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ANESTH ANALG 433 1990;70:43?-44

Review Article

Pro- and Anticonvulsant Effects of (Part 11)

Paul A. Modica, MD, Rene Tempelhoff, MD, and Paul F. White, PhD, MD

Key Words: ANTICONVULSANTS. BRAIN, PRO- , , and AND ANTICONVULSANTS. COMPLICATIONS, produce varying effects on electroencephalographic . TOXICITY, CONVULSIONS. (EEG) activity. In the first part of this review article, we described the pro- and anticonvulsant effects of Part I the inhaled anesthetics and the () Introduction . Variations in dosages, methods of Inhalation anesthetics drug administration, and EEG documentation, as Volatile agents well as differences in the patient populations, con- tribute to the contrasting effects of these drugs on central (CNS) activity. In the second part of this pharmacologic review, Investigational volatile agents we describe the reported EEG effects of the - compounds (including the , Intravenous analgesics , , , and propo- Opioid (narcotic) analgesics fol), local anesthetics, muscle relaxants, anticholines- Meperidine terases, and . The evidence for drug- and its analogues induced changes in EEG activity will be critically Summary reviewed with respect to the patient population (i.e., epileptic nonepileptic), documentation (i.e., EEG Part I1 vs clinical signs), and methodology (i.e., surface vs Introduction depth electrodes). Intravenous anesthetics Sedative-h ypnotics Intravenous Anesthetics Barbiturates Etomidate Sedu f ive-Hypnat ics Benzodiazepines Ke tamine Barbiturates. In patients without a history of sei- zure disorder, low doses of thiopental and methohex- Local anesthetics ital can cause activation of the EEG producing 15- Anesthetic adjuvants 30-Hz waves. With increasing doses of these seda- Muscle relaxants tive-hypnotic drugs, slower waveforms of higher An ticholines terases amplitude appear that progress to Anticholinergics at high doses (157-161) (Figure 3). Electroencephalo- Summary graphic or clinical activity has not been re- ported in nonepileptic patients treated with these Part I of this review article appeared in the previous issue ultrashort-acting barbiturates (Table 5). However, (Anesth Analg 1990;70:303-15). Received from the Department of Anesthesiology, Washington excitatory phenomena such as abnormal muscle University School of Medicine, St. Louis, Missouri. Accepted for movements, hiccoughing, and may occur publication October 10, 1989. with both thiopental and methohexital. These excita- Address correspondence to Dr. White, Department of Anesthe- siology, Box 8054, Washington University School of Medicine, 660 tory side effects are more common with methohexital South Euclid Avenue, St. Louis, MO 63110. (64,162,163).

01990 by the International Research Society 434 ANESTH ANALG MODICA ET AL. 1990;70:43344

THIOPENTAL EEG produced EEG patterns in these epileptics, which closely resembled the changes produced by the drug Awake in normal patients (16,25) (Table 5). In patients with psychomotor in whom methohexital pro- stage 1 1duced EEG and clinical seizure activity, subsequent administration of thiopental did not (12). In humans, thiopental has well-known anticonvul- sant properties (Table 6). After an initial intravenous injection of 250-1000 mg given slowly until cessation of , continuous thiopental infusions (80-120 34mg/h) for as long as 13 days have been used success- fully in intubated and ventilated patients to control refractory to more conventional anticonvulsant drugs (170,171). The infusions were titrated to produce a burst suppression EEG pattern. 5 - I Interestingly, the seizures did not recur after discon- tinuation of the infusion. 50 crV I - In one series of more than 900 patients with 2s unspecified types of epilepsy, the frequency of epi- Figure 3, The EEG changes induced by thiopental. Consciousness is lost early in stage 1. Stages 2 and 3 represent surgical anesthesia. leptiform activity during anesthetic induction with coma is indicated in stages 4 and 5. (From Hudson R, methohexital was much less when compared with the Stanski D, Saidman L, Meathe E. A model for studying depth of previous sleep and awake EEGs of these epileptics anesthesia and acute tolerance to thiopental. Anesthesiology 1983; 59:301-8, with permission.) (53). Methohexital has never been demonstrated to provoke either EEG or clinical seizure activity in The tendency of methohexital to provoke convul- patients with generalized convulsive disorders sions during intravenous induction (0.5-1 .O mgikg) in (11,159). Thus, although the epileptogenic effects of patients with a history of epilepsy is well known methohexital in patients with psychomotor epilepsy (164-166) (Table 5). Seizure activity has also been are well established, the ultrashort-acting barbitu- reported after intramuscular (10 mg/kg) or rectal (25 rates are predominantly potent anticonvulsant mg/kg) methohexital administration in children with agents. (167). Low-dose (50.5 mgikg) methohexital has proved valuable in the activation of Etomidnte. The EEG patterns produced by etomi- cortical EEG seizure discharges in patients with psy- date are similar to those associated with thiopental chomotor (temporal lobe) epilepsy (11,12,168). This (144,157,172). The main EEG difference between technique has been used during intraoperative elec- equihypnotic doses of etomidate (0.3 mg/kg) and trocorticography to activate epileptic foci during tem- thiopental(3.5 mg/kg) is a lack of beta activity during poral lobectomy (12). Methohexital also adds valuable ”light stages” of etomidate anesthesia (157). Higher negative EEG evidence in cases of suspected behavior doses of etomidate produce burst suppression pat- disorders (11). Only nonspecific EEG effects have terns analogous to the barbiturate compounds been reported after methohexital administration to (157,172). Involuntary myoclonic movements are patients with a history of generalized seizure disor- common during induction of anesthesia with etomi- ders (11,159). date, and occasionally resemble generalized convul- In three epileptic patients, thiopental activated sive seizures (145,157,173). This can per- brief periods (<7 s) of bilateral atypical and polyspike sist into the recovery period (144-146). There have waves during induction, which were not associated also been reports of generalized or focal convulsive- with observable seizures (63). The brief periods of like movements occurring in ventilated patients re- spike waves detected in this report were most likely ceiving long-term etomidate infusions for sedation associated with “light” levels of thiopental anesthe- (174,175). However, EEG correlation was not per- sia, an accepted method for eliciting convulsive ten- formed and none of these patients had a previous or dencies (25,53,169).Similar intermittent spiking activ- subsequent history of epilepsy. In one of these re- ity also was detected with depth electrodes after low ports (175), the involuntary motor activity was sup- doses of thiopental (<1.5 mg/kg, IV) administered to pressed with higher doses of etomidate. patients with temporal lobe epilepsy (53). Further- Whether these convulsivelike movements associ- more, larger doses of thiopental (>5 mg/kg, IV) ated with etomidate administration in nonepileptic ANESTHETICS AND SEIZURES ANESTH ANALG 435 1990;70:43344

