Serum Thiopental Research Articles

An Autopsy Case of Death After Deep Sedation of Thiopental

The victim was a morbidly obese and bull-necked woman in her twenties. She had the disorders, due to Down's syndrome, including severe mental retardation, advanced hearing loss, congenital cataract surgery, and amblyopia at postoperative glaucoma. She was deeply sedated for rest with an intravenous drip infusion of 350 mg of thiopental (TP) for 5 minutes during an intraocular pressure examination with secondary glaucoma at a hospital. The examination was finished within 10 minutes after the TP injection, but her respiratory condition deteriorated rapidly when the doctor left the patient. Although immediate artificial respiration was carried out, she was declared dead about 20 hours after the examination. Medical malpractice was suspected for her death. At autopsy, no fatal disease or injury was observed in the victim. The serum TP level was 0.80 µg /ml. TP is an ultra-short-acting intravenous anesthetic, and usually only the smallest amount should be administered by frequent additions after pre-anesthesia administration while maintaining contact with patients. Although contact with patients with a disability can be difficult, it was diagnosed that the death was caused by both respiratory arrest due to a single dose of TP and delay in resuscitation due to the absence of a doctor.

Comparison between a high-perfomance liquid chromatographic method and a gas chromatographic method for the quantification of serum thiopental for the diagnosis of brain death in critically ill patients

Background Thiopental, as many other centrally acting drugs, can depress the electroencephalogram, so serum levels of these drugs must be well below their therapeutic range for a reliable diagnosis of brain death. While for many of these drugs fast and simple immunossays are available, for thiopental only chromatographic tests are available.

Thiopental pharmacokinetics in newborn infants: a case report of overdose

Thiopental may be used for sedation before intubation in newborn infants. A boy, born at 33 weeks of gestation (gw); birth weight 2435 g, was prescribed thiopental 3 mg/kg before intubation. He developed temporary hypotension and oxygen desaturation, and remained unconscious for longer than expected with a suppressed electroencephalography for 48 h. Serum thiopental concentration was 82, 59, 42 and 32 micromol/L after 20 min and 6, 24 and 68 h respectively. Serum concentrations from five newborn infants at the same time points after intubation with the same thiopental dose were used as reference values, and indicated a 10-fold overdose in the index case. The cause of the overdose could not be identified. The infant recovered; cerebral magnetic resonance imaging at the age of 42 gw and psychomotor development at 2 years were normal. These results show that thiopental concentrations are variable in neonates and there is a high risk of dosage error as no specific paediatric formulation is available. Well-designed procedures and continuous education are required to prevent errors and adverse events during drug delivery to newborn infants. To develop a safe method of administration for thiopental, an extended pharmacokinetic and pharmacodynamic study in neonates is warranted.

Brain stem death testing after thiopental use: a survey of UK neuro critical care practice*

A postal survey was conducted to determine how thiopental is used in UK neurosurgery critical care units. Thirty units were contacted and 26 replied. Thiopental is used in 23 units. The majority (60%) of these units govern the use of thiopental with protocols or guidelines and 74% use cerebral monitoring to guide dosage. When patients have had thiopental, 20 units delay brain stem testing, two will not perform tests and one unit incorporates cerebral angiography into their protocol. Twelve units use serum thiopental assays in their brain stem testing procedures, but there is wide variation in the interpretation of the results. We found inconsistency and confusion surrounding brain stem testing in this patient group, raising the possibility of misdiagnosis of brain stem death.

Klinisch-neurologische und neurophysiologische Befunde unter Thiopental-Infusionstherapie

Twenty comatous, recently brain damaged patients, seventeen suffering from head injury, three from spontaneous intracranial bleeding, mean age 28 years, 75 % male were treated against elevated intracranial pressure with continuous infusion of thiopental during a mean time of four days. Serum thiopental level, brainstem reflexes, electroencephalogram and evoked potentials (early auditory evoked potentials and early somatosensory potentials of the median nerve) were measured every day.

Thiopental pharmacodynamics. I. Defining the pseudo-steady-state serum concentration-EEG effect relationship.

