Pharmacokinetics Of Sufentanil Research Articles

Population pharmacokinetic modeling of sufentanil in adult Korean patients undergoing cardiopulmonary bypass surgery.

Sufentanil is frequently used as an anesthetic agent in cardiac surgery owing to its cardiovascular safety and favorable pharmacokinetics. However, the pharmacokinetics profiles of sufentanil in patients undergoing cardiopulmonary bypass (CPB) surgery remain less understood, which is crucial for achieving the desired level of anesthesia and mitigating surgical complications. Therefore, this study aimed to develop a population pharmacokinetic model of sufentanil in patients undergoing CPB surgery and elucidate the clinical factors affecting its pharmacokinetic profile. Adult patients who underwent cardiac surgery with CPB and were administered sufentanil for anesthesia were enrolled. Arterial blood samples were collected to quantify plasma concentrations of sufentanil and clinical laboratory parameters, including inflammatory cytokines. A population pharmacokinetic model was established using nonlinear mixed-effects modeling. Simulations were performed using the pharmacokinetic parameters of the final model. Overall, 20 patients were included in the final analysis. Sufentanil pharmacokinetics were modeled using a two-compartment model, accounting for CPB effects. Sufentanil clearance increased 2.80-fold during CPB and warming phases, while the central compartment volume increased 2.74-fold during CPB. CPB was a significant covariate affecting drug clearance and distribution volume. No other significant covariates were identified despite increased levels of the inflammatory cytokines, including IL-6, IL-8, and TNF-α during CPB. The simulation indicated a 30 μg loading dose and 40 μg/h maintenance infusion for target-controlled infusion. Additionally, a bolus dose of 60 μg was added at CPB initiation to adjust for exposure changes during this phase. Considering the target sufentanil concentrations, a uniform dosing regimen was acceptable for effective analgesia.

The use of population modeling to optimize dosing of drugs used in anaesthesiology and intensive care

Effective pharmacotherapy requires an adequate drug dose that maximizes the effectiveness of therapy while minimizing adverse effects. Difficulties in dose selection arise from interindividual differences in drug pharmacokinetics and pharmacodynamics. Population modeling describes pharmacokinetic and pharmacodynamic processes in a population, taking into account the relationships in each patient, differences between patients, and the influence of covariates on drug pharmacokinetics and pharmacodynamics. The aim of this study was to develop population models for drugs used in anesthesiology and intensive care in special patient populations. The pharmacokinetics of sufentanil was described in infants and children after epidural and intravenous administration. The estimated absorption rate constant from the epidural space suggests slow systemic absorption of sufentanil and the possibility of flip-flop kinetics, which results in a slower decline in plasma concentrations at the end of drug administration compared with intravenous administration. The dependence of metabolic clearance on body weight and age was also demonstrated. A population model for the pharmacokinetics of tigecycline was developed for patients with sepsis or septic shock. No relationship between pharmacokinetic parameters and patient characteristics was detected, and the estimated interindividual and inter-occasion variability for clearance was small. This suggests that a universal dose is sufficient to achieve homogeneous drug exposure in critically ill patients. The pharmacokinetics of caspofungin was described in critically ill patients. The clearance and volume of central compartment showed systematic increase over time that was not explained by the covariates. The estimated increase in clearance values for three consecutive doses results in a clinically relevant reduction in drug exposure. The developed population models extend the knowledge of the pharmacokinetics of sufentanyl, tigecycline, and caspofungin. Simulations based on these models can aid the dosing decision-making process.

