Hyperlipidemia sink for anesthetic agents.

We present a case that involves anesthetic resistance during anesthesia for electroconvulsive therapy. Despite adequate dosing of both intravenous and inhalation anesthetics, our patient was resistant to induction of the state of general anesthesia. Subsequently, we noticed extreme hyperlipidemia. We hypothesized that the patient's extreme hyperlipidemia served as an anesthetic "sink" and prevented the full dose of intravenous agents from quickly reaching their intended site of action.

Magnetic motor evoked potentials during methohexital anesthesia in the dog.

Magnetic motor evoked potentials (MMEPs) were recorded from the right cranial tibial muscle after magnetic stimulation of the left motor cortex in six dogs sedated with oxymorphone. Anesthesia was induced with an intravenous bolus of 5.5 mg/kg of methohexital and maintained with a methohexital infusion. The dogs inspired 100% oxygen during anesthesia. Blood pressure, heart rate, respiratory rate, esophageal temperature, and end-tidal carbon dioxide tension were recorded. The depth of anesthesia was increased until the amplitude of the MMEP was less than 5% of the control value, and the dogs were then allowed to recover. Every 5 minutes during anesthesia, a blood sample was taken for methohexital assay and at the same time, four replicate MMEPs were recorded. Plasma methohexital levels were significantly (P < 0.05) correlated with heart rate (p = 0.38) and end-tidal carbon dioxide tension (p = 0.49) and negatively correlated with respiratory rate (p = 0.74). There was no significant correlation between blood pressure and methohexital levels. The dogs regained consciousness at a plasma methohexital level of 10.4 +/- 3.8 micrograms/ml (mean +/- SD). The amplitude of the MMEP decreased significantly with increasing methohexital levels. In four dogs, the relationship was reasonably linear. The MMEP disappeared at a plasma methohexital level of 23 +/- 6.6 micrograms/ml. The latency of onset of the MMEP increased significantly from its control value of 14.7 +/- 1.0 ms to 17.5 +/- 1.3 ms at the highest methohexital levels at which MMEPs were recordable. This study demonstrated that MMEPs can be reliably recorded under methohexital anesthesia.

Pharmacokinetics of methohexital during cardiovascular surgery with cardiopulmonary bypass.

The pharmacokinetics of methohexital after intravenous bolus administration was studied during cardiovascular surgery with cardiopulmonary bypass. The effect of body temperature (normothermia and hypothermia) during cardiopulmonary bypass on methohexital pharmacokinetics was investigated. The pharmacokinetic data obtained were compared with those from vascular surgery without cardiopulmonary bypass. A marked decrease in plasma methohexital concentrations and therefore in area under curve and a significant increase in clearance and in volume of distribution were observed in the cardiopulmonary bypass groups compared to the vascular surgery group without cardiopulmonary bypass. However, the elimination half-life and the mean residence time were similar in the 2 groups. Furthermore, the study shows that body temperature during cardiopulmonary bypass does not influence methohexital pharmacokinetics.

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.

Clearance of fentanyl, alfentanil, methohexitone, thiopentone and ketamine in relation to estimated hepatic blood flow in several animal species: application to prediction of clearance in man.

We have used estimated hepatic blood flow (Qhep) as an aid to evaluate clearance (CL) values in animals and to predict clearance in man of five anaesthetic agents: fentanyl, alfentanil, methohexitone, thiopentone and ketamine. The disposition of methohexitone was determined in rats and that of ketamine in rats, rabbits and pigs. Further data were compiled from the literature and supplemented experimentally as needed. Allometric interspecies scaling, according to three different methods, was used to estimate blood clearance and unbound clearance (CLu) in man. The results of scaling according to the three different methods were evaluated in relation to estimated hepatic extraction ratio (CL/Qhep) of the drugs. In most animals the clearance of the drugs were comparable with or lower than estimated Qhep. However, ketamine showed extensive extrahepatic clearance in rabbits. Prediction of clearance in man was successful by at least one method for all five drugs, while prediction of CLu generally failed. Estimates of CL/Qhep gave no indication as to the choice of the best method. Volume of distribution at steady state could be predicted for alfentanil, thiopentone and ketamine. Comparison of clearance with Qhep should be used to evaluate clearance data in animals, however estimation of hepatic extraction ratios appears to be of little use for allometric scaling. The use of ketamine as an anaesthetic agent in rabbits is questionable, while the use of fentanyl in pigs, methohexitone in rats and ketamine in rats and pigs is well supported by the pharmacokinetic data.