Table 5. Proconvulsant Effects of Sedative- and Local Anesthetics in Humans Seizure documenta tion Type of EEG Clinical EEG electrodes Agent Population report study used in study Reference

Thiopental Nonepileptic - - Surface 157, 158, 161 Epileptic - - SurfaceIdepth 16, 25, 63 Methohexital Nonepileptic - - Surface 159, 160, 168 Epileptic + + Surface 11, 12, 164 Etomidate Nonepileptic + + Surface 174-176 Epileptic + + Surface/depth 53, 176, 180, 181 Benzodiazepines Nonepileptic - - Surface 186, 187 Epileptic + + Surface 18&190 Ketamine Nonepileptic + - Surface 140, 186, 197-204 Epileptic + + SurfaceIdepth 16, 63 Propofol Nonepilep tic - - Surface 214, 215 Epileptic - + Surface 216 Local anesthetics Nonepileptic + + Surface 221-225, 230, 231 Epileptic + + Depth 220

t, presence of seizures; -, absence of seizures; EEG, electroencephalographic.

Table 6. Anticonvulsant Effects of Sedative-Hypnotics and Etomidate infusion produces a 2- to 12-fold in- Local Anesthetics in Humans crease in the amplitude of median (177) and posterior Anticonvulsant tibia1 (178) nerve somatosensory evoked potentials. Type of EEG documentation electrodes The increased amplitude may represent an alteration Clinical EEG used in of the balance of inhibitory and excitatory influences Agent report study study Reference in the thalamocortical tracts (178,179). This suggests Thiopental + + Surface 170, 171 that etomidate could produce myoclonus either by Methohexital NIA NIA blockade of inhibition or enhancement of excitability Etomidate + + Surface 184, 185 in these subcortical CNS tracts. Higher plasma levels Benzodiazepines + + Surface 191-193 Ketamine + NIA 9, 10, 212 of etomidate may prevent myoclonic movements by Propofol + NIA 217 depressing both inhibitory and excitatory neuronal Local anesthetics + NIA 23%241 firing (175).

