A comparison of parametric and non-parametric approaches to target-controlled infusion of propofol.

Nineteen adult patients of either gender received intravenous infusions of propofol, scaled to estimated lean body mass (LBM), for 150 minutes as part of a balanced anaesthetic. Arterial blood was assayed for whole blood propofol. The first subject received propofol at a fixed rate of 0.058 mg x min(-1) x kg(LBM)(-1). Subsequent groups received variable rate infusions based on the ratio of the infusion rate to the propofol concentration at each sampling point in the previous group, multiplied by the target concentration. After groups of one, two, five and 11 subjects, the median weighted residual was 0.040 and median absolute weighted residual was 0.153. Population pharmacokinetic analysis of the final group of six females and five males, aged 29 to 70 years and of 16.5 to 44.2% body fat, resulted in a two compartment pharmacokinetic model with coefficients and standard errors of V = 0.102 (0.0155) l/kg(LBM), V2 = 0.257 (0.079) l/kg(LBM), k10 = 0.423 (0.069)/min, k12 = 0.222 (0.051)/min, k21 = 0.084 (0.02)/min and clearance = 0.0418 (0.0023) L x min(-1) x kg(LBM)(-1). The only significant covariate was LBM. Within infusion data improved prediction when compared with data derived in previous studies from random observations.

Remifentanil concentration during target-controlled infusion of propofol.

After institutional approval and with written informed consent, eight surgical patients were infused intravenously with remifentanil at 250 ngkg lean body mass (LBM)(-1) x min(-1) for 30 min. Cardiovascular and respiratory parameters were recorded and arterial blood samples were taken at regular intervals. In each patient, the same protocol was repeated 40 min later during propofol infused to a target concentration of 3.0 microg x ml(-1). Blood concentrations of remifentanil and propofol were assayed using capillary gas chromatography and high performance liquid chromatography techniques respectively. The number of subjects enrolled was determined by testing the successive areas under the remifentanil time-concentration curve (AUC) for significant difference or non-difference using sequential analysis. The median measured propofol concentration was 3.5 (range: 2.6-4.5) microg x ml(-1) which did not change significantly during the second remifentanil infusion. The median AUC during propofol infusion was greater than control in all subjects, although there was considerable variation of 94.4 (64.3-129.6) versus 64.6 (34.8-126.9) ng x ml(-1) x min; P=0.008, n=8. After 30 min, there was no significant difference in remifentanil concentration during propofol infusion when compared with remifentanil alone of 4.6 (3.2-5.7) versus 3.8 (1.6-4.9) ng x ml(-1); P=0.73, n=8. Co-administration of propofol and remifentanil may result in greater remifentanil concentrations than when remifentanil is infused alone.

Determination of remifentanil in human blood by capillary gas chromatography with nitrogen-selective detection.

A validated method for the determination of remifentanil in human blood, applicable to all therapeutic concentrations, using capillary GC with nitrogen-specific detection and fentanyl as the internal standard has been developed. Citrated whole blood samples were extracted into 1-chlorobutane following precipitation of proteins with methanol. The drugs were back extracted into 10 mM HCl and re-extracted into methanol-1-chlorobutane. The extracts were reconstituted in methanol and injected onto a 25-m BPX-5 column. The lower limit of quantitation was 0.2 ng/ml with within- and between-day coefficients of variation of less than 15%.

Determination of eltanolone in human plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the determination of eltanolone in plasma has been developed. Plasma samples containing eltanolone were diluted with acetonitrile to precipitate plasma proteins, and derivatized with 2,4-dinitrophenylhydrazine before direct injection onto a C18 column. The mobile phase was acetonitrile-water (70:30, v/v) containing 0.1% trifluoroacetic acid and detection was by UV absorbance at 367 nm. The quantitation limit was 0.020 microg/ml. The method has proven to be rapid, precise and sensitive in the range of concentrations found during and following intravenous anaesthesia.

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.

Determination of (R)-(+)- and (S)-(-)-isomers of thiopentone in plasma by chiral high-performance liquid chromatography.