Endotoxin-induced fever increases the clearance of methohexitone in rabbits.

We have previously observed that the clearance of methohexitone, given by continuous infusion for sedation in the intensive care unit, was influenced by body temperature in patients with post-operative fever. The aim of the present study was to reproduce this finding in an animal model that can then be used to predict similar influences for other anaesthetic agents. Sixteen rabbits were infused for 2.0 h with methohexitone (8.4 +/- 0.5 mg kg-1 h-1 (mean +/- s.d.)) and in eight of them fever was induced with intravenous Escherichia coli endotoxin. Arterial blood samples were taken over 6 h and plasma concentrations of methohexitone were assayed by gas chromatography. The mean body temperatures of the rabbits over the periods of measurement varied between 38.5 and 41.8 degrees C, and the total clearance of methohexitone (mean 50.7 mL min-1 kg-1) was positively correlated with temperature (r = 0.545, P = 0.029). No significant correlations with temperature were found for other pharmacokinetic parameters. We conclude that these observations correspond to the findings in the clinical pharmacokinetic study, showing the validity of the animal model.

Induction and maintenance of anesthesia in dogs by intravenous administration of methohexital.

OBJECTIVE: To devise and test an i.v. methohexital infusion regimen for induction and maintenance of surgical anesthesia in dogs from which they would rapidly recover. DESIGN: Dose-response and plasma concentration-effect study. ANIMALS: 11 clinically normal dogs. PROCEDURE: Bolus methohexital pharmacokinetic variables were determined in ketamine- and pentobarbital-anesthetized dogs. Plasma methohexital concentrations required to inhibit purposeful movement in response to painful stimuli were determined during a stepped methohexital infusion in the same dogs on a second occasion. These pharmacokinetic/pharmacodynamic data were next used to design a bolus and two-stage infusion regimen that would result in stable plasma methohexital concentrations with prolonged infusion. This regimen was tested in a second group of dogs. RESULTS: Mean steady-state volume of distribution of methohexital in the anesthetized dogs was 1.50 L/kg of body weight and mean elimination clearance was 10.2 ml/kg/min. Mean plasma concentrations required to prevent movement response to a noxious stimulus and at which the dogs could be extubated were 11.8 and 6.9 micrograms/ml, respectively. After a 6-hour infusion, recovery of airway reflexes sufficient to allow extubation required 67 minutes. CONCLUSIONS: An easily implemented i.v. methohexital infusion regimen for induction and maintenance anesthesia in dogs was developed. During a 6-hour infusion, hemodynamic variables did not change. Use of this regimen resulted in anesthesia of sufficient depth to prevent withdrawal in response to noxious stimuli and in reliable and acceptable emergence times for use in canine survival studies in a cost-effective manner.

Transfer of methohexital across the perfused human placenta.

STUDY OBJECTIVES: To evaluate the transfer properties of methohexital and the influence of protein binding using the in vitro human placental perfusion model. DESIGN: Fresh term human placentae from healthy parturients were perfused bidirectionally via a cannulated fetal chorionic artery and vein and needles placed into the maternal intervillous space. Maternal-to-fetal (M-->F) and fetal-to-maternal (F-->M) transfer and ultimate distribution of methohexital was investigated using a closed (recirculating) placental perfusion model. SETTING: Obstetric anesthesia laboratories of two university medical centers. PATIENTS: No patient participation occurred as placentae were obtained after delivery. INTERVENTION: M-->F and F-->M transfer of methohexital was compared in vitro in perfusates with equal protein concentrations (2 g/100 mL in both perfusates) or albumin-simulated physiologic protein binding concentrations (maternal 8 g/100 mL; fetal 4 g/100 mL). MEASUREMENTS AND MAIN RESULTS: Data obtained consisted of measurements of methohexital and antipyrine concentrations by high-performance liquid chromatography. Glucose and lactate concentrations and perfusate loss were measured to assess placental viability. Methohexital protein binding was assessed at 2, 4, and 8 g/100 mL of albumin by equilibrium dialysis. The transfer index of 0.83 +/- 0.11 for the M-->F perfusions was significantly greater (p < or = 0.05) than in the F-->M direction (0.61 +/- 0.04) when albumin concentration was equal in both perfusates. This transfer asymmetry disappeared when albumin concentrations simulating maternal (8 g/100 mL) versus fetal (4 g/100 mL) protein concentrations in the perfusate were used (M-->F 0.87 +/- 0.12 and F-->M 0.95 +/- 0.11). CONCLUSION: Methohexital readily crosses the placenta in both directions. Protein binding has significant effects on the degree of transfer of methohexital at any time when compared with antipyrine and its ultimate fetal/maternal distribution.

