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Anesth Analg 2000;90:142
© 2000 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

The Anticonvulsant Effects of Volatile Anesthetics on Penicillin-Induced Status Epilepticus in Cats

Kohei Murao, MD, Koh Shingu, MD, Koichi Tsushima, MD, Kazuyo Takahira, MD, Sakahiro Ikeda, MD, Hideo Matsumoto, MD, Shin-ichi Nakao, MD, and Takashi Asai, MD, PhD

Department of Anesthesiology, Kansai Medical University Hospital, Moriguchi, Osaka, Japan

Address correspondence and reprint requests to Koh Shingu, MD, Department of Anesthesiology, Kansai Medical University Hospital, Fumizono-cho 10–15, Moriguchi, Osaka 570-8507, Japan. Address e-mail to shingu{at}takii.kmu.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Volatile anesthetics may be used to treat status epilepticus when conventional drugs are ineffective. We studied 30 cats to compare the inhibitory effects of sevoflurane, isoflurane, and halothane on penicillin-induced status epilepticus. Anesthesia was induced and maintained with one of the three volatile anesthetics in oxygen. Penicillin G was injected into the cisterna magna, and the volatile anesthetic discontinued. Once status epilepticus was induced (convulsive period), the animal was reanesthetized with 0.6 minimum alveolar anesthetic concentration (MAC) of the volatile anesthetic for 30 min, then with 1.5 MAC for the next 30 min. Electroencephalogram and multiunit activity in the midbrain reticular formation were recorded. At 0.6 MAC, all anesthetics showed anticonvulsant effects. Isoflurane and halothane each abolished the repetitive spike phase in one cat; isoflurane reduced the occupancy of the repetitive spike phase (to 27% ± 22% of the convulsive period (mean ± SD) significantly more than sevoflurane (60% ± 29%; P < 0.05) and halothane (61% ± 24%; P < 0.05), and the increase of midbrain reticular formation with repetitive spikes was reduced by all volatile anesthetics. The repetitive spikes were abolished by 1.5 MAC of the anesthetics: in 9 of 10 cats by sevoflurane, in 9 of 9 cats by isoflurane, and in 9 of 11 cats by halothane. In conclusion, isoflurane, sevoflurane, and halothane inhibited penicillin-induced status epilepticus, but isoflurane was the most potent.

Implications: Convulsive status epilepticus is an emergency state and requires immediate suppression of clinical and electrical seizures, but conventional drugs may be ineffective. In such cases, general anesthesia may be effective. In the present study, we suggest that isoflurane is preferable to halothane and sevoflurane to suppress sustained seizure.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Convulsive status epilepticus is associated with high morbidity and mortality (1,2). It is important to suppress clinical and electrical seizure activity because the longer the seizure, the more difficult it is to treat (3,4) and the more frequent the morbidity (5,6). The first choice of drugs include benzodiazepines, phenytoin, and phenobarbital (1); as the second choice, IV anesthetics such as barbiturates (1), ketamine (7), and propofol (8–10) are usually selected. However, if these drugs are ineffective, volatile anesthetics, which also have anticonvulsant effects (2,11), may be used. Isoflurane has been used to treat status epilepticus (12–15), and it has more potent anticonvulsant effects than halothane (2,13).

However, deep anesthesia with isoflurane, enflurane, or sevoflurane (but not halothane) induces spontaneous sporadic spikes in electroencephalograms (EEGs) (16–18). Enflurane or sevoflurane at a large concentration induces a tonic-clonic convulsion in cats (16), and a few clinical case reports have shown that epileptoid EEGs were observed in patients anesthetized with sevoflurane (19,20). However, Oshima et al. reported that enflurane had anticonvulsant actions in several epilepsy models in cats (21), and we reported that sevoflurane had anticonvulsant effects on lidocaine-induced seizures similar to isoflurane in cats (22). Therefore, sevoflurane may be effective in treating status epilepticus, although it has proconvulsant effects. In this study, we compared the inhibitory effects of halothane, isoflurane, and sevoflurane on penicillin-induced status epilepticus in cats.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After obtaining approval from our committee on animal research, we studied 30 cats weighing 2.5–4.0 kg. The cats were randomly allocated to one of three groups: sevoflurane (n = 10), isoflurane (n = 9), or halothane (n = 11) was used. Each cat was anesthetized with one of these volatile anesthetics in oxygen in a 50-L box. After a catheter was placed in the cephalic vein, vecuronium 1 mg was injected, and the trachea was intubated. Vecuronium was injected as required during the study. The lungs were ventilated mechanically using a nonrebreathing ventilator. End-tidal concentrations of carbon dioxide (CO2) and anesthetics were measured by using an infrared anesthetic monitor (Capnomac Ultima; Datex, Helsinki, Finland) that was calibrated each experimental day. The end-tidal CO2 concentration was maintained at 30–35 mm Hg by adjusting the tidal volume. Anesthesia was maintained with 1.3 minimum alveolar anesthetic concentration (MAC). A cannula was inserted into the femoral artery to monitor arterial blood pressure and to sample blood for gas analysis. Noradrenaline was infused IV at 0.1 mg · kg-1 · h-1 when the systolic arterial pressure decreased below 70 mm Hg. A thermometer was inserted into the rectum, and the temperature was maintained at 37–39°C by using a warm water mattress and heating lamp.

