Pharmacokinetics Of Propofol Research Articles

Propofol Pharmacokinetics and Pharmacodynamics for Depth of Sedation in Nonventilated Infants after Major Craniofacial Surgery

To support safe and effective use of propofol in nonventilated children after major surgery, a model for propofol pharmacokinetics and pharmacodynamics is described. After craniofacial surgery, 22 of the 44 evaluated infants (aged 3-17 months) in the pediatric intensive care unit received propofol (2-4 mg . kg-1 . h-1) during a median of 12.5 h, based on the COMFORT-Behavior score. COMFORT-Behavior scores and Bispectral Index values were recorded simultaneously. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). In the two-compartment model, body weight (median, 8.9 kg) was a significant covariate. Typical values were Cl = 0.70 . (BW/8.9)0.61 l/min, Vc = 18.8 l, Q = 0.35 l/min, and Vss = 146 l. In infants who received no sedative, depth of sedation was a function of baseline, postanesthesia effect (Emax model), and circadian night rhythm. In agitated infants, depth of sedation was best described by baseline, postanesthesia effect, and propofol effect (Emax model). The propofol concentration at half maximum effect was 1.76 mg/l (coefficient of variation = 47%) for the COMFORT-Behavior scale and 3.71 mg/l (coefficient of variation = 145%) for the Bispectral Index. Propofol clearance is two times higher in nonventilated healthy children than reported in the literature for ventilated children and adults. Based on the model, the authors advise a propofol dose of 30 mg/h in a 10-kg infant to achieve values of 12-14 on the COMFORT-Behavior scale and 70-75 on the Bispectral Index during the night. Wide pharmacodynamic variability emphasizes the importance of dose titration.

The Performance of a Target-Controlled Infusion of Propofol in Combination with Remifentanil: A Clinical Investigation with Two Propofol Formulations

Target-controlled infusion (TCI) incorporates the pharmacokinetic variables of an IV drug to facilitate safe and reliable administration. In this clinical study we investigated the performance of propofol TCI in combination with remifentanil. Fifty-four adult patients scheduled for general surgery lasting longer than 1 h received a combined TCI of propofol (Marsh parameter set; propofol randomly either dissolved with long- or middle-/long-chain triglycerides) and remifentanil. Arterial propofol plasma concentrations and hemodynamic and derived electroencephalogram variables were determined at various stages before, during, and after surgery. Measured propofol plasma concentrations exceeded the predicted values by 59%, and 48% when recalculated with the Schnider parameter set. Pharmacokinetic population analysis showed a small central volume of distribution (3.55 L) and reduced clearance (1.31 L/min) for propofol. ASA status and sex were the only variables that had a significant influence on propofol pharmacokinetics. In a second step, a new pharmacokinetic variable set for propofol was determined in the first 27 patients. Post hoc performance analysis of the remaining 27 patients showed improved accuracy using the new variable set. Our results show that when remifentanil and propofol are combined, the Marsh and Schnider parameter sets systematically underestimate propofol plasma concentrations. Presented, in part, at the Annual Meeting of the European Society of Anesthesiologists, Amsterdam, The Netherlands, June 1, 1999, and the Annual Meeting of the American Society of Anesthesiologists, Dallas, Texas, October 12, 1999.

PIII-74Population pharmacokinetics of propofol in Korean populations

PIII-74Population pharmacokinetics of propofol in Korean populations

Changes in the effect of propofol in response to altered plasma protein binding during normothermic cardiopulmonary bypass

During normothermic cardiopulmonary bypass (CPB), the effect on propofol pharmacokinetics of changes in its binding to plasma proteins is consistent with the predictions of the well-stirred model of hepatic elimination for nonrestrictively cleared drug. However, whether changes in binding lead to clinically significant changes in the drug effect remains unclear. The purpose of this study was to assess changes in the drug effect of propofol in response to altered plasma binding using quantitative EEG measurements. Thirty patients undergoing cardiac surgery were assigned randomly to receive propofol infusions at 4 (Group P-4) or 6 (Group P-6) mg kg(-1) h(-1) during surgery. The concentration of propofol in blood samples, collected from the radial artery at predetermined intervals, was determined by HPLC. The unbound fraction of drug in plasma was estimated using equilibrium dialysis. Bispectral index (BIS) and burst suppression ratio (BSR) were measured at the time blood samples were collected. The total concentration of propofol in blood was unchanged during CPB relative to the pre-CPB value in both groups. However, the fraction of unbound propofol in blood increased by 2-fold during CPB. While BIS values were unchanged during CPB in Group P-4, there was a slight, but significant, decrease in Group P-6. In both groups, BSR significantly increased during CPB. BIS values showed a weak correlation with the concentration of unbound propofol (r(2)=0.19, P<0.001). BSR showed a moderate correlation with the concentration of unbound propofol (r(2)=0.56, P<0.001). The anaesthetic effect of propofol significantly increased during CPB without any alteration in the total drug concentration. The enhanced efficacy may be caused by a reduction in plasma binding of the drug.