Population pharmacokinetics of intravenous sufentanil in critically ill patients supported with extracorporeal membrane oxygenation therapy

BackgroundSufentanil is commonly used for analgesia and sedation during extracorporeal membrane oxygenation (ECMO). Both ECMO and the pathophysiological changes derived from critical illness have significant effects on the pharmacokinetics (PK) of drugs, yet reports of ECMO and sufentanil PK are scarce. Here, we aimed to develop a population PK model of sufentanil in ECMO patients and to suggest dosing recommendations.MethodsThis prospective cohort PK study included 20 patients who received sufentanil during venoarterial ECMO (VA-ECMO). Blood samples were collected for 96 h during infusion and 72 h after cessation of sufentanil. A population PK model was developed using nonlinear mixed effects modelling. Monte Carlo simulations were performed using the final PK parameters with two typical doses.ResultsA two-compartment model best described the PK of sufentanil. In our final model, increased volume of distribution and decreased values for clearance were reported compared with previous PK data from non-ECMO patients. Covariate analysis showed that body temperature and total plasma protein level correlated positively with systemic clearance (CL) and peripheral volume of distribution (V2), respectively, and improved the model. The parameter estimates of the final model were as follows: CL = 37.8 × EXP (0.207 × (temperature − 36.9)) L h−1, central volume of distribution (V1) = 229 L, V2 = 1640 × (total plasma protein/4.5)2.46 L, and intercompartmental clearance (Q) = 41 L h−1. Based on Monte Carlo simulation results, an infusion of 17.5 μg h−1 seems to reach target sufentanil concentration (0.3–0.6 μg L−1) in most ECMO patients except hypothermic patients (33 °C). In hypothermic patients, over-sedation, which could induce respiratory depression, needs to be monitored especially when their total plasma protein level is low.ConclusionsThis is the first report on a population PK model of sufentanil in ECMO patients. Our results suggest that close monitoring of the body temperature and total plasma protein level is crucial in ECMO patients who receive sufentanil to provide effective analgesia and sedation and promote recovery.Trial registrationClinicaltrials.gov NCT02581280, December 1st, 2014.

Influence of Cardiac Output on the Pharmacokinetics of Sufentanil in Anesthetized Pigs.

Sufentanil is used for general anesthesia and analgesia. The study aim was to determine the effect of pharmacologically induced changes in cardiac output on the pharmacokinetics of sufentanil in anesthetized pigs. Twenty-four pigs were randomly assigned to low, high, and control cardiac output groups. Cardiac output was decreased or increased from baseline by at least 40%, or maintained within ± 10% of baseline, respectively. Sufentanil was administered as a bolus followed by a continuous infusion for 120 min. Timed arterial samples were drawn for sufentanil concentration measurements. Data from 20 animals were analyzed. The cardiac outputs (means ± SD) were 2.9 ± 0.7, 5.4 ± 0.7, and 9.6 ± 1.6 l/min in the low, control, and high cardiac output groups, respectively. The parameters of the two-compartment pharmacokinetic model for these cardiac outputs were: CL1: 0.9, 1.2, and 1.7 l/min; CL2: 0.9, 3.1, and 6.9 l/min; V1: 1.6, 2.9, and 5.2 l; and V2: 27.5, 47.0, and 79.8 l, respectively. Simulated sufentanil doses to maintain a target plasma concentration of 0.5 ng/ml for 3 h were 99.5, 128.6, and 157.6 μg for cardiac outputs of 3, 5, and 7 l/min, respectively. The context-sensitive half-times for these cardiac outputs increased from 3.1 to 19.9 and 25.9 min, respectively. Cardiac output influences the pharmacokinetics of sufentanil. Simulations suggest that in the case of increased cardiac output, the dose should be increased to avoid inadequate drug effect at the expense of prolonged recovery, whereas for low cardiac output the dose should be reduced, and a faster recovery may be expected.

Pharmacokinetics of sufentanil during long-term infusion in critically ill pediatric patients.

The aim of this study was to develop a population pharmacokinetic model of sufentanil and to assess the influence of covariates in critically ill children admitted to a pediatric intensive care unit. After institutional approval, 41 children were enrolled in the study. Blood samples for pharmacokinetic (PK) assessment were collected from routinely placed arterial catheters during and after discontinuation of infusion. Population nonlinear mixed-effects modeling was performed using NONMEM. A 2-compartment model described sufentanil PK sufficiently. Typical values of the central and peripheral volume of distribution and the metabolic and intercompartmental clearance for a theoretical patient weighing 70 kg were VC = 7.90 l, VT = 481 L, Cl = 5.3 L/h, and Q = 38.3 L/h, respectively. High interindividual variability of all PK parameters was noted. Allometric/isometric principles to scale sufentanil PK revealed that to achieve the same steady-state sufentanil concentrations in plasma for pediatric patients of different body weights, the infusion rate should follow the formula (infusion rate for a 70-kg adult patient, μg/h) × (body weight/70 kg)(0.75). Severity of illness described by PRISM score, the monitored physiological and laboratory parameters, and coadministered drugs such as vasopressors were not found to be significant covariates.

