Thiopental is an intravenous drug commonly used to induce general anesthesia. When clinical doses are administered, thiopental reversibly depresses brain activity and causes loss of consciousness within 10-20 s for a duration of 5-8 min. [1] Drug disposition plays an important role in onset and offset of thiopental's hypnotic effect. A greater understanding of the relationship between patient physiology and thiopental pharmacokinetics would enhance the scientific basis for the clinical usage of this drug.
Physiological pharmacokinetic models have provided insight into the physiological determinants of thiopental disposition. The first physiological model for thiopental disposition in humans suggested that "lean," i.e., chiefly muscle tissue, was primarily responsible for the depletion of thiopental from the central nervous system and consequent termination of thiopental's anesthetic effect. [2] Others found that the role of muscle was equal to the combined contribution of metabolism and fat uptake [3] and predicted changes in blood concentrations caused by hemorrhage, [3,4] different metabolic rates, [3,5] apprehension, [4] and different injection sites. [5] However, these physiological models were validated with limited data. For example, predicted jugular venous blood concentrations, as a percent of the concentration at 1 min, were compared with 15 internal jugular vein concentrations measured between 2-16 min in six humans. [2] Also, the models did not discriminate between arterial and venous blood. Because thiopental induction can occur before thiopental distributes uniformly in blood, these models are limited in their ability to predict induction pharmacokinetics. More detailed pharmacokinetic models have incorporated protein binding and multiple tissues with distinction between arterial and venous blood, but did not validate or simulate the models extensively in humans. [6,7]
We have previously reported a physiological model that predicted accurately thiopental disposition in arterial plasma and 11 other tissues in rats between 1-360 min. [8] The goals of the present investigation were first to improve the model in rats to predict plasma concentrations more accurately in the first minute, to scale the model to humans, and to validate the human model with published arterial serum data collected between 1 min to 24 h in 64 subjects. [9-11] Second, the validated human model was then used to predict arterial concentrations after a 1-min intravenous thiopental infusion, 250 mg, for subjects with different cardiac outputs, degrees of obesity, gender, and age. Our model complements and extends previous works by demonstrating that physiological pharmacokinetic models can be scaled to humans and can be used to investigate the putative physiological determinants of the induction pharmacokinetics of thiopental.
Methods
Rat Pharmacokinetic Model
We reported a physiological pharmacokinetic model for thiopental in rats, which predicted plasma concentrations accurately between 1-360 min after a 20 mg/kg infusion administered in 45 s, but predicted twice the measured concentrations during the infusion. [8] In the current work, we used new information in an attempt to improve the early model predictions. Namely, we incorporated the time profile of thiopental-induced regional blood flows, [12] a blood-plasma partition coefficient of 0.95,* and an increased total body blood volume.** The modeling methodology is described elsewhere. [8]
Human Pharmacokinetic Model
The pharmacokinetic model for rats was scaled to human dimensions by substituting human values for elimination clearance, blood flows, organ weights, and great vessel blood volumes, while retaining the rat pharmacokinetic parameters for the individual tissues and organs. The scaling procedure has been described previously. [13] Figure 1(A) displays the total body model, and Figure 1(B) displays the model of a typical organ. Because thiopental uptake in the lung of the rat could not be measured adequately, [8] lung distribution clearance in humans was adjusted until first-pass retention of thiopental equaled 13.8%, a value directly measured in humans. [14] The blood-plasma partition coefficient was set to 0.94. [15,16] Organ masses and flows characteristic of a 73-kg man and 60-kg woman are presented in Table 1 and Table 2. The organ masses are increased slightly from reference values to account for the distribution of vascular volume. [17] Organ masses and flows for a 67-kg human are averaged from the female and male data. Cardiac output ranges from 5.7 l/min in women to 6.8 l/min in men, with a value of 6.3 l/min in humans. Plasma elimination clearance (Cle) is assumed to be of metabolic origin and is modeled as a pathway exiting from the shallow parenchymal compartment of the liver with clearance rate Cl20. The value of Cl sub 20 can be calculated from Cle, liver blood flow, the blood-to-plasma partition coefficient, and other liver pharmacokinetic parameters. [8] Once Cl20 is determined, this same relationship allows calculation of Cle for different liver blood flows. The volume of distribution at steady state and distribution extraction were calculated using methods described previously. [13] Volume of distribution describes the extent of thiopental partitioning in body tissues. Distribution extraction is the dose fraction that exits blood and enters tissue parenchyma on a single pass through the systemic circulation.