Pharmacokinetics of a Single Bolus of Propofol in Chinese Children of Different Ages

There is no information about the pharmacokinetic profile of propofol in Chinese children younger than 3 yr. This study was designed to determine a complete pharmacokinetic profile of a single dose of propofol in Chinese children of different ages. Arterial blood samples were obtained from 35 children with an American Society of Anesthesiologist physical status of I or II at 2, 4, 6, 8, 10, 20, 30, 45, 60, 90, 120, and 180 min after a single bolus intravenous injection of propofol (3 mg/kg). The plasma concentrations of propofol were measured using high-performance liquid chromatography with an ultraviolet detector. A population model was used to estimate the pharmacokinetics of propofol. A three-compartment pharmacokinetic model best described the pharmacokinetics of propofol. Clearance was 0.185 l/min, the volume of distribution of the central compartment was 7.41 l, the peripheral volumes of distribution were 54.6 and 7.2 l, and the intercompartmental clearances were 0.614 and 0.692 l/min for a child of the average weight of 13.7 kg. The half-lives were 2.67, 14.89, and 310.60 min. Covariate models were applied, and weight was found to be significant covariate for the clearance and volume of distribution parameters. No significant age effect could be demonstrated on clearance or volume of distribution parameters after weight was taken into account. This study supports the case that the pharmacokinetic properties of propofol do not differ substantially across Chinese children of different ages after weight has been accounted for.

The Effect of Obesity on Awareness in General Anesthesia with Propofol

Background: Recently obesity population is epidemically rapidly increasing. But, in the anesthetic field the study for obesity patients is not good enough. So, we designed the study to see the effect of obesity on awareness in general anesthesia with propofol. Methods: The 52 subjects were between 20 to 60 years old and ASA physical status 1, 2 undergoing general anesthesia for elective surgery. According to asia pacific obesity criteria, we divided the patients into the obesity group (BMI 25) and the non-obesity group (BMI ＜ 25). Propofol was infused using TCI for induction and maintenance. BIS was used for monitoring the depth of anesthesia. During operation, we tried to keep BIS between 40-49 by manipulate the target concentration of TCI. After the operation, without stimulating patients, we measured the time (T-BIS) from the BIS passes 50 then goes to 70. We compare the T-BIS between the obesity and the non-obesity group. Results: The obesity and the non-obesity group do not show significant difference in age, sex, height, body temperature, anesthesia time, and total used propofol amounts. BMI in obesity group was 27.3 1.9 kg/m and in non-obesity group was 22.2 1.8 kg/m. T-BIS, the awareness time was significantly different between the obesity group (170.3 54.8 sec) and the non-obesity group (212.7 81.8 sec). Conclusions: Our data suggest that in general anesthesia with propofol the obesity group's awareness time is shorter compared with the non-obesity group and the effects may come from the uniqueness of the propofol's pharmacokinetics and the obesity patient's physical characteristics.

Enhanced Clearance of Propofol in Patients with Major Burns

Background: Major burns can alter the pharmacokinetics of the commonly used drugs during the perioperative period. This study was carried out to define the pharmacokinetics of propofol in the burned patients during the subacute hyperdynamic phase of the injury. Methods: Twenty adults, aged 43.7 2.3 years, with total body surface area burn of 44.0 22.2%, were examined at 14.1 2 days after the injury (mean SD). Age and sex gender matched unburned patients were used as controls. Propofol 2 mg/kg was given intravenously over 10 seconds as a single bolus in both groups. Blood samples (n = 20) were collectedat predetermined intervals. A noncompartmental approach was used for the pharmacokinetic analyses of the propofol concentrations, which were determined by HPLC. The cardiac index was measured by esophageal echocardiography. Results: The burns patients had a significantly higher cardiac index (CI). The clearance (Cl) and total volume of distribution (Vd) of propofol were higher in the burns patients, compared with the controls, yielding a smaller area under the curve. The total half-life (t1/2) was similar in both groups. Conclusions: There is a large increase in Vd and Cl in the burns patients compared to with the controls. The increased Cl in the burns patients is most likely to be related to the increased CI. Therefore, the initial bolus dose and maintenance infusion may have to be increased in the burns patients, provided the pharmacodynamic sensitivity is unaltered.

