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Original Article

Excitatory effects of fentanyl upon the rat electroencephalogram and auditory-evoked potential responses during anaesthesia

Antunes, L. M.*†; Roughan, J. V.*; Flecknell, P. A.*

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European Journal of Anaesthesiology (EJA): October 2003 - Volume 20 - Issue 10 - p 800-808
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Abstract

Several recent human studies have used auditory-evoked potential (AEP) changes to assess the depth of anaesthesia. Dose-dependent reductions in AEP peak amplitudes and increased latencies are accepted as useful indices of the depth for some anaesthetics [1]. However, the value of electroencephalogram (EEG) measurements is not certain as similar studies have produced conflicting data [2,3]. The need for a more reliable and objective assessment technique has arisen in part due to the more frequent use of neuromuscular blocking agents that obstruct the possibility of patient response (movement) to inadequate anaesthesia both in humans and in animals. The development of a rat model to evaluate the depth of anaesthesia based on the EEG and AEP could provide the ability to undertake definitive studies, which in humans may be restricted by ethical considerations. Investigations with EEG and AEP in rats similarly should provide information of direct relevance when this species is used in other fields of research (i.e. pharmacological studies for measuring the effects of drugs upon the central nervous system or the testing of new anaesthetic drugs). For welfare reasons, it is also essential that animals be maintained at an adequate depth of anaesthesia avoiding awareness or unnecessarily deep levels of anaesthesia, increasing the risk of mortality.

Auditory-evoked responses are generated as an average of EEG activity following repetitive stimulus presentation. When recorded from the extradural cortex; their amplitude and latency are thought to reflect the activation state of neuronal populations [4]. They are enhanced in amplitude and reduced in latency when arousal levels are high, a fact contrasting with the circumstances encountered during anaesthesia. Although there is general agreement concerning the effects upon AEP responses during anaesthesia induced with volatile agents, findings concerning the effects of fentanyl have been somewhat tenuous [5,6].

The use of EEG assessments during anaesthesia is based on power spectral analysis, which allows quantitative assessment of the various frequency components of the signal, e.g. the frequency below which 50% of the total power resides (median frequency, MF) or that below which 95% resides (spectral edge frequency, SEF). In human beings, opioids have been related with reduced EEG frequency and increasing power in the delta frequency band (0.5-4 Hz) [7,8]. Similar effects of opioids have been observed in rats [9,10], dogs [11] and horses [12].

In a previous study, we showed that the combination fentanyl/fluanisone/midazolam had excitatory effects on AEP responses [13]. The present study was undertaken to characterize clearly the AEP and EEG responses to fentanyl when it was administered to provide additional analgesia during light anaesthesia in rats. We hypothesized that fentanyl had no effects or excitatory effects on the EEG and AEP responses. The possibility of using these responses for the determination of the depth of anaesthesia when supplemented bolus of fentanyl were used was also investigated.

Methods

The study was conducted in accordance with the Animals (Scientific Procedures) Act 1986, with the approval of the local Ethics Committee and under Project License No. PPL60/2362.

Surgical procedures and anaesthesia

Anaesthesia for electrode implantation was initially induced in a chamber with isoflurane 4% in oxygen (4 L min−1) until the righting and tail pinch reflexes were lost. Animals were then transferred to a face-mask delivery and gas-scavenging system and anaesthesia was maintained with isoflurane 2% in oxygen (2 L min−1). A heating blanket (Harvard Apparatus, Edenbridge, Kent, UK) maintained body temperature. Ophthalmic ointment was applied to the eyes to prevent corneal desiccation or abrasions. An estimation of the depth of anaesthesia was made at each stage using the pedal withdrawal response (PWR) by retraction of a hind paw after the web between the toes was pinched. This was scored between 1 and 5 for response absence and strong withdrawal, respectively; clinical signs were also incorporated in this overall evaluation of the depth of anaesthesia [13]. Subjective responses were minimized by ensuring that a single experimenter assessed all reflexes, generated the stimuli and processed the data.

