Abstract: The time-course of the neuromuscular blocking effect of rocuronium depends on circulatory mixing and the rate of distribution into the interstitial space. In order to quantitatively evaluate these processes, a physiologically meaningful model of distribution kinetics based on circulatory transport and interstitial diffusion, was fitted to rocuronium disposition data in 10 patients using a population approach. Information on cardiac output and circulatory mixing was obtained from the kinetics of indocyanine green (ICG), which was injected simultaneously with rocuronium. As a compromise between physiological reality and parameter identifiability, the organs of the systemic circulation were lumped into a heterogeneous subsystem, described by an axially distributed model of extravascular diffusion. Diffusion into the interstitial space determines the rate of rocuronium distribution in the body (diffusional time constant 89Â min). The resulting whole body distribution kinetics depends both on cardiac output and on the apparent permeability surface area product (0.16Â l/min). The analysis of the ICG data revealed that heterogeneity of blood transit time through the systemic circulation decreased and that cardiopulmonary volume increased, respectively, with cardiac output. The approach should be useful for studying the effect of disease states on distribution kinetics of drugs.
Abstract: Sporadic pheochromocytomas are detected by clinical signs and symptoms, whereas pheochromocytomas in patients with a known hereditary predisposition for these tumors are detected by repetitive screening for catecholamine excess.
Abstract: Indocyanine green plasma disappearance rate (ICG-PDR) is used to evaluate hepatic function. Although hepatic failure is generally said to occur with an ICG-PDR <18%/min, ICG disappearance rate is poorly defined in the healthy population, and a clear cutoff value of ICG-PDR that discriminates between normal hepatic function and hepatic failure has not yet been described. We therefore defined the ICG disappearance rate in an otherwise healthy patient population. In addition, we evaluated the noninvasive measurement of ICG-PDR (transcutaneously by pulse dye densitometry [PDD] at the finger and the nose) and compared these with the simultaneously performed invasive measurements of ICG-PDR (in arterial blood).
Abstract: 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.
Abstract: Lumbar epidural anaesthesia induces cardiovascular changes and decreases liver blood flow (Qh). We studied the effects of age on haemodynamics, blood volumes and Qh before and after epidural anaesthesia.
Abstract: Noninvasive cardiac output (CO) monitoring is possible by indocyanine green (ICG) dilution measured by pulse dye densitometry (PDD). To validate the precision of this method, we compared hemodynamic variables derived from PDD (DDG-2001, Nihon Kohden, Japan) with those derived from simultaneously taken arterial blood ICG concentrations.
Abstract: 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.
Abstract: Vuyk, Jaap, Jan Van Den Bos, Kees Terhell, Rene De Bos, Ad Vletter, Pierre Valk, Martie Van Beuzekom, Jack Van Kleef, and Albert Dahan. Acetazolamide improves cerebral oxygenation during exercise at high altitude. High Alt. Med. Biol. 7:290-301, 2006.--Acute mountain sickness is thought to be triggered by cerebral hypoxemia and be prevented by acetazolamide (Actz). The effect of Actz on cerebral oxygenation at altitude remains unknown. In 16 members of the 2005 Dutch Cho Oyu (8201 m, Tibet) expedition, the influence of Actz and exercise (750 mg PO daily) on heart rate, peripheral and regional cerebral oxygen saturation (Sa(O(2) ) and rS(O(2) )), the Lake Louise score (LLS), and psychomotor function were studied at 0 m 14 days prior to the expedition, after arrival at 3700 m on day 3, after arrival at 5700 m on day 29, and again at 5700 m before the end of the expedition on day 51. After arrival at 3700 m, the LLS of the climbers taking Actz (n = 8) was significantly lower compared to those who did not take Actz (n = 8): 0.75 +/- 1.0 versus 2.9 +/- 2.0, p < 0.05 (ANOVA). High LLSs were associated with low rS(O(2) ) values in rest and exercise (p < 0.01 and p < 0.001). With altitude, resting Sa(O(2) ) and resting rS(O(2) ) decreased significantly (p < 0.001), irrespective of Actz use. Exercise at 3700 m and 5700 m reduced Sa(O(2) ) and rS(O(2) ) even further compared to rest (p < 0.001), although at 3700 m the rS(O(2) ) was preserved better in those who took Actz (55.3 +/- 4.3% versus 47.9 +/- 5.7%, p < 0.05). Irrespective of Actz use, with altitude, the percentage of omissions in the vigilance and tracking test increased while the climbers' scores on vigor decreased (p < 0.05). In conclusion, at altitude, exercise-induced reduction in cerebral oxygenation is less in climbers on Actz compared to climbers not taking Actz. This effect is nullified after several weeks at altitude due to acclimatization in climbers not taking Actz.
