Plasma Sufentanil Concentrations Research Articles

Long-term stability of sufentanil quantified by UPLC-MS-MS in human plasma frozen for 11 years at -20°C.

The long-term stability of drug concentrations in human plasma samples when stored under normal laboratory conditions over several years is important for research purposes and clinical re-evaluation, but also for forensic toxicology. Fifty human plasma samples from a former clinical trial were re-analyzed after storage at -20°C for 11 years. Plasma samples were extracted using solid-phase extraction. Isotope labelled sufentanil-D5 was used as internal standard. Sufentanil plasma concentrations were determined by ultra-performance liquid chromatography (UPLC) with gradient elution, followed by tandem mass spectrometry with electrospray ionization. The linear dynamic range (LDR) was 25 - 2500 pg/mL, the limit of detection was 10 pg/mL, and the lower limit of quantification was 25 pg/mL. Intra- and inter-assay error did not exceed 6%. The deviation of the measured sufentanil plasma concentrations between the reanalysis and the first analysis was -63 ± 14% (mean ± SD). Therefore, sufentanil concentrations in human plasma were not stable in samples frozen at -20°C over 11 years.

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.

Analgesic efficacy of sufentanil in dressings after surgical treatment of burn wounds

BackgroundThe aim of this study was to assess the analgesic efficacy of sufentanil in dressings after surgical treatment of burn wounds. Patients and methodsTwenty adult patients, who underwent surgical treatment of third–degree burn wounds under general anesthesia, were included. Two of the patients underwent surgery twice. During surgery, patients received 50–100 μg fentanyl every 20–30 min and, after surgery, patients received 100 mg ketoprofen twice daily. Additionally, ten patients (group 1) received 50 μg sufentanil added to the burn wound dressings soaked in octenidine and phenoxyethanol while 10 patients (group 2) received 25 μg sufentanil added to the same dressings. The rescue analgesic, which was administered when pain intensified, was 5 mg subcutaneous morphine. Plasma sufentanil concentrations were assayed at 1, 2, 3, and 6 h after surgery completion and when pain was reported, along with pain intensity evaluation. ResultsSufentanil was not detected in the serum of any patients. Rescue morphine was given during the postoperative period (24 h) in one patient in group 1 (who underwent surgery twice) and three patients in group 2. The mean sufentanil concentration in dressings was higher in group 1 (0.13 ± 0.03) than group 2 (0.06 ± 0.03 μg/mL; p < 0.001). The group 1 patient who received rescue morphine had a sufentanil concentration of 0.10 μg/mL, which was the lowest concentration in group 1. Group 2 patients who received rescue morphine had sufentanil concentrations of at least two–fold lower (0.03–0.05 μg/mL). No adverse effects were observed. ConclusionsSufentanil in dressings after burn wound surgery provides effective and safe analgesia and the sufentanil concentration in dressings should be ≥0.10 μg/mL in a solution of octenidine and phenoxyethanol.

Effects of different sufentanil target concentrations on the MACBAR of sevoflurane in patients with carbon dioxide pneumoperitoneum stimulus