Pharmacokinetics of sufentanil administered with 0.2% ropivacaine as a continuous epidural infusion for postoperative pain relief in infants.

Our objective was to assess plasma sufentanil concentrations and postinfusion pharmacokinetics in infants receiving 0.2% ropivacaine with sufentanil as a continuous epidural infusion for postoperative pain relief. With consent of local ethics committee and informed parental consent, 20 infants 3-36months old (m.o.) (median 9.3m.o., 9.0 [3.5-15] kg, ASA PS I/II) were enrolled. Epidural catheter was placed under general anesthesia in L3-L4, L4-L5, or L2-L3 interspace and threaded not farther than 4cm into epidural space. After initial bolus of 0.2% ropivacaine, 0.5ml·kg(-1) and sufentanil 200ng·kg(-1) , continuous infusion of 0.2% ropivacaine, 0.3mg·kg(-1) ·h(-1) with sufentanil 112ng·kg(-1) ·h(-1) was started. For the postoperative period, sufentanil dose was reduced to 37ng·kg(-1) ·h(-1) . Blood samples were drawn at the end of surgery, 24h later, by the end of 2nd day of infusion and after 3, 6, and 18h from the end of infusion. Sufentanil was measured using liquid-liquid extraction (LLE) procedure and HPLC-MS/MS method with LOQ=5pg·ml(-1) . Elimination of sufentanil following epidural administration was very slow, with MRT=28.25 [18.36-44.75] h and t1/2 MRT =19.57 [12.72-31.01] h. In infants, during a long-term infusion of sufentanil with ropivacaine, the opioid concentration in plasma increases during the postoperative infusion itself, then increases even further after discontinuation of the infusion, in some cases reaching the values consistent with a potential risk of respiratory depression. Meticulous monitoring of the infants' vital signs is therefore mandatory not only during the infusion, but also for several hours after its discontinuation.

Pharmacokinetics of Sublingual Sufentanil Tablets and Efficacy and Safety in the Management of Postoperative Pain

A sublingual sufentanil tablet is being developed as a potential alternative to intravenous (IV) opioids for the management of postoperative pain. The objective of these studies was to evaluate the pharmacokinetics, efficacy, and safety of sublingual sufentanil tablets for postoperative pain management. The pharmacokinetics of sublingual sufentanil 10 and 80 µg were compared with IV sufentanil in 12 subjects in a phase 1 study. The safety and efficacy of sublingual sufentanil (5-15 µg) were evaluated in double-blind, randomized, placebo-controlled phase 2 studies in patients undergoing knee replacement surgery (n = 101) or open abdominal (ABD) surgery (n = 94). The primary efficacy measurement was the summed pain intensity difference compared with baseline over 12 hours (SPID-12). Sublingual sufentanil pharmacokinetics were dose proportional following single doses of 10 and 80 µg. Plasma half-time (time from peak plasma concentration to 50% of peak concentration) was 80 to 90 minutes for sublingual sufentanil compared with 15 minutes or less for IV sufentanil. In the phase 2 studies, greater SPID-12 scores (ie, lower pain intensity) compared with placebo were observed for sublingual sufentanil 15 µg in the knee replacement study (P < 0.05) and for 10 and 15 µg in the ABD study (P < 0.01). All doses of sublingual sufentanil were well tolerated, and the incidence of adverse events was similar between the sublingual sufentanil and placebo groups. Sufentanil formulated as a sublingual solid dosage form provides a duration of action that allows effective analgesia for postoperative patients in a medically supervised setting.

