Multi-level approach to anaesthetic effects produced by sevoflurane or propofol in humans: 1. BIS and blink reflex
1 Department of Anaesthesia, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6500 HB Nijmegen, The Netherlands
2 Department of Anaesthesia and Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium
3 Department of Clinical Neurophysiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
* Corresponding author. E-mail: j.mourisse{at}anes.umcn.nl
Accepted for publication March 19, 2007.
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Abstract |
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Background: The relative roles of forebrain and brainstem in producing adequate anaesthesia are unclear.
Methods: We simultaneously analysed the effects of sevoflurane (Group S; n = 18) or propofol (Group P; n = 29) on the bispectral index (BIS) and the first component of the blink reflex (R1). The dose of anaesthetic agent was increased until loss of blink reflex. After discontinuation and reappearance of blink reflex activity, the amount was increased again. The area under curve R1 (area-R1) of the electromyogram of the orbicularis oculi muscle after electrical stimulation of the supraorbital nerve was measured. Using a sigmoid Emax model and a first-order rate constant ke0, we characterized the dose–response relationships for BIS and area-R1.
Results: Concentration-dependent depression of BIS and area-R1 was adequately modelled. The concentration that causes an effect midway between minimum and maximum (EC50) for area-R1 was smaller than EC50 for BIS in both groups [0.34 (0.19) vs 1.29 (0.19) vol% and 1.78 (0.65) vs 2.69 (0.67) µg ml–1; mean (SD)]. At doses of sevoflurane and propofol with equivalent depression of BIS, sevoflurane depressed area-R1 more than propofol. The ke0 for area-R1 was about half that for BIS in both groups: 0.24 (0.19–0.29) vs 0.48 (0.38–0.60) min–1 for Group S; 0.28 (0.23–0.34) vs 0.46 (0.40–0.54) min–1 for Group P, geometric mean (95% CI).
Conclusions: The blink reflex (brainstem function) is more sensitive to sevoflurane or propofol than BIS (forebrain function). Sevoflurane suppresses the blink reflex more than propofol. Different ke0s for blink reflex vs BIS indicate different effect sites.
Keywords: anaesthetic volatile; sevoflurane; anaesthetics i.v., propofol; monitoring, bispectral index; monitoring, depth of anaesthesia
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Introduction |
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Hypnosis and immobility after noxious stimulation may be separate components of general anaesthesia. Hypnotic effects of anaesthetics occur in the forebrain, whereas immobilizing effects occur mainly at the level of the spinal cord.1 Therefore, adequacy of anaesthesia must be measured at least at both sites. Our aim is to assess simultaneously the relative roles of forebrain and brainstem in humans. The brainstem is the source for all cranial nerves that deal with sensory and motor function in the head and neck. The bispectral index (BIS) was used in the present study as an indicator of the level of hypnosis.
An electrically evoked blink reflex was used to assess brainstem function. The traditional eyelash reflex, commonly used as a clinical endpoint of anaesthesia induction, is initiated by a non-standardized stimulus and is evaluated by subjective observation. With the use of electrical stimulation and electromyography (EMG), the stimulus is standardized, the response is objectively recorded, and additional information is obtained. We used the early ipsilateral reflex component (R1), which is less depressed by sedatives and anaesthetics than the late bilateral components R2 and R3.2–4
We have assessed the relationships between varying concentrations of sevoflurane or propofol and two surrogate anaesthetic measures, BIS and blink reflex, using pharmacokinetic–pharmacodynamic (PKPD) modelling, yielding two important measures: the concentration that causes an effect midway between minimum and maximum (EC50) and the rate constant of equilibration between end-expired (or plasma) and effect-site concentrations (ke0).
We focused on answering four specific questions. (1) Which of the two anaesthetic measures, the blink reflex or BIS, is more sensitive? (2) Is the blink reflex more sensitive to either sevoflurane or propofol? (3) Does the ke0 for the blink reflex differ from that for BIS? Different values for ke0 may be an argument for distinct anatomical substrates, and thus different effect sites, for the two measures of anaesthetic effect. (4) Is the blink reflex a good candidate to detect awareness or to assess immobility?