BackgroundThis study aims to observe the effects of different target controlled plasma sufentanil concentrations on the minimum alveolar concentration (MAC) of sevoflurane for blocking adrenergic response (BAR) in patients undergoing laparoscopic cholecystectomy with carbon dioxide pneumoperitoneum stimulation.MethodsEighty-five patients undergoing laparoscopic cholecystectomy, aged 30–65 years, with American Society of Anesthesiologists physical status I-II, were enrolled in this study. All the patients were randomly divided into 5 groups (S0, S1, S2, S3, S4) with different sufentanil plasma target concentration (0.0, 0.1, 0.3, 0.5, 0.7 ng ml− 1). Anesthesia was induced by inhalation of 8% sevoflurane in 100% oxygen, and 0.6 mg kg− 1 of rocuronium was intravenously injected to facilitate the insertion of a laryngeal mask airway. The end-tidal sevoflurane concentration and sufentanil plasma target concentration were adjusted according to respective preset value in each group. The hemodynamic response to pneumoperitoneum stimulus was observed after the end-tidal sevoflurane concentration had been maintained stable at least for 15 min. The MACBAR of sevoflurane was measured by a sequential method. Meanwhile, epinephrine (E) and norepinephrine (NE) concentrations in the blood were also determined before and after pneumoperitoneum stimulus in each group.ResultsWhen the method of independent paired reversals was used, the MACBAR of sevoflurane in groups S0, S1, S2, S3, S4 was 5.333% (confidence interval [CI] 95%: 5.197–5.469%), 4.533% (95% CI: 4.451–4.616%), 2.861% (95% CI: 2.752–2.981%), 2.233% (95% CI: 2.142–2.324%) and 2.139% (95% CI: 2.057–2.219%), respectively. Meanwhile, when the isotonic regression analysis was used, the MACBAR of sevoflurane in groups S0, S1, S2, S3, S4 was 5.329% (95% CI: 5.321–5.343%), 4.557% (95% CI: 4.552–4.568%), 2.900% (95% CI: 2.894–2.911%), 2.216% (95% CI: 2.173–2.223%) and 2.171% (95% CI: 2.165–2.183%), respectively. The MACBAR was not significantly different between groups S3 and S4 when using 0.5 and 0.7 ng ml− 1 of sufentanil plasma target concentrations. No significant difference was found in the change of E or NE concentration between before and after pneumoperitoneum stimulation in each group.ConclusionsThe MACBAR of sevoflurane can be decreased with increasing sufentanil plasma target concentrations. A ceiling effect of the decrease occurred at a sufentanil plasma target concentration of 0.5 ng ml− 1. When the sympathetic adrenergic response was inhibited in half of the patients to pneumoperitoneum stimulation in each group, the changes of E and NE concentrations showed no significant differences.Trial registrationThe study was registered at http://www.chictr.org.cn (ChiCTR1800015819, 23, April, 2018).

Accuracy of target-controlled infusion of sufentanil from termination of cardiopulmonary bypass until the end of surgery in patients undergoing cardiac surgery

Objective To evaluate the accuracy of target-controlled infusion (TCI) of sufentanil from termination of cardiopulmonary bypass (CPB) until the end of surgery in the patients undergoing cardiac surgery.Methods Twenty adult patients,aged 25-64 yr,of ASA physical status Ⅱ or Ⅲ,scheduled for elective coronary artery bypass graft under CPB,were enrolled in the study.Immediately after termination of CPB,sufentanil was given by TCI using Gepts pharmacokinetic parameters.The initial target effect-site concentration (Ce) of sufentanil was 0.4 ng/ml.The Ce increased by 0.2 ng/ml every 10 min until it finally decreased to 0.8 ng/ml,and then the Ce decreased by 0.2 ng/ml every 10 min until it finally decreased to 0.4 ng/ml which was maintained until the end of surgery.At 10 min of infusion at each preset target Ce 0.4,0.6,0.8 and 0.6 ng/ml (T1-4) and 1,3,5,10,20,40 and 60 min of infusion at the last concentration of 0.4 ng/ml (T5-11),arterial blood samples were collected for measurement of sufentanil concentrations by using ELISA.For each sample,the bias,accuracy and wobble were calculated.Results Compared with the predicted plasma concentrations of sufentanil,the measured plasma concentrations of sufentanil were significantly decreased at T1-11.The bias,accuracy and wobble were-37.63 ％,37.63％ and 5.09％,respectively.Conclusion The accuracy of sufentanil TCI using Gepts pharmacokinetic parameters is not high from termination of CPB until the end of surgery in the patients undergoing cardiac surgery. Key words: Sufentanil; Drug delivery systems; Coronary artery bypass

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.