Changes in apparent systemic clearance of propofol during transplantation of living related donor liver

Propofol is used during living-related donor liver transplantation because its metabolism is not greatly affected by liver failure. However, the pharmacokinetics of propofol during liver transplantation have not been fully defined. The purpose of this study was to evaluate the apparent systemic clearance of propofol during the dissection, anhepatic and reperfusion phases of living-related donor liver transplantation, and to estimate the role of the small intestine and lung as extrahepatic sites for propofol disposition. Ten patients scheduled for living-related donor liver transplantation were enrolled in the study. Anaesthesia was induced with vecuronium 0.1 mg kg(-1) and propofol 2 mg kg(-1), and then maintained by 60% air, 0.5-1.5% isoflurane in oxygen and a constant infusion of propofol at 2 mg kg(-1) h(-1). Apparent systemic clearance during the dissection, anhepatic and reperfusion phases was calculated from the pseudo-steady-state concentration for each phase. Disposition in the small intestine was determined by measuring arteriovenous blood concentration in 10 liver transplantation donors. Pulmonary disposition was determined by measuring the arteriovenous blood concentration in 10 recipients during the anhepatic phase. The data are expressed as mean (sd). Apparent systemic clearances in the dissection, anhepatic and reperfusion phases were 1.89 (sd 0.48) litre min(-1), 1.08 (0.25) litre min(-1) and 1.53 (0.51) litre min(-1), respectively. The concentration of propofol in the portal vein was lower than in the radial artery. The intestinal extraction ratio calculated from the concentration in the radial artery and portal vein was 0.24 (0.12). There were no significant differences in propofol concentrations between the radial and pulmonary arteries. Apparent systemic clearance was decreased by approximately 42 (10)% during the anhepatic phase compared with the dissection phase. After reperfusion, liver allografts rapidly began to metabolize propofol. The small intestine also participates in the metabolism of propofol.

Influence of landiolol on the dose requirement of propofol for induction of anesthesia

It was reported that the pharmacokinetics of propofol was influenced by cardiac output (CO). The purpose of this study was to evaluate the effect of landiolol (short-acting beta-1-adrenergic blocker) on the dose requirement of propofol for induction of anesthesia. Forty patients were randomly allocated to the control and landiolol group. Induction of anesthesia commenced 10 min after the infusion of 0.9% saline or landiolol, using a Diprifusor set to achieve propofol plasma concentration of 6.0 microg/mL. Induction of anesthesia was defined as the first lack of response to command. Propofol dose was 2.22+/- 0.21 mg/kg for the control group and 1.79+/- 0.28 mg/kg for the landiolol group (P<0.0001). The quantity of propofol required for the induction of anesthesia was reduced by the administration of landiolol.

Effect of clonidine pre-medication on propofol requirements during lower extremity vascular surgery: a randomized controlled trial

Pre-medication with clonidine reduces the requirement for volatile agents during general anaesthesia. This may also be true for anaesthesia with propofol, but the amount of dose reduction has not been measured. Because clonidine also affects cardiac output and thus regional blood flow it could alter the pharmacokinetics of propofol. This randomized, double-blind placebo-controlled trial aimed to study the effect of clonidine pre-medication on dose requirement for propofol during lower extremity vascular surgery using the bispectral index (BIS) as a measure of anaesthetic depth. After oral pre-medication with either clonidine 3 microg kg(-1) or placebo, 39 subjects had lower limb vascular surgery using propofol infusion for anaesthesia. Anaesthetic depth was adjusted to a BIS of 45. Predicted plasma propofol concentrations were noted every 30 min from a target-controlled propofol infusion pump and arterial samples were taken at the same time for propofol measurements. Patients in both groups were anaesthetized to similar depths of anaesthesia as indicated by BIS readings (P=0.44). The groups had comparable mean (95% CI) arterial concentrations of propofol, 4.8 (3.5-6.1) microg ml(-1) in the patients given clonidine, and 4.6 (3.4-5.7) microg ml(-1) in the patients given placebo (P=0.81). However, the average plasma concentration predicted by the target-controlled infusion was less in the clonidine group [3.2 (2.9-3.5)] than in the group given placebo [3.6 (3.3-3.9)] microg ml(-1) (P<0.05). Pre-medication with clonidine reduces the requirement for propofol, which is a pharmacokinetic effect and not a pharmacodynamic central sedative effect.