A 24-G intravenous (i.v.) cannulae was inserted into the lateral tail vein and flushed with heparinized saline. This was used to administer propofol (Diprivan®; AstraZeneca, Macclesfield, UK) at 50-70 mg kg−1 h−1 with an SE 200B® syringe pump (Vial Medical, St-Etienne de St-Geoirs, France) to maintain anaesthesia during the surgical preparation. A midline subcutaneous injection of lidocaine 0.2 mL 1% was then given into the scalp. Two to 3 min later, the skull was exposed by a 2 cm midline incision in the scalp and right lateral resection of the temporalis muscles. Electrodes were silver/silver chloride balls (0.5 mm diameter) soldered to 0.7 mm diameter with polyvinylchloride-insulated multicore leads. These were completely insulated with varnish; only the contact point was uninsulated. Two electrodes were implanted through apertures bored in the cranium at the near vertex (Vx) and over the auditory cortex (Acx) so that they made gentle contact with the dura. The near vertex electrode was 5-6 mm anterior to the interaural line and 1 mm lateral to the central suture. The Acx electrode was 4-5 mm anterior to the interaural line and 4-5 mm ventral to the dorsal skull on the right side. A reference electrode (Ref) was located over the frontal sinus. Electrodes were fixed with methyl methacrylate-activated dental cement (Simplex Rapid, Associated Dental Products Ltd, Purton, Wiltshire, UK). The preparation was earthed with a length of fine copper wire sutured to the skin overlying the nape of the neck.

Pulse rate, arterial pressure and capnographic data were collected using an electronic monitor (Vitalmax 4000 CL®; Pace Tech, Clearwater, FL, USA) following catheterization of the femoral artery and endotracheal intubation. Animals were intubated with a 14-G i.v. cannula. Temperature, respiratory rate, end-tidal carbon dioxide (ETCO2) and minimum inspired CO2 were monitored continuously. Samples were withdrawn for arterial blood-gas analysis at the beginning and end of the recording period during the propofol study. Intermittent positive pressure ventilation of the lungs was carried out using a volume-cycled rodent ventilator (Harvard Apparatus). With the exception of animals from the first study (propofol/fentanyl group), which were ventilated more rapidly (60 breaths min−1), a ventilation rate of 45-50 breaths min−1 with a tidal volume of 4 mL, and fresh gas flow of 300 mL min−1 was used. Animals used in the propofol/fentanyl, naloxone/fentanyl and control studies had a second 24-G i.v. cannulae inserted into the lateral tail veins for separate administration of propofol and fentanyl or naloxone.

Recording

Animals were placed in a sound-attenuated box and positioned in ventral recumbence. A loudspeaker was placed in the right external auditory meatus. This was secured with tape and used to deliver broadband click stimuli (0.1 ms/105 dB). Electrode leads were soldered to a Jermyn® 14-way DIL pin socket for connection to preamplifiers (gain ×1000) (World Precision Instruments, Stevenage, UK). EEG and AEP signals were band-pass-filtered 1-300 Hz (Neurolog® NL125, Welwyn Garden City, Hertfordshire, UK), and proceeded to an analogue-to-digital laboratory interface (CED Micro 1401®; Cambridge Electronic Design Ltd, Cambridge, UK). This was time-synchronized with two microcomputers installed with CED software (Signal), one for the averaging of stimulus-evoked responses and the other to record the contiguous EEG. Stimuli were 100 clicks presented at 6 Hz for recording averaged AEP responses. Evoked responses were sampled at 5000 Hz and recorded from 5 ms before to 150 ms following stimulus presentation. The contiguous EEG was sampled in 4 s bins over 3 min.

Data collection and anaesthesia

Propofol/fentanyl. In an initial study, eight rats were used to examine the effects of fentanyl during light propofol anaesthesia. The propofol infusion was reduced to 20-30 mg kg−1 h−1 and animals were allowed to recover to a plane of anaesthesia (PWR 4-5) just sufficient to maintain the loss of the righting reflex. Thirty minutes after the propofol infusion rate was reduced, EEG and AEP responses were recorded before administration of a bolus of fentanyl (6-10 μg kg−1, T1). This was sufficient to deepen anaesthesia to a point whereby the PWR was completely suppressed (PWR 1). One minute after fentanyl administration, the EEG and AEP recordings were repeated (T2). This was followed by a 30 min interval to allow recovery of the PWR. Preceding a second fentanyl administration (10-20 μg kg−1), AEP and EEG recordings were again recorded (T3). This was followed by a fourth recording period (T4) 1 min after the second administration of fentanyl.

