Advantages of methohexital over amobarbital in determining hemispheric language and memory lateralization in the Wada test - A retrospective study.

OBJECTIVE: Due to supply shortage, amobarbital, the traditional anesthetic agent in Wada testing, was replaced by methohexital in many epilepsy centers. This study aimed to compare the two barbiturates to identify possible advantages or disadvantages of methohexital as compared to amobarbital with regard to the adequacy of language and memory testing during the Wada test. METHODS: Data from 75 patients with temporal lobe epilepsy who underwent bilateral Wada tests using either amobarbital (n = 53) or methohexital (n = 22) as part of presurgical work-up were analyzed retrospectively. The two subgroups were compared regarding hemispheric language and memory lateralization results and Wada testing characteristics, and the adequacy of language and memory testing was assessed. RESULTS: We observed shorter durations of motor-, speech-, and EEG recovery after each injection in patients receiving methohexital compared to amobarbital. In addition, significantly more items could be presented during effective hemispheric inactivation in the methohexital group. Moreover, significant correlations of Wada memory scores with standard neuropsychological memory test scores could be found in the methohexital group. SIGNIFICANCE: Our findings confirm that methohexital is not only equally suitable for Wada testing but has several advantages over amobarbital. Wada testing can be performed more efficiently and under more constant hemispheric inactivation using methohexital. Furthermore, the adequacy of language and memory testing during the Wada test might be affected by the anesthetic agent used.

Comparison of methohexital and propofol as induction agents for evaluation of laryngeal function in healthy dogs.

OBJECTIVE: To determine the influence of propofol or methohexital, with and without doxapram, on the examination of laryngeal function in dogs. STUDY DESIGN: Experimental study. ANIMALS: Forty healthy dogs randomly assigned to 4 groups: propofol with saline (n = 10), propofol with doxapram (n = 10), methohexital with saline (n = 10), or methohexital with doxapram (n = 10). METHODS: Propofol and methohexital were administered to effect. Investigators examined laryngeal function (initial) simultaneously with video laryngoscopy. Doxapram or saline was administered, and laryngeal function was reevaluated (second). Laryngeal motion, quality of laryngeal exposure, and the degree of swallowing, laryngospasm, and jaw tone were scored at each evaluation. Adverse events were recorded. Initial and second videos were evaluated by a masked observer, and still images obtained from both evaluations were evaluated for change in rima glottidis size by 2 masked observers. RESULTS: Administration of doxapram and saline was delayed with propofol (P = .001). Laryngeal function did not differ between dogs receiving propofol or methohexital, irrespective of doxapram administration. Doxapram improved breathing scores in both groups (P < .001). Jaw tone increased with propofol during the second evaluation (P = .049). Swallowing was more prevalent at initial examination (P = .020). Methohexital resulted in an increased heart rate (P < .001) compared with propofol. Twenty-five percent of dogs receiving methohexital developed seizure-like activity (n = 5/20). CONCLUSION: Evaluation of laryngeal function did not differ between healthy dogs anesthetized with propofol or methohexital. Methohexital provided shorter examination times with less jaw tone but was associated with adverse events. CLINICAL SIGNIFICANCE: This study provides evidence to recommend propofol over methohexital as an induction agent for laryngeal function examination.

Evaluation of methohexital as an alternative to propofol in a high volume outpatient pediatric sedation service.

BACKGROUND: Propofol is a preferred agent for many pediatric sedation providers because of its rapid onset and short duration of action. It allows for quick turn around times and enhanced throughput. Occasionally, intravenous (IV) methohexital (MHX), an ultra-short acting barbiturate is utilized instead of propofol. OBJECTIVE: Describe the experience with MHX in a primarily propofol driven outpatient sedation program and to see if it serves as an acceptable alternative when propofol is not the preferred pharmacologic option. METHODS: Retrospective chart review from 2012 to 2015 of patients receiving IV MHX as their primary sedation agent. Data collected included demographics, reason for methohexital use, dosing, type of procedure, success rate, adverse events (AE), duration of the procedure, and time to discharge. RESULTS: Methohexital was used in 240 patient encounters. Median age was 4years (IQR 2-7), 71.8% were male, and 80.4% were ASA-PS I or II. Indications for MHX use: egg+soy/peanut allergy in 93 (38.8%) and mitochondrial disorder 9 (3.8%). Median induction bolus was 2.1mg/kg (IQR, 1.9-2.8), median maintenance infusion was 4.5mg/kg/h (IQR, 3.0-6.0). Hiccups 15 (6.3%), secretions requiring intervention 14 (5.8%), and cough 12 (5.0%) were the most commonly occurring minor AEs. Airway obstruction was seen in 28 (11.6%). Overall success rate was 94%. Median time to discharge after procedure completion was 40.5min (IQR 28-57). CONCLUSION: Methohexital can be used with a high success rate and AEs that are not inconsistent with propofol administration. Methohexital should be considered when propofol is not a preferred option.