Allometric relationships between the pharmacokinetics of propofol in rats, children and adults

Allometric equations have proven useful for the extrapolation of animal data to determine pharmacokinetic parameters in man. It has been proposed that these equations are also applicable over the human size range including the paediatric population. The aim of this work was to study the relationship between various pharmacokinetic parameters for propofol and body weight using data from rats, children and adults. Furthermore, the utility of allometric scaling is evaluated by the prediction of propofol concentrations in humans based on data obtained in the rat. The relationship between the pharmacokinetic parameters of propofol obtained in rats, children and adults was analyzed by plotting the logarithmically transformed parameters against the corresponding logarithmically transformed body weights. In addition, based on allometric equations, pharmacokinetic parameters obtained in rats were scaled to humans. These parameters were used to simulate propofol concentrations in long-term sedated critically ill patients using NONMEM. Simulated concentrations were then compared with actually observed concentrations in humans. The relationship between pharmacokinetic parameters of propofol from rats, children and adults was in good agreement with those from the literature on allometric modelling. For clearance, intercompartmental clearance, central volume of distribution and peripheral volume of distribution, the power parameters were 0.78, 0.73, 0.98 and 1.1, respectively, and r2 values for the linear correlations were 0.990, 0.983, 0.977 and 0.994, respectively. On the basis of data obtained after a single bolus injection in the rat, adequate predictions of propofol concentrations in critically ill patients can be made using allometric equations, despite the long-term nature of the use of the drug, the large number of infusion changes per day and/or differences in state of health and age. For propofol, allometric scaling has proved to be valuable for cross species extrapolation. Furthermore, the use of the allometric equation between adults and children seems to be an adequate tool for the development of rational dosing schemes for children of varying body weights, and requires further study.

The relationship between bispectral index and targeted propofol concentration is biphasic in patients with major burns

Many pathophysiologic alterations in major burns can cause changes in the distribution of, and perhaps response to, drugs commonly used in anesthesia practice. This study was conducted to assess changes in bispectral index (BIS) caused by increasing the target propofol effect-site concentration during a target-controlled infusion (TCI) in major burns. Eighteen patients, ASA physical status 2 or 3, aged from 20 to 55 years old, weighing 50-70 kg, with major burns, scheduled for elective early escharectomy less than a week after injury were recruited. A further 18 ASA physical status class 1 or 2, non-burns, age, sex- and weight-matched adult patients scheduled for elective surgery under general anesthesia were recruited as controls. During anesthesia induction, target propofol effect-site concentrations were increased by increments of 0.5 microg ml(-1) up to 4.5 microg ml(-1). The BIS responses to each target concentration using TCI were compared in both groups. In the burns group, significantly greater BIS values relating to increasing propofol TCI were noted at deeper anesthesia when compared with controls; at > or =3.5 microg ml(-1); mean BIS remained at a plateau of about 50. Patients with burns had higher cardiac indices, and lower hemoglobin and albumin concentrations than the controls. They consumed more vecuronium to maintain the same degree of neuromuscular blockade than the controls. In major burns, the final biphasic BIS responses appeared to be determined by numerous other variables such as BIS algorithm, TCI performance, and altered propofol pharmacokinetics and pharmacodynamics. According to our results the importance of an individually tailored approach, including careful anesthetic titration, based upon the patient's clinical condition and responses can not be overemphasized.

Influence of hemorrhagic shock followed by crystalloid resuscitation on propofol: a pharmacokinetic and pharmacodynamic analysis.

