Infusion Scheme Research Articles

Propofol Reduces the Distribution and Clearance of Midazolam

Midazolam, at sedative levels, increases blood propofol concentrations by 25%. We evaluated the reverse interaction and determined the influence of propofol on the pharmacokinetics of midazolam. Eight healthy male volunteers were studied on 2 occasions in a random crossover manner. During session A, volunteers received midazolam 0.035 to 0.05 mg x kg(-1) IV for 1 minute followed by an infusion of 0.035 to 0.05 mg x kg(-1) x h(-1) for 59 minutes. During session B, in addition to this midazolam infusion scheme, a target-controlled infusion of propofol (constant C(T): 0.6 or 1.0 microg x mL(-1)) was given from 15 minutes before the start until 6 hours after termination of the midazolam infusion. Arterial blood samples for propofol and midazolam concentration analysis were taken until 6 hours after termination of the midazolam infusion. Nonlinear mixed-effect models examining the influence of propofol and hemodynamic variables on midazolam pharmacokinetics were constructed using Akaike's information-theoretic criterion for model selection. In the presence of a mean blood propofol concentration of 1.2 microg x mL(-1), the plasma midazolam concentration was increased by 26.9% + or - 9.4% compared with midazolam given as a single drug. Propofol (C(blood): 1.2 microg x mL(-1)) reduced midazolam central volume of distribution from 5.37 to 2.98 L, elimination clearance from 0.39 to 0.31 L x min(-1), and rapid distribution clearance from 2.77 to 2.11 L x min(-1). Inclusion of heart rate further improved the pharmacokinetic model of midazolam. Propofol reduces the distribution and clearance of midazolam in a concentration-dependent manner. In addition, inclusion of heart rate as a covariate improved the pharmacokinetic model of midazolam predominantly through a reduction in the intraindividual variability.

Contrast-enhanced whole heart coronary MRI with a bolus infusion of gadobenate dimeglumine at 1.5 t

We sought to investigate the T1 kinetics of blood and myocardium after three infusion schemes of gadobenate dimeglumine (Gd-BOPTA) and subsequently compared contrastenhanced whole-heart coronary MRI after a bolus Gd-BOPTA infusion with nonenhanced coronary MRI at 1.5 T. Blood and myocardium T1 was measured in seven healthy adults, after each underwent three Gd-BOPTA infusion schemes (bolus: 0.2 mmol/kg at 2 mL/sec, hybrid: 0.1 mmol/kg at 2 mL/sec followed by 0.1 mmol/kg at 0.1 mL/sec, and slow: 0.2 mmol/ kg at 0.3 mL/sec). Fourteen additional subjects underwent contrast-enhanced coronary MRI with an inversion-recovery steady-state free precession sequence after bolus Gd-BOPTA infusion. Images were compared with nonenhanced T2-prepared steady-state free precision whole-heart coronary MRI in signal-to-noise ratio, contrast-to-noise ratio, depicted vessel length, vessel sharpness, and subjective image quality. Bolus and slow infusion schemes resulted in similar T1 during coronary MRI, whereas the hybrid infusion method yielded higher T1 values. A bolus infusion of Gd-BOPTA significantly improved signal-to-noise ratio, contrast-to-noise ratio, depicted coronary artery length, and subjective image quality, when all segments were collectively compared but not when compared segment by segment. In conclusion, whole-heart steady-state free precision coronary MRI at 1.5 T can benefit from a bolus infusion of 0.2 mmol/kg Gd-BOPTA. Magn Reson Med 000:000–000, 2010. V C 2010 Wiley-Liss, Inc.

Predictive ability of propofol effect-site concentrations during fast and slow infusion rates

