Departments of 1 Anesthesia and Pain Management, 2 Neurosurgery, and 3 Medicine (Neurology), The Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8
Corresponding author. E-mail: beheiry@uhnres.utoronto.ca
Accepted for publication: June 6, 2003
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Thirteen patients undergoing temporal lobe epilepsy surgery under general anaesthesia received alfentanil 30 µg kg1 and remifentanil 1 µg kg1 as i.v. boluses in sequence. The design was a randomized double-blind cross-over study. After opening the dura, electrocorticogram (ECoG) electrode contact strips were placed over the temporal and supratemporal neocortex and depth electrodes were inserted in the amygdala and hippocampus. Alfentanil 30 µg kg1 or remifentanil 1 µg kg1 were administered randomly in a blinded fashion. The ECoG was recorded continuously before and after the injection of each drug. The interictal epileptiform activity (spikes and sharp waves) above baseline was analysed.
Results. Both drugs increased epileptiform activity especially that recorded from depth electrodes in the temporal limbic structures. No epileptiform activity was recorded from the electrodes overlying the supratemporal neocortex before or after drug administration. The more potent activator was alfentanil, which caused an increase in activation from baseline of 99.8% compared with 67.4% for remifentanil. In addition, alfentanil activated the epileptiform activity in 3 patients in which remifentanil had no effect. There were no changes in heart rate after the opioid boluses. Both remifentanil and alfentanil caused significant reductions in blood pressure at 3 and 5 min after administration.
Conclusion. We conclude that at the doses used in this study, alfentanil is the better opioid for intraoperative activation of the ECoG in neurosurgical patients undergoing resection of a temporal lobe epileptic focus. This pharmacological activation of epileptiform activity assists in localizing and confirming the site of surgical excision. Neither alfentanil nor remifentanil activated epileptiform activity in non-epileptic brain tissue.
Br J Anaesth 2003; 91: 6515
Keywords: analgesics opioid, alfentanil; analgesics opioid, remifentanil; complications, epilepsy; measurement techniques, electrocorticogram; surgery, neurological
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Opioids also may cause signs of neuroexcitation such as nystagmus, muscle rigidity, myoclonus, and seizure-like activity.4 Hence, opioids could be candidates for evoking epileptic activity to identify epileptogenic foci. In keeping with this concept, we previously studied the activation of epileptiform discharges in patients with temporal lobe epilepsy during the administration of fentanyl and alfentanil.5 Both agents consistently increased spike and sharp wave activity on the intraoperative electrocorticogram (ECoG), however, alfentanil was found to be the most potent. These results and others69 showed that short-acting opioids are capable of inducing ECoG activation in epileptic patients. The objective of the current study was to complement the understanding of the potency profile of opioid-induced activation by comparing the effects of the newer short-acting opioid remifentanil with those of alfentanil on the ECoG during epilepsy surgery under general anaesthesia.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
No premedication was administered. The patients remained on their oral anticonvulsant medications until the day of surgery. Anaesthesia was administered according to a standardized procedure. At induction, propofol 12 mg kg1, fentanyl 35 µg kg1 and a neuromuscular blocking agent (succinylcholine, atracurium, or rocuronium) were given. Maintenance of anaesthesia consisted of nitrous oxide 70%/oxygen 30%, isoflurane and with further doses of atracurium or rocuronium as necessary. Routine anaesthetic monitoring was performed, including direct arterial blood pressure monitoring using a radial arterial line. The local anaesthetic bupivacaine 0.5% with epinephrine 1:100 000 was injected at the site of head pin insertion and the surgical wound to lessen the possibility of pain if awareness occurred. The end-tidal partial pressure of carbon dioxide was maintained at 2830 mm Hg.
After opening the craniotomy, the surgeon positioned three rows of eight contact ECoG electrode strips along the surface of the first and second temporal gyri and immediately above the sylvian fissure over the frontocentral neocortex. In addition, two four-contact depth electrodes were inserted orthogonally through the second temporal gyrus with their tips situated to record from the region of the amygdala and anterior hippocampus, respectively. Twenty minutes before ECoG monitoring, isoflurane was discontinued to lower the seizure threshold and droperidol 0.02 mg kg1 administered i.v. to provide some additional sedation.