t, successful termination of status epilepticus reported; EEG, electroen- It is also possible that the convulsivelike move- cephalographic; NIA, information not available. ments associated with etomidate could be due to subcortical seizure activity. Depth electrode investiga- patients represent seizure activity is unclear. Surface tions during etomidate administration have been per- EEG studies performed in patients without a history formed in two patients, both suffering from temporal of epilepsy treated with etomidate have not revealed lobe epilepsy (180). In these two cases, etomidate spiking activity during these myoclonic movements (0.2-0.3 mgikg, IV) induced an electrographic seizure (144,157,172). In some of these patients, simulta- originating from the known subcortical seizure foci. neous electromyographic, plantar reflex, and soleus Because of concomitant nondepolarizing muscle relax- muscle M-wave/H-reflex recordings indicated that ant administration, it is unknown whether or not the etomidate-induced myoclonus was of spinal myoclonic or convulsivelike movements would have (nonepileptic) origin (144). Conversely, in one report been associated with this subcortical seizure activity. of more than 30 nonepileptic patients undergoing Surface EEG studies in patients with a history of open heart surgery, surface EEG monitoring demon- epilepsy have further documented the proconvulsant strated generalized epileptiform activity in approxi- effects of etomidate (53,176,181) (Table 5). In 39 mately 20% of the cases after etomidate induction epileptic patients, convulsionlike potentials were re- (176) (Table 5). However, no myoclonic or convul- corded within 30 s after anesthetic induction with sivelike movements were reported during these epi- etomidate and occurred more frequently than during sodes of apparent EEG seizure activity. sleep or awake EEG testing (53). Interestingly, no 436 ANESTH ANALG MODICA ET AL. 1990;70:43344

myoclonic or convulsivelike movements were re- The occurrence of status epilepticus has been re- ported during these episodes of etomidate-induced ported with (188-190). Although observed EEG seizure activity. In patients undergoing electro- in one child with petit ma1 seizures (189), this para- corticography before temporal lobectomy for intrac- doxical effect of diazepam usually occurs in patients table complex partial seizure disorders, etomidate with Lennox-Gastaut syndrome, a form of secondary (0.2-0.3 mg/kg, IV) administered during or within 10 (188,190). In these epileptics, min of discontinuation of 50%-70% nitrous oxide benzodiazepines can induce brief episodes of EEG (N,O) activated EEG epileptiform activity in more and clinical seizure activity (Table 5). than 75% of the patients (176,181). The well-known In general, the benzodiazepines used in anesthetic EEG activating effects of N,O cannot be ruled out as practice possess potent anticonvulsant properties in an additive factor in these two reports. Furthermore, both humans and animals. In humans, diazepam correlation between EEG and clinical seizure activity (191) and (192,193) have been widely used may have been prevented by concomitant nondepo- to terminate episodes of status epilepticus (Table 6). larizing neuromuscular blockade. Interestingly, after Suppression of EEG seizure activity has been demon- etomidate induction, one of the epileptics studied strated after intravenous (191), intramuscular (194), exhibited grand ma1 convulsivelike movements be- and rectal (195) routes of administration. The absorp- fore the institution of muscle relaxation and EEG tion and efficacy of rectal diazepam appears to be monitoring (176). Thus, it was unclear whether the analogous to or superior to that of the intramuscular clinical seizure observed in this case was due to route (195). (15 mg, IM) is as effective as corticalisubcortical epileptiform activity or exagger- diazepam (20 mg, IV) in abolishing interictal spikes ated nonepileptic myoclonus. (194). Thus, although intravenous diazepam (or mi- Etomidate appears to possess anticonvulsant prop- dazolam) is often regarded as the drug of choice in erties in both humans and animals. The drug in- the emergency therapy of generalized seizure disor- creased the threshold for both narcotic-induced EEG ders, it appears that both intramuscular midazolam seizures in dogs (8) and -induced seizures and rectal diazepam are acceptable alternative routes in rats (182). In amygdaloid kindled rats, etomidate of administration in situations where it is not possible suppressed seizure activity (183). In humans, suc- to establish intravenous access (194). Not surpris- cessful termination of EEG-documented status epi- ingly, the duration of antiseizure activity after lepticus has been demonstrated after etomidate ad- lorazepam (4-8 mg, IV) is longer than that achieved ministration (184,185) (Table 6). with intravenous diazepam (193). Because of its high Overall, etomidate has both pro- and anticonvul- affinity for the (196), repet- sant effects on EEG. In view of the finding that higher itive doses of lorazepam are rarely required for con- doses of the drug suppress low dose-induced invol- tinuing control of seizures. Overall, the benzodiaz- untary motor activity, it appears that the dose and epines are effective in controlling status epilepticus rate of etomidate administration probably determines occurring in more than 90% of patients with general- which of its contrasting effects on the seizure thresh- ized seizure disorders. Also, they are effective in old will occur in a particular clinical setting. Further- approximately 60% of cases of status epilepticus more, additional studies of the EEG effects of pro- occurring in partial epilepsy (188). gressively higher doses of etomidate (without concomitant muscle relaxation) are required to deter- Ketarrrine. In patients without a history of seizure mine if etomidate-induced myoclonus is of epileptic disorder, cortical EEG recordings 1-2 min after ket- or nonepileptic origin. amine (1-3 mg/kg, IV) are characterized by the initial appearance of fast beta activity at 3040 Hz, which is Benzodiazepines. After diazepam (10-20 mg, IV) an followed by moderate-voltage theta activity mixed increase in EEG amplitude can be seen in the beta with high-voltage delta waves recurring at 3-4-s band between 12 and 22 Hz. There is also a reduction intervals (140,186). Higher doses of ketamine (>2 in activity and transient increases in amplitude mgikg, IV) produce a burst suppression EEG pattern. in the deltaitheta band (186,187). The increased activ- The 30-40-Hz activity is maximal frontally and tends ity in the beta range is probably related to the major to persist even when the theta and delta activity clinical effect of the benzodiazepines (e.g., sedation, appears. The variety of EEG patterns produced by ). The percentage of beta activity appears to racemic ketamine have been attributed to differences correlate with diazepam levels (187). Electroen- between the drug’s two optical isomers with regard cephalographic or clinical seizure activity has not to their anesthetic potency and EEG effects (Figure 4) been reported in nonepileptic patients treated with (197,198). When the more potent S(+) isomer of benzodiazepines (Table 5). ketamine is infused to produce a state of clinical ANESTHETICS AND SEIZURES ANESTH ANALG 437 1990;70:43N44