Individual differences in rhesus monkeys' demand for drugs of abuse.

A relatively small percentage of humans who are exposed to drugs of abuse eventually become addicted to or dependent on those drugs. These individual differences in likelihood of developing drug addiction may reflect behavioral, neurobiological or genetic correlates of drug addiction and are therefore important to model. Behavioral economic measures of demand establish functions whose overall elasticity (rate of decrease in consumption as price increases) reflects the reinforcing effectiveness of various stimuli, including drugs. Using these demand functions, we determined the reinforcing effectiveness of five drugs of abuse (cocaine, remifentanil, ketamine, methohexital and ethanol) in 10 rhesus monkeys with histories of intravenous drug-taking. There was a continuum of reinforcing effectiveness across the five drugs, with cocaine and remifentanil showing the most reinforcing effectiveness. There was also a continuum of sensitivity of the monkeys; two of the 10 animals, in particular, showed greater demand for the drugs than did the remaining eight monkeys. In addition, monkeys that demonstrated greater demand for one drug tended to show greater demand for all drugs but did not show a similar relatively greater demand for sucrose pellets. These findings suggest that the tendency to find drugs to be reinforcing is a general one, not restricted to particular drugs and also, that a minority of animals show a substantially enhanced sensitivity to the reinforcing effects of drugs. The possibility that differences in responsiveness to the reinforcing effects of drugs may form the basis of individual differences in drug-taking in humans should be considered.

Fenfluramine: amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey.

Fenfluramine, over a dose range from 0.003 to 3 milligrams per kilogram of body weight, failed to maintain self-injection behavior in rhesus monkeys that had initiated and maintained responding for cocaine or methohexital. This absence of a positive reinforcing effect could not be attributed to a slow onset of drug effect or to the use of behaviorally inactive doses. Fenfluramine, because of its distinctive properties, may produce fewer problems of human abuse than do amphetamine-type agents.

Cardiac effects of induction agents in the septic rat heart.

INTRODUCTION: The current debate about the side effects of induction agents, e.g. possible adrenal suppression through etomidate, emphasizes the relevance of choosing the correct induction agent in septic patients. However, cardiovascular depression is still the most prominent adverse effect of these agents, and might be especially hazardous in septic patients presenting with a biventricular cardiac dysfunction--or so-called septic cardiomyopathy. Therefore, we tested the dose-response direct cardiac effects of clinically available induction agents in an isolated septic rat heart model. METHODS: A polymicrobial sepsis was induced via cecal ligation and single puncture. Hearts (n = 50) were isolated and randomly assigned to five groups, each receiving etomidate, s(+)-ketamine, midazolam, propofol, or methohexitone at concentrations of 1 x 10-8 to 1 x 10-4 M. Left ventricular pressure, contractility and lusitropy, and coronary flow were measured. Cardiac work, myocardial oxygen delivery, oxygen consumption, and percentage of oxygen extraction were calculated. RESULTS: All of the induction agents tested showed a dose-dependent depression of cardiac work. Maximal cardiac work dysfunction occurred in the rank order of s(+)-ketamine (-6%)

Positive pharmacologic provocative testing with methohexital during cerebral arteriovenous malformation embolization.

