Pharmacokinetics Of Thiopental Research Articles

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.

Anesthesia: A Discipline That Incorporates Clinical Pharmacology Across the DDRU Continuum

he dawn of the modern discipline of anesthesia can be traced to 16 October 1846, when William Morton administered ether to a patient who was undergoing surgical removal of a vascular malformation. The event took place in the surgical amphitheater in the Bullfinch Building of Massachusetts General Hospital, now known as the Ether Dome, and was memorialized by Robert C. Hinckley in a painting that is reproduced on the cover of this issue. Although Crawford Long first administered ether as a general anesthetic in 1842, this operation was not recorded, so official credit went to Morton. By today’s evidentiary standards, Morton’s experiment lacked the statistical safeguards of placebo control, double-blinding, and randomization, but the crowd shown in Hinckley’s painting certainly documents substantial peer review.Subsequent to this demonstration, anesthesia developed slowly as a medical discipline—the American Board of Anesthesiology not being founded until 1937—but it can be argued that anesthesia today stands out as the major primary medical specialty that routinely incorporates clinical pharmacology principles in patient care. In turn, scientists trained in anesthesia or working with compounds used in anesthesia have made major contributions to clinical pharmacology across the entire continuum of drug discovery, development, regulation, and utilization (DDRU). Most notable have been major contributions in the areas of physiological pharmacokinetics, pharmacokinetic–pharmacodynamic (PK-PD) modeling, and pharmacogenetics.

Retention of nociceptor responses during deep barbiturate anesthesia in frogs

Bullfrogs ( Rana catesbeiana) anesthetized with a large dose of thiopental (42.8 mg/kg) retained movement responses to nociceptor stimuli despite an average plasma drug level of 51 mg/l, of which 63% was bound to plasma proteins. This concentration, when corrected to include only unbound and uncharged drug, was 2-fold greater than those reported to abolish nociceptor response (NR) during surgical anesthesia in man. The median anesthetic dose (AD 50) for loss of the righting reflex was 11.2 mg/kg by s.c. injection into the abdominal lymph sac; however, at 54.0 mg/kg, all frogs retained NRs, although otherwise deeply anesthetized. The ratio of NR-blocking dose to light AD was thus >4.8, as compared to <2 in mammalian studies. Whole body levels of thiopental determined at 3 h after intralymphatic injection showed that about half the injected drug had been eliminated by this time and that termination of anesthesia was chiefly due to drug elimination. Even though the pharmacokinetics of thiopental appears to differ markedly in frogs and men, the poor analgesia seen in the present study frequently has been reported during clinical barbiturate anesthesia. Since this deficiency is much more pronounced in the bullfrog than in man, its neurophysiological basis might profitably be studied using the bullfrog as a model; however, the high mortality associated with deep thiopental anesthesia in the frog should preclude its use as a practical anesthetic in amphibia.

Thiopental in CSF and Serum Correlates with Prolonged Loss of Cortical Activity

Barbiturate coma is initiated in brain-injured patients whenever elevated intracranial pressure remains unresponsive to other therapeutical strategies. However, barbiturates alter cortical activity resulting in difficulties in clinical evaluation. Therefore, we investigated the impact of long-term thiopental administration on responsiveness to exteroceptive stimuli in relation to pharmacokinetics of thiopental in CSF and serum. Long-term infusion increases thiopental levels which remain elevated for 6 and 9 days in CSF and serum, respectively, after termination of its administration. Prolonged unresponsiveness to exteroceptive stimuli correlates with persisting thiopental in CSF and serum. Thus, quantitative analysis of thiopental in serum becomes indispensable in predicting the length of drug-induced neurological impairment and in avoiding misinterpretation of the neurological status.

Pharmacokinetic and pharmacodynamic consequences of thiopental in renal dysfunction rats: evaluation with electroencephalography.