A method for the determination of R-(+)- and (S)-(-)-isomers of thiopentone in plasma was developed. Following liquid-liquid extraction, the separation of enantiomers of thiopentone and the internal standard (racemic ketamine) was achieved by high-performance liquid chromatography on an alpha1-acid glycoprotein (AGP) column with ultraviolet detection at 280 nm. The mobile phase consisted of 20 mM KH2PO4 buffer-2-propanol-methanol (93.5:5.0:1.5) at pH 5.0. The flow-rate was 0.9 ml/min. The limit of quantification for each isomer was approximately 10 ng/ml. The assay is suitable for pharmacokinetic studies of (R)-(+)- and (S)-(-)-isomers of thiopentone, following usual bolus intravenous clinical doses of the racemic drug.

Prediction of movement during propofol/nitrous oxide anesthesia. Performance of concentration, electroencephalographic, pupillary, and hemodynamic indicators.

BACKGROUND: Movement in response to painful stimulation is the end point classically used to assess the potency of anesthetic agents. In this study, the ability of modeled propofol effect-site concentration to predict movement in volunteers during propofol/nitrous oxide anesthesia was tested, then it was compared with the predictive abilities of the Bispectral Index and 95% spectral edge frequency of the electroencephalogram, pupillary reflex amplitude, and systolic arterial blood pressure. In addition, the relationships between simple end points of loss and recovery of consciousness, and pupillary, hemodynamic, and propofol concentration indicators were studied. METHODS: Ten healthy volunteers were anesthetized with an infusion of propofol, which was increased in three equal steps to 21 mg.kg lean body mass-1.h-1. After loss of the ability to hold a syringe and of the eyelash reflex, 60% nitrous oxide was introduced and the trachea was intubated without the use of muscle relaxants. The propofol infusion rate then was decreased to 15.4 mg.kg lean body mass-1.h-1. Ten minutes later, tetanic electrical stimulation was administered to the thigh via needle electrodes: if movement was observed within 1 min, the propofol infusion rate was increased by 1.75 mg.kg lean body mass-1.h-1 5 min after the stimulus; if not, it was similarly decreased. This 15-min sequence was repeated until volunteers "crossed over" from movement to no movement (or vice versa) four times. The propofol infusion rate then was increased to 21 mg.kg lean body mass-1.h-1, nitrous oxide was discontinued, the trachea was extubated, and the infusion rate was decreased in five equal steps over 50 min. The times at which the eyelash reflex returned and the birth date was recalled were recorded. The electroencephalogram was monitored continuously (FP1, FP2, ref: nasion, ground: mastoid). Measurements of the pupillary response, arterial blood pressure, and heart rate were recorded during induction and awakening, just before and for 5 min after each stimulation. Arterial blood samples were obtained for propofol assay, and propofol effect-site concentrations were calculated at each time. The predictive value of indicators was compared using a new static, the prediction probability (PK). RESULTS: Loss and return of the eyelash reflex occurred at greater propofol effect-site concentrations than either dropping the syringe or recall of the birthday. The propofol effect-site concentration (in the presence of 60% nitrous oxide) predicted to prevent movement after a supramaximal stimulus in 50% of volunteers was 1.80 micrograms/ml (95% confidence limits: 1.40-2.34 micrograms/ml). The Bispectral Index (PK = 0.86), 95% spectral edge frequency (PK = 0.81), pupillary reflex amplitude (PK = 0.74), and systolic arterial blood pressure (PK = 0.78) did not differ significantly from modeled propofol effect-site concentration (PK = 0.76) in their ability to predict movement. CONCLUSIONS: Indicators of pharmacodynamic effect, such as the electroencephalogram, pupillary light reflex, and systolic arterial blood pressure, predict movement as well as effect-site concentration during propofol/nitrous oxide anesthesia. Loss and return of the eyelash reflex correspond to a deeper level of anesthesia than syringe-dropping or recall of the birth date.

Subanesthetic concentrations of desflurane and propofol suppress recall of emotionally charged information.

