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Update in Intravenous Anaesthesia: Original Papers

Propofol: pro- or anticonvulsant?

Borgeat, A.

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European Journal of Anaesthesiology: May 1997 - Volume 14 - Issue - p 17-20

Abstract

Introduction

In the normally functioning nervous system, inhibitory factors balance excitatory mechanisms to permit normal activity. For this balance to be maintained, all of the biochemical apparatus of the central nervous system must be intact. Therefore acute changes in energy production, electrolyte balance or neurotransmitter concentration, as well as any abnormalities in protein synthesis or alterations in synaptic, membrane or network structure may provide the conditions leading to a seizure.

The sudden alteration in the central nervous system due to a high voltage electrical discharge corresponds to the definition of an epileptic seizure. This abnormal activity may arise from a group of neurones in either cortical or subcortical tissues. The tonic phase of the seizure and the loss of consciousness corresponds to the spread of the excitatory effect to the subcortical, thalamic and brainstem centres [1]. On the other hand, myoclonic activity refers to a series of rhythmic and/or arrhythmic muscular contractions which may be divided into either epileptic or non-epileptic activity [2]. In clinical practice it is extremely difficult, without EEG monitoring, to determine whether abnormal appearing seizure-like muscle movements are due to epileptiform activity or non-epileptic myoclonia.

Brain electrical stability is maintained by a subtle balance between excitatory and inhibitory impulses. Any event associated with either an increase of excitatory neurotransmitters (glutamate, aspartate), a decrease of inhibitory neurotransmitters (GABA, glycine) or a neuronal hyperexcitability (pentylene-tetrazol) may be linked with an epileptic seizure. Numerous anaesthetics (methohexitone, ketamine, enflurane) and analgesic drugs (high-dose opioids, local anaesthetics) have been reported to cause seizures clinically [3]. The role of propofol in this setting is still controversial. Although systemic investigations in both animals and humans strongly suggest that propofol possesses anticonvulsant properties [4-6], several case reports of post-propofol 'seizures' or opisthotonus have implicated propofol as a proconvulsant [7-9].

Proconvulsant properties

Abnormal movements, posturing and seizure-like activity related to the use of propofol have been reported in the literature. However, the significance of the case reports dealing with propofol as a proconvulsant agent must be interpreted with caution for the following reasons. First, the majority of the reported excitatory movements appeared either in patients with known epilepsy [7,10], or in patients receiving drugs with a known epileptogenic potential [11,12]. Secondly, in none of the reported cases of excitatory movements was a simultaneous EEG recording performed to confirm true cortical epileptic activity. One peculiar case report describes the occurrence of a seizure 5 days after propofol anaesthesia for no apparent reason [13]. In such circumstances it is clearly difficult to implicate propofol as the main factor. Only one case clearly involved propofol as a proconvulsant agent [14]. Here the clinical setting was special in that the patient was scheduled for a temporal lobectomy for intractable temporal epilepsy; infusion of propofol 2 mg kg−1 i.v. was associated with discharges of spikes, polyspikes and spike and slow wave complexes appearing 20-30 s after administering propofol and lasting for up to 7 min. In the same setting, electrocorticogram activation occurred in 17 out of 20 patients undergoing surgery for medically intractable epilepsy; of interest is the increase and extension of spike-waves that were observed with low-dose propofol [15].

Seizure-like behaviour, characterized by clonus of all four limbs, facial grimacing and tongue clonus were observed in mice receiving 75 mg kg−1 or more of propofol via the intraperitoneal route during induction and recovery from anaesthesia [6]. EEG recordings showed a generalized decrease in activity and the absence of any cortical epileptic activity. The timing and the nature of the excitatory movements are similar to those found in children (aged 6-12 years) during induction of anaesthesia with 3 mg kg−1 i.v. of propofol [17].

Dolin et al.[18] hypothesized that glycine antagonism may underlie the excitatory effects of propofol since they showed that strychnine, a glycine antagonist, but not bicuculline, an antagonist at the GABAA receptor, potentiated both excitatory and epileptic-like behaviour; however, their hypothesis remains debatable as they were not able simultaneously to correlate EEG and behaviour as the mice were given a neuromuscular blocking drug when the EEG was recorded.

In summarizing these publications two points emerge: first, propofol has never been proved to cause cortical fits in the absence of severe pre-existing epilepsy. Secondly, the excitatory phenomena reported might be the results of disinhibition in the context of low dosages of propofol depressing inhibitory - but not excitatory - subcortical centres. The fact that inhibitory central nervous system structures are more sensitive to depression than excitation is well known for all hypnotic agents. Thus it is possible to avoid pro-excitatory effects of propofol by using an adequate dosage regimen [17].