The purpose of this work was to investigate the disposition characteristics and pharmacodynamics of a barbiturate, thiopental, in renal dysfunction rats. Normal and renal dysfunction rats were infused with 40 and 20 mg/kg of thiopental, respectively. The quantitative electroencephalographic (EEG) method was used as the surrogate measure of pharmacological response. Signals from two electrodes fitted on the skull of rats were continuously measured, recorded and subjected to off-line analysis. Total amplitude (0.5-29.9Hz) from aperiodic analysis was taken as the EEG parameter. Thiopental concentration in plasma and cerebrospinal fluid (CSF) was assayed by an HPLC method. Steady-state volume of distribution was increased in renal dysfunction rats due to decreased plasma protein binding, while no change in clearance or volume of distribution based on the plasma unbound concentration was observed. Amplitude changes induced by thiopental in both normal and renal dysfunction rats were characterized by the sigmoidal Emax model. The unbound plasma concentration at half maximal effect was lowered by 30% in renal dysfunction rats as compared to the normal rats. In addition to considerable alteration in the pharmacokinetics of thiopental, it was also evident that renal impairment is associated with an increase in apparent pharmacological sensitivity, which is related to affinity.

Pharmacodynamics and pharmacokinetics of thiopental.

Thiopental is an ultra short-acting barbiturate which remains the standard against which other induction agents are judged; it is also indicated for the therapy of brain hypoxic-ischaemia injuries and status epilepticus. Aspects of drug distribution that govern the onset and end of drug effect have been intensively studied to determine which parameters (in patient characteristics, diseases and administration modalities) influence effective dose and concentrations in individual patients. Thiopental has been used as a reference for pharmacokinetic and/or pharmacodynamic models in the study of rapid and short acting effect drugs. In anaesthesiology the pharmacokinetics of thiopental are described as linear; when doses and duration of treatment increase, nonlinear pharmacokinetics occur because of the saturation and/or the induction of the metabolism.

A case of heart failure caused by continuous intravenous infusion of thiopental sodium

A case of heart failure caused by thiopental sodium in an 18-year-old female was reported. She was admitted to the PICU (Pediatric Intensive Care Unit) because of intractable epilepsy which required mechanical ventilation and continuous intravenous infusion of thiopental sodium. Her cardiac function deteriorated (ejection fraction=48%) even though thiopental was tapered off.The negative inotropic effect of thiopental induced by drug overdose is well known. In this case serum concentration of thiopental was within normal limits for the entire clinical course. The delayed side effect of thiopental appears to have developed as a result of the peculiar pharmacokinetics of thiopental. The tissue concentration of thiopental presumably increased although serum concentration was within the normal range.It is important to be aware of the possible side effects of thiopental even when the serum concentration of thiopental is normal. Barbiturate therapy should be initiated in the ICU because of this potentially life-threatening cardiorespiratory complication.

Computer simulation of the effects of alterations in blood flows and body composition on thiopental pharmacokinetics in humans.

Understanding the influence of physiological variables on thiopental pharmacokinetics would enhance the scientific basis for the clinical usage of this anesthetic. A physiological pharmacokinetic model for thiopental previously developed in rats was scaled to humans by substituting human values for tissue blood flows, tissue masses, and elimination clearance in place of respective rat values. The model was validated with published serum concentration data from 64 subjects. The model was simulated after intravenous thiopental administration, 250 mg, over 1 min, to predict arterial plasma concentrations under conditions of different cardiac outputs, degrees of obesity, gender, or age. The human pharmacokinetic model is characterized by a steady state volume of distribution of 2.2 l/kg, an elimination clearance of 0.22 l/min, and a terminal half-life of 9 h. Measured thiopental concentrations are predicted with an accuracy of 6 +/- 37% (SD). Greater peak arterial concentrations are predicted in subjects with a low versus a high cardiac output (3.1 and 9.4 l/min), and in subjects who are lean versus obese (56 and 135 kg). Acutely, obesity influences concentrations because it affects cardiac output. Prolonged changes are due to differences in fat mass. Changes with gender and age are relatively minor. The physiological pharmacokinetic model developed in rats predicts thiopental pharmacokinetics in humans. Differences in basal cardiac output may explain much of the variability in early thiopental disposition between subjects.

Pharmacokinetics of thiopental and pentobarbital enantiomers after intravenous administration of racemic thiopental.