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Methods |
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Fifty-four patients, aged >18 yr, ASA I or II, undergoing elective plastic and reconstructive surgery, participated in this study. They had no neurological or ophthalmic disease, and did not use analgesics, psychotropic agents, or excessive amounts of alcohol. The Hospital Ethical Committee approved the study, and all subjects gave informed, written consent. No premedication was given. The study took place in a quiet, warm anaesthesia induction room. Before the start of the study, the patient was prepared as usual for anaesthesia (i.v. access, ECG, non-invasive blood pressure measurement, pulse-oximeter). The patient lay in bed with eyes closed.
One of the supraorbital nerves was stimulated transcutaneously to obtain blink reflexes. Paediatric ECG monitoring electrodes were cut to an ellipse to fit above (anode) and beneath (cathode) the eyebrow (Red Dot, 3M, St Paul, MN, USA). Only adhesive material was removed. The cathode was placed over the supraorbital notch (Supplementary Figure).
The supraorbital nerve was stimulated every 15 s throughout the study, using a pair of constant-current, square-wave pulses of 0.1 ms duration and 5 ms interstimulus interval. The stimulus was delivered by a multi-channel EMG system (Medelec Synergy, Oxford Instruments, Abingdon, UK).
The resulting EMG signals were recorded from the orbicularis oculi muscles of both eyes through surface electrodes (silver disc diameter 9 mm). The active electrode was placed in the middle of the inferior rim of the orbit and the reference electrode was placed halfway on the eye–ear line. A ground electrode was placed under the chin. Before the application of electrodes, all skin surfaces were cleaned with alcohol, and electrodes were coated with conductive paste (Mingograf, Siemens-Elema AB, Sweden) (electrode impedance <8 k
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The EMG recording of an electrically evoked blink reflex shows three components, namely R1, R2, and R3 (Fig. 1). The anatomy and neurophysiology of the blink reflex are reasonably well known.2–4 The first or early response (R1) is brief and occurs after a latency of about 10 ms on the side of the stimulation. Clinically, this response is not visible.5 The second response (R2) has a latency of about 30 ms, which is more prolonged and bilateral.6 The R2 response causes contraction of the orbicularis oculi muscle.5 A third response (R3), produced bilaterally, occurs after strong stimulation,7 has a latency of around 75–90 ms, and is more related to a startle reaction. Neurophysiological studies report that the R1 component of the blink reflex is stable in the awake, normal human2 and in subjects receiving nitrous oxide for at least 30 min.8
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We first sought for the optimal stimulus intensity by gradually increasing the current until visual observation of the EMG showed that, in the presence of a clearly visible R3 component, the R2 component ceased to increase. This stimulus intensity was then maintained throughout the study. The multi-channel EMG system recorded and stored EMG signals from both orbicularis oculi muscles. Band pass filters were used (20 Hz–3 kHz). Sweep duration was 200 ms and sensitivity 200 µV.
A BISXP monitor (A-2000; software version 4.0) calculated the BIS with 15 s smoothing rate. Electrodes (BISXP sensor, type standard) were applied according to the instructions of the manufacturer. BIS data were stored every 5 s using AK2logger (Aspect Medical Systems, Newton, MA, USA).
The level of sedation and anaesthesia was assessed clinically using an observer's assessment of anaesthesia and sedation scale (OAAS), which is a modification of the observer's assessment of alertness/sedation scale (OAA/S) score.3 9 A score of 5 corresponds with readily responding to name spoken in normal tone, 4 with a lethargic response, 3 is a response only after name is called loudly or repeatedly, 2 is a response only after prodding or shaking, and 1 is no response after prodding or shaking. Loss of consciousness (LOC) was defined as reaching an OAAS of 2, and return of consciousness (ROC) as reaching—in the reversed direction—an OAAS of 3.
Control blink reflexes, BIS, and OAAS were recorded during 3 min before administration of sevoflurane or propofol.