Isoflurane/fentanyl. In a second study, five rats were used to investigate the effects of fentanyl during light isoflurane anaesthesia. Animals were maintained at a light plane of anaesthesia (PWR 4-5) with a low concentration of isoflurane (0.8%, n = 5). Twenty minutes after the anaesthetic concentration was reduced, EEG and AEP responses were recorded before administration of a bolus of fentanyl (6 μg kg−1, T1). This was sufficient to deepen anaesthesia to a point whereby the PWR was completely suppressed (PWR 1). One minute after fentanyl administration, the EEG and AEP recordings were repeated (T2). This was followed by two more recordings at 5 and 10 min (T3 and T4, respectively) after fentanyl administration during recovery of the PWR. Times for recordings were changed based on observations from the propofol/fentanyl study and doses of fentanyl were reduced after preliminary studies during isoflurane showing effectiveness to suppress the PWR.

Naloxone/fentanyl and control studies. A control group consisted of five animals that were maintained with a 20-30 mg kg−1 h−1 propofol infusion. A saline injection (0.2 mL) was administered on a first occasion, and EEG and AEP results were compared between, before and after the administration. Subsequently, 5-10 min later, an administration of water 0.2 mL for injection was performed and a similar comparison of results effectuated.

As an additional control, the capacity of naloxone (Narcan®; Dupont Pharmaceuticals Ltd, Stevenage, Hertfordshire, UK) to block any response to fentanyl administration was also evaluated. In this group (n = 5), rats underwent a similar procedure as those that received fentanyl, except that before fentanyl administration they received an injection of naloxone (100 μg kg−1) intravenously. AEP and EEG responses were obtained both before (T1) and after (T2) naloxone administration and before and after (T3 and T4, respectively) fentanyl administration. No anaesthesia monitoring parameters were obtained at T3 because of the short time interval (approximately 4 min) between the naloxone and fentanyl administration.

Statistics and analysis

Analyses of the waveform components of the averaged AEP data obtained during light anaesthesia identified three characteristic peaks occurring around 9, 22 and 40 ms (Fig. 1). Specifically, the AEP waveform recorded at Acx was biphasic, consisting of one major positive peak (P40) and two smaller peaks (P9, N22). Qualitative analysis indicated that AEP responses obtained at the Vx recording site were on the whole less consistent and clearly defined than those at Acx, while the opposite was true for the EEG recordings. All AEP analyses therefore used data for peaks P9, N22 and P40 obtained from Acx and EEG analyses used data obtained from the Vx electrode.

Figure 1
Figure 1:
Averaged AEP responses obtained at the Acx electrode in one rat undergoing light propofol anaesthesia (top waveform) and 1 min after administration of fentanyl (lower waveform). A higher amplitude response and a delay in peak latency were observed after the fentanyl administration. P9, N22 and P40 latency values, and A1, A2 and SDI amplitude values are indicated. Each trace represents 100 clicks at 6.1 Hz.

The latency and amplitude of each AEP was measured. Latency was the time (ms) of stimulus onset to the maximum amplitude of each of the three main peaks in the averaged response waveform. Amplitude changes were calculated and presented as A1 and A2 being, respectively, the difference (μV) between the amplitudes measured at P9 and N22 and between N22 and P40. The AEP responses were also quantified using a second differential index (SDI) [14] calculated as:

where x(n) is the nth sample value, d is a sample interval used in the calculation and y(n) is the second differential estimate for sample n. This value described the 'waviness' inside a selected interval (5-70 ms), such that increasing SDIs were related with increasing activity within the brain and lower SDIs with depression.