Changes in total and unbound concentrations of sufentanil during target controlled infusion for cardiac surgery with cardiopulmonary bypass

Target controlled infusion (TCI) with sufentanil is usually performed using the Gepts model, which was derived from patients undergoing general surgery. It is, however, known that pharmacokinetics of sufentanil can be changed during cardiopulmonary bypass (CPB). We tested whether TCI during coronary artery bypass surgery with CPB produces constant total, unbound sufentanil concentration-time course or both. After IRB approval, written informed consent was obtained from 38 male patients (48-74 yr) undergoing coronary artery bypass surgery. Anaesthesia was managed with propofol and TCI of sufentanil, using the Gepts model, targeting plasma concentrations of 0.4 (n=18) or 0.8 ng ml(-1) (n=20). Arterial blood samples were taken before, during, and after CPB. Total and unbound sufentanil concentrations were measured by HPLC with tandem mass spectrometry. The accuracy of the TCI model was assessed by the prediction error, and a pharmacokinetic model was determined by population analysis. The median prediction error of the TCI with the Gepts model before, during, and after CPB was 59.6, 3.9, and -10.4%, respectively. The unbound sufentanil concentrations increased significantly during CPB. Pharmacokinetic modelling showed an increase in elimination and intercompartmental clearance after initiation of CPB. Neither total nor unbound sufentanil concentrations remained constant when performing a TCI with the Gepts model in coronary artery bypass surgery with CPB. A pharmacokinetic model derived from patients undergoing cardiac surgery with CPB might improve the performance of TCI in this population.

Sufentanil pharmacokinetics during coronary artery bypass surgery: the impact of changes in protein binding during cardiopulmonary bypass

Sufentanil pharmacokinetics during coronary artery bypass surgery: the impact of changes in protein binding during cardiopulmonary bypass

Effect of different ages on sufentanil pharmacokinetics in patients undergoing cardiac valve replacement

Objective To assess the effect of different ages on sufentanil pharmacokinetics in patients undergoing cardiac valve replacement.Methods Sixteen NYHA Ⅱ or Ⅲ patients undergoing selective cardiac valve replacement were randomly divided into two groups:elderly group (aged 65-69 years,group Ⅰ,n =8) and young adult group (aged 36-45 years,group Ⅱ,n =8).Intravenous and intra-arterial cannulae were placed.Sufentanil 5 μg/kg injected intravenously during anesthesia induction.Blood samples from the radial artery were obtained at 1,3,5,10,20,30,60,120,180,240 and 360 min after sufentanil injection (3 ml each).Then 1 ml plasma was immediately separated from the 3 ml blood sample and stored at - 80 ℃ until being assayed.Plasma sufentanil concentration was determined with liquid chromatography mass spectrometry and pharmacokinetic parameters were calculated with 3P97 pharmacologicl program.Results Plasma sufentanil concentration versus the time decay curve in patients undergoing cardiac valve replacement before cardiopulmonary bypass (CPB) was fitted to a twocompartment model and could be expressed by bi-exponential equations:Cp (t) =27.4 e-0.41t + 3.2 e-0.029t in group Ⅰ and Cp (t) =14.4 e-0.51t +3.4 e-0.032t in group Ⅱ,respectively.There were significant differences in t 1/2 α,t1/2 β and CL between the two groups ( P ＜ 0.05 or 0.0l ).During CPB,plasma sufentanil concentration versus the time decay curve in patients undergoing cardiac valve replacement was fitted to a three-compartment model and could be expressed by tri-exponential equations:Cp(t) =22 e-0.51t + 3.5 e-0.045t + 0.21 e-0.0029 t in group Ⅰand Cp(t) =15 e-0.52t + 3.9 e-0.048t + 0.32 e-0.004t in group Ⅱ,respectively.There were no significant differences in pharmacokinetic parameters between the two groups ( P ＞ 0.05).Conclusion There are significant differences in sufentanil phannacokinetic characteristics before CPB but different ages have no obvious influence on sufentanil pharmaco-kinetics during CPB. Key words: Age factors; Sufentanil; Heart valve prosthesis; Pharmacokinetics