S (+) Ketamine R(-) Ketamine tion, catalepsy, muscle twitching, and bizarre pos- turing. Furthermore, ketamine-induced subcortical activation was implicated as the cause of severe myoclonus in infants with myoclonic (Kinsborne syndrome) (208). In view of these find- F2-02 ings, it is possible that depth electrode EEG record- ings in nonepileptic patients treated with ketamine cz-01 would detect subcortical seizure activity with or with- out convulsivelike movements. It is well-established that ketamine will activate epileptogenic foci in patients with known seizure disorders (16,63) (Table 5). In nine epileptics with cortical and depth electrode implants, Ferrer-Allado - [ 5oFV et al. (16) demonstrated seizure activity originating IS subcortically in the limbic and thalamic areas after Figure 4. A four-lead EEG pattern demonstrating the maximal ketamine (24 mg/kg, IV) (Figure 5). The seizures slowing during or immediately after the infusion of S(+) ketamine or the R(-) isomer. (From White PF, Schuttler J, Shafer A, Stanski were accompanied by tonic-clonic activity in half the DR, Horai Y, Trevor AJ. Comparative of the ket- patients; however, they were not always manifested amine isomers: studies in volunteers. Br J Anaesth 1985;57:197- on the surface EEG recordings. Furthermore, admin- 203, with permission.) istration of a smaller dose of ketamine (0.5-1.0 mg/kg, IV) produced only subcortical seizure activity (with- anesthesia, a progressive decrease in EEG amplitude out loss of consciousness) and/or increased frequency and frequency occurs, followed by intermittent high- in the 15-50-Hz range, similar to that demonstrated amplitude polymorphic delta activity. In contrast, in nonepileptics. Thus, it appears that 22 mg/kg of larger doses of the less potent R(-) ketamine are intravenous ketamine is required to activate either unable to produce the same degree of EEG suppres- cortical EEG or clinical seizure activity in epileptics. sion. Celesia et al. (209) in a study of 26 epileptic patients Electroencephalographic seizure activity has not given ketamine (0.5-2.0 mg/kg, IV) did not report any been reported in nonepileptic patients during ket- cortical or clinical seizure activity with surface EEG amine administration. However, the occurrence of monitoring. Conversely, intermittent paroxysmal ep- myoclonic and seizurelike motor activity has been ileptiform discharges were recorded on surface EEG observed clinically in nonepileptic children and in six of eight epileptic patients given ketamine (4-10 adults after intravenous (2 mg/kg) or intramuscular mg/kg, IM, followed by 1-20 mg/kg, IV, in divided (10-12 mgikg) ketamine (199-203) (Table 5). These doses) (63). Three of these patients manifested clini- movements were noted soon after induction (199) cal convulsions with increases in seizure activity for and later after additional incremental doses (202- up to 3 mo after ketamine administration. Subcortical 204). Unfortunately, simultaneous EEG recordings withdrawal seizures have been reported for up to 5 were not available. In four nonepileptic asthmatics days after discontinuation of ketamine in rats that receiving aminophylline, extensor-type seizures oc- were chronically exposed to the drug (210). curred within minutes after induction with ketamine Ketamine appears to possess anticonvulsant prop- (1-2 mg/kg, IV) (205). In mice, aminophylline appears erties in both humans and animals. In mice, ketamine to decrease the seizure threshold for ketamine (205). prevented both electrical and - Although surface EEG recordings have not re- induced seizures (21l), whereas in rats, the drug vealed seizure activity in nonepileptic patients terminated 3-mercaptopropionic acid-induced sei- treated with ketamine, it is conceivable that the zures (84). Corssen et al. (212) suggested that ket- convulsivelike movements observed in these nonepi- amine may have anticonvulsant properties because it leptic patients could be due to subcortical seizure effectively terminated tonic-clonic convulsions in two activity. After ketamine administration to normal patients (Table 6). Fisher (9) reported that ketamine cats, subcortical seizure activity has been recorded (5-20 mg/kg, IM) produced cessation of grand ma1 from chronically implanted depth electrodes. In these seizure movements in two children with a history of cats, ketamine produced intermittent hypersyn- multiple admissions for resistant status epilepticus. chrony with spiking activity in the limbic system, Furthermore, in three children with febrile convul- which subsequently spread to subcortical nuclei and sions unresponsive to conventional antiepileptic ther- the neocortex (6,206,207). This subcortical and corti- apy, ketamine (14 mg/kg, IV, and 2.5 mg/kg, IM, on cal EEG seizure activity was associated with excita- separate occasions) rapidly terminated clinical seizure 438 ANESTH ANALG MODICA ET AL. 1990;70:433-44

