The influence of target concentration,equilibration rate constant (ke0) and pharmacokinetic model on the initial propofol dose delivered in effect‐site target‐controlled infusion

One advantage of effect‐site target‐controlled infusion is the administration of a larger initial dose of propofol to speed up the induction of anaesthesia. This dose is determined by the combination of the pharmacokinetic model parameters, the target setting and the blood‐effect time‐constant, k_e0. With the help of computer simulation, we determined the k_e0 values required to deliver a range of initial doses with three pharmacokinetic models for propofol. With an effect site target of 4 μg.ml^?1, in a 35‐year‐old, 170‐cm tall, 70‐kg male subject, the k_e0 values delivering a dose of 1.75 mg.kg^?1 with the Marsh, Schnider and Eleveld models were 0.59 min^?1, 0.20 min^?1 and 0.26 min^?1, respectively. These k_e0 values have the attractive feature that, when used to simulate the administration schemes used in two previous studies, predicted effect site concentrations at loss of consciousness were close to those required for maintenance of anaesthesia.     

Estimation of the plasma effect site equilibration rate constant (ke0) of propofol in children using the time to peak effect: comparison with adults

BACKGROUND: Targeting the effect site concentration may offer advantages over the traditional forms of administrating intravenous anesthetics. Because the lack of the plasma effect site equilibration rate constant (ke0) for propofol in children precludes the use of this technique in this population, the authors estimated the value of ke0 for propofol in children using the time to peak effect (tpeak) method and two pharmacokinetic models of propofol for children. METHODS:: The tpeak after a submaximal bolus dose of propofol was measured by means of the Alaris A-Line auditory evoked potential monitor (Danmeter A/S, Odense, Denmark) in 25 children (aged 3-11 yr) and 25 adults (aged 35-48 yr). Using tpeak and two previously validated sets of pharmacokinetic parameters for propofol in children, Kataria's and that used in the Paedfusor (Graseby Medical Ltd., Hertfordshire, United Kingdom), the ke0 was estimated according to a method recently published. RESULTS: The mean tpeak was 80 +/- 20 s in adults and 132 +/- 49 s in children (P < 0.001). The median ke0 in children was 0.41 min(-1) with the model of Kataria and 0.91 min(-1) with the Paedfusor model (P < 0.01). The corresponding t1/2 ke0 values, in minutes, were 1.7 and 0.8, respectively (P < 0.01). CONCLUSIONS:: Children have a significantly longer tpeak of propofol than adults. The values of ke0 of propofol calculated for children depend on the pharmacokinetic model used and also can only be used with the appropriate set of pharmacokinetic parameters to target effect site in this population.     

Induction of general anaesthesia by effect‐site target‐controlled infusion of propofol: influence of pharmacokinetic model and ke0 value

We studied the use of a new k_e0 value (0.6 min^?1) for the Marsh pharmacokinetic model for propofol. Speed of induction and side‐effects produced were compared with three other target‐controlled infusion systems. Eighty patients of ASA physical status 1–2 were studied in four groups in a prospective, randomised study. Median (IQR [range]) induction times were shorter with the Marsh model in effect‐site control mode with a k_e0 of either 0.6 min^?1 (81 (61–101 [49–302])s, p < 0.01), or 1.2 min^?1 (78 (68–208 [51–325])s, p < 0.05), than with the Marsh model in blood concentration control (132 (90–246 [57–435])). The Schnider model in effect‐site control produced induction times that were longer (298 (282–398 [58–513])s) than those observed with the Marsh model in blood control (p < 0.05), or either effect‐site control mode (p < 0.001). There were no differences in the magnitude of blood pressure changes or frequency of apnoea between groups.     