At the time of the study, nitrous oxide was discontinued and a baseline ECoG was recorded for 10 min. Gas analysis monitoring ensured the end-tidal nitrous oxide and isoflurane were zero. The study drug (either alfentanil 30 µg kg1 or remifentanil 1 µg kg1) was injected i.v. according to the randomization schedule. The ECoG was again recorded for at least another 10 min after drug administration. When the ECoG had returned to baseline the sequence was then repeated with the second study drug. Blood pressure and pulse rate readings were continuously recorded during the duration of the study. Only the anaesthetist was aware of the identity of the study drug administered and its dosage. After the ECoG recordings were completed, the anaesthetic agents were resumed and the surgical resection performed.
The ECoG recordings were supervised and interpreted by the neurologist (RW) who was present in the operating room and blinded to the study drug. Postoperatively, the drug-induced ECoG epileptiform activity was quantified by the neurologist using standard criteria for identification of interictal epileptiform spikes or sharp waves (hereafter referred to as sharp waves).10 The number of sharp waves per epoch was tabulated from the most active site for each patient. An epoch was arbitrarily identified as a period of 1 min, and the epileptiform activity was quantified for at least 10 epochs (i.e. at least 10 min before and after each drug administration). The baseline activity was defined as the median number of spikes per epoch recorded during the 3 min before administration of each study drug. The peak activation of the study drug was the number of spikes at the epoch that showed the maximal effect in the 5 min after administration. ECoG activation was determined by the difference between the baseline spikes per epoch before drug administration subtracted from the peak spikes per epoch observed after drug administration. The percentage activation was calculated according to: [(peak spikes per epoch observed after drug administration baseline spikes per epoch before drug administration) / baseline spikes per epoch before drug administration] x 100. The location in the brain of ECoG activation was recorded as well as any evidence of ictal electrographic seizure activity.
Parametric and non-parametric data are expressed as mean (SEM), and median and range respectively. Changes in blood pressure and heart rate were analysed using the paired Students t-test with Bonferronis correction. The Friedman test (non-parametric two-way ANOVA) was used to test the hypothesis that there was no difference between the ECoG activity level (spikes per epoch) before and after administration of both study drugs. Multiple comparisons among baseline, drug effects and recovery were determined using the Wilcoxon signed ranks test. P<0.05 was considered statistically significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The characteristics of the patients were as follows: male/female ratio 7/6, mean age 30.6 yr (range 2056) and mean weight 67.5 (3.72) kg. The mean total dose of propofol administered before the beginning of ECoG recording was 208.5 (24.6) mg. The mean dose of droperidol was 1.6 (0.13) mg. The mean total dose of fentanyl given before the administration of the first study drug, and the time interval between the last dose of fentanyl and the administration of the first study drug were 334.62 (27.45) µg and 96.15 (8.48) min, respectively. This indicates that the fentanyl was unlikely to have any measurable effects on the ECoG activation induced by the study drugs, as our previous investigations showed that the action of fentanyl in activating epileptogenic brain tissue lasted for about 10 min.5 The interval between the administrations of the two study drugs in all patients ranged from 10 to 16 min. The second drug was always given after the ECoG returned to baseline activity in 11 patients or near baseline activity (±15% of baseline) in two patients.
The effects of the i.v. bolus of the two study drugs on blood pressure and heart rate are shown in Table 1. There were no statistical differences in heart rate over the 10-min period after the bolus of either drug. Both remifentanil and alfentanil reduced systolic blood pressure significantly at 3 and 5 min after the bolus. Two patients required doses of a vasoactive drug to maintain systolic blood pressure within 80% of the pre-operative level. One patient required 5 mg of ephedrine after the alfentanil bolus. A second patient received 10 mg of ephedrine after the remifentanil bolus and 5 mg of ephedrine after the alfentanil bolus. The mean PaCO2 value during the study period was 32.56 (3.2) mm Hg.
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Although the results of the present investigation and our previous report5 confirm that alfentanil, fentanyl and remifentanil all activate epileptic discharges; they suggest that these short-acting opioids in the doses employed had differing effects on the epileptic thresholds. Among these drugs, alfentanil seems to have more pronounced epileptogenic effects. The reproducibility and dose-dependency of the effects of the short acting opioids on the degree of ECoG activation remains to be determined. For example, in the current study, alfentanil 30 µg kg1 produced a similar degree of ECoG activation as did alfentanil 50 µg kg1 in our previous study.5 Moreover, Wass and colleagues9 showed that intraoperative remifentanil 2.5 µg kg1 i.v. bolus injection caused similar ECoG activation compared with remifentanil 1 µg kg1 in the present investigation.
