Monitoring sodium methohexital distribution with [99mTc]HMPAO with single photon emission computed tomography during Wada test.

Twenty-five consecutive patients being considered for surgery for intractable epilepsy had intracarotid sodium methohexital procedures (ISM) as part of their evaluation. The lipophilic brain SPECT agent, [99mTc]hexamethylpropylene aminoxime (HMPAO), was administered intravenously during the procedure to determine the intracerebral distribution of methohexital. The validity of the ISM depends on consistent delivery of the anesthetizing agent to one hemisphere, including the mesial structures of the temporal lobe. To prevent postoperative language and memory deficits, correct interpretation of the test results supposes a reliable knowledge of which regions of the brain have been anesthetized. Currently, no absolute criteria allow determination of the level and topographical extent of the anesthesia. We compared results of HMPAO-SPECT with clinical and EEG video-monitoring data and with results of digital subtraction angiography (DSA) performed during the test. In all patients, the effect of SM was ipsilateral cerebral hypoperfusion on SPECT and crossed cerebellar diaschisis. The distribution of HMPAO varied from patient to patient. The delivery of SM to mesial temporal lobe structures was not constant. Using nonparametric tests, we demonstrated a statistically significant relationship between hypoperfusion on SPECT and duration of hemiplegia but not with the duration of aphasia. Hypoperfusion on SPECT was also related to the onset and duration of drug-induced delta activity on EEG. SPECT showed a statistically different distribution of SM in the brain from that predicted with DSA. We present our experience with HMPAO-SPECT use for mapping the distribution of methohexital's effects during the ISM (Wada test). We confirm the results of previous studies that SPECT assessment may be an excellent way of determining the distribution of barbiturate during the examination. It increases confidence in interpreting results of speech and memory testing by detecting either contralateral diffusion of the drug due to crossflow between hemispheres or insufficient quantitative delivery to the homolateral hemisphere.

Metabolites of methohexitone do not contribute to its prolonged action on the central nervous system.

Methohexitone has been reported to have a prolonged action on the central nervous system (CNS) despite its relatively short elimination half-life. A hydroxy metabolite of methohexitone was identified, purified and isolated from the urine collected from eight surgical patients and five mongrel dogs anaesthetized with methohexitone. Using a rotarod device, the CNS-activity of the human and canine metabolites was tested in mice and compared to that of methohexitone. In this test, the metabolites showed CNS-depressant activity, but the ED50 (dose needed to affect 50% of the animals) of the metabolites was ten times higher than the ED50 of the parent drug. Because in patients, no traces of the hydroxy metabolite could be found in blood, and in dogs the plasma concentration of the metabolite was about two-thirds of that of the parent compound, it is unlikely that the residual CNS-effects of methohexitone are due to its major metabolite, hydroxymethohexitone.

Barbiturate anesthesia and alcohol tolerance in a rat model.

Anesthetic responses to a variety of barbiturates were examined in adult male rats rendered alcohol-tolerant by administration of an ethanol-containing balanced liquid diet for 3 weeks. Within 9 hours of withdrawing the diets, groups of 10-15 ethanol-fed rats and pair-fed controls were injected intraperitoneally with one of the following drug/dose combinations: thiamylal 20, 40, or 60 mg/kg; methohexital 10, 20, or 40 mg/kg; secobarbital 20, 30, or 40 mg/kg; pentobarbital 10, 20, or 40 mg/kg; or phenobarbital 80, 120, or 160 mg/kg. Each animal was monitored for time to loss of righting reflex (onset of anesthesia), absence of response to a painful stimulus (analgesia), and sleeping time (duration of anesthesia). None of these three anesthetic responses differed significantly in ethanol-fed and control rats with any dose of thiamylal, methohexital, or secobarbital. In contrast, all three responses were significantly less in rats given the middle dose of pentobarbital (20 mg/kg) than they were in control rats. Onset and duration of anesthesia were also shorter with the middle dose of phenobarbital (120 mg/kg), but analgesia was not. The results of this study, in combination with others, suggest that 1) cross-tolerance to anesthetic effects of barbiturates in ethanol-tolerant rats is not uniform with all barbiturates: and 2) because shorter-acting barbiturates show negligible cross-tolerance with alcohol, higher doses of these agents may not be required for satisfactory anesthesia in chronically alcoholic humans.

Quantitative analysis of serum methohexital by GLC using capillary column and nitrogen-selective detection.