Whether anesthetized patients register emotionally charged information remains controversial. We tested this possibility using subanesthetic concentrations of propofol or desflurane. Twenty-two volunteers (selected for hypnosis susceptibility) received propofol and desflurane (on separate occasions, and in a random order) at a concentration 1.5-2 times each individual's minimum alveolar anesthetic concentration (MAC)-awake (or equivalent for propofol). We gave vecuronium, intubated the trachea of each volunteer, controlled ventilation, and then presented a neutral (control) drama or a "crisis" drama stating that the oxygen delivery system had failed, assigning crisis and control dramas in a blinded, randomized, and balanced manner. One day later, interviewers blinded to the assigned drama conducted a 2-h structured interview (including hypnosis) to determine whether the contents of the interviews after crisis and control dramas differed. In addition, messages permitting subsequent assessment of learning of matter-of-fact information (Trivial Pursuit-type question task and a behavior task) were presented at the anesthetic concentration just sufficient to prevent response to command in each volunteer. No analyses of the tasks involving matter-of-fact information revealed learning except one which correlated hypnosis susceptibility with behavior task performance. Both propofol and desflurane suppressed memory of the crisis. Consistent with previous findings for isoflurane and nitrous oxide, propofol and desflurane suppressed learning of matter-of-fact information at concentrations just above MAC-awake, except that volunteers' susceptibility to hypnosis correlated with performance of a behavior suggested during anesthesia. Propofol and desflurane suppressed learning of emotionally charged information at anesthetic concentrations 1.5-2 times MAC-awake (less than MAC), a different result from that previously reported for ether.

Concentrations of desflurane and propofol that suppress response to command in humans.

The anesthetic concentration just suppressing appropriate response to command (minimum alveolar anesthetic concentration awake [MAC-awake] for volatile anesthetics or plasma concentration to prevent a response in 50% of patients [Cp50]-awake for intravenous anesthetics) provides three important measures. First, along with pharmacokinetics, the ratio of the awakening concentration to the anesthetizing concentration (MAC-awake/MAC or Cp50-awake/Cp50) determines time to awakening. Second, a correlation between MAC-awake and the anesthetic concentration sufficient to prevent learning suggests MAC-awake provides a surrogate measure of amnestic potency. Third, population values for MAC-awake provide evidence for or against commonality in anesthetic mechanisms. We studied 22 male volunteers twice to determine both MAC-awake for desflurane (2.60% +/- 0.46%) and Cp50-awake for propofol (2.69 +/- 0.56 microgram/mL). Awakening with desflurane occurs at a concentration closer to its anesthetizing concentration (36% of MAC) than propofol (18% of Cp50); that is, 1) desflurane requires less of a decrement in anesthetic concentration at the effect site for arousal; and 2) if MAC-awake (Cp50-awake) values reflect the concentrations providing amnesia, propofol is a more potent amnestic. Of interest, the dose response curves of desflurane and propofol were equivalently steep, a finding consistent with a common mechanism of action. In contrast, sensitivity of each volunteer to desflurane did not correlate with sensitivity to propofol (r2 < 0.01, P = 0.98) arguing against a common mechanism.

Effect of body build on the clearance of atracurium: implication for drug dosing.

To determine factors that influenced the clearance (Cl) of atracurium, 80 adult patients of varying body build were given an atracurium infusion according to a predetermined profile, which was scaled by lean body mass (LBM). Cl was estimated at 50-60 min by the constant infusion rate required to maintain the steady-state plasma concentrations. The efficacy of scaling the absolute Cl estimate by body build variables, in which the absolute Cl estimate is divided by the body build variable to achieve similar scaled estimates in all patients, was assessed by the bias and precision of the individual scaled Cl estimates to those in patients with a "normal" body build (23%-27% body fat). The efficacy of scaling the dose of atracurium by differing body build variables to achieve similar plasma concentrations was also assessed by bias and precision, in which the plasma concentrations from an infusion scaled by other body build variables were generated by linear simulation. Body size, as quantified by LBM, total body mass (TBW), height, and body surface area, had a significant influence on Cl, with the effect best described by LBM (respective R2, 0.487, 0.368, 0.265, 0.445). No other factors could be identified, including blood pH, serum creatinine, and drugs given during the peroperative period. The efficacy of scaling Cl by TBW (absolute Cl estimate divided by patient TBW) to achieve similar estimates in all patients was poor; Cl.TBW estimates varied inversely with patient body fat content and resulted in obese patients having smaller estimates, a mean bias of -29%, compared with those in patients with a normal body build (P = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Preprogrammed infusion of alfentanil to constant arterial plasma concentration.