Using a tight-fitting facemask, 20 consecutive patients inhaled sevoflurane (Group S) delivered by a vaporizer (Tec 5, Ohmeda, Madison, WI, USA) into a circle system (Cicero, Dräger AG, Lubeck, Germany) with a fresh-gas flow of 5 litre min–1 oxygen. The vaporizer setting was increased by 1 vol% every 3 min. End-expired sevoflurane and carbon dioxide (CO2) concentrations were measured with a calibrated gas analyser (Capnomac Ultima, Datex, Helsinki, Finland) connected to a nasal catheter introduced 30 mm into the widest nostril. Patients were asked to breathe through their nose. Patients breathed spontaneously throughout the study. The airway was maintained with chin lift or jaw thrust if needed. Data from the gas analyser were stored every 15 s on a patient data management system (CompuRecord, Philips, Andover, MA, USA).
Thirty-four consecutive patients received propofol 5 mg kg–1 h–1, followed by 10, 15, and 20 mg kg–1 h–1, each during 3 min, by continuous i.v. infusion (Group P). Thus, a staircase function was used for both drugs to obtain rather slow and comparable increases in concentrations. Oxygen was supplied if the oxygen saturation decreased. Four patients participated twice in the study, once for sevoflurane and once for propofol with an interval of several months.
After blink reflexes had disappeared, administration of anaesthetic agent was stopped and restarted only when blink reflexes had reappeared. Then, the same sequence of anaesthetic delivery, starting with sevoflurane 1 vol% or propofol 5 mg kg–1 h–1, was recommenced. This part of the study ended when the patient lost consciousness for the second time (Fig. 2). From this time, the tetanic stimulus-induced withdrawal reflex was assessed (reported in accompanying paper).10
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Latency, duration, and area under the curve of the components of the blink reflex (R1, R2, and R3) were measured, using the marker tool of the EMG system. A trained individual, blinded for the other variables, put markers in place after the session took place. The area under the curve R1 (area-R1) is expressed in millivolt millisecond, but may also be normalized to the average in the control period and therefore expressed as per cent of control. EMG, burst suppression (BS) ratio, and signal quality index (SQI) data were obtained from the BISXP monitor. BIS data obtained during periods of excitation (defined as simultaneous occurrence of EMG >40 dB, OAAS <3, and an increasing BIS) and periods of BS (BS ratio >50%) were excluded from the PKPD modelling.
Artifacts in the end-expired sevoflurane data, as a result of interruption of nasal breathing or technical difficulties, such as inability to fit the facemask, were deleted. Remaining data were then linearly interpolated to obtain one data point per second. Thus, synchronization with other measures was possible without additional time lag.
Propofol plasma concentrations in arterial blood, one data point per second, were calculated for each patient based on the individual infusion rate using Matlab-Simulink (version 6.5.1) software (Mathworks, Natick, MA, USA). The pharmacokinetic set of Marsh and colleagues11 was used.
We performed PKPD modelling using a two-stage approach. Individual concentration–response functions were fitted to the data (Solver Tool in Excel, Microsoft, Redmond, WA, USA) using a sigmoid model defining the relationship between the apparent effect-site concentration of a drug (CE) and a measure for its anaesthetic effect (E) as:
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is a coefficient, determining shape and slope of the curve. E0 and Emax were derived from the data of the individual patients. E0 BIS is the average BIS during the control period and Emax BIS is the average BIS during the plateau phase,12 which is easily recognized visually either in the first cycle or in the next cycle. The time delay between changes in concentration and observed effect was modelled by an effect compartment and a first-order rate constant, ke0:
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measured is the average measured effect and n is the number of data points. The individual parameters were averaged to obtain population parameters. We also performed non-linear mixed effects modelling (NONMEM version V level 1.0, GloboMax LLC, Hanover, MD, USA). Before we run NONMEM successfully, we reduced the number of BIS and blink data to one data point per 30 s (see Supplementary data). For comparison purposes, the reduced data were also used for the two-stage approach.
The ratio EC50 blink/EC50 BIS was used to compare the potency of sevoflurane or propofol to suppress the blink reflex with respect to their potency to suppress BIS. For this purpose, it was necessary to demonstrate that BIS values at different clinical endpoints (LOC and ROC) for sevoflurane or propofol were comparable.