Estimation of the plasma effect-site equilibration rate constant (ke0) of rocuronium by the time of maximum effect: a comparison with non-parametric and parametric approaches

BACKGROUND: The first order plasma-effect-site equilibration rate constant (k(e0)) links the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. For the calculation of the k(e0), one method uses a single point of the response curve corresponding to the time to peak effect of a drug (t(peak)); however, it has not been validated. This study compares the k(e0) calculated with the method of t(peak) and the k(e0) calculated with traditional non-parametric and parametric methods. METHODS: Fifteen adult patients receiving total intravenous anaesthesia (TIVA) were studied. All patients were monitored with an NMT Monitor 221 (GE Healthcare, Helsinki, Finland) to obtain the evoked compound EMG of the adductor pollicis to a train-of-four stimuli at 10 s intervals. During TIVA, rocuronium 0.15 mg kg(-1) was given i.v. as a bolus, and the neuromuscular response was recorded until recovery from block. Using the t(peak) and the complete response curve, k(e0) of rocuronium was calculated with the three methods using the predicted plasma concentrations of rocuronium from a PK model. Values of k(e0) are median (range). RESULTS: The k(e0)s obtained were 0.19 min(-1) (0.09-0.72) with the 't(peak)' method, 0.20 min(-1) (0.14-0.44) with the non-parametric method, and 0.19 min(-1) (0.11-0.38) [typical value (range)] with the parametric method (NS). CONCLUSIONS: If the t(peak) can be adequately estimated from the data, the 't(peak) method' is a valid alternative to traditional methods to calculate the k(e0).     

A novel technique to determine an ‘apparent ke0’ value for use with the Marsh pharmacokinetic model for propofol

Debate continues over the most appropriate blood–brain equilibration rate constant (k_e0) for use with the Marsh pharmacokinetic model for propofol. We aimed to define the optimal k_e0 value. Sixty‐four patients were sedated with incremental increases in effect‐site target concentration of propofol while using six different k_e0 values within the range 0.2–1.2 min^?1. Depth of sedation was assessed by measuring visual reaction time. A median ‘apparent k_e0’ value of 0.61 min^?1 (95% CI 0.37–0.78 min^–1) led to the greatest probability of achieving a stable clinical effect when the effect‐site target was fixed at the effect‐site concentration displayed by the target‐controlled infusion system, at the time when a desired depth of sedation had been reached. By utilising a clinically relevant endpoint to derive this value, inter‐individual pharmacokinetic and pharmacodynamic variability may be accounted for.     

术前患者异丙酚血浆-效应室平衡速率常数的估测

目的采用峰效应时间法测定异丙酚的血浆-效应室平衡速率常数(Ke0)。方法拟在全身麻醉下择期手术的患者36例,ASAⅠ级,不用术前药,静脉注射异丙酚1.5 mg/kg后,用AAI A-Line听觉诱发电位监测仪测定从开始注射异丙酚至听觉诱发电位指数降至最低的时间(T_(PEAK)),用T_(PEAK)和Marsh、Shafer等报道的异丙酚药代动力学模型,按照Minto等提出的方法计算Ke0。结果T_(PEAK)为(142±62)s。Marsh模型相关的Ke0为0.626 min~(-1),Shafer模型相关的Ke0为0.914 min~(-1)(P＜0.01)；对应的t_(1/2)Ke0分别为1.107、0.759 min,模型间Ke0和t_(1/2)Ke0的差异有统计学意义(P＜0.01)。结论术前患者异丙酚Ke0与药代动力学模型有关,且与国外报道的结果不一致。     

靶控输注右美托咪定对丙泊酚致意识消失效应室半数有效浓度的影响

目的观察静脉靶控输注(target-controlled infusion,TCI)右美托咪定对丙泊酚致患者意识消失效应室半数有效浓度(Ce_(50))的影响。方法选择择期行喉罩全麻下手术患者64例,男28例,女36例,年龄20~60岁,ASAⅠ或Ⅱ级,随机分为四组:空白组(P组)、低浓度右美托咪定组(D1组)、中浓度右美托咪定组(D2组)和高浓度右美托咪定组(D3组),每组16例。麻醉诱导时分别以0、0.4、0.6和0.8ng/ml的血浆靶浓度靶控输注右美托咪定15min,然后以初始效应室靶浓度(Ce)1.0μg/ml靶控输注丙泊酚。每次待丙泊酚的效应室浓度与靶浓度平衡时以0.2μg/ml逐步升高丙泊酚的靶浓度,直至患者意识消失。观察和计算患者意识消失时丙泊酚的Ce50及其95%CI,观察麻醉诱导过程中不良反应情况。结果 P、D1、D2和D3组丙泊酚致意识消失Ce50及其95%CI分别为2.30(2.24~2.36)、1.92(1.87~1.96)、1.60(1.55~1.65)和1.41(1.35~1.45)μg/ml。丙泊酚致意识消失的效应室浓度与右美托咪定的血浆靶浓度呈负相关关系(r=-0.84,P0.01)。与P、D1和D2组比较,D3组心动过缓的发生率明显增加(P0.05)。结论随着右美托咪定血浆靶浓度的升高,丙泊酚致意识消失Ce_(50)逐渐降低。靶控输注右美托咪定0.4或0.6ng/ml能明显降低丙泊酚致意识消失Ce50,心动过缓发生率较低,适合辅助丙泊酚进行麻醉诱导。     