A middle-aged patient underwent staged endovascular embolization of a Spetzler-Martin grade V right parietal arteriovenous malformation(AVM).In the fifth endovascular embolization, after methohexital 10 mg injection into a right posterior choroidal artery feeding the AVM nidus, there was an immediate change in the electroencephalogram (EEG) with simultaneous loss of motor evoked potentials (MEPs) in the bilateral upper and lower extremities and a delayed change in somatosensory evoked potential responses (SSEPs). No embolization was made and procedure was terminated. This case demonstrates the utility of intraoperative neurophysiologic monitoring (IONM) with pharmacologic provocative testing in predicting and mitigating the risks prior to the proposed embolization.

Relationship of aggregated intramembranous particles to water permeability in vasopressin-treated toad urinary bladder.

It has been previously demonstrated with freeze-fracture electron microscopy that vasopressin induces specific structural alterations of the luminal membrane of granular cells from toad urinary bladder in a dose-dependent fashion. These alterations consist of aggregated intramembranous particles and are observed both in the presence and absence of an osmotic gradient. We examined the effect of methohexital, a selective inhibitor of vasopressin-stimulated water flow, and the effect of phloretin, a selective inhibitor of urea permeability, on the structure of the granular cell luminal membrane. Methohexital treatment of the vasopressin-stimulated toad bladder reduced both the osmotic water flow and vasopressin-induced alterations of membrane structure to the same extent. Phloretin reduced urea permeability but not water flow or particle aggregation. Since neither agent affects vasopressin-stimulated sodium movement, these findings indicate that the phenomenon of particle aggregation is specifically related to vasopressin-induced water permeability and not to changes in urea or sodium permeability.

Selective inhibition of osmotic water flow by general anesthetics to toad urinary bladder.

Vasopressin increases the permeability of the total urinary bladder, an analogue of the mammalian renal collecting duct, to water and small solutes, especially the amide urea. We have observed that three general anesthetic agents of clinical importance, the gases methoxyflurane and halothane and the ultrashortacting barbiturate methohexital, reversibly inhibit vasopressin-stimulated water flow, but do not depress permeability to urea, or the the lipophilic solute diphenylhydantoin. In contrast to their effects in vasopressin-treated bladders, the anesthetics do not inhibit cyclic AMP-stimulated water flow, consistent with an effect on vasopressin-responsive adenylate cyclase. The selectivity of the anesthetic-induced depression of water flow suggests that separate adenylate cyclases and cyclic AMP pools may exist for control of water and urea permeabilities in to toad bladder. Furthermore, theophylline's usual stimulatory effect on water flow, but not its effect on urea permeability, was entirely abolished in methoxyflurane-treated bladders, suggesting that separate phosphodiesterases that control water and urea permeabilities are present as well. We conclude that the majority of water and urea transport takes place via separate pathways across the rate-limiting luminal membrane of the bladder cell, and that separate vasopressin-responsive cellular pools of cyclic AMP appear to control permeability to water and to urea.

Anaesthetic sensitivity of fMLP-induced cell signalling in Xenopus oocytes.

FMLP stimulation of Xenopus oocytes expressing fMLP receptors leads to a concentration-dependent biphasic inward current. To identify the evolution of these currents we have examined the effects of blocking various cell signalling pathways. In addition we have analysed the effects of three intravenous anaesthetics on these fMLP-induced currents. Xenopus oocytes were microinjected with cRNA encoding the fMLP receptor and fMLP-stimulated (100 nM) currents measured, using two-electrode voltage-clamp (-70 mV), before and after injection of heparin (120 ng ml-1), wortmannin (1 microM), U73122 (5 microM) or buffer. Concentration-response curves were established for the action on fMLP-stimulated currents of thiopentone (5-500 microM), methohexitone (0.2-200 microM) and propofol (0.5-500 microM). Heparin significantly enhanced the fast current (p<0.05). Wortmannin had no effect on either current. U73122 inhibited only the slow current (p<0.05). All anaesthetics inhibited both currents, with the maximum inhibition for the fast/slow currents 70%/100%, 60%/60% and 100%/100% for thiopentone (IC50 147/120 microM), methohexitone (IC50 4.7/2.2 microM) and propofol (IC50 33/8 microM), respectively. We suggest (a) the slow current arises via the PLC/PKC pathway because it is reduced by the PLC inhibitor U73122, (b) the PI3K- and PLD-mediated pathways are not involved because wortmannin had no effect and (c) activation of the two conductance channels must be different because U73122 reduced the slow but not the fast current. Since both currents are decreased by all three anaesthetics, their inhibition might be mediated through an action at the agonist/receptor, although, since the slow current is consistently more sensitive than the fast, there may be additionally an action on cell signalling.