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Figure 5. Electroencephalographic changes SPONTANEOUS SE/ZUU€ ACJIVIJl: BIZARRE B€HAV/OR H after ketamine (2-4 mgikg, IV). The EEG 1 5 shows the onset of electrical seizure activity in the left mid gyrus and its spread to other limbic and thalamic areas. The cortical elec- trodes (C,-P,) do not reflect seizure activity. LT MID PES ----,-- --A --.----Ad I (From Ferrer-Allado T, Brechner VL, Dy- LT ANT GYRUS --____1,-- y___- Ic mond A, Cozen H, Crandall P. Ketarnine- LT MID GYRUS ~*n~~~~~~~\-.-,~-.~-~*r~-.mv.~r~~.rryr*rinduced electroconvulsive phenomena in RT AMYG human limbic and thalamic regions. Anes- I RTANTPES . -. thesiology 1973;38:33344, with permis- RT MID PES -I-- --__u__I I sion.)

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activity (10). In these children, ketamine's rapid onset has been reported to produce excitatory activity (e.g., of anticonvulsant action via the intramuscular route movements, myoclonus, muscle , and hic- appeared to be a potential advantage over conven- coughs) during induction of anesthesia (213). Al- tional intravenous anticonvulsants in treating status though the incidence of the excitatory effects with epilepticus. Unfortunately, in all of these reports, propofol may be higher than with thiopental, the simultaneous EEG recordings were not available to incidence appears to be less than with either metho- further support these apparent anticonvulsant ac- hexital or etomidate (213). Whether these abnormal tions for ketamine. In addition, the available evidence movements associated with propofol induction rep- indicates that ketamine possesses primarily potent resent true seizure activity or merely nonepileptic cerebral stimulatory properties, especially in patients myoclonia is unknown, as simultaneous EEG record- with seizure disorders in whom the drug activates ings have not been performed during these excitatory subcortical seizure activity. side effects. Unlike etomidate (174,175) prolonged seizurelike excitatory movements during or after con- Propofol. Propofol is a newer intravenous anes- tinuous infusion of propofol have not been observed. thetic that can be used for both induction and main- In patients without a history of seizure disorder, tenance of general anesthesia. In humans, propofol cortical EEG changes similar to those produced by ANESTHETICS AND SEIZURES ANESTH ANALG 439 1990;70:43344