七氟烷最低肺泡有效浓度和异丙酚意识消失半数有效浓度麻醉下患者BIS值的比较

目的 比较七氟烷最低肺泡有效浓度(MAC)和异丙酚意识消失半数有效浓度(EC50)麻醉下患者的脑电双频谱指数(BIS)值.方法 择期手术患者60例,年龄18～60岁,ASA分级Ⅰ或Ⅱ级,体重为标准体重的80％～120％.采用随机数字表法,将患者随机分为七氟烷吸入麻醉组(Sev组)和异丙酚静脉麻醉组(Pro组),每组30例.Sev组采用Datex-Ohmeda麻醉机气体监测仪监测呼气末七氟烷浓度.静脉注射依托咪酯0.3 mg/kg、罗库溴铵1 mg/kg、瑞芬太尼0.2μg/kg诱导气管插管后行机械通气,12.5 min后Pro组TC1异丙酚,设置血浆靶浓度3.8 μg/ml,当效应室浓度达到异丙酚意识消失EC50 (2.2 μg/ml)、1.3 EC50(2.86μg/ml)、1.5 EC50(3.3μg/ml),呼气七氟烷浓度达到1.0 MAC、1.3 MAC、1.5 MAC时记录BIS值、MAP和HR.结果 与Sev组比较,Pro组1.3 MAC或1.3 EC50和1.5 MAC或1.5 EC50时HR升高(P＜0.05),各时点MAP差异无统计学意义(P＞0.05).与1.0 MAC或EC50时比较,2组1.3 MAC或1.3 EC50和1.5 MAC或1.5 EC50时BIS值降低(P＜0.05).组间比较各时点BIS值差异无统计学意义(P＞0.05).结论 七氟烷1.0、1.3、1.5 MAC和异丙酚1.0、1.3、1.5 EC50麻醉下BIS值无差别.     

The course of blood concentrations of propofol administered at a constant rate, combined with fentanyl

The blood concentration of propofol was studied in 14 ASA 1 informed patients, who were to undergo orthopaedic or plastic surgery lasting at least 90 min. Anaesthesia was induced with a 2 mg.kg-1 bolus of propofol together with 0.86 microgram.kg-1 fentanyl. This was followed by a constant rate infusion of propofol and fentanyl, 5 mg.kg-1.h-1 and 3 micrograms.kg-1.h-1 respectively. The mean duration of propofol infusion was 153 +/- 63 min, with extremes of 90 and 315 min. Propofol concentration was measured using gas phase chromatography on total arterial blood; the lower limit of detection was 0.05 mg.l-1. During the infusion, blood concentrations were found between 2 and 4 mg.l-1. It was 2.25 mg.l-1 at the fifth min; this was 80% of the concentration found at the 120th min. There was in fact no statistically significant difference between the values found at the 90th, 120th and 150th min. On stopping the infusion, the concentrations fell rapidly during the first 5 min, and then more slowly. By the 30th min, it had reached a value 4.5 times less than that at the end of the infusion. However, individual variations were found, which could explain delayed recovery. The calculated pharmacokinetic parameters were: elimination half-life = 41.7 +/- 20 min, clearance = 2.14 +/- 0.55 l.min-1 and equilibrium distribution volume = 43.4 +/- 15.2 l. These results are discussed. It is therefore possible to give propofol continuously at a constant rate without having any accumulative effect.     

Early pregnancy does not reduce the C(50) of propofol for loss of consciousness.