[Pharmacokinetic and clinical evaluation of rectal hydrophilic gel of methohexital in pediatric surgery]. / Evaluation pharmacocinétique et clinique d'un gel rectal hydrophile de méthohexital en chirurgie pédiatrique.

The purpose of the study was to develop and to test a new form of rectal systemic gel for methohexitone administration in children undergoing minor surgery. Pharmacokinetics of methohexitone were determined in children following intravenous or intrarectal administration either at low or therapeutic dosage. Anaesthesic efficacy of this gel was performed in 11 patients receiving a therapeutic dosage (25 mg/kg). Pharmacokinetics of methohexitone appears independent of both dosage and route of administration in children. The bioavailability of the rectal gel appears sufficient to provide efficient clinical plasmatic concentrations. As a consequence of the rapid and good resorption of methohexitone from rectal lumen and of the low variability of plasmatic concentrations, a rapid and reliable sedation was observed in all patients. The clinical anaesthesic efficacy of the rectal hydrophilic gel associated with the absence of an apparent local intolerance and important side effects, make this new form suitable for methohexitone administration in children.

[Pharmacokinetics of methohexital given by constant rate intravenous infusion]. / Pharmacocinétique du méthohexital administré en perfusion intraveineuse à débit constant.

The pharmacokinetic characteristics of a constant rate methohexitone infusion were studied in young ASA 1 patients undergoing maxillofacial surgery. They were randomly assigned to two groups; group M patients (n = 7) were given 9 mg.kg-1.h-1 of methohexitone for one hour, and group MF patients (n = 7) 9 mg.kg-1.h-1 of methohexitone with 7 micrograms.kg-1.h-1 of fentanyl, also for one hour. Blood samples for determining methohexitone concentrations were obtained at various times, from before the start of the methohexitone infusion up to 19 h afterwards. In twelve patients, a two-compartment model was appropriate to characterize the decrease of methohexitone concentration; for the other two (one in each group), a three-compartment model was applied. There were no statistically significant differences between the two groups. Elimination half-life in group M was 3.22 +/- 1.96 h, and total plasma clearance 8.54 +/- 2.8 ml.kg-1.min-1. The wide variations in pharmacokinetic parameters between subjects may explain some unpredictable variations in duration of action of methohexitone. Fentanyl did not modify methohexitone pharmacokinetics, which remained of the first order. However, it potentiated the barbiturate's action: extubation was only possible after stopping the infusion for 39.4 min +/- 22 min in group MF, and 15.4 min +/- 6 min in group M (p less than 0.01). At that time, plasma concentrations were respectively 3.12 +/- 0.99 mg.l-1 (group MF) and 5.71 +/- 2.09 mg.l-1 (group M), (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetics of etomidate]. / Pharmacocinétique de l'étomidate.

Etomidate is the ester of a carboxylated imidazole. This lipophilic (octanol/water partition coefficient: 1000) and weak base (pKa = 4.5) is a potent short-acting hypnotic agent, which can be used for anaesthetic induction or maintenance. The plasma concentration curve fits an open three compartment pharmacokinetic model, with distribution half-lives of 2.6 and 20 min, and terminal elimination half-life of about 4-5 h. Hypnotic plasma concentrations (greater than 0.2 microgram.ml-1) are observed during the intermediate distribution phase (t1/2 approximately 20 min); they reflect the short lasting pharmacodynamic effect. The slow elimination phase is of importance for intravenous infusions lasting more than 2 h; it is recommended to decrease by half the maintenance dose (0.005 mg.kg-1.min-1) so as to prevent a cumulative effect. Etomidate is hydrolysed by hepatic esterases to the corresponding carboxylic acid, which is inactive. The pharmacokinetics of etomidate are altered in the elderly, with a decrease initial distribution volume and clearance (a decreased of 2 ml.min-1.kg-1 every decade) as well as in cirrhotic patients (a 100% increase in terminal half-life).