thiopental were demonstrated after propofol (2 mg/ monkeys treated with have revealed a char- kg, IV) (214,215). Neither epileptiform activity nor acteristic preconvulsive pattern of diffuse slowing excitatory movements were reported (Table 5). How- and irregular appearance of large spikes leading ever, in three patients with a history of intractable directly into generalized seizure activity (232). How- temporal lobe epilepsy, Hodkinson et al. (216) de- ever, similar to the findings for lidocaine in humans, scribed activation of epileptogenic foci after a bolus of mepivacaine, bupivacaine, and etidocaine do not propofol (2 mg/kg, IV). In each case, electrocorticog- consistently produce distinctive preconvulsive EEG raphy revealed frequent discharges of spikes, poly- changes in animals (229,232,233). spikes, and spike and wave complexes 20-30 s after Depth electrode EEG studies in both animals injection, continuing for up to 7 min. No patient (232,234,235) and epileptic patients (220) have re- exhibited excitatory motor effects and the EEG sei- vealed a seizure focus in the limbic system (amyg- zure activity ceased spontaneously. dala, ) after the administration of local Propofol appears to possess anticonvulsant prop- anesthetics. Ablation of the amygdala has also been erties clinically. However, there is no EEG documen- reported to prevent -induced seizures tation of this effect (Table 6). In a 21-yr-old woman (64). In rats (236), selective metabolic activation of the with refractory status epilepticus caused by viral limbic system has been demonstrated during , Wood et al. (217) reported that a single lidocaine-induced preseizure activity. These findings bolus of propofol(lO0 mg, IV) completely suppressed support a subcortical origin for local anesthetic- clinicaI seizure activity. After this, a continuous induced seizures and suggest that the preconvulsive propofol infusion at 5-7 mg.kg-'.h-' continued to signs and symptoms of CNS toxicity in humans may control her convulsions for 18 days. However, her be manifestations of psychomotor seizures (64,237). seizures recurred whenever the infusion was discon- Local anesthetics have also been demonstrated to tinued. In two reports of patients with depressive possess anticonvulsant properties in both humans disorders undergoing electroconvulsive therapy, the and animals. In general, the anticonvulsant activity of mean clinical seizure duration was significantly re- local anesthetic agents occurs at subtoxic blood levels duced after propofol (1.3-1.5 mg/kg, IV) compared (64,229). In cats in which seizures were produced by with methohexital (1 mg/kg, IV) (218,219). intracortical , a marked anticonvulsant effect was noted at lidocaine blood levels of <4.0 pg/mL (229). Blood levels >4.5 FgIrnL produced signs of cortical irritability, with seizure activity at levels B7.5 Local Anesthetics pg/mL. In humans, subtoxic doses of lidocaine (1-2 Local anesthetics are well-known in pa- mg/kg, IV), followed by an infusion of 1-3 mgkg-'. tients with and without a history of seizure disorder h-', have been used to terminate status epilepticus (220,221) (Table 5). Clonic or tonic-clonic activity (238-241) (Table 6). In patients undergoing electro- (64) has occurred after the administration of local convulsive therapy, investigators (242,243) have anesthetics via the intravenous (220-222), epidural found that prior administration of lidocaine (or pro- (223,224), or peripheral nerve block (225) routes. caine) prevents and/or reduces the duration of elec- Local anesthetic-induced convulsions have not been trically induced seizures. In one of these studies reported after subarachnoid administration (226- (242), after induction of anesthesia with thiopental 228). High blood levels result from accidental intra- (4 mg/kg, IV) progressively higher doses of lidocaine vascular injection, accumulation after repeated injec- (1-11.2 mg/kg, IV) failed to produce seizure activity tions, and rapid systemic absorption from a highly and were associated with progressively shorter dura- vascular area (229). Thus, seizures may be either tions of electrically induced convulsions. Further- immediate or delayed after local anesthetic adminis- more, a lidocaine dose of 16.5 mg/kg, IV (which tration. produced tonic-clonic convulsions in 50% of the pa- Surface EEG recordings have not correlated well tients) prevented electroshock-induced seizures. Un- with the preconvulsive signs and symptoms of local fortunately, none of these studies regarding the an- anesthetic toxicity (64,229). Abnormal preseizure ticonvulsant effects of local anesthetics had the EEG activity was not found in humans after the benefit of simultaneous EEG documentation. production of preconvulsive signs and symptoms of Local anesthetics can possess both proconvulsant toxicity by a variety of local anesthetic compounds and anticonvulsant properties because of their mem- (222,230,231). The onset of cortical EEG seizure activ- brane-stabilizing effects (244). Although local anes- ity was simultaneous with tonic-clonic muscle activ- thetics generally inhibit neuronal activity, it appears ity. In contrast, depth electrode EEG recordings in that excitatory pathways are more resistant than 440 ANESTH ANALG MODICA ET AL. 1990;70:43?44