Anticonvulsant properties

On the other hand systematic studies in both humans and animals strongly suggest that propofol possesses antiepileptic properties. During electroconvulsive therapy, propofol consistently reduces seizure duration when compared to equipotent doses of methohexitone, whatever the measurement techniques used. Using a Cerebral Function Monitor, Dwyer et al.[19] compared propofol 1.51 mg kg−1 i.v. and methohexitone 1.19 mg kg−1 i.v.: the duration of seizures were 25% shorter with propofol. Simpson et al.[2] observed that seizure durations were 40% shorter following propofol 1.3 mg kg−1 i.v. than those following methohexitone 1.0 mg kg−1 i.v. using an isolated forearm technique. Propofol has been successfully used to control status epilepticus in a patient suffering from an overdose of chlormethiazole and unresponsive to therapeutic doses of phenytoin [2]. In another report, a patient with coxsackie encephalitis developed uncontrolled seizures despite combined treatment with diazepam, phenytoin, phenobarbitone and chlormethiazole. The fits were completely suppressed by a single bolus of propofol 100 mg i.v. and a continuous infusion of 5.7 mg kg−1 h−1[22]. Borgeat et al. successfully used propofol to manage a status epilepticus unresponsive to combined phenytoin, clonazepam and thiopentone boluses in a patient with a drained post-traumatic subdural haematoma [23].

These results are confirmed by animal studies. In mice, Lowson et al.[4] compared intraperitoneal administration of propofol 50 mg kg−1 i.v. and thiopentone 25 mg kg−1 i.v. against epileptiform seizures induced by electroshock and pentylene-tetrazol. Both drugs were equally effective against electroshock seizures but with these doses propofol provided a greater degree of protection against pentylene-tetrazol fits than thiopentone. In rabbits, De Riu et al.[5] demonstrated that a bolus of propofol 12 mg kg−1 i.v. and an infusion of 50 mg kg−1 h−1 suppressed cortical paroxysmal electrical activity in pentylene-tetrazol seizures. The infusion prevented the reappearance of epileptic patterns in the EEG and tonic-clonic attacks. Hartung et al.[24] demonstrated that propofol in a dose-dependent manner prevents, or elevates the threshold for, lignocaine-induced seizures in rats. The same results were obtained by Heavner et al.[25] in the treatment of bupivacaine-induced seizures in rats. Propofol also exhibits a dose-dependent anticonvulsant effect against bicuculline, kainic acid and N-methyl-d-aspartic acid when injected i.p. or i.v. [26].

In patients with documented epilepsy, Ebrahim et al.[27] found that propofol was safe but may interfere with the recording of EEG spikes. During awake craniotomies for surgery of epileptogenic foci, Soriano et al.[28] concluded that propofol has neither proconvulsant nor anticonvulsant effects in this particular setting; they also found that propofol did not disrupt the epileptiform activity on electrocorticography.

Postulated mechanisms of action

Although previous original investigations by Glen et al.[29] did not associate propofol with either anticonvulsant or proconvulsant properties, recent systematic investigations and well-documented case reports strongly support propofol as an effective anticonvulsant agent [4,5,17].

The efficacy of anticonvulsants is based on their ability either to prevent the spread of epileptic activity in the central nervous system or to increase the threshold of discharge of an epileptic focus. In this context, propofol possesses properties that further support the hypothesis of anti-epileptic efficacy.

Propofol, like benzodiazepines and barbiturates, potentiates GABA-mediated pre- and postsynaptic inhibition and interferes with di- and poly-synaptic excitation by decreasing the release of excitatory transmitters [30]. Propofol, in common with many other general anaesthetic agents, reduced membrane conductance and excitability [1,31].

Moreover, when compared to barbiturates whose antiepileptic action is mainly via their effect on GABAA receptors, propofol has a more uniform depressant action on the central nervous system including, in particular, subcortical centres. Thus, propofol may exert antiepileptic activity by interacting with multiple mechanisms involved in the genesis of epilepsy: interactions with GABA transmission membrane excitability and via NMDA receptors by decreasing the release of L-glutamate and L-aspartate - a property not shared by thiopentone - thus explaining its efficacy in patients resistant to conventional treatment and supported by its successful action against epileptic models involving different physiopathological mechanisms [4,5,25,26].

We may surmize that the vast majority of the reported propofol-induced 'seizures' during induction or emergence from anaesthesia were probably due to spontaneous excitatory movements of subcortical origin. We still do not have definitive explanations for the development of postoperative spasms of opisthotonus and myoclonus. Strong subcortical actions of propofol are well known; one of the possible explanations is that propofol would act in the spinal cord as a glycine antagonist like strychnine [32]. The 'cortical-subcortical' interactions of propofol are more pronounced at low plasma levels, which is consistent with the development of these at early induction or during the recovery from anaesthesia. It is unlikely that propofol gives rise to epileptiform convulsions; however, Ahmad and Pleuvry [26] demonstrated in mice that propofol offered no protection against the proconvulsant actions of the opioid drugs. They conclude that propofol may not be proconvulsant in its own right, but it may open the door to seizures elicited by other mechanisms. It may be possible, therefore, in certain susceptible patients whose cortical epileptic foci are inhibited by subcortical activity that propofol at low doses would favour the development of a seizure.

References

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    Section Description

    Seventh International Symposium on Intravenous Anaesthesia, Lausanne, Switzerland, 2-3 May 1997

    This publication is supported by grants from various pharmaceutical companies. The views in this publication are those of the authors and not necessarily those of supporting companies. Drugs and administration techniques referred to should only be used as recommended in the manufacturers' prescribing information.

    Keywords:

    Anaesthetics Intravenous, propofol; Anti-convulsants; Brain, convulsions, electroencephalography

    © 1997 European Society of Anaesthesiology