We studied the pharmacokinetics of thiopental enantiomers in 14 healthy patients aged 37-73 yr receiving racemic thiopental by intravenous (IV) bolus or IV infusion. Plasma concentration of each enantiomer was measured by chiral high-performance liquid chromatography. After IV bolus, the total plasma clearance (CL) (295 +/- 132 mL/min) and volume of distribution at steady state (Vss) (139 +/- 38.5 L) of R-thiopental were significantly greater than those of S-thiopental (230 +/- 104 mL/min and 114 +/- 47.5 L, respectively). The plasma unbound fraction (fu) was determined by ultrafiltration of plasma from six healthy volunteers. The fu of R-thiopental (12.4% +/- 0.6%) was significantly greater than that of S-thiopental (10.0% +/- 1.0%). When the CL and Vss of the two enantiomers were corrected for the difference in mean fu, there were no significant differences between enantiomers for these variables. As the 20%-30% difference between the enantiomers in total CL and total Vss could be accounted for by stereoselectivity in fu, these differences are not likely to be clinically significant. During 105-180 min IV infusion of racemic thiopental to the other patients, there was no difference between enantiomers in mean plasma concentrations of total or unbound thiopental or total pentobarbital, a major metabolite of thiopental (P > 0.05). Therefore, it is appropriate to relate pharmacodynamic effects to racemic plasma concentrations of thiopental during IV infusion of racemic thiopental.

Pharmacokinetics of Thiopental and Pentobarbital Enantiomers After Intravenous Administration of Racemic Thiopental

We studied the pharmacokinetics of thiopental enantiomers in 14 healthy patients aged 37-73 yr receiving racemic thiopental by intravenous (IV) bolus or IV infusion. Plasma concentration of each enantiomer was measured by chiral high-performance liquid chromatography. After IV bolus, the total plasma clearance (CL) (295 +/- 132 mL/min) and volume of distribution at steady state (Vss) (139 +/- 38.5 L) of R-thiopental were significantly greater than those of S-thiopental (230 +/- 104 mL/min and 114 +/- 47.5 L, respectively). The plasma unbound fraction (fu) was determined by ultrafiltration of plasma from six healthy volunteers. The fu of R-thiopental (12.4% +/- 0.6%) was significantly greater than that of S-thiopental (10.0% +/- 1.0%). When the CL and Vss of the two enantiomers were corrected for the difference in mean fu, there were no significant differences between enantiomers for these variables. As the 20%-30% difference between the enantiomers in total CL and total Vss could be accounted for by stereoselectivity in fu, these differences are not likely to be clinically significant. During 105-180 min IV infusion of racemic thiopental to the other patients, there was no difference between enantiomers in mean plasma concentrations of total or unbound thiopental or total pentobarbital, a major metabolite of thiopental (P > 0.05). Therefore, it is appropriate to relate pharmacodynamic effects to racemic plasma concentrations of thiopental during IV infusion of racemic thiopental. (Anesth Analg 1996;83:552-8)

Myocardial Pharmacokinetics of Thiopental in Sheep after Short-Term Administration: Relationship to Thiopental-Induced Reductions in Myocardial Contractility

The myocardial kinetics and dynamics of thiopental (750mg over 2 min) were examined in chronically instrumented sheep (five studies in four sheep). The myocardial kinetics were studied by simultaneous rapid sampling of arterial and coronary sinus blood for 30min. The myocardial kinetics for four of the five studies were best described by a single flow-limited compartment with apparent volumes of between 42 and 113mL. These volumes equated to half-lives of equilibration between blood and myocardium of between 0.49 and 1.00min when baseline blood flow was taken into account. The remaining study was better described by a model with a slight membrane limitation (permeability/flow ratio of approximately 2). Myocardial contractility was studied as a measure of myocardial pharmacodynamics and was reduced to 53% of baseline at approximately 2.5min after the start of the dose. Effect compartment analysis showed that there was hysteresis between the time course of these contractility changes and the time course of the arterial concentrations, with effect compartment half-lives between 0.08 and 0.87min. There was significantly less hysteresis for the coronary sinus concentrations. It is concluded that thiopental equilibrated rapidly with a component of the myocardium, and that consequently its effects on myocardial contractility also rapidly equilibrated with both afferent and effluent myocardial blood.

