Plasma Thiopental Concentrations Research Articles

What Determines Anesthetic Induction Dose? It’s the Front-End Kinetics, Doctor!

What Determines Anesthetic Induction Dose? It’s the Front-End Kinetics, Doctor!

Quantitation of depth of thiopental anesthesia in the rat.

In contrast to that of inhalational anesthetics, quantitation of anesthetic depth for intravenous agents has not been well defined. In this study, using rodents, the relationship between the constant plasma thiopental concentrations and the clinical response to multiple nociceptive stimuli were investigated characterizing the anesthetic state from light sedation to deep anesthesia and correlated to the degree of electroencephalogram (EEG) drug effect. Thirty rats were instrumented with chronically implanted EEG electrodes, arterial and venous catheters. A computer-driven infusion pump was used to rapidly attain and then maintain constant, target plasma thiopental concentrations ranging from 7 to 100 micrograms/ml. Three different target plasma thiopental concentrations were achieved in each rat. Electroencephalographic effects were monitored with aperiodic waveform analysis. The following nociceptive stimuli were applied: (1) unprovoked righting reflex, (2) provoked righting reflex, (3) noise stimulus, (4) tail clamping with an alligator clip, (5) constant tail pressure with an analgesiameter, (6) corneal reflex, and (7) tracheal intubation. For tail clamping, tail pressure, and intubation, either purposeful extremity movement or abdominal muscle contraction response was noted to be present or absent. The clinical responses (present or absent) were modeled using logistic regression to estimate the Cp50, the plasma thiopental concentration with a 50% probability of no response. The following mean Cp50 values (95% confidence interval) were obtained: unprovoked righting reflex, 15.9 (15.1-16.6) micrograms/ml; provoked righting reflex, 21.4 (20.2-22.7) micrograms/ml; noise stimuli, 31.3 (29.7-33.0) micrograms/ml; tail clamp and limb movement, 38.3 (36.1-40.4) micrograms/ml; tail pressure and limb movement, 39.2 (37.1-41.3) micrograms/ml; tail pressure and abdominal muscle contraction, 52.5 (50.0- 55) micrograms/ml; tail clamping and abdominal muscle contraction, 56.1 (50.0-56.2) micrograms/ml; corneal reflex, 60.0 (56.6-63.4) micrograms/ml; and limb movement or muscle abdominal contraction response to intubation, 67.7 (59.2-76.1) micrograms/ml. At an EEG-effect of 9.1 and 2.2 waves/s, there was a 50% chance of limb movement response to tail clamping and tracheal intubation, respectively. There was a poor relationship between the plasma thiopental concentration and the percent increase of either heart rate or mean arterial blood pressure after applying either tail pressure or tail clamp stimuli. A range of nociceptive stimuli and their observed clinical responses can be used to quantitate thiopental anesthetic depth, ranging from light sedation to deep anesthesia (isoelectric EEG and unresponsive to intubation) in the rodent. Clinical response can be mapped to surrogate EEG measures.

Local cerebral glucose utilization in stimulated rats sedated with thiopental.

Recent studies have suggested that supraspinal structures are involved in barbiturate-induced enhancement of nociceptive processing. The goal of the study was to determine whether cortical and subcortical regions involved in nociception were relatively activated or depressed by noxious stimulation during infusion of small doses of thiopental. Local cerebral glucose utilization (LCGU) was measured with the 14C-2-deoxyglucose radioautographic technique in 14 rats. During the LCGU experiment, pressure was applied to the tail every 2 min, and the somatic motor response threshold was recorded. Seven animals received thiopental infusions to produce a steady-state plasma concentration (target concentrations of 10 micrograms/ml), and seven untreated animals served as controls. A steady-state plasma thiopental concentration (11.1 +/- 1.8 to 13.0 +/- 2.1 micrograms/ml) was accompanied by a decrease in the somatic motor response threshold from 277 +/- 32 g (before thiopental) to 215 +/- 41 g (P < 0.001). The somatic motor response threshold remained unchanged in the control group. Average LCGU was 29% less in the thiopental-treated animals than in the untreated controls (P < 0.001). In cortical regions associated with nociception, LCGU was relatively increased (+3% +/- 14%) during the thiopental infusion in comparison to the visual and auditory cortices (-18% +/- 13%; P < 0.001). Individual structures that showed relative changes during thiopental infusion included the nucleus accumbens (+17%, P < 0.05) and the habenula (-17%, P < 0.05). Heterogenous relative changes (P < 0.05) in LCGU were observed in the auditory system: auditory cortex (-22%), medial geniculate (-16%), lateral lemniscus (+26%), superior olive (+38%). Noxious stimulation during low-dose thiopental infusions relatively increased LCGU in cortical regions postulated to be responsible for processing of noxious stimuli. Nuclei in the descending pain modulating system were not relatively depressed.