Abstract: Until recently, no measure was available that provided objective and reproducible information on the level of consciousness in patients under general anaesthesia. Several decades of research to find a reliable measure for determining the depth of anaesthesia has now led to the clinical introduction of the bispectral index scale (BIS), a parameter derived from the electroencephalogram. Implementation of the BIS-monitor in anaesthetic practice leads to a reduced use of hypnotic agents, a more rapid recovery phase and possibly a reduced incidence of awareness.
Abstract: Propofol-opioid combinations are widely used in today's anaesthetic practice. Over the past 20-30 years the pharmacology of these agents has been described in increasingly greater detail. Together with novel intravenous administration devices and improved anaesthetic depth monitoring, this has created a basis for the optimisation of the administration of propofol-opioid anaesthesia. This article describes the current strategies regarding the application of this type of anaesthesia, focusing on three strategic tools: (i) application of pharmacokinetic-pharmacodynamic knowledge of propofol and the opioids, with particular attention to pharmacodynamic interactions between them; (ii) the use of state-of-the-art administration techniques; and (iii) the application of bispectral index monitoring. Together, these techniques have improved the level of control, the flexibility and the safety of anaesthetic practice.
Abstract: The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol.
Abstract: Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans.
Abstract: Remifentanil is often combined with propofol for induction and maintenance of total intravenous anesthesia. The authors studied the effect of propofol on remifentanil requirements for suppression of responses to clinically relevant stimuli and evaluated this in relation to previously published data on propofol and alfentanil.
Abstract: An overview is given of the influence of age on the pharmacodynamics of drugs used during general and locoregional anaesthesia. For some groups of agents a distinct separation into age-related changes in the pharmacokinetics and pharmacodynamics is possible, whereas for others the literature indicates only that responses in the elderly are enhanced. I start with an overview of the influence of age on cardiovascular and neuroendocrine function and include a short account of the state-of-the-art in pharmacodynamic modelling. The physiological changes that occur with age are associated with an increased sensitivity to the effects of anaesthetic agents. For most intravenous hypnotic agents, and inhalational anaesthetic agents, the increased sensitivity with age is, at least in part, explained by altered pharmacodynamics. For opioids and local anaesthetics applied for blockade of the central nervous system, the pharmacodynamic involvement is not always clear. For neuromuscular blocking agents, pharmacodynamic involvement appears to be nearly absent in the reduced dose requirements seen with age--so that the latter appear to be caused by altered pharmacokinetics. Future studies, using pharmacokinetic-pharmacodynamic (PK-PD) mixed-effects modelling, should further explore this area to obtain clinically applicable data for improving our insight into the delivery of anaesthetics to the elderly and improving the quality of anaesthesia in this fast-growing population.
Abstract: The predictive performance of the available pharmacokinetic parameter sets for remifentanil, when used for target-controlled infusion (TCI) during total i.v. anaesthesia, has not been determined in a clinical setting. We studied the predictive performance of five parameter sets of remifentanil when used for TCI of remifentanil during propofol anaesthesia in surgical patients.