A variable rate infusion regimen, designed to rapidly achieve and maintain a target arterial concentration (CT) of 100 micrograms.L-1 of alfentanil, was developed using the method of Plasma Drug Efflux. This method uses a series of clearance values (Ep), calculated as the ratio of instantaneous infusion rate/arterial plasma drug concentration normalized to lean body mass (LBM), at various sampling times during a suboptimal infusion regimen. Values of Ep are used to calculate an infusion rate versus time profile to achieve CT, and the process is repeated in consecutive small groups of subjects to yield an optimal result, i.e., it is an iterative process. Thirty-three adult surgical patients were given alfentanil during anesthesia for approximately 1 h before cardiopulmonary bypass. In an initial group of four patients, who received a simple two-stage infusion, plasma alfentanil concentration was measured at frequent intervals and Ep(L.min-1.kg LBM-1) was estimated at each sampling time. The calculated infusion-rate-versus-time profile to produce CT was obtained from the product Ep x CT for each time point and was transferred to the read-only memory of a computerized infusion pump. This new variable infusion profile was used in four patients, and the process was repeated in three further groups of 5, 8, and 12 patients using infusion profiles calculated from the previous group. Each set of concentration data was assessed by calculating the performance error (PE), the median performance error (MDPE), i.e., bias, and the median absolute value of PE (MDAPE), i.e., inaccuracy.(ABSTRACT TRUNCATED AT 250 WORDS)

Lean tissue mass is a useful predictor of induction dose requirements for propofol.

The effect of age and sex on ED50 values for propofol was studied in 92 patients aged between 16 and 85 years. All doses were based on lean tissue mass (LTM). The end-point for loss of consciousness was loss of the ability to hold a light object. The mean of the ED50 values for males was 1.31 mg.kg LTM-1 and for females 1.28 mg.kg LTM-1. For males the ED50 values ranged from 0.94 to 1.69 mg.kg LTM-1. For females, the range was 1.06-1.57 mg.kg LTM-1. On statistical analysis, these differences were not significant. These data contrast with other studies in which dosage was based on total body mass where a decrease in dose requirement with age was demonstrated. We propose that by using lean tissue mass to calculate dosage, considerable normalisation of patient response can be achieved. There is considerable inter-individual variation in response to propofol. Age is less important than this variation in determining the correct dose for each patient, provided doses are based on LTM.

Pharmacokinetics of atracurium during continuous infusion.

The pharmacokinetics of atracurium were investigated by a model-independent method during continuous infusion under propofol anaesthesia. Following an intubating dose of suxamethonium, atracurium was infused according to a predetermined profile which continually set the infusion rate to maintain stable muscle paralysis and a target steady state plasma concentration when equilibrium between the biophase and plasma had occurred. Atracurium was infused for the first 1 h to maintain a target steady state plasma concentration of 1.0 microgram ml-1. Thereafter, the target plasma concentration was adjusted to maintain 90% muscle paralysis. The maintenance infusion rate required to maintain 90% paralysis was 4.25 (SD) 1.11 micrograms kg-1 min-1, with an estimated steady state plasma concentration of atracurium required to maintain 90% paralysis (Cpss90) of 1.13 (0.24) microgram ml-1. The clearances of atracurium, estimated by the constant infusion rate required to maintain the steady state plasma concentration, at 50-60 min and during estimation of Cpss90 were 3.8 (1.0) and 3.9 (1.1) ml kg-1 min-1 (ns), respectively. The volume of distribution at steady state of atracurium after 1 h of infusion, calculated using the clearance and the area under the plasma concentration-time curve to 1 h, was 130 (50) ml kg-1. These estimates of the pharmacokinetic parameters of atracurium are markedly different from those derived from pharmacokinetic analysis of single bolus dose data. Normalization of the pharmacokinetic parameter estimates by lean body mass decreased interpatient variability and improved precision in comparison with the un-weighted data and normalization by total body weight.