inhibitory pathways (64,229,242,245). Thus, at sub- line-induced increases in afferent muscle spindle ac- toxic doses, local anesthetics can act as anticonvul- tivity and to increases in Paco, generated by in- sants, , and analgesics (238,246,247). At creased muscle carbon dioxide (CO,) production higher drug concentrations, resistant unopposed ex- (258). In addition, the lack of EEG activation after citatory pathways can cause frank convulsions. Ulti- succinylcholine injection in dogs with disrupted mately, with further increases in local anesthetic blood-brain barriers (259) further supports this hy- blood levels all pathways are inhibited, resulting in a pothesis and indicates that intravenous succinylcho- generalized state of CNS (64,229,234). line does not possess proconvulsant properties. Usubiaga et al. (260) reported that succinylcholine terminated procaine- and lidocaine-induced muscle Anesthetic Adjuvants seizure activity in humans, but did not affect the duration or pattern of EEG seizure activity. In mon- Muscle Relaxants keys, prior administration of gallamine increased the In humans, none of the muscle relaxants used in lidocaine EEG convulsive threshold (229). In humans, clinical anesthesia have been reported to cause either none of the muscle relaxants used in clinical anesthe- EEG or clinical seizure activity. However, at high sia have been reported to possess anticonvulsant concentrations, the primary metabolite of atracurium, properties. , can produce EEG and clinical seizure activity in animals (248-250). In anephric patients, short-term infusion of atracurium (3-5 pg.kg-'. min-') for renal transplantation produced maximum Anticholinesterases laudanosine blood levels of 0.3-1.0 pg/mL (251). No None of the inhibitors (CHEIs) used in intraoperative EEG changes or postoperative seizures clinical anesthesia have been reported to cause EEG were associated with these laudanosine concentra- or clinical seizure activity in humans. However, ace- tions. However, chronic infusion of atracurium (10- tylcholine is an important component of seizure ac- 15 pg.kg-'.min-') to renally impaired patients in the tivity (261). In contrast to the , brain intensive care unit was associated with laudanosine levels and cerebrospinal fluid turnover concentrations as high as 5.1 pg/mL (252), blood increase during seizures. In animals monitored with levels shown to produce convulsions in rabbits (249). depth electrodes (262), CHEIs induced cortical and/or Significantly higher laudanosine concentrations (>17 subcortical EEG seizure activity. These drugs also pg/mL) are required to induce seizures in dogs lower the threshold for - and pentylene- (248,249). Thus, although it appears that laudanosine tetrazol-induced convulsions (261). levels during surgery are of little (if any) clinical In humans, appears to reverse CNS concern, additional studies regarding the CNS effects depression by increasing central activity of long-term atracurium infusions are needed, espe- (263). Its tertiary amine structure allows it to more cially in patients with hepatic failure in whom the freely cross the blood-brain barrier. Physostigmine half-life of laudanosine is significantly prolonged can reverse -induced sedation by revers- (253). ing the acetylcholine depletion (264). For drugs such In animals, succinylcholine applied topically to the as diazepam (265), which cause sedation via non- produced intense EEG stimulation cholinergic pathways (e.g., GABAnergic mecha- and seizure activity that was believed to be due to nisms), physostigmine-induced central cholinergic direct depolarization of (254). In both hu- activation may produce awakening because of a gen- mans (255,256) and animals (257,258) anesthetized eralized "arousal" effect (263). This CNS "arousal" with halothane, intravenous succinylcholine pro- effect of physostigmine has been noted on EEG. In duced EEG arousal that was associated with signifi- both dogs (266) and humans (263) anesthetized with cant increases in cerebral blood flow and intracranial halothane, clinical doses of physostigmine (0.3 mg/ pressure. Prior administration of large doses of non- kg, IV) shifted EEG activity from a low-frequency, depolarizing muscle relaxants prevented both the high-amplitude pattern characteristic of anesthesia, EEG activation and intracranial pressure increases to a higher frequency, lower amplitude awake-type induced by intravenous succinylcholine, whereas pattern. Physostigmine also reverses the CNS ex- smaller defasciculating doses had no effect (255,258). citation associated with the central As little (if any) of the drug crosses the blood-brain syndrome produced by and scopolamine barrier, the EEG arousal with increases in cerebral (267,268). The underlying mechanism of these para- blood flowhntracranial pressure after intravenous doxical effects for both physostigmine and anticholin- succinylcholine is most likely related to succinylcho- ergic agents is unclear. ANESTHETICS AND SEIZURES ANESTH ANALG 441 1990;70:433-44