To assess depth of anesthesia for intravenous anesthetics using clinical stimuli and observed responses, it is necessary to achieve constant serum concentrations of drug that result in constant biophase or central nervous system concentrations. The goal of this investigation was to use a computer-controlled infusion pump (CCIP) to obtain constant serum thiopental concentrations and use the electroencephalogram (EEG) as a measure of thiopental's central nervous system drug effect. The number of waves per second obtained from aperiodic waveform analysis was used as the EEG measure. A CCIP was used in six male volunteers to attain rapidly and then maintain for 6-min time periods the following pseudo-steady-state constant serum thiopental target concentrations: 10, 20, 30, and 40 micrograms/ml. The median performance error (bias) of the CCIP using 149 measurements of thiopental serum concentrations in six subjects was +5%, and the median absolute performance error (accuracy) was 16%. Following the step change in serum thiopental concentration, the EEG number of waves per second stabilized within 2-3 min and the remained constant until the target serum thiopental concentration was changed. When the constant serum thiopental concentration was plotted against the number of waves per second for each subject, a biphasic serum concentration versus EEG effect relationship was seen. This biphasic concentration:response relationship was characterized with a nonparametric pharmacodynamic model. The awake, baseline EEG was 10.6 waves/s; at peak activation the EEG was 19.1 waves/s and occurred at a serum thiopental concentration of 13.3 micrograms/ml. At a serum thiopental concentration of 31.2 micrograms/ml the EEG had slowed to 10.6 waves/s (back to baseline) and at 41.2 micrograms/ml was 50% below the baseline, awake value. Zero waves per second occurred at serum thiopental concentrations greater than 50 micrograms/ml. Using a CCIP it is possible to establish constant serum thiopental concentration rapidly and characterize the concentration versus EEG drug effect relationship.

Thiopental Pharmacodynamics II. Quantitation of Clinical and Electroencephalographic Depth of Anesthesia

This study examined the relationship among pseudo-steady-state (constant) serum thiopental concentrations, clinical anesthetic depth as assessed by several perioperative stimuli, and the electroencephalogram (EEG). Twenty-six ASA physical status 1 or 2 patients participated in the study. Two constant serum thiopental concentrations were maintained in each patient using a computer-controlled infusion pump. The first randomly assigned target serum concentration of 10-30 micrograms/ml was maintained for 5 min to allow serum:brain equilibration. Then the following stimuli were applied at 1-min intervals: verbal command, tetanic nerve stimulation, trapezius muscle squeeze, and laryngoscopy. A second, higher, randomly assigned target serum concentration of 40-90 micrograms/ml was then achieved and maintained by the computer-controlled infusion pump. The previously described stimuli were reapplied, after which laryngoscopy and intubation was performed. A positive response was recorded if purposeful extremity movement or coughing was observed. Using the quantal movement or cough response and the measured constant serum thiopental concentration, the probability of no movement to each stimulus was characterized using logistic regression. The serum thiopental concentrations that produced a 50% probability of no movement response for the clinical stimuli were as follows: 15.6 micrograms/ml for verbal command, 30.3 micrograms/ml for tetanic nerve stimulation, 39.8 micrograms/ml for trapezius muscle squeeze, 50.7 micrograms/ml for laryngoscopy, and 78.8 micrograms/ml for laryngoscopy followed by intubation. The EEG was analyzed using aperiodic waveform analysis to derive the number of waves per second. A biphasic relationship between constant serum thiopental concentration and the EEG number of waves per second was observed. Loss of responsiveness to verbal stimulation occurred when the EEG was activated at 15-18 waves/s.(ABSTRACT TRUNCATED AT 250 WORDS)

Thiopental as an adjunct to hypothermia for EEG suppression in infants prior to circulatory arrest