The performance of propofol effect-site pharmacokinetic models during target-controlled infusion (TCI) might be affected by propofol administration rate. This study compares the predictive ability of three effect-site pharmacokinetic models during fast and slow infusion rates, utilizing the cerebral state index (CSI) as a monitor of consciousness. Sixteen healthy volunteers, 21-45 years of age, were randomly assigned to receive either a bolus dose of propofol 1.8 mg/kg at a rate of 1200 ml/h or an infusion of 12 mg/kg/h until 3-5 min after loss of consciousness (LOC). After spontaneous recovery of the CSI, the bolus was administered to patients who had first received the infusion and vice versa. The study was completed after spontaneous recovery of CSI following the second dose scheme. LOC was assessed and recorded when it occurred. Adequacies of model predictions during both administration schemes were assessed by comparing the effect-site concentrations estimated at the time of LOC during the bolus dose and during the infusion scheme. LOC occurred 0.97 +/- 0.29 min after the bolus dose and 6.77 +/- 3.82 min after beginning the infusion scheme (P<0.05). The Ce estimated with Schnider (ke0=0.45/min), Marsh (ke0=1.21/min) and Marsh (ke0=0.26/min) at LOC were 4.40 +/- 1.45, 3.55 +/- 0.64 and 1.28 +/- 0.44 microg/ml during the bolus dose and 2.81 +/- 0.61, 2.50 +/- 0.39 and 1.72 +/- 0.41 microg/ml, during the infusion scheme (P<0.05). The CSI values observed at LOC were 70 +/- 4 during the bolus dose and 71 +/- 2 during the infusion scheme (NS). Speed of infusion, within the ranges allowed by TCI pumps, significantly affects the accuracy of Ce predictions. The CSI monitor was shown to be a useful tool to predict LOC in both rapid and slow infusion schemes.

Mixed-Effects Modeling of the Influence of Midazolam on Propofol Pharmacokinetics

The combined administration of anesthetics has been associated with pharmacokinetic interactions that induce concentration changes of up to 30%. Midazolam is often used as a preoperative sedative in advance of a propofol-based anesthetic. In this study, we identified the influence of midazolam on the pharmacokinetics of propofol. Eight healthy male volunteers were studied on two occasions in a random crossover manner. During Session A, volunteers received propofol 1 mg/kg in 1 min followed by an infusion of 2.5 mg x kg(-1) x h(-1) for 59 min. During Session B, in addition to this propofol infusion scheme, a target-controlled infusion of midazolam (constant C(t): 125 ng/mL) was given from 15 min before the start until 6 h after termination of the propofol infusion. Arterial blood samples for blood propofol and plasma midazolam concentration analysis were taken until 6 h after termination of the propofol infusion. Nonlinear mixed-effects models examining the influence of midazolam and hemodynamic variables on propofol pharmacokinetics were constructed using Akaike criterion for model selection. In the presence of midazolam (C(blood): 224.8 +/- 41.6 ng/mL), the blood propofol concentration increased by 25.1% +/- 13.3% compared with when propofol was given as single drug. Midazolam (C(blood): 225 ng/mL) reduced propofol Cl(1) from 1.94 to 1.61 L/min, Cl(2) from 2.86 to 1.52 L/min, and Cl(3) from 0.95 to 0.73 L/min. Inclusion of mean arterial blood pressure further improved the propofol pharmacokinetic model. Midazolam reduces the metabolic and rapid and slow distribution clearances of propofol. In addition, a reduction in mean arterial blood pressure is associated with propofol pharmacokinetic alterations that increase the blood propofol concentration.

Insights into the biology of mobilized hematopoietic stem/progenitor cells through innovative treatment schedules of the CXCR4 antagonist AMD3100

The CXCR4 antagonist AMD3100 mobilizes hematopoietic stem/progenitor cells (HSPC) in several species. Few data are available on the biology of HSPC mobilized with AMD3100 as single agent. To further study the kinetics and properties of AMD3100-mobilized HSPC, and to explore the size of mobilizable pools of HSPC targeted by AMD3100, we studied the effect of a continuous infusion scheme with saturating doses of AMD3100 [AMDi]. Using established procedures, we evaluated mice mobilized with AMD3100, or those transplanted with AMD3100-mobilized HSPC. Relative to single-bolus AMD3100 [AMDb], the number of circulating CFU-C or CRU was dramatically higher after [AMDi]. During [AMDi], circulating CFU-C accumulated slowly, but after its discontinuation, CFU-C disappeared rapidly. Compared to bone marrow (BM)-c-kit(+) cells, AMD3100-mobilized (AMDb or AMDi) c-kit(+) cells showed reduced expression of several cytoadhesion molecules, similar to granulocyte colony-stimulating factor-mobilized c-kit(+) cells. In contrast to the latter, expression of CXCR4 and CD26 were not reduced on AMD3100-mobilized c-kit(+) cells. BM homing of [AMDi]-mobilized CFU-C was >50% increased over normal BM-CFU-C. Hematopoietic recovery after transplantation of [AMDi]-mobilized peripheral blood was comparable to that of continuous infusion granulocyte colony-stimulating factor-mobilized peripheral blood. AMD3100-mobilized HSPC were predominantly in G(0), and partial bromodeoxyuridine-labeling experiments documented underrepresentation of labeled cells (<5%) among [AMDb]-mobilized c-kit(+) cells, suggesting that cycling cells in BM, or those that recently completed cell cycle, are not targeted for mobilization by AMD3100. Our data demonstrate that [AMDi] is an efficacious mobilization scheme fully supporting transplantation demands and expands previous knowledge about properties and size of AMD3100-sensitive BM-HSPC pools.