Mechanism of the Negative Inotropic Effect of Thiopental in Isolated Ferret Ventricular Myocardium

Thiopental's myocardial depressant effects are well known and most likely involve some alteration in intracellular Ca2+ homeostasis. The aim of this study was to investigate the mechanisms of thiopental's negative inotropic effects and its underlying mechanism in isolated ferret ventricular myocardium (which shows physiologic characteristics similar to human ventricular myocardium), and in frog ventricular myocardium, in which Ca2+ ions for myofibrillar activation are derived almost entirely from transsarcolemmal influx. The authors analyzed the effects of thiopental after beta-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca2+ transient detected with the Ca(2+)-regulated photoprotein aequorin. Thiopental's effects also were evaluated in ferret right ventricular papillary muscles in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine and in frog ventricular strips with little or no SR function. At concentration > or = 10(-4) M, which is in the high range of the clinically encountered free plasma thiopental concentrations, thiopental decreased contractility and the amplitude of the intracellular Ca2+ transient. At equal peak force, peak aequorin luminescence in 10(-4) M thiopental and [Ca2+]0 > 2.25 mM was slightly smaller than that in control conditions at [Ca2+]o = 2.25 mM. This indicates that thiopental causes a small increase in myofibrillar Ca2+ sensitivity. After inactivation of sarcoplasmic reticulum Ca2+ release with 10(-6) M ryanodine, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca2+ influx, thiopental caused a further decrease in contractility and in the amplitude of the intracellular Ca2+ transient, and thiopental's relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Thiopental, > or = 10(-4) M, decreased contractility in frog ventricular myocardium. These findings indicate that the direct negative inotropic effect of thiopental results from a decrease in intracellular Ca2+ availability. At least part of thiopental's action is caused by inhibition of transsarcolemmal Ca2+ influx. These effects become apparent at concentrations routinely present during intravenous induction with thiopental.

Mechanism of the Negative Inotropic Effect of Propofol in Isolated Ferret Ventricular Myocardium

The aim of this study was to investigate propofol's effect on myocardial contractility and relaxation and examine its underlying mechanism of action in isolated ferret ventricular myocardium. The effects of propofol on variables of contractility and relaxation and on the free intracellular Ca++ transient detected with the Ca(++)-regulated photoprotein aequorin were analyzed. Propofol's effects were evaluated in a preparation in which the sarcoplasmic reticulum function was impaired by ryanodine. The effects of propofol's solvent, intralipid, on myocardial contractility, relaxation, and the intracellular Ca++ transient also were examined. Propofol, at concentrations of 10 microM or greater, decreased contractility and, at concentrations of 30 of microns or greater, decreased the amplitude of the intracellular Ca++ transient. At equal peak force, control peak aequorin luminescence in [Ca++]o = 2.25 mM and peak aequorin luminescence in 300 microM [Ca++]o = 2.25 mM and peak aequorin luminescence in 300 microM propofol in [Ca++]o > 2.25 mM did not differ, which suggests that propofol does not alter myofibrillar Ca++ sensitivity. After inactivation of sarcoplasmic reticulum Ca++ release with 1 microM ryanodine, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca++ influx, propofol caused a decrease in contractility and in the amplitude of the intracellular Ca++ transient. Under these conditions, propofol's relative negative inotropic effect did not differ from that in control muscles not exposed to ryanodine. Propofol's solvent, 10% intralipid, exerted a modest positive inotropic effect in this preparation. The intracellular Ca++ transient was unchanged by intralipid. Neither propofol nor intralipid altered the load sensitivity of relaxation. These findings suggest that the negative inotropic effect of propofol results from a decrease in intracellular Ca++ availability with no changes in myofibrillar Ca++ sensitivity. At least part of propofol's action is attributable to inhibition of transsarcolemmal Ca++ influx.