Requirements for inhaled anesthetics decrease during pregnancy. There are no published data, however, regarding propofol requirements in these patients. Because propofol is often used for induction of general anesthesia when surgery is necessary in early pregnancy, we investigated whether early pregnancy reduces the requirement of propofol for loss of consciousness using a computer-assisted target-controlled infusion (TCI). Propofol was administered using TCI to provide stable concentrations and to allow equilibration between blood and effect-site (central compartment) concentrations. Randomly selected target concentrations of propofol (1.5-4.5 microg/mL) were administered to both pregnant women (n = 36) who were scheduled for pregnancy termination and nonpregnant women (n = 36) who were scheduled for elective orthopedic or otorhinolaryngologic surgery. The median gestation of the pregnant women was 8 wk (range, 6-12 wk). Venous blood samples for analysis of the serum propofol concentration were taken at 3 min and 8 min after equilibration of the propofol concentration. After a 10-min equilibration period of the predetermined propofol blood concentration, a verbal command to open their eyes was given to the patients twice, accompanied by rubbing of their shoulders. Serum propofol concentrations at which 50% of the patients did not respond to verbal commands (C(50) for loss of consciousness) were determined by logistic regression. There was no significant difference in C(50) +/- SE of propofol for loss of consciousness between the Nonpregnant (2.1 +/- 0.2 microg/mL) and Pregnant (2.0 +/- 0.2 microg/mL) groups. These results indicate that early pregnancy does not decrease the concentration of propofol required for loss of consciousness. IMPLICATIONS: The C(50) of propofol for loss of consciousness in early pregnancy did not differ from that in nonpregnant women, indicating that there is no need to decrease the propofol concentration for loss of consciousness when inducing general anesthesia for termination of pregnancy.     

Effect-compartment equilibrium rate constant (k eo) for propofol during induction of anesthesia with a target-controlled infusion device

The effect-compartment concentration (C_e) of a drug at a specific pharmacodynamic endpoint should be independent of the rate of drug injection. We used this assumption to derive an effect-compartment equilibrium rate constant (k_eo) for propofol during induction of anesthesia, using a target controlled infusion device (Diprifusor). Eighteen unpremedicated patients were induced with a target blood propofol concentration of 5 μg · ml⁻¹ (group 1), while another 18 were induced with a target concentration of 6 μg · ml⁻¹ (group 2). The time at loss of the eyelash reflex was recorded. Computer simulation was used to derive the rate constant (k_eo) that resulted in the mean C_e at loss of the eyelash reflex in group 1 being equal to that in group 2. Using this population technique, we found the k_eo to be 0.57 min⁻¹. The mean (SD) effect compartment concentration at loss of the eyelash reflex was 2.39 (0.70) μg · ml⁻¹. This means that to achieve a desired C_e within 3 min of induction, the initial target blood concentration should be set at 1.67 times that of the desired C_e for 1 min, after which it should revert to the desired concentration.     

The pharmacokinetics and pharmacodynamics of propofol in a modified cyclodextrin formulation (Captisol) versus propofol in a lipid formulation (Diprivan): an electroencephalographic and hemodynamic study in a porcine model

The currently marketed propofol formulation has a number of undesirable properties that are in part a function of the lipid emulsion formulation, including pain on injection, serious allergic reactions, and the support of microbial growth. A modified cyclodextrin-based formulation of propofol (sulfobutyl ether-beta-cyclodextrin) has been developed that may mitigate some of these formulation-dependent problems. However, reformulation may alter propofol's pharmacologic behavior. Our aim in this study was to compare the pharmacokinetics and pharmacodynamics of propofol in the currently marketed lipid-based formulation with those of the novel cyclodextrin formulation. We hypothesized that the pharmacokinetics and pharmacodynamics of the propofol in cyclodextrin would be substantially similar to those of the propofol in lipid. Thirty-two isoflurane-anesthetized animals were instrumented with pulmonary artery, arterial, and IV catheters and were randomly assigned to receive either propofol in lipid or propofol in cyclodextrin by continuous infusion. Arterial blood samples for propofol assay were collected. The processed electroencephalogram, heart rate, mean arterial blood pressure, and cardiac output were measured continuously. The propofol formulations were compared by using model-independent analysis techniques. Combined kinetic/dynamic models were also constructed for simulation purposes. There were no significant differences in the pharmacokinetics or pharmacodynamics of the two propofol formulations. The simulations based on the combined pharmacokinetic/pharmacodynamic models confirmed the substantial similarity of the two formulations. The hypothesis that the propofol-in-cyclodextrin formulation would exhibit pharmacokinetic and pharmacodynamic behavior that was substantially similar to the propofol-in-lipid formulation was confirmed. IMPLICATIONS: A modified cyclodextrin-based formulation of propofol has been developed that may mitigate some of the problems associated with propofol in lipid emulsion. However, reformulation of propofol may change its clinical characteristics. This study in a pig model showed that the novel propofol formulation was substantially similar to the lipid emulsion propofol formulation.     