Sufentanil for chronic pain management

Sufentanil is a highly potent synthetic opioid that is approximately 1000-fold more potent than morphine and up to tenfold more potent than fentanyl. It is most commonly used by anesthesiologists to provide intraoperative analgesia. Although sufentanil is not yet approved for chronic pain management, it is being explored for chronic pain therapy. Owing to its physical properties, high potency, high lipid solubility, high therapeutic index and short duration of action, sufentanil has the potential to provide effective analgesia via multiple routes of administration. The superior pharmacokinetics of sufentanil make it ideal for treatment of breakthrough pain via the sublingual/buccal and nasal routes. Similarly, the transdermal route of sufentanil administration should provide analgesia for a prolonged period. The adverse effects of sufentanil are similar to those of other opioids that are commonly used for chronic pain management (e.g., fentanyl and morphine). Future research is necessary to define the role of sufentanil in the treatment of chronic pain.

Pharmacokinetics of sufentanil administered by target-controlled infusion in Chinese surgical patients

Background Target-controlled infusion (TCI) has been recently developed and successfully implemented in clinical practice. This study was conducted to determine the pharmacokinetics of TCI administered sufentanil in Chinese surgical patients. Methods The pharmacokinetics of sufentanil was investigated in 12 adult patients, aged 23–76 years, scheduled for prolonged surgery under general anesthesia. Anesthetic induction was carried out with propofol, rocuronium and TCI administered sufentanil aiming for target effect-site concentration of sufentanil 4 or 6 ng/ml. Sufentanil TCI lasted for 30 minutes. Frequent arterial blood samples (1.5 ml) were drawn during and up to 24 hours after sufentanil TCI. Plasma sufentanil concentrations were measured by liquid chromatography-tandem mass spectrometry; limit of sensitivity of mass spectrometry was 5 pg/ml. The data were analyzed with the nonlinear mixed-effect model program. Results The pharmacokinetics of TCI administered sufentanil were optimally described by a three-compartment model with the following parameters: the central volume of distribution (V1) = 5.4 L, the volume of distribution at steady-state (Vdss) = 195.4 L, systemic clearance (Cl1) = 1.10 L/min, and elimination half-life (t1/2 γ) = 271.8 minutes. Both age and gender affected the pharmacokinetic parameters. The rapid distribution clearance (Cl2) was negatively correlated with patient age, and the volume of slowly equilibrating compartment (V3) was positively correlated with age. The Cl2 and the volume of rapidly equilibrating compartment (V2) were influenced by gender with male patients showing higher values of Cl2 and V2 than female patients. There was no relationship of body weight, lean body mass, plasma albumin, or target effect-site concentration of sufentanil with any of the pharmacokinetic parameters studied. Conclusions The pharmacokinetics of TCI administered sufentanil in Chinese patients can be adequately described by a three-compartment model. Pharmacokinetics adjusted to the individual patient should improve the accuracy of TCI systems.

Effects of cardiopulmonary bypass on sufentanil pharmacokinetics in patients undergoing coronary artery bypass surgery.