Abstract: Ventilatory control in humans depends on complex mechanisms which aim to maintain a cellular CO2-, O2- and H(+)-homeostasis under physiological conditions. This regulation is based on chemical control which predominantly acts via peripheral chemoreceptors in the carotid bodies and central chemoreceptors in the ventral medulla of the brainstem on the one hand, and behavioural control on the other, by which it is possible to adapt respiration to conditions of daily living. The influence of anaesthesia and related conditions may depress respiration and have a sustained effect on ventilatory control. Perioperative respiratory depression remains a serious clinical problem in perioperative medicine. This review will give an overview of ventilatory control and discuss the most relevant responses, describe the effects of pain, anaesthetics and opioids on ventilatory control and their interaction. The current body of knowledge is put into perspective to identify patients at risk for perioperative respiratory depression.
Abstract: The influence of propofol on the pharmacokinetics of alfentanil is poorly understood. The authors therefore studied the effect of a pseudo-steady state concentration of propofol on the pharmacokinetics of alfentanil.
Abstract: This manuscript describes the pharmacokinetic and pharmacodynamic interactions between propofol and the opioids. PHARMACOKINETIC INTERACTIONS: In vitro studies describe the reduced clearance of opioids in the presence of propofol, midazolam and etomidate due to interaction at the cytochrome P450 enzyme system. In vivo, however, pharmacokinetic interaction studies by mixed effects modelling predominantly focus on haemodynamic factors affecting distribution and elimination of concomitantly administered agents. In the presence of propofol the elimination clearance and rapid and slow distribution clearance of alfentanil is decreased. Consequently, plasma alfentanil concentrations are increased in the presence of propofol. Vice versa alfentanil reduces propofol elimination clearance and increases the deep volume of distribution. PHARMACODYNAMIC INTERACTIONS: Propofol and the opioids interact in a synergistic manner for various clinical end points. The magnitude of interaction is similar between the various opioids and hypnotic agents, taken into consideration the differences in potency between the opioids. CLINICAL INTERPRETATION OF PK/PD INTERACTIONS: A. Speed of induction. Using PK/PD interaction data speed of induction can be optimised. Of importance are the magnitude of PD interaction between propofol and the various opioids, the rate of administration and the time to peak effect of the agents involved. B. Haemodynamic stability. In ASA 1-2 patients the opioid induced hypnotic dose reduction is not associated with an increased haemodynamic stability of induction of loss of consciousness. In elderly patients or patients known with cardiovascular instability high opioid-low propofol anaesthesia may be associated with improved haemodynamic stability during induction of anaesthesia, however, no data are available regarding this yet. C. Speed of recovery. Time to return of consciousness after termination of propofol-opioid infusions of various duration can be reduced using optimal propofol-opioid concentrations. In general, optimal propofol target concentrations to assure this are 5 micrograms/ml in the presence of fentanyl, 3.5 micrograms/ml in the presence of alfentanil and sufentanil and 2.5 micrograms/ml in the presence of remifentanil. D. Spontaneous respiration. For single agents some data allow proper targeting of a drug concentration that is associated with adequate intraoperative respiration. However, no data exist on drug interactions regarding the respiratory depressant effects of hypnotic-opioid combinations. CONCLUSION: The proper exploration and use of published pharmacokinetic and pharmacodynamic interaction data allows the clinical anaesthesiologist to optimise the clinical administration of propofol and the various opioids when given alone or in combination.