Renal Contrast-enhanced MR Angiography: Timing Errors and Accurate Depiction of Renal Artery Origins

To investigate bolus timing artifacts that impair depiction of renal arteries at contrast material-enhanced magnetic resonance (MR) angiography and to determine the effect of contrast agent infusion rates on artifact generation. Renal contrast-enhanced MR angiography was simulated for a variety of infusion schemes, assuming both correct and incorrect timing between data acquisition and contrast agent injection. In addition, the ethics committee approved the retrospective evaluation of clinical breath-hold renal contrast-enhanced MR angiographic studies obtained with automated detection of contrast agent arrival. Twenty-two studies were evaluated for their ability to depict the origin of renal arteries in patent vessels and for any signs of timing errors. Simulations showed that a completely artifactual stenosis or an artifactual overestimation of an existing stenosis at the renal artery origin can be caused by timing errors of the order of 5 seconds in examinations performed with contrast agent infusion rates compatible with or higher than those of hand injections. Lower infusion rates make the studies more likely to accurately depict the origin of the renal arteries. In approximately one-third of all clinical examinations, different contrast agent uptake rates were detected on the left and right sides of the body, and thus allowed us to confirm that it is often impossible to optimize depiction of both renal arteries. In three renal arteries, a signal void was found at the origin in a patent vessel, and delayed contrast agent arrival was confirmed. Computer simulations and clinical examinations showed that timing errors impair the accurate depiction of renal artery origins.

A computerized infusion pump for control of tissue tracer concentration during positron emission tomography in vivo pharmacokinetic/pharmacodynamic measurements.

BackgroundA computer controlled infusion pump (UIPump) for regulation of target tissue concentration of radioactive compounds was developed for use in biological research and tracer development for PET.MethodsBased on observed tissue or plasma kinetics after a bolus injection of the tracer an algorithm calculates the infusion needed to obtain a specified target kinetic curve. A computer feeds this infusion scheme into an infusion pump connected to an animal via a venous catheter. The concept was validated using [11C]Flumazenil administrated to Sprague-Dawley rats where the whole brain distribution and kinetic of the tracer was measured over time using a microPET-scanner. The accuracy and precision of the system was assessed by producing steady-state levels of the tracer and by mimicking kinetics after oral administration.ResultsVarious kinetic profiles could be generated, including rapid achievement of constant levels, or step-wise increased levels. The resulting tissue curves had low deviation from the target curves according to the specified criteria: AUC (%): 4.2 ± 2.8, Maximal deviation (%): 13.6 ± 5.0 and R2: 0.95 ± 0.02.ConclusionThe UIPump-system is suitable for use in PET-research for assessment of PK/PD properties by simulation of different tracer tissue kinetics in vivo.

The Predictive Performance of a Pharmacokinetic Model for Manually Adjusted Infusion of Liquid Sevofluorane for Use with the Anesthetic-Conserving Device (AnaConDa): A Clinical Study

The Anesthetic-Conserving Device (AnaConDa) can be used to administer inhaled anesthetics using an intensive care unit (ICU) ventilator. We evaluated the predictive performance of a simple manually adjusted pump infusion scheme, for infusion of liquid sevoflurane to the AnaConDa. We studied 50 ICU patients who received sevoflurane via the AnaConDa. They were randomly divided into three groups. A 6-h infusion of liquid anesthetic was adjusted according to the infusion scheme to a target end-tidal sevoflurane concentration of 1% (Group 1%, n = 15) and 1.5% (Group 1.5%, n = 15). The initial rate was adjusted to reach the target concentration in 10 min and then the infusion was reduced to the first hour maintenance rate and readjusted once each hour afterwards. The actual concentrations were measured in the breathing circuit and compared with the target values. In the third group (n = 20) we used the model to increase and decrease the target concentration (+/-0.3%) for 3 h and evaluated the actual change in concentration achieved. The ability of the infusion scheme to provide the target concentration was quantified by calculating the performance error (PE). Infusion scheme performance was evaluated in terms of accuracy (median absolute PE, MDAPE) and bias (median PE, MDPE). Performance parameters (mean +/- SD, %) were for 1%, 1.5%, increase of concentration by 0.3% and decrease of concentration by 0.3% groups, respectively: MDAPE 5.3 +/- 5.5, 2.6 +/- 4.0, 5.0 +/- 5.6, 5.5 +/- 5.4; MDPE -5.3 +/- 5.5, -2.3 +/- 4.1, -0.1 +/- 7.1, 0.2 +/- 5.4. No significant differences were found between means of all performance parameters when the 1% and 1.5% groups were compared. There is an excellent 6-h predictive performance of a simplified pharmacokinetic model for manually adjusted infusion of liquid sevoflurane when using the AnaConDa to deliver sevoflurane to ICU patients.