Power spectral analysis was used to calculate the EEG median and 95% spectral edge frequencies (Hz). Because the amplitude-related data were skewed, they were log-transformed before statistical analysis. All analyses were performed using the software package SPSS® v.9.0 (SPSS, Inc., Chicago, IL, USA). In the propofol/fentanyl, naloxone/fentanyl and control studies, the assessed physiological parameters and AEP and EEG measurements were compared between data obtained before drug administration and those obtained immediately following injections. During isoflurane/fentanyl studies, observations were compared with data obtained during each subsequent recording period during recovery (T1 versus T2, T2 versus T3, T3 versus T4). The results of averaged univariate analyses are quoted in the form:

where df1 and df2 are the degrees of freedom for the numerator and denominator respectively. Data are means ± SD, and where data were log-transformed for analysis (amplitude measures) geometric means and lower and upper bound 95% confidence intervals (CI) are presented. The number of animals used per group was determined based on preliminary studies and after a statistical power calculation.

Results

Propofol/fentanyl administration

The PWR response was abolished in all animals following each successive injection of fentanyl. A significant increase in the latency of AEP peak P40 occurred following both the first and second fentanyl injection. Although P9 and N22 showed a latency increase, the changes were not significant. All amplitude parameters (A1, A2, SDI) increased significantly after both fentanyl administrations (Table 1, Fig. 1).

Table 1
Table 1:
Results of analyses of variation of P40 latency (ms); A1 and A2 amplitudes (μV); SDI, SEF (Hz) and MF (Hz) comparison under propofol anaesthesia before (T1, T3) and after (T2, T4) fentanyl administration.

Significant increases in SEF and MF were observed after both fentanyl administrations. No burst suppression was observed during either of these periods (Table 1).

A light opioid-induced muscular rigidity was noticed in some animals after fentanyl administration and an increase in temperature was observed approximately 5 min after drug administration. With the exception of a pulse rate reduction from 360 (±29) to 314 (±41) after the first fentanyl bolus and from 342 (±38) to 317 (±32) after the second administration (average F(1,7) = 24.5, P = 0.002, and average F(1,7) = 8.6, P = 0.022, respectively) and a significant decrease on CO2 rebreathing from 0.64 to 0.41 kPa (average F(1,7) = 10.6, P = 0.014) after the first bolus of fentanyl, all physiological responses remained stable following administration of fentanyl.

Isoflurane/fentanyl

The PWR response during isoflurane anaesthesia was abolished in all animals following the bolus of fentanyl. This was then followed by a latency increase in all AEP peaks and 5-10 min later by their return to the previous values. These changes were only significantly different for peak P40. All studied amplitude parameters (A1, A2, SDI) significantly increased after fentanyl administration, and this was followed by a reduction in amplitude on the subsequent records (Table 2).

Table 2
Table 2:
Results of analyses of variation of P40 latency (ms); A1 and A2 amplitudes (μV) and SDI comparison during isoflurane anaesthesia before (T1) and after 1 (T2), 5 (T3) and 10 (T4) min fentanyl administration.

It was found to be somewhat more difficult to identify and measure accurately the characteristic AEP peaks during isoflurane anaesthesia than during propofol anaesthesia. Peaks P9 and N22 could not be measured reliably in one animal. In some cases, a clearer and easily analysed AEP was obtained after fentanyl administration. This is the reason why the number of observation entered into the analyses (Table 2) differs from the number of animals originally entered into the study.

There was a tendency for SEF and MF to increase after the fentanyl bolus administration. No burst suppression periods were observed during these periods.

There were no significant differences in respiratory rate, inspired and end-tidal CO2. Pulse rate, systolic, diastolic and mean arterial pressures showed an initial decrease after fentanyl administration. These reductions were not significant and recovered to values higher then the initial ones 5 min after injection. Body temperature significantly increased from 37.2 (±0.5) 1 min after fentanyl administration to 37.3 (±0.5) 5 min following fentanyl administration (average F(1, 4) = 12.2, P = 0.025). A minor opioid-induced muscular rigidity was again observed in some animals after the fentanyl administration.