Establishment of modified gas chromatography-mass spectrometry for determination of plasma sufentanil concentrations

Objective To modify gas chromatography-mass spectrometry (GC-MS) for determination of plasma sufentanil concentrations.Methods Fentanyl was used as the internal standard.The plasma samples were extracted with ethyl acetate and petroleum ether.An HP-5MS capillary column was used.The initial temperature of the column was set at 130 ℃,and the final temperature was 320 ℃.The injector port temperature was set at 290 ℃,and the interface temperature was 300 ℃.The carrier gas was high purity helium (purity 99.999％) with a constant flow rate of 1 ml/min.The injection volume was 1 μl with splitless injection.The MS conditions were as follows:EI source,ion source temperature 230 ℃,four-pole temperature 150 ℃,electron bombardment energy 70 eV,multiply voltage 2112 V,selective ion monitoring mode,solvent delay 7 min.The characteristic ions of sufentanil and fentanyl were obtained in 8.20-8.40 min and 7.60-7.80 min,respectively,according to the characteristic ion curve of sufentanil and fentanyl.Results The standard curve of sufentanil had good linear relationship in the range of 0.02-10.00 ng/ml and the equation was Y =0.1625X + 0.0316,R2 =0.9987.The extraction recovery was more than 80％,intra-day and inter-day determinations were less than 8％,and the limit of detection was 0.02 ng/ml.Conclusion When modified GC-MS is applied to determine the concentrations of sufentanil in plasma,not only the determination is sensitive and accurate,but also the procedures are simplified,and it is more suitable for the pharmacological research of sufentanil. Key words: Gas chromatography-mass spectrometry ; Sufentanil; Plasma concentration

Pharmacokinetic Assessment of Sufentanil in Cardiac Surgery

Plasma monitoring and pharmacokinetic assessment are important tools used in therapeutic control. Sufentanil is responsible for the hemodynamic stabilization of patients, providing better suppression of the neuroendocrine response compared to its analogue fentanyl. This study aims to use the plasma monitoring of sufentanil in patients undergoing cardiac surgery with extracorporeal circulation (ECC, group 1) or without ECC (group 2) to assess the pharmacokinetics of the compound.The 42 patients in this study received 0.5 μg/kg of sufentanil through bolus injection followed by a maintenance infusion of 0.5 μg/kg.h. Serial blood samples were collected during the post induction intraoperative period and during the postoperative period until 36 h after sufentanil administration. The plasma concentrations were determined by a validated method utilizing liquid chromatography coupled to mass spectrometry. The pharmacokinetic modeling was performed using a 3-compartment model fit.The surgical patients included in the protocol were adults of both genders, with 30 patients in the ECC group and 12 in the group without ECC. The plasma concentrations obtained were significantly different between the 2 groups. During the extracorporeal circulation procedure, intense fluctuations were observed in the sufentanil plasma concentrations. Compared with the results of group 2, the ECC procedure reduced the terminal or gamma half-life from 36.35 ± 6.37 h to 23.25 ± 2.75 h in group 1. In addition, the ECC procedure promoted higher fluctuations in the sufentanil plasma concentrations without causing alterations in the area under the curve, distribution volume, clearance or the distributional (alpha) and rapid elimination (beta) half-lives (t1/2α and t1/2β, respectively).

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

Rapid UPLC–MS/MS method for the determination of sufentanil in human plasma and its application in target-controlled infusion system

A rapid, selective and highly sensitive ultra-performance liquid-chromatography mass-spectrometry (UPLC–MS/MS) method has been developed and validated for the determination of sufentanil in human plasma. Sufentanil was separated on an ACQUITY™ UPLC BEH C18 column (50mm×2.1mm, ID 1.7μm) and analyzed in positive-ion (PI) electrospray-ionization (ESI) mode. The mobile phase (MP) consisted of acetonitrile:water (45:55, v/v) under isocratic conditions at a flow rate of 0.2ml/min. Sufentanil and internal-standard (IS) fentanyl were eluted at 1.47 and 1.16min, respectively, and their responses were optimized at the transitions m/z 387.2>238.0 and m/z 337.2>188.0, respectively. The calibration curve was linear over the range 0.071–4.56ng/ml, with coefficients of determination >0.999. The accuracy and precision of the method were between 96.49% and 100.37% (RSD<9%), and the mean recovery of sufentanil was 84.08±7.29%. The method was successfully applied to evaluate the predictive accuracy of Gepts pharmacokinetic sets in a target-controlled infusion (TCI) model, and the Gepts parameters were capable of predicting sufentanil plasma concentrations when multi-level target concentrations were acquired during surgery.