Fifteen infants were studied to evaluate the effect of profound hypothermia (16°C to 18°C) and hypothermia plus thiopental on the electroencephalogram (EEG) prior to circulatory arrest. Mean patient age and weight were 5.5 ± 1.2 months and 4.9 ± 0.3 kg, respectively. After core cooling on cardiopulmonary bypass (CPB), all patients received thiopental, 8 mg/kg, 5 minutes prior to circulatory arrest. Satisfactory EEG recordings were obtained for 9 patients, and serum thiopental concentration was measured in 12 patients. Hypothermia (mean venous return temperature, 17.8°C ± 1.6°C) alone was associated with persistent cerebral electrical activity in 8 of 9 patients (89%). The addition of thiopental, 8 mg/kg, produced an isoelectric EEG in 6 of these 8 patients (75%). Mean circulatory arrest duration was 44 ± 4 minutes. EEG activity resumed after reinstitution of CPB in all patients. Serum thiopental concentration at the end of CPB was negligible. It is concluded that hypothermia alone often may not produce EEG isoelectricity, and that the associated cerebral metabolic activity may be suppressed by adjunctive use of thiopental.

Estimating the rate of thiopental blood-brain equilibration using pseudo steady state serum concentrations

The equilibration between drug serum concentration and drug effect under non-steady state concentrations has been classically modeled using an effect compartment where the transfer from the serum to the effect compartment is considered to be a first-order process. The purpose of the present study was to examine whether an effect compartment with first-order transfer was adequate for describing thiopental serum concentration-EEG pharmacodynamics. The study has two facets: (i) Successive pseudo steady state serum concentrations of thiopental having a square wave shape were produced and maintained in six human subjects by means of a computer-driven infusion pump. An aperiodic wave form transformation of the electroencephalogram (EEG) was used as a continuous measure of thiopental EEG drug effect. The time course of the EEG effect following each thiopental serum concentration square wave showed an exponential pattern. The first-order rate constant for equilibration of the effect site concentration with the drug serum concentration (keo) was estimated by fitting a monoexponential model to the effect vs. time data resulting from the pseudo steady state thiopental serum concentration profile. (ii) In a second experiment, data were obtained from a classical design, i.e., a zero-order intravenous infusion of thiopental. The same subjects were studied. The keo was estimated by means of a semiparametric iterative method using convolution (effect compartment, transfer of drug from serum to site of action is assumed to be a first-order process). The mean pseudo steady state value for keo of 0.51 min-1 was not different from the mean value of 0.46 min-1 from the semi parametric approach when data from a linear portion of the drug concentration vs. effect curve were examined. The pseudo steady state technique gave inaccurate estimates of keo in the nonlinear portion of the thiopental concentration vs. response curve, i.e., at the peak of the biphasic concentration-effect relationship.

Population Pharmacokinetics and Pharmacodynamics of Thiopental

The authors have previously attributed the mechanism for the 50-67% decrease in the required dose of thiopental for induction of anesthesia in aged human patients to a decrease in the initial distribution volume for thiopental. Using a larger group of patients and volunteers studied in the laboratory, the authors have re-examined thiopental pharmacokinetics and EEG pharmacodynamics relative to age. A population data analysis approach (NONMEM), using a three-compartment model, was used to analyze bolus and rapid iv infusion thiopental serum concentration versus time data from 64 subjects. A one-compartment model was also used on the first 10 min of serum concentration data to focus only on the initial distribution phase. The population pharmacokinetic analysis demonstrated that when thiopental is administered via an iv bolus injection, traditional pharmacokinetic models limit the accurate characterization of thiopental distribution phenomena. Using the rapid iv infusion data, the pharmacokinetic mechanism for the decreased thiopental dose requirement in the elderly was a decreased rapid intercompartment clearance. Thiopental distribution from the central compartment of the three-compartment model to the rapidly equilibrating compartment (rapid intercompartment clearance) decreased 27% between the ages of 35-80 yr and decreased 34% in the one-compartment analysis. EEG spectral edge versus time data from 37 subjects was analyzed with a semiparametric modelling approach to remove the disequilibrium between thiopental serum concentration and the spectral edge. A population data analysis (NONMEM) was performed with several pharmacodynamic models. There was no age-related change in brain responsiveness or pharmacodynamics when the spectral edge is used as a measure of drug effect.