Effect of anesthetic agent on lung tumor induction in hamsters given benzo[a]pyrene-ferric oxide.

The effects of an anesthetic agent on lung tumor induction in noninbred Syrian golden hamsters were investigated after intratracheal instillation of a benzo[a]pyrene-ferric oxide mixture. Inhalation anesthesia with ether or methoxyflurane was accomplished with a closed recirculatory system that allowed a short induction time for anesthesia and a good control over the concentration of anesthetic. This type of anesthetic induction was compared with systemic induction by Brevital. Survival rates during the 10 weekly instillations were least for the Brevital-treated group and greatest for the methoxyflurane-treated group. Body weight gain was lower in both the ether- and Brevital-treated groups as compared to the group anesthetized with methoxyflurane. The animals anesthetized with Brevital had the shortest tumor latency, but the tumor incidence during the weeks of the experiment was similar in the group treated with this agent and the group treated with ether. Exposure to methoxyflurane and the carcinogen produced a slow onset of deaths from tumors and lower tumor incidence. These results are discussed in relation to retention of the dose of carcinogen in the respiratory tract and effect of inhalation anesthia on consequent lung tissue pathology.

The effects of nicotine self-administration and withdrawal on concurrently available chow and sucrose intake in adult male rats.

Carbohydrate intake, preference, and taste thresholds may be altered in current and former cigarette smokers, which may mediate weight gain and risk for obesity in individuals who quit smoking. Attempts to model these effects in rodents have primarily used noncontingent nicotine administration. The purpose of this research was to characterize changes in chow and sucrose intake in rats during a 23-h access model of i.v. nicotine self-administration (NSA), in which rats lever-pressed for chow, sucrose, and nicotine under concurrent fixed-ratio (FR) 1 schedules. Male rats were assigned to one of three groups that differed in food and drug availability. The Nicotine C+S group had concurrent access to nicotine, chow, and sucrose. The Saline C+S group had access to saline, chow, and sucrose. The Nicotine C-Only group had access to nicotine and chow, but not sucrose. Changes in food intake and weight gain were assessed during baseline, NSA, and nicotine withdrawal (i.e., saline extinction). Weight gain was significantly slowed during NSA and increased during withdrawal, but did not differ between the nicotine groups. NSA produced a significant decrease in both chow and sucrose intake. Gradual tolerance to nicotine's effects on sucrose, but not chow intake, occurred. During withdrawal, chow and sucrose intake increased, with a larger percent increase in sucrose intake compared to chow. The proportion of total food intake from sucrose was greater at the end of withdrawal compared to baseline, indicating a history of nicotine intake changed dietary preference. Combined, these results indicate that sucrose intake is more resistant to nicotine's appetite suppressant effects and withdrawal from nicotine produces a greater increase in sweet food intake alongside general increases in chow intake. Changes in overall food intake in current and ex-smokers may lead to increased risk for obesity and other health problems, potentially limiting the benefit of quitting smoking.

Evaluation by capacitance measurements of antidiuretic hormone induced membrane area changes in toad bladder.

A technique for estimating effective transepithelial capacitance in vitro was used to investigate changes in epithelial cell membrane area in response to antidiuretic hormone (ADH) exposure in toad bladder. The results indicate that transepithelial capacitance increases by about 30% within 30 min after serosal ADH addition and decreases with ADH removal. This capacitance change is not blocked by amiloride and occurs whether or not there is a transepithelial osmotic gradient. It is blocked by methohexital, a drug which specifically inhibits the hydro-osmotic response of toad bladder to ADH. We conclude that the hydro-osmotic response of toad bladder to ADH is accompanied by addition of membrane to the plasmalemma of epithelial cells. This new membrane may contain channels that are permeable to water. Stimulation of Na+ transport by ADH is not related to membrane area changes, but appears to reflect activation of Na+ channels already present in the cell membrane before ADH challenge.

Self-administration of methohexital, midazolam and ethanol: effects on the pituitary-adrenal axis in rhesus monkeys.