Previous work has demonstrated that ongoing hemorrhagic shock dramatically alters the distribution, clearance, and potency of propofol. Whether volume resuscitation after hemorrhagic shock restores drug behavior to baseline pharmacokinetics and pharmacodynamics remains unclear. This is particularly relevant because patients suffering from hemorrhagic shock are typically resuscitated before surgery. To investigate this, the authors studied the influence of an isobaric bleed followed by crystalloid resuscitation on the pharmacokinetics and pharmacodynamics of propofol in a swine model. The hypothesis was that hemorrhagic shock followed by resuscitation would not significantly alter the pharmacokinetics but would influence the pharmacodynamics of propofol. After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock-resuscitation groups. Swine randomized to the shock-resuscitation group were bled to a mean arterial blood pressure of 40 mm Hg over a 20-min period and held there by further blood removal until 42 ml/kg of blood had been removed. Subsequently, animals were resuscitated with lactated Ringer's solution to maintain a mean arterial blood pressure of 70 mm Hg for 60 min. After resuscitation, propofol (750 microg x kg(-1) x min(-1)) was infused for 10 min. The control group underwent a sham hemorrhage and resuscitation and received propofol at the same dose and approximate time as the shock-resuscitation group. Arterial samples (20 from each animal) were collected at frequent intervals until 180 min after the infusion began and were analyzed to determine drug concentrations. Pharmacokinetic parameters for each group were estimated using a three-compartment model. The electroencephalogram Bispectral Index Scale was used as a measure of drug effect. Pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. The raw data demonstrated minimal differences in the mean plasma propofol concentrations between groups. The compartment analysis revealed some subtle differences between groups in the central and slow equilibrating volumes, but the differences were not significant. Hemorrhagic shock followed by resuscitation shifted the concentration effect relationship to the left, demonstrating a 1.5-fold decrease in the effect-site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale. Hemorrhagic shock followed by resuscitation with lactated Ringer's solution did not alter the pharmacokinetics but did increase the potency of propofol. These results demonstrate that alterations in propofol pharmacokinetics observed in moderate to severe blood loss can be reversed with resuscitation. These results suggest that a modest reduction in propofol is prudent to achieve a desired drug effect after resuscitation from severe hemorrhagic shock.

Left Ventricular Function After Cardiopulmonary Bypass Is Related to the Length-Dependent Regulation of Myocardial Function: In Response

We thank Drs. de Hert and Van der Linden for their insightful comments on our article (1) and we would like to respond on some of the issues brought forward. The aim of our study was two-fold: first, to describe our approach to quantify perioperative LV function, and second, to obtain a reference data set for future studies in patients undergoing cardiac surgery. The comments of de Hert and Van der Linden focus on the latter aspect of our study. We fully agree that the published literature indicates a substantial variability in recovery of LV function after cardiopulmonary bypass, and we acknowledge the extensive list of possible factors influencing this variable outcome. In fact, this is exactly the reason why we felt it was necessary to generate a data set that would be applicable to the anesthetic and cardioprotective approach followed in our institute. Specifically, we use low-dose target-controlled infusion of propofol, remifentanil, and sufentanil, and intermittent antegrade warm-blood cardioplegic arrest during normothermic cardiopulmonary bypass. The metabolic advantages of this approach have already been published, but few data are available on the acute hemodynamic effects. Our study was performed in patients with relatively preserved LV function undergoing elective CABG, to ensure that the possible changes in LV function could be contributed mainly to the effects of anesthesia and cardioplegic arrest, rather than to the surgical intervention. This selection may partly explain the preserved postoperative systolic function in our patient group. However, de Hert et al. studied a similar patient group and reported a more variable outcome that could not be explained by preoperative LV function (2). Therefore, differences in anesthesia and cardioplegic approaches between our study and the studies by de Hert et al. may need to be considered. One such difference is the use of normothermic arrest with blood cardioplegia in our study, whereas the studies of de Hert et al. included the use of hypothermia and crystalloid cardioplegia. This may be important because recent studies indicate less myocardial cell damage after normothermic blood cardioplegia (3). Furthermore, the use of propofol in both studies may not be comparable, because hypothermia has an important influence on propofol pharmacokinetics (4). However, we certainly agree that extrapolation of our findings to patients with poor baseline LV function and prolonged cardiac arrest should be done with caution. But despite this, we would still conclude that the new data provided by our study constitute valuable background information when interpreting the acute hemodynamic effects of complex surgical interventions such as LV reconstruction in heart failure patients in whom the same anesthesia and cardioplegia approach is used. Sven A. F. Tulner Robert J. M. Klautz Gerda L. van Rijk-Zwikker Frank H. M. Engbers Jeroen J. Bax Jan Baan Ernst E. van der Wall Robert A. Dion Paul Steendijk