Model Validation
Arterial serum thiopental concentrations from 64 experiments in 58 surgical patients and 6 volunteers were used to validate the human pharmacokinetic model. [9-11] Subjects ranged in age from 23-88 yr (50 +/- 13 SD), and the weight range was 52-118 kg (75 +/- 13 SD). Four subjects were female. These data were used previously to develop a population pharmacokinetic model for thiopental. [10] In 16 experiments, the subject received an intravenous bolus (200-500 mg over 6 s), and arterial concentrations were measured intermittently for 24-48 h. In another 48 experiments, thiopental was administered at a constant rate (60-200 mg/min) over 2-13 min to reach a hypnotic end-point defined by 1-3 s of isoelectric electroencephalogram. The mean infusion duration was 7.4 min. Arterial samples were collected during the first half-hour of the infusion experiments, and venous samples were collected up to 24-48 h thereafter. We excluded data after 24 h, and assumed that venous concentrations equaled arterial concentrations and that serum concentrations equaled plasma concentrations.
All subjects were American Society of Anesthesiologists' (ASA) physical status I or II without hepatic, respiratory, cardiovascular, or renal disease. Surgical subjects receiving an intravenous infusion were induced after 20-30 min with 1-2 mg/kg methohexital, and general anesthesia was maintained with 1-2% inspired enflurane and 70% nitrous oxide. Surgical patients receiving a bolus were intubated after 3-5 min and maintained with enflurane and nitrous oxide. Eleven of the subjects receiving an infusion were chronic alcoholics participating in an inpatient alcohol rehabilitation program. [11] The plasma elimination clearance for the physiological model was determined from the data of 51 of the 64 patients in whom plasma concentrations were measured for at least 24 h. Clearance was calculated for each subject as the ratio of dose to the area under the concentration versus time curve. [18] The equation Cle = 0.00336 x body weight described a proportional relationship between clearance (l/min) and total body weight (kg). For the standard woman, man, and human, elimination clearance was 0.20, 0.25, and 0.22 l/min, respectively. The pharmacokinetic model was simulated using data for the standard human according to each subject's infusion rate and duration. Arterial plasma concentrations were simulated and compared with respective measurements. Prediction error per sample (PE) was calculated as Equation 1.
The mean and SD of the prediction error for all data were used as the principle measure of predictive performance. Median absolute prediction error was calculated to gauge predictive performance per individual. [19] Simulations were repeated with clearances that were calculated from each individual's concentration data or with gender- or age-specific physiologic data. The body composition and blood flow data for the gender and age simulations are presented in the next section.
Model Predictions
Arterial plasma concentrations were simulated over 120 min after intravenous thiopental administration, 250 mg in 1 min, with the following comparisons:
1. Cardiac output: low (3.1 l/min), standard (6.3 l/min), and high (9.4 l/min) cardiac outputs.
2. Obesity: lean (56 kg), standard (67 kg), overweight (100 kg), and obese humans (135 kg).
3. Gender: male and female adults.
4. Age: standard (35-yr), elderly (70-yr), and geriatric (90-yr) adults.
Organ masses and flows are summarized in Table 1 and Table 2. Details of the simulations are as follows:
1. Cardiac output: humans with a 50% increase (high) or decrease (low) in cardiac output from the standard human, and humans with a 20% thiopental-induced decrease. The coefficient of variation of blood flows to brain, heart, skin, adipose, muscle, and the splanchnic region is reported to be 15-30% in adults. [20-26] Consequently, to simulate the 50% increase or decrease in basal cardiac output, all regional blood flows were also changed 50%. To simulate dynamic blood flow changes during thiopental anesthesia, brain and renal blood flows were decreased by 50% and 30%, respectively. [27,28] Coronary and skin blood flows were increased by 50% and 100%, respectively. [29,30] Hepatosplanchnic tissues were not changed, and muscle, fat, and carcass flows were decreased by 50%. [30,31] The resulting cardiac output decreased by 20% from 6.3 to 5.0 l/min. The blood flows were changed linearly with time to the new values during thiopental administration and fixed at the new level until the end of the simulation.
