1 Department of Anesthesiology and Pain Medicine and 2 Section of Neurobiology, Physiology and Behavior, University of California, Davis, CA, USA. 3 Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
* Corresponding author: Department of Anesthesiology TB-170, University of California, Davis, CA 95616, USA. E-mail: jfantognini{at}ucdavis.edu
Accepted for publication May 31, 2005.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Rats were anaesthetized with halothane (n=8) or propofol (n=8), at 0.8x or 1.2x the amount required to produce immobility in response to tail clamping [minimum alveolar concentration (MAC) for halothane and median effective dose (ED50) for propofol]. We recorded EEG responses to repetitive electrical stimulus trains (delivered to the tail at 0.1, 1 and 3 Hz) as well as supramaximal noxious tail stimulation (clamp; 50 Hz electrical stimulus, each for 30 s).
Results. Under halothane anaesthesia, noxious stimuli evoked an EEG activation response manifested by increased spectral edge frequency (SEF) and median edge frequency (MEF). At 0.8 MAC halothane, the tail clamp increased the MEF from 6 to
8.5 Hz, and the SEF from
25.5 to
27 Hz. At both 0.8 and 1.2 MAC halothane, similar patterns of EEG activation were observed with the 1 Hz, 3 Hz and tetanic stimulus trains, but not with 0.1 Hz stimulation, which does not evoke wind-up. Under propofol anaesthesia, noxious stimuli were generally ineffective in causing EEG activation. At 0.8 ED50 propofol, only the tail clamp and 1 Hz stimuli increased MEF (
8 to
1010.5 Hz). At the higher propofol infusion rate (1.2 ED50) the repetitive electrical stimuli did not evoke an EEG response, but the tetanic stimulus and the tail clamp paradoxically decreased SEF (from
23 to
21.5 Hz).
Conclusions. Propofol has a more significant blunting effect on EEG responses to noxious stimulation compared with halothane.
Keywords: anaesthetics i.v., propofol ; anaesthetics volatile, halothane ; brain, electroencephalography ; model, rat ; pain, experimental
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Two commonly used anaesthetics (propofol and halothane) have divergent effects on ligand-gated neurotransmitter receptors. Propofol acts almost exclusively at the -aminobutyric acid (GABAA) receptor, while halothane acts at numerous receptors, including GABAA receptors, N-methyl-D-aspartate (NMDA) receptors and glycine receptors.6 In a previous study we found that halothane, at concentrations that prevented movement, did not prevent EEG activation in response to noxious stimulation.5 Furthermore, halothane appears to have a major action in the spinal cord, at least for the production of immobility.7 Propofol, however, has a major effect in the brain to produce anaesthesia,8 and blunts EEG activation responses to noxious stimulation.3 4 These data38 suggest that propofol and halothane might differ in terms of their ability to modulate EEG responses to noxious stimulation.
In the present study we examined the effects of halothane and propofol anaesthesia on the ability of supramaximal noxious stimulation to cause EEG activation. We included repetitive electrical C-fibre stimulation because it induces wind-up of nociceptive spinal neurons, a mechanism contributing to temporal summation of pain that is depressed by some anaesthetic agents.911 We hypothesized that propofol would blunt EEG responses to supramaximal and repetitive noxious stimulation more than halothane.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In the halothane group, the minimum alveolar concentration (MAC) needed to prevent movement was determined in each individual rat. The halothane concentration was equilibrated at 0.91% and maintained for at least 1520 min. A clamp was applied at the base of the tail and oscillated at 12 Hz for up to 1 min or until the rat displayed gross and purposeful movement. Depending on the initial response, the halothane concentration was increased or decreased by 0.2%, stabilized for 15 min, and the tail clamp was applied again. This process was continued until two halothane concentrations were found that just prevented and just permitted gross and purposeful movement. MAC was the average of these.