Effects of Thiopental on Regional Blood Flows in the Rat

The goal of this investigation was to characterize the effects of thiopental on cardia output and regional blood flows in the rat. Blood flows influence thiopental pharmacokinetics. Acquisition of these data may ultimately permit evaluation of the contribution of thiopental-induced alterations in regional blood flows to the disposition and hypnotic effect of this drug. Chronically instrumented unrestrained Wistar rats (n=20) aged 3-4 months received either a dose of thiopental sufficient to induce a brief period of unconsciousness (20 mg.kg(-1)) or a larger dose achieving electroencephalographic burst suppression (45 mg.kg(-1)). Cardiac output and blood flows to 14 tissues were determined at 4 times in each rat for a period of 420 min using injections of radioactive microspheres (expressed as mean +/- SD). Mean arterial pressure, heart rate, and blood gas tensions were determined at all measurement times. Arterial plasma concentrations were sampled at postinfusion times. No important changes in systemic cardiovascular measurements were detected after the smaller dose of thiopental. One minute after the larger dose, cardiac output decreased from baseline (123 +/- 14 to 84 +/- ml.min (-1), P< 0.01), flow to muscle and fat decreased, and muscle and fat resistance increased. At 5 min, compared to baseline, no difference in cardiac output was detected (123 +/- vs. 119 +/- ml.min (-1)), intestinal flows increased and intestinal resistances decreased. Cardiac output was again depressed at 30, 90, and 180 min. Brain blood flow decreased 25 +/- 19 % (P< 0.01) from baseline for the duration of the study. Thiopental acutely decreases cardiac output, and blood flows to muscle and fat tissue. The temporary return of cardiac output to baseline may be related to intestinal vasodilation. These blood flow alterations may influence the pharmacokinetics of thiopental.

Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients.

Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three-compartment model and linear kinetics. After a single iv bolus, the mean initial volume of distribution (V1) was 0.481 l.kg-1, and the steady-state volume of distribution (Vss) was 2.16 l.kg-1. The distribution (t1/2 alpha) and elimination (t1/2 beta) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml.min-1.kg-1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CVintra) as it was between patients (CVinter). The steady-state trough plasma concentration (Cmin obs) ranged from 4.8 to 30 mg.l-1 (mean 16.0 mg.l-1 and median 14.3 mg.l-1). Peak concentrations (Cmax obs) ranged from 8.35 to 45 mg.l-1 (25.4 mg.l-1, and median 23.3 mg.l-1). The values of V1 and Vss were similar to those obtained after a single dose. For V1, the mean was 0.333 l.kg-1. The mean Vss was 2.68 l.kg-1, with a CVintra of 12.6 to 56% and a CVinter of 13.2%. A shorter distribution half-life t1/2 alpha was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t1/2 beta and the mean residence time became longer due to a decrease in clearance. For t1/2 beta the mean value was 16.3 h. The mean MRT was 21.9 h, CVintra 9.19 to 48.5%, and the CVinter 35.3%. The mean clearance was 2.16 ml.min-1.kg-1, CVintra 7.28 to 25.5%, and the CVinter 20.4%. This value is 50% lower than after a single dose. Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.

Arterial and Venous Differences of Thiopental Pharmacokinetics as an Intravenous Anesthesia Induction Agent and its Pharmacodynamic Inplication

Arterial and Venous Differences of Thiopental Pharmacokinetics as an Intravenous Anesthesia Induction Agent and its Pharmacodynamic Inplication

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)

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.

High-dose thiopental pharmacokinetics in brain-injured children and neonates.

