The anticonvulsant effects of volatile anesthetics on penicillin-induced status epilepticus in cats

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.     

静脉麻醉药抑制利多卡因致大鼠惊厥作用的比较

目的比较静脉麻醉药丙泊酚、依托咪酯、咪达唑仑及硫喷妥钠拮抗利多卡因致大鼠惊厥的作用。方法雄性Wistar大鼠36只,体重(250±20)g,随机均分为六组:空白对照组(C组)、利多卡因组(L组:利多卡因4mg·kg-1·min-1)、利多卡因+丙泊酚组(P组:利多卡因+丙泊酚12.5mg/kg)、利多卡因+依托咪酯组(E组:利多卡因+依托咪酯1.85mg/kg)、利多卡因+咪达唑仑组(M组:利多卡因+咪达唑仑0.65mg/kg)和利多卡因+硫喷妥钠组(T组:利多卡因+硫喷妥钠30.85mg/kg),惊厥后2h处死大鼠,取出脑组织分离双侧海马,一侧用于检测c-fos阳性细胞蛋白的表达。另一侧用于测定一氧化氮(NO)含量及一氧化氮合酶(NOS)活性。结果除C组外,其它五组大鼠均出现了惊厥,给予静脉麻醉药抑制惊厥,五组惊厥持续时间差异无统计学意义。L、P、E、M和T组c-fos阳性细胞表达、NO含量和NOS活性显著高于C组(P<0.05);P、E、M和T组c-fos阳性细胞表达、NO含量及NOS活性均显著降低于L组(P<0.05);M、T组c-fos阳性细胞表达、NO含量及NOS活性显著低于P、E组(P<0.05)。结论静脉麻醉药咪达唑仑、丙泊酚、依托咪酯及硫喷妥钠均可有效抑制利多卡因致惊厥作用,其中咪达唑仑与硫喷妥钠效果更显著。     

The effects of volatile anesthetics on the Q-Tc interval

OBJECTIVE: To examine the effects of halothane, isoflurane, and sevoflurane on Q-Tc interval (corrected for heart rate) during inhalation induction of anesthesia. DESIGN: Prospective, double-blind, randomized study. SETTING: Departments of Cardiology and Anesthesiology in a university hospital. PARTICIPANTS: Patients undergoing noncardiac surgery. INTERVENTIONS: A total of 65 American Society of Anesthesiologists physical status I-II patients, aged 16 to 50 years, undergoing general anesthesia, were randomly allocated to receive halothane, isoflurane, or sevoflurane. MEASUREMENTS AND MAIN RESULTS: The time to reach the predetermined end-tidal concentrations of 3 minimum alveolar concentration was 6 to 10 minutes. When compared with preinduction values, heart rate decreased after halothane (p < 0.01) and sevoflurane (p < 0.05) administration; in contrast, heart rate increased after induction of anesthesia with isoflurane (p < 0.05). The mean QRS intervals were not significantly changed after halothane, isoflurane, or sevoflurane. The Q-Tc interval was increased with isoflurane compared with baseline (465 +/- 23 v 441 +/- 18 msec, p < 0.01), not changed with sevoflurane (441 +/- 17 v 434 +/- 19 ms, p > 0.05), and shortened with halothane (426 +/- 23 v 445 +/- 21 msec, p < 0.01). CONCLUSION: Sevoflurane or halothane may be preferred to isoflurane in patients with conditions that are known to induce a prolonged Q-Tc interval. The effects of Q-Tc interval changes resulting from different anesthetic agents on morbidity and the incidence of arrhythmias during anesthesia warrant further investigation.     