A gas chromatographic method for routine quantitation of methohexital in plasma samples is reported. One-step extraction in organic phase, the use of a fused silica capillary column, and nitrogen-selective detection permit simple, precise, and sensitive determination of methohexital in plasma. A linear relationship is described between peak height ratio and methohexital concentrations ranging from 0.125 to 50.0 micrograms/ml (r = 0.998). The sensitivity limit of the assay was 6 ng/ml in plasma. No interfering peak was observed with numerous other drugs. The procedure was successfully applied to the determination of pharmacokinetic parameters of methohexital after IV administration or continuous infusion in a child and an adult.

Closed-loop feedback control of methohexital anesthesia by quantitative EEG analysis in humans.

A combined pharmacokinetic and pharmacodynamic model of methohexital was used to establish and evaluate feedback control of methohexital anesthesia in 13 volunteers. The median frequency of the EEG power spectrum served as the pharmacodynamic variable constituting feedback. Median frequency values from 2-3 Hz were chosen as the desired EEG level (set-point). In 11 volunteers, the feedback system succeeded in maintaining a satisfactory depth of anesthesia (i.e., unresponsiveness to verbal commands and tactile stimuli). During feedback control, 75% of all measured median frequency values were in the preset range of 2-3 Hz. This distribution of median frequency was obtained by applying random stimulation (six different acoustic and tactile stimuli) to the volunteers approximately every 1.5 min. The decrease of median frequency from baseline to anesthetic values was primarily induced by increasing the fractional power in the frequency band of 0.5-2 Hz from 12.6 +/- 4.5% (mean +/- SD) to 46.0 +/- 2.5%. The median time to recovery (as defined by opening eyes on command) after cessation of the feedback control period was 20.6 min (10.7-44.5 min) when median EEG frequency was 5.2 Hz (4.7-8.4 Hz). The average requirement of methohexital (mean +/- SD) during the 2 h was 1.02 +/- 0.16 g. It is concluded that pharmacokinetic-pharmacodynamic models of intravenous anesthetics established previously may be used to form a suitable background for model-based feedback control of anesthesia by quantitative EEG analysis. This approach gives a possible solution to the problem of adapting pharmacokinetic and pharmacodynamic data to individuals when using population mean data as starting values for drug therapy.

[The effect of rectal pH values on the absorption of methohexital]. / Der Einfluss des rektalen pH-Wertes auf die Resorption von Methohexital.

The factors underlying the unpredictability of the pharmacokinetics of rectally administered methohexitone remain unclear. The "pH partition hypothesis" offers an explanation. We investigated six children with rectal pH values ranging from 7.5 to 9.8, who were given 25 mg/kg methohexitone 10% via the rectal route under general anaesthesia. Blood samples were taken at zero, 3, 5, 7, 10, 15, 20, 30, 40, 60, 90 and 120 min; rectal pH was measured at zero and 1 min. The methohexitone plasma levels reached a maximum (Cmax) of 2.63 micrograms/ml (median) after 17.5 min (median). The elimination half-life ranged from 37 to 218 min. No positive correlation between lower pH and better resorption (AUC and Cmax) was found. The resorption kinetics of rectally administered methohexitone cannot be explained by its electrochemical properties alone.

Comparative pharmacokinetics and anesthetic effects of methohexital, pentobarbital, thiamylal, and thiopental in Greyhound dogs and non-Greyhound, mixed-breed dogs.

Pharmacokinetics and duration of anesthesia of methohexital, pentobarbital, thiamylal, and thiopental in Greyhound and non-Greyhound, mixed-breed dogs were compared. In all dogs evaluated, pentobarbital induced the longest duration of anesthesia and methohexital induced the shortest duration. Pharmacokinetics of pentobarbital and methohexital were similar in both groups of dogs. Thiobarbiturates induced longer anesthetic effects in Greyhound dogs than in mixed-breed dogs. Plasma thiobarbiturate concentrations remained above normal longer in Greyhound dogs than in mixed-breed dogs. Disposition of thiobarbiturates in Greyhound dogs was characterized by nonlinearity from 45 minutes to 8 hours after dosing.

The pharmacokinetics of methohexital in young and elderly subjects.

The pharmacokinetics of methohexital were investigated in ten young adult volunteers and in seven young and seven elderly patients. The latter two groups underwent enflurane and nitrous oxide anesthesia and surgery. Each subject received a bolus dose of 2 mg/kg of methohexital intravenously. Plasma levels of the drug were measured for 8 h after injection by gas chromatography using a nitrogen detector. Anesthesia (combined with surgery) and increase in age did not separately affect the kinetics of the drug; however, the elimination half-life was longer in the elderly patients group than in the young non-anesthetized volunteers.

Rectal induction of anaesthesia in children with methohexitone. Patient acceptability and clinical pharmacokinetics.