Control and naloxone studies

Administration of physiological saline and water for injection produced no detectable changes in either the AEP or EEG recordings. Administration of naloxone before fentanyl prevented the changes in AEP and EEG parameters. Excepting a reduction in the diastolic pressure after fentanyl administration from 116 (±13) to 107 (±9) (average F(1,4) = 7.9, P = 0.048), no significant changes in the other anaesthesia-related measurements occurred in response to fentanyl after naloxone. Administration of fentanyl after naloxone failed to abolish the PWR.

Discussion

The present study was designed to characterize the AEP and EEG responses to fentanyl when it was administered to provide additional analgesia during light anaesthesia in rats.

Each bolus of fentanyl increased anaesthetic depth such that the PWR was lost, and at the same time the latency of AEP peak P40 was increased under all anaesthetics. Although this response gave preliminary support that such a measure might be a valuable tool for anaesthetic depth assessments, increases in AEP amplitude measures A1, A2 and SDI, and in the EEG parameters SEF and MF recorded at the near vertex cast considerable doubt over this view. Furthermore, a decrease in these effects was observed 5 min after administration and vanished altogether at 10 min. Such ambiguous data recorded at two different sites were unexpected, but were confirmed by the blocking of this response by prior administration of the specific μ-antagonist naloxone. The specificity of the response was confirmed using physiological saline and water for injection as controls. No response was seen when these substances were administered, indicating that the effect was not a non-specific response to handling the animal, lifting the insulated chamber lid and administration of a small bolus of intravenous fluid.

These data were contradictory to previous reports of decreased EEG frequency when opioids were administered as the sole anaesthetic in human beings [7,8], dogs [15] and in rats breathing ambient air and using anaesthetic doses of fentanyl [10]. Opioids used as supplemental agents during halothane anaesthesia in horses [12], isoflurane/nitrous oxide in dogs [11] and midazolam anaesthesia in rats [9] also produced a reduction in EEG frequency. However, in accordance with our studies, Vaughan and colleagues showed that tramadol, a centrally acting opioid-like analgesic, activated EEG parameters [16].

As an alternative to EEG measurements, studies involving the assessment of evoked responses following opioid administration in humans have produced similarly conflicting data, with decreased AEP amplitudes reported following administration of high doses of remifentanil [17] and alfentanil [18]. In contrast, Schwender and colleagues reported no change in AEP responses with increasing doses of alfentanil, fentanyl and morphine [19], and Crabb and colleagues observed an increase in AEP amplitude with low doses of remifentanil [17]. Recent studies in human beings [20,21] found an increase in the bispectral index when propofol was supplemented with fentanyl. Furthermore, Haberham and colleagues followed the induction and recovery of anaesthesia induced with fentanyl in rats. They showed clear evidence that the MLAEP recorded at the Vx location may be used to assess the level of hypnosis, but curiously also observed an increase in an interpeak variable (N23-P63) immediately after drug administration [10]. These findings confirmed the observations previously reported by our group of AEP amplitude increase in rats following additional doses of fentanyl/fluanisone/midazolam combination [13] and fentanyl supplementation during halothane anaesthesia [22].

A possible explanation for the responses observed in the current study might be related with the low doses of fentanyl used in comparison with the higher and anaesthetic doses used in the other studies. The opioid effect was recently selected as an example of a non-monotonic drug effect on the EEG; while anaesthetic doses produce a slow down of the EEG frequencies, the opposite occurs when lower doses are used [23]. This is also supported by observations in human beings and animals of a biphasic effect of anaesthetics on the EEG. This response is identified in human beings by an increase in high-frequency activity observed in response to an initial dose of thiopental [2] and propofol [24], followed by a decrease in frequency with higher anaesthetic doses. Similarly, in rats a complex dose-dependent relationship showing an increase in the EEG frequency with lower thiopental and propofol doses has been observed [25,26]. In addition, in rats, increased AEP waveform amplitudes recorded over the somatosensory cortex with subanaesthetic pentobarbital doses and reduction with higher doses [27] have been demonstrated. This observation supports the possibility of a similar biphasic effect on the AEP responses. In addition, amplitude enhancement in early components of the Acx recorded AEP under pentobarbital or chlorpromazine anaesthesia followed by a gradual increase in latency have also been reported in rats [28]. Alternatively, failure to obtain effective and stable tissue concentrations and variations in the times of recording in relation to drug administration in some studies may also account for the wide range of responses recorded by different research groups.