Power calculation showed that a minimum of 16 patients in each group was required for an unpaired t-test to have an 80% power of detecting a difference in means of the ratio EC50 blink/EC50 BIS of 1 SD at the level of 5% significance. To compensate for dropouts, the number of patients in each group was adjusted upwards.
Graphical analysis of data preceded formal statistical analysis. Lilliefors test was used to test if the data were normally distributed. Non-normally distributed data were compared with non-parametric tests (Wilcoxon signed ranks test or Mann–Whitney U-test) and normally distributed data with parametric tests (paired or unpaired two-sided t-test). Data skewed to the right were analysed using parametric tests on log-transformed data. For categorical data, Fisher's exact test was used. Data are presented as mean (SD), unless stated otherwise. Data skewed to the right were given as geometric mean (95% CI). P < 0.05 was considered statistically significant. The Statistical Package for Social Sciences was used (SPSS version 11.0, IL, USA).
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Data from 18 and 29 patients in Groups S and P, respectively, were finally analysed, after excluding a total of 7 patients. In Group S, data from 2 patients were discarded (accidental disconnection of the expiratory limb of the circle system in one patient and prolonged paradoxical BIS elevation in another patient). In Group P, two patients had no reliable control values for R1, and in three patients we could not find a solution to model the blink reflex model.
Patients in Groups S and P had similar characteristics and control values for the latencies of blink reflex components (Table 1). The control area-R1 (12 blinks) was similar in both groups: 0.94 mV ms for Group S (0.23 mV ms within-patient SD, 0.65 mV ms between-patient SD) and 1.11 mV ms for Group P (0.27 mV ms within-patient SD, 0.58 mV ms between-patient SD). Individual values for ke0 and EC50 are shown in Figure 3. The PKPD models are given in Table 2. Figure 4 displays full relationships between anaesthetic effects and effect-site concentrations for both sevoflurane and propofol.
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2 is the coefficient of determination. Data are given as mean (SD), except Suppression of the blink reflex started at concentrations where BIS was virtually unaffected and consciousness was preserved (Fig. 4). This suppression rapidly increased with increasing effect-site concentrations. EC50 for the blink reflex was smaller than that for BIS for each of the two anaesthetics (Fig. 4; Table 2). No differences were found between the values for
for the blink reflex and the corresponding values for BIS (Table 2). The ratio EC50blink/EC50BIS for sevoflurane was smaller than that for propofol: 0.27 (0.16) for sevoflurane compared with 0.70 (0.29) for propofol (P < 0.001). Area-R1 is nearly extinguished by sevoflurane at 1 EC50 BIS, but not by propofol (Fig. 4). The use of individual results for area-R1 at 1 EC50 BIS (not as in Fig. 4) shows that area-R1 was much smaller for sevoflurane than for propofol: 6.9 (3.8)% of control compared with 27.2 (21.5)% of control, respectively (P < 0.001).
BIS values in Group S were higher than in Group P at the clinical endpoints LOC, ROC, and second LOC: 70 (14), 80 (12), and 78 (9) compared with 61 (12), 70 (8), and 64 (8), respectively (for all, P < 0.05). EMG activity in Group S was also consistently higher than in Group P at the same endpoints: 44 (7), 50 (9), and 49 (7) compared with 39 (7), 45 (9), and 39 (7), respectively (only for LOC, P < 0.05). There was no difference in the SQI in both groups: 80 (15), 81 (14), and 87 (11) compared with 86 (9), 83 (16), and 89 (9), respectively.
In contrast to the BIS, the normalized area-R1 in Group S was lower than in Group P for LOC, ROC, and second LOC: 24 (19), 19 (20), and 12 (15)% of control compared with 41 (30), 27 (24), and 25 (24)%, respectively (P < 0.05, only for first LOC). Within each group, area-R1 was smaller for the second LOC, compared with the first LOC (P < 0.05). The opposite was found for BIS (P < 0.05, only for sevoflurane).
The rate constants for the blink reflex were much smaller than those for BIS: 0.24 and 0.48 min–1 for sevoflurane and 0.28 and 0.46 min–1 for propofol (Table 2).