Pharmacodynamics of atracurium during propofol, thiopentone and opioid anaesthesia.

We have assessed in 20 patients the accuracy and precision of an infusion profile for atracurium, which continually set the infusion rate to maintain stable muscle paralysis and a target steady state plasma concentration, when equilibrium between the biophase and plasma had occurred. Muscle paralysis was stable after 20 min, with a mean absolute drift in muscle paralysis in the succeeding 40 min of 0.13 (SD 0.07)% T1/Tc (height of first twitch/height of control twitch) per min. The plasma samples after 30 min, which were assessed empirically as being in equilibrium with the biophase, had an overall mean bias of 8.0 (SEM 3.7)% (P less than 0.05) and an overall mean absolute prediction error of 16.4 (SEM 2.5)% from the target steady state concentration being delivered by the infusion. The profile was then used to estimate the steady state plasma concentration of atracurium required to maintain 90% paralysis (Cpss90), by manually adjusting the delivered target concentration of the infusion until muscle paralysis was stable at 88-92% inhibition of T1/Tc for 15-20 min, with three plasma samples taken over the next 10 min. Measurements were completed within 60-90 min. The mean Cpss90 of atracurium with propofol was 1.039 (SD 0.224) microgram ml-1 (n = 10), with thiopentone 1.334 (0.378) microgram ml-1 (n = 10), and with opioid anaesthesia 0.915 (0.221) microgram ml-1 (n = 10). These differences in the Cpss90 explain some of the variability in response which occurs with neuromuscular blocking drugs. The technique enables the Cpss90 of a myoneural blocker to be determined by a simple model-independent method.

Pharmacokinetics of propofol when given by intravenous infusion.

We have previously shown with i.v. bolus studies that the elimination of propofol is much slower than previously reported. Now we have studied the implications of this for prolonged i.v. infusion of propofol in seven patients who received continuous infusions of propofol for up to 9 h. Values of elimination half-life ranged from 13.1 to 44.7 h, systemic clearance from 1.02 to 1.63 l h-1 and volume of distribution from 1390 to 3940 l and these were similar to those obtained with bolus administration. The large volume of distribution is consistent with the high octanol/blood partition coefficient, which was found to be 72.0. Despite the very long elimination half-life, blood propofol concentrations appeared to approach steady state within 20 min rather than the 4-5 half-lives normally expected. This is because for this drug, which displays multicompartment pharmacokinetics, the rate of initial rise of blood concentrations is governed primarily by the very short distribution half-life of the drug. Therefore, the long elimination half-life of propofol is probably of little significance in designing infusions regimens, but the lower systemic clearance should be taken into account to avoid unwanted accumulation.

Potency of propofol for loss of consciousness after a single dose.

A dose-response curve for loss of consciousness after administration of propofol was obtained using 56 unselected, premedicated patients presenting for surgery. Propofol was given in doses according to the calculated lean tissue mass (LTM) of the patient. The end-point for loss of consciousness was loss of ability to grasp a light object. Using probit analysis, the ED50 for propofol was found to be 1.34 mg/kg of LTM and the ED95 was found to be 2.56 mg/kg of LTM. Comparison with previously published data for thiopentone showed propofol to be approximately twice as potent as thiopentone at ED50 and the slope of its dose-response curve to be shallower than that of thiopentone.

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

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

Production of laudanosine following infusion of atracurium in man and its effects on awakening.

Twenty patients were given maximal doses of atracurium or vecuronium by infusion during surgery. Anaesthesia was maintained with an infusion of thiopentone, nitrous oxide and fentanyl. In patients administered atracurium, the plasma laudanosine concentration at cessation of surgery was 0.34 (SD 0.22) micrograms ml-1; there was little tendency to cumulate during operation. A 20% higher arterial concentration of thiopentone was found at awakening in patients given atracurium, suggesting CNS stimulation by laudanosine, although the effect is too modest to be of clinical significance.