Abstract: Differences in the pharmacokinetics of propofol between male and female patients during and after continuous infusion have not been described in detail in patients aged 65 yr and older. To increase our insight into the pharmacokinetics of propofol in this patient population and to obtain pharmacokinetic parameters applicable in target controlled infusion (TCI), the pharmacokinetics of propofol during and after continuous infusion were studied in 31 ASA class 1 and 2 patients, aged 65-91 yr, scheduled for general surgery. Patients received propofol 1.5 mg kg(-1) i.v. in 1 min followed by 7 mg kg(-1) h(-1) until skin closure in the presence of a variable rate infusion of alfentanil during oxygen-air ventilation. On the basis of arterial blood samples that were taken up to 24 h post-infusion, the pharmacokinetics of propofol were evaluated in a two-stage manner. Multiple linear regression analysis was used to explore the effect of age, weight, gender and lean body mass as covariates. Gender significantly affected the pharmacokinetics of propofol. V3, Cl1 and Cl2 were significantly different between male and female patients, weight only affected Cl1. The pharmacokinetic parameters were: V1=4.88 litre, V2=24.50 litre, V3 (litre)=115+147 x gender (gender: male=1, female=2), Cl1 (litre min(-1))=-0.29+0.022 x weight+0.22 x gender, Cl2 (litre min(-1))=2.84-0.65 x gender (male=1, female=2), and Cl3=0.788 litre min(-1).
Abstract: Drug delivery by target-controlled infusion (TCI) allows automatic adjustments of the infusion rate of a drug to maintain a desired target concentration. Since drug effect is more closely related to blood concentration than to infusion rate, drug delivery via TCI is capable of creating stable blood concentrations of intravenous anaesthetics and analgesics. In this article the concept and history of TCI are described. The rational administration of TCI requires an appropriate pharmacokinetic data set and knowledge of the concentration-effect relationship; therefore, general pharmacokinetic and pharmacodynamic aspects of intravenous anaesthetics and analgesics are also addressed. Intraoperative investigations have demonstrated that TCI drug delivery allows rapid titration to a desired effect. The use of TCI for postoperative analgesia is still experimental, but TCI can, in part, overcome the disadvantages associated with continuous infusions and patient-controlled analgesia regimens in the postoperative period. Although TCI is capable of creating stable blood concentrations, when the target concentration is changed the resulting effect correlates better with a theoretical effect site concentration. The efficacy of TCI systems that can perform effect-site steering are still to be explored.
Abstract: Anaesthesia is nowadays seldom accomplished by a single agent because no single agent is able to provide all components of anaesthesia without seriously compromising haemodynamic and/or respiratory function, reducing operating conditions, or postponing postoperative recovery. Because of the small therapeutic window a detailed characterisation of the concentration-effect relationships of anaesthetic agents is required to allow a proper selection of the various intravenous agents and the combinations thereof to an optimal therapeutic pharmacological effect in the absence of significant side effects. During the past decade, for propofol and the various opioids fentanyl, alfentanil, sufentanil, and remifentanil considerable progress has been made in the characterisation of the pharmacokinetics and pharmacodynamics of these agents and of the combinations thereof. This manuscript describes the pharmacokinetic and dynamic interactions between these agents and the determination of optimal concentrations that assure adequate anaesthesia and a rapid return of recovery.
Abstract: We have studied the influence of eltanolone on intraoperative alfentanil requirements in 18 female patients undergoing lower abdominal surgery receiving target-controlled infusions of eltanolone and alfentanil. While target concentrations of eltanolone were maintained constant, target concentrations of alfentanil changed in response to the presence or absence of responses. With serum eltanolone concentrations increasing from 500 to 2000 ng ml-1, the EC50 of alfentanil for suppression of responses to surgical stimulation decreased from 233 to 9 ng ml-1. The findings suggest that the interaction between eltanolone and alfentanil is synergistic.
Abstract: The pharmacokinetic and pharmacodynamic interactions between propofol and adjuvant agents have increasingly been recognised as clinically important and the improved knowledge of these interactions is being used to optimise the quality of intravenous anaesthesia. It is now known that propofol interferes with opioid metabolism, thereby increasing the plasma concentrations of the opioids, while opioids such as alfentanil increase propofol concentrations by reducing both the distribution and clearance of propofol. The pharmacokinetic interactions, however, are of relatively minor clinical importance compared with pharmacodynamic interactions. The pharmacodynamic interaction between propofol and other sedative agents, or one of the synthetic opioids, is synergistic. From the pharmacodynamic interaction data, optimal target propofol-opioid concentrations and optimal infusion regimens have been developed that ensure adequate anaesthesia in 50% and 95% of patients with the most rapid recovery possible. These optimal target propofol concentrations and infusion regimens are affected by the opioid with which propofol is combined, as well as the duration of infusion.