In one of the isoflurane-anaesthetized rats and in an additional five rats, we determined the propofol requirements to prevent movement in response to supramaximal noxious stimulation. In brief, the six rats were anaesthetized with isoflurane and ventilated via tracheostomy. A jugular catheter was inserted and a propofol infusion initiated at 400 µg kg1 min1. The isoflurane was discontinued and after 3045 min, when the expired isoflurane was <0.2%, a clamp was applied to the base of the tail and oscillated at 12 Hz for up to 1 min or until the rat displayed gross and purposeful movement. Depending on the response, the infusion rate was increased or decreased 20%, and after 1520 min the tail clamp was reapplied. This process was repeated until two infusion rates were found that just permitted and just prevented movement; the median effective dose (ED50) for the infusion rate was the average of these rates. The average of these values for all six rats was used as the population ED50 for the propofol EEG studies.
The electroencephalogram was recorded via four stainless steel screws placed into the skull. Two screws were placed 0.5 cm from the midline on each side near lambda. One screw was placed near the midline in the frontal region while the fourth screw was placed near the base of the skull. Leads from an Aspect 1050 EEG machine (Aspect Medical Systems, Newton, MA, USA) were attached to the screws to record EEG responses. The EEG signals were digitized at 256 Hz and filtered at 270 Hz. The A-1050 monitor performed a power analysis to generate the median edge frequency (MEF) and spectral edge frequency (SEF), which are the frequencies below 50 and 95% of the EEG power, respectively. MEF and SEF were downloaded every 5 s to a computer. The EEG monitor used a rolling average of the previous 30 s when generating these numbers. In addition, the raw EEG was recorded onto a computer hard drive using Chart5 (AD Instruments, Colorado Springs, CO, USA).
In the halothane rats, the halothane concentration was stabilized at 0.8 or 1.2 MAC for 1520 min before application of noxious stimuli. The animals anaesthetized with isoflurane were administered propofol via infusion, starting at 0.8 or 1.2 ED50 (480 µg kg1 min1 or
720 µg kg1 min1), and the isoflurane was discontinued. We waited at least 3045 min to permit the expired isoflurane concentration to decrease to less than 0.2% before beginning the noxious stimulation.
Noxious stimuli were applied in the following manner. After two needle electrodes (E-2; Grass Instruments, West Warwick, RI, USA) had been inserted into the skin at the base of the tail, trains of 20 C-fibre strength electrical stimuli (40 V, 0.5 ms pulse duration) were delivered at 0.1, 1 and 3 Hz, with 34 min between each train. In addition, two supramaximal stimuli were used: a tetanic stimulus (50 Hz, 60 mA current passed via the electrodes) and a tail clamp, each applied for 30 s. Pancuronium (0.20.3 mg kg1 every 12 h) was administered intravenously to eliminate electromyographic artefacts. Once EEG responses had been recorded at one anaesthetic concentration (or propofol infusion rate), the anaesthesia was switched to the other concentration (or infusion rate) and stabilized for 1520 min, and the noxious stimuli were applied as described above. The order in which the anaesthetic concentrations were administered was alternated between experiments. When data collection was complete, the animals were euthanized with additional anaesthesia and i.v. potassium chloride.
The MEF and SEF data were evaluated using repeated measures analysis of variance for the 30s period before stimulation and the 200 s period after initiation of stimulation. Post hoc testing was performed using the StudentNewmanKeuls test. Baseline MEF and SEF at 0.8 MAC (average of 30 s before stimulation) were compared with the respective values at 1.2 MAC using a paired t-test when comparing within an anaesthetic or an unpaired t-test when comparing between anaesthetics. P<0.05 was considered significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Figure 1 shows individual examples of the electroencephalogram under propofol anaesthesia. At 0.8 ED50 propofol (Fig. 1A), both repetitive electrical stimulation (upper trace) and the noxious tail clamp (lower trace) produced limited activation responses in the EEG. At 1.2 ED50 propofol, the same noxious stimuli did not evoke EEG changes (Fig. 1B). The EEG pattern during propofol anaesthesia included large spikes (Fig. 1C). Data are summarized in Fig. 2, where filled symbols represent EEG responses at 0.8 ED50 propofol and the open symbols 1.2 ED50 propofol. At 0.8 ED50, significant EEG activation in the MEF occurred for the 1 Hz stimulus train (Fig. 2B) and the tail clamp (Fig. 2E). At 1.2 ED50 propofol, none of the noxious stimuli resulted in EEG activation; in fact, the tetanic electrical stimulus and the tail clamp evoked a paradoxical decrease in SEF (Figs 2D and E).