Pharmacokinetics of two per cent rectal methohexitone in children.

Plasma methohexitone concentrations were determined in 60 children, aged one to six years, following administration of 15 mg.kg-1, 20 mg.kg-1, 25 mg.kg-1 or 30 mg.kg-1 two per cent rectal methohexitone. Time to the onset of sleep was determined by a blinded observer and venous blood samples obtained 15, 30, 45 and 120 minutes following drug administration. Fifty of 60 children were asleep within 15 minutes. Nine of the ten children that did not fall asleep were sedate and could be separated easily from their parents to undergo inhalational induction of anesthesia. Time to the onset of sleep was inversely related to the dose of rectal methohexitone administered. Sleep was achieved more reliably following the use of 25 to 30 mg.kg-1 rectal methohexitone. In addition, plasma methohexitone concentrations following 30 mg.kg-1 rectal methohexitone were significantly higher for up to 120 minutes following drug administration than the plasma concentrations achieved after 15 mg.kg-1 or 20 mg.kg-1 methohexitone. There was no difference in the incidence of complications. The authors recommend that clinical circumstances be carefully considered and the dose of rectal methohexitone administered be individualized to meet the specific anaesthetic requirements of each child.

Pharmacokinetics of i.v. and rectal methohexitone in children.

The pharmacokinetics of methohexitone were investigated in 15 healthy children undergoing minor surgery under inhalation anaesthesia. Six received 1% methohexitone 1-2 mg kg-1 i.v. and nine received 10% methohexitone 20-25 mg kg-1 per rectum. On i.v. administration, three-compartment pharmacokinetics generally applied. The mean elimination half-life of methohexitone was 193 +/- 75 min; that is, considerably longer than previously reported for children, but in good agreement with findings in adults. The mean clearance was 17.9 +/- 8.3 ml min-1 kg-1, the volume of distribution at steady state was 2.1 +/- 0.24 litre kg-1 and the mean residence time was 134 +/- 47 min. The pharmacokinetic model used for the i.v. data was easily modified to suit the plasma concentration curves obtained on rectal administration. The mean bioavailability of methohexitone administered per rectum was 17%, with a six-fold variation between individuals.

Threshold hypnotic concentration of methohexitone.

Methohexitone was administered to 8 healthy adult volunteers as a microprocessor controlled infusion that generated 3 cycles of linearly increasing plasma levels with an anticipated slope of 0.2 microgram.ml-1.min-1. When a deep unconscious state was obtained, as indicated by burst suppression in the EEG, the infusion was stopped and then restarted when the volunteer was fully orientated. Frequent venous blood samples were obtained during and after the infusions to evaluate the threshold concentration at induced sleep and the return of orientation, at the loss and return of the eye lid reflex and corneal reflex, and the appearance and disappearance of EEG burst suppression patterns. From the first to the third infusion cycle only a slight and insignificant increase in the mean threshold concentrations was observed so the plasma levels were averaged over all three infusion cycles. The concentrations (microgram/ml) found were: asleep 3.39 and orientated 3.35, loss 4.42 and recurrence 4.32 of eye lid reflex, loss 6.51 and recurrence 5.18 of corneal reflex, and appearance 10.7 and disappearance 9.3 of burst suppression. Acute tolerance that would have led to a significant increase in threshold concentration from the first to the last infusion cycle was not demonstrated. If induced sleep and the appearance of EEG burst suppression are considered as clinical endpoints of anaesthesia, the therapeutic window of methohexitone covers a mean venous serum concentration range of 3.4 to 10.7 micrograms/ml.

Effect of upper abdominal surgery and cirrhosis upon the pharmacokinetics of methohexital.

The pharmacokinetic profile of methohexital was studied in cirrhotic patients (n = 8), patients undergoing upper abdominal surgery (n = 8) and orthopaedic patients under general anaesthesia (n = 8). The total plasma clearance of methohexital was unchanged in cirrhotics: 54 +/- 22 l.h-1 (mean +/- s.d.) as well as in patients undergoing upper abdominal surgery: 60 +/- 14 l.h-1 in comparison to orthopaedic surgery: 70 +/- 24 l.h-1. The central volume and total volume of distribution and the distribution and elimination half-lives were similar between the three groups. Despite its hepatic dependent elimination, methohexital elimination kinetics were unchanged in patients undergoing upper abdominal surgery and in cirrhosis. Owing to the high hepatic extraction ratio of methohexital, its elimination should be influenced by the hepatic blood flow. The unchanged elimination kinetics presently observed in patients with cirrhosis or those undergoing upper abdominal surgery suggest that the hepatic blood flow is less diminished than expected in these patients.