Positron emission tomography and target-controlled infusion for precise modulation of brain drug concentration

There are several instances when it is desirable to control brain concentration of pharmaceuticals, e.g., to modulate the concentration of anesthetic agents to different desired levels fitting to different needs during the course of surgery. This has so far only been possible using indirect estimates of drug concentration such as assuming constant relation between tissue and blood including extrapolations from animals. A system for controlling target tissue concentration (UIPump) was used to regulate whole-brain concentrations of a central benzodiazepine receptor antagonist at therapeutic levels with input from brain kinetics as determined with PET. The system was tested by using pharmacological doses of flumazenil mixed with tracer amounts of [11C]flumazenil. Flumazenil was used as a model compound for anesthesia. An infusion scheme to produce three different steady-state levels in sequence was designed based on kinetic curves obtained after bolus injection. The subjects (Sprague-Dawley rats, n=6) were monitored in a microPET scanner during the whole experiment to verify resulting brain kinetic curves. A steady-state brain concentration was rapidly achieved corresponding to a whole-brain concentration of 118+/-6 ng/ml. As the infusion rate decreased to lower the exposure by a factor of 2, the brain concentration decreased to 56+/-4 ng/ml. A third increased steady-state level of anesthesia corresponding to a whole-brain concentration of 107+/-7 ng/ml was rapidly achieved. The experimental setup with computerized pump infusion and PET supervision enables accurate setting of target tissue drug concentration.

Simulation of propofol anaesthesia for intracranial decompression using brain hypothermia treatment

BackgroundAlthough propofol is commonly used for general anaesthesia of normothermic patients in clinical practice, little information is available in the literature regarding the use of propofol anaesthesia for intracranial decompression using brain hypothermia treatment. A novel propofol anaesthesia scheme is proposed that should promote such clinical application and improve understanding of the principles of using propofol anaesthesia for hypothermic intracranial decompression.MethodsTheoretical analysis was carried out using a previously-developed integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems. Propofol kinetics is described using a framework similar to that of this model and combined with the thermoregulation subsystem through the pharmacodynamic relationship between the blood propofol concentration and the thermoregulatory threshold. A propofol anaesthesia scheme for hypothermic intracranial decompression was simulated using the integrative model.ResultsCompared to the empirical anaesthesia scheme, the proposed anaesthesia scheme can reduce the required propofol dosage by more than 18%.ConclusionThe integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems is effective in analyzing the use of propofol anaesthesia for hypothermic intracranial decompression. This propofol infusion scheme appears to be more appropriate for clinical application than the empirical one.

A discrete Single Delay Model for the Intra-Venous Glucose Tolerance Test

BackgroundDue to the increasing importance of identifying insulin resistance, a need exists to have a reliable mathematical model representing the glucose/insulin control system. Such a model should be simple enough to allow precise estimation of insulin sensitivity on a single patient, yet exhibit stable dynamics and reproduce accepted physiological behavior.ResultsA new, discrete Single Delay Model (SDM) of the glucose/insulin system is proposed, applicable to Intra-Venous Glucose Tolerance Tests (IVGTTs) as well as to multiple injection and infusion schemes, which is fitted to both glucose and insulin observations simultaneously. The SDM is stable around baseline equilibrium values and has positive bounded solutions at all times. Applying a similar definition as for the Minimal Model (MM) SI index, insulin sensitivity is directly represented by the free parameter KxgI of the SDM.In order to assess the reliability of Insulin Sensitivity determinations, both SDM and MM have been fitted to 40 IVGTTs from healthy volunteers. Precision of all parameter estimates is better with the SDM: 40 out of 40 subjects showed identifiable (CV < 52%) KxgI from the SDM, 20 out of 40 having identifiable SI from the MM. KxgI correlates well with the inverse of the HOMA-IR index, while SI correlates only when excluding five subjects with extreme SI values. With the exception of these five subjects, the SDM and MM derived indices correlate very well (r = 0.93).ConclusionThe SDM is theoretically sound and practically robust, and can routinely be considered for the determination of insulin sensitivity from the IVGTT. Free software for estimating the SDM parameters is available.