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Various studies have examined propofol and halothane EEG effects. Propofol is associated with progressive EEG depression, including burst suppression and isoelectricity at higher doses.13 We examined a narrow dose range (0.81.2 MAC or ED50) and cannot comment on any possible effects outside that range. Furthermore, although propofol depressed the EEG response to noxious stimulation, the baseline electroencephalogram was active. Our finding that the baseline SEF was unaffected by the increased propofol dose is consistent with the data reported by Antunes and colleagues,14 although they reported that MEF was also unchanged, while we observed a slight decrease in MEF at the greater propofol dose. Some studies have described EEG activation after propofol administration in low doses associated with the transition from consciousness to unconsciousness.15 16 Halothane also appears to cause EEG activation, followed by depression.17 18 Unlike other more commonly used volatile anaesthetics, such as isoflurane, halothane will usually induce burst suppression only at concentrations that exceed the clinically relevant range.7 19 Interestingly, at 1.2 ED50 for propofol, we observed a paradoxical decrease in the SEF during application of the tetanic stimulus and the tail clamp. The mechanism by which this occurs is unknown, but has been reported before with noxious stimuli applied during isoflurane anaesthesia.20 21 In the present study with halothane, the 1 and 3 Hz stimuli increased SEF and MEF in a manner similar to those occurring with the tail clamp and electrical tetanic stimulus. The 0.1 Hz stimulus does not normally cause neuronal wind-up and did not evoke significant EEG changes, probably reflecting much lower temporal summation compared with the 1 Hz, 3 Hz, tail clamp and tetanic stimuli.5 22
While many previous studies have reported anaesthetic effects on spontaneous EEG activity, few studies have examined the effect of noxious stimulation on cerebral activity and the electroencephalogram during anaesthesia.13520 In general, when clinically relevant concentrations of anaesthetic are administered, noxious stimulation causes EEG activation,1 5 20 although less EEG activation occurs during propofol anaesthesia.34 We found that propofol blunted EEG activation resulting from noxious stimulation.2 Hofbauer and colleagues23 investigated in humans the relationship between propofol administration, subjective pain ratings and cerebral activation, as determined by positron emission tomography. When propofol was infused at doses that caused mild sedation, pain ratings of noxious heat increased, as did neural activity in the anterior cingulate cortex and thalamus. As the propofol dose was increased, the pain rating decreased, as did the neural responses; however, even when unconsciousness occurred, noxious heat evoked increased activity in the cingulate cortex and thalamus.23 Greater propofol concentrations, however, are associated with blunted EEG responses to noxious stimulation,3 4 suggesting that this depressant effect occurs between propofol concentrations that produce unconsciousness and those needed to produce immobility.
Although the exact mechanisms by which propofol and halothane produce anaesthesia are unclear, emerging evidence suggests that action at specific ligand-gated receptors might be critically involved.6 Propofol acts at the GABAA receptor to enhance the effect of GABA. A mutation in the ß3 subunit of the GABAA receptor renders mice resistant to propofol, but only slightly increases halothane requirements.24 Halothane probably acts at several receptors, including GABAA, glycine and NMDA receptors.6 Furthermore, propofol and halothane might have different modes of action with respect to sites within the central nervous system. The sedative effect of propofol probably occurs by actions at discrete supraspinal sites, including a sleep-promoting pathway in the tuberomamillary nucleus.8 In addition, propofol and halothane may act in the septohippocampal system to induce anaesthesia.25 Halothane appears to have an action in the spinal cord to ablate movement that occurs in response to noxious stimulation.7 Furthermore, propofol and volatile anaesthetics such as isoflurane can suppress nociception in the spinal cord and thereby affect EEG responses to noxious stimulation.2 26 Thus, in the present study, propofol and halothane could have acted in the brain directly to suppress the EEG response, and in the spinal cord to indirectly suppress the response.