The effects of volatile anesthetics on Ca++ mobilization in rat hepatocytes

This study provides direct evidence that in hepatocytes, intracellular Ca++ is released from internal stores by halothane, enflurane, and isoflurane. Hepatocytes isolated from rat livers were used fresh or treated with saponin and then incubated in 45Ca++ media. The uptake of 45Ca++ by hepatocytes was maximal following 13-16 min of incubation (untreated or saponin-treated) and the effects of various agents on the release of 45Ca++ was studied following maximal loading. The agents used included halothane, enflurane, isoflurane, and several putative intracellular second messengers. The anesthetics, to various degrees, all stimulated a significant release of 45Ca++ from internal stores at concentrations that were at or less than clinical concentrations. The release of intracellular 45Ca++ by each of the anesthetic agents was dose-dependent with halothane and enflurane being equally potent at concentrations equivalent to 1 MAC exposure. The halothane-induced release was only somewhat suppressed by preincubation in either 2 mM LaCL3 or 10 microM dantrolene, both suggested Ca++ channel blockers. Transient increases in intracellular Ca++ regulates a number of enzyme systems, including glycogenolysis, while prolonged elevation in Ca++ concentrations have been implicated in the mechanism of hepatotoxicity.     

The effects of sevoflurane on lidocaine-induced convulsions

The influence of sevoflurane on lidocaine-induced convulsions was studied in cats. The convulsive threshold (mean ± SD) was 41.4 ± 6.5mg·l ^–1 with lidocaine infusion (6mg·kg^–1·min^–1), increasing significantly to 66.6 ± 10.9mg·l ^–1 when the end-tidal concentration of sevoflurane was 0.8%. However, the threshold (61.6 ± 8.7mg·l ^–1) during 1.6% sevoflurane was not significant from that during 0.8% sevoflurane, indicating a celling effect. There was no significant difference in the convulsive threshold between sevoflurane and enflurane. The rise in blood pressure became less marked when higher concentrations of sevoflurane or enflurane were administered and the blood pressure at convulsions decreased significantly in 1.6% sevoflurane, and in 0.8% and 1.6% enflurane. However, there was no significant difference in the lidocaine concentrations measured when the systolic blood pressure became 70mmHg. Apamin, a selective blocker of calcium-dependent potassium channels, was administered intracerebroventricularly in rats anesthetized with 0.8% sevoflurane to investigate the mechanism of the anticonvulsive effects. Apamin (10ng) had a tendency to decrease the convulsive threshold (21.6 ± 2.2 to 19.9 ± 2.5mg·l ^–1) but this was not statistically significant. It is suggested that sevoflurane reduces the convulsive effect of lidocaine toxicity but carries some risk due to circulatory depression.(Karasawa F: The effects of sevoflurane on lidocaine-induced convulsions. J Anesth 5: 60–67, 1991)     

The effects of volatile anesthetics on nonadrenergic,noncholinergic depressor responses in rats

The effects of volatile anesthetics on nonadrenergic, noncholinergic (NANC) transmission mediated by calcitonin gene-related peptide (CGRP) are unclear. We studied the effects of isoflurane, halothane, and sevoflurane on NANC depressor responses to electrical spinal cord stimulation in pithed rats whose mean arterial blood pressure was maintained near 120 mm Hg by continuous infusion of methoxamine. Autonomic outflow was blocked by hexamethonium. After 30 min of inhalation of different concentrations of anesthetics, spinal cord stimulation at the lower thoracic level (10 V at 4 Hz; duration, 1 ms) was applied for 30 s to induce a NANC depressor response. Isoflurane at 2% and halothane at 1.5% attenuated NANC depressor responses significantly, whereas isoflurane at 1%, halothane at 0.75%, and sevoflurane at 2% or 4% did not. Volatile anesthetics did not attenuate the release of CGRP after spinal cord stimulation, whereas isoflurane at 2% and halothane at 1.5% significantly inhibited depressor responses to exogenously administered CGRP. Sevoflurane at 4% did not significantly affect CGRP-induced depressor responses. Thus, isoflurane and halothane at large concentrations attenuate NANC depressor responses by attenuating the depressor action of CGRP, not CGRP release. IMPLICATIONS: The anesthetics isoflurane and halothane attenuate nonadrenergic, noncholinergic depressor responses mediated by calcitonin gene-related peptide in the rat without affecting the release of the peptide.     