High-dose thiopental was administered in 8 children with uncontrollable seizures or hypoxic encephalopathy (group A) and 7 full-term neonates with neonatal asphyxia (group B). All of them were submitted to artificial hyperventilation to maintain pCO2 near 3.5 kPa. Rectal temperature was kept at about 35 degrees C. Thiopental was infused with a rate of 2-4 mg X h-1 X kg-1, with treatment lasting 32-192 h for group A (mean 103 h), and 36-48 h for group B (mean 38.5 h). Plasma concentration-time data were analysed pharmacokinetically. Thiopental elimination half-life was 14.5 h (group A) and 20.9 h (group B). The clearance of thiopental was 0.27 liters X h-1 X kg-1 (group A) and 0.32 liters X h-1 X kg-1 (group B). The volume of distribution at steady-state was 5.41 liters X kg-1 (group A) and 8.26 liters X kg-1 (group B). These results show that high-dose thiopental pharmacokinetics is not very different for full-term newborns, children and adults. Elimination half-life and volume of distribution are changed when compared to single-dose studies, while clearance is only slightly modified. The time for disappearance of thiopental from blood is also very long (2 to 5 days). These pharmacokinetic characteristics would be worthy of consideration in cases where there may be prolonged use of thiopental, considering the risk of accumulation and toxicity.

Thiopental pharmacokinetics under conditions of long-term infusion.

Thiopental was used in long-term infusion (3-4.5 mg . kg-1 . h-1 during 4-8 days) to protect the brain from injury following trauma. Thiopental plasma concentrations were measured during infusion (48 patients) and after infusion (14 patients) to determine the kinetics of the drug in continuous infusion. All mean values were mean +/- SD. Steady state concentrations (Css) were 31.8 +/- 10.7 mg/l for an infusion rate of 3.05 +/- 0.37 mg . kg-1 . h-1 and 48.9 +/- 14.6 mg/l for a rate of 4.2 +/- 0.3 mg . kg-1 . h-1. Corresponding steady state clearance decreased when Css increased, indicating possible saturation of the metabolic enzymatic system. Michaelis-Menten kinetics were confirmed by postinfusion data that give, for higher Css, a nonlinear decay of log C versus time. First-order kinetics were only obtained with Css below 30 mg/l. The maximum rate of elimination (Vm) was 1.76 +/- 1.15 mg . l-1 . h-1 (n = 11), and the Michaelis constant (Km) was 26.7 +/- 22.9 mg/l (n = 11). Hepatic enzyme saturation was between 35 and 85%. The volume of distribution at steady state was 4.35 +/- 1.83 l/kg (n = 11). Apparent half-lives of elimination were between 18 and 36 h at the end of infusion, and predicted terminal half-lives were 10.15 +/- 5.43 h (n = 11). Phases of burst-suppression were observed on electroencephalographic traces for concentrations greater than 40 mg/l. The authors' results suggest that a continuous infusion at a dose of 4 mg . kg-1 . h-1 induces EEG changes consistent with a near-maximum reduction in cerebral metabolism. Because of the thiopental Michaelis-Menten kinetics at doses above 4 mg . kg-1 . h-1, the authors suggest that thiopental plasma concentrations be measured and/or the drug effect be measured with the EEG to prevent excessive thiopental overdosage, causing a prolonged recovery time.

Thiopental Pharmacokinetics in Patients with Cirrhosis

Thiopental Pharmacokinetics in Patients with Cirrhosis

Pharmacokinetics and pharmacodynamics of thiopental in patients undergoing renal transplantation.

The effects and pharmacokinetics of thiopental were studied in eight patients undergoing renal transplantation. The results were compared with findings in a group of patients with normal renal function. No differences were observed in induction doses or between arterial or venous sleep concentrations. The average V3 in the renal failure group was 1441 or 2.5 times the value of the control group (P less than 0.01). The apparent differences indicating longer elimination half-lives and higher serum clearances in the renal patients were not significant. The average binding of thiopental to serum protein shortly after the induction was 83.9% (78.2-88.1) in the renal patients and 89.0% (85.2-91.6) in the control patients (P less than 0.05). The difference in V3 could be explained by the differences in protein binding and when the serum clearance was calculated by using the unbound fraction, this "intrinsic clearance" was significantly lower in the renal failure group (P less than 0.05). Haemodynamic parameters were determined during the initial 5 min. No significant difference was observed between the thiopental-induced changes in stroke volume. Cardiac output was unchanged in both patient groups.