The lower propofol infusion rate may have already surpassed the infusion rate needed to blunt the EEG responses. If so, this was not because of excessive EEG depression. We used the same fractions (0.8 and 1.2) of the amount needed to produce immobility, and our values for halothane MAC and propofol ED50 are similar to those previously published.27 28 We found that SEF and MEF during propofol anaesthesia were greater than those during halothane anaesthesia. At the greater propofol infusion rate (720 µg kg1 min1), the MEF was 8 Hz. Tzabazis and colleagues29 used a modified MEF that incorporated the occurrence of spikes and burst suppression; these authors maintained a modified MEF of 3 Hz by infusing propofol at a dose similar to the higher dose used in the present study [730 (200) µg kg1 min1]. Although we did observe spikes in the EEG during propofol infusion, we did not routinely observe burst suppression. Antunes and colleagues14 observed burst suppression at infusion rates greater than those used in our study (1000 µg kg1 min1). Because of the modified MEF used by Antunes and colleagues, it is difficult to make a direct comparison with our data. Nonetheless, we believe that excessive EEG depression does not explain the stronger blunting effect of propofol on EEG activation by noxious stimuli.
In summary, we found that propofol, in a dose range that prevents movement, caused significant depression of EEG responses to noxious electrical and mechanical stimulation, while halothane did not.
![]() |
Acknowledgments |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Antognini JF, Saadi J, Wang XW, et al. Propofol action in both spinal cord and brain blunts electroencephalographic responses to noxious stimulation in goats. Sleep 2001; 24: 2631[ISI][Medline]
3 Inada T, Shingu K, Nakao S, et al. Effects of nitrous oxide on haemodynamic and electroencephalographic responses induced by tetanic electrical stimulation during propofol anaesthesia. Anaesthesia 1999; 54: 4236[CrossRef][ISI][Medline]
4 Wilder-Smith OH, Hagon O, Tassonyi E. EEG arousal during laryngoscopy and intubation: comparison of thiopentone or propofol supplemented with nitrous oxide. Br J Anaesth 1995; 75: 4416
5 Barter L, Dominguez CL, Carstens E, Antognini JF. The effect of isoflurane and halothane on electroencephalographic activation elicited by repetitive noxious c-fiber stimulation. Neurosci Lett 2005; 382: 2427
6 Krasowski MD, Harrison NL. General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci 1999; 55: 1278303[CrossRef][ISI][Medline]
7 Antognini JF, Carstens E, Atherley R. Does the immobilizing effect of thiopental in brain exceed that of halothane? Anesthesiology 2002; 96: 9806[CrossRef][ISI][Medline]
8 Nelson LE, Guo TZ, Lu J, et al. The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci 2002; 5: 97984[CrossRef][ISI][Medline]
9 Cuellar JM, Antognini JF, Eger EI, et al. Halothane depressesC-fiber-evoked windup of deep dorsal horn neurons in mice. Neurosci Lett 2004; 363: 20711[CrossRef][ISI][Medline]
10 Cuellar JM, Dutton RC, Antognini JF, et al. Differential effects of halothane and isoflurane on lumbar dorsal horn neuronal windup and excitability. Br J Anaesth 2005; 94: 61725
11 Dutton RC, Zhang Y, Stabernack CR, et al. Temporal summation governs part of the minimum alveolar concentration of isoflurane anesthesia. Anesthesiology 2003; 98: 13727[CrossRef][ISI][Medline]