BI‐RADS 3 (short‐interval follow‐up) assessment rate at diagnostic mammography: Correlation with recall rates and utilization as a performance benchmark

The purpose of this study was to identify a correlation between the screening BI‐RADS 0 (recall) rates and diagnostic BI‐RADS 3 (short‐interval follow‐up) rates of individual interpreting radiologists, with the goal of utilizing the BI‐RADS 3 rate as an acceptable performance metric in the diagnostic population. A multicenter retrospective analysis of medical audit statistics was conducted on annual radiologist performance data collected over a 14‐year period in a community hospital‐based practice. Mixed regression models were used to estimate the association between screening BI‐RADS 0 and diagnostic BI‐RADS 3 examinations while adjusting for calendar year, annual radiologist screening volume, annual radiologist diagnostic volume, and diagnostic examination indication. A moderate statistically significant positive correlation was established between the screening BI‐RADS 0 rates and Diagnostic BI‐RADS 3 rates (Pearson correlation coefficient + 0.349, P ≤ .001). Furthermore, when utilizing a national benchmark range of 8%‐12% as an acceptable BI‐RADS 0 rate within a screening population, the correlative BI‐RADS 3 assessment rate was demonstrated to be approximately 16%. We propose that this BI‐RADS category 3 rate may represent an additional acceptable performance metric in the diagnostic population. Routine inclusion of an interpreting mammographer's diagnostic BI‐RADS 3 rate in the annual medical audit may help reduce inappropriate and/or excess use of the BI‐RADS 3 category, which may lead to significant potential reductions in follow‐up examinations with their associated healthcare‐related costs, resource expenditure, and induced patient anxiety.     

Rosiglitazone modulates the behaviors of diabetic host‐derived fibroblasts in a carboxymethyllysine‐modified collagen model

Utilizing a three‐dimensional in vitro glycated collagen model, we evaluated the therapeutic effects of a peroxisome proliferator‐activated receptor‐γ ligand, rosiglitazone, and its potential as a topical treatment of diabetic chronic wounds. Rosiglitazone induced fibroblast migration, α‐smooth muscle actin production, and transformation into myofibroblasts in the presence of advanced glycation end products. Both transforming growth factor β and peroxisome proliferator‐activated receptor‐γ expression were induced, while the receptor for advanced glycation end products was suppressed. Lastly, the reduced activities of matrix metalloproteinase‐2 and matrix metalloproteinases‐9 in the carboxymethyllysine‐modified collagen matrices by rosiglitazone increases extracellular matrix deposition. Our findings identify rosiglitazone as a candidate for localized topical treatment of diabetic chronic wounds.     

Modeling graft loss in patients with donor‐specific antibody at baseline using the Birmingham‐Mayo (BirMay) predictor: Implications for clinical trials

Predicting which renal allografts will fail and the likely cause of failure is important in clinical trial design to either enrich patient populations to be or as surrogate efficacy endpoints for trials aimed at improving long‐term graft survival. This study tests our previous Birmingham‐Mayo model (termed the BirMay Predictor) developed in a low‐risk kidney transplant population in order to predict the outcome of patients with donor specific alloantibody (DSA) at the time of transplantation and identify new factors to improve graft loss prediction in DSA+ patients. We wanted define ways to enrich the population for future therapeutic intervention trials. The discovery set included 147 patients from Mayo Cohort and the validation set included 111 patients from the Paris Cohort—all of whom had DSA at the time of transplantation. The BirMay predictor performed well predicting 5‐year outcome well in DSA+ patients (Mayo C statistic = 0.784 and Paris C statistic = 0.860). Developing a new model did not improve on this performance. A high negative predictive value of greater than 90% in both cohorts excluded allografts not destined to fail within 5 years. We conclude that graft‐survival models including histology predict graft loss well, both in DSA+ cohorts as well as DSA‐ patients.