Three-dimensional drip infusion CT cholangiography in patients with suspected obstructive biliary disease: a retrospective analysis of feasibility and adverse reaction to contrast material.

BackgroundComputed Tomography Cholangiography (CTC) is a fast and widely available alternative technique to visualise hepatobiliary disease in patients with an inconclusive ultrasound when MRI cannot be performed. The method has previously been relatively unknown and sparsely used, due to concerns about adverse reactions and about image quality in patients with impaired hepatic function and thus reduced contrast excretion. In this retrospective study, the feasibility and the frequency of adverse reactions of CTC when using a drip infusion scheme based on bilirubin levels were evaluated.MethodsThe medical records of patients who had undergone upper abdominal spiral CT with subsequent three-dimensional rendering of the biliary tract by means of CTC during seven years were retrospectively reviewed regarding serum bilirubin concentration, adverse reaction and presence of visible contrast media in the bile ducts at CT examination. In total, 153 consecutive examinations in 142 patients were reviewed.ResultsContrast media was observed in the bile ducts at 144 examinations. In 110 examinations, the infusion time had been recorded in the medical records. Among these, 42 examinations had an elevated bilirubin value (>19 umol/L). There were nine patients without contrast excretion; 3 of which had a normal bilirubin value and 6 had an elevated value (25–133 umol/L). Two of the 153 examinations were inconclusive. One subject (0.7%) experienced a minor adverse reaction – a pricking sensation in the face. No other adverse effects were noted.ConclusionWe conclude that drip infusion CTC with an infusion rate of the biliary contrast agent iotroxate governed by the serum bilirubin value is a feasible and safe alternative to MRC in patients with and without impaired biliary excretion.In this retrospective study the feasibility and the frequency of adverse reactions when using a drip infusion scheme based on bilirubin levels has been evaluated.

Pharmacokinetics of Intravenous Insulin Delivery in Humans with Type 1 Diabetes

Insulin pharmacokinetics models describe the distribution and elimination of insulin in the body. These models can be useful in designing infusion schemes to produce a desired plasma insulin profile. We evaluated the pharmacokinetics of intravenous insulin delivery in five human subjects with type 1 diabetes; one subject was studied on three separate occasions for a total of seven experiments. Each subject consumed an identical 829 Kcal meal of solid food for breakfast and lunch, followed by exercise on a stationary bicycle. Regular human insulin was infused into a peripheral vein at a basal rate (0.5 U/h) for the entire study. Coinciding with the consumption of each meal, insulin was infused at a higher rate for 120 min (average dose 8.5 +/- 2.1 U). The bolus dose was based upon preprandial and 60-min postprandial blood glucose measurements and a sliding scale regimen. Blood glucose levels were allowed to fluctuate throughout the protocol (mean 174 mg/dL, range 55-340 mg/dL). Human insulin levels were measured from plasma samples obtained every 10 min throughout the 8.5-h protocol. A total of 346 plasma samples were assayed to measure the concentration of human insulin. Data were used to compare (previously developed) insulin kinetics models consisting of one, two, and three first-order linear differential equations. The ability of each model to simulate the input/output data (intravenous insulin infusion rate/plasma insulin concentration) was assessed. Our main finding is that the first-order linear insulin kinetics model was sufficient to describe the clinical data. The model had a fractional insulin loss rate of 0.112 +/- 0.063 min(1) and a distribution volume of 15.6 +/- 4.0 L.