Pro- and anticonvulsant effects of anesthetics (Part I)

Many inhaled anesthetics and intravenous analgesics have been alleged to produce both proconvulsant and anticonvulsant activity in humans. The reasons for these contrasting actions on the CNS are poorly understood at the present time. However, biologic variability plays an important role in determining individual patient's responses to anesthetic and analgesic drugs. In addition, variations in the responsiveness of inhibitory and excitatory neurons to the central depressant effects of these drugs could also explain these apparently conflicting data. Depending on the brain concentration, centrally active drugs may produce differing effects on the CNS inhibitory and excitatory neurotransmitter systems. The availability of increasingly powerful magnetic resonance imaging techniques to provide noninvasive information about tissue chemistry (e.g., neurotransmitters and citric acid cycle metabolites) and positron emission tomography to noninvasively evaluate CNS drug-receptor interactions should lead to a more in-depth understanding of the in vivo effects of anesthetics and analgesics on the CNS. In the second part of this review article, we discuss the pro- and anticonvulsant effects of the sedative-hypnotics, local anesthetics, and other anesthetic adjuvant drugs.     

Pro- and anticonvulsant effects of anesthetics (Part II)

Perioperative seizures have numerous potential etiologies. In general, when seizures occur during surgery, their onset often coincides with the introduction of a specific anesthetic or analgesic drug. Conversely, postoperative seizures are more commonly due to nonanesthetic causes. However, there have been reports of postoperative convulsions that appeared to be caused by anesthetic or analgesic drugs administered intraoperatively via inhalation or injection (e.g., intravenous, epidural, or peripheral nerve block). Some anesthetics appear to possess both proconvulsant and anticonvulsant properties. One possible factor is an inherent pharmacodynamic variability in the responsiveness of inhibitory and excitatory target tissues in the CNS. This is well illustrated by the anticonvulsant and proconvulsant effects of progressively higher doses of local anesthetic drugs. This variability in neuronal responsiveness could also explain the conflicting findings for low versus high doses of fentanyl and etomidate. Furthermore, biological variation in the individual patient's responsiveness to certain anesthetic drugs could be an additional contributory factor. Differing structure-activity relationships might also explain why some anesthetic agents possess both proconvulsant and anticonvulsant properties. Relatively minor modifications in a drug's structure can influence its affinity for a specific receptor site and its intrinsic pharmacologic activity. For example, when methohexital was first introduced, convulsions were commonly encountered in patients with and without a history of epilepsy. Subsequent fractionation of the original compound into its two isomeric forms resulted in the identification of the isomer primarily responsible for this convulsive activity. In its present formulation (Brevital; Eli Lilly, Indianapolis, Ind.), the epileptogenic properties of methohexital are limited to patients with psychomotor epilepsy. However, compared with thiopental, excitatory effects are still more common with methohexital. The excitatory effects of methohexital are presumably due to its methylated structure. The inhaled anesthetic flurothyl (hexaflurodiethyl) ether and the intravenous anesthetic ketamine also illustrate how subtle changes in stereoisomerism can result in significant changes in structure-activity relationships. Flurothyl, a fluorinated ether analogue, reliably produces convulsions in nonepileptic patients, whereas its structural isomer isoindoklon has not been associated with seizure activity. Other examples of isomer or structural analogue relationships that produce differential effects on neuronal hyperexcitability include enflurane-isoflurane and meperidine-normeperidine. In conclusion, the patient population (epileptic or nonepileptic), the method of documentation (EEG study or clinical observation), and the method of EEG analysis (cortical or depth electrodes) must be considered to properly analyze the proconvulsant and/or anticonvulsant properties of an anesthetic or analgesic drug.(ABSTRACT TRUNCATED AT 400 WORDS)     