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.

Effect of target-controlled infusion sufentanil in different doses combined with nitrogen monoxide inhalation on hemodynamics and postoperative recovery

To investigate the effect of target-controlled infusion sufentanil in different doses combined with inhalation anesthesia at 0.9 minimum alveolar concentration (MAC) on the intraoperative hemodynamics and postoperative recovery of spontaneous breathing. Sixty patients aged 18-65, weighing 45-80 kg, undergoing colectomy or pedical screw intermix were randomized into 3 groups: Groups S3, S4, and S5 to receive sufentanil at the fixed target plasma concentrations of 0.3, 0.4, and 0.5 ng/ml respectively in combination of nitrogen monoxide inhalation at 0.9 MAC. The arterial blood pressure (ABP), heart rate (HR), electrocardiogram (ECG), and pulse blood oxygen saturation during anesthesia were monitored, the time between the termination of anesthetic use and recovery of spontaneous breathing and extubation were observed, and the use of vasoactive drug and other intravenous anesthetics were recorded. The BP and HR were nearly stable during the anesthesia in three groups. The values of time from termination of anesthesia to recovery of spontaneous breathing of Groups S2, S3, and S5 were (3.3 +/- 2.0) min, (2.8-2.5) min, and (6.1-3.4) min) respectively without significant differences among them. The time from termination of anesthetic use to extubation of Group S5 was 14.6 +/- 10.9 min, significantly longer than those of Groups S3 and S4: [(9.6 +/- 8.0) and (9.4 +/- 6.4) min, both P < 0.05]. When the concentration of inhalation anesthetic is at 0.9 MAC, the target plasma sufentanil concentration of 0.3 ng/ml is adequate in anesthesia. If sufentanil infusion was terminated 50 min before the end of surgery, the patients can recover safely and quickly.

Effects of sufentanil or ketamine administered in target-controlled infusion on the cerebral hemodynamics of severely brain-injured patients*

The manual injection of a bolus of opioid in patients with brain injury induces an increase in intracranial pressure related to a decrease in mean arterial pressure. Such an effect has not been observed with the use of ketamine. The use of target-controlled infusion would minimize or suppress this adverse effect of opioid. This study evaluated the effects of an increase in plasma concentrations of sufentanil or ketamine administered by target-controlled infusion on cerebral hemodynamics. Prospective, randomized study. Intensive care unit in a trauma center. Thirty patients with severe traumatic brain injury. Patients were assigned to receive sedation consisting of sufentanil-midazolam or ketamine-midazolam using target-controlled infusion. Twenty-four hours after the onset of sedation, the target concentrations of sufentanil or ketamine were doubled for 15 mins. Blood samples were collected to determine the actual plasma concentration of sufentanil and ketamine, before and 15 mins after concentration change. The baseline values of intracranial pressure and cerebral perfusion pressure were similar in both groups. The two-fold increase in drug concentrations did not involve a significant change for intracranial pressure, cerebral perfusion pressure, and mean velocity of middle cerebral artery in both the ketamine and the sufentanil groups. The measured plasma concentrations of sufentanil and ketamine were 0.4 +/- 0.2 ng/mL and 2.6 +/- 2.2 mug/mL, respectively, before the increase in concentrations and 0.7 +/- 0.4 ng/mL and 5.5 +/- 3.8 mug/mL after. The present study shows that the increase in sufentanil or ketamine plasma concentrations using a target-controlled infusion is not associated with adverse effects on cerebral hemodynamics in patients with severe brain injury. The use of target-controlled infusion could be of interest in the management of severely brain-injured patients. However, there is a need for specific pharmacokinetic models designed for intensive care unit patients.

Fetal plasma concentrations after intraamniotic sufentanil in chronically instrumented pregnant sheep.