Kinetics and EEG Effects of Midazolam during and after 1‐Minute, 1‐Hour, and 3‐Hour Intravenous Infusions

The objective of this study was to evaluate the kinetics and dynamics of midazolam when administered by three different infusion schemes, using electroencephalography to measure pharmacodynamic effects. In a three-way crossover study, 8 volunteers received midazolam (0.1 mg/kg) by constant-rate intravenous infusion. The durations of midazolam infusions for the three trials were 1 minute, 1 hour, and 3 hours. Plasma midazolam concentrations and electroencephalographic (EEG) activity in the 13- to 30-Hz range were monitored for 24 hours. Based on separate analysis of each subject-trial, mean values for volume of distribution and distribution or elimination half-life did not significantly vary. Central compartment volume and clearance differed among the three midazolam infusion trials; however, the magnitude of change was small. EEG activity in the 13- to 30-Hz range significantly increased for all three midazolam infusion trials. Plots of midazolam plasma concentration versus pharmacodynamic EEG effect for the 1-hour and 3-hour infusion trials did not reveal evidence of either counterclockwise or clockwise hysteresis. Plots from the 1-minute infusion trial demonstrated counterclockwise hysteresis, consistent with an equilibration effect-site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model. Analysis of all three infusion trials together yielded the following mean estimates: maximum EEG effect, 16.3% over baseline; 50% maximum effective concentration, 31 ng/mL; and an apparent rate constant for drug disappearance from the effect compartment which approached infinity. Despite the delay in effect onset during the 1-minute midazolam infusion, midazolam infusions in duration of up to 3 hours produce CNS sedation without evidence of tolerance.

Drugs and human memory (part 2). Clinical, theoretical, and methodologic issues.

Drugs and human memory (part 2). Clinical, theoretical, and methodologic issues.

Feasibility of a new in vitro approach to evaluate cellular damage following co-infusion of red blood cell concentrates and intravenous drug solutions.

Transfusion guidelines may result in unwanted delay in infusion schemes, as simultaneous infusion of blood components and drug solutions is universally prohibited. The aim of this study was to measure possible damage to red cells by drug solutions, as manifested by haemolysis, using a dynamic model that resembles the clinical setting. Stored filtered and irradiated RBC concentrates and drug solutions were co-infused in an in vitro dynamic model. Also, incubation in a static model was performed. The haemolytic potency of the drug solutions was measured by determining free haemoglobin (fHb) levels. Neither in the dynamic tests nor in the static tests did fHb levels exceed the maximally acceptable standard for filtered RBC concentrates according to Dutch specification guidelines. In the static test model, fHb levels were slightly elevated compared with those of control samples, as well as those in the dynamic test model. A novel in vitro dynamic infusion system appears to represent a useful technique to calculate possible damage to RBCs resulting from co-infused drug solutions. Co-infusion of the drug solutions tested with filtered and irradiated RBC concentrates did not produce fHb levels above the levels accepted by the Dutch national guidelines. Apart from haemolysis, other parameters reflecting RBC damage should be investigated in future studies.

Pharmacokinetics of Hydroxyethyl Starch (70/0.5) following Repeated Infusions

Background: For the purpose of haemodilution different medium substituted hydroxyethyl starches (HES) are available. These plasma substitutes can be further characterized by their average molecular weight (Mw) into medium Mw (HES 200/0.5) and low Mw (HES 70/0.5) starches. Patients and Methods: Pharmacokinetic data were collected in a trial with a design similar to clinical use. 8 healthy volunteers were given 50 g HES on 5 consecutive days (=250 g) to estimate the in vivo changes of the chemical structures of HES (70/0.5). Results: Calculated half-life of serum elimination were 6–10 h which was representative for medium substituted HES and the chosen infusion scheme. The mild accumulation of HES (70/0.5) should be without clinical relevance. The in vivo Mw is equivalent to the in vitro Mw of the infused HES (70/0.5). The in vivo Mw is about 60,000 Dalton for most medium substituted HES. Nevertheless, regarding molar substitution and pattern of substitution (C2:C6) there are some differences between applied HES (70/0.5) and HES recovered in urine. These changes also indicate a shift in the chemical properties of infused HES in the organism. Only 60% of infused HES were recovered in urine. The destination of the remaining 40% (∼100 g in this clinical trial) is still unexplained. A fractional amount might be stored in the reticuloendothelial system. Concerning the measured data of medium substituted HES (70/0.5) it stands to reason that differences in the approximate substituted HES (200/0.5) with a higher molecular weight are without clinical relevance. Conclusion: The in vivo Mw is independent of the in vitro Mw of the applied HES. Pharmacokinetic data suggest that HES (70/0.5) is a good option for the purpose of haemodilution.