Changes in drug plasma concentrations of an extensively bound and highly extracted drug, propofol, in response to altered plasma binding

Cardiopulmonary bypass is known to result in a reduction in the plasma binding of drugs. The resulting effect on the hepatic clearance of drugs with low extraction is well understood. However, the situation with those that are highly extracted is less clear. Studies were, therefore, undertaken with one such drug, propofol, for which plasma binding was changed during cardiac surgery with cardiopulmonary bypass. After induction of anesthesia with midazolam in 19 patients, propofol was infused continuously at a rate of 4 mg. kg(-1). h(-1) during surgery. Propofol's concentration was measured by HPLC in blood samples collected from the radial artery and hepatic vein during surgery at predetermined intervals. The drug's unbound fraction in arterial plasma was estimated via equilibrium dialysis. The total concentration of propofol in blood was unchanged during surgery except shortly after the initiation of cardiopulmonary bypass. By contrast, the fraction of unbound propofol in blood increased by 2-fold during cardiopulmonary bypass and then decreased after the completion of cardiopulmonary bypass. The hepatic extraction ratio of propofol was greater than 0.8 and remained constant throughout surgery. The ratio of propofol concentration in erythrocytes to that in blood increased by 1.6-fold during cardiopulmonary bypass. During cardiopulmonary bypass, a significant increase in the concentration of unbound propofol occurred without alteration in the total propofol concentration in blood. The effect of the changes of propofol's protein binding on its kinetics was consistent with the predictions based on the well-stirred model of hepatic elimination for an intravenously infused high-clearance drug. Our finding on propofol pharmacokinetics may be the first example demonstrating the theoretic prediction of the well-stirred model.

Mixed-effects Modeling of the Intrinsic Ventilatory Depressant Potency of Propofol in the Non-steady State

Despite the ubiquitous use of propofol for anesthesia and conscious sedation and numerous publications about its effect, a pharmacodynamic model for propofol-induced ventilatory depression in the non-steady state has not been described. To investigate propofol-induced ventilatory depression in the clinically important range (at and below the metabolic hyperbola while carbon dioxide is accumulating because of drug-induced ventilatory depression), the authors applied indirect effect modeling to Paco2 data at a fraction of inspired carbon dioxide of 0 during and after administration of propofol. Ten volunteers underwent determination of their carbon dioxide responsiveness by a rebreathing design. The parameters of a power function were fitted to the end-expiratory carbon dioxide and minute ventilation data. The volunteers then received propofol in a stepwise ascending pattern with use of a target-controlled infusion pump until significant ventilatory depression occurred (end-tidal pressure of carbon dioxide > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 microg/ml. Propofol pharmacokinetics and the Paco2 were determined from frequent arterial blood samples. An indirect response model with Bayesian estimates of the pharmacokinetics and carbon dioxide responsiveness in the absence of drug was used to describe the Paco2 time course. Because propofol reduces oxygen requirements and carbon dioxide production, a correction factor for propofol-induced decreasing of carbon dioxide production was included. The following pharmacodynamic parameters were found to describe the time course of hypercapnia after administration of propofol (population mean and interindividual variability expressed as coefficients of variation): F (gain of the carbon dioxide response), 4.37 +/- 36.7%; ke0, CO2, 0.95 min-1 +/- 59.8%; baseline Paco2, 40.9 mmHg +/- 12.8%; baseline minute ventilation, 6.45 l/min +/- 36.3%; kel, CO2, 0.11 min-1 +/- 34.2%; C50,propofol, 1.33 microg/ml +/- 49.6%; gamma, 1.68 +/- 21.3%. Propofol at common clinical concentrations is a potent ventilatory depressant. An indirect response model accurately described the magnitude and time course of propofol-induced ventilatory depression. The indirect response model can be used to optimize propofol administration to reduce the risk of significant ventilatory depression.

Is it Safe to Use Target-Controlled Propofol Infusion with DiprifusorTM for Children of School Age?