RATIONALE: There is disagreement in the literature with respect to how drugs of abuse affect the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, and whether these changes in endocrine function may be related to the rewarding effects of these drugs. OBJECTIVES: To determine whether reinforcing drugs with different mechanisms of action affect HPA axis function at doses at which they serve as reinforcers. METHODS: Seven monkeys (6 male) were randomly assigned to self-administer methohexital-a barbiturate (n=4), midazolam-a benzodiazepine (n=3), or ethanol (n=5). Each monkey had a surgically implanted indwelling venous catheter, and was trained to respond on a fixed ratio of 30 lever presses to receive an injection of drug or saline. Blood samples were obtained before, during, and after the self-administration sessions for the measurement of ACTH and cortisol by radioimmunoassay. RESULTS: Although methohexital, midazolam, and ethanol all maintained self-administration behavior across a range of doses, they differed in their effects on ACTH and cortisol. Ethanol inhibited ACTH and cortisol secretion. Methohexital and midazolam both tended to decrease ACTH and cortisol at large doses, and increase these hormones at small doses, but the HPA effects of neither drug differed significantly from when saline was available. CONCLUSIONS: The neutral overall effect of methohexital and midazolam on HPA activity is consistent with other monkey and human studies, whereas the inhibitory effect of self-administered ethanol in the monkey contrasts with both the rat and human literature. The data in this study suggest that a change in HPA axis activity is not a requirement for drug-reinforced behavior in monkeys.

Deep sedation with methohexital or thiamylal with midazolam for invasive procedures in children with acute lymphoblastic leukemia.

Pediatric oncology/hematology patients, especially those with acute lymphoblastic leukemia (ALL), often undergo repeated painful invasive procedures. Deep sedation, mandatory for these procedures in young children, can reduce patient anxiety and get their compliance during procedures. This study assessed clinical experience of employing methohexital or thiamylal with midazolam as sedative for elective invasive procedures in children with ALL. Between November 1997 and March 2004, 20 out of 33 ALL children received deep sedation after evaluation, mainly because of relatively young age (mean age 4.60 +/- 2.03 years). A total of 176 procedures were done, with 139 being intrathecal therapy. There were 98 and 78 procedures for the methohexital and thiamylal groups, respectively. The average dosages to complete the procedures were 2.2 +/- 1.2 mg/kg for methohexital and 3.4 +/- 2.1 mg/kg for thiamylal. One out of the 176 procedures was failed due to bradycardia, hypotension and cyanosis, in the methohexital group. Otherwise, no significant adverse events were found. Increased heart rate (HR) during stable blood pressure (BP) was observed in both groups. In conclusion, under careful monitoring and performed by experienced practitioners, the application of methohexital or thiamylal combined with midazolam to achieve deep sedation for invasive procedures in young children with ALL is safe.

Drug modification of ECT: methohexital and diazepam. II.

A systematic comparison of methohexital and diazepam as anesthetics in the drug modification of ECT was done by holding atropinizaton, succinylcholine-depolarizing neuromuscular blockade, and resuscitation constant while monitoring four ECT in each of 24 patients. Each patient served as his own control, and two dosages of each drug (0.25 and 0.35 mg/kg diazepam, 0.9 and 1.1 mg/kg methohexital) were given each patient in all possible orderings (4! = 24) in a scheduled experimental design in which methohexital was given by very rapid (5 sec) and diazepam was given by the recommended slower (60 sec) infusion. The data revealed significant differences and methohexital was superior. Eight of 48 (17%) EKGs were abnormal post-ECT with methohexital, 18 of 48 (38%, phi = 5.3, p < 0.025) with diazepam. Five of 24 (21%) patients had an abnormal post-ECT EKG with methohexital, 15 of 24 (60%, phi 8.6, p < 0.005) with diazepam. Significantly more ventricular premature contractions (VPCs) occurred after diazepam. Diazepam records contained both more numerous and more extensive EKG abnormalities. Methohexital induction was clinically superior as well; there was little of the induction restlessness seen in seven treatments with diazepam (phi2 7.6, p < 0.01). The differences were less marked than in a previous study in which diazepam was given as rapidly as methohexital. Methohexital has been demonstrated to be the anexthesia of safety and choice for ECT when compared to diazepam.

Factors affecting amnesia, seizure duration, and efficacy in ECT.