Local cerebral blood flow during lidocaine-induced seizures in rats

Neurophysiologic and local cerebral metabolic mapping techniques indicate that seizures associated with lidocaine toxicity originate in subcortical brain structures. Normally local cerebral blood flow (l-CBF) is quantitatively coupled to local cerebral metabolic rate for glucose (l-CMRg). In the present study the response of l-CBF to a lidocaine-induced preconvulsive state (localized seizure activity in the absence of a grand mal seizure) was evaluated in rats anesthetized with 60% nitrous oxide. Lidocaine administered as a bolus (20 mg/kg) followed by an infusion (4 mg/kg) over 5.5 min resulted in progressive alteration in the electroencephalogram (EEG). L-CBF was studied with the 14C-iodoantipyrine autographic method when the preconvulsive EEG pattern consisted of a repetitive spike and wave complex at a frequency of 14 +/- 1 X min-1 complexes, superimposed on practically isoelectric background activity. Under these conditions high doses of lidocaine significantly (P less than 0.05) decreased (range -30% to -68%) l-CBF in 71% of the 34 brain regions studied. The greatest exception to this trend for l-CBF to decrease was observed in the limbic system wherein l-CBF remained within control ranges in eight of the 11 structures evaluated. Qualitative comparison of lidocaine l-CBF changes with l-CMRg changes obtained under similar conditions indicated a general trend for local flow and metabolism to decrease in parallel. Exceptions to this were confined to certain limbic areas (amygdala and hippocampus) in which increases in l-CMRg were more than 100% greater than slight (P greater than 0.05) increases in l-CBF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of midazolam on the threshold of lidocaine-induced seizures in the dog

The anticonvulsive effect of midazolam was compared with that of diazepam in ten dogs. Lidocaine-induced seizure waves on the electroencephalogram were used to observe the suppressive effect of the drugs. Midazolam, 0.2mg·kg^–1, was found to possess a stronger suppressive effect against lidocaine-induced seizures than the same dose of diazepam. These two drugs showed to possess similar effects on cerebral and systemic circulations and cerebral metabolism during seizures.(Horikawa H, Tada T, Sakai M et al.: Effects of midazolam on the threshold of lidocaine-induced serizures in the dog. J Anesth 4: 265–269, 1990)     

Organ protective effects of volatile anesthetics and perioperative outcomes

Anesthetic agents, especially, volatile anesthetics are considered to exert organ toxicity such as nephrotoxicity and hepatotoxicity; however, recent aggressive researches explored the beneficial effects of volatile anesthetics as an organ protectant. Ischemic preconditioning is a phenomenon in which single or multiple brief periods of ischemia have been shown to protect the myocardium and brain against prolonged ischemic insult. General anesthesia showed the protection against both ischemic myocardial and brain reperfusion injuries. This phenomenon is called anesthetic preconditioning. Regarding the organ protection, anesthetic preconditioning is one of the useful ways to diverse the organ protective effects not only to heart but also brain. Nowadays, ischemic postconditioning, consisting of repeated brief cycles of ischemia-reperfusion performed immediately after reperfusion following a prolonged ischemic insult, dramatically reduces infarct size in experimental models and such clinical studies are reported. Both preconditioning and postconditioning share the same signal transduction pathway and inhibit the mitochondrial permeability transition (MPT) that leads to either apoptosis or necrosis of myocardium and neuronal cell. Both phenomena look very promising, but we still lack the real evidence for human reserach in terms of the clinical outcome and further analysis is necessary. Neurotoxicities of anesthetic agents are very crucial problems for the patient and they are considered to be due to the activation of IP3 receptor in ER after exposure to volatile anesthetics. Massive release of Ca2+ from ER induces Ca2+ overload leading to mitochondria permeability transition (MPT) and induces apoptosis in the brain or aggravates the neurodegenerative disease. Susceptible mechanisms and beneficial treatment for the toxicity of general anesthesia is considered as a critical subject to discuss and challenge to solve for our future.     

The effects of volatile anesthetics on calcium regulation by malignant hyperthermia-susceptible sarcoplasmic reticulum.

To clarify the mechanism by which volatile anesthetics initiate malignant hyperthermia (MH), we examined the effect of halothane, isoflurane, and enflurane on Ca2+ uptake and release by sarcoplasmic reticulum vesicles isolated from MH-susceptible (MHS) and normal pig muscle. Clinical concentrations of these anesthetics (0.1-0.5 mM) stimulated sarcoplasmic reticulum ATP-dependent Ca2+ uptake (maximal at approximately 4 mM), whereas 10-20 times the clinical anesthetic concentration inhibited Ca2+ uptake. There was no significant difference between MHS and normal sarcoplasmic reticulum in any aspect of Ca2+ uptake. Ca2+ release from 45Ca(2+)-filled sarcoplasmic reticulum vesicles in a 10(-8) M Ca(2+)-containing medium (pH 7.0) was significantly stimulated at clinical concentrations of all three volatile anesthetics (anesthetic concentration for the 50% stimulation of Ca2+ release = 0.096-0.22 mM); however, the rate constant for Ca2+ release from MHS sarcoplasmic reticulum was in all cases significantly greater than that from normal sarcoplasmic reticulum. Furthermore, 0.5 mM halothane had no effect on Ca2+ release from normal sarcoplasmic reticulum at pH values less than 6.8, although it could still significantly stimulate Ca2+ release from MHS sarcoplasmic reticulum even at pH 6.4; similar results were obtained for isoflurane and enflurane. These studies thus demonstrate that the interaction of volatile anesthetics with the sarcoplasmic reticulum Ca(2+)-release channel is altered in MHS porcine muscle such that the channel may be activated even at a Ca2+ concentration or pH that would be expected to maintain the channel in the closed state.     