Complete pharmacokinetic modeling, including assessment of the effect of cardiopulmonary bypass (CPB) on sufentanil disposition, has not been reported. The aims of this investigation were to define a model that accurately predicted sufentanil concentrations during and after cardiac surgery and to determine if CPB had a clinically significant impact on sufentanil pharmacokinetics. Population pharmacokinetic modeling was applied to data from 21 patients undergoing coronary artery bypass grafting. The predictive ability of models was assessed by calculating bias, accuracy, and measured:predicted concentration ratios versus time. A simple three-compartment model, without covariates, was initially compared with models having weight or gender as covariates and was subsequently used as the foundation for multiple CPB-adjusted models (allowing step-changes of parameters at the start or end of CPB). The primary criterion for choosing more complex models was a significant improvement in log-likelihood; secondary criteria were significant improvement in bias or accuracy. Neither covariate (weight or gender) models improved bias or accuracy compared with the simple three-compartment model. A final CPB-adjusted model with V2 and Cl3 changing at the start of CPB and V1, Cl2, and Cl3 changing at the end of CPB had significantly greater log-likelihood values when compared with the simple three-compartment model and with less elaborate CPB-adjusted models. However, bias and accuracy for this final model were not significantly different from the simple three-compartment model. When sufentanil is infused at a constant rate, with initiation of CPB, a pharmacokinetic model adjusted for CPB predicts that the sufentanil concentration will decrease approximately 17% and that it will begin to return to the prebypass concentration 12 min after initiation of CPB. At the end of CPB, this model also predicts a brief spike of the sufentanil concentration. These predictions reflect changes in the measured sufentanil concentrations. However, compared with a simple, three-compartment model, incorporating step-changes of pharmacokinetic parameters at the start or end of cardiopulmonary bypass (or both) did not significantly improve overall perioperative prediction of measured sufentanil concentrations. This suggests that CPB has clinically insignificant effects on sufentanil kinetics in adults.

Pilot study on the effect of tourniquet use on sufentanil pharmacokinetics

Study objective To test our hypothesis that sequestration of sufentanil can occur during surgery when a pneumatic tourniquet is used. Design Prospective, randomized study. Setting Operating room and recovery room of a university hospital. Patients 16 ASA physical status I and II patients scheduled for orthopedic surgery with pneumatic tourniquet use. Intervention Patients were randomized to three groups. Sufentanil was given intravenously at 0.5 μg kg −1 bolus at the same time that a constant infusion was started at 0.5 μg kg h −1. In Group 1, continuous infusion of sufentanil was stopped when the tourniquet was released (n = 6). In Group 2, continuous infusion of sufentanil was stopped 15 minutes after tourniquet release (n = 6). In Group 3, as a control group, the sufentanil bolus was started after tourniquet inflation (n = 4). Measurements Plasma sufentanil concentrations were determined by radioimmunoassay. To compare pharmacokinetic results, a simulation of the sufentanil plasma concentrations was achieved. Main results Exsanguination and inflation of the pneumatic tourniquet had no significant effect on pharmacokinetic results. In 75% of patients, a significant increase in sufentanil plasma concentration occurred between 30 and 60 minutes after tourniquet deflation in all three groups, probably as a result of patient mobilization. One respiratory distress event occurred in a Group 2 patient following extubation at 55 minutes after the end of the sufentanil infusion. The rebound of sufentanil concentration was higher in Group 2; it may be due to a reduced effect of the restoring circulation in the ischemic leg by a prolonged infusion after tourniquet deflation. Conclusions Using a pneumatic tourniquet induces transient changes in the pharmacokinetics of sufentanil. These changes may have clinical relevance during the first hour after tourniquet release.

Pharmacokinetics of sufentanil in patients undergoing coronary artery bypass graft surgery

Objective: To determine the pharmacokinetics of sufentanil in patients undergoing coronary artery bypass graft surgery. Design: Prospective, multigroup study. Setting: University-affiliated hospital. Participants: Patients with good left ventricular function undergoing elective surgery (n = 103). Interventions: Sufentanil was administered by target-controlled infusion, with target effect-site concentrations ranging from 0.4 to 4.5 ng/mL. Isoflurane was administered as required to maintain stable hemodynamics. Sufentanil pharmacokinetics were determined by population modeling. The potential effects of gender, weight, different premedications (lorazepam, morphine-scopolamine, or clonidine), and coinduction with propofol on sufentanil pharmacokinetics were explored. Measurements and Main Results: The first model determined was a simple 3-compartment model, without any covariates, which had these parameters: V1 = 5.7 L, V2 = 18.1 L, V3 = 225 L, Cl1 = 0.69 L/min, Cl2 = 3.1 L/min, and Cl3 = 1.4 L/min. The overall predictive ability during the entire pre–cardiopulmonary bypass period of this model was excellent, with virtually no bias (median prediction error, −0.4%) and good precision (median absolute prediction error, 18.4%). More complex models with the various premedications used or coinduction with propofol as covariates did not improve the predictive accuracy or precision compared with the simple 3-compartment model. Similarly, including either gender or weight as a covariate did not improve predictive ability. Conclusion: The authors have determined a pharmacokinetic model for sufentanil that can be used to maintain desired target concentrations of sufentanil before cardiopulmonary bypass, with a high degree of accuracy and acceptable variability. Concomitantly administered medications (lorazepam, morphine-scopolamine, clonidine, or propofol) do not appear to have any clinically important effects on distribution-phase sufentanil pharmacokinetics. Copyright © 2001 by W.B. Saunders Company