Rapid progress is being made in fetal surgery. Because the fetus is capable of pain perception after the 26th week of gestation, adequate postoperative fetal pain management is essential. The preferred approach would provide fetal analgesia without affecting the mother. Intraamniotically administered sufentanil may be an interesting option if it achieves therapeutic plasma concentrations (PCs) in the fetus but not the mother. After approval of the study, 25 or 50 microg sufentanil was administered intraamniotically in 10 chronically instrumented pregnant ewes. Maternal and fetal vital signs, arterial blood gases, and uterine blood flow were recorded over 120 min. Sufentanil PCs were determined before and 1, 3, 5, 10, 15, 30, 45, 60, 90, and 120 min after injection. Statistical analysis was performed using one- or two-way analysis of variance followed by Dunnett or Tukey test, as appropriate (P < 0.05; data presented as median [95% confidence interval]). After 25 microg sufentanil, fetal PC stabilized at 134 +/- 89 pg/ml (after 10 min), and maternal PCs stabilized at 44 +/- 11 pg/ml (after 15 min). After 50 microg sufentanil, fetal PCs stabilized at 134 +/- 35 pg/ml (after 15 min), and maternal PCs reached 80 +/- 25 pg/ml (at 30 min). Injection of 25 microg sufentanil intraamniotically did not affect maternal or fetal hemodynamics, uterine blood flow, or arterial blood gases. Fetal heart rate increased after administration of 50 microg sufentanil (maximum change at 10 min: +16 +/- 12%). The sheep fetus absorbs sufentanil after intraamniotic instillation. Significantly greater PCs were obtained in the fetal lamb as compared with the ewe. This suggests that investigation of intraamniotic opioids for fetal analgesia might be worthwhile.

THIS MONTH IN ANESTHESIOLOGY

THIS MONTH IN ANESTHESIOLOGY

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.

More Epidural than Intravenous Sufentanil is Required to Provide Comparable Postoperative Pain Relief

UNLABELLED The extent to which epidurally administered sufentanil acts directly on spinal opioid receptors remains controversial. We tested the hypothesis that small-dose boluses of sufentanil, given epidurally or IV, provide comparable analgesia at similar plasma sufentanil concentrations. The lipophilicity of sufentanil makes it likely to be absorbed into fat surrounding the epidural space. We therefore also tested the hypothesis that more epidural than IV sufentanil is required to produce comparable analgesia. Analgesia and plasma sufentanil concentrations were evaluated in 20 postoperative patients randomly assigned to patient-controlled epidural or IV sufentanil. Pain was evaluated with visual analog scales by blinded observers. Sufentanil doses and plasma concentrations were measured. Analgesia was similar with epidural and IV sufentanil administration. Plasma sufentanil concentrations were virtually identical in the two groups. However, significantly larger sufentanil doses were required with epidural administration: 238 +/- 50 microg vs 160 +/- 32 microg (P < 0.01). The primary mechanism by which small-dose boluses of epidurally-administered sufentanil produce analgesia seems to be systemic absorption of the drug with subsequent recirculation to the supraspinal opioid receptors. This study demonstrates that the cumulative dose of sufentanil, when administered as a small epidural bolus, is approximately 50% more than that administered IV to provide comparable analgesia. This indicates that the bioavailability of epidurally-administered sufentanil is reduced and suggests that a large proportion of the drug may be absorbed into the epidural fat. IMPLICATIONS More epidural than IV sufentanil was required to provide comparable postoperative pain relief and similar plasma sufentanil concentrations. These data suggest that when sufentanil is administered in small-dose boluses, much of the drug is absorbed into the epidural fat and that the primary mechanism by which epidurally administered sufentanil produces analgesia is via systemic absorption.