12 Salford LG, Siesjo BK. The influence of arterial hypoxia and unilateral carotid artery occlusion upon regional blood flow and metabolism in the rat brain. Acta Physiol Scand 1974; 92: 13041[ISI][Medline]
13 Ravussin P, de Tribolet N. Total intravenous anesthesia with propofol for burst suppression in cerebral aneurysm surgery: preliminary report of 42 patients. Neurosurgery 1993; 32: 23640[ISI][Medline]
14 Antunes LM, Roughan JV, Flecknell PA. Effects of different propofol infusion rates on EEG activity and AEP responses in rats. J Vet Pharmacol Ther 2003; 26: 36976[CrossRef][ISI][Medline]
15 Veselis RA, Reinsel RA, Wronski M, et al. EEG and memory effects of low-dose infusions of propofol. Br J Anaesth 1992; 69: 24654[Abstract]
16 Forrest FC, Tooley MA, Saunders PR, et al. Propofol infusion and the suppression of consciousness: the EEG and dose requirements. Br J Anaesth 1994; 72: 3541[Abstract]
17 Reilly EL, Fuller GN, Wiggins RC, et al. Chronic halothane modification of EEG-like activity recorded from somatosensory cortex and deep nuclei in freely behaving rats. Neurotoxicology 1981; 2: 8390[ISI][Medline]
18 Dutta S, Matsumoto Y, Gothgen NU, et al. Concentration-EEG effect relationship of propofol in rats. J Pharm Sci 1997; 86: 3743[CrossRef][ISI][Medline]
19 Michenfelder JD, Theye RA. In vivo toxic effects of halothane on canine cerebral metabolic pathways. Am J Physiol 1975; 229: 10505
20 Kochs E, Bischoff P, Pichlmeier U, et al. Surgical stimulation induces changes in brain electrical activity during isoflurane/nitrous oxide anesthesia. A topographic electroencephalographic analysis. Anesthesiology 1994; 80: 102634[ISI][Medline]
21 Otto KA, Mally P. Noxious stimulation during orthopaedic surgery results in EEG arousal or paradoxical arousal reaction in isoflurane-anaesthetised sheep. Res Vet Sci 2003; 75: 10312[CrossRef][ISI][Medline]
22 Cuellar JM, Montesano PX, Antognini JF, et al. Application of nucleus pulposus to L5 dorsal root ganglion in rats enhances nociceptive dorsal horn neuronal windup. J Neurophysiol 2005; 94: 3548
23 Hofbauer RK, Fiset P, Plourde G, et al. Dose-dependent effects of propofol on the central processing of thermal pain. Anesthesiology 2004; 100: 38694[CrossRef][ISI][Medline]
24 Jurd R, Arras M, Lambert S, et al. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J 2003; 17: 2502
25 Ma J, Shen B, Stewart LS, et al. The septohippocampal system participates in general anesthesia. J Neurosci 2002; 22: RC200
26 Antognini JF, Wang XW, Carstens E. Isoflurane action in the spinal cord blunts electroencephalographic and thalamic-reticular formation responses to noxious stimulation in goats. Anesthesiology 2000; 92: 55966[CrossRef][ISI][Medline]
27 Sonner JM, Zhang Y, Stabernack C, et al. GABA(A) receptor blockade antagonizes the immobilizing action of propofol but not ketamine or isoflurane in a dose-related manner. Anesth Analg 2003; 96: 70612
28 Jinks SL, Martin JT, Carstens E, et al. Peri-MAC depression of a nociceptive withdrawal reflex is accompanied by reduced dorsal horn activity with halothane but not isoflurane. Anesthesiology 2003; 98: 112838[CrossRef][ISI][Medline]
29 Tzabazis A, Ihmsen H, Schywalsky M, Schwilden H. EEG-controlled closed-loop dosing of propofol in rats. Br J Anaesth 2004; 92: 5649