The Cerebrospinal Fluid and Plasma Pharmacokinetics of Sufentanil After Thoracic or Lumbar Epidural Administration

The cerebrospinal fluid (CSF) and plasma pharmacokinetics of sufentanil were studied in 29 adult patients undergoing thoracotomy under general anesthesia.Sufentanil, 75 micro gram, diluted in 10 mL saline, was given preoperatively in either the lumbar or thoracic epidural space to 14 and 15 patients, respectively. Lumbar CSF and plasma were frequently sampled for 10 h and analyzed for sufentanil concentration by radioimmunoassay. In plasma, the area under the concentration curve (AUC) did not differ between the groups. The fraction of the lumbar epidural dose found in CSF was calculated to be 2.7%. The time to peak CSF sufentanil concentration differed (P < 0.01) after epidural administration in the lumbar (0.76 +/- 0.50 h) and thoracic (2.1 +/- 1.4 h) region. In the lumbar group, the AUC and Cmax values in CSF were 19 (P < 0.01) and 45 (P < 0.01) times higher than in plasma, and 4.7 (P < 0.01) and 8.2 (P < 0.001) times higher than in CSF in the thoracic group. The decline in sufentanil concentration was more rapid in CSF than plasma; in the lumbar group the CSF/plasma concentration-ratio was eight and five at 6 and 10 h, respectively, after sufentanil administration. This study shows that after epidural administration sufentanil concentrations are higher in CSF than in plasma, and are highly localized within CSF to the site of administration. (Anesth Analg 1995;80:724-9)

Sufentanil Disposition

Because oral erythromycin administration has been associated with reduced elimination of alfentanil, suspicion has been raised about related opioids with similar metabolic pathways. A controlled crossover study of sufentanil pharmacokinetics was undertaken to resolve this issue. Six subjects had measurements of plasma concentrations for 9 h after intravenous administration of sufentanil (3 micrograms/kg). Each subject was studied following no erythromycin (control) and after 1- and 7-day courses of erythromycin base. Plasma concentrations during the 9 h of measurement were similar before and after erythromycin. Terminal half-life and clearance and distribution volume did not change significantly among treatment groups. Values measured after 7 days of erythromycin were similar to controls. Prior administration of erythromycin does not alter pharmacokinetics of sufentanil in the 9 h following sufentanil administration. Thus, there are no apparent clinical consequences of prior or concomitant erythromycin administration in patients receiving sufentanil for procedures of 9 h or less.

Evaluation of sufentanil anesthesia obtained by a computer-controlled infusion for cardiac surgery.

To determine the "therapeutic window" for sufentanil in cardiac surgery, nine hemodynamically stable, lightly premedicated patients were anesthetized with sufentanil to undergo coronary artery bypass grafting. Sufentanil was administered by a computer-controlled infusion pump programmed with an infusion scheme based on average sufentanil pharmacokinetics. The presence of somatic or hemodynamic responses to tracheal intubation, skin incision, sternotomy, and during electrocauterization, to isolate the internal mammary artery were correlated with plasma concentrations of sufentanil. The concentration versus response/no response relationships were analyzed by application of the logistic (Hill) equation. The CP50 of sufentanil to suppress responses to intubation, incision, and sternotomy was 7.1 ng/mL and for mediastinal dissection it was 12.7 ng/mL. Interpatient variability was as much as that reported previously for other opioids in other types of surgical patients. The computer-controlled infusion scheme consistently produced sufentanil plasma concentrations in excess of the target concentrations, but there was a strong correlation between target and actual sufentanil concentrations (r = 0.88, P < 0.05).