Abstract: The pharmacokinetic and pharmacodynamic interactions between opioids and propofol increasingly have been described and used in clinical practice. It is now known that propofol inhibits both alfentanil and sufentanil metabolism, thereby increasing the plasma concentrations of these opioids, while alfentanil also elevates propofol concentrations. Pharmacodynamically the interaction between propofol and the opioids is generally found to be synergistic. From the interaction data, the optimal propofol concentrations have been extracted that assure adequate anesthesia and the most rapid recovery possible. In the presence of fentanyl, sufentanil, and alfentanil, the optimal propofol concentration is approximately 3.5 microgram/ml, whereas in the presence of remifentanil, lower propofol concentrations of 2.5 to 3 microgram/ml are required.
Abstract: Propofol and alfentanil often are combined during induction of anesthesia. However, the interaction between these agents during induction has not been studied in detail. The influence of alfentanil on the propofol concentration-effect relationships was studied for loss of eyelash reflex, loss of consciousness, and hemodynamic function in 20 unpremedicated ASA physical status 1 patients aged 20-55 yr.
Abstract: Propofol and alfentanil are frequently combined to provide general anesthesia. The purpose of this study was to characterize the pharmacodynamic interaction between propofol and alfentanil for several clinically relevant end points.
Abstract: Computer-controlled infusion of propofol is used with increasing frequency for the induction and maintenance of anesthesia. The performance of computer-controlled infusion devices is highly dependent on how well the implemented pharmacokinetic parameter set matches the pharmacokinetics of the patient. This study examined the performance of a computer-controlled infusion device when provided with five different pharmacokinetic parameter sets of propofol in female patients. The infusion rate-time data that had been stored on a disk from 19 female patients who had been given propofol by computer-controlled infusion, using the pharmacokinetic parameter set from Gepts et al. (Anesth Analg 1987;66:1256-63), were entered into a computer simulation program to recalculate predicted propofol concentrations that would have been obtained with four other pharmacokinetic parameter (Shafer et al., Anesthesiology 1988;69:348-56; Kirkpatrick et al., Br J Anesth 1988;60:146-50; Cockshott et al., Br J Anesth 1987;59:941P; Tackley et al., Br J Anesth, 1989;62:46-53) sets of propofol, had these been implemented. The performance error (PE) was determined for each measured blood propofol concentration, on the basis of each of the five pharmacokinetic parameter sets. Then, for each of the five pharmacokinetic parameter sets, the performance in the population was determined by the median absolute performance error (MDAPE), the median performance error (MDPE), the wobble (the median absolute deviation of each PE from the MDPE), and the divergence (the percentage change of the absolute PE with time). The MDPE and MDAPE were compared between the parameter sets by the multisample median test. The initially used pharmacokinetic parameter set from Gepts et al. resulted in a MDPE of 24% and MDAPE of 26%.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Although propofol and alfentanil are given in combination in clinical practice, the pharmacodynamic interaction between these drugs has not been described.
Abstract: Although the clinical properties of propofol have been studied extensively, the pharmacodynamics have not yet been described fully. We studied the propofol concentration-effect relationships for loss of eyelash reflex, loss of consciousness, and hemodynamic changes in 18 female patients, ASA physical status 1, aged 20-49 yr. Propofol was given by computer-controlled infusion. The initial target concentration of 0.5-1 microgram/ml was increased every 12 min by 0.5-1 microgram/ml until the patients lost consciousness. Every 3 min, loss of eyelash reflex and loss of consciousness were tested and an arterial blood sample was taken for analysis of the blood propofol concentration. The concentration-response relationships for loss of eyelash reflex and loss of consciousness were defined by fitting a sigmoid Emax function (where Emax = the maximum effect that can be reached; i.e., 100% of the patients showing loss of eyelash reflex or loss of consciousness) to the response/no response data versus the propofol concentration, using nonlinear regression. The effect of propofol on hemodynamic parameters was analyzed by linear regression. The propofol concentrations at which 50% and 90% of the patients showed loss of eyelash reflex were 2.07 and 2.78 micrograms/ml, respectively. The corresponding values for loss of consciousness were 3.40 and 4.34 micrograms/ml. The systolic and diastolic blood pressure decreased with increasing blood propofol concentration. The correlation coefficients for the decrease in systolic and diastolic blood pressure versus the blood propofol concentration were r2 = -0.663 and r2 = -0.243, but heart rate did not change. In conclusion, propofol concentrations inducing loss of eyelash reflex are less than those inducing loss of consciousness.