In previous clinical studies, the short-acting opioids have been found to activate epileptiform activity only in epileptogenic areas in patients with epilepsy.5 8 9 In the present study, there was no activation of the temporal neocortex except in the two patients with structural lesions situated in the temporal cortex responsible for their neocortical temporal lobe seizures. Most significantly, there was no activation of epileptiform activity recorded in the frontocentral region above the Sylvian fissure in any of these patients with temporal lobe epilepsy. This supports the view that the activating properties of the short-acting opioids are specific for epileptogenic brain tissue.11 Despite these observations, only half of the centres using baseline ECoG during epilepsy surgery modify cortical resections based on intraoperative recordings.12 Hence, further investigations are necessary to evaluate the diagnostic yield of the short-acting opioids in localizing epileptogenic areas and the prognostic advantage of using these drugs.
The proconvulsant properties of opioids may be mediated by directly stimulating both the - and µ-opioid receptors13 or by enhancing excitatory glutamatergic neurotransmitter activity.14 The stimulatory opioid actions may also be induced by facilitation of excitatory influences on neuronal networks. Such actions might be a consequence of coupling between excitatory postsynaptic transients and spontaneously spiking epileptogenic neurones or attenuation of inhibitory GABAergic interneurones.15 16
In conclusion, this study showed that both alfentanil 30 µg kg1 and remifentanil 1 µg kg1 cause significant activation of epileptogenic areas in epileptic patients undergoing temporal lobe epilepsy surgery. The use of short-acting opioids in temporal lobe epilepsy surgery can assist in distinguishing the epileptogenic zones from nonepileptogenic brain tissue. However, further investigations are necessary to elucidate the rationale of opioid selection and the clinical utility of opioid activation in epilepsy surgery.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Kofke WA, Tempelhoff R, Dasheiff RM. Anesthetic implications of epilepsy surgery. J Neurosurg Anesthesiol 1997; 9: 34972[ISI][Medline]
3 Wennberg R, Quesney F, Olivier A, Dubeau F. Induction of burst suppression and activation of epileptiform activity after methohexital and selective amygdalo-hippocampectomy. Electroencephal Clin Neurophysiol 1997; 102: 44351[CrossRef][ISI][Medline]
4 Scott JC, Sarnquist FH. Seizure like movements during a fentanyl infusion with absence of seizure activity in a simultaneous EEG recording. Anesthesiology 1985; 62: 81290[ISI][Medline]
5 Manninen P, Burke S, Wennberg R, et al. Intraoperative localization of an epileptogenic focus with alfentanil and fentanyl. Anesth Analg 1999; 88: 11016
6 Templehoff R, Modica PA, Bernardo KL, et al. Fentanyl induced electrocorticographic seizures in patients with complex partial epilepsy. J Neurosurg 1992; 77: 2018[ISI][Medline]
7 Cascino GD, So EL, Sharbrough FW, et al. Alfentanil-induced epileptiform activity in patients with partial epilepsy. J Clin Neurophysiol 1993; 10: 5205[ISI][Medline]
8 Ross J, Kearse LA, Barlow MK, et al. Alfentanil-induced epileptiform activity: a simultaneous surface and depth electroencephalographic study in complex partial epilepsy. Epilepsia 2001; 42: 2205[ISI][Medline]
9 Wass CT, Grady RE, Fessler AJ, et al. The effects of remifentanil on epileptiform discharges during intraoperative electro corticography in patients undergoing epilepsy surgery. Epilepsia 2001, 42: 13404
10 Gloor P. Contributions of electroencephalography and electrocorticography to the neurosurgical treatment of epilepsies. In: Purpura D, Penry J, Walter R, eds. Neurosurgical Management of the Epilepsies. New York: Raven Press, 1975; 59105
11 Wennberg R. Alfentanil-induced epileptiform activity. Epilepsia 2002; 43: 206[ISI][Medline]
12 Spencer DD, Ojemann GA. Overview of therapeutic procedures. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies. New York: Raven Press, 1993; 455471
13 Zhu H, Zhou W. Morphine induces synchronous oscillatory discharges in the rat locus coeruleus. J Neurosci 2001; 21: 15
14 Siggins GR, Henriksen SJ, Chavkin C, et al. Opioid peptides and epileptogenesis in the limbic system: cellular mechanisms. Adv Neurol 1986; 44: 50112[Medline]
15 Zieglgansberger W, French ED, Siggins GR, Bloom FE. Opioid peptides may excite hippocampal pyramidal neurons by inhibiting adjacent inhibitory interneurons. Science 1979; 205: 41517[ISI][Medline]
16 Nicoll RA, Alger BE, Jahr CE. Enkephalin blocks inhibitory pathways in the vertebrate CNS. Nature 1980; 287: 225[ISI][Medline]