Pharmacokinetics of Sufentanil in Obese Patients

The pharmacokinetics of sufentanil were determined in eight obese (94.1 +/- 14 kg, mean +/- SD) and eight control patients (70.1 +/- 13 kg) anesthetized for neurosurgery. After induction of anesthesia, 4 micrograms/kg of sufentanil was administered in a single intravenous bolus. Multiple arterial samples were obtained at timed intervals over 6 h, and plasma concentrations of sufentanil were measured by radioimmunoassay. Calculation of pharmacokinetic variables from the derived compartmental models demonstrated an increased volume of distribution of sufentanil in the obese (9098 +/- 2793 mL/kg ideal body weight, mean +/- SD) when compared with a control group (5073 +/- 1673 mL/kg ideal body weight) (P less than 0.01) and a prolonged elimination half-life (208 +/- 82 min vs 135 +/- 42 min, P less than 0.05). The total volume of distribution correlated linearly with the degree of obesity, as expressed in percent ideal body weight (r = 0.67). In contrast, plasma clearance was similar in both obese and control groups (32.9 +/- 12.5 vs 26.4 +/- 5.7 mL/kg ideal body weight). The high lipid solubility of sufentanil probably explains the altered pharmacokinetics of this opioid in obese patients.

Pharmacokinetics of Sufentanil in the Elderly Surgical Patient

The effect of age on the distribution and elimination of sufentanil was studied in seven elderly (77 ± 5 yr, mean ± SD) and seven younger (41 ± 15 yr) neurosurgical patients. Following a single IV bolus of sufentanil 2 μg · kg−1 multiple arterial samples were obtained at timed intervals and plasma concentrations of sufentanil were measured by radioimmunoassay. Pharmacokinetic variables were calculated from the derived compartmental models. The initial volume of distribution was significantly smaller in the elderly patients (310 ± 109ml · kg−1 vs 491 ± 112 ml · kg−1 mean ± SD). Elimination halflives, plasma clearances, and total volumes of distribution were similar for elderly and younger subjects. Six of seven elderly patients required administration of naloxone at the termination of surgery to achieve an adequate rale of ventilation (> eight breaths · min−1) while only one younger patient required antagonism of ventilatory depression. The authors believe that agerelated differences in the action of sufentanil cannot be accounted for by the observed differences in the initial volume of distribution. It is concluded that alterations in pharmacodyamics appear to be of greater importance in the prolonged opioid effect seen in the elderly. L’effet de l’âge sur la distribution et l’elimination du sufentanil a ete etudie chez sept patients âges (77 ± 5 ans, moyenne ± SD) et sept patients moins âges (41 ± 15 ans) devant subir des procedures neurochirurgicales. Apres un bolus intraveineux unique de sufentanil de 2 μg · kg−1, des echantillons arteriels multiples out ete obtenus a des intervalles reguliers et des concentrations plasmatiques de sufentanil out ete mesurees par radio-immuno-essai. Les variables pharmacocinetiques out ete calculees. Le volume initial de distribution etait significativement plus petit chez les patients plus ages (310 ± 109 ml · kg−1 moyenne ± SD). Les demivies d’elimination, les clairances plasmatiques, les volumes totaiix de distribution etaient similaires pour les patients ages et les sujets pl us jeunes. Six des sept patients ages out requis l’administration de naloxone a la fin de la chirurgie afin d’acquerir une frequence de ventilation adequate (> 8 respirations · min−1) alors qu’un sent patient plus jeune a requis un antagonisme de sa depression respiratoire. Les auteurs croienl que les differences reliees a l’âge dans l’effet du sufentanil ne peuvent etre attribuees aux differences du volume de distribution initial. On conclut que les alterations de la pharmacodynamique apparaissent plus importante dans la prolongation des effets des opiaces observes chez les gens ages.