Rectal induction of anaesthesia with 10% methohexitone 100 mg ml-1 was used in 50 healthy children, using a standard dose of 25 mg/kg body weight. The absorption of methohexitone was rapid and reliable: the children fell asleep within 10-15 min. The plasma concentration peaked at 10-15 min and then decayed rapidly. The terminal half-life of rectal methohexitone was 1-2 h. Overall patient acceptability was good, and there were no major complications.

[Pharmacokinetic studies following intravenous, intramuscular and rectal administration of methohexital in children]. / Pharmakokinetische Untersuchungen nach intravenöser, intramuskulärer und rektaler Applikation von Methohexital bei Kindern.

In pediatric patients methohexitone is used increasingly in different application forms for induction of anesthesia. Plasma concentrations of methohexitone were measured after rectal induction with 25 mg/kg, and after intramuscular injection of 5 mg/kg in 10 children each aged 2-7 years and were compared with 4 children after intravenous administration of 2 mg/kg. The pharmacokinetic parameters of the i.v. administered methohexitone were calculated and compared with the known pharmacokinetics in adults, showing that the open two-compartment-model is also applicable to children with a substantial shorter beta-half-life and a higher clearance. After rectal and i.m. induction with methohexitone the individual plasma concentrations scatter in a relatively wide range. The mean value curves of both application forms are similar with a maximum plasma concentration of 2.76 micrograms/ml between minutes 7-15 (rectal) respectively 2.6 micrograms/ml between minutes 15-30 (i.m.); 2 h later they are 0.57 micrograms/ml (rectal) and 1.03 micrograms/ml (i.m.). In contrast to the 100% available bioactivity of methohexitone after i.m. administration it amounts to only about 17% after rectal induction. As a result one can consider children to be able to eliminate methohexitone sufficiently in the observed plasma concentration range.

General kinetic and dynamic principles and their application to continuous infusion anaesthesia.

The use of intravenous anaesthetic agents by continuous infusion requires knowledge of their pharmacokinetic properties. In this article, the general pharmacokinetic principles behind the use of infusions of intravenous agents are presented and the literature with regard to the individual drugs used in this way is reviewed.

[Drug metabolism in patients with liver disease (author's transl)]. / Arzneimittelmetabolismus bei Patienten mit Lebererkrankungen.

Patients with acute hepatitis and patients with compensated or decompensated cirrhosis of the liver have a decreased plasma clearance of hexobarbital. This however could not been demonstrated in patients with intra- or extrahepatic cholestasis and patients with primary biliary cirrhosis of the liver. The plasma clearance of methohexital, - a high clearance drug - is not changed in the same way. Also there is no evidence as yet, that patients with liver disease and without a collateral portal circulation do have an increased bioavailability of oral high clearance drugs.

Pharmacokinetics of methohexitone following intravenous infusion in humans.

A sensitive method, using gas chromatography with nitrogen selective detection, has been developed for the accurate measurement of methohexitone, in plasma, in concentrations of less than 0.05 mug/ml, and which makes it possible to study the pharmacokinetics of the drug after clinical doses in man. Methohexitone sodium 3.0 mg/kg was administered by zero-order infusion to healthy volunteers and plasma concentrations were measured during and after infusion. The decrease in the plasma concentration of methohexitone can be described by two-compartment kinetics. The terminal elimination half-life of the drug is relatively short (70-125 min), which is a result of a high metabolic clearance rate (657-999 ml plasma/min). It was concluded that uptake of the drug by adipose tissue does not contribute significantly to its pharmacokinetics in man. In addition to the initial redistribution of an anaesthetic dose of methohexitone, the quick recovery of patients is a result of rapid metabolism of the drug.

Nonlinear pharmacokinetic model of intravenous anesthesia.

A nonlinear pharmacokinetic model was constructed to describe the body distribution of intravenous anesthetics, using the physiological modeling approach for drug distribution kinetics. The model considers the physiological parameters of tissue volumes and blood flow rates for the standard four phases of blood, viscera, lean tissue, and adipose tissue and also the associated drug parameters known to influence drug distribution. A simple ramp function having a characteristic time (volume per flow rate) is used to describe the rate of approach to equilibrium conditions for each tissue phase. The model was evaluated for the distribution of methohexital and thiopental by comparing calculated values to experimental drug concentrations taken from the literature. The physiological alteration of obesity also was programmed into the model to evaluate its capability for predicting the influence of body alterations on drug distribution. The results indicated that a preliminary mathematical model of relatively simple design is capable of at least a semiquantitative prediction of intravenous anesthetic drug concentrations in body tissues and has the potential of accounting for differences in drug distribution in the presence of selected physiological alterations.