Comparison of the effects of volatile anesthetics on brain glucose metabolism in rats

The objective of this investigation was to compare the effects of the commonly used volatile anesthetics on concentrations of plasma and cerebral glucose and cerebral intermediary metabolites. Fasted male Long-Evans rats were anesthetized with a volatile anesthetic and, after tracheostomy and paralysis, were mechanically ventilated. Each of three groups received one MAC concentration of anesthesia with halothane, enflurane, or isoflurane. At the end of 60-75 min of anesthesia, blood was sampled for arterial blood gas and plasma glucose analysis, and the brain was rapidly sampled and frozen for analysis of energy metabolites. Physiologic variables were maintained as follows: PaCO2 30-40 mmHg, pHa 7.20-7.40, PaO2 greater than 60 mmHg, MAP greater than 60 mmHg, and rectal temperature 37.5-38.5 degrees C. Mean plasma glucose concentrations in the three groups were as follows (muMol/ml +/- SEM): halothane, 7.45 /- .62; enflurane, 6.95 +/- .22; isoflurane, 10.11 +/- 1.00. Mean brain glucose concentrations in the three groups were (muMol/gm wet weight): halothane, 2.04 +/- .20; enflurane, 2.07 +/- .26; isoflurane, 3.04 +/- .31. Plasma and brain glucose levels were significantly increased in the isoflurane group compared to the other two groups (P less than .05) with no differences occurring in the brain/plasma glucose ratio among the three groups. No differences were present between groups in brain lactate, pyruvate, fructose diphosphate, malate, alpha-ketoglutarate, phosphocreatine, or adenine nucleotides. Thus, at one MAC concentration, major differences between volatile anesthetics on brain energy availability are not present, although isoflurane raised cerebral glucose levels.     

Effects of flumazenil on intravenous lidocaine-induced convulsions and anticonvulsant property of diazepam in rats.

We investigated the effect of flumazenil on intravenous (IV) lidocaine-induced convulsions with and without diazepam pretreatment in rats. Wistar rats (200-250 g) were divided into four groups of seven each and were pretreated with IV diazepam or normal saline solution at 6 min and flumazenil or normal saline solution at 3 min before lidocaine infusion. The control group received normal saline solution; the diazepam group received 0.2 mg/kg of diazepam and normal saline solution; the diazepam+flumazenil group received 0.2 mg/kg of diazepam and 0.1 mg/kg of flumazenil; and the flumazenil group received normal saline solution and 0.1 mg/kg of flumazenil. After surgical preparation and recovery from anesthesia, all groups received a continuous IV infusion of lidocaine (15 mg/mL) at a rate of 4 mg.kg-1.min-1 until tonic/clonic convulsions occurred. The values of pH and blood gases were maintained within physiologic ranges. Heart rate was significantly decreased after 5 min of lidocaine infusion, but arterial blood pressure did not change until convulsions occurred in all groups. Pretreatment with diazepam alone increased both cumulative convulsant doses and plasma concentrations of lidocaine at the onset of convulsions. Flumazenil reversed these effects of diazepam. Pretreatment with flumazenil alone changed neither cumulative convulsant doses nor plasma concentrations of lidocaine at the onset of convulsions. Our data show that IV flumazenil reverses the anticonvulsant property of IV diazepam against lidocaine-induced convulsions and that flumazenil itself has no effect on lidocaine-induced convulsions in rats.