The animal was placed on a stereotaxic apparatus. Six stainless steel screws, 2.0 mm in diameter, were inserted bilaterally in the frontal bone of the skull (reference electrode) and over the temporal and occipital cortex to record the cortical EEG. Four parallel stainless steel wire electrodes, 0.2 mm in diameter and insulated with epoxylite resin except at the tips, with the distance of 0.5–1.0 mm between the tips, were inserted bilaterally into the dorsal hippocampus [A2, L8, H9, according to the atlas of Snider and Niemer (23)] and the medial amygdala (A12, L9, H-6) to record the EEG. These wire electrodes were also inserted into the midbrain reticular formation (A2, L3, H-2) to record the firing of reticular neurons. The electrodes were connected to a socket that was fixed to the skull with dental cement. Neuronal firing in the midbrain reticular formation was measured by using a method of multiunit activity (R-MUA), as described previously (24). In brief, the neuronal firing was obtained between the two active points of electrodes, amplified, then sent to a high-pass filter. Because neuronal firings are high-frequency activities, the obtained signal was rectified and smoothed with an electronic circuit with a smoothing time constant of 50 ms and was expressed by the oscillation of DC voltage: the higher the DC level, the greater the firing of a population of units. The R-MUA level was measured as the height of the lower limit of the trace from the DC level obtained by input short in place of the animal. The EEG, R-MUA, and arterial blood pressure were recorded on an eight-channel polygraph.

A 22-gauge needle was then inserted into the cisterna magna, and penicillin G sodium 100,000 U in 0.4 mL of isotonic sodium chloride solution, was injected. Thirty minutes after the injection of penicillin G, the anesthetic was discontinued, and pure oxygen was inspired. Once status epilepticus was established on the EEG for 30 min (convulsive period), the volatile anesthetic was readministered. The anesthetic was given at 0.6 MAC for 30 min, then at 1.5 MAC for the next 30 min. Values in the convulsive period were taken 10 min before the second exposure to the anesthetic, and the effects of the anesthetics were investigated during the final 10 min of each step of concentrations. In cats, 1 MAC is 1.2% for halothane, 1.6% for isoflurane (25), and 2.6% for sevoflurane (26). After studying the effects of 1.5 MAC of each anesthetic, administration of the anesthetic was discontinued, and the reappearance of status epilepticus on the EEG was confirmed 30 min after discontinuation (second convulsive period). After the study, the animals were killed with lethal doses of pentobarbital IV.

Penicillin-induced status epilepticus was characterized with regular cycles of three phases on the EEG, as shown in Figure 1: sporadic spikes, repetitive spikes, and flat EEG. The anticonvulsant effects of each anesthetic were expressed as the percent occupancy of the period of the repetitive spike phase, the increase of R-MUA associated with the repetitive spikes, and the frequency of the spikes during the phase of sporadic spikes (21). The level of R-MUA was expressed as a percentage of that during the phase of flat EEG in the convulsive period in each animal.



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  		Figure 1. Electroencephalogram (EEG) and reticular multiunit activity (R-MUA) during status epilepticus induced by penicillin in the cat. After 100,000 U of penicillin G sodium was injected into the cisterna magna under anesthesia, the volatile anesthetic was discontinued. Changes in the level of neuronal unit firing were measured as the distance from the multiunit tracing to the input short line. The upward shift indicates the increase in the firing rate of units, and the downward shift indicates the decrease. Status epilepticus is characterized by three phases: 1) sporadic spike phase, as seen in the initial part of the EEG traces recorded from the cortex (Cx), amygdala (Amy), and dorsal hippocampus (DH); 2) repetitive spike phase with a sustained increase in R-MUA, as seen in the middle part of the figure of EEG recorded from all sites; and 3) flat EEG phase, as seen in the last part of the EEG traces. R-MUA decreases with cessation of the repetitive spikes.

 
Data are presented as mean ± SD. The data within each group were analyzed by using repeated-measures analysis of variance. The data among groups were analyzed by using the Newman-Keuls test. Requirements of noradrenaline among groups were compared by using a {chi}2 test. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Penicillin produced status epilepticus in all cats before and after studying the effects of a volatile anesthetic. The values of PaO2, PaCO2, pH, and base excess in the convulsive period were similar among groups (Table 1). Both the occupancy of the repetitive spike phase and the increase of R-MUA with repetitive spikes were similar among groups during the first and second convulsive periods (Table 2). Noradrenaline was infused in two cats in the sevoflurane group, in five cats in the isoflurane group, and in four cats in the halothane group. The incidence in requirements of noradrenaline was not significantly different among groups.