Background: A commercially available target-controlled propofol infusion system, the is used for the induction and maintenance of anesthesia in adults, not in children because the pharmacokinetics of propofol in children. We wondered whether it is safe to use the in children weighing over 30 kg in clinical practice? Methods: Twenty unpremedicated children (8-15 yr, group 1) and sixty five unpremedicated adults (16-65 yr, group 2) scheduled for elective surgery were enrolled. After intravenous injection of fentanyl 1/kg, a propofol infusion was started at a target concentration of 4/ml using a ‘Diprifusor'TM. We recorded the time to loss of eyelash reflex and effect site concentration at the time of loss of consciousness. Anesthesia was maintained with propofol-fentanyl-50% N2O-rocuronium. We also checked the effect site concentration at the time of eye opening to verbal command. Results: The effect site concentrations at loss of eyelash reflex were 1.19 1 0.66/ml (group 1) and 0.96 0.55/ml (group 2), and these were not significantly different between the two groups. But the effect site concentrations at eye opening were 1.66 0.38/ml (group 1) and 1.47 0.32/ml (group 2) which were significantly different (P can be used safely in children weighing over 30 kg with a similar effect site concentration at loss of eyelash reflex as adults, but the effect site concentration at eye opening in children is slightly higher than that of adults.

Pharmacologic and technologic updates in office-based anesthesia practice

Several anesthetic agents including propofol and sevoflurane are relatively new arrivals to the office-based practice. The pharmacokinetics of propofol compare favorably to methohexital. If the latter returns to the marketplace, it can be mixed with propofol to incorporate the “best qualities” of both. The induction doses for both are similar whether for deep sedation or general anesthesia. If anything, higher doses of propofol are needed to accomplish the same clinical endpoint. Programmable pumps are available and an efficient method of delivering either propofol or a mixture of propofol/methohexital.

Propofol in paediatric anaesthesia

In this review we intend to ascertain trends in propofol administration for paediatric anaesthesia and sedation. Propofol is being 'discovered' by non-anaesthesiologist practitioners of paediatric sedation. However it appears that the drug is not infrequently administered alone for painful procedures, necessitating large doses that result in uncontrolled general anaesthesia with a high potential for adverse events. An elegant technique comprises small doses of short-acting opioid (e.g. fentanyl 1 mug/kg) with low-dose propofol infusion. This does not result in worsening of pre-existing right-to-left intracardiac shunts. The dilemma is to educate non-anaesthesiologists about propofol pharmacokinetics and pharmacodynamics and in particular about the advantages of combined drug therapy. A paediatric target-controlled system for propofol has undergone preliminary clinical evaluation and it is hoped that administration according to pharmacokinetic principles will refine administration to infants and children. Sporadic cases of the propofol infusion syndrome in patients receiving prolonged sedation in intensive care units continue to be reported (characterized by metabolic acidosis, rhabdomyolysis and myocardial failure). It appears that one mechanism may be a deficiency of mitochondrial oxidative processes possibly induced by a dialyzable substance, perhaps a propofol metabolite. Propofol has been used with some success in treating postoperative laryngospasm and for tracheal intubation without muscle relaxants. Propofol should be used with extreme caution for prolonged sedation in intensive care unit patients, at dose rates of below 5 mg/kg per h, while maintaining extreme vigilance for signs of developing propofol infusion syndrome. If used correctly propofol is a suitable drug for sedation outside the operating room.

Transplacental transfer of propofol in pregnant ewes

Propofol is an injectable anaesthetic that is currently used both in veterinary and human medicine for the induction and maintenance of anaesthesia. Although little is known about the pharmacokinetics of propofol in fetuses, it is widely used in obstetric procedures, particularly in caesarean section. This study determines the pharmacokinetics of propofol in pregnant ewes in the last third of pregnancy, and placental transfer and pharmacokinetics in fetuses after the administration of a 6 mg/kg intravenous (i.v.) bolus (phase 1) or a 6 mg/kg i.v. bolus followed by continued infusion of 0.4 mg/kg/min. In ewes, the area under the blood concentration–time curve (AUC) and C max (8.6 mg h/mL and 9.5 mg/mL, respectively) was higher than those of the fetus (1.6 mg h/mL and 1.19 mg/mL, respectively). The mean half-life was 0.5 h in the dam and 1.1 h in the fetus.