Plasma, Brain, and Spinal Cord Concentrations of Thiopental Associated with Hyperalgesia in the Rat

Although low doses of barbiturates are widely believed to increase sensitivity to pain, studies of the electrophysiologic effects of these drugs on the neurons involved in nociception in the spinal cord have detected only depressant effects. The goal of the studies reported here was to quantify the hyperalgesia resulting from low-dose thiopental infusions and to measure the associated concentrations of thiopental in the plasma, brain, and spinal cord. Nociception was measured using the threshold for motor response to pressure stimulation of the tail (nociceptive threshold) and tail flick latency in the rat. Thiopental was administered by intravenous infusions designed to produce plasma concentrations that either slowly increased or remained at a steady state. Plasma and tissue thiopental concentrations were measured by high-performance liquid chromatography. We observed a reduction in nociceptive threshold that was correlated with the plasma thiopental concentration over the range 2-20 micrograms.ml-1 (7.6-76 microM). The relationship was nonlinear. Nociceptive threshold reached a nadir (36% less than control values) at a mean plasma thiopental concentration of 13.7 micrograms.ml-1 (51.9 microM). The steady-state study showed a similar reduction in nociceptive threshold, with an equilibrium plasma thiopental concentration of 7.6 +/- 1.3 micrograms.ml-1 (28.8 +/- 4.9 microM). Concentrations of thiopental in brain and spinal cord samples were 1.7 +/- 0.03 and 3.5 +/- 1.7 micrograms.g-1, respectively. These studies confirm previous reports of hyperalgesia in association with small doses of thiopental. Reductions in nociceptive threshold and tail flick latency were observed in association with spinal cord concentrations of thiopental in a range reported by others to depress the electrophysiologic activity of neurons involved in nociception.

Thiopental Reduces Halothane MAC in Rats

The anesthetic contribution of specific plasma concentrations of thiopental has not been previously defined in laboratory animals. The plasma thiopental concentrations needed to reduce the anesthetic requirement for halothane by fractions of the minimum alveolar anesthetic concentration (MAC) were assessed in the rat. After steady-state thiopental plasma concentrations were established with a constant infusion, the tail-clamp technique was used to determine control MAC and the MAC of halothane with increasing concentrations of thiopental. We observed progressive reductions in halothane MAC. This required logarithmic increases in thiopental concentration rather than linear ones. A nonlinear reduction in anesthetic requirement was noted with an approximate 50% reduction in MAC at a thiopental plasma concentration of 7.4 micrograms/mL and an approximate 90% reduction at 32 micrograms/mL. Thiopental appears to provide essentially complete anesthesia in the rat model with a logarithmic contribution of increasing plasma concentrations.

Plasma concentration clamping in the rat using a computer-controlled infusion pump.

We have developed a computer-controlled infusion pump to achieve rapidly and then maintain stable plasma thiopental concentrations in rats. Initially we derived the parameters of a triexponential pharmacokinetic model for thiopental, administered as a brief infusion to 10 rats, using nonlinear regression and standard pharmacokinetic equations. These parameters were incorporated into the pharmacokinetic model of a computer-controlled infusion pump. In a second group of animals this device was used to maintain three consecutive target thiopental concentrations ranging from 5 to 100 micrograms/ml in a stepwise fashion. Arterial blood gases were kept normal through controlled ventilation when necessary. The plasma thiopental concentrations in this second group of animals were generally higher than the target concentrations. The bias in pump performance (median prediction error) was +25%, and the inaccuracy (median absolute prediction error) was 26%. We fit the parameters of a three-compartment model to the plasma thiopental concentrations observed in the second group of animals. This produced a second set of thiopental pharmacokinetic parameters with the unique characteristic of having been derived from a computer controlled infusion study. These parameters were tested prospectively with a computer-controlled infusion pump in a third group of animals. This second set of thiopental pharmacokinetic parameters performed better, with a median prediction error of 0% and a median absolute prediction error of 15%. This study shows that it is possible to achieve rapidly and maintain steady plasma thiopental concentrations in the rat. Our results suggest that it is feasible to derive robust pharmacokinetic parameters from unusual drug dosing approaches, such as employed by a computer-controlled infusion pump.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative study of the pharmacokinetics of thiopental in the rabbit, sheep and dog