These AEP data are in agreement with information available for human beings indicating the lack of significant effects of fentanyl on brainstem responses [5,6], and increased latency of later AEP components [29]. The delay in P40 latency could be caused by impaired synaptic transmission, a common effect of most anaesthetics [30], but the mechanism responsible for producing the amplitude changes is more speculative. Similar amplitude increases have been reported in the 40-Hz auditory steady-state evoked response (ASSR) recorded in human beings during the first 4 min of sufentanil infusion [8] and in the rat brainstem responses under ketamine anaesthesia [31]. Excitatory effects of opioids on both cultured hippocampal pyramidal cells [32] and in vivo[33] and in the production of seizures in rats after intraventricular administration of opioids [34] have been reported. These observations may be explained by neuronal disinhibition [35] and evidence that opioids' excitatory properties in animals may be related with the release of inhibition of GABA-ergic interneurons [36,37]. Alternatively, other mechanisms that increase the number of neural units firing and their synchronization could be involved.

The only AEP peak to present consistent statistically significant increases in latency after fentanyl administration under all anaesthetic regimes, P40, could be considered as a potential parameter to distinguish between levels of anaesthesia. Although due to the high variation between individuals and the degree of overlapping values, it is impossible to select a latency time as a cut-off value to demarcate periods of surgical anaesthesia (negative PWR) from periods of light anaesthesia (positive PWR).

The present results obtained in rats are likely to be relevant to other species and human beings. EEG and AEP responses in rats during different levels of anaesthesia with propofol, halothane or isoflurane showed similar results to data available in human beings; it was a dose-dependent depression [22]. On the contrary, opioids are one group of anaesthetic agents that have been related with brain hypermetabolism, excitement and seizure-like activity both in rats [38,39], other species [40] and human beings [41-43].

The observed increase in temperature most likely resulted from the light opioid-induced muscular rigidity observed. This phenomenon appears after the administration of high doses of opioids in both human beings [44] and rats [45]. The latter authors used a very high dose of fentanyl (100 μg kg−1 i.v.) to induce muscular rigidity in rats anaesthetized with ketamine. The response in human beings is characterized by a rapid onset of profound muscle rigidity, including decreased pulmonary compliance, tonic posturing of the extremities and clonic movements of the hands or feet giving the appearance of seizures, without accompanying changes in the EEG [44]. These responses were considered unlikely to have contributed to any of the AEP and EEG effects observed, given the very mild degree of rigidity that occurred. No electromyographic interference was observed at any point during the recordings. The technique used for electrode implantation and insulation and the muscular resection should, in any event, have prevented possible interference from muscle activity. Furthermore, studies conducted elsewhere showed that the injection of neuromuscular blocking agents did not affect the morphology of the AEP in rats, indicating that any muscular potentials elicited by the auditory stimulation were not the sources of the AEP peaks [46].

In conclusion, the amplitude and frequency responses seen in the present study were unusual in being inconsistent with the classical concept of EEG depression as an indicator of deepening anaesthesia. It is proposed that the observed changes are due to excitatory effects upon EEG and AEP parameters following fentanyl administration, and that such variables may therefore have little value as predictors of adequate anaesthesia in rats when opioid supplementation is used as part of a balanced anaesthetic regimen. Furthermore, the data from the present study suggest that in some brain research projects a significant level of artefacts may be induced by the anaesthetic protocols, which may contribute to the disparity in results and also to the drawing of erroneous conclusions.

Acknowledgements

L. A. was sponsored by scholarships from PRAXIS XXI, Science and Technology Foundation, Lisbon, Portugal, and from the Gulbenkian Foundation, Portugal.

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Keywords:

ANAESTHETICS, GENERAL, isoflurane, propofol; ANALGESICS, OPIOID, fentanyl; MENTAL PROCESS, arousal, awareness; MONITORING, INTRAOPERATIVE, auditory, electroencephalography, evoked potentials

© 2003 European Academy of Anaesthesiology