A method for implementing programmed infusion of thiopentone and methohexitone with a simple infusion pump.

We have tabulated the series of steps in infusion rate required to maintain constant arterial levels of thiopentone and methohexitone. The tables are based on multiexponential equations for infusion rate, derived from plasma drug efflux studies. In each table an initial bolus is followed by nine steps in infusion rate over three hours. The tables provide rates suitable for delivery by a standard syringe pump to achieve and maintain an arterial concentration of 10 mg/l of thiopentone and 5 mg/l of methohexitone. Other desired drug concentrations can be derived from the table by simple multiplication.

Comparison of the pharmacokinetics of methohexital during cardiac surgery with cardiopulmonary bypass and vascular surgery.

The aim of this study was to assess the pharmacokinetics of methohexital (ME) in major vascular surgery (VASC) and to compare these data with the pharmacokinetics of ME during hypothermic cardiopulmonary bypass (HCPB) (temperature: 28 degrees C) and normothermic cardiopulmonary bypass (NCPB) (temperature: 37 degrees C). An ME bolus (2 mg/kg) was administered to 8 VASC patients at the start of surgery and to 11 HCPB patients and 11 NCPB patients at the start of cardiopulmonary bypass (CPB). Twenty-one arterial blood samples were withdrawn over the following 24 hours for ME assays. All of the patients were given similar anesthesia (fentanyl, diazepam) and muscle relaxation (pancuronium). In the VASC group, ME total body clearance (TBC) was 6 +/- 2 mL/kg/min (mean +/- SD), which is less than in previous studies. When comparing HCPB and NCPB groups, elimination half-life (T1/2), TBC, volume of distribution (VD), area under the curve (AUC), and mean residence time (MRT) were similar. When comparing VASC and CPB patients, TBC and VD were greater in CPB patients than in VASC patients; thus, T1/2 (equal to 0.693 x VD/TBC) was similar. AUC was smaller in CPB patients because of hemodilution, but MRT was similar. It is concluded that ME clearance is lower in patients undergoing major vascular surgery than in healthy patients. The temperature and the duration of CPB do not seem to substantially influence the pharmacokinetics of ME when a bolus is administered. Parameters such as AUC, TBC, and VD appear modified by hemodilution during CPB; however, T1/2 and MRT, which allow comparisons between CPB and non-CPB patients, were similar in these patients.

Pharmacokinetics and clinical experience of 20-h infusions of methohexitone in intensive care patients with postoperative pyrexia.

We have studied the pharmacokinetics of 20-h infusions of methohexitone in young patients with postoperative fever undergoing artificial ventilation of the lungs. The infusion rate was adjusted so that patients were unresponsive to vocal stimulation but reacted to tracheal suction. The mean steady state concentration of methohexitone required was 2.6 mg litre-1 (unbound 0.53 mg litre-1). The mean (SD) total clearance of methohexitone was 16.3 (4.2) ml min-1 kg-1, which is greater than that for volunteers or normal surgical patients. The unbound clearance correlated positively with body temperature during the infusion (r = 0.796, P = 0.017). The terminal half-life of methohexitone was 6.3 (3.8) h and that of the 4'-hydroxy metabolite 5.8 (2.1) h. There were no marked haemodynamic effects of the infusion, and no excessive sedation after the infusion. However, the clearance of methohexitone was high and variable, possibly as a direct effect of postoperative fever. Consequently, the need for individual titration of the rate of infusion is emphasized.

Hepatic disposition of methohexitone in patients undergoing coronary bypass surgery.

In order to clarify the relative contribution of hepatic metabolism to the short term disposition of methohexitone, we have measured hepatic blood flow during induction of anaesthesia with a 1.5-mg kg-1 i.v. bolus dose of methohexitone. Median hepatic clearance was 1.01 litre min-1 and hepatic extraction 87%. As a consequence of the high hepatic extraction, the hepatic clearance of methohexitone was closely dependent on hepatic plasma flow.