Propofol in rats: testing for nonlinear pharmacokinetics and modelling acute tolerance to EEG effects

Background and objective: Pharmacokinetics of propofol in rats have usually been described using linear models. Furthermore, there are only a few investigations for a pharmacodynamic model of the electroencephalographic effects of propofol in rats. We investigated pharmacokinetics and pharmacodynamics of propofol in rats with special regard to linearity in pharmacokinetics and development of tolerance. Methods: Twelve adult male Sprague-Dawley rats received propofol in three successive infusion periods of 30 min each with infusion rates of 0.5, 1 and 0.5 mg kg−1 min−1. Propofol plasma concentrations were determined from arterial blood samples. Pharmacokinetics were tested for linearity using the ratio of the concentrations at the end of the first and second infusion interval as a model independent criterion. Several linear and nonlinear models were investigated with population pharmacokinetic analysis. Pharmacodynamics were analysed using the median frequency of the electroencephalographic power spectrum as a quantitative measure of the hypnotic effect. Results: Pharmacokinetics were found to be nonlinear and were best described by a two-compartment model with Michaelis-Menten elimination (Vm = 2.17 μg mL−1 min−1, Km = 2.65 μg mL−1, k12 = 0.30 min−1, k21 = 0.063 min−1, Vc = 0.13 L). Acute tolerance to the electroencephalographic effect of propofol was observed. The hypnotic effect was best described by a sigmoid Emax model (E0 = 17.8 Hz, Emax = 17.7 Hz, EC50 = 4.1 μg mL−1, γ = 2.3, ke0 = 0.36 min−1) with competitive antagonism of propofol and a hypothetical drug in an additional tolerance compartment. Conclusions: For the applied infusion scheme, propofol pharmacokinetics in rats were nonlinear and a development of tolerance to the electroencephalographic effect of propofol was observed during an infusion time of 90 min.

Propofol in rats: testing for nonlinear pharmacokinetics and modelling acute tolerance to EEG effects.

Pharmacokinetics of propofol in rats have usually been described using linear models. Furthermore, there are only a few investigations for a pharmacodynamic model of the electroencephalographic effects of propofol in rats. We investigated pharmacokinetics and pharmacodynamics of propofol in rats with special regard to linearity in pharmacokinetics and development of tolerance. Twelve adult male Sprague-Dawley rats received propofol in three successive infusion periods of 30 min each with infusion rates of 0.5, 1 and 0.5 mg kg(-1) min(-1). Propofol plasma concentrations were determined from arterial blood samples. Pharmacokinetics were tested for linearity using the ratio of the concentrations at the end of the first and second infusion interval as a model independent criterion. Several linear and nonlinear models were investigated with population pharmacokinetic analysis. Pharmacodynamics were analysed using the median frequency of the electroencephalographic power spectrum as a quantitative measure of the hypnotic effect. Pharmacokinetics were found to be nonlinear and were best described by a two-compartment model with Michaelis-Menten elimination (Vm = 2.17 microg mL(-1) min(-1), Km = 2.65 microg mL(-1), k12 = 0.30 min(-1), k21 0.063 min(-1), Vc = 0.13 L). Acute tolerance to the electroencephalographic effect of propofol was observed. The hypnotic effect was best described by a sigmoid Emax model (E0 = 17.8 Hz, Emax = 17.7 Hz, EC50 = 4.1 microg mL(-1), gamma = 2.3, ke0 = 0.36 min(-1)) with competitive antagonism of propofol and a hypothetical drug in an additional tolerance compartment. For the applied infusion scheme, propofol pharmacokinetics in rats were nonlinear and a development of tolerance to the electroencephalographic effect of propofol was observed during an infusion time of 90 min.

Paediatric applications of concentration-orientated anaesthesia

Although several hypnotic and opioid drugs are suitable for administration by continuous intravenous infusion, it is somewhat disquieting to realize just how little we know of their concentration–effect relationships during the early years of life; there remains great scope for clinical research in this area. Nevertheless, in the past few years we have gained sufficient information about the pharmacology of suitable drugs to formulate appropriate infusion dosage algorithms for children older than 2 years of age. Hence, target-controlled infusions (TCI) are becoming a practical proposition in paediatric anaesthesia. This review concentrates on the pharmacokinetics and pharmacodynamics of propofol, remifentanil and alfentanil when given by infusion to children. Evidence-based practical guidelines are given to enable manual infusion schemes to be utilized, although it is envisaged that commercially available TCI systems for young children will be available within a few years.