The central arterial pharmacokinetics of thiopental were studied in six rabbits, six sheep and six dogs after a short infusion at approximately 10 mg/kg min. Thiopental was infused to a defined electro-encephalographic endpoint (EEG burst suppression). The time to reach early burst suppression was longer in the dog (3.9 +/- 0.5 min) compared with the sheep (3.0 +/- 0.6 min) and the rabbit (2.5 +/- 0.5 min). The total dose required to produce the same level of EEG activity was higher in the dog (35.9 +/- 6.8 mg/kg) compared with the sheep (24.3 +/- 5.3 mg/kg) and the rabbit (21.6 +/- 6.8 mg/kg). The plasma concentration-time data for each animal was fitted using non-linear regression to a bi- or tri-exponential function. In all animals, the plasma-time profile was best described as a tri-exponential decay. The initial volume of distribution was similar in all three species (rabbit, 38.6 +/- 10.0 mg/kg; sheep, 44.5 +/- 9.1 ml/kg; dog, 38.1 +/- 18.4 ml/kg). The maximum arterial plasma thiopental concentration achieved at EEG burst suppression was higher in the sheep (221.8 +/- 27.9 micrograms/ml) than the dog (164.7 +/- 29.9 micrograms/ml) or the rabbit (112.3 +/- 15.1 micrograms/ml). Thiopental distribution clearance was slower in the sheep (43.6 +/- 15.1 ml/min/kg) compared with the rabbit (110.5 +/- 18.7 ml/min kg) and the dog (97.2 +/- 47.2 ml/min kg). Elimination half-life was extended in the sheep (251.9 +/- 107.8 min) and dog (182.4 +/- 57.9 min) relative to the rabbit (43.1 +/- 3.4 min).(ABSTRACT TRUNCATED AT 250 WORDS)

A computer controlled infusion pump rapidly achieves and maintains stable plasma thiopental concentrations and EEG-effects in the rat

A computer controlled infusion pump rapidly achieves and maintains stable plasma thiopental concentrations and EEG-effects in the rat

Myocardial Sensitization by Thiopental to Arrhythmogenic Action of Epinephrine in Dogs

This study examined the interaction between thiopental and epinephrine in inducing ventricular arrhythmias in dogs. The arrhythmogenic threshold of epinephrine was determined during anesthesia with either halothane alone, thiopental alone, etomidate plus different doses of thiopental, or halothane plus different doses of thiopental. The arrhythmogenic dose and the corresponding plasma concentration of epinephrine during thiopental anesthesia (plasma thiopental concentration: 46-57 micrograms/ml) were 0.77 +/- 0.04 micrograms.kg-1.min-1 and 10.7 +/- 1.5 ng/ml, respectively. During halothane anesthesia (end-tidal: 1.3 MAC) they were 2.59 +/- 0.49 micrograms.kg-1.min-1 and 45.3 +/- 9.2 ng/ml, respectively. The dose-effect relationship for the thiopental action was examined during etomidate plus thiopental and halothane plus thiopental anesthesia. The arrhythmogenic plasma concentration of epinephrine was inversely proportional to the plasma thiopental concentration during both anesthetics. During etomidate plus thiopental anesthesia, at plasma thiopental concentrations of 0, 11.2 +/- 0.83, 20.1 +/- 1.34, and 33.2 +/- 1.95 micrograms/ml, the corresponding epinephrine concentrations were 201.3 +/- 34.3, 142 +/- 19.5, 69.1 +/- 21.2, and 22.7 +/- 4.5 ng/ml. During halothane plus thiopental anesthesia, at plasma thiopental concentrations of 0, 10 +/- 0.86, 18.3 +/- 0.87, and 31.8 +/- 1.05 micrograms/ml, the corresponding epinephrine concentrations were 45.3 +/- 9.2, 34.6 +/- 8.9, 16.2 +/- 1.74, and 15.1 +/- 1.32 micrograms/ml, respectively. These results suggest that thiopental sensitizes the heart to epinephrine in a dose-dependent manner. This sensitizing action of thiopental would in part explain the thiopental potentiation of hydrocarbon anesthetic-epinephrine arrhythmias.