In humans, none of the CHEIs used in clinical gery, their onset often coincides with the introduc- anesthesia have been reported to possess anticonvul- tion of a specific anesthetic or analgesic drug. sant properties. In cats, physostigmine reversed a Conversely, postoperative seizures are more com- scopolamine-induced increase in enflurane EEG sei- monly due to nonanesthetic causes (277). However, zure activity (26). These unexpected effects probably there have been reports of postoperative convulsions involve noncholinergic pathways (269). In clinically that appeared to be caused by anesthetic or analgesic relevant doses, none of the CHEIs used in anesthetic drugs administered intraoperatively via inhalation practice would be expected to have significant effects (30,3436) or injection (e.g., intravenous [63,128], on the seizure threshold in humans. epidural [115], or peripheral nerve block (2251). Some anesthetics appear to possess both procon- vulsant and anticonvulsant properties (Table 1). One possible factor is an inherent pharmacodynamic vari- Anticholinergics ability in the responsiveness of inhibitory and excita- Based on their central cholinergic inhibitory actions, a tory target tissues in the CNS. This is well illustrated sedative effect would be expected after clinical doses by the anticonvulsant and proconvulsant effects of of the tertiary amine anticholinergic drugs. However, progressively higher doses of local anesthetic drugs both atropine and scopolamine can produce unex- (64,229). This variability in neuronal responsiveness pected CNS excitation and (267,268). Al- could also explain the conflicting findings for low though the precise mechanism of these excitatory versus high doses of fentanyl(l36,142) and etomidate effects is not known, it may involve central non- (175,178). Furthermore, biological variation in the cholinergic antagonist actions (270) and/or a paradox- individual patient’s responsiveness to certain anes- ical activation of nicotinic receptors in the brain (271). thetic drugs could be an additional contributory fac- These CNS excitatory effects have not occurred with tor. the quaternary amine compound, glycopyrrolate. Differing structure-activity relationships might Because the central cholinergic system appears to also explain why some anesthetic agents possess both be an important component in generating seizure proconvulsant and anticonvulsant properties. Rela- activity, anticholinergic drugs with tertiary amine tively minor modifications in a drug’s structure can structures would be expected to possess anticonvul- influence its affinity for a specific receptor site and its sant properties. When given alone, clinical doses of intrinsic pharmacologic activity. For example, when atropine (0.5 mg, IV), which can cause drowsiness, methohexital was first introduced, convulsions were typically produce mild increases in deltakheta activity commonly encountered in patients with and without with slight decreases in beta activity. The dominant a history of epilepsy (278). Subsequent fractionation alpha band is variably affected (272). Both atropine of the original compound into its two isomeric forms and scopolamine also depress the arousal response to resulted in the identification of the isomer primarily photostimulation (273). In humans, atropine (1.2 mg, responsible for this convulsive activity. In its present IV) inhibits the increased EEG activity produced by formulation (Brevital; Eli Lilly, Indianapolis, Ind.), di-isopropyl fluorophosphate, a CHEI (274). These the epileptogenic properties of methohexital are lim- investigators also observed that atropine reduced ited to patients with psychomotor epilepsy (11). abnormal discharges of the EEG in patients with However, compared with thiopental, excitatory ef- grand ma1 epilepsy. Spontaneous and hyperventila- fects are still more common with methohexital. The tion-induced petit ma1 EEG paroxysmal discharges excitatory effects of methohexital are presumably due can also be blocked with atropine (275). In animal to its methylated structure (64). The inhaled anes- studies, large doses of atropine and scopolamine thetic (hexaflurodiethyl) ether and the intra- have blocked seizures produced by exogenous acetyl- venous anesthetic ketamine also illustrate how subtle and CHEIs (276), and also significantly de- changes in stereoisomerism can result in significant creased enflurane-induced EEG spiking activity (51). changes in structure-activity relationships (Figure 4). In clinically relevant doses, neither atropine nor sco- Flurothyl, a fluorinated ether analogue, reliably pro- polamine would be expected to have a significant duces convulsions in nonepileptic patients, whereas therapeutic effect on seizure activity in humans. its structural isomer isoindoklon has not been associ- ated with seizure activity (279). Other examples of isomer or structural analogue relationships that pro- duce differentialeffects on neuronal hyperexcitability Summary include enflurane-isoflurane and meperidine-norme- Perioperative seizures have numerous potential etiol- peridine. ogies. In general, when seizures occur during sur- In conclusion, the patient population (epileptic or 442 ANESTH ANALG MODICA ET AL. 1990;70:43344

nonepileptic), the method of documentation (EEG 170. Brown AS, Horton JM. Status epilepticus treated by intrave- study or clinical observation), and the method of EEG nous infusions of thiopentone sodium. Br Med J 1967;1:27-8. 171. Young GB, Blume WT, Bolton CF, Warren KG. Anesthetic analysis (cortical or depth electrodes) must be consid- barbiturates in refractory status epilepticus. Can J Neurol Sci ered to properly analyze the proconvulsant and/or 1980;7:291-2. anticonvulsant properties of an anesthetic or analge- 172. Doenicke A, Loffler B, Kugler J, Suttmann H, Grote B. Plasma sic drug. As more information regarding the site and concentration and EEG after various regimens of etomidate. of these drugs within the CNS Br J Anaesth 1982;54:39,1-9. 173. Morgan M, Lumley J, Whitwam JG. Respiratory effects of becomes available with advances in in vivo imaging etomidate. Br J Anaesth 1977;49:233-6. techniques (e.g., magnetic resonance imaging, pos- 174. Grant IS, Hutchison G. Epileptiform seizures during pro- itron emission tomography), our understanding of longed etomidate sedation (letter). Lancet 1983;ii:511-2. the conditions responsible for producing either pro- 175. Cohn BF, Reiger V, Hagenouw-Taal JCW, Voormolen JHC. or anticonvulsant properties should im- Results of a feasibility trial to achieve total immobilization of patients in a neurosurgical intensive care unit with etomidate. prove. Further advances in neurophysiology and Anaesthesia 1983;38(Suppl):47-50. neurochemistry will lead to improvements in the 176. Krieger W, Copperman J, Laxer KD. Seizures with etomidate cIinical use of anesthetic and analgesic drugs during anesthesia (letter). Anesth Analg 1985;64:1226-7. the perioperative period. 177. McPherson RW, Sell B, Traystman RJ. Effects of thiopental, fentanyl and etomidate on upper extremity somatosensory ~ ~~ evoked potentials in humans. Anesthesiology 1986;65:584-9. The authors thank their chairman, William D. Owens, MD, for his 178. 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