Twenty-nine patients given unilateral ECT were tested for memory with each treatment. Forgetting of nonverbal material correlated positively with seizure duration and with anesthetic dose. Seizure duration did not correlate with forgetting of verbal material or with changes in Hamilton depression ratings. Seizure duration was inversely related to succinylcholine and methohexital doses. These findings suggest that muscle relaxant and anesthetic doses can be adjusted to lessen the amnestic effects of ECT. There are, however, insufficient data on the relationship between seizure length and ECT efficacy to specify a minimum duration for seizures, individually or cumulatively.

Dissociation of anosognosia for hemiplegia and aphasia during left-hemisphere anesthesia.

The stroke literature indicates that the explicit denial of hemiplegia, a form of anosognosia, is associated more commonly with right- than left-hemisphere lesions. Some investigators have suggested that this asymmetry may be an artifact and that the aphasia that often accompanies left-hemisphere dysfunction may mask some instances of anosognosia. Mechanisms suggested for anosognosia have been either "global" or "modular" in nature. Mechanisms posited in global explanations include psychological denial and general mental deterioration; modular explanations include feedback and feedforward theories. Videotapes of 54 patients with medically intractable seizures who had selective barbiturate anesthesia (Wada test) as part of their evaluation for seizure surgery were assessed for anosognosia of hemiplegia and aphasia after hemispheric anesthesia had worn off. The results suggest that, although aphasia may confound the reported rate of anosognosia for hemiplegia following left-hemisphere dysfunction, the frequency of anosognosia for hemiplegia is still higher with right- than left-side dysfunction. Anosognosia for hemiplegia and aphasia were dissociable, providing support for the postulate that awareness of dysfunction is mediated by a modular system.

Alpha subunit isoform influences GABA(A) receptor modulation by propofol.

We have investigated the role of the alpha subunit in the modulation of gamma-aminobutyric acid type A (GABA(A)) receptors by the general anesthetic propofol, using whole-cell patch clamp recordings made from distinct stable fibroblast cell lines which expressed only alpha1beta3gamma2 or alpha6beta3gamma2 GABA(A) receptors. At clinically relevant anesthetic concentrations, propofol potentiated submaximal GABA currents in alpha1beta3gamma2 receptors to a far greater degree than those in alpha6beta3gamma2 receptors. The alpha subunit influenced the efficacy of propofol for modulation, but not its potency. In contrast, direct gating of the ion channel by propofol, in the absence of GABA, was significantly larger in the alpha6 than the alpha1 containing receptors. The potentiation of submaximal GABA by trichloroethanol, and the potentiation and direct gating by methohexital was also studied, and showed the same relative trends as propofol.

The effects of four general anesthetics on intracellular [Ca2+] in cultured rat hippocampal neurons.

It has been suggested that general anesthesia might arise as a consequence of increased cytoplasmic free ionized calcium concentration ([Ca2+]i). The effect of increased [Ca2+]i might be to activate K+ channels or to modulate other ion channels important for the control of excitability, such as the GABAA receptor. A direct test of this hypothesis has not been reported. Microfluorimetry with the calcium-sensitive dye fura-2 was used to study the effects of four anesthetic agents on the regulation of intracellular free Ca2+ in hippocampal neurons cultured from the embryonic rat hippocampus. Basal intracellular free ionized calcium concentration [Ca2+]i in the neurons was 50-100 nM. Depolarization of the neurons with 50 mM K+ resulted in the elevation of [Ca2+]i to 200-800 nM, with subsequent recovery of [Ca2+]i over several minutes. The volatile anesthetics halothane, enflurane and isoflurane did not alter basal [Ca2+]i, even above clinically relevant concentrations; however, they did inhibit elevation of [Ca2+]i by high K+ stimulation. The intravenous anesthetic methohexital caused small increases in basal [Ca2+]i at concentrations > or = 50 microM; methohexital (5-50 microM) also inhibited elevations of [Ca2+]i induced by high K+. The evidence presented here suggests that the anesthetics studied do not produce their actions via sustained or transient increases in [Ca2+]i. However, all of the anesthetics studied appear to possess inhibitory effects on hippocampal voltage-dependent Ca2+ channels, in addition to their previously described effects at GABAA receptors.