2. Obesity: humans with 50% excess weight (overweight), 100% excess weight (obese), and humans who are 15% underweight (lean). Of the absolute change in weight, 71% was allocated to fat and 29% to lean body mass. [32] Gut and liver mass were increased by 30% for every 100% increase in body weight. [33] Skin mass was increased in proportion to body surface area, which was calculated from body height and mass. The remaining increase in lean body mass was allocated to muscle and carcass, which were increased by 40% for every 100% increase in body weight. Organ blood flows were increased proportionately to organ size, resulting in a cardiac output ranging from 5.8 l/min in the lean patient to 8.8 l/min in the obese patient. Blood volume was changed in direct proportion to cardiac output. [34]
3. Gender: Blood flows and body compositions or male and female adults are presented in Table 1 and Table 2.
4. Age: 35-yr (young), 70-yr (elderly), and 90-yr (geriatric) humans. Adipose mass was increased 9% per decade relative to the standard 35-yr human. [24] Liver mass was decreased for patients older than 55 yr by 9% for every 10 yr in excess of 55 yr. [35] Muscle mass was decreased to maintain body weight at 67 kg. Specific blood flows to kidney, hepatosplanchnic organs, brain, and adipose were decreased 5%, 8%, 8%, and 12% per decade, respectively. [20,21,22,24] Coronary blood flow was changed in proportion to cardiac output. Specific flows to the muscle, skin, and remaining organs were not changed. [25,26] The net effect on cardiac output is a decrease from 6.3 to 4.2 l/min as age increases from 35 to 90 yr.
The benefits of adjusting the thiopental dose to total body mass, lean body mass, or cardiac output were evaluated by calculating dose ratios. For a fixed peak plasma concentration Cpmax, the dose ratio for a particular patient type is D/Ds, where D is the dose administered in 1 min that achieves Cpmax in this patient, and D sub s is the dose that achieves Cpmax in the standard human. D and Ds are expressed in mg, mg per kg of total body mass, mg per kg of lean body mass, or mg per l/min of cardiac output. A dose ratio close to unity indicates proper dose adjustment.
Results
Rat Pharmacokinetic Model
The revised pharmacokinetic model predicts arterial plasma concentrations more accurately than the old one between 0-1 min and at 420 min (Figure 2). Parameters of the model are reported in Table 3. The improvement in the first minute is due to a revised blood-plasma partition coefficient of 0.95, and a blood volume of 8.3% of total body weight. Previously we had used values of 0.83 and 5.0%, respectively. The improvement at 420 min is due to inclusion of saturable metabolism with maximum elimination rate Vm = 30.4 micro gram/min and Michaelis-Menten constant Km = 5.14 micro gram/ml, wheras the old model assumed first-order elimination kinetics.
Human Pharmacokinetic Model
The human pharmacokinetic model uses the rat parameters in Table 3. The intrinsic metabolic clearance from liver parenchyma, Cl sub 20, is 0.13 l/min per kg of liver. The plasma elimination clearance is 0.22 l/min, the total volume of distribution is 2.21 per kg of body weight, the distribution extraction is 76%, and the terminal half-life is 9 h.
Model Validation
(Figure 3(A and B)) demonstrate that the spread of the measured data covers the model simulations over 24 h after a bolus or short infusion. Figure 3(C and D) show that the prediction errors are distributed similarly, and that to a reasonable extent, the prediction errors are randomly and evenly spread about zero. The mean prediction error for all data points is 6% with an SD of 37%, and the spread of prediction errors always includes zero. Per subject, the mean prediction error ranges from -40% to 57%, and the median absolute prediction error ranges from 7% to 54%, with a population median of 19%.
The mean prediction error is based primarily on data collected in the first 6 h. The median sample time is 15 min, and only 15% of the measurements are taken after 6 h. There is a positive prediction error in the first 15 min (16% +/- 37%), and a negative prediction error between 6-24 h (-14% +/- 41%). The greatest prediction errors occur at 1 min in the bolus simulation (53% +/- 120%) and the infusion simulation (-24% +/- 35%).
When each subject is assigned an individualized clearance, the prediction error for all data points is 8% +/- 33%. When gender- or age-related physiology is considered, the prediction errors are 10% +/- 40% and 10% +/- 35%, respectively.