Chronic Alcohol Intake Does Not Change Thiopental Anesthetic Requirement, Pharmacokinetics, or Pharmacodynamics

The anesthetic requirements of chronic alcoholics for induction of anesthesia with thiopental were investigated using an electroencephalographic (EEG) measure of thiopental's CNS drug effect and pharmacodynamic modeling to relate thiopental serum concentrations to drug effect. Eleven patients with a history of excessive alcohol intake were studied from an inpatient alcohol rehabilitation program and compared with nine control patients or volunteers who were social drinkers. The alcoholic population had consumed ethanol 9-17 days prior to the study. They had no evidence of acute intoxication or acute withdrawal at the time of the study. Five of the 11 alcoholic patients were restudied after 1 month of abstinence from alcohol consumption. Each study consisted of a thiopental infusion until EEG burst suppression (1-3 s of isoelectric signal) was achieved. Timed arterial and then venous blood samples were obtained for measurement of thiopental serum concentrations for up to 36 h. Pharmacokinetic differences between groups were analyzed using a three-compartment model. Power spectral analysis of the EEG allowed determination of spectral edge frequency. An inhibitory sigmoid Emax pharmacodynamic model combined with an effect compartment was used to analyze concentration-response relationships and to provide an estimate of brain sensitivity to thiopental in the study populations. The thiopental anesthetic dose requirement using the EEG was not different between alcoholics and nonalcoholics. The mean dose requirement (+/- SD) of alcoholics was 823 +/- 246 mg and the mean dose requirement of nonalcoholics was 733 +/- 218 mg. There were no differences in thiopental pharmacokinetic and pharmacodynamic parameters between alcoholics and nonalcoholics.(ABSTRACT TRUNCATED AT 250 WORDS)

The Hemodynamic Consequences of High-Dose Thiopental Anesthesia

The hemodynamic and electroencephalographic effects of a 60 min infusion of thiopental, given at the rate of 1.25 mg X kg-1 X min-1 (total dose 75 mg/kg), were studied in 10 patients without cardiorespiratory disease undergoing surgery for the removal of large and/or deeply seated arteriovenous malformations. Data on heart rate, arterial, right atrial, pulmonary arterial, and pulmonary capillary wedge pressures, thermodilution cardiac output (expressed as cardiac index), the electroencephalogram, arterial blood gases, and serum thiopental concentrations were collected during a sedated, resting control period, and then every 15 min during drug infusion. Lactated Ringer's solution (total volume 1-2 liters) was infused throughout the study period at rates sufficient to maintain pulmonary capillary wedge pressure at control values. In doses sufficient to render the electroencephalogram isoelectric [t approximately equal to 30 min, 37.5 mg/kg cumulative dose, serum concentration 51 +/- 17 micrograms/ml (mean +/- SD)], drug infusion resulted in significant increases in heart rate (to 116% of control), and decreases in arterial pressure (to 87% of control), stroke volume index (to 87% of control), systemic resistance (84% of control), and both left and right ventricular stroke work indices (66% and 69% of control, respectively). Cardiac index was unchanged (following a transient increase at t = 15 min). There were no changes in pulmonary vascular resistance, or blood gases. A large total dose of thiopental (8-11 gm) was needed to maintain electroencephalogram suppression for the remainder of these 10-20 hr procedures, and emergence was slow (48-72 hr). The resultant prolonged ICU support may have contributed to serious postoperative complications in two patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of increasing age on thiopental disposition and anesthetic requirement.

The dose of thiopental required to induce anesthesia in adults decreases with age. The pharmacokinetic and pharmacodynamic properties of thiopental were studied in two groups of surgical patients to determine the mechanism of this decrease. In one group (29 patients 19-88 yr of age), thiopental was infused at a rate of 75-150 mg/min until the electroencephalogram (EEG) demonstrated early burst suppression (phase III). Arterial blood samples were obtained frequently during and after the infusion to measure serum thiopental concentrations, and power spectral analysis was used to calculate the spectral edge (Hz), defined as the frequency below which 95% of the EEG power is located. Pharmacodynamic modeling was used to relate the serum thiopental concentrations to the spectral edge in order to estimate the individual patient's brain sensitivity to thiopental. In a second group (28 patients 24-88 yr of age), pharmacokinetics were determined after a bolus or rapid infusion of thiopental. Arterial blood samples were obtained frequently to characterize the initial distribution phases, sampling continued for 24-48 h to characterize elimination processes. The dose of thiopental required to achieve early burst suppression on the electroencephalogram (EEG) decreased linearly and significantly with age. Pharmacodynamic modeling also demonstrated that brain sensitivity to thiopental does not change with age. The age-related decrease of the thiopental dose requirement is due to a change in the initial distribution of the drug. That is, the initial distribution volume (central compartment, or V1) of thiopental decreases exponentially with age. This smaller initial distribution volume in the elderly results in higher serum levels after a given dose of thiopental.

