent when varying the balance between hypnosis, analgesia and surgical stimulation.
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References |
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