Tissue Disposition
(Figure 4) displays the important organs governing the arterial plasma concentration curve after thiopental administration in the standard human. Figure 4(A) shows that thiopental predominantly resides in the great vessel blood and lung during the 1-min infusion. At 1 min, 39% of the dose resides in great vessel blood or the lung, 32% resides in the well-perfused organs liver, brain, heart, kidney, gut, pancreas, or the spleen, and 0.3% has been eliminated. Figure 4(C) shows that the rate at which thiopental enters the lung and eventually the arterial blood is the sum of the infusion rate and the rate at which thiopental recirculates via venous blood. At the time of peak arterial concentration, the venous concentration is 23% of the arterial concentration. Therefore, peak arterial concentrations are determined primarily by the first pass of the infused thiopental through the lung. The acute decrease in arterial concentrations immediately after the infusion stops is determined by the rate at which thiopental exits the lung and arterial blood. When the exit rate is increased by reducing the mass of the arterial blood and lung by 95%, peak arterial concentrations decrease to 17 micro gram/ml.
(Figure 4(A)) shows that the liver and muscle are important organs of distribution between 1-2 min, whereas metabolism is unimportant. During this time, 60 mg of thiopental is lost from blood and lung, of which 28% enters the liver, 22% enters the muscle, and 4% has been metabolized. The well-perfused organs, excluding the liver, do not play a role during this time; the dose fraction in these organs increases negligibly from 19-20% between 1-2 min. Thiopental concentrations in the nonhepatic visceral organs peak between 1.2 and 1.6 min and follow a similar time course to venous blood concentrations.
Between 2 and 10 min, thiopental distributes out of blood and visceral tissues into muscle, fat, and carcass. At 10 min, 4% of the dose remains in great vessel blood, 65% has distributed to muscle, fat, or carcass, and 8% has been eliminated. Figure 4(B) shows that between 10 and 180 min, thiopental continues to distribute to fat or to be eliminated. Muscle concentrations peak at 10 min, and fat concentrations peak at 163 min in Figure 4(D). After 180 min, all tissues are releasing thiopental back to the blood.
Different Cardiac Outputs
(Figure 5(A)) demonstrates the effect of changes in cardiac output on the early disposition of thiopental. As cardiac output decreases from 9.4 to 3.1 l/min, peak arterial concentrations increase by 103%. Between 1 and 1.5 min, arterial concentrations decrease 67% in the subject with a cardiac output of 9.4 l/min and decrease 51% in the subject with a cardiac output of 3.1 l/min.
Differences do not persist beyond 30 min because hepatic elimination is not much affected by large changes in cardiac output. When cardiac output is 9.4 l/min, the elimination clearance is 0.24 l/min, and 14% of the dose is eliminated at 30 min. When cardiac output is 3.1 l/min, the elimination clearance is 0.19 l/min, and 18% of the dose is eliminated at 30 min.
When cardiac output decreases, well-perfused tissues generally receive more thiopental despite lesser blood flows because tissue concentrations will increase to meet the increased arterial concentrations. For example, heart concentrations at 2 min increase from 14 to 18 micro gram/g as cardiac output decreases from +50% to -50%. Conversely, poorly perfused tissues generally receive less thiopental because the reduction in tissue perfusion overcompensates for the increased arterial concentrations. For example, the dose fraction in fat at 30 min decreases from 32% to 19% as cardiac output decreases from +50% to -50%.
A 20% thiopental-induced depression of cardiac output produces thiopental concentrations that are similar to those in the standard human during the infusion and in the subject with low cardiac output after the infusion. The change decreases within the boundaries imposed by variations in basal cardiac output.
Obesity
(Figure 5(B)) demonstrates the effect of obesity on arterial plasma concentrations. Peak arterial concentrations decrease from 54 to 35 micro gram/ml in the lean versus the 100% overweight (obese) subject. On average, arterial concentrations in the obese subject are 52% less than in the lean subject over the first 5 min and 73% less over 120 min. The decreased concentrations in the first 5 min are caused by increased cardiac output in heavier people. When the simulation for the obese subject is repeated with blood flows of the lean human, the arterial concentrations become 88% of those in the lean human over the first 5 min. The persistent difference over 120 min is primarily attributed to the capacity for thiopental uptake into fat. At 120 min, 69% of the dose resides in the fat in 100% overweight humans, but only 25% of the dose in lean humans. The difference is not explained by increased elimination clearance in obese people. Although elimination clearance increases from 0.21 to 0.29 l/min with increasing weight, the percent eliminated at 120 min is 39% in lean humans and 18% in 100% overweight humans.
Gender
(Figure 5(C)) indicates that gender has little effect on thiopental plasma concentrations. Peak arterial concentrations are 57 and 45 micro gram/ml in women and men, respectively. On average, arterial concentrations are 1% less in men than in women between 5-120 min. As discussed previously, the altered peak concentrations are explained by the different cardiac outputs.
Age
(