All patients were already unconscious when they lost their R1 component. The OAAS at loss of R1 was identical in both groups [1.1 (0.3)]. Only a few patients were already responsive when R1 reappeared (2/18 in Group S and 4/29 in Group P). The R2 component was lost at a lower OAAS score than R3 (P < 0.001), but there were no differences between groups. The OAAS score at the loss of R2 for Groups S and P was 3.8 (0.71) and 3.9 (0.8), respectively, and 4.8 (0.43) and 5.0 (0.2) at the loss of R3.
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Discussion |
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This study shows that the relationship between end-expired sevoflurane or arterial propofol concentrations and area-R1 of the blink reflex may adequately be described by a sigmoid Emax model and a first-order rate constant. The same is true for BIS.
The first of our four questions was whether blink reflex was more sensitive than BIS. The blink reflex proved to be more sensitive than BIS. Figure 4 shows that, at a BIS of 80, the blink reflex is already substantially suppressed, especially by sevoflurane. Consequently, the blink reflex may be a sensitive measure for the level of sedation.
The second was whether the blink reflex was more sensitive to sevoflurane or propofol. Our results show that, for an equivalent depression of BIS, the blink reflex is more than twice as sensitive to sevoflurane than to propofol. Potencies (EC50) of sevoflurane and propofol are expressed in different units, hindering direct comparisons between agents. If sevoflurane and propofol depress BIS in a similar manner, then the ratio EC50 blink/EC50 BIS for both anaesthetics would be useful and meaningful (Fig. 4). Alternatively, a third abscissa is used in EC50 BIS units. This is similar to using minimum alveloar concentration (MAC) units instead of vol% (or % atm) to compare effects of different inhaled anaesthetics. The area-R1 at LOC, ROC, and second LOC is smaller for Groups S vs P, although statistical significance is reached only for LOC. This also supports the finding that sevoflurane depresses the blink reflex more than propofol.
Periods of ‘excitation’ were excluded in Group S to allow valid comparisons between sevoflurane and propofol. BIS values at clinically important endpoints as LOC, ROC, and second LOC were higher for sevoflurane than for propofol. Others found similar results.13 14 The difference may be explained by the appearance of high-frequency frontal EMG activity, giving erroneously high BIS values. However, the differences between Groups S and P were relatively small, and the EMG activity was not large enough (<50 dB) to be solely responsible for this difference. The SQI indicated that an adequate signal quality was maintained in both groups. It has been observed that higher frequencies of the EEG and even epileptiform activity in the sevoflurane group can be responsible for the increase in BIS values.15–17 Periods of ‘excitation’ occurred more frequently in group S. As this might invalidate comparisons between sevoflurane and propofol, periods of ‘excitation’ were excluded before PKPD modelling.
The same reasoning can be applied to the more frequent occurrence of BS during propofol administration. Because we did not observe BS >50% in this study, we did not have to exclude periods with BS from analysis.
The third question was whether the ke0 for blink reflex differed from that for BIS. The smaller rate constant for the blink reflex, showing that it lags behind BIS, may be an argument for distinct effect sites for the two surrogate anaesthetic measures. This implies, however, that the blink reflex is not a useful measure for the state of consciousness. Area-R1 can only be of clinical value (e.g. to monitor the hypnotic component of anaesthesia, when the time lag with BIS is considered). In contrast to BIS values, the area-R1 was lower at second LOC than at first LOC. This is consistent with a ke0 for the blink reflex different from that for BIS.
When comparing ke0s of the blink reflex and BIS, one must consider the time delay for calculating the BIS value.18 If the ke0 for BIS could be corrected for this delay, ke0 BIS would become larger, and the difference from ke0 blink would increase. As we were mainly interested in relative differences between ke0 for blink reflex vs BIS, absolute ke0 values are not critical to our findings. Nevertheless, we need carefully to address the absolute values for ke0 and their relative differences.