The effects of cardiopulmonary bypass on plasma concentrations and protein binding of methohexital and thiopental

The effects of cardiopulmonary bypass (CPB) on plasma concentrations and protein binding of methohexital and thiopental were studied during continuous infusions in two groups of ten cardiac surgical patients. Patients were administered an infusion regimen designed to produce a stable total plasma concentration at 5 mg/L for methohexital and 10 mg/L for thiopental. Prior to the commencement of CPB the mean (±SD) total plasma methohexital concentration was 5.00 ± 0.69 mg/L. This fell to 3.12 ± 0.89 mg/L at two minutes after commencement of CPB, and rose to 4.67 ± 1.11 mg/L by 75 minutes after commencement of CPB. The unbound fraction rose from 27.1 ± 5.1% to 42.8 ± 9.2% at five minutes after the start of CPB, and gradually decreased to 32.1 ± 4.9% by 75 minutes. The unbound concentration (1.37 ± 0.32 mg/L) was unaffected by the onset of CPB, being 1.51 ± 0.49 mg/L at 75 minutes after the start of CPB. Thiopental followed a similar pattern to methohexital, with the total plasma thiopental concentration failing from 9.22 ± 0.73 mg/L to 4.90 ± 0.83 mg/L at two minutes after commencement of CPB, and rising again to 7.13 ± 1.03 mg/L 75 minutes later. During the same period the unbound fraction of thiopental rose from 16.1 ± 2.5% to 30.3 ± 7.3% five minutes after the start of CPB, and fell gradually to 22.8 ± 5.8% after 75 minutes. The unbound concentration (1.51 ± 0.21 mg/L) was again unchanged by the onset of CPB, being 1.71 ± 0.29 mg/L at 75 minutes. Plasma protein binding of both drugs correlated strongly with plasma albumin concentration, which decreased by 40% during CPB. It is concluded that hemodilution caused the reduction in total drug concentration and protein binding at the onset of CPB, but that the decrease in protein binding counteracted the dilution of unbound drug, resulting in a stable unbound concentration throughout CPB, and that this effect may be common for barbiturates.

Effect of Sulfadimethoxine on Thiopental Distribution and Elimination in Rats

The effect of sulfadimethoxine on the distribution and elimination of thiopental was examined by comparing the change in the steady-state volume of distribution (Vss) determined from both in vivo plasma elimination and in vitro serum and tissue binding studies in rats. The plasma disappearance of thiopental after a 12-mg/kg iv dose followed a biexponential decline in both the control and sulfadimethoxine-treated rats. The plasma thiopental concentrations under the steady-state plasma sulfadimethoxine concentration (500 μg/ml) were significantly lower than those of the control rats. In the sulfadimethoxine-treated rats, the pharmacokinetic parameter β significantly decreased while Vss significantly increased to 3.6-fold that of the control rats. With sulfadimethoxine, a significant increase was observed in the apparent dissociation constant (Kd) of thiopental to serum protein by equilibrium dialysis, but the total number of binding sites was not altered. The in vitro serum free fraction of thiopental was increased to about 2.6-fold in the presence of sulfadimethoxine. The free fraction of thiopental in the main distribution tissues (liver, muscle, and adipose) was determined by equilibrium dialysis with and without sulfadimethoxine. No significant changes were observed in the presence of sulfadimethoxine. The calculated Vss, determined by the free fractions from in vitro binding experiments, also showed a significant increase. The ratio of Vss with sulfadimethoxine to that of the control rats was 2.8. The total clearance did not change, but the intrinsic clearance decreased to one-half of that of the control rats due to the increase of the serum free fraction by sulfadimethoxine. It was concluded that sulfadimethoxine caused a displacement of thiopental in plasma protein binding, which significantly increased the free fraction of thiopental, and this result may explain the significant increase of Vss and the decrease of both β and intrinsic clearance. Tissue binding of thiopental, however, was unaffected by sulfadimethoxine.

Plasma thiopental concentrations in the newborn following delivery under thiopental—nitrous oxide anesthesia

Plasma thiopental concentrations in the newborn following delivery under thiopental—nitrous oxide anesthesia

Plasma Thiopental Concentrations in the Newborn Following Delivery Under Thiopental-Nitrous Oxide Anesthesia

Departments of Anesthesiology Obstetrics and Gynecology, and Pediatrics, College of Physicians and Surgeons, Columbia University and New York University Research Service, Coldwater Memorial Hospital, New York City.

EFFECT OF HEMORRHAGE ON PLASMA THIOPENTAL CONCENTRATIONS.

EFFECT OF HEMORRHAGE ON PLASMA THIOPENTAL CONCENTRATIONS.

Effect of Hemorrhage on Rate of Fall of Plasma Thiopental Concentration

Effect of Hemorrhage on Rate of Fall of Plasma Thiopental Concentration