Comparative Study of Liquid-Liquid Extraction and Solid-Phase Extraction Methods for the Separation of Sufentanil from Plasma before Gas Chromatographic–Mass Spectrometric Analysis

Sufentanil (SF) is a highly potent synthetic opioid (1) used extensively in anesthesia (2)(3). Most of the techniques proposed for SF analysis in plasma samples are based on the RIA method described by Michiels et al. (4). Some methods using gas chromatography–mass spectrometry (GC-MS) have been reported (5)(6)(7). Plasma concentrations of SF in the analgesic range are extremely low, and pharmacokinetic studies require the development of sensitive GC-MS assay methods. Reliable and reproducible isolation of SF from plasma is the most important and most critical step in pharmacokinetic analysis. Among different extraction methods currently used in pharmaceutics, the use of solid-phase extraction (SPE) has grown dramatically. However, according to the literature, liquid-liquid extraction (LLE) is the technique used most frequently for isolating morphinomimetic compounds (4)(5)(6)(7)(8), whereas only one method using SPE with RIA has been reported (9). We performed comparative studies on the isolation of SF and alfentanil (AF; used as an internal standard) from plasma using LLE and SPE methods, and extracts were assessed using GC-MS. The method was applied to drug monitoring in intensive care patients. SF citrate and AF hydrochloride were purchased from Janssen Pharmaceutica. Lyophilized plasma (Lyphochek®) was purchased from Bio-Rad Laboratories. Deionized water was prepared using a MilliQ® Water System (Millipore). Methanol (Uvasol® grade), dichloromethane (Uvasol grade), isoamyl alcohol (analytical grade), propan-2-ol (analytical grade), 13.2 mol/L ammonia, and sodium hydroxide (Normapur®) were purchased from Merck. n -Heptane (analytical grade), 18 mol/L sulfuric acid, and ammonium phosphate monobasic were purchased from Carlo Erba. Acetic acid and Sigmacote® were purchased from Sigma Aldrich. Oasis® MCX 60-mg SPE columns (Waters Corporation) were used, and the vacuum manifold for semiautomatic processing of the columns was purchased from Supelco. The Oasis MCX is a mixed-mode, …

Continuous infusion versus bolus administration of sufentanil and midazolam for mitral valve surgery

Objective: In the present study, the authors compared continuous infusion to bolus administration of sufentanil and midazolam in patients undergoing mitral valve surgery. The purpose of the study was to evaluate the hemodynamic variability, total dose, effective plasma drug concentrations, and simplicity of the two anesthetic techniques. Design: Prospective, randomized study. Setting: University hospital. Participants: Thirty patients scheduled for elective mitral valve surgery. Interventions: Induction of anesthesia was similar in both groups and consisted of sufentanil, up to 2 μg/kg, and midazolam, 0.05 to 0.15 mg/kg, followed by atracurium, 0.5 mg/kg. Anesthesia was maintained in the bolus group with predetermined boluses of sufentanil, 2 μg/kg, and midazolam, 0.03 mg/kg. Boluses were not administered if blood pressure was within 20% of baseline. The continuous-infusion group received sufentanil, 3.6 μg/kg/h, and midazolam, 0.08 mg/kg/h, started immediately after induction. The infusion rate was reduced to sufentanil, 1.8 μg/kg/h, and midazolam, 0.04 mg/kg/h, after sternotomy and was discontinued at skin closure. Atracurium was infused at a rate of 0.5 mg/kg/h up to sternal closure in both groups. No inhalation agents were used. Measurements and Main Results: Hemodynamic variability between the groups was not significant. Total sufentanil dose was 773 ± 186 μg in the continuous-infusion group and 610 ± 184 μg in the bolus group ( p = 0.01). Total midazolam dose was 14.4 ± 3 mg and 11.2 ± 3 mg in the continuous-infusion and bolus groups, respectively. There were 3.46 (range, 0 to 7) additional bolus injections in the bolus group and 0.31 (range, 0 to 1) in the continuous-infusion group ( p < 0.001). Plasma sufentanil concentrations at extubation were similar in both groups (0.5 ng/mL). Plasma midazolam concentrations at extubation in the bolus group (17 ± 6.7 ng/mL) were similar to those in the continuous-infusion group (23 ± 5 ng/mL). Conclusion: The simplicity of the continuous infusion is a major advantage. This technique provides hemodynamically safe and stable conditions similar to those of bolus administration.

Ocular Transmucosal Absorption and Toxicity of Sufentanil in Dogs

Ocular Transmucosal Absorption and Toxicity of Sufentanil in Dogs