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  		Table 1. Blood Gas Values in the Convulsive Period
 

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  		Table 2. Occupancy of the Repetitive Spike Phase and the Increase of Reticular Multiunit Activity (R-MUA)
 
At 0.6 MAC, isoflurane and halothane each abolished the repetitive spikes in one cat (Table 3). At 0.6 MAC, all volatile anesthetics significantly reduced both the occupancy of the repetitive spike phase (P < 0.05) and the increase of R-MUA with repetitive spikes (P < 0.05) (Table 3). At 0.6 MAC, isoflurane reduced the occupancy of the repetitive spike phase significantly more than sevoflurane (P < 0.05) and halothane (P < 0.05).


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  		Table 3. Anticonvulsant Effects of Volatile Anesthetics on Penicillin-Induced Epileptic Model
 
At 1.5 MAC, isoflurane abolished the repetitive spikes in all cats, whereas sevoflurane abolished it in 9 cats and halothane abolished it in 8 cats. These drugs did not significantly alter the frequency of sporadic spikes (Table 3). Figures 2 and 3 show representative traces of the EEG and R-MUA in each group.



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  		Figure 2. Effects of volatile anesthetics on cortical electroencephalogram (Cx-EEG) and reticular multiunit activity (R-MUA) in penicillin-induced status epilepticus. Volatile anesthetics decreased both the occupancy of the repetitive spike phase and the increase of R-MUA associated with repetitive spikes. The lower limit of the R-MUA trace decreased with increasing concentration of the volatile anesthetics. After discontinuation of the volatile anesthetics, the seizure was resumed and R-MUA increased.

 


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  		Figure 3. Effects of volatile anesthetics on the electroencephalogram recorded from the cortex (Cx), amygdala (Amy), and dorsal hippocampus (DH), and reticular multiunit activity (R-MUA) in penicillin-induced status epilepticus. Spikes are synchronized in all recorded sites, and increases in R-MUA are associated with spikes. Any volatile anesthetic at 1.5 minimum alveolar anesthetic concentration (MAC) suppressed the increase of R-MUA by spikes much stronger than those at 0.6 MAC.

 
The level of R-MUA during the flat EEG phase was suppressed by volatile anesthetics in a dose-dependent manner (P < 0.05); isoflurane suppressed it significantly more than halothane (P < 0.05) (Table 3).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We showed that sevoflurane, isoflurane, and halothane all have anticonvulsant dose-dependent effects in the feline penicillin-induced status epilepticus model. The anticonvulsant effect of isoflurane was significantly greater than that of halothane or sevoflurane. This is consistent with studies that report that isoflurane inhibited status epilepticus in patients in whom halothane was ineffective (2,13). The resumption of status epilepticus after discontinuation of a volatile anesthetic indicates that the anticonvulsant effects of anesthetics were exerted only during the period of administration; thus, another appropriate therapy for terminating convulsions should be instituted during the administration of anesthetics.

The proconvulsant properties of isoflurane and sevoflurane are different, although large concentrations of both induce sporadic spikes on the EEG (16–18). Peripheral electrical stimuli can induce spikes on the EEG during deep sevoflurane anesthesia, but not during isoflurane anesthesia, in cats (16). The amplitude of photic stimuli-evoked potential increased during sevoflurane anesthesia, but not during isoflurane anesthesia, in cats (18). These different proconvulsant properties may affect the potency of the anticonvulsant effects of these anesthetics.

The mechanism of the anticonvulsant effects of volatile drugs is not known. Penicillin is an antagonist of the GABAA-benzodiazepine receptor complex (27), and like other GABAA receptor antagonists, such as bicuculline and picrotoxin, it induces seizures on the EEG. Halothane, isoflurane, and sevoflurane enhance GABAA receptor functions (28). Therefore, enhancing effects of volatile anesthetics on the GABAA receptor functions might have contributed, in part, to their anticonvulsant effects on penicillin-induced status epilepticus.

One limitation of our study was that we did not randomize the order of concentrations of the volatile anesthetics studied. However, the time course of status epilepticus had not changed during the study period because status epilepticus recurred after discontinuation of the anesthetics.

This study also has several limitations for applying the results to clinical situations. First, effects of volatile anesthetics were investigated only on the status epilepticus induced by penicillin in the present study; therefore, it is not known whether they also produce anticonvulsant effects on epileptogenesis by different mechanisms. Second, volatile anesthetics may be useful when conventional anticonvulsant therapies and IV anesthetics have been ineffective, but we did not compare the effectiveness of volatile anesthetics with conventional anticonvulsants or IV anesthetics. Third, although isoflurane has strong inhibitory effects on status epilepticus, other factors, such as organ toxicity from prolonged exposure to volatile anesthetics, cardiovascular depression, development of tolerance to anticonvulsant effects, and neurological outcomes, should also be taken into consideration before concluding that isoflurane is the anesthetic of choice for treating status epilepticus.

In conclusion, isoflurane, halothane, and sevoflurane suppressed penicillin-induced status epilepticus in cats. Isoflurane exerted the most potent anticonvulsant effects in the present model of status epilepticus.


   Acknowledgments
 
Supported in part by Grant-in-Aid for Scientific Research 08457415 from the Ministry of Education, Science and Culture, Japan.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 30, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press