The ke0 values we found for BIS are much larger than those reported by others.19–25 There are three key reasons to explain this. First, a major difference to other investigations was that we did not ventilate the lungs of the patients. Hypercapnia with increased cerebral blood flow can explain a larger ke0 when compared with normocapnia. For sevoflurane, we developed a physiologically based pharmacokinetic model to evaluate quantitatively the impact of different alveolar ventilations on ke0.26 We showed that reported values for ke0, including ours, are within the expected ranges dictated by alveolar ventilation. Second, ke0 values from different studies cannot always be directly compared. Some report the arithmetic mean, whereas inspection of our ke0 data and those of others reveals a distribution skewed to the right.1920 A geometric mean is then the obvious approach. Calculating ke0 directly from a reported average t1/2ke0 (or vice versa) can lead to a >2-fold error (appendix in Lerou and Mourisse26). Third, other possible contributing factors include a shorter processing time for BIS (newer software version) and the choice of pharmacokinetic set to calculate propofol concentrations.
It was not our purpose to search for distinct effect-sites for propofol or sevoflurane by comparing the ke0s of the two drugs. The concept of ke0 is that it reflects the time delay between changes in concentrations in arterial blood and corresponding changes in effect. Thus, any direct comparison of experimental ke0 values for sevoflurane with those for propofol is not meaningful, because: (1) we used end-expired concentrations for sevoflurane compared with predicted arterial concentrations for propofol; (2) there is a time delay between sampling and calculating end-expired concentrations. Our sevoflurane model may be used to correct our result for ke0.26 It can be shown that the ke0 BIS, after correction for investigation-specific conditions, is in the range from 0.42 to 0.45 min–1.
Our fourth question was whether the blink reflex was a candidate for detection of awareness or assessment of immobility. The blink reflex is an unreliable tool to detect awareness, because most patients, though not all, were unconscious when R1 was absent. Furthermore, the high variability of R1 at LOC and ROC prevents a precise prediction of these endpoints. This is also true for BIS, although to a lesser extent. In contrast, the OAAS score at loss of R1, R2, and R3 shows no overlap (with each other), and thus the different sensitivity of the components of the blink reflex can be used to monitor sedation. The smaller ke0 for blink reflex vs BIS reflects the clinical use of blink reflex (eyelash) to determine the endpoint for anaesthesia induction.
The blink reflex is also not a candidate for the measurement of immobility, although it activates motor neurones in the facialis nucleus. To be a good predictor of immobility after noxious stimuli, the concentration–response curve for R1 must be in the same range as other measures of motor reactions to skin incision. Concentrations needed to suppress motor responses after skin incision in 50% of the patients were 10 µg ml–1 for propofol27 and 1.8% atm for sevoflurane (1 MAC).28 At these values, the blink reflex is completely abolished.
We used area-R1 because it was already shown34 that: (1) R1 is the component that is most resistant to propofol and midazolam; (2) area-R1 correlates best with OAAS and BIS; and (3) R1 shows the least between- and within-patient variability. As in our previous studies,34 we found that between-patient variability is roughly twice the within-patient variability. Although neurophysiologists routinely average blink reflexes to reduce within-patient variability, we could not do so because we performed a dynamic study. Within-patient variability remains a considerable problem and would make these measurements less useful in a clinical setting. Between-patient variability was reduced by normalizing measurements to control.
In conclusion, the blink reflex is more sensitive than BIS to both sevoflurane and propofol, and is a sensitive measure of sedation. At an equivalent depression of BIS, sevoflurane suppresses the blink reflex more than propofol, indicating different pharmacodynamic properties of these anaesthetics at brainstem level. The longer time delay in the production of an effect measured by the blink reflex compared with BIS, by both propofol and sevoflurane, lends credence to the existence of different effect sites for the two anaesthetics.
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Supplementary data |
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Details on the analysis of our data with non-linear, mixed effect modelling can be found as supplementary data in British Journal of Anaesthesia online. Furthermore, a sketch illustrates our method of data acquisition for the blink reflex.
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Acknowledgements |
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We thank Patty Bökkerink, Johan Santosa, and Tom Gevers for their help with data collection. We are grateful to Dr Jörgen Bruhn for his helpful suggestions in the preparation of this manuscript.
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Footnotes |
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This article is accompanied by Editorial I. 
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References |
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