Thiopental after Brain Ischemia in Monkeys. Cardiovascular and Electroencephalographic Effects

The cardiovascular and electroencephalographic (EEG) effects of thiopental were investigated, with and without preceding global brain ischemia (GBI). Four groups of pigtailed monkeys were used: Group I received thiopental 90 mg/kg over 1 h after 16 min GBI. Group II received thiopental 90 mg/kg over 1 h without preceding brain ischemia. Group III received 90 mg/kg over 1, 3, 6, or 8 h with varying infusion rates and no brain ischemia. Group IV, after 16 min GBI, received thiopental 90 mg/kg over 12 h with a gradually reduced infusion rate, keeping thiopental serum levels around 120-140 mumol X l-1 throughout the infusion. Large doses of thiopental (Group II) produced serious cardiovascular side-effects. With co-existing brain ischemia (Group I), these side-effects were much worse; five of six animals not receiving lidocaine prophylaxis suffered circulatory arrest. A prolongation of the Q-T interval on the electrocardiogram may be of pathogenetic importance. In contrast, lower thiopental blood levels, sufficient to depress the EEG to burst suppression or isoelectricity, were well tolerated with and without preceding brain ischemia (Groups IV and III).

Assay of Serum Thiopental Concentrations by High-Performance Liquid Chromatography

Abstract A description is given of a specific and simple liquid chromatographic method for the determination of thiopental In protein-free serum. The analysis time per sample is only 4 min, the retention time of thiopental being 2.32 min. No drug interferences were found and the detection limit is about 0.3 mg/1. The day-to-day coefficient of variation is less than 4.3%, and the within-day variation is less than 4.0%, The method recovered 98.6% of thiopental supplemented to a blank serum.

Pharmacodynamic modeling of thiopental anesthesia.

We have pharmacodynamically modeled the relationship between the thiopental serum concentration and its effects on the electroencephalogram (EEG). Power spectral analysis was used to calculate the spectral edge, a measure of the underlying EEG frequency that characterizes the progressive slowing of the EEG induced by thiopental. Eight male volunteer subjects had venous thiopental serum concentrations measured, and 10 surgical patients had arterial serum concentrations measured. Thiopental was infused at a rate of 75 to 150 mg/min until a burst suppression EEG pattern was evident. Frequent blood samples were obtained during and after the infusion for measurement of serum thiopental concentrations, and the EEG was recorded for subsequent off-line power spectral analysis to calculate the spectral edge. With venous blood sampling, it was not possible to demonstrate significant hysteresis between the thiopental serum concentration and the spectral edge, allowing thiopental concentrations to be directly related to the spectral edge. With arterial blood sampling, significant hysteresis was present, requiring an effect compartment to relate concentration to effect. The half-time for equilibration (mean +/- SD) between concentration and response for the arterial data was 1.2 +/- 0.30 min. This value for Keo is consistent with known values for cerebral blood flow and thiopental brain: blood partition coefficient. Arterial-venous concentration differences cause the apparent lack of hysteresis with venous blood sampling. An inhibitory sigmoid Emax pharmacodynamic model optimally characterized the relationship between thiopental concentrations and the spectral edge. This model allows estimation of the thiopental serum concentration that causes one-half of the maximal EEG slowing (IC50), which is a measure of an individual's sensitivity to thiopental. Except for the hysteresis, there was no statistical difference in the parameters of the inhibitory sigmoid Emax pharmacodynamic model when venous and arterial blood samplings were compared. Arterial blood sampling offers some distinct advantages when pharmacodynamically modeling continuous, rapidly changing measures of drug effect, such as the EEG.

Monitoring serum thiopental concentrations by liquid chromatography.

Monitoring serum thiopental concentrations by liquid chromatography.