Abstract: Hemodynamic function during induction of anesthesia, the alfentanil and naloxone requirements, and the speed of recovery from total intravenous anesthesia with alfentanil/midazolam (group M, n = 10) or alfentanil/propofol (group P, n = 10) were compared in patients undergoing lower limb surgery. Twenty patients were randomly assigned to receive either 2 mg/kg propofol in 5 min followed by 9 mg.kg-1.h-1 for 30 min and 4.5 mg.kg-1.h-1 until skin closure, or 0.42 mg/kg midazolam in 5 min followed by 0.125 mg.kg-1.h-1 until skin closure. Simultaneously, a variable-rate infusion of alfentanil was given. Patients were ventilated with 30% oxygen in air. In both groups blood pressure and heart rate decreased significantly (P less than 0.02) and to a similar extent during induction. The total dose of alfentanil was similar in both groups. No patient in group P and nine patients in group M needed naloxone (average dose 130 +/- 70 micrograms, P less than 0.001). Recovery, as judged by psychomotor tests (90% score was reached at 1 h in the P group and at about 4 h in the M group, P less than 0.001), sedative scores, and orientation in time and place, was shorter in group P than in group M. The conclusion is reached that propofol is superior to midazolam in total intravenous anesthesia with alfentanil.
Abstract: The anesthesiologist attempts to balance the dose or concentration of an anesthetic against the intensity of noxious stimulation so as to: 1) maintain a satisfactory anesthetic state, 2) minimize side effects and toxicity of the anesthetic, and 3) allow for a rapid recovery from anesthesia. The development of infusion pumps controlled by computers programmed according to pharmacokinetic principles should facilitate the achievement of these objectives for intravenous drugs. To test this hypothesis, the authors compared anesthetic conditions achieved with a computer-controlled infusion to those produced by the traditional method of intermittent intravenous injections. In both cases, the intravenous opiate, alfentanil, was used to supplement nitrous oxide anesthesia, and the dose/dose-rate of alfentanil after the induction dose was guided by the use of precisely defined clinical signs of inadequate anesthesia. One group of ten patients received 10 mg of alfentanil and 66% N2O to induce anesthesia, and was subsequently given 1 or 2 mg iv doses of alfentanil whenever the depth of anesthesia was inadequate. A second group of ten patients had a target alfentanil concentration of 475 ng/ml of plasma established by the computer-controlled infusion, which subsequently raised or lowered the concentration by 50 or 100 ng/ml according to the presence or absence of clinical signs of inadequate anesthesia. Regular measurements of alfentanil concentrations in plasma showed that the computer-assisted infusion produced relatively stable concentrations that closely paralleled those predicted (prediction error of -64 +/- 40 ng/ml [+/- SD] in the range of 150-600 ng/ml). The traditional method of intermittent injections resulted in continuous, rapid fluctuations in alfentanil concentrations. Both methods were successful in controlling the patients' responses to noxious stimuli, but the infusion group had: 1) a lower incidence of responsiveness, 2) greater hemodynamic stability, 3) no patients requiring naloxone for satisfactory ventilation postoperatively, and 4) an incidence of side effects that tended to be lower. The previously reported alfentanil concentration versus anesthetic effect relationships were confirmed.
